Fetal/Perinatal Insults: Overview of Hypoxia\Ischemia Injuries

1. Fetal /Perinatal Insults Scott M. Kulich Department of Pathology Division of Neuropathology University of Pittsburgh School of Medicine

2. Fetal /Perinatal Insults: Overview • Hypoxia\ Ischemia injuries • Early gestational (porencephaly, hydranencephaly) • Late gestational • White matter(Periventricular leukomalacia, multicystic encephalomalacia) • Gray matter (Cerebral necrosis, pontosubicular necrosis, thalamic and basal ganglia lesions) • Hemorrhage • Germinal matrix hemorrhage • Kernicterus

3. Fetal /Perinatal Insults • Hypoxia\ Ischemia injuries • Early gestational (porencephaly, hydranencephaly) • Late gestational • White matter(Periventricular leukomalacia, multicystic encephalomalacia) • Gray matter (Cerebral necrosis, pontosubicular necrosis, thalamic and basal ganglia lesions) • Hemorrhage • Germinal matrix hemorrhage • Kernicterus

4. Hypoxia\Ischemia: Overview • Very common injury • 1.8-47 per 1000 live births • Sequela variable but include • Cerebral palsy • Mental retardation • Seizures

5. Hypoxia\Ischemia: General concepts • Hypoxia • Can occur in a variety of clinical settings • Hypoxemic (low O2 content in blood e.g. CO) • Histotoxic: Cyanide poisioning • Anoxic: Drowning • Stagnant: Inadequate blood supply (ISCHEMIA) • Most common form of CNS hypoxia

6. Hypoxia\Ischemia: General concepts • Selective vulnerability to hypoxia • Certain cell types are more vulnerable • Neurons more vulnerable than glia • Certain neurons more vulnerable to hypoxia • Adults: CA1 region of hippocampus, Purkinje cells of cerebellum, laminae 3 and 5 of cortex • Infants: Pons, subiculum, thalamus\basal ganglia

7. Hypoxia\Ischemia: General concepts • Timing of lesion during development critical to determining type of lesion produced (Hydr = hydranencephaly, BB=basket brain, Por=porencephaly, MCE=multicystic encephalopathy SHE=germinal matrix hemorrhage, CPH=choroid plexus hemorrhage, WMN=white matter necrosis PSN=pontosubicular necrosis, C/Ul=cortical necrosis/ulegyria, Th/BG=thalamic/basal ganglia lesions) Modified from Neuropathology, Ellison and Love, 1998

8. Hypoxia\Ischemia: General concepts • Timing of lesion during development critical to determining type of lesion produced • Lack of astrocytes during early development • Smooth-walled cystic lesions of hydran\porencephaly • Metabolic demands of different regions of the brain differ at various points of development • White matter necrosis in 3rd trimester injuries • Hypoxic change in neurons differ depending upon time of injury • Karyorrhexis versus eosinophilia

9. Hypoxia\Ischemia: Early developmental lesions • Hydranencephaly • Porencephaly • (Basket brain, Schizencephaly)

10. Hydranencephaly • Due to hypoxic-ischemic injury during second trimester • Usually affects the territories of middle and anterior cerebral arteries • Sparing of posterior fossa • May live up to several years depending upon extent of central gray matter involvement

11. Hydranencephaly: Gross • Cystic hemispheres replaced by thin translucent membrane • Sparing of inferior portions of frontal, temporal, and occipital lobes • Posterior fossa structures also spared

12. Hydranencephaly: Gross

13. Hydranencephaly: Micro • Cyst wall composed of outer connective tissue and inner layer with admixed neurons, glia, and macrophages • Adjacent cortex usually with polymicrogyria

14. Porencephaly • Circumscribed hemispheric defect • Also due to hypoxic-ischemic injury during second trimester • Usually bilateral, symmetrical, and involves the Sylvian fissure or central sulcus • Severe bilateral cases may also be called by other terms (schizencephaly, basket brain) • Variable clinical manifestations • Severe cases: MR, epilepsy, blindness, tetrapelegia • Mild cases may survive into adulthood

15. Porencephaly: Gross Smooth-walled defect Modified from Slide Atlas of Neuropathology, Okazaki and Scheithauer, 1988

16. Porencephaly: Gross • Abnormal gyration pattern in surrounding tissue • Irregularly thickened disorganized cortical ribbon leading into smooth-walled defect Modified from Neuropathology, Ellison and Love, 1998

17. Hypoxia\Ischemia: Late developmental lesions • White matter lesions • Periventricular leukomalacia • Multicystic encephalomalacia • Gray matter lesions • Cerebral necrosis • Pontosubicular necrosis • Status marmoratus • Ulegyria

18. Periventricular Leukomalacia • AKA: PVL, white matter necrosis, white matter ischemia, and periventricular leukoencephalopathy • 5 % of all hospital births and up to 35 % of low birth weight newborns • Pathogenesis: Late 3rd trimester (28-32 weeks gestational age) hypoxic/ischemic damage • Watershed area • Area of high metabolic demand • Cystic lesions after resolution • Most infants develop spastic motor dysfunction (cerebral palsy)

19. PVL: Gross • Sharply circumscribed periventricular foci • Common locations • Anterior to frontal horns • Angles of lateral ventricles • Lateral trigone

20. PVL: Acute micro Zone of Pallor • Coagulative necrosis • Nuclear pyknosis • Vacuolization • axonal spheroids Modified from Neuropathology, Ellison and Love, 1998

21. PVL: Micro

22. PVL: Micro • Subacute • Capillary hyperplasia • Foam cells • Chronic • Gliosis

23. Multicystic Encephalomalacia • Believed to result from hypoxic\ischemic insults near term or in the early post-natal period • Can be seen with other conditions (e.g. Herpes) • Usually results in death within weeks to months after insult.

24. Multicystic Encephalomalacia

25. Hypoxia\Ischemia: Late developmental lesions • White matter lesions • Periventricular leukomalacia • Multicystic encephalomalacia • Gray matter lesions • Cerebral necrosis • Pontosubicular necrosis • Basal ganglia/thalamic lesions • Ulegyria

26. Cerebral Necrosis • Observed in term infants associated with • Intrapartum vascular complication (e.g. placental abruption) • Perinatal vascular problems • Congenital heart defects, hypotension • Lesion common between anterior and middle cerebral artery distributions • Neurological consequences • Hypotonia,abnormal eye movement, seizures, coma

27. Cerebral Necrosis: Gross • Diffuse cerebral edema • Ribbon effect • Dusky white matter with cortical pallor Modified from Neuropathology, Ellison and Love, 1998

28. Cerebral Necrosis: Gross

29. Cerebral Necrosis: Micro Pseudolaminr pattern Astrocytic hyperplasia Preferential Necrosis at depth of gyri Lipid laden Macrophages And capillary proliferation Modified from Neuropathology, Ellison and Love, 1998

30. Pontosubicular Necrosis -Hypoxic/ischemic insult to brain results in neuronal nuclear karyorrhexis -Seen in subiculum of hippocampal formation and scattered brain stem nuclei (other areas will exhibit more “mature” type of neuronal death)

31. Ulegyria • “Scarred gyrus” • Chronic healed hypoxic ischemic insult to the cortex • Preferential involvement of • Depths of sulci (mushroom morphology) • Anterior-middle cerebral artery territories

32. Ulegyria: Gross • Mushroom-shaped lesion • Border of anterior and posterior cerebral artery distribution

33. Ulegyria: Micro

34. Thalamic and Basal Ganglia Lesions • Microinfarcts of thalamus and basal ganglia • Abnormal myelination (Status Marmoratus) • Clinical manifestations • choreoathetosis • mental retardation • spastic paraplegia • epilepsy • hyperkinetic if caudate is involved • Average age of death 12 years old

35. Thalamic and basal ganglia lesions:Pathogenesis • Complicated parturition in 70 % of cases • cyanosis • resuscitation • convulsions • neurological signs • 1/3 have umbilical cord complications • Male predilection 2:1

36. Gross Atrophy and discoloration of thalamus and basal ganglia Modified from Neuropathology, Ellison and Love, 1998

37. Gross: Status marmoratus Mottled basal ganglia Modified from Neuropathology, Ellison and Love, 1998

38. Gross: Status marmoratus

39. Fetal /Perinatal Insults • Hypoxia\ Ischemia injuries • Early gestational (porencephaly, hydranencephaly) • Late gestational • White matter(Periventricular leukomalacia, multicystic encephalomalacia) • Gray matter (Cerebral necrosis, pontosubicular necrosis, thalamic and basal ganglia lesions) • Hemorrhage • Germinal matrix hemorrhage • Kernicterus

40. Neonatal Hemorrhages • Subdural hemorrhage • Subarachnoid hemorrhage • Subpial hemorrhage • Intracerebral hemorrhage of Hemorrhagic Infarction • White matter hemorrhage or hemorrhagic infarction • Germinal matrix hemorrhage • Choroid plexus hemorrhage Modified from Neuropathology, Ellison and Love, 1998

41. Germinal Matrix Hemorrhage (GMH) • AKA: Subependymal hemorrhage, intraventricular hemorrhage • Primarily occurs in low birth weight, premature babies under 34 weeks of age • Common associations include: • Respiratory distress syndrome, congenital heart disease, hypernatremia, coagulopathy • Occurs before 48 hours postpartum in 60 % of cases

42. Pathogenesis of GMH • Fragile microcirculation at germinal matrix lacking support • Hypoxia -> Autoregulation failure -> Overperfusion • Focal endothelial cell necrosis • High levels of tissue plasminogen activator

43. Normal Germinal Matrix • Large number of small dark blue cells in subependymal region • Most prominent: 22 to 30 weeks gestation.

44. Grades of GMH Modified from Neuropathology, Ellison and Love, 1998

45. Grade 1 GMH

46. Grade 1 GMH

47. Grade 2 GMH

48. Grade 2 GMH

49. Grade 3 GMH

50. Grade 3 GMH