Classical patterns of neonatal brain injury are:

• combined grey and white matter lesions - intrauterine damage
• isolated white matter lesions - prematurity
• isolated grey matter lesions - perinatal injury

This classical view is not entirely accurate, much more complex than this. "Hypoxic-ischemic encephalopathy" encompasses a large number of pathological findings, including hydranencephaly, porencephaly, schizencephaly, basket brain, cystic or mylticystic encephalopathy, twin-twin transfusions syndrome, arterial infarction, leukomalacia, etc.

HIE Neuropathology

• necrosis/hemorrhage of the white/grey matter
• rapid growth and interference with development of the CNS
• Primary lesions
  • wide spectrum of abnormalities ranging from minimal focal infartcts to cavitary lesions
  • must consider
    (1) ability of immature brain to respond to injury and
    (2) fast growing evolution of lesions
  • lesional age
    • astrocytic and macrophage reactions not prominent or specific prior to 20 wks GA
    • insults from 16-22 wks GA - interferes with cortical plate organization, e.g., polymicrogyria, neuronal heterotopia
    • later insults - laminar or total necrosis of the cortical plate
    • polymicrogyria with necrosis of cortical plate -> persistent insult
  • lesional distribution
    • sharp demarcation of arterial infarction
    • diffuse nature of global perfusion failure
  • white vs. grey
    • severe necrosis of cerebral mantle results in rim of vascular neuroglial tissue with mineralization, reactive astrocytes, and foamy/hemmosiderin-filled macrophages, thickened leptomeninges with vascular proliferations and neuroglial ectopia
    • white matter necrosis leads to hemorrhage and/or calcification, cavitation, and hydrocephalus
  • Overproduction of TNF-alpha (tumour necrosis factor alpha) and beta-APP (beta-amyloid precursor protein) are good lesional markers
• Secondary changes
  • effects differ with time of insult:
    • brain atrophy
    • abnormal gyral pattern (pachygyria, microgyria, ulegyria)
    • ventriculomegaly
    • septal rupture
  • atrophy of fibers and tracts
    • corpus callosum atrophy
    • corticospinal tract atrophy - peduncle and medullary pyramid atrophy
    • secondary thalamic atrophy
    • secondary striatum and pallidum neuronal alteration and mineralization
    • lateral tract atrophy of spinal cord

Spectrum of antenatal HIE

• detected on fetal U/S and MRI
• usually not detectable before 20 wks GA
• Hydranencephaly
  • "hydro-anencephaly"
  • severe, diffuse necrosis of the cerebral mantle leading to ex vacuo hydrocephaly
  • cerebral mantle replaced by floating membrane of thickened leptomeninges and the remnant of the underlying necrotic cerebral mantle
  • only remaining components: medial temporal lobes, caudal thalamus (posterior circulation), cerebellum (may be cystic also)
    
    
  • cystic or atrophic olfactory and optic nerves, pituitary tract, basal ganglia
  • secondary atrophy of brainstem and spinal cord
  • due to internal carotid distribution perfusion failure before 15-16 wks GA
  • etiologies include maternal trauma, twin-twin transfusion syndrome, massive hemorrhage, familial vascular malformations (proliferative glomeruloid vasculopathy)
• Porencephaly
  • cavitary necrosis of the cerebral mantle of one or both hemispheres (often left)
  • usually MCA territory, resulting in septum pellucidum destruction and dilated ventricles
    
    
  • residual mantle has radial gyri around edges of defect
  • residual cortex can be gliotic with dystrophic calcifications and polymicrogyria
  • usually contralateral hemisphere partially affected
  • in bilateral lesions, only mid-sagittal territories not affected - "basket brain"
• Schizencephaly
  • "cleft" in cerebral mantle without communication with ventricle
    
    
  • overgrowth and disorganization of surrounding hemisphere
  • edges may seem to fuse (closed lips) or stay apart (open lips)
• Multicystic encephalopathy
  • diffuse cortical and subcortical white matter necrosis
  • results in lace-like cavities
    
    
  • late occurring lesion during partuition or first postnatal month of term pregnancy
  • can be due to infectious encephalopathy, e.g., CMV, toxoplasmosis, listeria
  • can be due to twin-twin transfusion
• Cerebellar cysts
  • one or both cerebellar hemispheres
  • liquid-filled cavities communicating with 4th ventricle
  • associated disruption of the cytoarchitecture and deep nuclei
• Brainstem damage
  • various cranial nerve nuclei lesions
  • seen in Möebius syndrome, Pierre-Robin sequence, Hanart (aglossia, adactylia), and fetal akinesia deformation sequence (FADS, Pena-Shokeir)

HIE causes and genetic counselling

• hypoxic-ischemic injury as a result of a number of etiologies including materal, placental, or fetal.
• maternal causes:
  • direct trauma
  • drug abuse
  • gas intoxication (CO, butane)
  • hypovolemia
  • coagulopathies
• placental causes:
  • placental insufficiency
  • twins
• fetal causes:
  • hydrops
  • infections
  • hemorrhages
  • vasculo-occlusive processes
• detailed familial analysis may uncover other siblings with disruptive lesions of other organs
• familial cases of HIE suggest risk factors including vasculopathy, coagulopathy, teratogens, enzyme deficiencies, mitochondrial angiopathies and cytopathies
• unclear etiologies make it hard to reduce HIE