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Vascular Neuropathology February 2002

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Title: Vascular Neuropathology February 2002


1
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

2
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

3
Cerebrovascular Disease
  • Third leading cause of death in the US
  • Most prevalent neurologic disorder
  • Hypoxia, ischemia, infarction
  • Intracranial hemorrhage
  • Herniation
  • Small vessel disease

4
Cerebrovascular Disease
  • Hypoxia, ischemia, infarction
  • Anatomy
  • Atherosclerosis and emboli
  • Hypotensive episode
  • Acute, subacute, chronic infarcts
  • Intracranial hemorrhage
  • Herniation
  • Vasculitis, small vessel disease

5
Vascular Supply to the Brain
Modified from Watson 1995 Basic Human
Neuro-anatomy, 5th Edition, p. 103. Little,
Brown Co.
6
PCA
ACA
MCA
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, Fig. 117, p. 88.
W.B. Saunders
7
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

8
Oil red O stain showing sites of AS
Courtesy of Dr. Julio Martinez
9
Plaque rupture
Atheromatous carotid stenosis
Modified from Poirier et al. 1990 Manual of Basic
Neuropathology, 3rd Edition, p. 85. WB Saunders
10
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

11
Recent infarct with gyral edema, softening,
discoloration
Courtesy of Dr. Julio Martinez
12
Subacute infarcts
Courtesy of Dr. Julio Martinez
13
Remote infarcts
Courtesy of Dr. Christine Hulette
14
Infarct 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

15
Infarct 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

16
Acute infarcts
17
Subacute infarct, HE/LFB stain
18
Remote cystic infarct
19
Multiple embolic infarcts
Courtesy of Dr. Christine Hulette
20
Diffuse hypoxia-ischemia
Vulnerable areas
  • Watershed or borderzone
  • CA1 region of hippocampus
  • Cerebellar Purkinje cells
  • Mid- to deeper layers of cortex (pyramidal) -
    laminar necrosis

21
Watershed infarcts
Courtesy of Dr. Christine Hulette
22
CA2
CA1
23
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-)

24
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

25
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

26
Evolution of Ischemic Stroke
Modified from Dirnagl et al. 1999. TINS 22391-397
27
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?

28
Cerebrovascular Disease
  • Hypoxia, ischemia, infarction
  • Intracranial hemorrhages
  • Epidural
  • Subdural
  • Subarachnoid
  • Intraparenchymal
  • Herniation
  • Vasculitis, small vessel disease

29
Epidural 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

30
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

31
Subdural membrane with rebleeding
32
SAH
33
Subarachnoid 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

34
MCA
ACA
ICA
Ruptured Aneurysms
Modified from Poirier et al.1990 Manual of Basic
Neuropathology, 3rd Edition, p. 73. W.B.
Saunders Co.
35
Intraparenchymal extension from ruptured anterior
communicating artery aneurysm
36
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37
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38
Intraparenchymal Hemorrhage
  • 15 mortality
  • Arterial hypertension - 80 of cases
  • Vascular malformations
  • Amyloid angiopathy
  • Neoplasms

39
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

40
Arterial 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

41
Intraparenchymal 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

42
Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
43
Hypertensive hemorrhage
Courtesy of Dr. Julio Martinez
44
Surgical 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

45
Congophilic angiopathy in resected hematoma
46
CNS Vascular Malformations

  • Arteriovenous malformation (AVM)
  • Cavernous hemangioma
  • Capillary telangiectasia - pons
  • Venous angioma (varices)

47
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 Wyburn-Mason
    syndrome
  • Sx seizures, focal deficits, increased ICP,
    catastrophic hemorrhage

48
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

49
Arteriovenous malformation
  • In children, deep AVMs draining into the great
    vein of Galen can cause cardiac decompensation
    from shunting

50
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51
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

52
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

53
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

54
SSS Thrombosis
Courtesy of Dr. Julio Martinez
55
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

56
Cerebrovascular Disease
  • Hypoxia, ischemia, infarction
  • Intracranial hemorrhages
  • Herniation
  • Symptoms
  • Anatomic basis
  • Vasculitis, small vessel disease

57
Herniation
  • Rigid skull, tough inelastic dura
  • Brain, CSF, blood
  • Symptoms of increased pressure
  • Headache
  • Papilledema - precedes herniation
  • Symptoms of transtentorial herniation
  • Remember anatomic basis

58
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

59
How 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.
60
Bilateral uncal herniation with midbrain
compression, secondary occipital infarcts
Courtesy of Dr. Christine Hulette
61
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

62
Primary 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

63
Temporal (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

64
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

65
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 57 30-38)
  • Petechial hemorrhages
  • Embolic - cholesterol, fat
  • Disruptions of coagulation - TTP, lupus

66
Hypertensive 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

67
arteriolosclerosis
68
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

69
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, Hodkins,
    lymphomatoid granulomatosis, systemic rheumatic
    disorders ( SLE, sarcoid), drug hypersensitivity

70
PACNS
71
Vasculitis secondary to arboviral infection, Am J
Surg Pathol, 23 1217-1226
Congophilic angiopathy
72
Petechial hemorrhages
Courtesy of Dr. Julio Martinez
73
TTP
Courtesy of Dr. Julio Martinez
74
Fat embolus, Oil red O
Courtesy of Dr. Julio Martinez
75
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?

76
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77
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

78
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).
  • Greenfields Neuropathology text - a must for all
    NP fellows
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