vascular neuropathology february 2002 charleen t. chu, m.d., ph.d. dept. of pathology, division of...

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

Systemic Systemic hypertensionhypertension

– Hypoxia, ischemia, infarction– Intracranial hemorrhage– Herniation– Small vessel disease

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 Neuro-

anatomy, 5th Edition, p. 103. Little, Brown & Co.

Modified from Poirier et al.1990 Manual of Basic Neuropathology, 3rd Edition,

Fig. 117, p. 88. W.B. Saunders

ACA PCA

MCA

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

Courtesy of Dr. Julio Martinez

Oil red O stain showing sites of AS

Plaque rupture

Atheromatous carotid stenosis

Modified from Poirier et al. 1990 Manual of Basic Neuropathology, 3rd Edition, p. 85. WB Saunders

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

Pathology of Cerebral Infarcts


Recent infarct with gyral edema, softening, discoloration


Subacute infarcts

Courtesy of Dr. Christine Hulette

Remote infarcts

Infarct Age - GrossAcute 6-48 h

Pale, soft, swollen, blurred gray-white jxn

Subacute 2 d - 3 wks2-10 d Gelatinous, friable, distinct infarct boundary

Then, gradual removal of tissue

Remote months-yearsCystic +/- hemosiderin staining

Secondary degeneration of axon tracts

Infarct Age - Microscopic> 1 h Neuronal and perineuronal

vacuolation, Dark neurons

4-12 h Red neurons, Pallor (BBB leaky)

15-24 h - 5 dNeutrophils

2-3 d - wks MØ, myelin phagocytosis

1-2 wks Astrocyte & vascular prolif.

mo-yrs Cyst, residual MØ, gliotic wall

Acute infarcts

Subacute infarct, H&E/LFB stain

Remote cystic infarct

Multiple embolic infarcts


Diffuse hypoxia-ischemia

“Watershed” or “borderzone” CA1 region of hippocampus Cerebellar Purkinje cells Mid- to deeper layers of cortex

(pyramidal) - laminar necrosis

Vulnerable areas


Watershed infarcts

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?


Hypoxia, ischemia, infarction Intracranial hemorrhages

– Epidural– Subdural– Subarachnoid– Intraparenchymal

Herniation Vasculitis, small vessel disease

pia

arachnoid

skulldura

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

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

Ruptured Aneurysms

Modified from Poirier et al.1990 Manual of Basic Neuropathology, 3rd Edition, p. 73. W.B. Saunders Co.

ACA

ICA

MCA

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

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 (-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 Wyburn-Mason 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


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


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

Modified from Watson 1995 Basic Human Neuro-

anatomy, 5th Edition Little, Brown & Co.

How do each of these colored structures relate to SSx of herniation listed on previous slide?


Bilateral uncal herniation with midbrain compression, secondary occipital infarcts


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 57: 30-38)

Petechial hemorrhages– Embolic - cholesterol, fat

– Disruptions of coagulation - TTP, lupus

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

Clinical mimics - hypertension, AD, amyloid angiopathy, glioma, antiphospholipid syndromes, moyamoya, fibromuscular dysplasia, cardiac myxoma embolism)

J Neuropath Exp Neurol 57: 30-38, 1998.

Pathologic DDx - viral infection, Hodkin’s, lymphomatoid granulomatosis, systemic rheumatic disorders ( SLE, sarcoid), drug hypersensitivity

Congophilic angiopathy

Vasculitis secondary to arboviral infection, Am J Surg Pathol, 23: 1217-1226


Petechial hemorrhages


TTP

Fat embolus, Oil red O


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?

D

A B

C

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

vascular neuropathology february 2002 charleen t. chu, m.d., ph.d. dept. of pathology, division of...

Documents