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(Stroke. 1997;28:1501-1506.)
© 1997 American Heart Association, Inc.

Articles

Etiology of Stroke

Panel
J. P. Mohr, MD, Chair; Gregory W. Albers, MD; Pierre Amarenco, MD; Viken L. Babikian, MD; José Biller, MD; Robin L. Brey, MD; Bruce Coull, MD; J. Donald Easton, MD; Camilo R. Gomez, MD; Cathy M. Helgason, MD; Carlos S. Kase, MD; Patrick M. Pullicino, MD; Alexander G. G. Turpie, MD

Key Words: AHA Medical/Scientific Statements • stroke • prevention • embolism • thrombosis

	Introduction

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 
The diagnosis of arterial stroke differentiates ischemia from hemorrhage. The former may be due to arterial occlusion or stenosis, the latter to leakage or rupture of an artery. Computed tomography (CT) and magnetic resonance imaging (MRI) have shown that this basic differentiation cannot be reliably made from the history and clinical examination alone. Of the clinical stroke syndromes, only Wallenberg's syndrome has not been reported to be due to hemorrhage. When CT or MRI is not available for diagnosis, spinal tap is reliably positive only when the aneurysm or arteriovenous malformation has ruptured into the subarachnoid space; the results are often normal when a small hemorrhage occurs in the parenchyma. For some therapies, notably neuroprotective agents, the potential benefits for ischemia do not seem to be offset by potential harm in the case of hemorrhage. However, because fibrinolytics, antithrombotic agents, or surgery are treatment options, diagnostic certainty is essential to avoid harming the patient.

Most—but not all—strokes have a sudden or rapidly evolving onset. Differential diagnosis of sudden change in focal neurological status includes seizures or postepileptic paralysis, hemorrhage into a tumor (itself a form of stroke), and migraine. Neuroimaging helps to differentiate between these and the cause of short-lived symptoms (transient ischemic attack [TIA]) usually presumed due to ischemia but possibly due to new-onset infarction or hemorrhage. More precise classification of stroke into a pathogenic subtype (embolism, thrombosis, decreased perfusion or "lacunar" infarction, leakage, or rupture) evades the best clinical skills.

	Diagnosis of Ischemic Stroke Mechanism

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The classification of stroke mechanism depends on the presence of risk factors for stroke (preexisting condition or circumstance epidemiologically related to stroke) and etiologies (disease directly causing the mechanism) that implicate the cause of stroke in a given patient. However, more than one risk factor and etiology are frequently present in the same patient and may be related to recurrence.

The currently recognized ischemic stroke mechanisms are embolism, decreased perfusion, and thrombosis. Lacunar infarction (infarct size 1.5 cm) may be caused by all three mechanisms but in "crisp" stroke subtype classifications has been named either a cause or a mechanism of ischemic stroke.

	Embolism to the Brain of Cardiac or Aortic Origin

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Embolism to the brain may be arterial or cardiac in origin. Commonly recognized cardiac sources for embolism include atrial fibrillation, sinoatrial disorder, recent acute myocardial infarction (AMI), marantic or subacute bacterial endocarditis, cardiac tumors, and valvular disorders, both native and artificial.

Myocardial Infarction
Stroke is an important complication in patients with AMI, occurring in 1% to 3% of all infarctions and in 2% to 6% of patients with anterior wall infarctions. The majority of strokes after AMI are thought to be embolic, arising from left ventricular wall mural thrombi, but a number may be atherothrombotic or, in the acute phase, secondary to hemodynamic compromise. Most strokes occur in the first weeks after the infarct, but some risk for stroke remains for an indefinite time. Echocardiographic studies have demonstrated that left ventricular mural thrombosis occurs in up to 40% of patients with anterior wall MI, particularly in association with wall motion abnormalities. Mural thrombosis is uncommon with inferior wall MI. Risk factors for left ventricular mural thrombosis are large infarctions, left ventricular dilation, or congestive heart failure. Atrial fibrillation may occur after AMI as an independent risk factor. The original studies comparing anticoagulant therapy with heparin and warfarin in the treatment of AMI showed, in addition to reduction in mortality and recurrent infarction, a large reduction in risk of stroke.

More recent long-term studies with oral anticoagulants in patients who survived AMI showed a reduction in risk of stroke of 40% to 50% over a 3-year period. The reduction in risk of stroke with oral anticoagulant therapy is greater than that demonstrated with aspirin, the most widely used antithrombotic treatment following AMI. Bleeding events, including intracerebral bleeding, are an uncommon but serious occurrence in patients treated with long-term oral anticoagulants. The rate for intracranial bleeding in long-term studies is approximately 1% per year. Patients identified as being at high risk for systemic embolism are similar to those at risk for left ventricular mural thrombosis. The presence of left ventricular mural thrombosis increases the risk of stroke.

Anticoagulation in the acute phase of MI reduces the risk of left ventricular mural thrombosis. Thrombolysis in combination with aspirin has resulted in a reduction in mortality of 40% to 50%. However, there is an increased risk of intracranial hemorrhage with thrombolysis. Factors that increase that risk are advanced age, hypertension, previous stroke, and use of tissue plasminogen activator (TPA).

There is no evidence that thrombolysis alone affects the risk of left ventricular mural thrombosis. Based on current evidence, anticoagulant therapy with a target international normalized ratio (INR) of 2.5 to 3.5 is recommended in patients at high risk for systemic embolism for 6 months after AMI.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Cairns JA, Lewis HD Jr, Meade TW, Sutton GC, Theroux P. Antithrombotic agents in coronary artery disease. Chest. 1995;108(suppl):380S-400S.
• Cairns JA, Fuster V, Gore J, Kennedy JW. Coronary thrombolysis. Chest. 1995;108(suppl):401S-423S.
• Fibrinolytic Therapy Trialists' (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1,000 patients. Lancet. 1994;343:311-322.

Atrial Fibrillation
Cerebral infarction in a patient with atrial fibrillation is presumed to result from embolization of intracardiac thrombi, which most commonly form in the left atrial appendage. Autopsy data indicate that stroke is a possibility throughout the life of persons with a history of atrial fibrillation. Duration of atrial fibrillation has not correlated with risk, and intermittent atrial fibrillation seems as great a risk as persistent atrial fibrillation.

The results of several prospective randomized stroke prevention trials show that the relative risk of stroke in atrial fibrillation patients can be reduced by up to 70% using oral anticoagulant therapy. The risk of major hemorrhage attributable to anticoagulation therapy was typically between 0.5% and 1.0% per year. The optimal intensity of anticoagulation appears to be an INR of 2.0 to 3.0.

Compared with placebo in prospective randomized trials, aspirin provides a reduction in risk of approximately 20% to 25%. In additional trials, when aspirin was compared directly with oral anticoagulation, it was found to be approximately 50% as effective as warfarin for preventing ischemic stroke. Aspirin is associated with a risk of major bleeding, estimated to be two thirds that of warfarin. Patients with atrial fibrillation associated with previous thromboembolism, hypertension, and congestive heart failure have a stroke risk of approximately 20% per year. In this group, anticoagulation provides an absolute reduction in risk of stroke of approximately 13% per year, even after accounting for the risk of major hemorrhage.

Brief isolated episodes of atrial fibrillation are not uncommon after cardiac surgery; these patients, who have not been shown to be at an increased risk of future stroke, were excluded from the atrial fibrillation–stroke prevention trials. Patients with atrial fibrillation and mechanical heart valves have also been excluded from the randomized trials because it has been an established clinical practice that anticoagulation is required for these persons regardless of age or associated cardiovascular disorders.

In a patient with atrial fibrillation who has acute stroke, recurrent stroke risk may be particularly high during the first week or two after the acute infarction. Immediate anticoagulation of acute cardioembolic infarct carries a risk of hemorrhagic transformation with clinical deterioration. For patients at high risk of recurrent embolism (such as those with mechanical heart valves, established intracardiac thrombus, or atrial fibrillation associated with mitral stenosis or congestive heart failure), early anticoagulation is generally recommended, especially if the acute infarct is not large and the patient does not have uncontrolled hypertension. For patients at relatively low risk for early recurrence, delaying anticoagulation for several days to a week may reduce the risk of early hemorrhagic deterioration, particularly for patients with large infarcts or uncontrolled hypertension.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Laupacis A, Albers G, Dalen J, Dunn M, Feinberg W, Jacobson A. Antithrombotic therapy in atrial fibrillation. Chest. 1995;108(suppl): 352S-359S.
• Albers GW. Atrial fibrillation and stroke: three new studies, three remaining questions. Arch Intern Med. 1994;154:1443-1448.

Valvular Disease
Ischemic stroke is a well known complication of cardiac valvular pathology. Its pathogenesis is generally accepted to be an embolism from the diseased native valve or the prosthetic valve that replaced it.

Native Valves
Of mitral and aortic valve disorders, rheumatic mitral stenosis is the most common associated with thromboembolism, irrespective of the coexistence of mitral regurgitation. Atrial fibrillation increases the risk of thromboembolism up to 18 times. Thrombi associated with mitral stenosis can be found on either the atrial wall or in its appendage. The risk of thromboembolism in rheumatic valve stenosis is related to age and low cardiac output, yet it does not correlate well with left atrial size, mitral calcification, or severity of mitral stenosis. The association of mitral regurgitation with thromboembolism correlates with the coexistence of mitral stenosis.

Oral anticoagulation reduces risk of stroke in patients with rheumatic mitral stenosis, particularly those with coexistent atrial fibrillation. The risk-benefit ratio in those without atrial fibrillation is not known. The benefit of antiplatelet agents in the prevention of stroke in patients with any type of rheumatic valvular disease has not been established. Of those patients who have had one event, early recurrent embolism has been reported in up to two thirds and aggressive anticoagulation instituted.

Mitral Valve Prolapse
Autopsy series have shown that patients with mitral valve prolapse (MVP) have fibrinous deposits on the valve, endothelial denudation, or annular thrombus at the junction with the atrial wall. Myxomatous and redundant valve leaflets seem to be more prone to production of thromboembolic events. Patients with MVP who are asymptomatic are not necessarily candidates for antithrombotic or anticoagulant agents. Those who have suffered ischemic brain events should be given prophylactic medication. Antiplatelet agents are used for MVP; long-term anticoagulation is reserved for patients who do not respond or have significant valvular dysfunction.

Mitral annulus calcification has been associated with mitral stenosis, mitral regurgitation, conduction abnormalities, arrhythmias, and cardiogenic brain embolism. Identification by echocardiography, irrespective of the coexistence of atrial fibrillation, suggests a twofold increase in risk for stroke. Association with embolism of fibrinated cell clot or calcium spicules has been reported.

Despite reports that show the potential for clots to form on the leaflets of aortic valves and the number of systemic emboli found in autopsy series included in this population (approaching 20%), the incidence of clinically evident events is small. Emboli associated with aortic insufficiency are most commonly seen in patients who also have endocarditis, atrial fibrillation, or coexistent mitral pathology.

Prosthetic Heart Valves
Diseased heart valves are replaced with either mechanical or bioprosthetic (tissue) valves. Tissue prosthetic valves are believed to be associated with a smaller risk of thromboembolism than mechanical valves. Mitral valve prostheses are associated with a greater risk of thromboembolism, possibly because of the higher incidence of atrial fibrillation and other thromboembolic risk factors in these patients.

Repaired Cardiac Valves
In general, surgical repair of mitral valves for mitral insufficiency has been reported to be longer lasting and to have lower morbidity and mortality and lower incidence of thromboembolism than valvular replacement. Percutaneous balloon valvuloplasty of the mitral valve continues to be associated with significant risk for embolization, despite systemic administration of heparin and careful selection of patients. Aortic valvuloplasty leads to fewer long-lasting beneficial effects and is currently reserved for patients who are poor candidates for surgery. Despite all precautions, the risk of stroke is approximately 2%.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Levine HJ, Pauker SG, Eckman MH. Antithrombotic therapy in valvular heart disease. Chest. 1995;108(suppl): 360S-370S.
• Stein PD, Alpert JS, Copeland J, Dalen JE, Goldman S, Turpie AGG. Antithrombotic therapy in patients with mechanical and biological prosthetic heart valves. Chest. 1995; 108(suppl):371S-379S.

Patients with mechanical prosthetic valves must receive lifelong anticoagulation with warfarin. The current recommended level of anticoagulation is an INR of 2.5 to 3.5. The addition of antiplatelet agents to this regimen reduces the risk of thromboembolism from prosthetic heart valves. Although it is believed that bioprosthetic valves carry a lesser risk of thromboembolism, at least two studies have failed to confirm lower risk. Anticoagulation is recommended for the first 3 months after valve replacement, after which antiplatelet agents can be used.

Embolism of Aortic Arch Origin
Complicated atherosclerotic plaques of the aortic arch constitute a source of atherothrombolic or cholesterol embolism. Transesophageal echocardiography (TEE) allows detection of plaques in the aortic arch. A causal link between brain infarcts and complicated plaques with highly mobile thrombi in the lumen of the aortic arch is likely. Plaques without mobile components might merely be markers for diffuse atherosclerosis. Recent work has established a statistical link between the presence of atherosclerotic disease in the aortic arch and ischemic stroke. The highest risk of ischemic stroke is associated with plaques >4 mm in the proximal arch—an independent risk factor even when the presence of carotid stenosis and atrial fibrillation are taken into account. Superimposed thrombotic material, as well as actual plaque, may be included within the measurement of the "plaque thickness" made with TEE. The presence of a thrombus may explain the more frequent mobile component in patients with plaques >4 mm in thickness.

The annual risk of recurrent ischemic stroke may be as high as 12% per year in patients with aortic arch plaques >4 mm; risk of stroke, MI, peripheral embolism, and vascular events is 26% per year. TEE is accurate, safe, and well tolerated for examination of the aortic arch, even in patients older than 85 years. Treatment with oral anticoagulants, platelet antiaggregants, and surgery to remove the plaque are all options whose relative superiority has not been determined.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Amarenco P, Duyckaerts C, Tzourio C, Hénin D, Bousser MG, Hauw JJ. The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med. 1992;326:221-225.
• Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med. 1994;331:1474-1479.

Patent Foramen Ovale
The diagnosis of a patent foramen ovale may be suspected in any stroke patient. Detection of a patent foramen ovale and a right-to-left (ie, venous-to-arterial) shunt can be appreciated by TEE (which insonates the atria easily, is preferred over the transthoracic route, and better insonates the ventricular chambers). Transcranial Doppler, using agitated saline injected into a convenient vein (usually the antecubital), may show the emergence of echogenic microbubbles in the brain circulation. It is not known if the stroke rate is dependent on characteristics of the patent foramen ovale, eg, size, spontaneous shunting, and shunting with Valsalva maneuver. A concomitant hypercoagulable state may be important. Whether antiplatelet or anticoagulant agents are most effective in prevention of recurrent stroke is unknown. When the patent foramen ovale is large, surgical closure may be an option. Catheter placement of a prosthetic device to block the foramen is in development.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Homma S, Di Tullio MR, Sacco RL, Mihalatos D, Li Mandri G, Mohr JP. Characteristics of patent foramen ovale associated with cryptogenic stroke: a biplane transesophageal echocardiographic study. Stroke. 1994;25:582-586.

	Cerebral Ischemia Due to Perfusion Failure and Artery-to-Artery Embolism

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Stroke due to perfusion failure occurs with severe stenosis of the carotid and basilar artery, and when there is microstenosis of the small deep arteries, the latter may be a common cause of lacunar infarction. The effects of perfusion failure fall on the most distal territories before the most proximal territories, a process termed "border zone" or "watershed infarction." Collateral flow into the region may retard development of tissue liquefaction, and CT scan may show few low-density changes and only slight contrast enhancement. Greatly reduced brain metabolism has been documented by single-photon emission CT (SPECT), positron emission tomography (PET), and diffusion-weighted MRI.

Large Artery Atherosclerotic Plaque
Pathology studies show that atherosclerotic lesions are not randomly distributed along the cerebral arterial tree. The carotid artery system is mostly affected at the common carotid artery bifurcation, the siphon, and the M1 segment of the middle cerebral artery. Along the vertebrobasilar circulation, the first and fourth segments of the vertebral artery and the first segment of the basilar artery are frequently affected. Factors that lead these lesions to become symptomatic are not well understood, but stenoses >70% are linearly associated with increased risk of distal brain infarct.

Cooperative studies have shown that in symptomatic patients with >70% carotid stenosis, carotid endarterectomy is effective in reducing the risk of subsequent ipsilateral stroke. The accuracy of cerebral angiography in determining the severity of stenosis of extracranial and intracranial lesions has been questioned. There is no consensus regarding a method to measure the degree of stenosis from radiographic films. It is frequently impossible to differentiate between recanalized emboli, thrombi, and actual atherosclerotic plaque at the site of artery occlusion. Angiography is considered the gold standard for assessment of the cerebral vasculature. Magnetic resonance angiography, color duplex, and transcranial Doppler are acceptable noninvasive techniques to screen patients with suspected lesions.

Artery-to-artery embolism is thought to be the most common cause of cerebral infarction associated with plaques of the large cerebral arteries. Watershed infarcts secondary to the hemodynamic compromise may be less common. In situ thrombosis may occur. Embolic infarcts associated with these plaques usually involve the middle and posterior artery territories and vary in size. These lesions tend to involve the cerebral cortex and frequently are wedge-shaped on neuroimaging studies.

Vasculitis
Inflammatory conditions can involve the cerebral vasculature. Some, like granulomatous angiitis, are primarily limited to intracranial arteries and arterioles. Others usually—but not always—present with systemic manifestations by the time the effects of cerebral involvement become clinically evident. Giant cell arteritis, systemic lupus erythematosus, and polyarteritis nodosa are examples of this group. These diseases are etiologically and pathologically heterogeneous. Their causes are poorly understood, and the bedside diagnosis is problematic for lack of an accurate noninvasive test and the relatively nonspecific nature of clinical manifestations. Because of studies reporting favorable results with immunosuppressive therapy, meningeal or cerebral biopsy is indicated in selected patients. The mechanism of stroke varies: necrotizing vasculitis, hypercoagulable state, artery-to-artery or cardiac embolism. An inflammatory infiltration of the arterial wall can be seen in patients with bacterial or tuberculous meningitis, cerebral cysticercosis, fungal infection, and herpes zoster arteritis. Diagnosis and treatment are specific for each instance.

Other Arterial Disease
Reviews of other arterial etiologies for stroke are found elsewhere.

	Selected Reading

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• Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Churchill Livingstone; 1992.
• Caplan LR, Stein RW. Stroke: A Clinical Approach. 2nd ed. Boston, Mass: Butterworth-Heinemann; 1993.

Surgical Management of Large Artery Occlusive Disease
The North American Symptomatic Carotid Endartectomy Trial (NASCET) demonstrated the benefit of surgery for patients with recent stroke or TIA with extracranial internal carotid artery stenosis ranging from 70% to 99%. The beneficial results in stroke prevention were largely dependent on the skill of the surgeons, who attained an acceptably low rate (5.8%) of perioperative stroke and death. In a European study, medical therapy was clearly superior to surgery at <30% stenosis. Results are awaited for the moderate phase of NASCET, for stenosis ranging from 30% to 69%.

The Asymptomatic Carotid Atherosclerosis Study (ACAS) demonstrated a benefit for surgery for stenosis 60% with low rates of perioperative complications. However, this conclusion is not universally accepted by the stroke community. Some believe the rate of complications does not warrant the 1% annual reduction in absolute risk of stroke.

The cooperative trials of carotid endarterectomy have not established whether the complication rates of the surgical arm would be even lower if the diagnostic workup was limited to duplex Doppler and magnetic resonance angiography instead of incurring the risk of conventional angiography. The risks and benefits of carotid angioplasty remain unsettled.

The hesitancy to perform carotid endarterectomy for acute stroke derives from an early study showing that more than 50% of such patients suffered a fatal intracranial hemorrhage within 72 hours of emergency carotid endarterectomy; many such complications at that time could be attributed to unrecognized postoperative hypertension. Angiographically demonstrated intraluminal thrombus is treated with administration of heparin followed by warfarin. In many patients the thrombus resolves without sequelae with medical therapy. Surgery for hyperacute complete carotid occlusion (hours to several days) may re-establish flow, depending on duration of the occlusion. Delayed surgery has had disappointing results.

Many cerebrovascular surgeons empirically recommend a delay of 3 to 6 weeks before performing carotid endarterectomy in patients with fresh but nondebilitating strokes (especially those with CT findings and presumed defective autoregulation); recent studies indicate neurologically stable patients probably have no greater surgical risk in the early poststroke period than patients with TIAs.

In an extensive study conducted a decade ago, external carotid–internal carotid (EC-IC) anastomoses were shown statistically to be no better than medical therapy. Brain resection after infarction is aimed at decompression during the acute period of brain swelling, when patient survival is deemed essential regardless of postoperative clinical syndrome severity. Decompressive surgery for cerebellar infarction can prevent sudden fatal posterior fossa compression syndromes, which are difficult to predict.

	Selected Reading

Top Introduction Diagnosis of Ischemic Stroke... Embolism to the Brain... Selected Reading Selected Reading Selected Reading Selected Reading Selected Reading Cerebral Ischemia Due to... Selected Reading Selected Reading Selected Reading Thrombosis Selected Reading Recommendations

 

• Asymptomatic Carotid Atherosclerosis Study Executive Committee. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421-1428.
• North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445-453.

Small Artery Occlusion
That small, deep cavitary (lacunar) infarcts are mainly due to small arterial occlusions continues to be a fundamental principle in the pathogenesis of small deep infarcts. Neuroimaging and pathology indicate a continuum of cerebral histological alteration due to small artery ischemia ranging from an isolated focal loss of neurons to cavitary infarction with loss of all tissue elements. In between these two extremes, ischemia may cause a variable rarefaction of all tissue elements with demyelination and axonal, neuronal, and oligodendroglial loss associated with astrocytosis. Focal zones of ischemia rarefaction—noncavitary, incomplete, or white matter infarcts—are not true infarcts histologically and may be caused by small arterial narrowing. Large arterial occlusive disease is probably also a cause.

Intrinsic Small Artery Disease
Microatheroma may be the most frequent pathology underlying symptomatic lacunar infarcts. Lipohyalinosis or segmental small arterial disorganization is a known cause of occlusions of very small penetrating arteries (<200 µm) in hypertensive persons and may give rise to small asymptomatic lacunar infarcts. This pathology may also underlie microaneurysms, a likely cause of intracerebral hypertensive hemorrhage. Small penetrating artery occlusion due to fibrinoid necrosis is occasionally seen in hypertensive brains or vasculitides, but the relation to cavitary infarction is unclear. Small artery pathologies are associated with ischemic rarefaction in patients with subcortical arteriosclerotic encephalopathy: hyaline arteriosclerosis seen in elderly normotensive persons, amyloid angiopathy which mainly involves the meningocortical segments of penetrating arteries, and sclerosing vasculopathy. Small granular arteriopathy associated with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy is responsible for both ischemic rarefaction and small, deep cavitary infarcts. This condition is dominantly inherited, and the gene locus has now been mapped to within 2 centimorgans on chromosome 19q123.

Other Causes of Small Vessel Occlusion
Cardiogenic embolism has been established as a potential cause of lacunar infarction. Lacunar infarcts have been found on autopsy in patients with rheumatic heart disease and nonbacterial thrombotic endocarditis. Artery-to-artery embolism is also an established cause of lacunar infarction. Lacunar and small deep infarcts have been reported as complications of aortic arch plaque or coronary angiography and have resulted from cholesterol embolism from an aortic dissection. There may be an association between carotid stenosis and asymptomatic small deep infarcts. A lacunar syndrome may thus be the first indication of a critical large intracranial artery stenosis. Penetrating arteries supplying a lacunar infarct may be stenosed but not occluded, making it likely that these infarcts resulted from hypoperfusion. Small, deep infarcts at the upper lateral borders of the lateral ventricles are in a deep watershed territory, are seen with ipsilateral carotid occlusion, and are called low-flow or internal watershed infarcts. Hypoperfusion caused by narrowing of small white matter, long penetrating arteries is probably the cause of subcortical arteriosclerotic encephalopathy. Hemodynamically significant cardiac disease may interact with stenosis of intracerebral small arteries to increase the risk of hypoperfusion injury. Small, deep infarcts may occasionally be seen in patients with other vasculitides and prothrombotic conditions.

	Selected Reading

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• Pullicino PM, Caplan LR, Hommel M, eds. Cerebral Small Artery Disease. New York, NY: Raven Press; 1993.
• Ducros A, Nagy T, Alamowitch S, Nibbio A, Joutel A, Vahedi K, Chabriat H. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval. Am J Hum Genet. 1996;58:171-181.

	Thrombosis

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Thrombosis may occur in the heart or the vessels and may be the cause of occlusion or embolism.

Prothrombotic States
Primary prothrombotic states include abnormalities of certain hemostatic regulatory proteins, including the antithrombins, heparin cofactor II, proteins C and S, and fibrinolytic system derangements. Genetic defects of the regulatory hemostatic proteins that produce prothrombotic states usually present clinically with thrombotic episodes by the second or third decade of life, whereas acquired deficiencies in these hemostatic proteins may be associated with stroke at any age. Definitive studies of hemostatic disorders of large populations of subjects with stroke are lacking.

In patients with prothrombotic states, other predisposing causes for stroke are not excluded. The plasma levels of antithrombins and proteins C and S may be reduced as a result of consumption in the thrombotic process, and repeat measurement can be obtained after 6 weeks when the acute phase has passed. Most patients with genetic causes of prothrombotic states who have had stroke require long-term anticoagulation with warfarin. For patients with protein C or S deficiency, treatment with heparin at the initiation of warfarin therapy is required to reduce the risk of necrotizing thrombosis of the skin.

Antiphospholipid antibodies (aPL) are associated with a syndrome of thrombosis, thrombocytopenia, fetal loss, and a variety of neurological manifestations but appear to be especially important with respect to recurrent cerebrovascular disease. aPL can be demonstrated indirectly by prolongation of phospholipid-dependent coagulation assays using platelet-poor plasma (lupus anticoagulant [LA] effect) or directly using an enzyme-linked immunosorbent assay (ELISA). There is an incomplete overlap for detection of aPL by these methods in an individual patient. Clinical aPL-related manifestations are considered primary if the patient does not have a diagnosis of systemic lupus erythematosus and secondary if systemic lupus erythematosus is present.

Antiphospholipid antibodies are an extremely heterogeneous group of antibodies directed against a variety of antigenic determinants: platelets, coagulation proteins, and endothelial cells. Cerebral ischemia associated with aPL is the most common arterial manifestation; however, the importance of aPL as a cardiovascular risk factor is controversial. In many studies aPL is associated with an increased risk for incidence and recurrence of cerebral ischemia, MI, and venous thrombosis. Intracardiac thrombus has been reported. Regardless of age, patients with cerebral ischemia often have other risk factors for cerebrovascular disease. aPL may act in concert with other vascular risk factors that damage endothelial cells. A variety of cardiac valvular lesions have been associated with aPL, and cardiac emboli are a possible cause of cerebrovascular symptoms. Any attempt to propose a standard form of treatment for aPL-associated thrombosis is premature at this time.

	Selected Reading

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• Bick RL, Pegram M. Syndromes of hypercoagulability and thrombosis: a review. Semin Thromb Hemost. 1994;20:109-132.
• Levine SR, Brey RL, Sawaya KL, Salowich-Palm L, Kokkinos J, Kostrzema B, Perry M, Havstad S, Carey J. Recurrent stroke and thrombo-occlusive events in the antiphospholipid syndrome. Ann Neurol. 1995;38:119-124.

Stroke due to intracranial parenchymatous hemorrhages is not discussed.

	Recommendations

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Patients with MI at high risk for systemic embolization should receive oral anticoagulation at a target INR range of 2.5 to 3.5 for 6 months or more.

Patients with cardiac valvular disorders, prosthetic heart valves, and repaired valves have a variable risk of ischemic stroke. Their need for antiplatelet or anticoagulant therapy should be evaluated.

In the absence of a mobile thrombus, the presence of aortic arch plaque >4 mm should be viewed as a marker of high risk of recurrent stroke, MI, peripheral embolism, and vascular death. The natural history of mobile aortic arch plaques, development of new noninvasive techniques to define plaque composition, and initiation of therapeutic trials may be topics for research in the future.

When faced with lacunar infarction or syndrome, the possibility of underlying large-vessel, especially intracranial, cardiac source embolism and hypercoagulable state should be considered as should small-vessel disease.

Carotid endarterectomy is beneficial for patients with recent cerebral ischemia and ipsilateral (nonocclusive) carotid artery stenosis of >70%. It is not beneficial for patients with 0% to 29% stenosis, and it remains uncertain if endarterectomy is beneficial for stenosis of 30% to 69%.

Much work is needed to define the spectrum and role of hypercoagulable states, including that of aPL, in stroke.

The etiology (hemorrhage, ischemia versus non–stroke-related potential causes) of transient cerebral symptoms should be diagnosed in every patient who experiences them. For those for whom the cause is likely to be ischemic and who do not require warfarin, the best dose of aspirin for stroke prophylaxis is debated. Ticlopidine is more effective than aspirin, but the cost and risk of adverse effects are higher.

	Footnotes

 
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