Transcript Vascular Diseases - University of Pittsburgh

Vascular Neuropathology
February 2002
Charleen T. Chu, M.D., Ph.D.
Dept. of Pathology, Division of Neuropathology
University of Pittsburgh School of Medicine
Pittsburgh Institute for Neurodegenerative Disease
http://path.upmc.edu/people/faculty/chu.html
Cerebrovascular Disease

Ischemic
– Atherosclerosis
– Embolism
– Hypotensive episode

Hemorrhagic
–
–
–
–
Trauma
Berry aneurysm
Hypertension, vascular malformations, amyloid
Superior sagittal sinus thrombosis
 Inflammatory - vasculitis, primary vs. secondary

Neoplastic - lymphoma, angiosarcoma,
hemangiopericytoma, hemangioblastoma
Cerebrovascular Disease
Third leading cause of death in the US
 Most prevalent neurologic disorder
– Hypoxia, ischemia, infarction
– Intracranial hemorrhage
– Herniation
– Small vessel disease
Systemic
hypertension

Cerebrovascular Disease
 Hypoxia,
ischemia, infarction
– Anatomy
– Atherosclerosis and emboli
– Hypotensive episode
– Acute, subacute, chronic infarcts
 Intracranial
hemorrhage
 Herniation

Vasculitis, small vessel disease
Vascular Supply to
the Brain
Modified from Watson
1995 Basic Human Neuroanatomy, 5th Edition, p.
103. Little, Brown & Co.
PCA
ACA
MCA
Modified from Poirier et al.1990 Manual
of Basic Neuropathology, 3rd Edition,
Fig. 117, p. 88. W.B. Saunders
Anatomic Considerations

Vascular anatomy
– Circle of Willis and anastomoses (Figs. 109-110 - Poirier)
– Internal carotid-middle cerebral artery
– Watershed zone

Rigid brain case and herniation (Robbins p. 1298)
– Falx
– Tentorium
– Foramen Magnum
Oil red O
stain
showing
sites of
AS
Courtesy of
Dr. Julio
Martinez
Plaque rupture
Atheromatous carotid stenosis
Modified from Poirier et al. 1990 Manual of Basic
Neuropathology, 3rd Edition, p. 85. WB Saunders
Pathology of Cerebral Infarcts

Distribution
–
–
–
–

Fits within vascular territory (atherosclerotic)
Multiple, grey-white jxn (embolic)
Vulnerable areas (hypotensive/hypoxic)
Centered at depths of sulci, sometimes with sparing of
subpial cortex (in contrast to contusion at tips of gyri)
Age
– Acute
– Subacute
– Remote
Recent infarct with gyral edema, softening, discoloration
Courtesy of
Dr. Julio
Martinez
Subacute infarcts
Courtesy of
Dr. Julio
Martinez
Remote
infarcts
Courtesy of
Dr. Christine
Hulette
Infarct Age - Gross
Acute
6-48 h
Pale, soft, swollen, blurred gray-white jxn
Subacute 2 d - 3 wks
2-10 d
Remote
Gelatinous, friable, distinct infarct boundary
Then, gradual removal of tissue
months-years
Cystic +/- hemosiderin staining
Secondary degeneration of axon tracts
Infarct Age - Microscopic
>1h
4-12 h
15-24 h - 5 d
2-3 d - wks
1-2 wks
mo-yrs
Neuronal and perineuronal
vacuolation, Dark neurons
Red neurons, Pallor (BBB leaky)
Neutrophils
MØ, myelin phagocytosis
Astrocyte & vascular prolif.
Cyst, residual MØ, gliotic wall
Acute infarcts
Subacute infarct,
H&E/LFB stain
Remote cystic infarct
Multiple
embolic
infarcts
Courtesy of
Dr.
Christine
Hulette
Diffuse hypoxia-ischemia
Vulnerable areas
“Watershed” or “borderzone”
 CA1 region of hippocampus
 Cerebellar Purkinje cells
 Mid- to deeper layers of cortex
(pyramidal) - laminar necrosis

Watershed
infarcts
Courtesy of
Dr. Christine
Hulette
CA1
CA2
Vulnerability of the Brain
High consumption of oxygen and glucose
 Dependence on oxidative phosphorylation

– Maintain membrane polarization

Relatively low levels of antioxidant
protection
– Growing evidence for physiologic role for free
radicals in neurotransmission (•NO, •O2-)
Clinical Course

“Stroke”
– Acute onset of focal neurologic syndrome
due to vascular event
– Acute change to pre-existing AS plaque
Symptoms tend to improve during 1st
week after stroke
 Believed to reflect acute neuronal death
followed by resolution of edema

Lessons from Experimental Systems
Core - rapid neuron death from lipolysis,
proteolysis, total bioenergetic failure
 Penumbra - Delayed neuronal death
continues for days/weeks after insult

–
–
–
–
–
Excitotoxicity
Spreading dopolarization
Reactive oxygen and nitrogen species
Apoptosis
Inflammation
Evolution of Ischemic Stroke
Modified from Dirnagl et al. 1999. TINS 22:391-397
Therapies to Salvage Penumbra
Hypothermia
 NMDA antagonists, block “excitotoxicity”

– Short window (1-2 h)
– Serious unwanted effects (like “off switch” of
tv)
– New selective antagonists (“volume control”)
Calcium channel blockers
 SOD mimetics - longer window
 Potential targets for therapies

– iNOS and COX2, anti-apoptotic agents?
Cerebrovascular Disease
Hypoxia, ischemia, infarction
 Intracranial hemorrhages
– Epidural
– Subdural
– Subarachnoid
– Intraparenchymal
 Herniation
 Vasculitis, small vessel disease

skull
dura
arachnoid
pia
Epidural Hemorrhages


Trauma with skull fx
Arterial
– Middle meningeal artery
– Can be rapidly expanding >> herniation
– Less common in children
• Meningeal vessels not yet deeply embedded in grooves of
the cranium’


Dense dark-red clot adherent to dura
Can be venous from infratentorial base of skull
fxs with laceration of dural sinus
Subdural Hemorrhage
Bridging veins
 Early (Acute and subacute)

– Trauma, associated with brain contusion
– Mixture of blood and CSF - may not clot

Chronic
– Mainly in elderly, may not recall trauma
– Slow development, may distort brain
– Fibrous organization and rebleeding
common - sepia/yellow staining
Subdural membrane with rebleeding
SAH
Subarachnoid Hemorrhage

Saccular (Berry) Aneurysms
–
–
–
–
1.8% of autopsies
Congenital defect in media at branch point
90% in anterior circulation
Repetitive bleeding > loculations > rupture
into adjacent parenchymal
– Plaques, calcifications, thrombi
– Associated with polycystic kidney disease
MCA
ACA
ICA
Ruptured Aneurysms
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, p. 73. W.B. Saunders Co.
Intraparenchymal extension
from ruptured anterior
communicating artery
aneurysm
Intraparenchymal Hemorrhage
 15%
mortality
 Arterial hypertension - 80% of cases
 Vascular malformations
 Amyloid angiopathy
 Neoplasms
Other intracranial aneurysms
Seldom present as SAH
 Fusifirm atherosclerotic aneurysms

– Basilar artery
– Compression of adjacent structures
– Infectious and post-traumatic

Mycotic, traumatic, dissecting
– Usually involve anterior circulation
Arterial dissection



Young adults - IC, MCA, vertebral, basilar
Hyperextension injury - may be “trivial”
Spontaneous dissection
– Arteritis, AS, HTN, birth control pill, Marfan’s,
cystic medial necrosis, fibromuscular dysplasia,
Ehlers-Danlos
– Focal absence, splitting, fraying of internal elastic
membrane
– 33% no identifiable pathology
Intraparenchymal Hemorrhage
Massive hemorrhage of the basal ganglia, WM,
pons, cerebellum >> Hypertension
 Superficial/lobar >> contusion, amyloid, AVM
 Parasagittal >> venous thrombosis, SSS
 Petechial >> blood dyscrasias, fat emboli
 Multiple hemorrhaghic infarcts >> emboli
(tumor, infectious, cardiac)
 Neoplasms can present as hemorrhage

Hypertensive hemorrhage
Courtesy of
Dr. Julio
Martinez
Hypertensive hemorrhage
Courtesy of
Dr. Julio
Martinez
Surgical Pathology
Hemorrhages

Usual dx - clotted blood
– May see erythrophagocytosis, fibrovascular
organization, subdural membrane > then can call
organizing hemorrhage/hematoma


Look for brain tissue and note in report
If present, look for underlying cause
– Congophilic angiopathy (b-APP, cystatin C)
– Tumor
– AVM
Congophilic angiopathy in resected hematoma
CNS Vascular Malformations
Arteriovenous malformation (AVM)
 Cavernous hemangioma
 Capillary telangiectasia - pons
 Venous angioma (varices)

Arteriovenous malformation
Medusa-like lesions with potential for
rupture
 Most over hemispheric surface of MCA
 Multiple lesions occasionally seen with
Rendo-Osler-Weber disease or WyburnMason syndrome
 Sx: seizures, focal deficits, increased ICP,
catastrophic hemorrhage

AVM - Pathology
Vessels vary in caliber
 Core may exclude brain parenchyma, but
feeding and draining vessels interdigitate
with intervening brain
 Presence of abnormal arteries possessing
internal elastic lamina is diagnostic
 “Arterialized” veins from the high
pressure
 Evidence of prior hemorrhage

Arteriovenous malformation

In children, deep AVMs draining into the
great vein of Galen can cause cardiac
decompensation from shunting
Cavernous Malformations
Compact spherical calcified mass
 Most often affect subcortical areas, but also
hindbrain
 Multiple lesions frequent
 Recently recognized that it can be
transmitted as an autosomal dominant trait
 Typically present with seizures.
Hemorrhages common, but usually small

Cavernous Malformations
Honeycomb of compact vessels, often
collagenized
 No muscle or elastic lamina
 Closely packed, no intervening brain
 Surrounding brain shows extensive
hemosiderin and iron laden
macrophages/astrocytes - dark MR signal

Venous Infarction
Hemorrhagic lesions involving
parasagittal meninges, cortex, WM
 Superior sagittal sinus thrombosis

– Centrum ovale and overlying cortex,
meninges, usually symmetric

Great vein of Galen
– Periventricular and thalamic regions
SSS Thrombosis
Courtesy of
Dr. Julio
Martinez
Brain tumors presenting with
hemorrhage


Classically associated with oligodendroglioma,
choriocarcinoma, metastatic melanoma
However, any glioma can present with
hemorrhage
– Recent examples include GBM, anaplastic
ependymoma

Post-operative hematoma from incompletely
excised tumors - clinical history often not given
Cerebrovascular Disease
 Hypoxia,
ischemia, infarction
 Intracranial hemorrhages
 Herniation
– Symptoms
– Anatomic basis
 Vasculitis,
small vessel disease
Herniation

Rigid skull, tough inelastic dura
– Brain, CSF, blood

Symptoms of increased pressure
– Headache
– Papilledema - precedes herniation

Symptoms of transtentorial herniation
– Remember anatomic basis
Herniation
 Symptoms
of transtentorial
herniation
– Pupillary dilation, lateral deviation
– Cortical blindness
– Coma
– Hemiparesis, usually contralateral, but
can be ipsilateral (false localizing sign)

Hydrocephalus, Duret hemorrhages of pons
How do each of
these colored
structures relate
to SSx of
herniation listed
on previous
slide?
Modified from Watson
1995 Basic Human Neuroanatomy, 5th Edition
Little, Brown & Co.
Bilateral uncal
herniation with
midbrain compression,
secondary occipital
infarcts
Courtesy of
Dr. Christine
Hulette
Cerebrovascular Disease
 Hypoxia,
ischemia, infarction
 Intracranial hemorrhages
 Herniation
 Vasculitis, small vessel disease
– Temporal arteritis
– Microvascular diseases
• HTN, amyloid angiopathy, primary angiitis of
the CNS
– Petechial hemorrhages
Primary vasculitides

Takayasu’s - aorta, carotid, subclavian
– Media, destruction of elastic lamellae
Temporal arteritis - extracranial aa
 Primary angiitis of the CNS - small
meningeal aa and penetrating arterioles

Temporal (giant cell) arteritis
>55 yrs old with headache and blindness
 Predominantly affects extracranial
arteries of the head
 High ESR
 Good, rapid response to corticosteroids
 Focal histopathological changes

– Need to sample thoroughly
Temporal arteritis - histology



It is a transmural process, focused on media and
adventitia
Nonspecific intimal proliferation, +/- lymphs
Inner media
– Multinucleated giant cells, epithelioid histiocytes
– Frayed internal elastic lamina

Adventitia
– Epithelioid histiocytes, lymphs

Chronic, healed - transmural fibrosis
“Microvascular diseases”


Disease of arterioles and other small parenchymal
vessels
Radiologic entity - white matter pallor
– Multiple divergent pathological causes
– Degenerative - HTN, amyloid angiopathy
– Inflammatory - vasculitis ( J Neuropath Exp Neurol

Petechial hemorrhages
– Embolic - cholesterol, fat
– Disruptions of coagulation - TTP, lupus
57: 30-38)
Hypertensive Angiopathy
Penetrating arteries, 75-400 m
 Vascular wall thickening
 Fibrinoid change or necrosis
 Segmental weakening and dilatation

– Charcot-Bouchard aneurysms

Lacunes
– <15 mm infarcts, +/- associated hemorrhage
arteriolosclerosis
Primary angiitis of the CNS






Noninfectious granulomatous angiitis or isolated
angiitis of the CNS
Untreated - almost universally fatal
Combination steroid and cytoxan
ESR variable and not diagnostically useful, CSF
resembles chronic meningitis
Transmural granulomatous or lymphocytic
inflammation, esp. intima, media
Rule out infectious vasculitides
PACNS - DDx
J Neuropath Exp Neurol 57: 30-38, 1998.

Clinical mimics - hypertension, AD,
amyloid angiopathy, glioma,
antiphospholipid syndromes, moyamoya,
fibromuscular dysplasia, cardiac
myxoma embolism)

Pathologic DDx - viral infection,
Hodkin’s, lymphomatoid granulomatosis,
systemic rheumatic disorders ( SLE,
sarcoid), drug hypersensitivity
PACNS
Vasculitis secondary to
arboviral infection, Am J
Surg Pathol, 23: 1217-1226
Congophilic
angiopathy
Petechial hemorrhages
Courtesy of
Dr. Julio
Martinez
TTP
Courtesy of
Dr. Julio
Martinez
Fat embolus, Oil red O
Courtesy of
Dr. Julio
Martinez
Self quiz (see next slide)
Which two panels show pathology related
to a common etiology (cause)?
 What panel results from trauma, what is
anatomic space occupied by the lesion,
and what vessel is commonly involved?
 Which panel reflects differential
neuronal susceptibility to injury?
 Which panel reflects a chronic process?

A
B
C
D
Self quiz (answers)




B shows hypertensive hemorrhage originating
in BG and C shows lacunar infarcts in the BG,
also related to hypertension.
The subdural hemorrhage in A results from
trauma, sometimes so mild it is not
remembered, and involves bridging veins
D shows acute neuronal injury (red neurons) in
the region of the hippocampus susceptible to
hypotensive-hypoperfusion injury?
C shows remote cerebellar infarct
Recommended Reading



Manual of Basic Neuropathology by Poirier et al.
– Pp. 52-56, 58-61, Chapter 4.
Robbins Pathologic Basis of Disease by Cotran, Kumar,
and Collins 6th Ed.
– Pertinent sections of Chapter 30 (CNS).
Greenfield’s Neuropathology text - a must for all NP
fellows