Offi cial reprint reprint from UpToDate UpToDate® www.uptodate.com ©2015 UpToDate® www.uptodate.com
Etiology, classification, and epidemiology of stroke Author Louis R Caplan, MD
Section Editor Scott E Kasner, MD
Deputy Editor John F Dashe, MD, PhD
All topics topics are are upda updated ted as new new evidence evidence becomes becomes availab available le and our peer review process process is complete. Literature review current through: Oct 2015. | This topic last updated: Nov 26, 2014. INTRODUCTION INTRODUCTION — The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite conditions: hemorrhage is characterized by too much blood within the closed cranial cavity, while ischemia is characterized by too little blood to supply an adequate amount of oxygen and nutrients to a part of the brain [ 1]. Each of these categories categories can be divided into subtypes that have somewhat different different causes, clinical pictures, clinical courses, outcomes, and treatment strategies. As an example, intracranial hemorrhage can be caused by intracerebral hemorrhage (ICH, also called parenchymal hemorrhage), which involves bleeding directly into brain tissue, and subarachnoid hemorrhage (SAH), which involves bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord [1 [ 1]. This topic will review the classification of stroke. The clinical diagnosis of stroke subtypes and an overview of stroke evaluation are discussed separately. (See "Clinical diagnosis of stroke subtypes" subtypes" and "Overview of the evaluation of stroke".) stroke" .) DEFINITIONS DEFINITIONS — Stroke is classified into two major types: ● Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion ● Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH) A stroke is the acute neurologi neurologic c injury that that occurs as a r esult of one of these pathologic processes. Approximately 80 percent of strokes are due to ischemic cerebral infarction and 20 percent to brain hemorrhage. An infarcted brain brain is pale pale initially. Within hour hours s to days, days, the gray matter becomes congested with engorged, dilated blood vessels and minute petechial hemorrhages. When an embolus blocking a major vessel migrates, lyses, or disperses within minutes to days, recirculation into the infarcted area can cause a hemorrhagic infarction and may aggravate edema formation due to disruption of the bloodbrain barrier. A primar primary y ICH damag damages es the brain brain directly directly at the site s ite of the
hemorrhage by compressing the surrounding tissue. Physicians must initially consider whether the patient with suspected cerebrovascular disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage. The great majority of ischemic strokes are caused by a diminished supply of arterial blood, which carries sugar and oxygen to brain tissue. Another cause of stroke that is difficult to classify is stroke due to occlusion of veins that drain the brain of blood. Venous occlusion causes a back-up of fluid resulting in brain edema, and in addition it may cause both brain ischemia and hemorrhage into the brain. BRAIN ISCHEMIA ISCHEMIA — There are three main subtypes of brain ischemia [2 [ 2]: ● Thrombosis (see 'Thrombosis' 'Thrombosis' below) generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. ● Embolism (see 'Embolism' 'Embolism' below) below) refers to particles of debris originating elsewhere that block arterial access to a particular brain region [ 3]. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. ● Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Blood disorders (see 'Blood disorders' disorders' below) are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. Transient ischemic attack (TIA) is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. The definition is changing with recognition that transient neurologic symptoms are frequently associated with permanent brain tissue injury. The definition of TIA is discussed in more detail separately. (See "Definition of transient ischemic attack".) attack" .) Thrombosis — Thrombosis — Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to-artery embolism). Thrombotic strokes can be divided into either large or small vessel disease (table (table 1). 1). These two subtypes of thrombosis
hemorrhage by compressing the surrounding tissue. Physicians must initially consider whether the patient with suspected cerebrovascular disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage. The great majority of ischemic strokes are caused by a diminished supply of arterial blood, which carries sugar and oxygen to brain tissue. Another cause of stroke that is difficult to classify is stroke due to occlusion of veins that drain the brain of blood. Venous occlusion causes a back-up of fluid resulting in brain edema, and in addition it may cause both brain ischemia and hemorrhage into the brain. BRAIN ISCHEMIA ISCHEMIA — There are three main subtypes of brain ischemia [2 [ 2]: ● Thrombosis (see 'Thrombosis' 'Thrombosis' below) generally refers to local in situ obstruction of an artery. The obstruction may be due to disease of the arterial wall, such as arteriosclerosis, dissection, or fibromuscular dysplasia; there may or may not be superimposed thrombosis. ● Embolism (see 'Embolism' 'Embolism' below) below) refers to particles of debris originating elsewhere that block arterial access to a particular brain region [ 3]. Since the process is not local (as with thrombosis), local therapy only temporarily solves the problem; further events may occur if the source of embolism is not identified and treated. ● Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory problem, manifesting itself in the brain and perhaps other organs. Blood disorders (see 'Blood disorders' disorders' below) are an uncommon primary cause of stroke. However, increased blood coagulability can result in thrombus formation and subsequent cerebral embolism in the presence of an endothelial lesion located in the heart, aorta, or large arteries that supply the brain. Transient ischemic attack (TIA) is defined clinically by the temporary nature of the associated neurologic symptoms, which last less than 24 hours by the classic definition. The definition is changing with recognition that transient neurologic symptoms are frequently associated with permanent brain tissue injury. The definition of TIA is discussed in more detail separately. (See "Definition of transient ischemic attack".) attack" .) Thrombosis — Thrombosis — Thrombotic strokes are those in which the pathologic process giving rise to thrombus formation in an artery produces a stroke either by reduced blood flow distally (low flow) or by an embolic fragment that breaks off and travels to a more distant vessel (artery-to-artery embolism). Thrombotic strokes can be divided into either large or small vessel disease (table (table 1). 1). These two subtypes of thrombosis
are worth distinguishing since the causes, outcomes, and treatments are different. Large vessel disease disease — Large vessels include both the extracranial (common and internal carotids, vertebral) and intracranial arterial system (Circle of Willis and proximal branches) (figure (figure 1 1 and figure 2). 2). Intrinsic lesions in large extracranial and intracranial arteries cause symptoms by reducing blood flow beyond obstructive lesions, and by serving as the source of intra-arterial emboli. At times a combina combination tion of mechan mechanisms isms is oper operan ant. t. Severe Severe stenosis promotes the formation of thrombi which can break off and embolize, and the reduced blood flow caused by the vascular obstruction makes the circulation less competent at washing out and clearing these emboli. Pathologies affecting large extracranial vessels include: ● Athero Atherosclero sclerosis sis ● Dissection ● Takayasu arteritis ● Giant cell arteritis ● Fibromuscular dysplasia Pathologies affecting large intracranial vessels include: ● Athero Atherosclero sclerosis sis ● Dissection ● Arteritis/v Arteritis/vasculitis asculitis ● Noninflammatory vasculopathy ● Moyamoya syndrome ● Vasoconstriction Athero Atherosclero sclerosis sis is by far the t he most common common cause of in situ local disease within the large extracranial and intracranial arteries that supply the brain. White platelet-fibrin and red erythrocyte-fibrin thrombi are often superimposed upon the atherosclerotic lesions, or they may develop without severe vascular disease in patients with hypercoagulable states. Vasoconstriction (eg, with migraine) is probably the next most common, followed in frequency by arterial dissection (a disorder much more common than previously recognized) and traumatic occlusion. Fibromuscular dysplasia is an uncommon arteriopathy, while arteritis is frequently mentioned in the differential diagnosis, but it is an extremely rare cause of thrombotic stroke. Aortic Aortic disease disease is really really a form of proxima proximall extracran extracranial ial large large vessel disease, but it is often considered together with cardioembolic sources because of anatomic proximity. (See 'Aortic atherosclerosis' atherosclerosis' below.) Identification of the specific focal vascular lesion, including its nature, severity, and localization, is important for treatment since local therapy may be effective (eg, surgery, angioplasty, intraarterial thrombolysis). It should be possible
clinically in most patients to determine whether the local vascular disease is within the anterior (carotid) or posterior (vertebrobasilar) circulation and whether the disorder affects large or penetrating arteries. (See "Clinical diagnosis of stroke subtypes", section on 'Neurologic examination' .) Delivery of adequate blood through a blocked or partially blocked artery depends upon many factors, including blood pressure, blood viscosity, and collateral flow. Local vascular lesions also may throw off emboli, which can cause transient symptoms. In patients with thrombosis, the neurologic symptoms often fluctuate, remit, or progress in a stuttering fashion (figure 3). (See "Clinical diagnosis of stroke subtypes", section on 'Clinical course' and "Etiology and clinical manifestations of transient ischemic attack", section on 'Clinical manifestations' .) Small vessel disease — Small vessel disease affects the intracerebral arterial system, specifically penetrating arteries that arise from the distal vertebral artery, the basilar artery, the middle cerebral artery stem, and the arteries of the circle of Willis. These arteries thrombose due to: ● Lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension) and fibrinoid degeneration ● Atheroma formation at their origin or in the parent large artery The most common cause of obstruction of the smaller arteries and arterioles that penetrate at right angles to supply the deeper structures within the brain (eg, basal ganglia, internal capsule, thalamus, pons) is lipohyalinosis (ie, blockage of an artery by medial hypertrophy and lipid admixed with fibrinoid material in the hypertrophied arterial wall). A stroke due to obstruction of these vessels is referred to as a lacunar stroke. (See "Lacunar infarcts".) Lipohyalinosis is most often related to hypertension, but aging may play a role. Microatheromas can also block these small penetrating arteries, as can plaques within the larger arteries that block or extend into the orifices of the branches (called atheromatous branch disease) [ 1]. Penetrating artery occlusions usually cause symptoms that develop during a short period of time, hours or at most a few days (figure 4), compared with large artery-related brain ischemia, which can evolve over a longer period. Embolism — Embolic strokes are divided into four categories (table 1). ● Those with a known source that is cardiac ● Those with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findings
● Those with an arterial source (artery to artery embolism) ● Those with a truly unknown source in which tests for embolic sources are negative The symptoms depend upon the region of brain rendered ischemic [4,5]. The embolus suddenly blocks the recipient site so that the onset of symptoms is abrupt and usually maximal at the start (figure 5). Unlike thrombosis, multiple sites within different vascular territories may be affected when the source is the heart (eg, left atrial appendage or left ventricular thrombus) or aorta. Treatment will depend upon the source and composition of the embolus. (See "Secondary prevention for specific causes of ischemic stroke and transient ischemic attack".) Cardioembolic strokes usually occur abruptly, although they occasionally present with stuttering, fluctuating symptoms. The symptoms may clear entirely since emboli can migrate and lyse, particularly those composed of thrombus. When this occurs, infarction generally also occurs but is silent; the area of infarction is smaller than the area of ischemia that gave rise to the symptoms. This process is often referred to as a TIA due to embolism, although it is more correctly termed an embolic infarction or stroke in which the symptoms clear within 24 hours. Cardioembolic strokes can be divided into those with a known source and those with a possible cardiac or ascending aortic source based upon transthoracic and/or transesophageal echocardiographic findings [ 3]. High-risk cardiac source — The diagnosis of embolic strokes with a known cardiac source is generally agreed upon by physicians (table 2) [6,7]; included in this category are those due to: ● Atrial fibrillation and paroxysmal atrial fibrillation ● Rheumatic mitral or aortic valve disease ● Bioprosthetic and mechanical heart valves ● Atrial or ventricular thrombus ● Sick sinus syndrome ● Sustained atrial flutter ● Recent myocardial infarction (within one month) ● Chronic myocardial infarction together with ejection fraction <28 percent ● Symptomatic congestive heart failure with ejection fraction <30 percent ● Dilated cardiomyopathy ● Fibrous nonbacterial endocarditis as found in patients with systemic lupus (ie, Libman-Sacks endocarditis), antiphospholipid syndrome, and cancer (marantic endocarditis) ● Infective endocarditis
● Papillary fibroelastoma ● Left atrial myxoma ● Coronary artery bypass graft (CABG) surgery With CABG, for example, the incidence of postoperative neurologic sequelae is approximately 2 to 6 percent, most of which is due to stroke [8]. Atheroemboli associated with ascending aortic atherosclerosis is probably the most common cause. (See "Neurologic complications of cardiac surgery".) Potential cardiac source — Embolic strokes considered to have a potential cardiac source ( table 2) are ones in which a possible source is detected (usually) by echocardiographic methods [6,7], including: ● Mitral annular calcification ● Patent foramen ovale ● Atrial septal aneurysm ● Atrial septal aneurysm with patent foramen ovale ● Left ventricular aneurysm without thrombus ● Isolated left atrial smoke on echocardiography (no mitral stenosis or atrial fibrillation) ● Complex atheroma in the ascending aorta or proximal arch (see 'Aortic atherosclerosis' below) In this group, the association of the cardiac or aortic lesion and the rate of embolism is often uncertain, since some of these lesions do not have a high frequency of embolism and are often incidental findings unrelated to the stroke event [ 9]. Thus, they are considered potential sources of embolism. A truly unknown source represents embolic strokes in which no clinical evidence of heart disease is present (table 1). Aortic atherosclerosis — In longitudinal population studies with nonselected patients, complex aortic atherosclerosis does not appear to be associated with any increased primary ischemic stroke risk [10-12]. However, most studies evaluating secondary stroke risk have found that complex aortic atherosclerosis is a risk factor for recurrent stroke [13-16]. The range of findings is illustrated by the following studies: ● A prospective case-control study examined the frequency and thickness of atherosclerotic plaques in the ascending aorta and proximal arch in 250 patients admitted to the hospital with ischemic stroke and 250 consecutive controls, all over the age of 60 years [ 14]. Atherosclerotic plaques ≥4 mm in thickness were found in 14 percent of patients compared with 2 percent of controls, and the odds ratio for ischemic stroke among patients with such plaques was 9.1 after adjustment for atherosclerotic risk factors. In addition, aortic atherosclerotic plaques ≥4 mm were much more common in patients with brain infarcts of unknown
cause (relative risk 4.7). ● In contrast, a population-based study of 1135 subjects who had transesophageal echocardiography (TEE) found that complex atherosclerotic plaque (>4 mm with or without mobile debris) in the ascending and transverse aortic arch was not a significant risk factor for cryptogenic ischemic stroke or TIA after adjusting for age, gender, and other clinical risk factors [ 11]. However, there was an association between complex aortic plaque and noncryptogenic stroke. The investigators concluded that complex aortic arch debris is a marker for the presence of generalized atherosclerosis. Methodologic differences are a potential explanation for the discrepant results of these reports assessing the risk of ischemic stroke related to aortic atherosclerosis, as the earlier case-control studies may have been skewed by selection and referral bias. However, many patients with aortic atherosclerosis also have cardiac or large artery lesions, a problem that may confound purely epidemiologic studies. In the author's opinion, there is no question that large protruding plaques in the ascending aorta and arch, particularly mobile plaques, are an important cause of stroke [17]. Systemic hypoperfusion — Reduced blood flow is more global in patients with systemic hypoperfusion and does not affect isolated regions. The reduced perfusion can be due to cardiac pump failure caused by cardiac arrest or arrhythmia, or to reduced cardiac output related to acute myocardial ischemia, pulmonary embolism, pericardial effusion, or bleeding. Hypoxemia may further reduce the amount of oxygen carried to the brain. Symptoms of brain dysfunction typically are diffuse and nonfocal in contrast to the other two categories of ischemia. Most affected patients have other evidence of circulatory compromise and hypotension such as pallor, sweating, tachycardia or severe bradycardia, and low blood pressure. The neurologic signs are typically bilateral, although they may be asymmetric when there is preexisting asymmetrical craniocerebral vascular occlusive disease. The most severe ischemia may occur in border zone (watershed) regions between the major cerebral supply arteries since these areas are most vulnerable to systemic hypoperfusion. The signs that may occur with borderzone infarction include cortical blindness, or at least bilateral visual loss; stupor; and weakness of the shoulders and thighs with sparing of the face, hands, and feet (a pattern likened to a "man-in-a-barrel"). Blood disorders — Blood and coagulation disorders are an
uncommon primary cause of stroke and TIA, but they should be considered in patients younger than age 45, patients with a history of clotting dysfunction, and in patients with a history of cryptogenic stroke [9]. The blood disorders associated with arterial cerebral infarction include: ● Sickle cell anemia ● Polycythemia vera ● Essential thrombocytosis ● Heparin induced thrombocytopenia ● Protein C or S deficiency, acquired or congenital ● Prothrombin gene mutation ● Factor V Leiden (resistance to activated protein C) ● Antithrombin III deficiency ● Antiphospholipid syndrome ● Hyperhomocysteinemia Factor V Leiden mutation and prothrombin 20210 mutations are associated mostly with venous rather than arterial thrombosis. They can result in cerebral venous thrombosis or deep venous thrombosis with paradoxical emboli. (See "Etiology, clinical features, and diagnosis of cerebral venous thrombosis".) Infectious and inflammatory disease such as pneumonia, urinary tract infections, Crohn's disease, ulcerative colitis, HIV/AIDS, and cancers result in a rise in acute phase reactants such as fibrinogen, C-reactive protein, and coagulation factors VII and VIII. In the presence of an endothelial cardiac or vascular lesion, this increase can promote active thrombosis and embolism. TOAST classification — The TOAST classification scheme for ischemic stroke is widely used and has good interobserver agreement [18]. The TOAST system (table 3) attempts to classify ischemic strokes according to the major pathophysiologic mechanisms that are recognized as the cause of most ischemic strokes (table 1). It assigns ischemic strokes to five subtypes based upon clinical features and the results of ancillary studies including brain imaging, neurovascular evaluations, cardiac tests, and laboratory evaluations for a prothrombotic state. The five TOAST subtypes of ischemic stroke are: ● Large artery atherosclerosis ● Cardioembolism ● Small vessel occlusion ● Stroke of other determined etiology ● Stroke of undetermined etiology The last subtype, stroke of undetermined etiology, involves cases where the cause of a stroke cannot be determined with any degree of confidence, and by definition includes those with two or more potential causes identified, those with a negative evaluation, and those with an incomplete
evaluation. (See "Cryptogenic stroke".) SSS-TOAST and CCS classification — Since the original TOAST classification scheme was developed in the early 1990s, advances in stroke evaluation and diagnostic imaging have allowed more frequent identification of potential vascular and cardiac causes of stroke [ 6]. These advances could cause an increasing proportion of ischemic strokes to be classified as "undetermined" if the strict definition of this category (cases with two or more potential causes) is applied. As a result, an evidenced-based modification of the TOAST criteria called SSS-TOAST was developed [ 6]. The SSSTOAST system divides each of the original TOAST subtypes into three subcategories as "evident," "probable," or "possible" based upon the weight of diagnostic evidence as determined by predefined clinical and imaging criteria. In a further refinement, an automated version of the SSS-TOAST called the Causative Classification System (CCS) was devised (table 4) to improve its usefulness and accuracy for stroke subtyping [19]. The CCS is a computerized algorithm that consists of questionnaire-style classification scheme. The CCS appears to have good inter-rater reliability among multiple centers [20]. It is available online at https://ccs.mgh.harvard.edu/ccs_title.php . The overall agreement between the original TOAST and CCS classification systems appears to be moderate at best, suggesting that two methods often classify stroke cases into different categories despite having categories with similar names [21]. BRAIN HEMORRHAGE — There are two main subtypes of brain hemorrhage [2]: ● Intracerebral hemorrhage (ICH) refers to bleeding directly into the brain parenchyma ● Subarachnoid hemorrhage (SAH) refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain Intracerebral hemorrhage — Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is directly into the brain, forming a localized hematoma that spreads along white matter pathways. Accumulation of blood occurs over minutes or hours; the hematoma gradually enlarges by adding blood at its periphery like a snowball rolling downhill. The hematoma continues to grow until the pressure surrounding it increases enough to limit its spread or until the hemorrhage decompresses itself by emptying into the ventricular system or into the cerebrospinal fluid (CSF) on the pial surface of the brain [ 22,23]. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use
(mostly amphetamines and cocaine), and vascular malformations [22,23]. (See "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and diagnosis" .) Less frequent causes include bleeding into tumors, aneurysmal rupture, and vasculitis. The earliest symptoms of ICH relate to dysfunction of the portion of the brain that contains the hemorrhage [ 22,23]. As examples: ● Bleeding into the right putamen and internal capsule region causes left limb motor and/or sensory signs ● Bleeding into the cerebellum causes difficulty walking ● Bleeding into the left temporal lobe presents as aphasia The neurologic symptoms usually increase gradually over minutes or a few hours. In contrast to brain embolism and SAH, the neurologic symptoms related to ICH may not begin abruptly and are not maximal at onset (figure 6) (and see below). Headache, vomiting, and a decreased level of consciousness develop if the hematoma becomes large enough to increase intracranial pressure or cause shifts in intracranial contents (figure 7) [22,23]. These symptoms are absent with small hemorrhages; the clinical presentation in this setting is that of a gradually progressing stroke. ICH destroys brain tissue as it enlarges. The pressure created by blood and surrounding brain edema is lifethreatening; large hematomas have a high mortality and morbidity. The goal of treatment is to contain and limit the bleeding. Recurrences are unusual if the causative disorder is controlled (eg, hypertension or bleeding diathesis). Subarachnoid hemorrhage — The two major causes of SAH are rupture of arterial aneurysms that lie at the base of the brain and bleeding from vascular malformations that lie near the pial surface. Bleeding diatheses, trauma, amyloid angiopathy, and illicit drug use are less common. (See "Clinical manifestations and diagnosis of aneurysmal subarachnoid hemorrhage".) Rupture of an aneurysm releases blood directly into the CSF under arterial pressure. The blood spreads quickly within the CSF, rapidly increasing intracranial pressure. Death or deep coma ensues if the bleeding continues. The bleeding usually lasts only a few seconds but rebleeding is very common. With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may continue over a longer period of time. Symptoms of SAH begin abruptly in contrast to the more gradual onset of ICH. The sudden increase in pressure causes a cessation of activity (eg, loss of memory or focus or knees buckling). Headache is an invariable symptom and is typically instantly severe and widespread; the pain may
radiate into the neck or even down the back into the legs. Vomiting occurs soon after onset. There are usually no important focal neurologic signs unless bleeding occurs into the brain and CSF at the same time (meningocerebral hemorrhage). Onset headache is more common than in ICH, and the combination of onset headache and vomiting is infrequent in ischemic stroke (figure 7) [24]. (See "Clinical manifestations and diagnosis of aneurysmal subarachnoid hemorrhage".) Approximately 30 percent of patients have a minor hemorrhage manifested only by sudden and severe headache (the so-called sentinel headache) that precedes a major SAH (figure 7) [24]. The complaint of the sudden onset of severe headache is sufficiently characteristic that a minor SAH should always be considered. In a prospective study of 148 patients presenting with sudden and severe headache, for example, subarachnoid hemorrhage was present in 25 percent overall and 12 percent in patients in whom headache was the only symptom [25]. The goal of treatment of SAH is to identify the cause and quickly treat it to prevent rebleeding. The other goal of treatment is to prevent brain damage due to delayed ischemia related to vasoconstriction of intracranial arteries; blood within the CSF induces vasoconstriction, which can be intense and severe. The treatment of SAH is discussed separately. (See "Treatment of aneurysmal subarachnoid hemorrhage".) EPIDEMIOLOGY — Globally, the incidence of stroke due to ischemia is 68 percent, while the incidence of hemorrhagic stroke (intracerebral hemorrhage and subarachnoid hemorrhage combined) is 32 percent, reflecting a higher incidence of hemorrhagic stroke in low- and middle-income countries [26]. In the United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively [27]. Worldwide, stroke is the second most common cause of mortality and the third most common cause of disability [ 28]. While the incidence of stroke is decreasing in high-income countries, including the United States [ 29], the incidence is increasing in low-income countries [30]. The overall rate of stroke-related mortality is decreasing in high and low income countries, but the absolute number of people with stroke, stroke survivors, stroke-related deaths, and the global burden of stroke-related disability is high and increasing [ 30]. In the United States, the annual incidence of new or recurrent stroke is about 795,000, of which about 610,000 are first-ever strokes, and 185,000 are recurrent strokes [ 27]. There is a higher regional incidence and prevalence of stroke and a higher stroke mortality rate in the southeastern United States (sometimes referred to as the "stroke belt") than in
the rest of the country [31-35]. Men have a higher incidence of stroke than women at younger but not older ages, with the incidence reversed and higher for women by age 75 years and older [ 27]. Blacks and Hispanics have an increased risk of stroke compared with whites in the United States, as illustrated by the following observations: ● The Northern Manhattan Study reported that the ageadjusted incidence of first ischemic stroke among whites, Hispanics, and blacks was 88, 149, and 191 per 100,000 respectively [36]. Among blacks compared with whites, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.85, 3.18, 3.09, and 1.58 respectively. Among Hispanics compared with whites, the relative rate of stroke attributed to intracranial atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.00, 1.71, 2.32, and 1.42. ● The Greater Cincinnati/Northern Kentucky Stroke Study showed that small vessel strokes and strokes of undetermined origin were nearly twice as common, and large vessel strokes were 40 percent more common, among blacks compared with whites [ 37]. The incidence of cardioembolic strokes was not significantly different among blacks and whites. ● An increased incidence of stroke has also been found among Mexican Americans compared with nonHispanic whites [38]. ● Stroke prevalence rates (age 18 and older) for blacks, whites, Asians, and American Indian/Alaska natives are 3.8, 3.0, 1.9, and 5.8 percent, respectively [ 27]. INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want indepth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.) ● Basics topics (see "Patient information: Hemorrhagic stroke (The Basics)" and "Patient information: Stroke (The Basics)") ● Beyond the Basics topics (see "Patient information: Stroke symptoms and diagnosis (Beyond the Basics)" ) Use of UpToDate is subject to the Subscription and License Agreement. Topic 1089 Version 17.0
GRAPHICS
Pathophysiologic ischemic stroke classification Large vessel atherothrombotic stroke More common Bifurcation of the common carotid artery Siphon portion of the common carotid artery Middle cerebral artery stem Intracranial vertebral arteries proximal to middle basilar artery Origin of the vertebral arteries Less common Origin of the common carotid artery Posterior cerebral artery stem Origin of the major branches of the basilarvertebral arteries Origin of the branches of the anterior, middle, and posterior cerebral arteries
Small vessel (lacunar) stroke Mechanism Lipohyalinotic occlusion Less frequently proximal atherothrombotic occlusion Least likely embolic occlusion Most common locations Penetrating branches of the anterior, middle, and posterior cerebral and basilar arteries
Cardioaortic embolic stroke Cardiac sources definite antithrombotic therapy generally used Left atrial thrombus Left ventricular thrombus Atrial fibrillation and paroxysmal atrial fibrillation Sustained atrial flutter Recent myocardial infarction (within one month) Rheumatic mitral or aortic valve disease
Bioprosthetic and mechanical heart valve Chronic myocardial infarction with ejection fraction <28 percent Symptomatic heart failure with ejection fraction <30 percent Dilated cardiomyopathy Cardiac sources definite anticoagulation hazardous Bacterial endocarditis (exception nonbacterial) Atrial myxoma Cardiac sources possible Mitral annular calcification Patent foramen ovale Atrial septal aneurysm Atrial septal aneurysm with patent foramen ovale Left ventricular aneurysm without thrombus Isolated left atrial smoke (no mitral stenosis or atrial fibrillation) Mitral valve strands Ascending aortic atheromatous disease (>4 mm) True unknown source embolic stroke
Other Dissection Moyamoya Binswanger's disease Primary thrombosis Cerebral mass Graphic 55099 Version 3.0
Anatomy of the cerebral arterial circul
Frontal view of the carotid arteries, vertebral arterie communication with each other via the Circle of Willi Reproduced with permission from: Uflacker R. Atlas Of Vas Approach, Second Edition. Philadelphia: Lippincott Williams Lippincott Williams & Wilkins. Graphic 51410 Version 5.0
Major cerebral vascular territories
Representation of the territories of the major cerebra a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebro Harrison's Principles of Internal Medicine, 13th ed, McGraw Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0
Stuttering time course of thrombotic s
The course of weakness of the right limb in a patient thrombotic stroke reveals fluctuating symptoms, var normal and abnormal, progressing in a stepwise or s with some periods of improvement. Graphic 64107 Version 2.0
Time course of lacunar infarction
Penetrating artery occlusions usually c ause symptom over a short period of time, hours or at most a few d large artery-related brain ischemia which can evolve period. A stuttering course may ensue, as with large thrombosis. This patient had a pure motor hemipares Graphic 52246 Version 1.0
Time course of embolic stroke
Embolic stroke occurs suddenly, with symptoms max This patient had multiple embolic events with diff ere symptoms (initially weakness, followed by paresthes Graphic 73261 Version 1.0
Cardioaortic sources of cerebral embolism Sources with
Sources with low or
high primary
uncertain primary
risk for ischemic
risk for ischemic stroke
stroke Left atrial
Cardiac sources of embolism
thrombus
Mitral annular
Left ventricular
calcification
thrombus
Patent foramen ovale
Atrial fibrillation
Atrial septal aneurysm
Paroxysmal
Atrial septal aneurysm
atrial fibrillation
and patent foramen
Sick sinus
ovale
syndrome
Left ventricular
Atrial flutter
aneurysm without
Recent
thrombus
myocardial
Left atrial smoke
infarction
Congestive heart failure
(within one
with ejection fraction
month prior to
<30 percent
stroke)
Apical akinesia
Mitral stenosis or rheumatic valve disease
Wall motion abnormalities (hypokinesia, akinesia,
Bioprosthetic
dyskinesia) other than
and mechanical
apical akinesia
heart valves Hypertrophic Chronic
cardiomyopathy
myocardial infarction together with
Left ventricular hypertrophy
low ejection
Left ventricular
fraction (<28
hypertrabeculation/non-
percent)
compaction
Dilated
Aortic sources of
cardiomyopathy
embolism
(prior established diagnosis or left ventricular dilatation with an ejection fraction of <40 percent or
Complex atheroma in the ascending aorta or proximal arch (protruding with >4 mm thickness, or mobile debris, or plaque ulceration)
fractional shortening of <25 percent) Nonbacterial thrombotic endocarditis Infective endocarditis Papillary fibroelastoma Left atrial myxoma
The high and low risk cardioaortic sources in this table are separated using an arbitrary 2 percent annual or one-time primary stroke risk threshold. Data from: 1. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. 2. Ay H, Furie KL, Singhal A, et al. An evidencebased causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. 3. Arsava EM, Ballabio E, Benner T, et al. The Causative Classification of Stroke system: an international reliability and optimization study. Neurology 2010; 75:1277. Reproduced and modified with permission from: Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification system for acute ischemic stroke. Ann Neurol 2005; 58:688. Copyright © 2005 American Neurological Association. Graphic 60843 Version 8.0
TOAST classification of subtypes of acute ischemic stroke Large-artery atherosclerosis Cardioembolism Small-vessel occlusion Stroke of other determined etiology Stroke of undetermined etiology Two or more causes identified Negative evaluation Incomplete evaluation
Graphic 62571 Version 1.0
Causative Classification System (CCS) of ischemic stroke etiology Stroke
Level of
mechanism
confidence
Large artery
Evident
atherosclerosis
Criteria
1. Either occlusive or stenotic (≥50 percent diameter reduction or <50 percent diameter reduction with plaque ulceration or thrombosis) vascular disease judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries 2. The absence of acute infarction in vascular territories other than the stenotic or occluded artery
Probable
1. History of ≥1 transient monocular blindness (TMB), TIA, or stroke from the territory of index artery affected by atherosclerosis within the last month 2. Evidence of near-occlusive stenosis or nonchronic
complete occlusion judged to be caused by atherosclerosis in the clinically relevant extracranial or intracranial arteries (except for the vertebral arteries) 3. The presence of ipsilateral and unilateral internal watershed infarctions or multiple, temporally separate, infarctions exclusively within the territory of the affected artery Possible
1. Th e presen ce of an atherosclerotic plaque protruding into the lumen and causing mild stenosis (<50 percent) in the absence of any detectable plaque ulceration or thrombosis in a clinically relevant extracranial or intracranial artery and history of ≥2 TMB, TIA, or stroke from the territory of index artery affected by atherosclerosis,
at least 1 event within the last month 2. Evidence for evident large artery atherosclerosis in the absence of complete diagnostic investigation for other mechanisms Cardio-aortic
Evident
embolism
1. The presence of a high-risk cardiac source of cerebral embolism
Probable
1. Evidence of systemic embolism 2. The presence of multiple acute infarctions that have occurred closely related in time within both right and left anterior or both anterior and posterior circulations in the absence of occlusion or near-occlusive stenosis of all relevant vessels. Other diseases that can cause multifocal ischemic brain injury such as vasculitides, vasculopathies, and haemostatic or hemodynamic disturbances must not be present.
Possible
1. Th e presen ce of a cardiac condition with low or uncertain primary risk of cerebral embolism 2. Evidence for evident cardioaortic embolism in the absence of complete diagnostic investigation for other mechanisms
Small artery
Evident
occlusion
1. Imaging evidence of a single and clinically relevant acute infarction <20 mm in greatest diameter within the territory of basal or brainstem penetrating arteries in the absence of any other pathology in the parent artery at the site of the origin of the penetrating artery (focal atheroma, parent vessel dissection, vasculitis, vasospasm, etc)
Probable
1. The presence of stereotypic lacunar transient ischemic attacks within the past week
2. The presence of a classical lacunar syndrome Possible
1. Presen ting with a classical lacunar syndrome in the absence of imaging that is sensitive enough to detect small infarctions 2. Evidence for evident small artery occlusion in the absence of complete diagnostic investigation for other mechanisms
Other causes
Evident
1. The presence of a specific disease process that involves clinically appropriate brain arteries
Probable
1. A specific disease process that has occurred in clear and close temporal or spatial relationship to the onset of brain infarction such as arterial dissection, cardiac or arterial surgery, and cardiovascular interventions
Possible
1. Eviden ce for an evident other cause in the absence of complete
diagnostic investigation for mechanisms listed above Undetermined causes
Unknown Cryptogenic
1. Angiographic
embolism:
evidence of abrupt cut-off consistent with a blood clot within otherwise angiographically normal looking intracranial arteries 2. Imaging evidence of complete recanalization of previously occluded artery 3. The presence of multiple acute infarctions that have occurred closely related in time without detectable abnormality in the relevant vessels
Other
1. Those not
cryptogenic:
fulfilling the criteria for cryptogenic embolism
Incomplete
1. The absence
evaluation:
of diagnostic tests that, under the examiner's judgment, their presence would have been essential to uncover the underlying etiology
Unclassified
1. The presence
of >1 evident mechanism in which there is either probable evidence for each, or no probable evidence to be able to establish a single cause Reproduced with permission from: Ay H, Benner T, Arsava EM. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke 2007; 38:2979. Graphic 57732 Version 3.0
Time course of neurologic changes in i hemorrhage
Schematic representation of rapid downhill course in behavior (green), hemimotor function (blue), and co in a patient with intracerebral (intraparenchymal) he Graphic 61491 Version 2.0
Headache and vomiting in stroke subt
The frequency of sentinel headache, onset headache three subtypes of stroke: subarachnoid hemorrhage intraparenchymal (intracerebral) hemorrhage (IPH), stroke (IS). Onset headache was present in virtually SAH and about one-half of those with IPH; all of the infrequent in patients with IS. Data from: Gorelick PB, Hier DB, Caplan LR, et al, Neurolog Graphic 60831 Version 3.0
