NEUROPATHOLOGY- VASCULAR DISEASE

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I. REVIEW OF ANATOMY OF CEREBRAL CIRCULATION
II. CEREBRAL VASCULAR DISEASE
III. CONCEPTS OF ISCHEMIA, HYPOXIA, AND ANOXIA
IV. INFARCTION
V. HEMORRHAGE

VOCABULARY
Terms you should be familiar with:

Cerebral vascular disease
Stroke
Circle of Willis
Anoxic/ischemic injury
Hypoxia
Gitter cell
Astrocytosis
Reactive astrocytosis
Gliosis
Cerebral edema
Wallerian degeneration
Hypertension
Thrombosis
Embolism
Lacunar infarct
Cerebral infarct
Borderzone infarct
Ischemia
Intracerebral hemorrhage
Subarachnoid hemorrhage
Arteriovenous malformation
Berry (saccular) aneurysm
Charcot Bouchard aneurysm
Transient ischemic attack
Collateral circulation
Cerebral amyloid angiopathy
Reversible ischemic neurologic deficit

OBJECTIVES: The objectives of these two hours are to review briefly the vascular circulation of the central nervous system, to familiarize you with the fact that cerebral vascular disease is the most significant cause of neurologic disability in the United States, to impress upon you the intimate relationship between hypertension and the development of cerebral vascular disease, and to discuss the most common sequelae (i.e., pathologic lesions) of cerebral vascular disease.

I. REVIEW OF ANATOMY OF CEREBRAL CIRCULATION

• The brain's blood supply is derived from anterior (carotid) and posterior (vertebral) blood vessels. Each carotid artery gives rise to a middle and anterior cerebral artery, and the two vertebral arteries give rise to the basilar artery that in turn gives rise to two posterior cerebral arteries. The anterior and posterior blood vessels have a significant collateral relationship in the form of the circle of Willis. The circle of Willis is composed principally of the anterior communicating artery that joins the two anterior cerebral arteries, and the two posterior communicating arteries, each of which joins a posterior cerebral artery with an ipsilateral carotid artery. In reality, only 20% of the population has an idealized circle of Willis, with the most common anomaly being an absence or atresia of one of the posterior communicating arteries. On the other hand, because of the constancy of the anterior communicating artery, it is rare to develop a vascular insult in the distribution of the anterior cerebral artery due to occlusion of the ipsilateral carotid artery.
  
  
• The next most significant collateral relationship to keep in mind is that between the external and internal carotid circulations (e.g., the ophthalmic artery).
  
  
• 20% of cardiac output goes to the brain, and 80% of carotid flow goes to the ipsilateral middle cerebral artery. It should not be surprising that vascular lesions of the brain are frequently associated with cardiac and carotid disease.
  
  
• You should be familiar with the specific vascular distributions of the three major intracranial vessels, since the clinical syndromes one sees with vascular disease of the brain correlate with these distributions.

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II. CEREBRAL VASCULAR DISEASE

The generic term that encompasses a large number of disorders and pathologic lesions caused by vascular disease of the brain. The combined incidence of all of these is 140/100,000/year (prevalence 500/100,000), making cerebral vascular disease the most common neurologic disorder encountered in the United States. Cerebral vascular disease causes 10% of all deaths annually, and is the third leading cause of death behind heart disease and cancer. Stroke is the general clinical term that is used to describe cerebral vascular disease (i.e., if a person suffers a pathologic lesion related to cerebral vascular disease and manifests clinical signs and symptoms, the individual is said to have suffered a stroke), but the term stroke does not define the underlying vascular lesion.

• Stroke Syndromes Include:
  
  
  • Transient ischemic attack (TIA): signs and symptoms last less than 24 hours (usually less than 30 minutes), and the patient is left with no neurologic deficit.
  • Reversible ischemic neurologic deficit (RIND): signs and symptoms last less than 48 hours, and the patient is left with no or subtle neurologic deficit.
  • Completed stroke: a neurologic deficit persists.
  • Please note that although these three terms are commonly applied to the clinical features of infarction, they may be equally applied to the clinical features of hemorrhage.
    
    
• Major risk factors associated with the development of cerebral vascular disease are hypertension and age. Other risk factors (e.g., smoking, diabetes, hypercholesterolemia) implicated in the development of heart disease may or may not be associated with cerebral vascular disease; the data are not yet conclusive.
  
  
• Two major pathologic outcomes of cerebral vascular disease
  
  
  • Infarction: necrosis of brain tissue secondary to a failure of circulation (see ischemia and hypoxia, thrombosis, and embolism below).
  • Hemorrhage: a blood clot that forms in the brain parenchyma or subarachnoid space due to the rupture of a blood vessel or congenital vascular anomaly.
    
    
• Classification (These are the cerebral vascular disease lesions that you should know something about.)
  
  
  • Types of infarction (Remember, infarction is the process and infarct is the outcome.)
    • Thrombotic infarct
    • Embolic infarct
    • Lacunar infarct
    • Borderzone infarct
  • Types of hemorrhage
    • Intracerebral hemorrhage
    • Subarachnoid hemorrhage
    • Related to arteriovenous malformation
    • Related to cerebral amyloid angiopathy

III. CONCEPTS OF ISCHEMIA, HYPOXIA, AND ANOXIA

• Ischemia is a decrease in blood flow that is incompatible with cell function.
  
  
• Hypoxia is a reduction in the oxygen tension of blood.
  
  
• Anoxia is the absence of oxygen in the blood.
  
  
• Ischemia and hypoxia usually accompany each other.
  
  
• The degree of ischemia (i.e., the extent and duration of) defines the clinical syndrome: TIA, RIND or completed stroke. Obviously, if the patient has a completed stroke, then a cerebral infarct of some type has occurred.
  
  
• Occlusive ischemia is usually due to thrombosis and embolism, and usually underlying atherosclerosis is present.
  
  
• Non-occlusive ischemia can be due to a variety of circumstances, including:
  • Cardiac arrest
  • Cardiac dysrhythmia or valveulopathies
  • Systemic arterial hypotension
  • Shock

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IV. INFARCTION

• Pathologic Features: grossly, brain tissue is initially softened and eventually liquified. With large infarcts, associated cerebral edema may be marked, leading to displacement of midline structures, herniation and death due to brain stem compression. Over time (weeks to months), the area of infarct is replaced by a cystic cavity surrounded by reactive astrocytosis and gliosis. If the infarct involves the motor strip, one will see Wallerian degeneration of the descending pyramidal system. Microscopic changes are related to the time after infarction has occurred and include:
  
  
  • Anoxic/ischemic injury of neurons: 0-24 hours
  • Infiltration of tissue by neutrophils: 24-72 hours
  • Astrocytosis: 72 hours and persisting
  • Gitter cells: 5 days-3 weeks
  • Reactive astrocytosis: 3 weeks and persisting
  • Gliosis: forms the scar tissue related to the cystic cavity and persists forever
    
    
• Infarction due to Thrombosis (thrombotic infarct)
  
  
  • Atherosclerosis the commonest cause
  • Sites of greatest concentration of atherosclerosis, in order of predilection
    • Common carotid bifurcation
    • Internal carotid siphon
    • Middle cerebral artery at bifurcation
    • Vertebral arteries as they enter cranium and at junction
    • Basilar artery just above its formation and at bifurcation
    • Posterior cerebral artery just beyond its origin
    • Anterior cerebral artery as it bends around corpus callosum
  • Phenomenon of thrombosis and clinical correlation: large vessel thrombosis produces a major infarct. Partial obliteration (stenosis) often precedes complete occlusion, so that symptoms of a TIA of RIND may precede a completed stroke. A carotid stenosis usually needs to be greater than 80% to be symptomatic. Stenosis and systemic hypotension may act in concert to produce symptoms of a completed stroke.
    
    
• Infarction due to Embolism (embolic infarct)
  
  
  • Although some clinical studies have indicated cerebral thrombosis to be more common than embolism, several pathologic investigations have demonstrated that one is about as common as the other.
  • Commonest sources of embolism
    • Thrombus in left auricle associated with atrial fibrillation
    • Thrombus in left ventricle associated with myocardial infarction
    • Endocardial vegetations of cardiac valves
    • Ulcerative atherosclerosis of the carotid arteries
  • Infarct may be large or small depending on the size of vessel occluded.
    
    
• Distinguishing Features of Thrombotic vs. Embolic Infarct
  
  
  • Thrombotic
    • Usually single vascular distribution
    • Usually non-hemorrhagic
    • Clinical syndrome of stepwise progression over hours to completed stroke
    • Often occurs in the a.m. just after arising
  • Embolic
    • Usually multiple vascular distributions
    • Usually hemorrhagic
    • Clinical syndrome of sudden onset of maximal neurologic deficit
    • Occurs anytime of day, often associated with activity
      
      
• Lacunar Infarct
  
  
  • One of the major complications of sustained systemic hypertension is small vessel atherosclerosis of intracranial vasculature, particularly involving vessels that come off their parent vessels at right angles. These include the lenticulostriate vessels (supplying basal ganglia and thalamus), midline pontine perforators (supplying the pons), and deep penetrating cerebellar vessels (supplying the cerebellar white matter).
  • Vascular pathogenesis
    • Sustained hypertension results in hypertrophy of blood vessel walls
    • Presumably, this is due to autoregulation and an attempt on the part of the CNS to maintain even blood flow.
    • Lipoprotein accumulation in these vessels leads to a disruption of internal elastica.
    • Fibrinoid necrosis of vessel wall occurs, leading to narrowing and marked segmental stenosis of the vessel wall.
  • Because of the vascular predilections mentioned above, lacunar infarcts occur most commonly in the basal ganglia and thalamus (70%), pons (15%), and cerebellar white matter (15%).
  • Lacunar infarcts by definition are less than 15mm in greatest diameter owing to the well circumscribed vascular distribution of the vessels involved.
  • The gross and microscopic pathology of lacunar infarcts is the same as for other types of infarcts.
  • Lacunar infarcts are the most come type of vascular lesion seen at autopsy, and the majority of these are probably clinically silent.
    
    
• Borderzone Infarct
  
  
  • The large intracranial vessels have defined borderzones. For example, there is a linear borderzone paramedially between the middle and anterior cerebral arteries. Likewise, there is a triangular borderzone among the middle, anterior and posterior cerebral arteries located at the inferior parietal lobule.
  • In situations of non-occlusive ischemia (see above), the lowest head of blood pressure occurs at the site of arterial borderzones.
  • If the ischemia/hypoxia is great enough, infarction occurs and the resulting lesion is termed a borderzone infarct.

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V. HEMORRHAGE

• Primary intracerebral hemorrhage: Hemorrhage into the parenchyma of the brain. Over 50% are related to the vascular affects of sustained systemic hypertension.
  
  
  • Vascular pathogenesis: Concerning the vascular pathogenesis described for lacunar infarcts above, all the statements apply except for the end result. Rather than narrowing and segmental stenosis of small vessels, there is weakening and the development of microscopic aneurysms, termed Charcot-Bouchard aneurysms. It is the rupture of one of these that leads to a blood clot in the brain called a primary intracerebral hemorrhage. It should come as no surprise that the distribution of intracerebral hemorrhages and lacunar infarcts is similar. Why one type of event occurs in one patient and the other in another is not clear. In fact, it is very common to find old lacunar infarcts in patients who have died from an intracerebral hemorrhage.
  • Sites of predilection include basal ganglia and thalamus (70%), pons (15%), and cerebellar white matter (15%).
  • Prognosis for survival related to size and location of clot. Large basal ganglia or thalamic hemorrhages produce massive extravasation of blood and intraventricular rupture. Usually fatal in hours to days. Displacement of midline structures and herniation occur. Pontine hemorrhages are invariably fatal, however cerebellar hemorrhages can be treated by surgical removal of the clot.
  • Occasionally hemorrhages are small and simulate infarction clinically.
  • Hemorrhage (a clot pushing aside cerebral tissue) can be distinguished pathologically from a hemorrhagic infarct (blood infiltrating necrotic cerebral tissue).
  • In the absence of hypertension, or if the hemorrhage is atypical in location, think of other causes including ruptured Berry (saccular) aneurysms, arteriovenous malformations, coagulopathies, blood dyscrasia, septicemia, trauma, brain neoplasms, and cerebral amyloid angiopathy.
    
    
• Subarachnoid Hemorrhage: Hemorrhage into the cerebral spinal fluid resulting in an accumulation of blood beneath the arachnoid membrane.
  
  
  • Clinically, sudden onset of headache and stiff neck, with or without loss of consciousness and associated focal signs and symptoms.
  • Most common cause is trauma.
  • Second most common cause is the rupture of a Berry (saccular) aneurysm. (N.B. to distinguish a Charcot-Bouchard aneurysm that is microscopic and intraparenchymal from a Berry aneurysm that is macroscopic and located in the subarachnoid space.) Berry aneurysms are thin-walled outpouchings usually at bifurcation of major vessels of the circle of Willis. They contain no smooth muscle or elastic tissue, or very little.
    • Propensity to develop and rupture not related to hypertension.
    • Thought to be due to developmental medial or elastic defect at junction point of vessels.
    • Most are located within 2 cm of the epicenter of the circle of Willis, and 85% involve vessels of the anterior circulation.
    • Incidence 4.0% in the population. 20% of patients have multiple aneurysms, and 20% are familial.
    • Factors related to rupture include size greater than 1 cm and increasing age.
  • Other types of aneurysms that may give rise to subarachnoid hemorrhage include mycotic, traumatic, and fusiform aneurysms, and carotid-cavernous sinus fistulas.
    
    
• Arteriovenous Malformations
  
  
  • Consist of tangles or masses of blood vessels, of capillary or of larger vessel size, either within substance or on surface of brain or cord, at any level of the CNS.
  • Large malformations may extend from pial to ventricular surface and form a significant A-V shunt, with dilatation of tributary and draining vessels.
  • Vessel walls vary in thickness and often contain chiefly fibrous tissue, frequently hyalinized, with little well-defined smooth muscle. Because of thinness and weakness of vessels, hemorrhage is common, especially when large vessels are present. This may be subarachnoid or intraparenchymal, depending on the site of rupture.
  • Seizures are a common complication due to pressure and circulatory effects on adjacent nerve cells.
  • Pathogenesis of vascular malformations thought to be failure of involution of normal primordial vasculature in a local area during embryonic development.
    
    
• Cerebral Amyloid Angiopathy
  
  
  • Angiopathy restricted to the small and medium sized vessels of the subarachnoid space and superficial cortex.
  • A peptide known as beta amyloid accumulates in the media of these vessels leading to weakening with the propensity of rupture.
  • No relationship to systemic or familial amyloidosis
  • 20% of individuals over the age of 60 develop this angiopathy, and there is a strong relationship to dementia and Alzheimer's disease.
  • Hemorrhages related to the angiopathy tend to be lobar, superficial, multiple and survivable.
  • Second most common cause of intracerebral hemorrhage in the elderly population after hypertension.

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