Maternal and fetal factors relating to perinatal damage

• fetal/neonatal brain injury involves both maternal and fetal factors
• normal condition of fetus is one of hypoxia and cyanosis
• critical organs (liver, heart, brain) receive most oxygenated blood
• fetal tolerance to oxygen deficit is related to carbohydrate stores, although hyperglycemia worsens hypoxic damage due to lactic acid buildup
• compensation for hypoxia include increased blood pressure and circulatory adjustments (fetal AV anastomoses to shunt blood from less critical organs
• prolonged vasoconstriction leads to increased peristalsis and passage of meconium, as well as "asphyxia pallida" (severe skin pallor)
• can be caused by maternal factors (shop, heart disease, drugs) or placental factors (abruption, infarction, cord knots, thromboses, hematomas, rupture)
• factors from labour include decreased blood flow at end of contraction, cord compression, kinking, twisting around neck, placenta abruptio/previa, uterine rupture

Differential vulnerability of developing brain to hypoxia

• Birth weight
  • Less than 2500g - IVH, white matter necrosis, neuronal destruction in deep grey nuclei, thalamus
  • More than 2500g - grey matter necrosis in cerebrum > cerebellum
• differences due to CNS and lung maturation (decreased risk for RDS and hypoxia/acidosis
• Fetal maturation (gestational age)
  • First trimester - death or major malformations, e.g., microgyria, schizencephaly
  • 2nd-3rd trimester - destructive lesions, unlike adults due to immaturity of glial cells and neurons
• Reactive cell types
  • major reactive cell <20wks GA is the macrophage, which leave smooth walled cysts with few macrophages left
  • astrocytes in later GA - need to differentiate between reactive glia vs. immature glia (normal myelinating glia have moderate sized, round/oval nuclei, loose chromatin, pale/basophilic cytoplasmic rim, can arrange in rows) vs. small neurons in white matter
• fetal brain also has a looser texture/higher water content
• metabolism of fetal brain is different, and maturation not concurrent
• Maturity of neurons
  • mature neurons (brainstem cranial nerve nuclei, spinal cord) - cytoplasnic microvacuolation, dissolution/chromatolysis of Nissl substance, nucleolar destruction, irregular nuclear membrane, pyknosis/karyorrhexis
  • immature neurons (neocortex, corpus striatum) - neuroblastic stage with little/no perikaryon or Nissl substance with primitive nuclear organization, thus most reliable criteria is karyorrhexis (although some karyorrhexis is normal part of development)
• severe necrosis best seen at low power as staining pallor and general looseness of tissue, followed by cavitation with macrophages and vascular response, or glial scarring
• HIE also more often results in hemorrhage (microscopic, clinically silent, large, or fatal)

Hemorrhages

• term neonates - traumatic causes resulting in large subdural, flacial, or tentorial hemorrhages
• immature neonates - parenchymal, focal/diffuse subarachnoid, intraventricular hemorrhages
• small amount of blood in the CSF is of no significance (0-15,000 RBCs in prems and 0-675 in terms)
• Subarachnoid hemorrhages
  • most commonly over lateral temporal lobes, over vertex, convexities of parietal/occipital lobes
  • unilateral/bilateral/extensive
  • usually not mechanical etiology
  • associated with abnormal clotting factors, hemolytic disease, sepsis, CVT, parenchymal hemorrhage
  • commonly localized in the basal cisterns, spreading to the cerebellar subarachnoid space or interpeduncular space and Sylvian fissures,obscuring basal vasculature, cranial nerve roots, ventral pons, medulla
  • usually an extension of intraventricular bleedings, sometimes from rupture of deep/superficial AV malformation
• Periventricular and intraventricular bleeding
  • IVH most common seen hemorrhage
  • most frequent in low birth weight babies (< 1500g) and in DOL#1-4
  • originate mostly from the periventricular matrix zone between the caudate and nucleus, posterior to foramina of Monro, but also the choroid plexus or the germinal zone in the cerebellar nodulus
    • periventricular matrix zone consists of proliferating cells between the primitive ventricular germinal zone (for development of neural tube) and mantle zone, with ability to undergo in situ mitosis, producing two cell types: macroglia (production continues postnatally) and microneurons
    • the periventricular matrix zone of the ventromedial angles of the lateral ventricles resolve by term, but the anterior horns keep it the longest
    • these cells have little supporting stroma, and fragile vessels that will become veins traverse this zone
  • combination of factors contribute to cause this
  • Acute clinical features:
    • most associated with congenital heart disease
    • symptoms can be absent or nonspecific
    • dropping Hb level, hypotension, bradycardia, abnormal glucose/water metabolism, increased ICP, hypotonia, coma, flaccid quadriparesis, decerebrate posturing, generalized tonic seizures, hypothermia, abnormal eye movements, fixed pupils
  • Acute pathological features:
    • blood in the basal subarachnoid space
    • distention of the ventricular system with liquid or clotted blood
    • hemorrhage in the subependymal matrix zones
    • lateral and 3rd ventricle relatively free of blood if bleeding in 4th ventricle or cerebellum
    • extension of bleed into the centrum ovale in a "sun-burst" pattern
    • if not associated with matrix zone, suspect ruptured vascular malformation
    • can be associated with other periventricular or cortical hemorrhages
    • blood in the spinal subarachnoid space or central canal, or even hematomyelia
    • hemorrhage from the choroid plexus shows (1) blood in ventricle (2) congestion of choroid plexus (3) absence of hemorrhage in matrix zone
    • matrix zone bleed can be localized in an infant > 1500g
  • Late clinical consequences:
    • death, but not all die
    • survivors can have no abnormalities or have varying levels of consciousness, jitteriness, seizures, hypertonia, and difficulties with sucking/swallowing
    • can have slowly increasing head circumference from obstructive hydrocephalus
    • matrix zone hemorrhages without rupture into ventricles generally are clinically silent
  • Late pathological features:
    • golden or olive green-gold staining of leptomeninges and possibly small rust-coloured clots of organized hemorrhage, sometimes mistaken for pus
    • cystic defect at site of hemorrhage containing macrophages filled with hemosiderin
    • diffuse fibrosis of the leptomeninges
    • ventricular dilatation and attenuated gyral pattern
    • red-brown staining of ependyma
    • hemosiderin-laden macrophages
    • can have excessive size of matrix zone ?impaired migration post hemorrhage
    • subependymal gliosis, overgrowth of glia over destroyed ependymal lining
    • reactive proliferation of the leptomeninges
    • neuronal loss and necrosis
    • can also result in smaller brains with attenuated gyral pattern
• Parenchymal hemorrhage
  • petechial and perivascular hemorrhages are common and of unclear significance, tend to remain localized, and cause no significant tissue necrosis
  • larger hemorrhages can be associated with tissue necrosis
  • subpial hemorrhages (associated or not with subarachnoid hemorrhages) can extend into the parenchyma, and may be associated with seizures later in life
  • multiple petechial hemorrhage in the cerebellum usually does not rupture into the subdural space, unless bleeding from the nodulus that can rupture into the 4th ventricle, sometimes with gitter cells (macrophages) filled with RBCs such that they have a morular appearance
  • intracerebral hemorrhages due to venous sinus thrombosis can occur later, and often are symmetrical
  • septic emboli can also produce petechial or larger hemorrhages, usually at the corticomedullary junction, though uncommon during neonatal period
  • spinal cord usually only has petechiae

Parenchymal lesions

Pathological observations are coloured by the fact that infants often have multiple different events, as well as repeated events, complicating the picture

White matter lesions
• high vulnerability of white matter due to multiple factors:
  • higher metabolic rate in white matter than grey matter
  • poor development of ventriculofugal arteries at < 8 months GA
• abnormalities can be necrosis or astrocytosis, but also fatty change of the white matter (unclear significance, hypoxia? inflammatory?)
• White matter gliosis
  • common lesion, with multiple possible etiologies
  • can be alone or associated with hemorrhage or necrosis
  • can occur anywhere in the CNS
  • associated with hypoxic-ischemic injury and nutritional deficiencies
  • clinical signs not established, but can include global intellectual deficit
  • Gross findings acutely include swelling of the white matter with slit-like ventricles
  • Chronic findings are mildly dilated ventricles with reduction of size of hte centrum ovale adn corpus callosum
  • Histological findings shows unusual pallor of the white matter, with rarefied, microcystic neuropil and abundant oligodendroglia and myelination glia, mostly in the periventricular white matter. Pathological astrocytes around blood vessels or diffusely, hypertrophic glia, gemistocytic astrocytes with or without eosinophilic cytoplasmic masses, glial nuclei occasionally karyorrhectic, with PAS+ globules, microgliacytes (rod cells and gitter cells).
  • Proliferation of pathological astrocytes could indicate damage in areas requiring high metabolism, with relative lack of myelination glia (replacement)
  • Myelination can be retarded with malnutruition or infection (rubella virus)
  • "Plasma skimming" - hyaline blobs caused by intermittent blood flow and contraction/obstruction of small arteries from intermittent cardiac insufficiency or right heart failure
  • chronic hyperoxemia can lead to decreased cortical vessels
  • Chronic hypercarbia can lead to injury of the blood-brain barrier and increased vascular permeability
  • chronic hypoxia can lead to increased vascularization with tortuous, dilated vessels with prominent endothelial nuclei.
• White matter necrosis
  • periventricular leukomalacia - white matter necrosis mostly in periventricular regions, but can also affect the corpus callosum, centrum ovale, subcortical white matter, internal capsule. Selective necrosis of deep cerebellar or spinal cord white matter is uncommon.
  • Clinical aspects:
    • cardiovascular disturbances, respiratory distress, congenital heart disease, sepsis (especially Gram-negative sepsis)
    • IUGR and hypoglycemia (more in low birth weight babies)
    • stillborn infants - in utero circulatory disturbances
    • five categories:
      1. congenital anomalies
      2. neonatal sepsis
      3. age
      4. unfavorable intrauterine environment
      5. socioeconomic factors
      
    • clinical symptoms are nonspecific - lethargy/stupor, weak cry, poor suck/Moro, lower limb weakness, inactivity, hyperactivity/seizures
    • long term consequences include mental retardation, neurological deficits including spastic diplegia (Little's disease)
  • Pathogenesis:
    • combination of edema, decreased perfusion to border zone regions (between the ventriculofugal and ventriculopetal arteries, or ACA/MCA/PCA), impaired autoregulation, venous stasis
    • any condition that interferes with normal cardiorespiratory function (RDS, shock, congenital cardiac malformations) can cause white matter necrosis
    • vascular and septic (unknown mechanism) causes
  • Acute pathology:
    • edema and slit-like ventricles, may show yellow-white spots or just generalized duskiness or focal softening, or hemorrhagic infiltration
    • consistently affected zones:
      1. small zone anterior to the anterior horn within the subcallosal, superior frontal-occipital, and superior longitudinal fasciculi
      2. corona radiata
      3. external and internal sagittal strata of the temporal and occipital horns of the lateral ventricles
      
    • early changes include loss of architecture, homogeneity of tissue, staining pale or brighter pink, more obvious at lower power
    • "retraction balls" - round, pink structures in zones of necrosis
    • at 3 hours: coagulation necrosis with occasional reactive microglia
    • at 8 hours: coagulated zone ringed by reactive microglia
    • at 12 hours: reactive astrocytes in peripheral zones and capillary endothelial hyperplaia
    • at 2 weeks: prominent macrophage activity (rod cells), less conspicuous gliosis, peripheral neovascularization
    • can also be hemorrhagic, with intact or hemolyzed RBCs or hemosiderin deposits
  • Chronic pathology:
    • retraction of the necrotic tissue, resulting in ventricular dilatation and reduced size of the corpus callosum
    • cysts can also occur
    • tissue cavitation and stick-like figures (axis cylinders incorporating cellular debris)
    • hypertrophic astrocytes and gitter cells, no PMNs
    • hemosiderin, cholesterol clefts
    • gemistocytes in cavity walls
• Corpus callosum lesions
  • often associated with necrosis in the periventricular and deep white matter, but can be the primary site of damage
  • the genu is particularly susceptible, and can be due to a number of etiologies
  • no clear clinical changes from this in infants

Grey matter lesions
• Localization can be to:
  • specific cell types, e.g., neurons and glia
  • specific structure groups, e.g., Sommer's sector or thalamus
  • all neural tissue
• necrosis can occur at any stage of development
• chronic intrauterine lesions can resemble a developmental malformation
• extent of damage depends on:
  • severity of insult
  • glucose and hemoglobin concentration in the blood
  • state of maturation of the nervous system
• relative resistance of hypoxic-ischemic damage results in patterns of damage specific to infants, e.g., status marmoratus
• other patterns are similar to adults, e.g., laminary, hippocampal, and Purkinje cell necrosis
• can occur in multiple structures, with hemorrhages, or extending to the white matter
• Clinical signs of gray matter necrosis
  • if minimal lesion, signs can be absent both acutely and chronically
  • if important areas lesioned, can have seizures, stupor, coma, hypotonia, oculomotor disturbances, poor suck/swallow, tongue movement abnormalities, abnormal Moro, paresis
  • chronic symptoms include seizures, movement disorders, ataxia, cranial nerve palsies, pareses/paralyses, spasticity, and mental retardation
• Pathological features of grey matter lesions
  • Cerebral necrosis
    • can involve entire brain, arterial distributions, or border zones between major vessels
    • can damage selectively mature neurons, e.g., Sommer's sector
    • specific metabolic activities at time of injury may dictate which areas are injured by anoxia
    • Acute and subacute lesions
      • tense anterior fontanelle, swollen brain with gyral widening and flattening
      • congested superficial vessels (or devoid of blood)
      • necrotic tissues pale, dusky, or livid
      • total brain necrosis results in a very soft brain, difficult to handle or fix
      • bilateral uncal or parahippocampal herniation
      • slit-like ventricles
      • can cause decreased demarcation between white and grey matter, or "ribbon effect" of accentuating the pale cortex vs. white matter congestion
      • severe asphyxia can result in reversal of colours of grey and white
      • associated necrosis of the thalamus and deep grey structures, or underlying white matter
      • can be greenish if jaundiced
      • associated necrosis to pyramidal cells of Sommer's sector, subiculum, and basis pontis
      • if death soon after injury, finding is tissue pallor (Erbleichung) which can affect certain cortical layers, in the depths of fissues or crowns of convolutions
      • sometimes grey matter necrosis can be eosinophilic or have irregular cracks from endothelial swelling
      • necrotic neurons (depends on maturation) - neuroblasts can be hard to differentiate with pyknosis
      • spongy neuropil
      • reactive astrocytes (rarely macrophages)
      • several weeks post-insult:
        • gyri soft, fluctuant, matted, translucent, yellow-white
        • decreased bulk, thinned cortical ribbon
        • can be cystic
        • mildly dilated ventricles
        • organizing infarction with multinucleated gitter cells, endothelial swelling and proliferation
        • neurons filled with granular debris (PAS+)
        • hypertrophic astrocytes
    • Chronic cortical necrosis
      • external appearance may be normal, or decreased brain weight, gaps between gyri, smooth/slightly depressed, or coarsely nodular
      • if extensively cystic, can have tense, bubble-like surface, and be sclerotic and dense
      • gyri can have "mushroom" appearance with preferential damage to teh depths of the sulci
      • cystic areas can have few blood vessels, gitter cells, gliotic neuropil, or collapse of entire cortical ribbon
      • border between normal and sclerotic brain can be hypermyelinated
      • linear bands of cortical necrosis can produce a pitted gyral surface ("walnut shell")
      • years later, astrocytes show rich fiber network and few Rosenthal fibers, without prominent vasculature, sometimes with macrophages, and descending tract degeneration
      • in utero injury can result in diffuse multicystic changes or hydranencephaly, porencephaly/schizencephaly
  • Lesions of cerebellum
    • Acute and subacute necrosis
      • less common than cerebrum, often coexists with cerebral necrosis
      • patterns of injury
        • bilateral lesions at boundaries of superior and inferior cerebellar arteries
        • lesions of foliar cortex bordering central white matter
        • focal necrosis of crowns of cerebellar gyri
        • foliar depths
        • entire cerebellar grey matter
        • single artery distribution
      • may not be evident on inspection, maybe edema, duskiness, petechial hemorrhage, abnormality of basis pontis
      • can be due to damage to vertebral arteries during delivery or kinking afterwards, due to atlanto-occipital instability
      • immature cerebellar neurons show pyknosis and karyorrhexis, spongy neuropil
      • variable macrophages/astrocyte response
      • mature Purkinje cells are relatively resistant to hypoxia, as is the granule cell layer
      • extensive damage to the external granular layer can result in hypoplasia of the cerebellum
      • in premature, low birth weight infants, the external granular layer is more likely damaged than the immature Purkinje cells
      • dentate nucleus can be necrotic, multifocal, or selectively damaged hilum
    • Cerebellar sclerosis
      • occurs 2-3 months after diffuse parenchymal damage
      • shrunken, increased tissue density, unusual white appearance, narrowed folia more widely separated, dense/white/translucent white matter, rarely cystic
      • partial or complete Purkinje cell loss, reduction in granule cell layer, proliferation of Bergmann's astrocytes, reactive astrocytes (large bipolar cells with oval nuclei), gitter cells, basophilic/metachromatic granular debris, sclerotic white matter with astrocytic hypertrophy, dentate and olivary gliosis
  • Lesions of deep grey nuclei and thalamus
    • "status marmoratus" - abnormal myelination of basal ganglia/thalamus
    • may be from decreased blood flow through basal penetrating vessels or thrombosis/stasis of vein of Galen, infarcts from lenticulo-striate or Huebner's arteries, or selective vulnerability due to earlier maturation
    • may not be apparent on gross observation, usually associated with swollen brain and slit-like ventricles
    • necrotic tissue can be congested, livid, or dusky
    • subacute appearance when severe can be soft, shrunken, dusky pink-grey, and granular
    • histological features are selevtive neuronal necrosis/infarction with or without hemorrhage, occasionally retraction balls, Alzheimer type 2 astrocytes, spongy neuropil, fine granules of metachromatic debris, hypercellularity of the myelin, neovascularization
    • chronic appearance is shrunken, dense, chalk-white, loss of demarcation between grey-white, cysts, dilated ventricles, marbling may be present
    • microscopic features of neuronal loss and gliosis, cystic infarction, astrocytes, gitter cells, possilized neurons
    • usually accompanies damage to other areas of the nervous system
  • Lesions of the brainstem
    • most commonly affected are inferior colliculus, nuclear groups in the tegmentum of midbrain, pons, and medulla, gracile and cuneate nuclei
    • often associated with widespread damage throughout the neuraxis
    • Ponto-subicular necrosis
      • necrosis of selective brainstem tegmental structures and olivary necrosis/gliosis
      • associated neuronal necrosis in the subiculum of the hippocampus
      • can be found with necrosis elsewhere, "the periventricular leukomalacia complex"
      • associated with cerebellar hemorrhage/necrosis
      • acute necrosis of the pontine neurons is not visible on gross observation, or can be grey/dusky
      • microscopic features of karyorrhexis of pontine neurons, with or without microcystic neuropil, eosinophilic transformation, astrocytic response, vascular, macrophage, astrocytic response
      • chronic decreased size of basis pontis, with neuronal los, astrocytosis, secondary degeneration in the medullary pyramids and spinal cord
    • Selective brainstem necrosis
      • damage to brainstem tegmentum in isolation or in association with other areas
      • few cases have been described of this
    • Inferior olivary lesions
      • often accompanies other levels of necrosis, rarely in isolation
      • focal or diffuse neuronal loss with replacement gliosis
      • may be microinfarctions, gemistocytic astrocytes
      • secondary olivary degeneration with long-standing cerebellar sclerosis
  • Lesion of the spinal cord
    • neurons of spinal cord mature earlier, but are not selectively damaged in hypoxia
    • in severe asphyxia, the spinal cord also undergoes necrosis
    • rare instances of localization of damage to specific cord levels, possibly due to impairment of blood flow in a speific region