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Developmental neuropathology of the second half of gestation
Early Human Development (2005) 81, 245 — 253
www.elsevier.com/locate/earlhumdev
Developmental neuropathology of the second half of gestation Floyd H. Gillesa,T, Ignacio-Gonzalez Gomezb a
Section of Neuropathology, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, MS #43, Los Angeles, CA 90027, USA b Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, MS #43, Los Angeles, CA 90027, USA
KEYWORDS Development; Brain; Human
Abstract In this review we focus primarily on the events taking place in the second half of gestation. At second trimester end, human brain weight gain accelerates rapidly. Germinal matrix attains maximal absolute volume, only to ablate 50% over two gestational weeks. At 10 weeks of gestation interhemispheric, choroidal, and transverse fissures exist. Germinal matrix hemorrhages peak during its devolution and some of these rupture into the lateral ventricle. By 28 weeks homologous primary sulci are present, having appeared in both hemispheres at slightly different gestational ages. Secondary sulcation, during the third trimester, is hemispherically unique. Despite emphasis on neuronal vulnerability, prevalence of lesions in white matter exceeds that of gray matter and, within white matter, diffuse white matter astrocytosis prevalence exceeds that of focal necroses. Gray matter hypotensive lesions most commonly occur in the upper brainstem and thalami followed by convexity borderzone lesions causing sclerotic microgyria. White matter hypoplasia with normal gray matter volume is sometimes associated with hypomyelination. D 2005 Published by Elsevier Ireland Ltd.
1. Introduction At midgestation the human brain is the site of recently migrated immature neurons, axon sprouts T Corresponding author. Tel.: +1 323 669 2523; fax: +1 323 669 4553. E-mail addresses: [email protected] (F.H. Gilles)8 [email protected] (I.-G. Gomez).
growing in different directions, glia, and microvessels that change with every growth change in the brain. It surrounds and is supported by a ventricular system with a relatively large nurturing choroid plexus containing large quantities of glycogen and other substances not found later in childhood. Much of the data reviewed here were obtained from the National Collaborative Perinatal Project (NCPP) [1]. Many investigators have con-
0378-3782/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2005.01.005
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F.H. Gilles, I.-G. Gomez
tributed to our understanding of fetal brain abnormalities, but we focus on the NCPP material because of its quantitative nature and prospective collection of antecedent information. Since most malformative lesions are embryonic or early fetal in origin, they will not be covered here. Evaluating the infant brain of 20—40 weeks of gestation dying in the neonatal period requires recognition of the expected gross and microscopic aspects of the changing brain. These aspects not only change with gestational age but with specific brain regions. Some normal tissue components disappear (germinal tissue in the subventricular zone), some appear (myelin) and others physically move relative to others (e.g., cerebellar external granule cells to the internal granule cell location). At any specific gestational age, differing regions exhibit components in differing degrees of maturation (e.g., brain stem and thalamic neurons are more mature than most isocortical and cerebellar cortical neurons throughout much of this period). At the gross level, brain atrophy occurs at all ages; failure of brain growth, on the other hand, or of some brain component is unique to the neonate and young child. Differentiation between atrophy (loss of tissue previously acquired) and developmental delay (in the above sense) is important, as the suspected etiologies of these two classes of disease are considerably different.
with group head circumference means and standard deviations is informative, but not as informative as the infant’s own internal relationships. A destructive lesion may result in cessation or slowing of cranial growth. If one hemisphere is smaller than the other, the ipsilateral cranium will be small and falx may deviate, with a higher orbital roof, a shallow middle cranial fossa and a malpositioned greater sphenoidal wing. The anatomic relationships among the components of the atlantooccipital articulation are surprisingly different in the neonate than in the older child or adult [8]. This articulation is worthy of specific attention when an infant has died unexpectedly and the cause is uncertain. The atlantoaxial ligaments are remarkably lax. The final modeling of these complex diarthrodial joints takes place after birth, during the first postnatal year. The foramen magnum at term is almost adult size at term. At birth, both the lateral atlantal mass and the occipital condyle are hypoplastic making the vertebral arteries vulnerable to compression in their course between the atlas lamina and the exoccipital bone during head extension because of herniation of the arch of the atlas upward through the foramen. These anatomic relationships may interrupt blood flow to brain stem, cerebellum and upper cervical spinal cord during extension.
1.1. General approach to infant’s brain dissection
1.2. Expected anatomic findings during the second half of gestation
If the fetus or infant to be autopsied has one of the difficult anatomic problems of hydrocephalus, posterior fossa tumor, posterior fossa malformation, retrocerebellar subdural hematoma, or retrocerebellar, supracerebellar or cerebellopontine angle arachnoidal or ependymal cyst, these abnormalities can be more easily studied if a suboccipital craniectomy and upper cervical laminectomy are carried out before opening the cranium using the modified Beneke procedure [2] (for details see [3]). Measurement of body parameters is important. Head circumference and body length are related [4,5]. An excessive head circumference for the infant’s body length is as informative as a head that is small for body length. In the fetus and neonate the calvarium reflects the growing brain within [6,7]. A head that is small for body length reflects a disproportionately small brain, because of malformation or gestational insult. After opening the calvarium excess space external to the brain but within the dura implies atrophy or a subdural effusion; a small head and a proportionally small brain imply failure of brain growth. Comparison
At midgestation, the fresh brain weighs about 60 g and, while growing rapidly, will not reach its maximum acceleration in weight accretion until several weeks later at 24—25 weeks (almost at second trimester end). It will reach its most rapid weight gain at the gestational end (about 360 g), thereafter slowing markedly until the end of the second postnatal year [9]. The formula, ð2:1080:0498Þðw Þ
g ¼ 1:065ee
where g equals brain weight in grams and w equals gestational age in weeks, predicts fresh brain weight at each week of gestation and allows the pathologist to reasonably estimate the expected brain weight. The third trimester range of this Gompertz function has been confirmed and fetal brain volume increases by an average of 25.2 ml per day [10]. One caveat, though, is that there is a wide range in brain weight at any specific gestational age. Brain weight after fixation is unreliable, as fetal and term brains may gain 30% during formalin fixation.
Developmental neuropathology of the second half of gestation Lateral ventricular shape changes throughout pregnancy. Shortly after telencephalic outpouching, early in the second postconceptional month, the lateral ventricle is almost globular except for the base, which is indented on its ventrolateral side by the striatum and ganglionic eminence. Subsequently, there is massive striatal growth, followed later by a separate spurt in remaining telencephalic wall growth, giving the lateral ventricle the shape of an inverted teardrop, but with relative ventriculomegaly. As the base, thalamus, telencephalic wall, and finally, the corpus callosum enlarge, the lateral ventricle gradually narrows and becomes more narrowed at the base with a flat top. At 15 gestational weeks, the lateral ventricular width is normally two-thirds that of cerebrum, at 17 weeks it is less than half, and at 20 weeks is approximately one-third cerebral width [11]. Thereafter it is relatively stable at 7.6F0.6 mm [12]. The cerebra grow more relatively than the lateral ventricles. During the second half of gestation ventricular ependyma is attenuated in several locations, namely the dorsolateral occipital horns, overlying CA2 sector, and the under surface of the frontal corpus callosum [13]. Thus, in these locations, absence of ependyma cannot be taken as a marker of prior insult unless there is a granulomatous ventriculitis. Dilation of the occipital horns or the trigone may be the earliest signs of ventriculomegaly [14,15]. Following normal vaginal delivery, most newborns have closed lateral ventricles that open partially by day three after birth [16]. The choroid plexus is an anatomically complex organ throughout gestation. It fills most ventricles (except for the olfactory, aqueduct, and spinal terminal ventricles), and its epithelium contains an extraordinary amount of glycogen, variable amounts of albumin and other proteins, and small amounts of lipid. The density of albumin-containing epithelial cells differs among the plexuses. A main function of diencephalic and myelencephalic plexuses early in gestation may be protein transport rather than glycogen synthesis and storage, which seems primarily located in the telencephalic plexuses [17,18]. The amount of plexus glycogen diminishes as regional maturation progresses, first in the fourth ventricle, and then the third and, finally, near the end of gestation, lateral ventricular epithelium loses its glycogen. Only a small amount of plexus glycogen remains after the first postnatal month. The cerebra develop entirely from migration of neuronal precursors from the germinal tissue of the subventricular zone (ganglionic matrix, ganglionic eminence) to the basal ganglia, cortex, etc. The subventricular zone can be divided into the gan-
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glionic (the germinal tissue overlying the head of the caudate nucleus) and the extraganglionic regions (the thinner layer covering the remainder of the lateral ventricles). The subventricular zone volume increases between 13 and 26 weeks of gestation [19]. It loses about one-half its volume between 26 and 28 weeks, and gradually regresses thereafter. This two-week period is the period of greatest risk for hemorrhage into the ganglionic eminence, in parallel with its high fibrinolytic activity at this time [20]. Gyri appear in regular sequence on the cerebral surface throughout the last half of gestation [21,22]. The extent and pattern of sulcation provides a developmental age estimate (except when intraventricular hemorrhage is present) and simultaneously provides the first clue about telencephalic abnormalities, such as small patches of sclerotic microgyria, micropolygyria, or pachygyria. The orientation of gyri adjacent to mantle defects provides information about gestational timing [23]. The gyri around an early gestational lesion tend to point towards the defect radially while mantle defects acquired later in gestation merely interrupt normally positioned gyri. The interhemispheric, transverse and choroidal fissures are in place by 10 weeks of gestation. By 20 weeks the parietooccipital and calcarine fissures, and olfactory, circular, cingulate sulci are recognizable. Two weeks later, most fetal brains have central (Rolandic) sulci and the precentral and postcentral gyri stand up from the brain surface marking the future precentral and postcentral sulci. The protruberance of these gyri is so marked that for some time they were known as Ecker’s lobule. Gyri, in general, grow outward from the brain surface leaving the bottoms of adjacent sulci as markers of the previous surface position. By the end of the second trimester, most primary sulci have been marked out (e.g., the first, second and third frontal gyri, the first, second and third temporal gyri, the interparietal sulcus, and, on the medial aspect of each hemisphere, the cingulate) except for the medial and lateral orbital sulci that appear in the third trimester [22,24]. At the end of the second trimester most human brains look quite similar, even though the developmental appearance of each gyrus may vary between the right and left cerebral hemispheres, and most right and left cerebral hemispheres have a similar primary gyral pattern. During the third trimester medial, lateral, anterior and posterior orbital gyri appear, and secondary sulcation takes place leaving unique sulcal patterns in each hemisphere. It is true that frontal, temporal and parietal opercula development usually covers the insula between 32 and 35
248 weeks of gestation; an open insula is a poor marker of prematurity as this can happen artifactually during removal of brain from the skull. At midgestation, the cerebrum has no visible myelin [25]. At the end of the second trimester, some myelin is present in specific brainstem tracts, but in cerebrum only the ansa lenticularis has begun. By 30 weeks myelin is found in 50% of brains in the ansa lenticularis and in 30% in the optic tract. Myelination then proceeds in an orderly fashion, one tract following another. In the internal capsule posterior limb myelinated fibers are found adjacent to thalamus (thalamocortical fibers) as well as more laterally placed (corticobulbar and corticospinal fibers) in 75% of brains at the end of gestation. Flechsig was able to demonstrate the anatomic differences between thalamocortical fibers and corticospinal fibers in the posterior limb in 1877 because of early myelination of the latter [26]. Subsequently, by gestational end in 40% of brains the corona radiata are myelinated up to the preand postcentral gyri and, caudally, 50% of brains contain myelin in corticospinal fibers in the crus cerebri, pons and pyramid. But the corticospinal tract in the spinal cord has only minimal myelination at term. At gestational end, optic radiation myelination just lateral to the lateral geniculate is present in 50% of brains, and occipitally just lateral to the occipital horn in 25% of brains. The cingulum, anterior limb of internal capsule, fornix, corpus callosum, anterior commissure, and the mammillothalamic tract have minimal myelination at the end of gestation, but virtually none is present elsewhere in the cerebrum. An efficient way to assess the state of myelination in a new fetal brain is based on the evaluation of the degree of myelination in 12 easy to locate sites in the fetal brain by comparing the degree of myelination to the large population of the NCPP (ridit score).
F.H. Gilles, I.-G. Gomez responses become increasingly comparable to the mature brain. The ability of forebrain glial cells to develop abundant cytoplasm and to construct glial fibrillary protein is weakly established between midgestation and second trimester end. Macrophages appear in cerebral lesions at about the same gestational age. Cells responding to cerebral injury may themselves be influenced by the damaging agent as evidenced by the varying periods for first appearance of hypertrophic astrocytes and macrophages in cerebra of neonatal kittens damaged by different insults [29]. Vulnerability differs dramatically between gray and white matter in fetuses of 20—40 weeks of gestation. Overall, in cerebral white matter widely distributed, hypertrophic astrocytes are present in 38% of brains and focal necroses are present in 8%. In contrast, only about 2% of brains contain neuronal necrosis. The high prevalence of fetal white matter astrocytosis has been confirmed [30].
2.1. Hemorrhage Hemorrhage in and around the fetal brain is common [31]. In the NCPP about two-thirds of autopsied fetal brains had hemorrhage into the leptomeninges. The second most frequent site was fetal white matter (45% of fetal or live born deaths). The ganglionic eminence and ventricles were frequently encountered sites of hemorrhages in 44% of live born deaths, but were less frequent in fetal deaths (25%). One-third of live born and fetal deaths had choroid plexus hemorrhages and almost equal proportions of cerebellar hemorrhages were found in live born and fetal deaths (14% and 12%, respectively). Parenchymal hemorrhages into late fetal brains are usually multiple and are often related to a coagulation defect; if single, a vascular malformation should be ruled out. Microglia-like cells are almost universally found in the forebrain by the end of the second trimester.
2. Neuropathology of the second half of gestation
2.2. Vascular
Major cerebral insults during the early months of gestation usually result in either death or malformation. Repair and reconstitution attempts in embryonic human neural tissue are largely unrecognized because, during the first few months of postconceptional life the brain does not respond to insult with macrophages, hypertrophic astrocytes, or glial fibrils. A histiocytic response occurs in the early cavum septi pellucidi about 12 weeks of gestation [27] and in the leptomeninges at about 20 weeks [28]. After the 6th fetal month, the cellular
The most frequent lesions involving both gray and white matter are vascular. Emboli to the fetal brain have been known since the late 1800s (summarized by Freud [32]). The middle cerebral artery is commonly involved, although most cerebral regions are vulnerable. The resultant infarct takes place in the vascular distribution expected in the hemisphere and, when absorbed, may leave a porus that communicates with the leptomeninges, multicystic encephalomalacia limited to the arterial distribution, or lobar sclerosis. Early
Developmental neuropathology of the second half of gestation investigators recognized secondary anterograde corticospinal degeneration of the crus, pons, pyramids and spinal cord and crossed cerebellar atrophy resulting from these lesions. A significant drop in perfusion pressure results in two varieties of lesions bilaterally located in fetal brain. The usual situation is that of damage bilaterally to upper brainstem, thalami, inferior colliculi, and sometimes basal ganglia following placenta previa, abruption placentae, or torn or compressed umbilical cord. The other variety is bilateral lesions of varying symmetry located in the borderzone high on the posterior convexity in the parietal and occipital lobes between the middle, anterior and posterior cerebral arteries. If small, they only involve parietal gray matter. When massive, they cover very large regions of the gray and white matter of each hemisphere including the frontal lobe, and if maximal, both entire hemispheres are involved as in hydranencephaly [33]. Hypoperfusion is responsible for sclerotic microgyria found bilaterally in parietal lobe borderzones. While these lesions are frequent in the cerebrum, the cerebellum is usually spared. Moreover, a significant proportion of fetal cases with hypotensive lesions in cerebrum also have comparable terminal arterial bed lesions in the caudal spinal cord [34]. We deliberately did not use the term bwatershedQ as it refers to the mountainous region supplying a river or a lake. Noell and Schneider first recognized the vulnerability of the cortex supplied by the distalmost branches of major cerebral arteries and coined the hemodynamic principle of the letzte Wiese or the blast fieldQ meaning the tissue supplied by the last branches of major arteries [35]. This term was, unfortunately, incorrectly translated into bwatershed.Q J. E. Meyer described it as boundary zones in infant brains [36] and Lindenberg and Friede expanded on the concept of the borderzone lesion [37,38]. Of course there are collateral connections between the distalmost major cerebral arteries, but these collateral vessels are of small caliber and are probably insufficient to handle adequate perfusion in a sudden drop in systemic perfusion pressure [39]. The lesions in borderzone regions between arterial supply beds or at the end of arterial beds are continuous necroses, not single or multiple focal lesions (e.g., as when focal necroses in fetal white matter are said to be bwatershedQ lesions).
2.3. Germinolysis Cystic degeneration of the ganglionic eminence, has been recognized since the first descriptions of congenital rubella syndrome [40—43]. Schwartz,
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who considered them residua of anterior terminal vein hematomas [44], first identified them. These lesions are usually bilateral and apparently occur during the time of maximal ganglionic eminence size (about 26 weeks). The term bgerminolysisQ is ideal in that it emphasizes premature loss of this fetal tissue by a process apparently different from that usually encountered in older brains [42]. These cysts may persist well after birth. The pathogenesis is unknown, but it seems likely that a large proportion reflect an encounter between fetus and a viral agent. The proportion remaining as posthemorrhagic cavities [44] must be small, as hemosiderin-filled macrophages are uncommon.
2.4. Fetal white matter abnormalities In 1969 a set of four frequent abnormalities in fetal white matter (hypertrophic astrocytes, focal necroses, amphophilic globules and the cluster hypertrophic astrocytes—amphophilic globules) were termed the perinatal telencephalic leucoencephalopathies [45]. Individual histologic features in this set clustered together in different combinations [46].
2.5. Hypertrophic astrocytes Glial cells that have medium to large pale vesicular nuclei, with fine chromatin stippling, and eosinophilic irregular hyaline cytoplasm are not found in normal human myelinating or premyelination hemispheral white matter [47] and are not part of the tract-specific increase in glial cell density immediately antedating myelination, so called myelination gliosis [48]. They are associated with a widely spread delicate fibrillary gliosis detectable with appropriate stains. The gliosis persists until adulthood following neonatal lesions in the kitten [29], as it probably does in the human. Although the cytoplasm of these cells is less voluminous than mature hypertrophic astrocyte, there are sufficient morphologic similarities to consider them small hypertrophic astrocytes. These diffusely spread abnormal astrocytes in white matter are not associated with macrophages. Their other characteristic is that they appear in bilaterally symmetric brain regions [45]. The symmetry is present even when patches of white matter astrocytosis are relatively restricted. The usual location of these cells is deep frontal or parietooccipital white matter. They are also frequent in corpus callosum, in gyral white matter cores, and in deep cerebellar white matter. When present, nearby gray matter is entirely normal. These findings contrast with the localized astrocytosis underlying an organized cort-
250 ical necrosis. Similarly, focal necroses in white matter may have a penumbra of hypertrophic astrocytes, but the abnormality we are focusing on is that of diffuse white matter astrocytosis, not the astrocytosis around focal regions of necrosis. The period between insult and appearance of these astrocytic changes is 2—3 days (kitten) [29,49] and may differ with various insults. This period and life cycle of hypertrophic astrocytes for the fetal human brain was estimated at 4 days [50], but there is difficulty in identifying the significant inciting event during intrauterine life. In rats the capacity of cortical astrocytes to respond in this fashion develops by the second postnatal week [51] and in fetal humans by late gestation [28]. In the NCPP population the encounter frequency increased from 9% of brains at midgestation to 59% at term. The long-term effect of diffuse white matter astrocytosis is widespread fibrillary gliosis without gray matter abnormality, as recognized by multiple authors from the middle of the 20th century [52— 56], and often associated with paucity or hypoplasia of hemispheral white matter.
2.6. Focal necroses in white matter Focal necroses in fetal and neonatal white matter were first recognized a century and a half ago [57,58]. Subsequently many pathologists contributed to the understanding of these lesions (e.g., Mo ¨ebius, Vivius, Herschfeld, and Hlava)(summarized by Schmorl in 1904 [59]). Virchow and Parrot found a general metabolic disorder in most neonates with focal necroses. Mo ¨ebius found thrombosed vessels. Vivius found icterus in his 300 cases. Herschfeld found omphalitis in most of his cases and Hlava found emboli. Schmorl found icterus in his 280 cases, but no omphalitis. Subsequent descriptions related these lesions to birth injury. Within 25 years, the search for antecedents turned to hypoxia and circulatory problems (summarized in [44]). Initially these small necroses are simple coagulative necroses that develop macrophages centrally and are surrounded by hypertrophic astrocytes, leaving glial scars or small cysts. Most foci range from 1 mm to 1—2 cm in size. Large cysts may subsequently collapse. Grossly they appear as small white or yellow-white opaque foci. If bilirubin is elevated, they may appear deeply yellow; occasionally they contain small amounts of blood. Other than macrophages, inflammatory cells are not a component. Axon retraction balls around these lesions may mineralize. In newborns fresh coagulative necroses may be found side by side with the glial scars or small cysts of older lesions. While
F.H. Gilles, I.-G. Gomez larger lesions tend to be located deep in white matter, many are scattered from the ventricular wall to gyral white matter cores (as described by all above authors and as was figured by Schwartz [44]). They tend to be preferentially located in white matter of the parietooccipital and frontal lobes but not temporal lobe [60,61]. In 1962 these same lesions were redescribed in a group of 51 infant brains without reference to the century of prior studies [62]. They were described as though only located next to lateral ventricle, despite many prior observations of their widely spread distribution in cerebral white matter. These authors coined a new term bperiventricular leucomalaciaQ implying two anatomic points: 1) a location only adjacent to lateral ventricle, and 2) that the lesions encircled (i.e., the prefix bperiQ) the ventricle. Both of these location implications seem not to be consistent with the historical data. The latter authors found clinical markers of hypoxia or anoxia in 80% of their cases, but, like their predecessors, failed to include control cases. When formally estimated in case-control studies, the risk factors of focal necroses are multiple and do not include hypoxia, anoxia, or systemic hypotension [60,63,64]. We found that a single dose of lipopolysaccharide administered intraperitoneally to the newborn kitten produced focal white matter necroses in a dose-dependent fashion [29] and in newborn monkey. This has been confirmed in the preterm ovine fetus [65]. Subsequently, in the NCPP, we found that infants with septicemia or prematures of less than 36 weeks of gestation were at increased risk of necrotic foci [66], and the risk factors include placental vascular anastomoses, funisitis, and purulent amniotic fluid [67].
2.7. Amphophilic globules Amphophilic globules are small deposits of amphophilic or basophilic material in telencephalic gray or white matter, usually in proximity to blood vessels. Multiple investigators have observed them [38,45,68,69]. In the NCPP population, they were found with a slightly increased frequency in the gestational age range of 30—32 weeks. One risk factor in a multivariate analysis was maternal urinary tract infection [70].
2.8. Cluster of hypertrophic astrocytes and amphophilic globules Hypertrophic astrocytes and amphophilic globules tend not to occur independently in fetal telencephalic white matter [46,70]. Maternal febrile urinary tract infection is the most prominent risk
Developmental neuropathology of the second half of gestation factor for this cluster of abnormalities in fetal white matter, which suggests that endotoxin in the mother crosses the placenta and this prenatal exposure contributes to the appearance of this abnormality in fetal white matter.
2.9. Two varieties of white matter damage in neonates In the broadest sense, it is clear from the above that there are two varieties of white matter damage in the neonate; diffuse white matter astrocytosis and white matter focal necroses. One, white matter astrocytosis, is more prevalent than the other. These two abnormalities have similar, but not the same risk factors. In most clinical studies focal necroses are the focus of the study because these are far more readily seen sonographically. In these studies a large number of investigators have confirmed an association between maternal sepsis, chorioamnionitis, proinflammatory cytokines and focal white matter necroses (summarized in Ref. [71]). Studies in experimental models have supported the association between E. coli chorioamnionitis or proinflammatory cytokines and their effect on developing white matter and between white matter astrocytosis in rabbit [72] and guinea pig [73], although there are a number of study design limitations in the last study. Furthermore, direct injection of the inflammatory cytokine interleukin-1 beta and, to a lesser extent, tumor necrosis factor-alpha into rat brain results in diffuse white matter damage in rats, while lipopolysaccharide does not [74]. However, we do not yet understand why systemic proinflammatory cytokines result in focal white matter lesions rather than only diffuse astrocytosis.
2.10. Delayed myelination Since myelination is age-related, delayed myelination was defined (in the NCPP) in terms of gestational age. In each of eight gestational age groups, the 15% of newborns with the lowest myelination scores were defined as having delayed myelination and the risk factors were evaluated. In this study, the important risk factors of delayed myelination were maternal cigarette smoking, low birth weight, gestational age of less than 36 weeks, third trimester uterine bleeding, and low maternal hematocrit [75]. Delayed myelination is not the same condition as hypoplasia of the white matter, although the two conditions can occur together.
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3. Best practice guidelines ! Know the gross and microscopic aspects of fetal brain that change during the last half of gestation. ! Differentiate between brain atrophy and failure of growth of brain. ! Compare head circumference to body length. ! Examine the atlantooccipital joint, vertebral arteries, and the cervicomedullary junction in sudden unexpected infantile death. ! Include control cases in clinicopathologic studies. ! Use the presence or absence of specific gyri to estimate gestational age, not the operculae covering the insula. ! Distinguish between delayed myelination and white matter hypoplasia. ! Train specialists in developmental neuropathology.
4. Future research directions ! Genetic susceptibility to insults at birth; ! Genetic susceptibility to brain insults during the last half of gestation; ! Genetic control of cell migration in the developing brain; ! Development of choroid plexus; ! Genetic control of cerebral microvascular development; ! Genetic control of repair in the embryonic and early fetal brain; ! Molecular biology of myelination.
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252 [8] Gilles FH, Bina M, Sotrel A. Infantile atlantooccipital instability. Am J Dis Child 1979;133:30 – 7. [9] McLennan JE, Gilles FH, Neff R. A model of growth of the human fetal brain. In: Gilles FH, Leviton A, Dooling EC, editors. The developing human brain: growth and epidemiologic neuropathology. Boston7 Wright PSG; 1983. p. 43 – 58. [10] Gong QY, et al. Fetal and fetal brain volume estimation in the third trimester of human pregnancy using gradient echo MR imaging. Magn Reson Imaging 1998;16:235 – 40. [11] Campbell S. Early prenatal diagnosis of neural tube defects by ultrasound. Clin Obstet Gynecol 1977;20:351 – 9. [12] Cardoza JD, Goldstein RB, Filly RA. Exclusion of fetal ventriculomegaly with a single measurement: the width of the lateral ventricular atrium. Radiology 1988;169:711 – 4. [13] Dooling EC, Chi JG, Gilles FH. Developmental change in ventricular epithelia. In: Gilles FH, Leviton A, Dooling EC, editors. The developing human brain: growth and epidemiologic neuropathology. Boston7 Wright PSG; 1983. p. 113 – 7. [14] Johnson ML, Dunne MG, Mack LA. Evaluation of fetal intracranial anatomy by static and real-time ultrasound. J Clin Ultrasound 1980;8:311 – 8. [15] Fiske CE, Filly RA. Ultrasound evaluation of the normal and abnormal fetal neural axis. Radiol Clin North Am 1982;20: 285 – 96. [16] Nelson Jr MD, et al. Changes in the size of the lateral ventricles in the normal term newborn following vaginal delivery. Pediatr Radiol 2003;33:831 – 5. [17] Jacobsen M, et al. Intracellular plasma proteins in human fetal choroid plexus during development: I. Developmental stages in relation to the number of epithelial cells which contain albumin in telencephalic, diencephalic, and myelencephalic choroid plexus. Brain Res 1982;255: 239 – 50. [18] Dziegielewska KM, et al. Development of the choroid plexus. Microsc Res Tech 2001;52:5 – 20. [19] Jammes JL, Gilles FH. Telencephalic development: matrix volume and isocortex and allocortex surface areas. In: Gilles FH, Leviton A, Dooling EC, editors. The developing human brain. Growth and epidemiologic neuropathology. Littleton7 John Wright-PSG Inc.; 1983. p. 87 – 93. [20] Gilles FH, et al. Fibrinolytic activity in the ganglionic eminence of the premature human brain. Biol Neonate 1971;18:426 – 32. [21] Retzius G. Das menschenhirn. Studien in der Makroskopischen Morphologie. Stockholm: ko ¨nigliche buchdruckerei. P.A. Norstedt and So ¨ner; 1896. [22] Chi JG, Dooling EC, Gilles FH. Gyral development of the human brain. Ann Neurol 1977;1:86 – 93. [23] Kundrat FH. Die Porencephalie; 1882. Graz. [24] Dooling EC, Chi J, Gilles FH. Telencephalic development: changing gyral patterns. In: Gilles FH, Leviton A, Dooling EC, editors. The developing human brain: growth and epidemiologic neuropathology. Boston7 Wright PSG; 1983. p. 94 – 104. [25] Gilles FH, Shankle W, Dooling EC. Myelinated tracts: growth patterns. In: Gilles FH, Leviton A, Dooling EC, editors. The developing human brain: growth and epidemiologic neuropathology. Boston7 Wright PSG; 1983. p. 117 – 83. [26] Flechsig P., Uber bSystemerkrankungenQ im Rqckenmark. Arch. Heilk., 1877. 18: 101—141, 289—343, 461—483. [27] Rakic P, Yakovlev PI. Development of the corpus callosum and cavum septi in man. J Comp Neurol 1968;132:45 – 72. [28] Dambska M. Encephalic necrosis and inflammatory reaction in fetuses and newborns. Pol Med J 1968;7:404 – 34. [29] Gilles FH, Averill Jr DR, Kerr CS. Neonatal endotoxin encephalopathy. Ann Neurol 1977;2:49 – 56.
F.H. Gilles, I.-G. Gomez [30] Squier M, Keeling JW. The incidence of prenatal brain injury. Neuropathol Appl Neurobiol 1991;17:29 – 38. [31] Dooling EC, Chi JG, Gilles FH. Intracranial hemorrhage: topography. The developing human brain: growth and epidemiologic neuropathology. Boston7 Wright PSG; 1983. p. 193 – 203. [32] Freud S. Infantile cerebral paralysis. In: Nothnagel S, editor. Handbuch. Coral Gables, Fla7 University of Miami Press; 1897. [33] Lindenberg R, Swanson PD. bInfantile hydranencephalyQ—a report of five cases of infarction of both cerebral hemispheres in infancy. Brain 1967;90:839 – 50. [34] Gilles FH, Nag D. Vulnerability of human spinal cord in transient cardiac arrest. Neurology 1971;21:833 – 9. ¨ ber die Durchblutung und Sauer[35] Noell W, Schneider M. U stoffversorgung des Gehirns im akuten Sauerstoffmangel. Pflqgers Arch Gesamte Physiol Menschen Tiere 1942;246: 181 – 249. ¨ ber die Lokalisation frqhkindlicher Hirnscha [36] Meyer JE. U ¨den in arteriellen Grenzgebieten. Arch Psychiatr Nervenkr 1953;190:328 – 41. [37] Lindenberg R. Patterns of CNS vulnerability in acute hypoxaemia, including anaesthesia accidents. In: JPaM, Schade ´ WH, editor. Selective vulnerability of the brain in hypoxaemia. Philadelphia7 F. A. Davis Company; 1963. p. 189 – 210. [38] Friede RL. Developmental neuropathology. Second ed. New York7 Springer-Verlag; 1989. [39] Vander Eechken HM, Adams RD. The anatomy and functional significance of the meningeal arterial anastomoses of the human brain. J Neuropathol Exp Neurol 1953;12: 132 – 57. [40] Rorke LB, Spiro AJ. Cerebral lesions in congenital rubella syndrome. J Pediatr 1967;70:243 – 55. [41] Larroche JC. Sub-ependymal pseudo-cysts in the newborn. Biol Neonate 1972;21:170 – 83. [42] Shaw CM, Alvord Jr EC. Subependymal germinolysis. Arch Neurol 1974;31:374 – 81. [43] De Leon GA, Girling DJ. Cystic degeneration of the telencephalic subependymal germinal layer in newborn infants. J Neurol Neurosurg Psychiatry 1975;38:265 – 71. [44] Schwartz P. Birth injuries of the newborn, morphology, pathogenesis, clinical pathology and prevention. New York7 Hafner Publishing; 1961. [45] Gilles F, Murphy S. Perinatal telencephalic leucoencephalopathy. J Neurol Neurosurg Psychiatry 1969;32:404 – 13. [46] Leviton A, Gilles FH. Clustering of the morphological components of perinatal telencephalic leucoencephalopathy. J Neurol Neurosurg Psychiatry 1971;34:642 – 5. [47] Mickel HS, Gilles FH. Changes in glial cells during human telencephalic myelinogenesis. Brain 1970;93:337 – 46. ¨ ber die feinere Morphologie des [48] Roback HN, Scherer HJ. U frqnkindlichen Gehirns unter besonderer Berqcksichtigung der Gliaentwicklung. Virchows Arch Pathol Anat Physiol Klin Med 1935;294:365 – 413. [49] Cajal R. Degeneration and regeneration of the nervous system. New York7 Hafner; 1959. [50] Roessmann U, Gambetti P. Pathological reaction of astrocytes in perinatal brain injury. Immunohistochemical study. Acta Neuropathol (Berl) 1986;70:302 – 7. [51] Sumi M, Hager H. Electron microscopic study of the reaction of the newborn rat brain to injury. Acta Neuropathol 1968;10:324 – 35. [52] McClelland JE. Syndrome of hydromicrocephaly. J Pediatr 1940;16:36 – 51. [53] Benda C. Late effects of cerebral birth injury. Med 1945;24:71 – 110.
Developmental neuropathology of the second half of gestation [54] Crome L. Some morbid-anatomical aspects of mental deficiency. J Ment Sci 1954;100:894 – 912. [55] Malamud N. Sequelae of perinatal trauma. J Neuropathol Exp Neurol 1959;18:141 – 55. [56] Chatta AS, Richardson EPJ. Cerebral white-matter hypoplasia. Arch Neurol 1977;34:137 – 41. [57] Bednar A. Die Krankheiten der Neugeborenen und Sa ¨uglinge; 1850. Wein. [58] Parrot, M.J., Etude sur la ste `atose interstitielle diffuse de l’ence `phale chez le nouveau-ne `. Arch Physiol Norm Patholol (Paris), 1868. 1: 530—550, 622—642, 706—715. [59] Schmorl CG. Zur kenntniss des ikterus neonatorum, inbesondere der dabei auftretenden gehirnveranderungen. Verhandl Dtsch Path Ges 1904;6:109 – 15. [60] Shuman RM, Selednik LJ. Periventricular leukomalacia. A one-year autopsy study. Arch Neurol 1980;37:231 – 5. [61] Clark DB, Anderson GW. Correlation of complications of labor with lesions in the brains of infants. J Neuropathol Exp Neurol 1961;20:275 – 8. [62] Banker BQ, Larroche JC. Periventricular leukomalacia of infancy. A form of neonatal anoxic encephalopathy. Arch Neurol 1962;7:386 – 410. [63] Trounce JQ, et al. Clinical risk factors and periventricular leucomalacia. Arch Dis Child 1988;63:17 – 22. [64] Leviton A, Gilles FH. Morphologic correlates of age at death of infants with perinatal telencephalic leukoencephalopathy. Am J Pathol 1971;65:303 – 9. [65] Duncan JR, et al. White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 2002;52:941 – 9. [66] Leviton A, Gilles FH. The epidemiology of the perinatal telencephalic leucoencephalopathy characterized by focal necroses. In: Gilles FH, Leviton A, Dooling EC, editors. The
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www.elsevier.com/locate/earlhumdev
Developmental neuropathology of the second half of gestation Floyd H. Gillesa,T, Ignacio-Gonzalez Gomezb a
Section of Neuropathology, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, MS #43, Los Angeles, CA 90027, USA b Department of Pathology and Laboratory Medicine, Childrens Hospital Los Angeles and the Keck School of Medicine, University of Southern California, 4650 Sunset Blvd, MS #43, Los Angeles, CA 90027, USA
KEYWORDS Development; Brain; Human
Abstract In this review we focus primarily on the events taking place in the second half of gestation. At second trimester end, human brain weight gain accelerates rapidly. Germinal matrix attains maximal absolute volume, only to ablate 50% over two gestational weeks. At 10 weeks of gestation interhemispheric, choroidal, and transverse fissures exist. Germinal matrix hemorrhages peak during its devolution and some of these rupture into the lateral ventricle. By 28 weeks homologous primary sulci are present, having appeared in both hemispheres at slightly different gestational ages. Secondary sulcation, during the third trimester, is hemispherically unique. Despite emphasis on neuronal vulnerability, prevalence of lesions in white matter exceeds that of gray matter and, within white matter, diffuse white matter astrocytosis prevalence exceeds that of focal necroses. Gray matter hypotensive lesions most commonly occur in the upper brainstem and thalami followed by convexity borderzone lesions causing sclerotic microgyria. White matter hypoplasia with normal gray matter volume is sometimes associated with hypomyelination. D 2005 Published by Elsevier Ireland Ltd.
1. Introduction At midgestation the human brain is the site of recently migrated immature neurons, axon sprouts T Corresponding author. Tel.: +1 323 669 2523; fax: +1 323 669 4553. E-mail addresses: [email protected] (F.H. Gilles)8 [email protected] (I.-G. Gomez).
growing in different directions, glia, and microvessels that change with every growth change in the brain. It surrounds and is supported by a ventricular system with a relatively large nurturing choroid plexus containing large quantities of glycogen and other substances not found later in childhood. Much of the data reviewed here were obtained from the National Collaborative Perinatal Project (NCPP) [1]. Many investigators have con-
0378-3782/$ - see front matter D 2005 Published by Elsevier Ireland Ltd. doi:10.1016/j.earlhumdev.2005.01.005
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tributed to our understanding of fetal brain abnormalities, but we focus on the NCPP material because of its quantitative nature and prospective collection of antecedent information. Since most malformative lesions are embryonic or early fetal in origin, they will not be covered here. Evaluating the infant brain of 20—40 weeks of gestation dying in the neonatal period requires recognition of the expected gross and microscopic aspects of the changing brain. These aspects not only change with gestational age but with specific brain regions. Some normal tissue components disappear (germinal tissue in the subventricular zone), some appear (myelin) and others physically move relative to others (e.g., cerebellar external granule cells to the internal granule cell location). At any specific gestational age, differing regions exhibit components in differing degrees of maturation (e.g., brain stem and thalamic neurons are more mature than most isocortical and cerebellar cortical neurons throughout much of this period). At the gross level, brain atrophy occurs at all ages; failure of brain growth, on the other hand, or of some brain component is unique to the neonate and young child. Differentiation between atrophy (loss of tissue previously acquired) and developmental delay (in the above sense) is important, as the suspected etiologies of these two classes of disease are considerably different.
with group head circumference means and standard deviations is informative, but not as informative as the infant’s own internal relationships. A destructive lesion may result in cessation or slowing of cranial growth. If one hemisphere is smaller than the other, the ipsilateral cranium will be small and falx may deviate, with a higher orbital roof, a shallow middle cranial fossa and a malpositioned greater sphenoidal wing. The anatomic relationships among the components of the atlantooccipital articulation are surprisingly different in the neonate than in the older child or adult [8]. This articulation is worthy of specific attention when an infant has died unexpectedly and the cause is uncertain. The atlantoaxial ligaments are remarkably lax. The final modeling of these complex diarthrodial joints takes place after birth, during the first postnatal year. The foramen magnum at term is almost adult size at term. At birth, both the lateral atlantal mass and the occipital condyle are hypoplastic making the vertebral arteries vulnerable to compression in their course between the atlas lamina and the exoccipital bone during head extension because of herniation of the arch of the atlas upward through the foramen. These anatomic relationships may interrupt blood flow to brain stem, cerebellum and upper cervical spinal cord during extension.
1.1. General approach to infant’s brain dissection
1.2. Expected anatomic findings during the second half of gestation
If the fetus or infant to be autopsied has one of the difficult anatomic problems of hydrocephalus, posterior fossa tumor, posterior fossa malformation, retrocerebellar subdural hematoma, or retrocerebellar, supracerebellar or cerebellopontine angle arachnoidal or ependymal cyst, these abnormalities can be more easily studied if a suboccipital craniectomy and upper cervical laminectomy are carried out before opening the cranium using the modified Beneke procedure [2] (for details see [3]). Measurement of body parameters is important. Head circumference and body length are related [4,5]. An excessive head circumference for the infant’s body length is as informative as a head that is small for body length. In the fetus and neonate the calvarium reflects the growing brain within [6,7]. A head that is small for body length reflects a disproportionately small brain, because of malformation or gestational insult. After opening the calvarium excess space external to the brain but within the dura implies atrophy or a subdural effusion; a small head and a proportionally small brain imply failure of brain growth. Comparison
At midgestation, the fresh brain weighs about 60 g and, while growing rapidly, will not reach its maximum acceleration in weight accretion until several weeks later at 24—25 weeks (almost at second trimester end). It will reach its most rapid weight gain at the gestational end (about 360 g), thereafter slowing markedly until the end of the second postnatal year [9]. The formula, ð2:1080:0498Þðw Þ
g ¼ 1:065ee
where g equals brain weight in grams and w equals gestational age in weeks, predicts fresh brain weight at each week of gestation and allows the pathologist to reasonably estimate the expected brain weight. The third trimester range of this Gompertz function has been confirmed and fetal brain volume increases by an average of 25.2 ml per day [10]. One caveat, though, is that there is a wide range in brain weight at any specific gestational age. Brain weight after fixation is unreliable, as fetal and term brains may gain 30% during formalin fixation.
Developmental neuropathology of the second half of gestation Lateral ventricular shape changes throughout pregnancy. Shortly after telencephalic outpouching, early in the second postconceptional month, the lateral ventricle is almost globular except for the base, which is indented on its ventrolateral side by the striatum and ganglionic eminence. Subsequently, there is massive striatal growth, followed later by a separate spurt in remaining telencephalic wall growth, giving the lateral ventricle the shape of an inverted teardrop, but with relative ventriculomegaly. As the base, thalamus, telencephalic wall, and finally, the corpus callosum enlarge, the lateral ventricle gradually narrows and becomes more narrowed at the base with a flat top. At 15 gestational weeks, the lateral ventricular width is normally two-thirds that of cerebrum, at 17 weeks it is less than half, and at 20 weeks is approximately one-third cerebral width [11]. Thereafter it is relatively stable at 7.6F0.6 mm [12]. The cerebra grow more relatively than the lateral ventricles. During the second half of gestation ventricular ependyma is attenuated in several locations, namely the dorsolateral occipital horns, overlying CA2 sector, and the under surface of the frontal corpus callosum [13]. Thus, in these locations, absence of ependyma cannot be taken as a marker of prior insult unless there is a granulomatous ventriculitis. Dilation of the occipital horns or the trigone may be the earliest signs of ventriculomegaly [14,15]. Following normal vaginal delivery, most newborns have closed lateral ventricles that open partially by day three after birth [16]. The choroid plexus is an anatomically complex organ throughout gestation. It fills most ventricles (except for the olfactory, aqueduct, and spinal terminal ventricles), and its epithelium contains an extraordinary amount of glycogen, variable amounts of albumin and other proteins, and small amounts of lipid. The density of albumin-containing epithelial cells differs among the plexuses. A main function of diencephalic and myelencephalic plexuses early in gestation may be protein transport rather than glycogen synthesis and storage, which seems primarily located in the telencephalic plexuses [17,18]. The amount of plexus glycogen diminishes as regional maturation progresses, first in the fourth ventricle, and then the third and, finally, near the end of gestation, lateral ventricular epithelium loses its glycogen. Only a small amount of plexus glycogen remains after the first postnatal month. The cerebra develop entirely from migration of neuronal precursors from the germinal tissue of the subventricular zone (ganglionic matrix, ganglionic eminence) to the basal ganglia, cortex, etc. The subventricular zone can be divided into the gan-
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glionic (the germinal tissue overlying the head of the caudate nucleus) and the extraganglionic regions (the thinner layer covering the remainder of the lateral ventricles). The subventricular zone volume increases between 13 and 26 weeks of gestation [19]. It loses about one-half its volume between 26 and 28 weeks, and gradually regresses thereafter. This two-week period is the period of greatest risk for hemorrhage into the ganglionic eminence, in parallel with its high fibrinolytic activity at this time [20]. Gyri appear in regular sequence on the cerebral surface throughout the last half of gestation [21,22]. The extent and pattern of sulcation provides a developmental age estimate (except when intraventricular hemorrhage is present) and simultaneously provides the first clue about telencephalic abnormalities, such as small patches of sclerotic microgyria, micropolygyria, or pachygyria. The orientation of gyri adjacent to mantle defects provides information about gestational timing [23]. The gyri around an early gestational lesion tend to point towards the defect radially while mantle defects acquired later in gestation merely interrupt normally positioned gyri. The interhemispheric, transverse and choroidal fissures are in place by 10 weeks of gestation. By 20 weeks the parietooccipital and calcarine fissures, and olfactory, circular, cingulate sulci are recognizable. Two weeks later, most fetal brains have central (Rolandic) sulci and the precentral and postcentral gyri stand up from the brain surface marking the future precentral and postcentral sulci. The protruberance of these gyri is so marked that for some time they were known as Ecker’s lobule. Gyri, in general, grow outward from the brain surface leaving the bottoms of adjacent sulci as markers of the previous surface position. By the end of the second trimester, most primary sulci have been marked out (e.g., the first, second and third frontal gyri, the first, second and third temporal gyri, the interparietal sulcus, and, on the medial aspect of each hemisphere, the cingulate) except for the medial and lateral orbital sulci that appear in the third trimester [22,24]. At the end of the second trimester most human brains look quite similar, even though the developmental appearance of each gyrus may vary between the right and left cerebral hemispheres, and most right and left cerebral hemispheres have a similar primary gyral pattern. During the third trimester medial, lateral, anterior and posterior orbital gyri appear, and secondary sulcation takes place leaving unique sulcal patterns in each hemisphere. It is true that frontal, temporal and parietal opercula development usually covers the insula between 32 and 35
248 weeks of gestation; an open insula is a poor marker of prematurity as this can happen artifactually during removal of brain from the skull. At midgestation, the cerebrum has no visible myelin [25]. At the end of the second trimester, some myelin is present in specific brainstem tracts, but in cerebrum only the ansa lenticularis has begun. By 30 weeks myelin is found in 50% of brains in the ansa lenticularis and in 30% in the optic tract. Myelination then proceeds in an orderly fashion, one tract following another. In the internal capsule posterior limb myelinated fibers are found adjacent to thalamus (thalamocortical fibers) as well as more laterally placed (corticobulbar and corticospinal fibers) in 75% of brains at the end of gestation. Flechsig was able to demonstrate the anatomic differences between thalamocortical fibers and corticospinal fibers in the posterior limb in 1877 because of early myelination of the latter [26]. Subsequently, by gestational end in 40% of brains the corona radiata are myelinated up to the preand postcentral gyri and, caudally, 50% of brains contain myelin in corticospinal fibers in the crus cerebri, pons and pyramid. But the corticospinal tract in the spinal cord has only minimal myelination at term. At gestational end, optic radiation myelination just lateral to the lateral geniculate is present in 50% of brains, and occipitally just lateral to the occipital horn in 25% of brains. The cingulum, anterior limb of internal capsule, fornix, corpus callosum, anterior commissure, and the mammillothalamic tract have minimal myelination at the end of gestation, but virtually none is present elsewhere in the cerebrum. An efficient way to assess the state of myelination in a new fetal brain is based on the evaluation of the degree of myelination in 12 easy to locate sites in the fetal brain by comparing the degree of myelination to the large population of the NCPP (ridit score).
F.H. Gilles, I.-G. Gomez responses become increasingly comparable to the mature brain. The ability of forebrain glial cells to develop abundant cytoplasm and to construct glial fibrillary protein is weakly established between midgestation and second trimester end. Macrophages appear in cerebral lesions at about the same gestational age. Cells responding to cerebral injury may themselves be influenced by the damaging agent as evidenced by the varying periods for first appearance of hypertrophic astrocytes and macrophages in cerebra of neonatal kittens damaged by different insults [29]. Vulnerability differs dramatically between gray and white matter in fetuses of 20—40 weeks of gestation. Overall, in cerebral white matter widely distributed, hypertrophic astrocytes are present in 38% of brains and focal necroses are present in 8%. In contrast, only about 2% of brains contain neuronal necrosis. The high prevalence of fetal white matter astrocytosis has been confirmed [30].
2.1. Hemorrhage Hemorrhage in and around the fetal brain is common [31]. In the NCPP about two-thirds of autopsied fetal brains had hemorrhage into the leptomeninges. The second most frequent site was fetal white matter (45% of fetal or live born deaths). The ganglionic eminence and ventricles were frequently encountered sites of hemorrhages in 44% of live born deaths, but were less frequent in fetal deaths (25%). One-third of live born and fetal deaths had choroid plexus hemorrhages and almost equal proportions of cerebellar hemorrhages were found in live born and fetal deaths (14% and 12%, respectively). Parenchymal hemorrhages into late fetal brains are usually multiple and are often related to a coagulation defect; if single, a vascular malformation should be ruled out. Microglia-like cells are almost universally found in the forebrain by the end of the second trimester.
2. Neuropathology of the second half of gestation
2.2. Vascular
Major cerebral insults during the early months of gestation usually result in either death or malformation. Repair and reconstitution attempts in embryonic human neural tissue are largely unrecognized because, during the first few months of postconceptional life the brain does not respond to insult with macrophages, hypertrophic astrocytes, or glial fibrils. A histiocytic response occurs in the early cavum septi pellucidi about 12 weeks of gestation [27] and in the leptomeninges at about 20 weeks [28]. After the 6th fetal month, the cellular
The most frequent lesions involving both gray and white matter are vascular. Emboli to the fetal brain have been known since the late 1800s (summarized by Freud [32]). The middle cerebral artery is commonly involved, although most cerebral regions are vulnerable. The resultant infarct takes place in the vascular distribution expected in the hemisphere and, when absorbed, may leave a porus that communicates with the leptomeninges, multicystic encephalomalacia limited to the arterial distribution, or lobar sclerosis. Early
Developmental neuropathology of the second half of gestation investigators recognized secondary anterograde corticospinal degeneration of the crus, pons, pyramids and spinal cord and crossed cerebellar atrophy resulting from these lesions. A significant drop in perfusion pressure results in two varieties of lesions bilaterally located in fetal brain. The usual situation is that of damage bilaterally to upper brainstem, thalami, inferior colliculi, and sometimes basal ganglia following placenta previa, abruption placentae, or torn or compressed umbilical cord. The other variety is bilateral lesions of varying symmetry located in the borderzone high on the posterior convexity in the parietal and occipital lobes between the middle, anterior and posterior cerebral arteries. If small, they only involve parietal gray matter. When massive, they cover very large regions of the gray and white matter of each hemisphere including the frontal lobe, and if maximal, both entire hemispheres are involved as in hydranencephaly [33]. Hypoperfusion is responsible for sclerotic microgyria found bilaterally in parietal lobe borderzones. While these lesions are frequent in the cerebrum, the cerebellum is usually spared. Moreover, a significant proportion of fetal cases with hypotensive lesions in cerebrum also have comparable terminal arterial bed lesions in the caudal spinal cord [34]. We deliberately did not use the term bwatershedQ as it refers to the mountainous region supplying a river or a lake. Noell and Schneider first recognized the vulnerability of the cortex supplied by the distalmost branches of major cerebral arteries and coined the hemodynamic principle of the letzte Wiese or the blast fieldQ meaning the tissue supplied by the last branches of major arteries [35]. This term was, unfortunately, incorrectly translated into bwatershed.Q J. E. Meyer described it as boundary zones in infant brains [36] and Lindenberg and Friede expanded on the concept of the borderzone lesion [37,38]. Of course there are collateral connections between the distalmost major cerebral arteries, but these collateral vessels are of small caliber and are probably insufficient to handle adequate perfusion in a sudden drop in systemic perfusion pressure [39]. The lesions in borderzone regions between arterial supply beds or at the end of arterial beds are continuous necroses, not single or multiple focal lesions (e.g., as when focal necroses in fetal white matter are said to be bwatershedQ lesions).
2.3. Germinolysis Cystic degeneration of the ganglionic eminence, has been recognized since the first descriptions of congenital rubella syndrome [40—43]. Schwartz,
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who considered them residua of anterior terminal vein hematomas [44], first identified them. These lesions are usually bilateral and apparently occur during the time of maximal ganglionic eminence size (about 26 weeks). The term bgerminolysisQ is ideal in that it emphasizes premature loss of this fetal tissue by a process apparently different from that usually encountered in older brains [42]. These cysts may persist well after birth. The pathogenesis is unknown, but it seems likely that a large proportion reflect an encounter between fetus and a viral agent. The proportion remaining as posthemorrhagic cavities [44] must be small, as hemosiderin-filled macrophages are uncommon.
2.4. Fetal white matter abnormalities In 1969 a set of four frequent abnormalities in fetal white matter (hypertrophic astrocytes, focal necroses, amphophilic globules and the cluster hypertrophic astrocytes—amphophilic globules) were termed the perinatal telencephalic leucoencephalopathies [45]. Individual histologic features in this set clustered together in different combinations [46].
2.5. Hypertrophic astrocytes Glial cells that have medium to large pale vesicular nuclei, with fine chromatin stippling, and eosinophilic irregular hyaline cytoplasm are not found in normal human myelinating or premyelination hemispheral white matter [47] and are not part of the tract-specific increase in glial cell density immediately antedating myelination, so called myelination gliosis [48]. They are associated with a widely spread delicate fibrillary gliosis detectable with appropriate stains. The gliosis persists until adulthood following neonatal lesions in the kitten [29], as it probably does in the human. Although the cytoplasm of these cells is less voluminous than mature hypertrophic astrocyte, there are sufficient morphologic similarities to consider them small hypertrophic astrocytes. These diffusely spread abnormal astrocytes in white matter are not associated with macrophages. Their other characteristic is that they appear in bilaterally symmetric brain regions [45]. The symmetry is present even when patches of white matter astrocytosis are relatively restricted. The usual location of these cells is deep frontal or parietooccipital white matter. They are also frequent in corpus callosum, in gyral white matter cores, and in deep cerebellar white matter. When present, nearby gray matter is entirely normal. These findings contrast with the localized astrocytosis underlying an organized cort-
250 ical necrosis. Similarly, focal necroses in white matter may have a penumbra of hypertrophic astrocytes, but the abnormality we are focusing on is that of diffuse white matter astrocytosis, not the astrocytosis around focal regions of necrosis. The period between insult and appearance of these astrocytic changes is 2—3 days (kitten) [29,49] and may differ with various insults. This period and life cycle of hypertrophic astrocytes for the fetal human brain was estimated at 4 days [50], but there is difficulty in identifying the significant inciting event during intrauterine life. In rats the capacity of cortical astrocytes to respond in this fashion develops by the second postnatal week [51] and in fetal humans by late gestation [28]. In the NCPP population the encounter frequency increased from 9% of brains at midgestation to 59% at term. The long-term effect of diffuse white matter astrocytosis is widespread fibrillary gliosis without gray matter abnormality, as recognized by multiple authors from the middle of the 20th century [52— 56], and often associated with paucity or hypoplasia of hemispheral white matter.
2.6. Focal necroses in white matter Focal necroses in fetal and neonatal white matter were first recognized a century and a half ago [57,58]. Subsequently many pathologists contributed to the understanding of these lesions (e.g., Mo ¨ebius, Vivius, Herschfeld, and Hlava)(summarized by Schmorl in 1904 [59]). Virchow and Parrot found a general metabolic disorder in most neonates with focal necroses. Mo ¨ebius found thrombosed vessels. Vivius found icterus in his 300 cases. Herschfeld found omphalitis in most of his cases and Hlava found emboli. Schmorl found icterus in his 280 cases, but no omphalitis. Subsequent descriptions related these lesions to birth injury. Within 25 years, the search for antecedents turned to hypoxia and circulatory problems (summarized in [44]). Initially these small necroses are simple coagulative necroses that develop macrophages centrally and are surrounded by hypertrophic astrocytes, leaving glial scars or small cysts. Most foci range from 1 mm to 1—2 cm in size. Large cysts may subsequently collapse. Grossly they appear as small white or yellow-white opaque foci. If bilirubin is elevated, they may appear deeply yellow; occasionally they contain small amounts of blood. Other than macrophages, inflammatory cells are not a component. Axon retraction balls around these lesions may mineralize. In newborns fresh coagulative necroses may be found side by side with the glial scars or small cysts of older lesions. While
F.H. Gilles, I.-G. Gomez larger lesions tend to be located deep in white matter, many are scattered from the ventricular wall to gyral white matter cores (as described by all above authors and as was figured by Schwartz [44]). They tend to be preferentially located in white matter of the parietooccipital and frontal lobes but not temporal lobe [60,61]. In 1962 these same lesions were redescribed in a group of 51 infant brains without reference to the century of prior studies [62]. They were described as though only located next to lateral ventricle, despite many prior observations of their widely spread distribution in cerebral white matter. These authors coined a new term bperiventricular leucomalaciaQ implying two anatomic points: 1) a location only adjacent to lateral ventricle, and 2) that the lesions encircled (i.e., the prefix bperiQ) the ventricle. Both of these location implications seem not to be consistent with the historical data. The latter authors found clinical markers of hypoxia or anoxia in 80% of their cases, but, like their predecessors, failed to include control cases. When formally estimated in case-control studies, the risk factors of focal necroses are multiple and do not include hypoxia, anoxia, or systemic hypotension [60,63,64]. We found that a single dose of lipopolysaccharide administered intraperitoneally to the newborn kitten produced focal white matter necroses in a dose-dependent fashion [29] and in newborn monkey. This has been confirmed in the preterm ovine fetus [65]. Subsequently, in the NCPP, we found that infants with septicemia or prematures of less than 36 weeks of gestation were at increased risk of necrotic foci [66], and the risk factors include placental vascular anastomoses, funisitis, and purulent amniotic fluid [67].
2.7. Amphophilic globules Amphophilic globules are small deposits of amphophilic or basophilic material in telencephalic gray or white matter, usually in proximity to blood vessels. Multiple investigators have observed them [38,45,68,69]. In the NCPP population, they were found with a slightly increased frequency in the gestational age range of 30—32 weeks. One risk factor in a multivariate analysis was maternal urinary tract infection [70].
2.8. Cluster of hypertrophic astrocytes and amphophilic globules Hypertrophic astrocytes and amphophilic globules tend not to occur independently in fetal telencephalic white matter [46,70]. Maternal febrile urinary tract infection is the most prominent risk
Developmental neuropathology of the second half of gestation factor for this cluster of abnormalities in fetal white matter, which suggests that endotoxin in the mother crosses the placenta and this prenatal exposure contributes to the appearance of this abnormality in fetal white matter.
2.9. Two varieties of white matter damage in neonates In the broadest sense, it is clear from the above that there are two varieties of white matter damage in the neonate; diffuse white matter astrocytosis and white matter focal necroses. One, white matter astrocytosis, is more prevalent than the other. These two abnormalities have similar, but not the same risk factors. In most clinical studies focal necroses are the focus of the study because these are far more readily seen sonographically. In these studies a large number of investigators have confirmed an association between maternal sepsis, chorioamnionitis, proinflammatory cytokines and focal white matter necroses (summarized in Ref. [71]). Studies in experimental models have supported the association between E. coli chorioamnionitis or proinflammatory cytokines and their effect on developing white matter and between white matter astrocytosis in rabbit [72] and guinea pig [73], although there are a number of study design limitations in the last study. Furthermore, direct injection of the inflammatory cytokine interleukin-1 beta and, to a lesser extent, tumor necrosis factor-alpha into rat brain results in diffuse white matter damage in rats, while lipopolysaccharide does not [74]. However, we do not yet understand why systemic proinflammatory cytokines result in focal white matter lesions rather than only diffuse astrocytosis.
2.10. Delayed myelination Since myelination is age-related, delayed myelination was defined (in the NCPP) in terms of gestational age. In each of eight gestational age groups, the 15% of newborns with the lowest myelination scores were defined as having delayed myelination and the risk factors were evaluated. In this study, the important risk factors of delayed myelination were maternal cigarette smoking, low birth weight, gestational age of less than 36 weeks, third trimester uterine bleeding, and low maternal hematocrit [75]. Delayed myelination is not the same condition as hypoplasia of the white matter, although the two conditions can occur together.
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3. Best practice guidelines ! Know the gross and microscopic aspects of fetal brain that change during the last half of gestation. ! Differentiate between brain atrophy and failure of growth of brain. ! Compare head circumference to body length. ! Examine the atlantooccipital joint, vertebral arteries, and the cervicomedullary junction in sudden unexpected infantile death. ! Include control cases in clinicopathologic studies. ! Use the presence or absence of specific gyri to estimate gestational age, not the operculae covering the insula. ! Distinguish between delayed myelination and white matter hypoplasia. ! Train specialists in developmental neuropathology.
4. Future research directions ! Genetic susceptibility to insults at birth; ! Genetic susceptibility to brain insults during the last half of gestation; ! Genetic control of cell migration in the developing brain; ! Development of choroid plexus; ! Genetic control of cerebral microvascular development; ! Genetic control of repair in the embryonic and early fetal brain; ! Molecular biology of myelination.
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