Title: Vascular Neuropathology February 2002
1Vascular 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
2Cerebrovascular 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
3Cerebrovascular Disease
- Third leading cause of death in the US
- Most prevalent neurologic disorder
- Hypoxia, ischemia, infarction
- Intracranial hemorrhage
- Herniation
- Small vessel disease
4Cerebrovascular Disease
- Hypoxia, ischemia, infarction
- Anatomy
- Atherosclerosis and emboli
- Hypotensive episode
- Acute, subacute, chronic infarcts
- Intracranial hemorrhage
- Herniation
- Vasculitis, small vessel disease
5Vascular Supply to the Brain
Modified from Watson 1995 Basic Human
Neuro-anatomy, 5th Edition, p. 103. Little,
Brown Co.
6PCA
ACA
MCA
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, Fig. 117, p. 88.
W.B. Saunders
7Anatomic 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
8Oil red O stain showing sites of AS
Courtesy of Dr. Julio Martinez
9Plaque rupture
Atheromatous carotid stenosis
Modified from Poirier et al. 1990 Manual of Basic
Neuropathology, 3rd Edition, p. 85. WB Saunders
10Pathology 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
11Recent infarct with gyral edema, softening,
discoloration
Courtesy of Dr. Julio Martinez
12Subacute infarcts
Courtesy of Dr. Julio Martinez
13Remote infarcts
Courtesy of Dr. Christine Hulette
14Infarct Age - Gross
- Acute 6-48 h
- Pale, soft, swollen, blurred gray-white jxn
- Subacute 2 d - 3 wks
- 2-10 d Gelatinous, friable, distinct infarct
boundary Then, gradual removal of tissue - Remote months-years
- Cystic /- hemosiderin staining
- Secondary degeneration of axon tracts
15Infarct Age - Microscopic
- gt 1 h Neuronal and perineuronal
vacuolation, Dark neurons - 4-12 h Red neurons, Pallor (BBB leaky)
- 15-24 h - 5 d Neutrophils
- 2-3 d - wks MØ, myelin phagocytosis
- 1-2 wks Astrocyte vascular prolif.
- mo-yrs Cyst, residual MØ, gliotic wall
16Acute infarcts
17Subacute infarct, HE/LFB stain
18Remote cystic infarct
19Multiple embolic infarcts
Courtesy of Dr. Christine Hulette
20Diffuse hypoxia-ischemia
Vulnerable areas
- Watershed or borderzone
- CA1 region of hippocampus
- Cerebellar Purkinje cells
- Mid- to deeper layers of cortex (pyramidal) -
laminar necrosis
21Watershed infarcts
Courtesy of Dr. Christine Hulette
22CA2
CA1
23Vulnerability 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-)
24Clinical 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
25Lessons 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
26Evolution of Ischemic Stroke
Modified from Dirnagl et al. 1999. TINS 22391-397
27Therapies 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?
28Cerebrovascular Disease
- Hypoxia, ischemia, infarction
- Intracranial hemorrhages
- Epidural
- Subdural
- Subarachnoid
- Intraparenchymal
- Herniation
- Vasculitis, small vessel disease
29Epidural Hemorrhages
- Trauma with skull fx
- Arterial
- Middle meningeal artery
- Can be rapidly expanding gtgt 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
30Subdural 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
31Subdural membrane with rebleeding
32SAH
33Subarachnoid Hemorrhage
- Saccular (Berry) Aneurysms
- 1.8 of autopsies
- Congenital defect in media at branch point
- 90 in anterior circulation
- Repetitive bleeding gt loculations gt rupture into
adjacent parenchymal - Plaques, calcifications, thrombi
- Associated with polycystic kidney disease
34MCA
ACA
ICA
Ruptured Aneurysms
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, p. 73. W.B.
Saunders Co.
35Intraparenchymal extension from ruptured anterior
communicating artery aneurysm
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38Intraparenchymal Hemorrhage
- 15 mortality
- Arterial hypertension - 80 of cases
- Vascular malformations
- Amyloid angiopathy
- Neoplasms
39Other 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
40Arterial dissection
- Young adults - IC, MCA, vertebral, basilar
- Hyperextension injury - may be trivial
- Spontaneous dissection
- Arteritis, AS, HTN, birth control pill, Marfans,
cystic medial necrosis, fibromuscular dysplasia,
Ehlers-Danlos - Focal absence, splitting, fraying of internal
elastic membrane - 33 no identifiable pathology
41Intraparenchymal Hemorrhage
- Massive hemorrhage of the basal ganglia, WM,
pons, cerebellum gtgt Hypertension - Superficial/lobar gtgt contusion, amyloid, AVM
- Parasagittal gtgt venous thrombosis, SSS
- Petechial gtgt blood dyscrasias, fat emboli
- Multiple hemorrhaghic infarcts gtgt emboli (tumor,
infectious, cardiac) - Neoplasms can present as hemorrhage
42Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
43Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
44Surgical Pathology Hemorrhages
- Usual dx - clotted blood
- May see erythrophagocytosis, fibrovascular
organization, subdural membrane gt 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
45Congophilic angiopathy in resected hematoma
46CNS Vascular Malformations
- Arteriovenous malformation (AVM)
- Cavernous hemangioma
- Capillary telangiectasia - pons
- Venous angioma (varices)
47Arteriovenous malformation
- Medusa-like lesions with potential for rupture
- Most over hemispheric surface of MCA
- Multiple lesions occasionally seen with
Rendo-Osler-Weber disease or Wyburn-Mason
syndrome - Sx seizures, focal deficits, increased ICP,
catastrophic hemorrhage
48AVM - 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
49Arteriovenous malformation
- In children, deep AVMs draining into the great
vein of Galen can cause cardiac decompensation
from shunting
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51Cavernous 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
52Cavernous 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
53Venous 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
54SSS Thrombosis
Courtesy of Dr. Julio Martinez
55Brain 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
56Cerebrovascular Disease
- Hypoxia, ischemia, infarction
- Intracranial hemorrhages
- Herniation
- Symptoms
- Anatomic basis
- Vasculitis, small vessel disease
57Herniation
- Rigid skull, tough inelastic dura
- Brain, CSF, blood
- Symptoms of increased pressure
- Headache
- Papilledema - precedes herniation
- Symptoms of transtentorial herniation
- Remember anatomic basis
58Herniation
- 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
59How do each of these colored structures relate to
SSx of herniation listed on previous slide?
Modified from Watson 1995 Basic Human
Neuro-anatomy, 5th Edition Little, Brown Co.
60Bilateral uncal herniation with midbrain
compression, secondary occipital infarcts
Courtesy of Dr. Christine Hulette
61Cerebrovascular 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
62Primary vasculitides
- Takayasus - aorta, carotid, subclavian
- Media, destruction of elastic lamellae
- Temporal arteritis - extracranial aa
- Primary angiitis of the CNS - small meningeal aa
and penetrating arterioles
63Temporal (giant cell) arteritis
- gt55 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
64Temporal 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
65Microvascular 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 57 30-38) - Petechial hemorrhages
- Embolic - cholesterol, fat
- Disruptions of coagulation - TTP, lupus
66Hypertensive Angiopathy
- Penetrating arteries, 75-400 ?m
- Vascular wall thickening
- Fibrinoid change or necrosis
- Segmental weakening and dilatation
- Charcot-Bouchard aneurysms
- Lacunes
- lt15 mm infarcts, /- associated hemorrhage
67arteriolosclerosis
68Primary 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
69PACNS - 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, Hodkins,
lymphomatoid granulomatosis, systemic rheumatic
disorders ( SLE, sarcoid), drug hypersensitivity
70PACNS
71Vasculitis secondary to arboviral infection, Am J
Surg Pathol, 23 1217-1226
Congophilic angiopathy
72Petechial hemorrhages
Courtesy of Dr. Julio Martinez
73TTP
Courtesy of Dr. Julio Martinez
74Fat embolus, Oil red O
Courtesy of Dr. Julio Martinez
75Self 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?
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77Self 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
78Recommended 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).
- Greenfields Neuropathology text - a must for all
NP fellows