Fetal Neuropathology 21
21.1 Malformations 425
21.2 Hypoxic−Ischemic Encephalopathy 427 21.2.1 Neuropathology 428
21.3 Intoxication 429 21.3.1 Cocaine 431 21.3.2 Heroin 431 21.4 Infection 431
Bibliography 432
References 432
The brains of fetuses should be removed using the same procedure as for newborns. Examination of the fetal brain should be preceded by an estimation of the gestational age based primarily on a comparison of body mass and length at autopsy with normal val- ues (cf. Chap. 20). When examining the brain itself factors other than brain mass should be considered for comparison with a pathological state: the pattern of sulcation, synaptogenesis, as well as the state of myelination and of the neuronal migration process.
The development of olfactory bulbs, optic nerves, pituitary stalk, and cranial nerve roots is recorded, and the mass and occipital-frontal length of each hemisphere and its biparietal width are measured.
Because of the friability and deformability of the fetal brain, these measurements are best obtained while the brain is floating in either fixative or water.
21.1
Malformations
Fetal malformations may be primarily caused by de- velopmental deficits attributable to genetic or chro- mosomal abnormalities. Such “constitutional” mal- formations contrast with secondary malformations related to destructive lesions caused by exogenous influences. Genetic malformations of the brain such
as microcephaly vera or lissencephaly type II are rare. Mental retardation is often attributable to chro- mosomal disorders. Chromosomal aberations are neither constant nor specific for the CNS abnormali- ties they cause (Encha-Razavi 1995).
The developing brain is especially susceptible to injury over the entire period of gestation and early postnatal life. Numerous noxious exogenous mecha- nisms inflict damage, the sequelae depending largely on the duration of the insult. Among the major exog- enous causes of injury are lack of oxygen, toxic and infectious agents, and mechanical loadings.
Brain malformations are not specific: diverse causes can produce similar changes. The malforma- tions have been classified according to Encha-Razavi (1995), Roessmann (1995) and recently Barkovich et al. (2001). Barkovich et al. (2001) have proposed a classification based mainly on differences in patho- genesis, i.e., developmental disturbances. The fol- lowing types of pathogenetic processes are differen- tiated.
1. Malformations due to abnormal neuronal and glial proliferation or apoptosis (e.g., megalen- cephaly − Fig. 21.1c, d, microcephaly − Fig. 21.1e, f).
2. Malformations due to abnormal neuronal migra- tion (Figs. 21.2, 21.3); for example, lissencephaly, heterotopia (Fig. 21.3b, arrows), and cobblestone complex.
3. Malformations due to abnormal cortical or- ganization (e.g., polymicrogyria − Fig. 21.3a, schizencephaly, cortical dysplasia, heterotopia − Fig. 21.3b).
4. Malformations of cortical development, not oth- erwise classified (including malformations sec- ondary to inborn errors of metabolism, i.e., mi- tochondrial disorders, peroxisomal disorders, etc.).
Syndromes associated with cortical dysplasias (Whit- ing and Duchowny 1999) can be classified separately according to their morphological features:
▬
Neurulation failure − with an incidence of 1 to
2 per 1,000 live births − is characterized by lack
of closure of the posterior neuropore: anen-
Fig. 21.1a−f. Malformations. a Brachiocephaly; b dolichocepha- ly; c, d megalencephaly as demonstrated in comparison with a foot-rule (c) and in comparison with a normal brain (d); the brain
mass was 2,170 g at autopsy. e, f Microcephaly as demonstrated in situ on occasion of the autopsy with distinct thickening of the skull and extreme enlargement of the paranasal sinus
cephaly, meningo-encephalocele, meningocele, Arnold−Chiari type II malformation.
▬
Prosencephalon growth failure: arhinencephaly, holoprosencephaly.
▬
Abnormalities of midline structure: agenesis of the corpus callosum, septum pellucidum malforma- tion, Arnold−Chiari malformation (Fig. 21.2d).
▬
Brain stem growth failure.
▬
Abnormalities of the aqueduct of Sylvius.
▬
Heterotopias: scattered neurons, nodular hetero- topia, polymicrogyria, cortical dysplasia.
▬
Faulty neuronogenesis: microcephaly, microgy- ria, agyria, lissencephaly.
▬
Microdysgenesis in the sense of cortical cytoar- chitectural abnormality as seen in patients with generalized epilepsy (Thom et al. 2000).
21.2
Hypoxic−Ischemic Encephalopathy
Hypoxic−ischemic encephalopathy is a special form of fetal injury whose prevalence is only now being
fully appreciated because neuroimaging enables ex- amination of the fetal brain during pregnancy. Inju- ry is attributable to hemodynamic mechanisms in up to 25% of preterm newborns (<1,500 g) at birth and in a much smaller but still meaningful proportion of more mature infants (Del Toro et al. 1991). Injury is caused by a wide spectrum of prenatal pathologic conditions, maternal, fetal, and placental, including ischemia (Callahan et al. 1990), hypertension (lead- ing to peri- and intra-ventricular hemorrhages), and reperfusion after ischemia (leading to peri- and in- tra-ventricular hemorrhage and hemorrhagic peri- ventricular leukomalacia). Hemorrhagic periven- tricular leukomalacia can also occur secondary to venous infarction if massive peri- and intra-ven- tricular hemorrhage has obstructed draining veins (Volpe 2001). The hemorrhaging can also be delayed (cf. Darrow et al. 1988). The factors associated with neuropathological findings in immature newborns are summarized in Table 21.1.
The basic principles of ischemic brain injury may be explained at the molecular level. Oxidative stress is suggested to be involved in normal aging, espe- cially also in the human fetal brain (Yamamoto et
Fig. 21.2a−d. Malformations due to abnormal neuronal (re- tarded) migration. a Opercularization is not finished (arrows);
b alteration of the left cortical surface caused by arachnoidal
cyst; c bilateral heterotopy at the angles of the ventricles (circles);
d Arnold−Chiari malformation (arrows)
al. 2002). Advanced glycation end products are gen- erally reported to be negative in neurons of normal young brains.
Hypoxia alone does not appear to inflict brain injury, but a combination of hypotension, reperfu- sion with ischemia or ischemia alone or hypoxia in combination with hypoglycemia does. The extent of injury also depends on disturbances in oxidative glucose and lactic acid metabolism (Vannucci 1992), as reviewed also by Takashima and Tanaka (1978) and Greisen and Børch (2001). Evidence from human neonates indicates that white matter is selectively ex- posed to ischemia. Blood flow to the white matter is particularly low in premature infants, amounting to only 17% of the flow to gray matter. Blood flow to the white matter, moreover, appears to be selectively re- duced when blood pressure is low, an effect explained
by the vascular anatomy: the periventricular white matter (germinal matrix) is a vascular end zone sup- plied by long penetrating arteries arising from pial arteries on the brain surface. The oligodendrocytes in particular are injured (Liu et al. 2002). Moreover, the subependymal veins appear vulnerable to rupture.
The structural immaturity of the veins in premature neonates is causally related to the high incidence of germinal matrix hemorrhage (Figs. 21.4c, d, 21.5a, b) (Anstrom et al. 2004). An additional increase in excitatory amino acids plus additional biochemical alterations are thought to mediate the pathogenesis of this type of encephalopathy.
21.2.1
Neuropathology
As stated above, the nature of morphological changes encountered in the infant brain depends on the time of insult and its duration.
Isolated white matter lesions, so-called leukoma- lacia or periventricular leukomalacia, are specific to immature brains peaking in incidence at around 34 weeks of gestation. This type of lesion occurs in the periventricular region, centrum semiovale, sub- cortical region, and in the corpus callosum. Hypoxia and/or ischemia are thought to be principal causes of white matter injury in preterm infants, a hypothesis based on the following two phenomena (Greisen and Børch 2001):
▬
The nature of the lesion: cystic or gliotic degen- eration with little or no evidence of hemorrhage
▬
The nature of the cerebral vasculature in the im- mature brain
The acute lesion is usually a coagulation necrosis with axonal disintegration combined with a microg- lial and astrocytic reaction. The necrotic tissue is increasingly incorporated, digested, and eliminated by macrophages, the resultant cavitation leading to multicystic leukoencephalopathy with calcium de- posits and/or hemorrhages.
Isolated gray matter lesions are seen exclusively in full-term infants. A variety of lesions occur de- pending on the timing of the insult and neuronal maturation: cerebral cortical necrosis, pontosubicu- lar necrosis (Ahdab-Barmada et al. 1980) related to ischemia, Möbius syndrome, and basal ganglia ne- crosis (Rorke 1992).
Combined gray and white matter necroses lead to various types of lesions, all producing different degrees of cavitation: cystic or multicystic encepha- lopathy, porencephaly, schizencephaly, basket brain, hydranencephaly, etc. (Larroche 1977).
Ischemic infarction also produces characteristic brain lesions, mainly in the territory of the middle cerebral artery. Fresh hemorrhage is the most com-
Fig. 21.3a, b. Malformation due to abnormal neuronal migra- tion. a Polymicrogyria; b glial nodules within the enlarged ven- tricular system
mon lesion found in the fetal brain (Fig. 21.4), char- acterized partly by petechial hemorrhages in the subarachnoid and/or subpial space, and partly in the subependymal region and in the germinal zone.
Hemorrhage of the choroidal plexus is also common.
Intraventricular hemorrhage may occur.
Consequent to the bleeding there are cellular re- actions and scarring which have been described by Darrow et al. (1988). The early reactions of macro- phages in infants occur at about the same rate as in adults. However, the transfer of iron from macro- phages to astrocytes occurs much more rapidly in infants. The same holds true of the absorption of ne- crotic tissue to form a cyst (see pp. 444 f).
21.3 Intoxication
The age-related particular susceptibility of develop- ing brain tissue to injury from drugs, alcohol, and ex- posure to environmental toxins has long been known (for review see Larson 1989). The teratogenic effect of individual drugs and alcohol on embryonic growth and the brain‘s general vulnerability are described in Chap. 16−20. It should be pointed out here that
mercury can cause cytoarchitectonic abnormalities;
alcohol abuse (see p. 383) and the use of drugs such as phenytoin (hydantoin) and warfarin (coumarin) can lead to microcephaly with polymicrogyria and mental retardation. Ionizing radiation (pp. 257 ff) as well as cytostatic treatment of the mother during pregnancy (p. 359) interferes with neuronal prolifer- ation and migration and is also capable of inducing microcephaly with mental retardation.
Growth processes susceptible to chemicals and drugs have been analyzed by Barone et al. (2000).
These authors highlight the following temporally and regionally dependent processes contributing to cerebral development: proliferation, migration, dif- ferentiation, synaptogenesis, gliogenesis, myelina- tion, apoptosis, and neurotrophic factors.
The morphological changes engendered by these substances closely resemble those described above (Sect. 21.1). Here we deal only with the consequences of illicit drug consumption by mothers during preg- nancy, which can have a major impact on the practice of obstetrics and pediatrics in urban areas the world over. The newborn exhibits withdrawal symptoms including staring, sneezing, excessive sweating, de- pressed respiratory status or mitotic pupils. In such cases, death may result from the deleterious effects
Table 21.1. Summary of factors associated with neuropathological alterations in immature newborns. Source: Del Toro et al.
1991, with adaptions from Brann 1986, Goddard-Finegold and Michael 1992, Volpe 2001
Predisposing problems
Immature infant with vulnerable cerebral vessels Abnormal respiratory status, mechanical ventilation May not be able to autoregulate brain blood flow Events associated with hypotension/hypoperfusion
Myocardial compromise (e.g., secondary to asphyxia, congenital heart disease, large patent ductus arteriosus) Significant blood loss
Other causes of shock
Events associated with hypotension/hypoperfusion or reperfusion
Physiologic redistribution of blood flow, especially during hemorrhagic hypotension Resuscitation
Rapid volume expansion Motor activity
Tracheal suctioning, other procedures Seizures and other systemic problems
Fig. 21.4a−e. Hypoxic−ischemic encephalopathy. a, b The brain surface still is smooth without gyri in a child born in the 24th week of gestation, while on the frontal sections a subependymal
hemorrhage is seen (c, d), as well as a bilateral subdural hemor- rhage along the falx cerebri (e)
of drugs on the placenta or on the fetus. Premature birth, perinatal hypoxia, and meconium aspiration are all known causes of death in the newborn off- spring of drug-dependent mothers.
Respiratory distress is an early consequence of the presence of various other drugs in the mother (and fetus) and may lead to death. The incidence of sudden infant death syndrome (SIDS) is estimated to be 5 to 10 times greater in these babies (Chavez et al.
1979). Drug-addicted parents are responsible for an alarming number of deaths attributable to physical abuse or neglect (Mayor‘s Task Force on Child Abuse and Neglect 1985; for review Larson 1989; Bays and Feldman 2001).
21.3.1 Cocaine
Death can occur from intracerebral hemorrhage in infants whose mothers have taken a large dose of cocaine just prior to precipitous and premature de- livery (Chasnoff et al. 1986). Cocaine intoxication is known to cause microinfarcts in adult brains and it is thought that fibrosis of the germinal matrix region of the brain can occur in infants and children born to mothers who have consumed large doses of cocaine periodically during pregnancy. A number of cocaine- related congenital malformations are known, includ- ing amniotic band syndrome, cerebro−hepato−renal syndrome (Zellweger) and generalized anasarca (hy- drops). Skull defects, including exencephaly, pari- etal bone defects and ossification center delays and interparietal encephalocele, have been documented in addition to intracerebral hemorrhage and infarc- tion (Bingol et al. 1987).
21.3.2 Heroin
Fetal death in utero, stillbirths, neonatal death, intra- uterine growth retardation, SIDS, meconium aspira- tion, respiratory depression, and hyperventilation are among the sequelae associated with maternal heroin use during pregnancy. Although uncommon, con- genital malformations do occur. Instances of cerebral atrophy, abnormal lamination of the lateral genicu- late body, hydrocephalus due to aqueductal stenosis, partial midline fusion of the cerebellum, polymicro- gyria, hypertelorism, low-set ears, and wide-spaced nipples have been described (Larson 1989).
Children of heroin-abusing mothers tend to be hyperactive, have temper tantrums, and exhibit a low tolerance to frustration. They have poor fine motor coordination and suffer from speech and language delays, bilateral hearing deficits, attention deficits, and learning disabilities. Impulsivity and the inabil-
ity to interact socially lead to behavioral problems during adolescence.
21.4 Infection
The neurotropism of infectious agents such as rubel- la virus, cytomegalovirus, Listeria monocytogenes, and Toxoplasma gondii is well known and has been described in pathologic reviews. Each can produce meningitis, choroiditis, and multicystic encephalop- athy leading to microcephaly and/or hydrocephalus.
Some viral infections may even mimic primary mal- formations such as microcephaly and hydrocepha- lus.
In human immunodeficiency virus (HIV) infec- tion, the virus may be transmitted directly from mother to child. While the neurotropism of HIV is well known, only a few neuropathological studies of fetuses born to HIV-infected mothers have been published. A study of a series of 65 fetuses from preg- nancies terminated for maternal HIV infection after 16−35 weeks of gestation found neuropathological
Fig. 21.5a, b. Subependymal hemorrhage as an indication of an asphyxial insult. a Supependymal hemorrhage without intra- ventricular involvement; b subependymal hemorrhage within an aggregation of matrix cells associated with intraventricular hem- orrhage
changes in only one fetus. The lesion consisted of non-specific necrosis of the hypoxic−ischemic type, apparently caused by prolonged labor. The only pathological findings in the other cases were edema and recent hemorrhages in various sites attributed to prostaglandin medication. The nests of migrat- ing cells found in most of the cases were regarded as common findings in the fetal brain (Encha-Razavi et al. 1992).
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