Central nervous system pathology

KRISTINE FAITH P. TABLIZO, RN
MD-MPA
pp. 1252-1263,
Robbins & Cotran Pathologic
Basis of Disease, 9th Ed.

Cellular
Patho
• Rxns of
Neurons
• Rxns of
Astrocytes
• Rxns of
Microglia
• Rxns of other
Glial cells
Cerebral
Edema,
Hydrocepha
lus,
Increased
ICP,
Herniation
Malformations
and
Developmental
Disorders
• Neural tube defects
• Forebrain anomalies
• Posterior Fossa
Anomalies
• Syringomyelia and
Hydromyelia
Perinatal
Brain
Injury
Trauma
• Skull Fractures
• Parenchymal Injuries
• Concussion
• Direct P. Injury
• Diffuse Ax. Injury
• Traumatic Vascular
Injury
• Epidural Hematoma
• Subdural hematoma
• Sequelae of Brain
trauma
• SC Injury

Reactions to Cellular Injury
Neurons Astrocytes Microglia Other Glial Cells
 Acute Neuronal Injury
“RED NEURONS”
 Cell body shrinkage
 Nucleal PYKNOSIS
 Nucleolus disappearance
 Loss of Nissl Bodies-
eosinophilia of cytoplasm
 Gemistocytic astrocytes
- Swollen reactive astrocyte
 Nuclei vesicular w/
prominent nucleoli
 Cytoplasm bright pink
irregular area around an
eccentric nucleus
 Alzheimer type II astrocyte
 Nucleus  2-3x larger,
 pale staining chromatin
 Intranuclear glycogen
droplet
 prominent nuclear
membrane and nucleolus
*in Chronic hyperammonemia
Respond to injury by:  OLIGODENDROCYTES
- Injury and apoptosis
of which is afeature
of acquired
demyelinating
disorders and
leukodystrophies
 NUCLEI- viral
inclusions (progressive
multifocal
leukoencephalopathy)
 Glial Cytoplasmic
inclusions
 α-synuclein
composition
-in MSA
(mult. sys.atrophy)
1. Proliferation
2. Elongation of
nuclei (rod cells)
e.g Neurosyphilis
3. microglial nodules
4. Neuronophagia-
 Subacute/Chronic* Injury
“DEGENERATION”
e.g. ALS, AD- ‘progressive’
 Cell loss
 Reactive Gliosis- proliferation
or hypertrophy of glial cells

NEURONAL INCLUSIONS
 AGING
- intracytoplasmic accumulations of
complex lipids (lipofuscin), proteins, or
carbohydrates
**Diorders of Metabolism-substrates or
intermediates accumulate
CYTOPLASMIC I.B.’s
ROSENTHAL fibers  thick, elongated, brightly eosinophilic,
irregular structures in astrocytic processes
 αB –crystalline and hsp27- heat shock proteins, as well as ubiquitin
 Glial tumor- pilocytic astrocytoma
 Alexander dse. (leukodystrophy associated w/ mutations in the gene encoding
GFAP) –in periventricular, perivascular, subpial regions
Corpora amylacea (polyglucosan bodies)
Round, faintly basophilic, PAS (+), concentrically lamellated
structures, 5-50 um in diameter
GLYCOSAMINOGLYCAN polymers, heat shock proteins and ubiquitin
Degenerative change
Lafora bodies- seen in cytoplasm of neurons* in myoclonic
epilepsy *(also in hepatocytes, myocytes, other cells)
-same composition as PGS bodies
 VIRAL INFXNS
a. intranuclear inclusions
 COWDRY BODY- herpetic infxn
b. Intracytoplasmic inclusions
 NEGRI BODY-rabies
b. both nucleus & cytoplasm
 CMG virus infxn
 DEGENERATIVE DISEASES
-neuronal intracytoplasmic inclusions
 Neurofibrillary tangles- AD
 Lewy bodies- PD

 Axonal Reaction-change in cell body during regeneration
- ↑ protein synthesis- axonal sprouting
 enlargement and rounding up of the cell body
 peripheral displacement of nucleus
 Central chromatolysis (dispersion of Nissl substance
from center to periphery)
EPENDYMAL CELLS
inflammation or marked dilation
of ventricular system
disruption of ependymal lining
Proliferation of subependymal astrocytes
Irregularities on ventricular surfaces
(ependymal granulations)

CNS Cellular Patho
RED NEURON
AXONAL REACTION

CNS Cellular Patho
NEGRI BODIES

CNS Cellular Patho
COWDRY BODIES

CNS Cellular Patho
NEUROFIBRILLARY TANGLES

CNS Cellular Patho
GEMISTOCYTIC ASTROCYTES
Alzheimer Type II ASTROCYTES

CNS Cellular Patho
ROSENTHAL FIBERS CORPORA AMYLACEA
(Polyglucosan Bodies)

CNS Cellular Patho
LAFORA BODIES

CNS Cellular Patho
ROD CELLS MICROGLIAL NODULES

CNS Cellular Patho
NEURONOPHAGIA

 MONRO-KELLIE HYPOTHESIS
 states that the cranial compartment is
incompressible, and the volume inside the
cranium is a fixed volume.
any increase in volume of one of the
cranial constituents (blood, CSF, and brain
tissue) must be compensated by a
decrease in volume of another.
Cerebral Edema, Hydrocephalus, Increased
ICP, Herniation

Cerebral Edema, Hydrocephalus, Increased
ICP, Herniation
 CEREBRAL EDEMA (brain parenchymal edema)
 Increased fluid leakage from blood vessels or injury to various cells in CNS
 HYDROCEPHALUS
 accumulation of excessive CSF w/in the ventricular system
 impaired flow and resorption
 overproduction- tumors of ch. Plexus
 HERNIATION
 displacement of brain tissue past rigid dural folds or through openings
in the skull because of ↑ ICP

Cerebral Edema
Vasogenic Edema Cytotoxic Edema Interstitial edema
↑ EXTRACELLULAR Fluid
Caused by B-B-B disruption
And ↑ vascular permeability
↑ INTRACELLULAR Fluid
- 2° CELL MEMBRANE INURY
HYDROCEPHALIC EDEMA
-occurs sp. around LATERAL
VENTRICLES
↑ Intravascular pressure
abnormal flow of fluid
from intraventricular CSF
across ependymal lining to
the periventricular white
matter
Localized- adjacent to
inflammation or neoplasms
* GENERALIZED HYPOXIC/
ISCHEMIC insult
* METABOLIC Derangement
affecting ionic gradient
Generalized-
 ff. ischemic injury; both
vasogenic & interstitial components
 Flattened gryi
 Narrowed sulci
 Compressed ventricular
cavities
 Herniation likely

Cerebral Edema
Vasogenic Edema- Flattened gyri, narrowed sulci

Hydrocephalus
 NORMAL CSF FLOW

Hydrocephalus
 HYDROCEPHALUS
before closure of sutures- Head enlargement
 after closure- expansion of ventricles, ^ ICP w/o head enlargement

Hydrocephalus
 HYDROCEPHALUS
NON-COMMUNICATING COMMUNICATING
‘OBSTRUCTIVE hydrocephalus’
 VS is obstructed, does not
communicate w/ subarachnoid
space
 e.g. 3rd ventricle mass
 Ventricular system is in
communication with the
subarachnoid space
 Enlargement of entire
ventricular system

Hydrocephalus
 HYDROCEPHALUS

HerniationSubfalcine (cingulate)
herniation
Transtentorial (uncinate, mesial temporal)
herniation
Tonsillar Herniation
Displaces cingulate
gyrus under the
falx.
Medial aspect of temporal lobe
compressed against the free margin of
the tentorium
Displacement of
cerebellar tonsils
through the foramen
magnum
Compromises CN III, and Posterior cerebral
artery
LIFE
THREATENING-
compression of
brainstem
(respiratory and
cardiac centers)
Compression of
anterior cerebral
artery and its
branches
Kernohan notch- compression in the contralateral
cerebral peduncle; may result in hemiparesis of the side
ipsilateral to the herniation
Duret hemorrhages- linear of flame-shaped lesions
usually in the middle and paramedian regions
-due to distortion or tearing off penetrating veins and
arteries supplying the upper brainstem

Herniation
Transtentorial herniation

 Neural tube defects
 failure to close by a portion a the neural
tube or reopening of a region of a tube
after successful closure
 account for most common CNS
malformation
 most common NTD– SC involvement
 frequency varies among ethnic groups
 high concordance rate among
monozygotic twins
 risk factor: folate deficiency during 1st
several weeks of gestation
Malformations and Devt’al Disorders

Neural Tube Defects
Spina Bifida/ spinal
dysraphism
Meningomyelocele/
Myelomeningocele
Encephalocele
(Cranium bifidum)
Anencephaly
SPINA BIFIDA OCCULTA
- asymptomatic bony
defect
- Mildest form
- Missing spinous process
Extension of CNS
tissue through a
defect in the vertebral
column
Diverticulum of
malformed brain
tissue extending
through a defect in
the cranium
Malformation of the
anterior end of the NT,
with absence of most of
the brain and calvarium
sacral region Most often in the
posterior fossa
*Area Cerebrovasculosa-
flattened remnant of
disorganized brain tissue w/
admixed ependyma, choroid
plexus, and meningothelial
cells
*MENINGOCELE
-meningeal outpouching only
Lower Motor and sensory
deficits ; bladder and bowel
control deficits
May also occur through the
cribiform plate in the anterior
fossa– “nasal glioma”
Risk for superimposed
infections- thin overlying skin

"area cerebrovasculosa" -scattered primitive
neuroglial tissue elements within an irregular
vascular proliferation

 Forebrain Anomalies
 Disruption in proper orchestration of
progenitor cell proliferation and migration to
the developing cortex
 single gene mutations, larger scale genetic
alterations, or exogenous factors
 Alteration in the size, shape, and
organization of the brain
 Overall, the earlier a malformation occurs,
the more severe the morphologic and

Forebrain Anomalies
Megalencephaly
Abnormally large volume of brain
Lissencephaly Polymicrogyria
- decreased # of gyri
AGYRIA- absence of gyri in
extreme cases
TYPE I-smooth surfaced
-mutations disrupting signaling
for migration and cytoskeletal
motor proteins
TYPE 2- rough or cobblestoned
- Disruption in “stop signal for
migration
Small unusually numerous
irregularly formed cerebral
convolutions
Causes:
-localized tissue injury
toward the end of neuronal
migration
- Genetically determined--
bilateral and symmetric
Microencephaly
Abnormally small volume of brain
-more common than megalo-
- chromosome
abnormalities,
FAS,
HIV-1 in utero
-simplification of gyral folds
-reduction in # of neurons
that reach neocortex

Malformations and Devt’al DisordersCont….. Forebrain Anomalies
Neuronal Heterotopias Holoprocencephaly Agenesis of
Corpus callosum
-migrational disorders
commonly associated w/
epilepsy
-presence of neurons in
inappropriate locations
along the pathway or
migration
-incomplete separation of the
cerebral hemispheres across the
midline
-associated with trisomy 13 and
other genetic syndromes
- Mutations in sonic hedgehog signaling
pathway
• Severe forms- midline facial
abnormalities, including cyclopia
• less severe variants-(arrhinencephaly)
absence of the olfactory cranial nerves
and related structures
-relatively common
-misshapen lateral
ventricles “bat-wing
deformity” in radiologic
imaging
- commonly associated
with mental retardation
- may occur in clinically
normal individuals

 Periventricular heterotropia- mutations-gene
encoding filamin A (an actin-binding protein
responsible for assembly of complex meshworks of
filaments) on the X chromosome
• mutant allele- causes male lethality
 Doublecortin (DCX)- microtubule-associated protein
 on X chromosome
• mutations result in lissencephaly in males
• in subcortical band heterotopias in females.

Polymicrogyria

Holoprosencephaly

Bat-wing or bull-horn sign

 Posterior Fossa Anomalies
 BRAINSTEM and CEREBELLUM involvement
 may be accompanied with morphologic
changes in other areas of the brain

Posterior Fossa Anomalies
Arnold-Chiari
Malformation
(Chiari Type II)
• small posterior fossa
• misshapen midline cerebellum
with downward displacement of
vermis and medulla through the
foramen magnum
• symptomatic
*May present w/
hydrocephalus (obstruction of
IV ventricle) and a lumbar
myelomeningocele
Chiari type I
malformation
• Mostly asymptomatic; less severe
• More common
• Low lying cerebellar tonsils extend down the vertebral canal
• SSx appear with compression

Malformations and Devt’al DisordersCont… Posterior Fossa Anomalies
Dandy-Walker
Malformation
• Enlarged posterior fossa.
• Absent cerebellar vermis* (or
rudimentary form in the anterior portion)
• Large midline cyst* (in place of vermis) lined
by ependyma
Other common
associated findings:
• Dysplasias of
brainstem nuclei
• Failure of Foramen of
Magendie and Luschka
to dilate
Joubert
Syndrome
• Hypoplasia of cerebellar vermis with
apparent elongation of superior
cerebellar peduncles and altered shape
of the brainstem
• ‘molar tooth sign’
Cause:
mutations in genes
encoding components of
the primary (non-motile)
cilium cellular signaling

JOUBERT SYNDROME
“MOLAR TOOTH SIGN”

Hydromyelia Syringomyelia, syrinx Syringobulbia
Expansion of the
ependymal-lined
central canal of the
cord
Formation of fluid-filled cleft-like
cavity in the inner portion of the cord
Extension of
syringomyelia to the
brainstem• Seen in Chiari malformations
• Associated w/ intraspinal tumors
Distinctive SSx:
• Isolated loss of pain and temperature
sensation in the upper extremities
HISTOLOGIC APPEARANCE:
• W/ destruction of adjacent gray and white matter
• Surrounded by dense feltwork of reactive gliosis
EPIDEMIOLOGY:
• Manifests in 2nd or 3rd decade

Hydromyelia

 Brain injury occurring in the
perinatal period
 important cause of childhood-onset
neurologic disability
Perinatal Brain Injury

 CEREBRAL PALSY*- nonprogressive neurologic
motor deficit attributable to insults during prenatal
and perinatal periods
COMBINATIONS:
Spasticity
Dystonia
Ataxia/ athetosis
Paresis
*s/sx may not apparent at birth

Destructive lesions associated w/ Cerebral Palsy
 Periventricular leukomalacia- white matter brain injury
esp. in premature infants
 chalky yellow plaques w/ discrete regions of white
matter necrosis and calcification
 Multicystic encephalopathy- both gray and white
matter involved
large destructive cystic lesions d/t extensive ischemic
damage

Destructive lesions associated w/ Cerebral Palsy
 Ulegyria
 thinned-out gliotic gyri
 status marmoratus
 marble-like appearance of the deep nuclei d/t
aberrant and irregular myelinization

STATUS MARMORATUS

Head injuries by
physical forces
 SKULL FRACTURES
 PARENCHYMAL
INJURY
 VASCULAR INJURY
* all 3 may
coexist
Trauma
CNS TRAUMA MAJOR DETERMINAN
 ANATOMIC location of LESION
 LIMITED CAPACITY of brain for rep
i.e. Several cubic mm of brain pare
injury
• Frontal lobe- clinically silent
• SC- severely disabling
• Brainstem- fatal

SKULL FRACTURES
 displaced skull fracture - bone displaced into the cranial
cavity by a distance greater than the bone’s thickness
 thickness of the cranial bones varies
Diastatic fractures - cross sutures
Trauma

SKULL FRACTURES (PRINCIPLES)
Pattern of falls
 Fall while awake- site of impact often the occipital
portion of the skull
 Fall following unconsciousness- frontal impact
kinetic energy is dissipated at a fused suture
Fracture lines of subsequent injuries do not extend
across those of prior injury with multiple points of impact
or repeated blows to the head
Trauma

Basal skull fracture
 typically follows impact to occiput or sides of
the head
 lower cranial nerves or cervicomedullary
region symptoms
 orbital or mastoid hematomas* distant from
the point of impact
 CSF rhinorrhea/ otorrhea, meningitis
Trauma

Trauma
Parenchymal Injuries
Concussion Direct Parenchymal Injury Diffuse axonal injury
• mild traumatic brain injury
with a transient loss of
brain fx
• commonly d/t change in
the momentum of the
head (against a rigid surface)
• Instantaneous onset of
transient neurologic
dysfunction
• Usually without
parenchymal changes
a. CONTUSION- bruise in the
brain caused by blunt trauma
• coup and contrecoup
injuries -head is mobile at
the time of impact
b. LACERATION- caused by
penetration of an object
and tearing of tissue
• injury to axons at
nodes of Ranvier with
impairment of
axoplasmic flow
• d/t acceleration/
deceleration even in
absence of impact
• coma after trauma
without evidence of
direct parenchymal
injuries

Trauma
Cont… MORPHOLOGIC CHANGES/ CHARACTERISTICS
Concussion Direct Parenchymal Injury Diffuse axonal injury
• Acute contusion- hemorrhage of brain tissue
in a wedge-shaped area
• Subacute contusion – necrosis/ liquefaction
• Remote contusion- yellowish depressed
area of cortex "plaque jaune*”
• (early)  edema and hemorrhage often pericapillary
• (next few hrs)  Blood extravasation
• (~24 hours) SSx of neuronal rxn to damage
• old contusions- gliosis and residual hemosiderin-
laden macrophages*
• often asymmetric appreciable in
the white matter
• Ag impregnation or
immunoperoxidase stains
(for amyloid/ a synuclein)
• predilection for the corpus
callosum, periventricular white
matter, and hippocampus,
cerebral and cerebellar
peduncles

Trauma
• PLAQUE JAUNE
• Old traumatic lesions
depressed, retracted,
yellowish brown patches
involving the crests of gyri
• Common at the sites of
contrecoup injuries (inferior
frontal cortex, temporal and
occipital poles)
• Can become an epileptic foci

Trauma
TRAUMATIC VASCULAR INJURY
direct trauma and disruption vessel wall
hemorrhage
 epidural, subdural, subarachnoid,
intraparenchymal or combination
 epidural and subdural hemorrhages- rare in
non trauma setting

Trauma
Epidural Hemorrhage
 associated with skull fracture
 tearing of dural arteries-- common: middle
meningeal artery
 accumulates slowly --("talk and die syndrome")
 smooth inner contour hematoma
 does not cross suture line
 may expand rapidly neurosx emergency
requiring prompt drainage
 if not promptly evacuated  cerebral herniation

Trauma
Subarachnoid hemorrhage
 Common cause: ruptured berry aneurysm
 sudden ("thunderclap") headache, nuchal
rigidity, neurological deficits on one side, and
stupor
 blood in the ventricles, sulci, and cisterns

Trauma
 Intracerebral (intraparenchymal) hemorrhage
Common cause: HTN
common area: basal ganglia, cerebellum,
pons, centrum semiovale
 SSx: severe headache, frequent
nausea/vomiting, steady progression of
symptoms over 1 5-20 minutes and coma
Other causes: vascular malformations (sp. AV
malformations), cerebral amyloid angiopathy, neoplasms,

Trauma
Subdural hemorrhage
 rupture of bridging veins* , may cross suture
lines
 Predisposing conditions:
Brain atrophy(due simply to aging)-
stretching of veins
 infants- thin-walled bridging veins
 abnormal hemostasis
 SSx: headache, drowsiness, focal neurological
deficits, and sometimes dementia

Trauma
Subdural hemorrhage (Clinical Features)
 Slowly progressive neurologic deterioration
 manifests within 48 hours of injury
 most common over lateral aspects of cerebral
hemispheres
 often nonlocalizing manifestations: headache
and confusion
 Tx: evacuation of blood clot and associated
organizing tissue

Trauma
 ACUTE Subdural hematoma (GROSS)
 freshly clotted blood along brain surface
without extension into sulci
 subarachnoid space clear
 venous bleeding, usually self-limited
 organization of hematoma:
 Lysis of the clot (about 1 week)*
 Growth of fibroblasts from the dural surface
(2 weeks)
 Early development of hyalinized connective

Trauma
 ACUTE Subdural hematoma
 organized hematoma*-firmly attached to the
inner surface of the dura by ingrowing fibrous
tissue
 multiple recurrent episodes of bleeding in chronic
subdural hematomas (d/t thin-walled vessels of the
granulation tissue)
 repeat bleeding risk: greatest in the 1st few months
after initial hemorrhage

Trauma
Intraparenchymal Hemorrhage

 Sequelae of Brain Trauma
 neurologic syndromes that may manifest
months or years after brain trauma of any cause
• Posttraumatic hydrocephalus - largely due to
obstruction from hemorrhage
Other important sequelae of brain trauma:
• posttraumatic epilepsy,
•risk of infection, and
•psychiatric disorders.
Trauma

Chronic traumatic encephalopathy (CTE)-
“dementia pugilistica” – dementing illness that
develops after repeated head trauma
 atrophic
 with enlarged ventricles
 w/ accumulation of tau-containing neurofibrillary
tangles in a characteristic pattern involving
superficial frontal and temporal lobe cortex
 Boxers, military personnel, athletes
Trauma

 Spinal Cord Injury
 associated w/ the transient or
permanent displacement of
vertebral column
 Lesion involvement and
manifestation
 thoracic segments or below -
paraplegia
 cervical segments -
tetraplegia
 above C4 - respiratory arrest
Trauma

SOURCES:
 Robbins & Cotran Pathologic Basis of
Disease, 9th Ed.
 KAPLAN USMLE Reviewer 2013
(Pathology)
 Pathology: a Color Atlas by Damjanov &
Linder
 Google images

Central nervous system pathology

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