Fetal and neonatal hypoxic–ischemic lesions

The most common neuropathology encountered in pediatric autopsies is that associated with hypoxia and/or ischemia. The great variety of lesions associated with these two pathologic processes, either alone or in combination, poses a special challenge to the histologist, whose principal task is to distinguish them from the rare inherited disorders with which they overlap morphologically. Unlike the static reactions of mature brains to acquired injury, fetal and neonatal pathologic reactions must be considered in the context of:

The extraordinarily rapid growth and plasticity of the immature nervous system.

The major changes in cell and tissue properties that occur during development.

The differences between the mature and the immature nervous system partly explain the enormous diversity of the morphologic changes associated with hypoxic–ischemic damage.

PATHOGENESIS OF HYPOXIC–ISCHEMIC LESIONS

Possible pathophysiologic schema

Principal factors involved in the production of lesions:

Cerebral blood flow: this is much greater in the fetus than in adults, but the autoregulatory range is narrower. Regional differences in flow vary during development and affect the pattern of lesions.

Nature of the injury: this is determined by whether it is produced by local or global ischemia or hypoglycemia. Seizures influence the severity of the lesions.

Duration or repetition of the injury: this affects the extent and number of lesions.

Selective vulnerability of neurons: this depends on many factors, including the release of endogenous excitotoxic amino acids, the role of calcium-binding proteins, regional differences of perfusion, and the maturity of the neurons.

Timing of the injury is paramount: developmental changes affect the water content of the brain, the maturation of metabolic pathways, the location of watershed zones, the vulnerability of mature neurons, and the histologic response to injury (e.g. the macrophage response predates the astrocyte response, and hypoxic change in immature neurons is karyorrhexis and not cytoplasmic eosinophilia).

Present knowledge of embryology and developmental physiology allows a tentative chronology to be assigned to individual lesions (Fig. 2.1) although this remains relatively imprecise and extreme caution is needed in the forensic arena. Although some pathologic changes closely parallel those found in older individuals, others such as intraventricular hemorrhage, white matter necrosis, and marbling are unique to the perinatal period.

2.1 A timetable for hypoxic–ischemic lesions in early life.
Hydr, hydranencephaly; BB, basket brain; Por, porencephaly; MCE, multicystic encephalopathy; SEH, subependymal hemorrhage; CPH, choroid plexus hemorrhage; WMN (PVL), white matter necrosis (periventricular leukomalacia); PSN, pontosubicular necrosis; C/UI, cortical necrosis/ulegyria; Th/BG, thalamus/basal ganglia damage.

FETAL LESIONS

Tissue repair in the immature brain differs significantly from repair in the adult CNS. Macrophages are able to mount a phagocytic response early in the second trimester, while fiber-forming astrocytes are detectable only from 20 weeks’ gestation. Consequently, resorption of necrotic tissue in the first half of gestation occurs without any trace of glial repair, leaving a smooth-walled defect, which is often associated with disorganization of the surrounding cerebral cortex. This gives the false impression of a primary malformation rather than an acquired lesion. In contrast, destruction in the latter part of gestation engenders a brisk astrocytic response, resulting in ragged gliovascular cysts.

CAUSES OF HYPOXIC–ISCHEMIC LESIONS

Maternal (intrauterine environment)

Effects of severe maternal disease such as hemorrhage and shock (abruption), cardiac arrest, hypoxia (e.g. drugs, anesthetics), anemia.

Intrauterine infection.

Teratogens.

Smoking.

Trauma.

Disorders inherited from the mother.

Twins (particularly fetus papyraceous).

Placenta and cord

The placenta should be examined for hemorrhage, infarction, infection, and meconium staining. Pathologic factors include:

Maternal hypertension, toxemia, diabetes mellitus, hematologic disease, sarcoid, autoimmune disease, neoplasia.

Short cord (tethering and placental separation).

Long cord (knots, cord around neck).

Problems immediately postpartum

Respiratory disease (obstruction, pulmonary insufficiency, neuromuscular disease).

Congenital heart disease.

CNS malformations.

Metabolic disease (inherited or acquired).

HYDRANENCEPHALY

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Much of the cerebral mantle is replaced by a thin translucent membrane. The hemispheres are cystic, and lack surface convolutions (Fig. 2.2). Inferior aspects of the temporal, occipital, and frontal lobes are usually spared, but sometimes only the hippocampi remain. The deep gray nuclei may be rotated outwards and the thalami are atrophied. The membranous cerebral mantle comprises an outer connective tissue layer and an inner irregular glial layer which also contains mineralized neurons, debris, and hemosiderin-laden macrophages. The ependyma is usually absent. At the interface with surviving cerebral tissue, the inner glial layer runs into the molecular layer, covering it for a short distance, while adjacent cortex is usually disorganized, often with a pattern of polymicrogyria (Fig. 2.3). This histologic appearance clearly distinguishes hydranencephaly from the macroscopically similar bubble brain in Fowler syndrome (see Fig. 7.2).

2.2 Hydranencephaly in a twin of 22 weeks’ gestation whose co-twin died at 17 weeks.
(a) The bubble-like hemispheres photographed under water and viewed from above. (b) Removal from water allows the diaphanous membrane of the cyst wall to collapse. Damage is largely restricted to the internal carotid artery territory with sparing of the orbitofrontal cortex and inferior temporal and occipital lobes.

2.3 Hydranencephaly.
Thinned and irregularly folded polymicrogyric cortex forming a transition between surrounding normal cortex and the cyst wall. Same case as Fig. 2.2.

BASKET BRAIN

MACROSCOPIC APPEARANCES

Basket brain is a rare intermediate state between porencephaly and hydranencephaly. It is characterized by extensive bilateral porencephalic defects, which leave only a thin strip of cingulate cortex connecting the frontal and occipital lobes.

ETIOLOGY AND PATHOGENESIS OF FETAL HYPOXIC–ISCHEMIC LESIONS

Clinical associations

Attempted abortion.

Maternal poisoning.

Attempted suicide.

Severe maternal hypoxia.

Anaphylactic shock.

Fetal infection.

Twinning.

Clinical histories relate some smooth-walled defects to maternal disasters occurring between 18 and 27 weeks’ gestation. Direct pathologic observations of the evolving lesion as early as 22 weeks’ gestation show a central zone of destruction and disorganization, with neuroblasts and macrophages surrounded by an early manifestation of polymicrogyria.

Features suggesting that pathogenesis is ischemia or infarction

Symmetric lesions.

Lesions in carotid artery, anterior communicating artery, or middle cerebral artery territories. (Animal experiments using carotid block or ligation show that these territories are the preferred sites for ischemic lesions or infarction.) The surrounding polymicrogyria may represent exposure to a less intense ischemic penumbra.

HYDRANENCEPHALY

Hydranencephaly is characterized by normocephaly at birth followed by excessive cranial growth in the first few months and a transilluminable head.

Hydranencephaly is associated with minimal psychomotor development, spasticity, and epilepsy.

Lifespan depends on the condition of the central gray matter. Severe involvement means impaired thermoregulation, sleep, sucking, and swallowing, and survival beyond the neonatal period is unlikely. If this region is preserved, the lifespan may be several years.

PORENCEPHALY AND SCHIZENCEPHALY

MACROSCOPIC AND MICROSCOPIC APPEARANCES

A porus is a smooth-walled defect in the cerebral mantle, usually surrounded by an abnormal gyral pattern. It varies in depth from a slight indentation or fissure to a full-thickness breach of the hemispheric wall connecting subarachnoid space with ventricle. Pori tend to be bilateral, approximately symmetric, and situated over the Sylvian fissures or central sulci. Unilateral defects may be parasagittal, orbital, or occipital, and associated with abnormal convolutions, especially polymicrogyria, which are symmetrically placed in the contralateral hemisphere. Gyri surrounding the defect form irregular or radiating patterns (Fig. 2.4). The cortex around the porus is broken into islands or folded into polymicrogyria, which extends down into the cleft to meet the ventricular wall. The latter is denuded of ependyma, but covered by glial tissue, which extends a short way over the adjacent gray matter (Fig. 2.5). Subependymal nodular heterotopia (Fig. 2.6d) and partial or complete absence of the septum pellucidum are other features.

2.4 Porencephaly.
(a) Two unilateral pori are present. The shallow depression in the orbitofrontal cortex contrasts with the wide-mouthed full-thickness defect in the occipital lobe allowing communication between the subarachnoid space and the ventricle. (b) The surrounding convolutions have a radiating pattern. (c) Coronal section through the frontal lobes showing the extent of the anterior defect, which is lined by nodules of gray matter. The septum pellucidum is absent.

2.5 Porencephaly.
Coronal section through a frontal porus in a 48-year-old man. The cortical gray matter dips down into the cleft to meet the white gliotic ependyma. The cortical ribbon around the edge of the defect is irregularly thickened and disorganized. (Courtesy of Dr T Moss, Frenchay Hospital, Bristol.)

2.6 Schizencephaly.
(a) Bilateral porencephalic clefts centered on the middle cerebral artery territory in a twin of 32 weeks’ gestation whose co-twin died at 19 weeks. The hemispheres are viewed from above. (b) Coronal section at anterior thalamic level. The cortex in the center of the lesion is a completely disorganized mixture of neuroblasts and macrophages surrounded either side by polymicrogyric cortex. (c) Coronal section at striatal level. Polymicrogyric cortex from the anterior border of the cleft. (d) Large bilateral full-thickness defects in a 4-year-old boy with cerebral palsy and epilepsy. The covering leptomeninges ruptured during the dissection, revealing a radial pattern of convolutions around the clefts. (e) Coronal sections through the posterior parts of the hemispheres show thick polymicrogyric cortex curling over the mouths of the clefts and deeply invaginating the ventricle. Note the heterotopic gray nodules in the inferior corners of the ventricles.

Extensive bilateral porencephalic clefts (Fig. 2.6) are sometimes termed schizencephaly, especially in the radiologic literature, although the term schizencephaly refers back to an outmoded concept of circumscribed growth failure of the cerebral wall. The narrowness of the cleft with either closed or open lips was thought to differentiate malformed from acquired lesions, but clinical, morphologic, and experimental evidence favors a destructive origin for most lesions. There is also recent evidence for familial occurrence of schizencephaly in brothers with defects in the homeobox gene EMX2.

CLINICAL DIAGNOSIS OF PERINATAL ASPHYXIA

There is increasing evidence that most cases of cerebral palsy are associated with prenatal damage.

PORENCEPHALY

The following are associated with porencephaly:

Congenital hemiplegia.

Mental retardation.

Chronic neurologic handicap (i.e. bilateral spasticity and epilepsy), which is more severe in patients with bilateral defects.

MULTICYSTIC ENCEPHALOPATHY

MACROSCOPIC APPEARANCES

In contrast to the smooth-walled defects of hypoxic–ischemic lesions of early gestation, third trimester insults produce many cysts throughout large areas of cerebral white matter and deeper cortical layers (Figs 2.7, 2.8). Occasional cases are unilateral and circumscribed (Fig. 2.9), but most are extensive and bilateral. Bilateral multicystic encephalopathy is often associated with cystic necrosis in the basal ganglia and brain stem tegmentum (Fig. 2.10).

2.7 Multicystic encephalopathy in a smaller first twin at 36 weeks’ gestation.
(a) Superior view of the brain within the skull. The convolutions are either massively cystically dilated or narrow and thin. (b) Coronal section showing dilated ventricles and replacement of much of the cortex and white matter by an irregular firm white cystic meshwork.

2.8 Multicystic encephalopathy.
(a) Tough gliovascular bands transform much of the deep cortex, white matter, and basal ganglia into a spongy mass. The thalamic nuclei are shrunken and extremely white. (b) Comparable histologic section from another patient showing that not only the cortex and white matter, but also the thalami and basal ganglia have been replaced by large cysts.

2.9 Unilateral circumscribed form of multicystic encephalopathy.
Destruction is limited to the occipital lobe in one of a pair of conjoined twins.

2.10 Horizontal sections of the brain stem in multicystic encephalopathy.
There is bilateral symmetric destruction running down through the tegmentum.

MICROSCOPIC APPEARANCES

A meshwork of thin gliovascular septa form numerous cysts containing lipid-laden macrophages. Global hemispheric necrosis (Fig. 2.11) is the term used to describe morphologically similar but particularly extensive cases following severe birth asphyxia and sudden hyperpyrexia and collapse in the postnatal period.

2.11 Global hemispheric necrosis.
(a) Extensive cystic destruction of the cortical white matter and basal ganglia following severe birth asphyxia. (Courtesy of Dr T Moss, Frenchay Hospital, Bristol.) (b) Low-power section of the frontal lobe.

MULTICYSTIC ENCEPHALOPATHY

Follows a history of reduced fetal movement, a twin dying in utero, or perinatal asphyxia.

Causes abnormalities from birth that include seizures, hypertonia, irritability, abnormal cry, and microcephaly.

Leads to death within weeks or months.

PERINATAL LESIONS

ACUTE HEMORRHAGE

Hemorrhage is the commonest pathology in fetal and neonatal brains. It can start in any intracranial compartment and rapidly spread elsewhere. The pathogenesis is multifactorial. The principal risk factors are immaturity, perinatal distress, and asphyxia, though a similar spatial distribution in still and live births also implicates antenatal factors. The variety of hemorrhages in the neonatal brain is shown in Fig. 2.12.

2.12 Types of hemorrhage in neonatal brain.

SUBDURAL HEMORRHAGE (SDH)

2.13 SDH resulting from a tentorial tear at an unassisted birth at 35 weeks’ gestation.

SUBARACHNOID HEMORRHAGE (SAH)

SAH (Figs 2.14–2.16) may manifest as:

2.14 Small petechial SAHs overlying the central sulcus in a 19-week fetus.

2.15 Well-demarcated subarachnoid hematomas localized over parietal cortex.
This was associated with a threatened abortion at 20 weeks’ gestation.

2.16 A small localized SAH on the temporal pole as well as extensive basal SAH secondary to hemorrhagic white matter infarction.
This occurred in a term infant with multiple congenital anomalies who was cyanosed at birth.

Petechial or diffuse extravasates.

Massive localized temporal or occipital hematomas.

Hemmorhage in the basal cisterns and cerebellar subarachnoid spaces.

Secondary SAH may follow SDH or ruptured intraparenchymal hematoma, or more frequently extension of intraventricular hemorrhage (IVH) through the fourth ventricular foramina. Primary SAH is also common in neonatal autopsies, especially in premature infants. Etiologic factors include hypoxia, capillary fragility, coagulopathy, and sepsis.

SUBPIAL HEMORRHAGE (SPH)

SPH is often confused with SAH. It is a focal hemorrhage, which is usually temporal, parietal, or cerebellar, and occurs with or without other signs of bleeding. It is most common in asphyxiated premature infants, but also occurs in premature or term infants with respiratory distress syndrome or congenital heart disease (Figs 2.17, 2.18).

2.17 SPH in a term infant with multiple congenital anomalies including cyanotic congenital heart disease.
(a) Anterior coronal sections in the frontal lobes showing right-sided central white matter softening and several superficial hemorrhages. (b) Microscopy reveals an entirely intracortical bleed covered by pia.

2.18 SPH in the cerebellum in a term infant with congenital heart disease.
This discrete hematoma displaces the external granular layer and lifts the pia.

SUBEPENDYMAL GERMINAL PLATE/MATRIX HEMORRHAGE (SEH)

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Acute SEH has variable appearances: small, multiple, and bilateral bleeds occur anywhere in periventricular matrix tissue (Fig. 2.19), including the roof of the fourth ventricle. Acute SEH is usually found

2.19 SEH in an infant with hypoplastic left heart syndrome born by cesarean section at 36 weeks’ gestation who survived 3 days.
(a) Small SEH that has remained within the matrix zone (grade 1) in the most typical position near the terminal vein close to the caudate nucleus and thalamus. (b) The small bleed remains in situ within the cellular matrix tissue. The ependyma is intact. No bleeding point can be ascertained.

GRADING OF SEH ON CRANIAL ULTRASOUND

Grade	Distribution of hemorrhage
1	Confined to germinal matrix
2	Germinal matrix and lateral ventricle, but no ventricular dilatation
3	Germinal matrix and lateral ventricle, which is acutely distended by hematoma within the ventricle
4	As above with extension of hemorrhage into adjacent brain parenchyma. (Note: the appearances may resemble those of pure venous infarction without IVH; see Fig. 2.36)