Grey matter lesions in neonates present a wide spectrum of pathological and clinical manifestations depending on pattern, timing, and etiology. Common etiology is hypoxic-ischemic injury, but also materno-fetal infection.

Hypoxic-Ischemic Injury

• ranges from
  - intrauterine chronic, partial HII from impaired placental function, preeclampsia, maternal infection or IUGR
  - intrauterine sudden, severe HII in uterine rupture, placental abruption, cord prolapse
  - postnatal chornic, partial HII from severe anemia, sepsis, prolonged ventilation
  - postnatal sudden, severe HII in cardiac arrest, status epilepticus
• age affects type of insult/injury
  - immature babies more prone to complications and prolonged HII
  - gestational age related to pattern of HII secondarily
  - possible relationship to changing neurotransmitter distribution
  - possible relationship to metabolic activity at developmental stage
  - possible relationship to myelination level at developmental stage
• most commonly involved areas are the cortex, basal ganglia, thalamus, hippocampus
• grading correlating to cognitive and motor outcome:
  • mild - lentiform and thalamus
  • moderate - lentiform, thalamus, central cortex
  • severe - lentiform, thalamus, central cortex, hippocampus
• moderate and severe forms lead to microcephaly

Cortical lesions

• first stage is perivascular pallor due to angiogenic edema and vacuolation of cytoplasm
• swelling subsides after 7 days
• nuclear pyknosis present after a few hours
• cytoplasmic eosinophilia and lysis of nuclear membrane (necrosis) of pyramidal neurons
• apoptotic cells present with pyknotic nuclei (shrunken, basophilic) which later fragments into multiple rounded, basophilic apoptotic bodies
• early microglial reaction, later reactive macrophages (few days)
• thickened endothelial cells with rounded nuclei, capillary proliferation in a week
• reactive gliosis - begins several days post-insult
• mineralization - 10-12 days post-insult, in macrophages, axons, and neuronal cell bodies

Watershed Infarcts
• infarction of parasagittal cortex between anterior, middle, and posterior cerebral arteries
• common in asphyxiated term infants
• manifests as ulegyria
• from prolonged hypoxic-ischemic insult


Central (peri-rolandic) cortex
• bordering central sulcus and underlying white matter
• seen in term HII, not in preterm
• associated damage to basal ganglia
Hippocampus
• associated with other grey matter areas
• in adults, CA1 and CA3 of Ammons horn and the hilum of the dentate gyrus most commonly affected
• reactive gliosis and neuronal loss
• hippocampal sclerosis usually occurs in damage at < 4yrs age, but > 28wks GA
• also targeted in seizures
Dentate microglial reaction
• HII before 8-9 months of life
• dense microglial collections beneath dentate gyrus
Ponto-subicular necrosis
• apoptotic cell damage in the pons and subiculum



Ulegyria
• preferential damage of cortical sulci with preservation of gyri
• rare in adults but characteristic of term HII, especially in watershed areas




columnar cortical damage
• only described in rat models of HII, around term, related to immature cortical vascular supply
• distal gliosis

Deep grey nuclei

• bilateral lesions of basal ganglia and thalamus found in most children with cerebral palsy and severe acute HII at term
• most metabolically active areas in term infants
• especially ventro-lateral nuclei of thalamus and posterior lentiform nuclei
• associated with edema and nuclear pyknosis in the posterior limb of the internal capsule (PLIC)
• acute phase - dusky, red-brown discoloration from vascular congestion/proliferation
• chronic phase - firm, white, gliotic with tiny cystic cavities, widening of 3rd ventricle
• histology similar as above
  - neurons with eosinophilia, nucleolysis and necrosis
  - glial cells pyknotic and karyorrhectic
  - gliosis and neuronal loss with mineralization of neurons
  
  
• Status marmoratus
  • marbled appearance of deep nuclei after 6 months of age
  • also seen on MRI
  • result of term damage with gliosis and aberrant myelination of glial fibers
• thalamic damage in PVL
  • in severe PVL in premature infants
  • small areas of abnormal signal in the posterior dorsal thalamus, unlike term infants
  • pathology of this not described

Cerebellum

• well-recognized HII pathology, but not as well seen on imaging (some cerebellar atrophy)
• cortex and dentate nucleus of the cerebellum is vulnerable to HII damage
• dentate - neurons die of necrosis, resulting gliosis
• cortical damage in the depths of major folia ("centrilobular pattern")
• apoptosis of the granular cells, Purkinje cells die of necrosis
• if cerebellar damage early, can be associated with failure of development of inferior olivary nuclei

Brainstem

• early maturation of brainstem nuclei means they are vulnerable to injury from early stage
• clinical syndromes include Möebius syndrome (facial diplegia, oculomotor paresis)
• "cardiac arrest encephalopathy" - severe ischemia from cardiac arrest, rare in adults
  - symmetrical necrosis of the dorsal tegmentum from lower meddula up to thalamus
  - high mortality

Spinal cord

• in cases of severe cerebral edema, there can also be upper cervical cord swelling and hemorrhagic necrosis
• trauma to cord from complicated delivery also described

Secondary Malformations of the Grey Matter

• secondary malformations occur when a structure is damaged early in its formation
• e.g., neuronal heterotopia, polymicrogyria, olivary dysplasia
• later insults - cortical dysplasia or hippocampal mossy fiber sprouting
• MRI studies show enhanced growth in areas adjacent to infarction

Early secondary malformation
• includes early brain damage from amniocentesis at 16-19wks GA, resulting in severe focal dysplasia and neuronal heterotopia in underlying white matter
  e.g. damage to upper brain stem showed unilateral atrophy of pyramidal tracts and simplified inferior olives
• Polymicrogyria
  • occurs after neuronal migration up to 28 wks GA
  • can occur at the borders of infarcts (in penumbra) and CMV infection (vascular insufficiency)
• Schizencephaly
  • destructive lesion before 28 wks GA, can be associated with polymicrogyria and neuronal heterotopia
  • some reports of familial occurrence, but unclear genetic origin

Late secondary malformation
Acquired cortical dysplasia
• can occur in ischemic injury in teh pernatal period
• cortex bordering ischemic area can show giant neurons, loss of lamination, clustering of neurons, and bundles of myelinated fibers in the cortex
• represents reorganization of cortex leading to epilepsy and cognitive impairment
Hippcampal sclerosis
• reorganization after insults in the first years of life
• loss of neurons espeically from CA1 and hilar regions of hippocampus, and dentate gyrus
• other changes:
  1. Granule cell dispersion: cell loss, gliosis and disportion of cells of granule cell layer. Can also show bilaminar dentate. Seizurs may promote hippocampal neurogenesis leading to the dispersion.
  2. Mossy fiber sprouting: granule cell mossy fibers proliferate through the dentate granule cell layer, resulting in new aberrant circuits (more seizure activity)
  3. Cytoskeletal abnormalities: balloon cells, accumulation of neurofilaments and dendritic alterations

Hypoglycemia

• few studies on pure hypoglycemia since it usually accompanies other insults including asphyxia
• immature brain is resistant to hypoglycemic damage due to ability to use alternate energy sources
• predominant involvement of grey matter and superficial cortical neurons
• imaging shows localization to cortex and white matter of posterior parietal and occipital lobes
• white matter damage may be secondary to cortical damage or also related to damage in intrauterine life in a diabetic mother