Etiology and classification of stroke Author Louis R Caplan, MD Section Editor Scott E Kasner, MD Deputy Editor John F Dashe,

MD, PhD

Last literature review version 19.1: January 2011 | This topic last updated: February 1, 2011 (More) 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 can be divided into subtypes that have somewhat 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]. 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" and "Overview of the evaluation of stroke".) DEFINITIONS Stroke is classified into two major types: Brain ischemia due to thrombosis, embolism, or systemic hypoperfusionBrain hemorrhage due to intracerebral hemorrhage or subarachnoid hemorrhage A stroke is the acute neurologic injury that occurs as a result 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 is pale initially. Within hours to 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 blood-brain barrier. A primary intracerebral hemorrhage damages the brain directly at the site 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 There are three main subtypes of brain ischemia [2]: Thrombosis (see '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' 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' 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".) 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 1). These two subtypes of thrombosis are worth distinguishing since the causes, outcomes, and treatments are different. Large vessel disease Large vessels include both the extracranial (common and internal carotids, vertebral) and intracranial arterial system (Circle of Willis and proximal branches) (figure 1 and figure 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 intraarterial emboli. At times a combination of mechanisms is operant. 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: AtherosclerosisDissectionTakayasu arteritisGiant cell arteritisFibromuscular dysplasia Pathologies affecting large intracranial vessels include: AtherosclerosisDissectionArteritis/vasculitisNoninflammatory vasculopathyMoyamoya syndromeVasoconstriction

Atherosclerosis is by far the most 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 disease is really a form of proximal extracranial large vessel disease, but it is often considered together with cardioembolic sources because of anatomic proximity. (See 'Aortic 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 sputtering 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 degenerationAtheroma 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, 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 cardiacThose with a possible cardiac or aortic source based upon transthoracic and/or transesophageal echocardiographic findingsThose 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 fibrillationRheumatic mitral or aortic valve diseaseBioprosthetic and mechanical heart valvesAtrial or ventricular thrombusSick sinus syndromeSustained atrial flutterRecent myocardial infarction (within one month)Chronic myocardial infarction together with ejection fraction <28 percentSymptomatic congestive heart failure with ejection fraction <30 percentDilated cardiomyopathyFibrous nonbacterial endocarditis as found in patients with systemic lupus (ie, Libman-Sacks endocarditis), antiphospholipid syndrome, and cancer (marantic endocarditis)Infective endocarditisPapillary fibroelastomaLeft atrial myxomaCoronary 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 calcificationPatent foramen ovaleAtrial septal aneurysmAtrial septal aneurysm with patent foramen ovaleLeft ventricular aneurysm without thrombusIsolated

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 populationbased 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 anemiaPolycythemia veraEssential thrombocytosisHeparin induced thrombocytopeniaProtein C or S deficiency, acquired or congenitalProthrombin gene mutationFactor V Leiden (resistance to activated protein C)Antithrombin III deficiencyAntiphospholipid syndromeHyperhomocysteinemia 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 atherosclerosisCardioembolismSmall vessel occlusionStroke of other determined etiologyStroke 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 has been developed [6]. The SSS-TOAST 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 (table 4). In a study that compared the original TOAST and the SSS-TOAST criteria applied to a series of 50 patients with acute ischemic stroke, patients classified as "undeterminedunclassified" decreased for TOAST and SSS-TOAST were 38 to 40 versus 4 percent, respectively, and inter-examiner reliability for SSS-TOAST was higher than for TOAST, although the difference was not statistically significant [6]. In a further refinement, an automated version of the SSS-TOAST called the Causative Classification System (CCS) was devised 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. BRAIN HEMORRHAGE There are two main subtypes of brain hemorrhage [2]: Intracerebral hemorrhage refers to bleeding directly into the brain parenchymaSubarachnoid hemorrhage refers to bleeding into the cerebrospinal fluid within the subarachnoid space that surrounds the brain Intracerebral hemorrhage Bleeding in intracerebral hemorrhage (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 [21,22]. The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations [21,22]. (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 [21,22]. As examples: Bleeding into the right putamen and internal capsule region causes left limb motor and/or sensory signsBleeding into the cerebellum causes difficulty walkingBleeding 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) [21,22]. 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 life-threatening; 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 "Etiology, clinical manifestations, and diagnosis of aneurysmal subarachnoid hemorrhage".) Rupture of an aneurysm releases blood directly into the cerebrospinal fluid (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) [23]. (See "Etiology, 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) [23]. 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 [24]. 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".) INFORMATION FOR PATIENTS Educational materials on this topic are available for patients. (See "Patient information: Stroke symptoms and diagnosis".) We encourage you to print or e-mail this topic, or to refer patients to our public web site www.uptodate.com/patients, which includes this and other topics.

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