Neuropathology Quiz

Cerebrovascular Disease (CVD)

• CVD is injury to the brain due to altered blood flow
• CVD includes ischemic and hemorrhagic etiologies, with tissue infarction as a consequence.
• The 3rd leading cause of death
• "Stroke" is the clinical designation for all CVD conditions.

Stroke

• A neurologic event caused by a vascular mechanism; symptoms begin suddenly and last longer than 24 hours.
• A transient ischemic event, if symptoms resolve in under 24 hours.

Pathophysiology of CVD

• Two main processes cause cerebrovascular disease:
  • Hypoxia, ischemia, and infarction due to inadequate blood supply or oxygenation in the CNS. This can be caused by embolus or thrombosis.
  • Hemorrhage: rupture of CNS vessels due to hypertension or vascular anomalies.

Hypoxia/Ischemia

• The brain requires a constant supply of glucose and oxygen.
• Although the brain accounts for only 1% to 2% of body weight, it receives 15% of resting cardiac output and 20% of the body's oxygen.
• The brain is critically dependent on aerobic metabolism for energy demands.
• Reduced oxygen can occur through hypoxemia (low blood oxygen content) or ischemia (inadequate blood flow).

Factors Affecting Survival

• When blood flow to a portion of the brain is reduced, the tissue's survival depends on:
  • Presence of collateral circulation
  • Duration of ischemia
  • Magnitude and rapidity of flow reduction

Acute Ischemic Injury

• Global cerebral ischemia (ischemic/hypoxic encephalopathy): widespread reduction of cerebral perfusion, as seen in cardiac arrest, shock, and severe hypotension
• Focal cerebral ischemia: reduction in blood flow to a localized region of the brain, due to large-vessel disease (embolic or thrombotic arterial occlusion), or small-vessel disease (vasculitis)

Focal Cerebral Ischemia

• Cerebral arterial occlusion can lead to focal ischemia and infarction within a specific brain region.
• This is measured by the size, location, shape of the infarct, and extent of tissue damage.
• Collateral circulation is a major source of blood flow, especially the circle of Willis, and extra-carotid-ophthalmic pathway.
• Deep penetrating vessels lack collateral sources, impacting the thalamus, basal ganglia, and white matter.

Infarction from Obstruction of Local Blood Supply

• Occlusions are caused by vascular disease:
  • Thrombosis
  • Embolism
  • Vasculitis

Thrombotic Occlusion of Cerebral Arteries

• Commonly caused by changes in vulnerable atherosclerotic plaques
• Sites associated with primary thrombosis:
  • Carotid bifurcation
  • Origin of the middle cerebral artery
  • Either end of the basilar artery

Atherosclerosis

• A complex process primarily based in the intima
• Involves layers of cells and extracellular material.

Thrombosis

• Rupture, ulceration, or erosion of atheromatous plaques exposes the blood stream to thrombogenic substances.
• This results in thrombosis that can partially or completely obstruct the vessel's lumen.

Thrombi

• Progressive narrowing of the lumen and anterograde extension can lead to fragmentation and distal embolization

Embolism

• Embolism originates from cardiac mural thrombi (common), thromboemboli that arise in arteries (mostly from plaques within carotid arteries), or other materials like tumors, fat, or air. Most frequently affected by embolic infarction: the territory of the middle cerebral artery. Emboli often lodge in areas of branching or existing stenosis.

Vasculitis

• An inflammation of blood vessels
• Infectious causes: tuberculosis, syphilis, CMV, aspergillosis, and fungal infections
• Non-infectious causes: primary angiitis of CNS (rare cause of cerebrovascular disease)

Focal Cerebral Infarcts

• Embolic events or multiple-confluent petechial hemorrhage
• Bleeding is secondary to reperfusion of damaged vessel

Secondary Hemorrhagic Transformation

• Secondary hemorrhages can result from ischemia-reperfusion injury
• Spontaneous or therapeutic dissolution of intravascular occlusive material develops if the causative ischemic event is long lasting and damages small vessels; these hemorrhages are largely petechial.

Ischemic Strokes vs. Hemorrhagic Strokes

• Ischemic stroke is characterized by a clot blocking blood supply to a brain area, while hemorrhagic stroke results from a blood vessel rupture.

Clinical Management

• Treatment of hemorrhagic and non-hemorrhagic infarcts differ greatly.
• Thrombolytic therapy is contraindicated in patients with brain hemorrhage of any etiology.

Non-Hemorrhagic (Pale Infarct) Gross Morphology

• The first 6 hours of irreversible injury: little change.
• 48 hours: tissue becomes pale, soft, and swollen
• 2 to 10 days: the brain becomes gelatinous and friable.
• 10 days to 3 weeks: tissue liquefies, leaving a fluid-filled cavity.

Acute Infarct-Microscopically

• Neuronal necrosis (increased eosinophilia of the cytoplasm), followed by nuclear pyknosis & karyorrhexis ("dead red neurons").
• Cytotoxic & vasogenic edema.
• Loss of the usual tinctorial characteristics of white & gray matter.
• Endothelial & glial cells swell and myelinated fibers disintegrate.
• Neutrophilic emigration starts and peaks around 48 hours.

Subacute (Evolving) Infarct-Microscopically

• Phagocytic cells become predominant (48-72 hours)
• Macrophages become filled with myelin breakdown/blood products.
• Reactive astrocytes & newly formed vessels observed as early as a week post-insult. These enlarge, divide, & develop networks of cytoplasmic extensions.
• Foci of old hemorrhage, infarction, and calcification frequently surround the abnormal vessels after about 10 days.

Healed Infarct

• After several months: astrocytic response precedes, leaving behind a dense meshwork of glial fibers.
• New capillaries and some perivascular connective tissue are mixed in.
• Remote small infarcts show tissue loss surrounded by residual gliosis.
• Cavitary portions are surrounded by reactive astrocytic zones (glial scars), which are visually seen as blue bands. This is evident 3 months after the ischemic infarct.

Hemorrhagic Infarctions

• Parallel to ischemic infarctions, with the addition of blood extravasation & resorption.
• Inflammatory cells & blood cells are seen in damaged, reperfused vessels after an ischemic period.

Lacunar Infarcts

• Hypertension affects deep penetrating arteries, supplying basal ganglia, the brainstem, and the hemispheric white matter.
• These cerebral vessels develop arteriolar sclerosis and may be occluded from thrombosis.
• Infarcts known as lacunes or lacunar infarcts form from complete vessel occlusion.
• Usually in the putamen (50-60%), thalamus, pons, and cerebellar hemispheres, as well as other locations.

Global Cerebral Hypoxia/Ischemia

• Global cerebral hypoxia/ischemia occurs due to a generalized reduction of cerebral perfusion (cardiac arrest, shock, severe hypotension).
• This can also originate from decreased oxygen-carrying capacity of the blood (carbon monoxide poisoning).
• The brain's hierarchy of sensitivity, most vulnerable at the neuronal level, impacting glial cells (oligodendrocytes and astrocytes) and neurons in specific regions of the CNS due to differences in regional cerebral blood flow and cellular metabolic requirements. Areas like the Cortical pyramidal neurons, Pyramidal cells in CA1 of hippocampus, and Purkinje cells of the cerebellum are especially sensitive to global ischemia.
• Mild cases result in only transient confusion; complete recovery is possible.
• Severe cases cause widespread neuronal death, leading to a persistent vegetative state and sometimes brain death.

Brain Death

• Irreversible diffuse cortical injury and brainstem damage.
• Absence of brain stem reflexes & respiratory drive
• Mechanical ventilation required
• Autolytic processes, with brain gradually degrading.

Border Zone ("Watershed") Infarcts

• Occurs in the most distal reaches of arterial blood supply.
• Border zones between the arterial territories (brain/spinal cord); anterior & middle cerebral artery distributions are most at risk; results in a "sickle-shaped" band of necrosis commonly observed in bilateral cerebral hemispheres.
• These infarcts are commonly seen after hypotensive episodes, especially in patients resuscitated after cardiac arrest.

Morphology of Global Ischemia

• Brain is swollen; gyri & sulci are widened and narrowed, respectively, based on observations of the cut surface, where poor demarcation between gray & white matter is evident. These details, along with neuronal injuries, differentiate global ischemia microscopically.

Intracranial Hemorrhage

• Hemorrhage occurs at multiple sites within the CNS.
  • Secondary hemorrhages occur in infarcts, from partial or transient vascular obstructions.
  • Primary hemorrhages involve:
    • Epidural/subdural space (trauma-related massive bleeding)
    • Brain parenchyma (underlying cerebrovascular disease)

Intracerebral (Intraparenchymal) Hemorrhage

• Rupture of a small intraparenchymal vessel causes primary bleeding within the brain.
• Often associated with sudden neurologic symptoms (stroke).
• Not to be mistaken with secondary hemorrhagic transformation.

Intracerebral Hemorrhage (most common causes)

• Most commonly observed in middle/late adult life with a peak at approximately 60 years.
• Major causes:
  • Hypertension
  • Cerebral amyloid angiopathy
• Other causes:
  • Systemic coagulation issues
  • Tumors
  • Vasculitis
  • Aneurysms and vascular malformations

Hypertensive Hemorrhage

• Underlying cause of most primary brain parenchymal hemorrhages (over 50%).
• Hypertension leads to vascular abnormalities:
  • Accelerated atherosclerosis in larger arteries
  • Hyaline arteriolosclerosis in smaller vessels
  • Proliferative changes in arterioles
  • Minute aneurysms (“Charcot Bouchard”) in basal ganglia. 

Cerebral Amyloid Angiopathy (CAA)

• Amyloidogenic (Aβ40) peptides deposit in the walls of medium and small caliber meningeal and cortical vessels.
• Weakening of vessel walls leads to small hemorrhages within the brain.
• The underlying vascular abnormality is typically confined to leptomeningeal and cerebral cortical vessels.

Morphology of Intraparenchymal hemorrhages

• Hemorrhages have central core of clotted blood, compressing the adjacent parenchyma.
• This will cause secondary damage to the brain cells from anoxia.
• Hemosiderin- and lipid-laden macrophages appear.
• Reactive astrocyte proliferation appears at the lesion's periphery.

Subarachnoid Hemorrhage

• Most frequent causes are rupture of a saccular (berry) aneurysm, traumatic hematoma extensions, rupture of a hypertensive intracerebral hemorrhage into the ventricular system, vascular malformations, and hematologic disturbances. Tumors are another possible cause.

Aneurysm

• A saccular aneurysm is the most common intracranial aneurysm type.
• Other aneurysm types include atherosclerotic (fusiform), mycotic, traumatic, and dissecting aneurysms. Saccular aneurysms, usually found in the anterior circulation (%90), are often congenital in origin, appearing as thin-walled outpouchings along the circle of Willis, measuring a few millimeters to a couple of centimeters in diameter. 
• The etiology is unknown, with risk factors including smoking and hypertension.
• Morphology includes a thickened hyalinized intima, a continuous adventitia of the parent artery, absence of a prominent muscular wall, and lack of an intimal elastic lamina. These sacs may show signs of prior hemorrhage.
• Mycotic aneurysms arise from bacterial, fungal, or viral vessel wall infections and are associated with systemic infections and atherosclerotic processes.
• Vascular malformations are grouped into arteriovenous malformations (AVMs), cavernous malformations, capillary telangiectasias, and venous angiomas.

Vascular Malformations

• Arteriovenous malformations (AVMs): tangled networks of worm-like vascular channels with prominent pulsatile arteriovenous shunting (high blood flow).
• Cavernous malformations: greatly dilated, loosely organized vascular channels of thin, collagenized walls. Mostly found in the cerebellum, pons, and subcortical regions.
• Capillary telangiectasias: microscopic, dilated, thin-walled vascular channels. Most frequently seen in the pons.
• Venous angiomas (varices): consist of aggregates of ectatic venous channels.

This quiz covers key concepts in neuropathology, focusing on vascular lesions, ischemic injury, and related conditions. It tests knowledge of aneurysm characteristics, amyloid angiopathy, infarct evolution, and arteriolar changes.