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 O2 content in blood e.g. CO)
—Histotoxic: Cyanide poisioning
—Anoxic: Drowning
—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
Abnormal
gyration
pattern in
surrounding
tissue
 Irregularly
thickened
disorganized
cortical ribbon
leading into
smooth-walled
defect

Modified from Neuropathology, Ellison and Love, 1998
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)
PVL: Gross
Sharply
circumscribed
periventricular foci
 Common locations

– Anterior to frontal
horns
– Angles of lateral
ventricles
– Lateral trigone
Zone of Pallor
PVL: Acute micro

Coagulative
necrosis
– Nuclear pyknosis
– Vacuolization
– axonal spheroids
Modified from Neuropathology, Ellison and Love, 1998
PVL: Micro
PVL: Micro

Subacute
– Capillary
hyperplasia
– Foam cells

Chronic
– Gliosis
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
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
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
Ulegyria: Gross
Mushroomshaped lesion
 Border of
anterior and
posterior
cerebral artery
distribution

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
Gross: Status marmoratus
Mottled
basal
ganglia
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
cases
before 48 hours postpartum in 60 % of
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