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

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

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

Hypoxia\Ischemia: Overview

•Very common injury •1.8-47 per 1000 live births •Sequela variable but include •Cerebral palsy •Mental retardation •Seizures

Hypoxia\Ischemia: General concepts

•Hypoxia –Can occur in a variety of clinical settings —Hypoxemic (low O —Anoxic: Drowning 2 content in blood e.g. CO) —Histotoxic: Cyanide poisioning —Stagnant: Inadequate blood supply (

ISCHEMIA

) •Most common form of CNS hypoxia

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

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

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

Hypoxia\Ischemia: Early developmental lesions

•Hydranencephaly •Porencephaly (Basket brain, Schizencephaly)

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

Hydranencephaly: Gross

 Cystic hemispheres replaced by thin translucent membrane  Sparing of inferior portions of frontal, temporal, and occipital lobes  Posterior fossa structures also spared

Hydranencephaly: Gross

Hydranencephaly: Micro

 Cyst wall composed of outer connective tissue and inner layer with admixed neurons, glia, and macrophages  Adjacent cortex usually with polymicrogyria

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

Porencephaly: Gross

Smooth-walled defect Modified from

Slide Atlas of Neuropathology,

Okazaki and Scheithauer, 1988

Porencephaly: Gross

Modified from

Neuropathology,

Ellison and Love, 1998  Abnormal gyration pattern in surrounding tissue  Irregularly thickened disorganized cortical ribbon leading into smooth-walled defect

Hypoxia\Ischemia: Late developmental lesions

•White matter lesions •Periventricular leukomalacia •Multicystic encephalomalacia •Gray matter lesions •Cerebral necrosis •Pontosubicular necrosis •Status marmoratus •Ulegyria

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)

 Sharply circumscribed periventricular foci  Common locations – Anterior to frontal horns – Angles of lateral ventricles – Lateral trigone

PVL: Gross

Zone of Pallor

PVL: Acute micro

 Coagulative necrosis – Nuclear pyknosis – Vacuolization – axonal spheroids Modified from

Neuropathology,

Ellison and Love, 1998

PVL: Micro

 Subacute – Capillary hyperplasia – Foam cells  Chronic – Gliosis

PVL: Micro

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.

Multicystic Encephalomalacia

Hypoxia\Ischemia: Late developmental lesions

•White matter lesions •Periventricular leukomalacia •Multicystic encephalomalacia •Gray matter lesions •Cerebral necrosis •Pontosubicular necrosis •Basal ganglia/thalamic lesions •Ulegyria

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

Cerebral Necrosis: Gross

 Diffuse cerebral edema  Ribbon effect – Dusky white matter with cortical pallor Modified from

Neuropathology,

Ellison and Love, 1998

Cerebral Necrosis: Gross

Preferential Necrosis at depth of gyri

Cerebral Necrosis: Micro

Pseudolaminr pattern Astrocytic hyperplasia Lipid laden Macrophages And capillary proliferation Modified from

Neuropathology,

Ellison and Love, 1998

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)

Ulegyria

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

 Mushroom shaped lesion  Border of anterior and posterior cerebral artery distribution

Ulegyria: Gross

Ulegyria: Micro

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

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

Atrophy and discoloration of thalamus and basal ganglia

Modified from

Neuropathology,

Ellison and Love, 1998

Gross

Mottled basal ganglia Gross: Status marmoratus

Modified from

Neuropathology,

Ellison and Love, 1998

Gross: Status marmoratus

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

Neonatal Hemorrhages

1. Subdural hemorrhage 2. Subarachnoid hemorrhage 3. Subpial hemorrhage 4. Intracerebral hemorrhage of Hemorrhagic Infarction 5. White matter hemorrhage or hemorrhagic infarction 6. Germinal matrix hemorrhage 7. Choroid plexus hemorrhage Modified from

Neuropathology,

Ellison and Love, 1998

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

Pathogenesis of GMH

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

Normal Germinal Matrix

1. Large number of small dark blue cells in subependymal region 2. Most prominent: 22 to 30 weeks gestation.

Grades of GMH

Modified from

Neuropathology,

Ellison and Love, 1998

Grade 1 GMH

Grade 1 GMH

Grade 2 GMH

Grade 2 GMH

Grade 3 GMH

Grade 3 GMH

Grade 4 GMH

Extension into parenchyma Modified from

Neuropathology,

Ellison and Love, 1998

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

Fetal /Perinatal Insults

• Hypoxia\ Ischemia injuries •White matter •Periventricular leukomalacia • Gray Matter Ischemia • Cerebral Necrosis • Pontosubicular Necrosis • Thalamic and Basal Ganglia Lesions •Hemorrhage •Germinal matrix hemorrhage •

Kernicterus

Kernicterus

 “Jaundiced Nuclei”  Selective yellow staining of the deep gray matter and brain stem due to deposition of unconjugated bilirubin  Associated with neuronal necrosis and resulting neurologic sequelae  Poor prognosis but condition is now rare in areas where hyperbilirubinemia can be predicted, monitored, and treated appropriately

Pathogenesis of Kernicterus

• Excessive production of unconjugated bilirubin (80 % from RBC’s)

or

insufficient conjugation/excretion by the liver • Unconjugated circulating form is neurotoxic • May occur in small or preterm infants at 10 mg/ml • Contributing factors • • Blood-brain barrier damage • Reduced albumin or albumin binding •Dose dependence 6-7 % of newborns > 12.9 mg/dl • 3 % of newborns > 15 mg/dl • Hyperbilirubinemia cause suggested by age of onset •< 1 day: Hemolysis\hematoma, infection •2-3 days: Infection, Criglar-Najjar, physiologic jaundice •1 week: Breast milk jaundice (pregnane-3beta, 20alpha-diol), congenital or drug-induced hemolytic anemias, hypothyroidism, biliary atresia, infections

Pathogenesis of Kernicterus

• Deposition of unconjugated bilirubin leads to necrosis of neurons in selected regions of the CNS •Mechanisms of anatomic specificity and molecular events leading to neuronal death are unclear •Neurologic sequelae vary •Acute: Lethargy, rigidity, hypotonia, opisthotonus •Chronic: Choreoathetoid movements, spasticity, ataxia, mental retardation

Kernicterus: Gross pathology Key Red: Most vulnerable Brown: Least vulnerable Pink: Intermediate

Modified from

Neuropathology,

Ellison and Love, 1998

Kernicterus: Gross pathology

Kernicterus: Gross pathology

Thalamus Hippocampus Modified from

Neuropathology,

Ellison and Love, 1998

Kernicterus: Gross pathology

Dentate Nucleus Modified from

Neuropathology,

Ellison and Love, 1998

Kernicterus: Gross pathology

Inferior olive Modified from

Neuropathology,

Ellison and Love, 1998

Kernicterus: Microscopic pathology

• Changes do not necessarily correspond to intensity of staining •Acute •Cytoplasmic vacuolization, eosinophilia, chromatolysis, and spongy neuropil •Subacute •Astrogliosis and neuronal drop-out

Acknowledgments and references

 Drs. Julio Martinez, Gutti Rao, and David Van Sickle 

Neuropathology,

Ellison and Love, 1998 

Greenfield’s Neuropathology,

Graham and Lantos, 1997 

Slide Atlas of Neuropathology,

Okazaki and Scheithauer, 1988