Stroke: Etiology, Classification, and Epidemiology

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Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Stroke: Etiology, classification, and epidemiology

Author: Louis R Caplan, MD
Section Editor: Scott E Kasner, MD
Deputy Editor: John F Dashe, MD, PhD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2023. | This topic last updated: Jun 15, 2022.
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 hypoperfusion
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● Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid hemorrhage

(SAH)
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. (See 'Epidemiology' below.)
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.
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, etiology, and clinical manifestations of transient ischemic attack", section on
'Definition of TIA'.)
A primary ICH 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 backup of fluid resulting in brain edema, and in addition it may cause both brain
ischemia and hemorrhage into the brain. (See "Cerebral venous thrombosis: Etiology, clinical
features, and diagnosis".)
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,
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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.
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 intra-arterial 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:
● Atherosclerosis
● Dissection
● Takayasu arteritis
● Giant cell arteritis
● Fibromuscular dysplasia
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Pathologies affecting large intracranial vessels include:
● Atherosclerosis
● Dissection
● Arteritis/vasculitis
● Noninflammatory vasculopathy
● Moyamoya syndrome
● Vasoconstriction
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 stuttering fashion ( figure 3).
(See "Clinical diagnosis of stroke subtypes", section on 'Clinical course of symptoms and signs'
and "Definition, etiology, and clinical manifestations of transient ischemic attack", section on
'Mechanisms and 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
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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) [3].
● 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 "Overview
of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)
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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.
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
● Sinus node dysfunction
● 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 [6,7,9], including:
● Patent foramen ovale

● Atrial septal aneurysm
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● Atrial septal aneurysm with patent foramen ovale

● Atrial cardiopathy (large or malfunctioning left atrium)
● 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 [10]. 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 [11-13]. However, most studies evaluating secondary stroke risk have found
that complex aortic atherosclerosis is a risk factor for recurrent stroke [14-17].
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 [15].
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, sex, and other clinical risk
factors [12]. 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
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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 [18]. (See
"Thromboembolism from aortic plaque".)
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 [10]. 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
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● Thrombotic thrombocytopenic purpura (TTP)
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 "Cerebral venous thrombosis: Etiology, clinical
features, and diagnosis".)
Infectious and inflammatory disease such as pneumonia, urinary tract infections, Crohn
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.
CLASSIFICATION SYSTEMS FOR ISCHEMIC STROKE
TOAST classification — The TOAST classification scheme for ischemic stroke is widely used and
has good interobserver agreement [19]. 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 and embolic stroke of undetermined source
(ESUS)".)
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].
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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 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. 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 [20]. 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 [21]. 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 [22].
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 [23,24].
The most common causes of ICH are hypertension, trauma, bleeding diatheses, amyloid
angiopathy, illicit drug use (mostly amphetamines and cocaine), and vascular malformations
[23,24] (see "Spontaneous intracerebral hemorrhage: Pathogenesis, clinical features, and
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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 [23,24]. 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) [23,24]. 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 "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)
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
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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) [25]. (See "Aneurysmal subarachnoid hemorrhage: Clinical
manifestations and diagnosis".)
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) [25].
The complaint of the sudden onset of severe headache is sufficiently characteristic that SAH
should always be considered. In a prospective study of 148 patients presenting with sudden
and severe headache, for example, SAH was present in 25 percent overall and 12 percent in
patients in whom headache was the only symptom [26].
EPIDEMIOLOGY
Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and

subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a higher incidence of
hemorrhagic stroke in low- and middle-income countries [27,28]. In the United States, the
proportion of all strokes due to ischemia, intracerebral hemorrhage, and subarachnoid
hemorrhage is 87, 10, and 3 percent, respectively [29].
The lifetime risk of stroke for adult men and women (25 years of age and older) is
approximately 25 percent [30]. The highest risk of stroke is found in East Asia, Central Europe,
and Eastern Europe. Worldwide, stroke is the second most common cause of mortality and the
second most common cause of disability [31]. In China, which has the greatest burden of stroke
in the world, the age-standardized prevalence, incidence, and mortality rates are estimated to
be 1115, 247, and 115 per 100,000 person-years, respectively [32]. These data suggest that the
stroke prevalence in China is relatively low compared with the prevalence in high-income
countries, but the stroke incidence and mortality rates in China are among the highest in the
world. While the incidence of stroke is decreasing in high-income countries, including the
United States [33-35], the incidence is increasing in low-income countries [36]. 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 [37].
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 [29]. There is a higher
regional incidence and prevalence of stroke and a higher stroke mortality rate in the
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southeastern United States (sometimes referred to as the "stroke belt") than in the rest of the
country [38-42].
The lifetime risk of stroke is higher for females compared with males [29].
Black and Hispanic Americans have an increased risk of stroke compared with White Americans,
as illustrated by the following observations:
● The Northern Manhattan Study reported that the age-adjusted incidence of first ischemic
stroke among White, Hispanic, and Black Americans was 88, 149, and 191 per 100,000
respectively [43]. Among Black compared with White Americans, 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 Hispanic compared
with White Americans, 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 Black compared with White patients [44].
The incidence of cardioembolic strokes was not significantly different.
● An increased incidence of stroke has also been found among Mexican Americans
compared with non-Hispanic White Americans [45].
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 5th 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 in-depth 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.)
3/29/23, 1:06 PM 1089
● Basics topics (see "Patient education: Hemorrhagic stroke (The Basics)" and "Patient
education: Stroke (The Basics)")
● Beyond the Basics topics (see "Patient education: Stroke symptoms and diagnosis (Beyond
the Basics)")
SUMMARY
● Classification – Stroke is classified into two major types (see 'Definitions' above):
• Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion

• Brain hemorrhage due to intracerebral hemorrhage (ICH) or subarachnoid
hemorrhage (SAH)
● Ischemia - There are three main subtypes of brain ischemia ( table 1):
• Thrombosis generally refers to local in situ obstruction of an artery. The obstruction

may be due to disease of the arterial wall, such as atherosclerosis, arteriosclerosis,
dissection, or fibromuscular dysplasia; there may or may not be superimposed
thrombosis. Thrombotic strokes can be divided into either large or small vessel
disease. These two subtypes of thrombosis are worth distinguishing since the causes,
outcomes, and treatments are different. (See 'Thrombosis' above.)
• Embolism refers to particles of debris originating elsewhere that block arterial access
to a particular brain region. The source of embolism is most often from the heart or
from an artery (artery-to-artery embolism). (See 'Embolism' above.)
• Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the

brain and perhaps other organs. (See 'Systemic hypoperfusion' above.)
Blood disorders 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. (See 'Blood disorders' above.)
● Ischemic stroke classification – The TOAST classification scheme for ischemic stroke
( table 3) is widely used and has good interobserver agreement. 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. The Causative Classification
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System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification

systems for ischemic stroke' above.)
● Brain hemorrhage – There are two main subtypes of brain hemorrhage:
• ICH refers to bleeding directly into the brain parenchyma. Accumulation of blood
occurs over minutes or hours. The most common causes of ICH are hypertension,
trauma, bleeding diatheses, amyloid angiopathy, illicit drug use (mostly amphetamines
and cocaine), and vascular malformations. Less frequent causes include bleeding into
tumors, aneurysmal rupture, and vasculitis. (See 'Intracerebral hemorrhage' above.)
• SAH refers to bleeding into the cerebrospinal fluid within the subarachnoid space that
surrounds the brain. 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. 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. (See 'Subarachnoid hemorrhage' above.)
● Epidemiology – Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28

percent, and subarachnoid hemorrhage 10 percent of all incident strokes, reflecting a
higher incidence of hemorrhagic stroke in low- and middle-income countries. In the
United States, the proportion of all strokes due to ischemia, intracerebral hemorrhage,
and subarachnoid hemorrhage is 87, 10, and 3 percent, respectively. (See 'Epidemiology'
above.)
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REFERENCES
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Topic 1089 Version 33.0
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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 basilar-vertebral 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
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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 spontaneous echo contrast ("smoke") without 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 4.0
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Anatomy of the cerebral arterial circulation
Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and
their communication with each other via the circle of Willis.
Reproduced with permission from: Uflacker R. Atlas Of Vascular Anatomy: An Angiographic Approach,
Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright © 2006 Lippincott Williams &
Wilkins.
3/29/23, 1:06 PM 1089
Major cerebral vascular territories
Representation of the territories of the major cerebral vessels shown

in a coronal section of the brain.
Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases.

Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994.
Copyright 1994 McGraw-Hill Companies, Inc.
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Stuttering time course of thrombotic stroke
The course of weakness of the right limb in a patient with a

thrombotic stroke reveals fluctuating symptoms, varying between
normal and abnormal, progressing in a stepwise or stuttering
fashion with some periods of improvement.
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Time course of lacunar infarction
Penetrating artery occlusions usually cause symptoms that develop

over a short period of time, hours or at most a few days, compared
to large artery-related brain ischemia which can evolve over a longer
period. A stuttering course may ensue, as with large artery
thrombosis. This patient had a pure motor hemiparesis.
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Time course of embolic stroke
Embolic stroke occurs suddenly, with symptoms maximal at onset.

This patient had multiple embolic events with different clinical
symptoms (initially weakness, followed by paresthesias).
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Cardioaortic sources of cerebral embolism
Sources with high primary risk for Sources with low or uncertain primary
ischemic stroke risk for ischemic stroke
Atrial fibrillation Cardiac sources of embolism:
Paroxysmal atrial fibrillation Mitral annular calcification
Left atrial thrombus Patent foramen ovale
Left ventricular thrombus Atrial septal aneurysm
Sick sinus syndrome Atrial septal aneurysm and patent foramen

ovale
Atrial flutter Left ventricular aneurysm without thrombus
Recent myocardial infarction (within one month Left atrial spontaneous echo contrast
prior to stroke) ("smoke")
Mitral stenosis or rheumatic valve disease Congestive heart failure with ejection fraction
<30%
Mechanical heart valves Bioprosthetic heart valves
Chronic myocardial infarction together with low Apical akinesia

ejection fraction (<28%)
Dilated cardiomyopathy (prior established Wall motion abnormalities (hypokinesia,

diagnosis or left ventricular dilatation with an akinesia, dyskinesia) other than apical akinesia
ejection fraction of <40% or fractional shortening
of <25%)
Nonbacterial thrombotic endocarditis Hypertrophic cardiomyopathy
Infective endocarditis Left ventricular hypertrophy
Papillary fibroelastoma Left ventricular hypertrabeculation/non-

compaction
Left atrial myxoma Recent aortic valve replacement or coronary

artery bypass graft surgery
Presence of left ventricular assist device Paroxysmal supraventricular tachycardia
Aortic sources of embolism:
Complex atheroma in the ascending aorta or

proximal arch (protruding with >4 mm
thickness, or mobile debris, or plaque
ulceration)
The high- and low-risk cardioaortic sources in this table are separated using an arbitrary 2% annual
3/29/23, 1:06 PM 1089
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 evidence-based 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.
4. Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of ischemic stroke. Stroke
2013; 44:1550.
5. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual INTERMACS report: Special focus on framing the impact of
adverse events. J Heart Lung Transplant 2017; 36:1080.
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.
3/29/23, 1:06 PM 1089
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
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Causative Classification System (CCS) of ischemic stroke etiology
Stroke Level of
Criteria
mechanism confidence
Large artery Evident 1. Either occlusive or stenotic (≥50 percent diameter reduction or
atherosclerosis <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, and
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, or
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), or
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. The presence 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 one event within the last month, or
2. Evidence for evident large artery atherosclerosis in the absence

of complete diagnostic investigation for other mechanisms
Cardio-aortic Evident The presence of a high-risk cardiac source of cerebral embolism

embolism
Probable 1. Evidence of systemic embolism, or
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 hemostatic or hemodynamic disturbances
must not be present.
Possible 1. The presence of a cardiac condition with low or uncertain

primary risk of cerebral embolism, or
3/29/23, 1:06 PM 1089
2. Evidence for evident cardio-aortic embolism in the absence of

complete diagnostic investigation for other mechanisms
Small artery Evident Imaging evidence of a single and clinically relevant acute
occlusion 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, or
2. The presence of a classical lacunar syndrome
Possible 1. Presenting with a classical lacunar syndrome in the absence of

imaging that is sensitive enough to detect small infarctions, or
2. Evidence for evident small artery occlusion in the absence of

complete diagnostic investigation for other mechanisms
Other causes Evident The presence of a specific disease process that involves clinically
appropriate brain arteries
Probable 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 Evidence for an evident other cause in the absence of complete

diagnostic investigation for mechanisms listed above
Undetermined Unknown (no Cryptogenic embolism:

causes evident,
1. Angiographic evidence of abrupt cut-off consistent with a blood
probable, or
clot within otherwise angiographically normal looking intracranial
possible
arteries, or
criteria for
the causes 2. Imaging evidence of complete recanalization of previously
above) occluded artery, or
3. The presence of multiple acute infarctions that have occurred

closely related in time without detectable abnormality in the
relevant vessels
Other cryptogenic: Those not fulfilling the criteria for cryptogenic

embolism
Incomplete evaluation: The absence of diagnostic tests that, under

the examiner's judgment, would have been essential to uncover
the underlying etiology
Unclassified The presence of >1 evident mechanism in which there is either

probable evidence for each, or no probable evidence to be able to
3/29/23, 1:06 PM 1089
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.
3/29/23, 1:06 PM 1089
Time course of neurologic changes in intracerebral

hemorrhage
Schematic representation of rapid downhill course in terms of

unusual behavior (solid line), hemimotor function (dotted line), and
consciousness (dash-dotted line) in a patient with intracerebral
(intraparenchymal) hemorrhage.
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Headache and vomiting in stroke subtypes
The frequency of sentinel headache, onset headache, and vomiting

in three subtypes of stroke: subarachnoid hemorrhage,
intraparenchymal (intracerebral) hemorrhage, and ischemic stroke.
Onset headache was present in virtually all patients with SAH and
about one-half of those with IPH; all of these symptoms were
infrequent in patients with IS.
SAH: subarachnoid hemorrhage; IPH: intraparenchymal

(intracerebral) hemorrhage; IS: ischemic stroke.
Data from: Gorelick PB, Hier DB, Caplan LR, Langenberg P. Headache in acute
cerebrovascular disease. Neurology 1986; 36:1445.
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Contributor Disclosures
Louis R Caplan, MD No relevant financial relationship(s) with ineligible companies to disclose. Scott E
Kasner, MD Grant/Research/Clinical Trial Support: Bristol Meyers Squibb [Stroke]; Medtronic [Stroke]; WL
Gore and Associates [Stroke]. Consultant/Advisory Boards: Abbott [Stroke]; Abbvie [Stroke]; Bayer [Stroke];
BMS [Stroke]; Boehringer Ingelheim [Stroke]; Diamedica [Stroke]; Janssen [Stroke]; Medtronic [Stroke]. All
of the relevant financial relationships listed have been mitigated. John F Dashe, MD, PhD No relevant
financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.
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Stroke: Etiology, classification, and epidemiology

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

There are three main subtypes of brain ischemia [2]:

● Thrombosis (see 'Thrombosis' below) generally refers to local in situ obstruction of an

dissection, or fibromuscular dysplasia; there may or may not be superimposed

● Systemic hypoperfusion (see 'Systemic hypoperfusion' below) is a more general circulatory

Pathologies affecting large extracranial vessels include:

Pathologies affecting large intracranial vessels include:

● Lipohyalinosis (a lipid hyaline build-up distally secondary to hypertension) and fibrinoid

● Atheroma formation at their origin or in the parent large artery

● Those with a known source that is cardiac

● Those with an arterial source (artery to artery embolism)

● Atrial fibrillation and paroxysmal atrial fibrillation

● Patent foramen ovale

● Atrial septal aneurysm with patent foramen ovale

Aortic atherosclerosis — In longitudinal population studies with nonselected patients,

The range of findings is illustrated by the following studies:

● A prospective case-control study examined the frequency and thickness of atherosclerotic

● In contrast, a population-based study of 1135 subjects who had transesophageal

● Sickle cell anemia

● Thrombotic thrombocytopenic purpura (TTP)

CLASSIFICATION SYSTEMS FOR ISCHEMIC STROKE

The five TOAST subtypes of ischemic stroke are:

● Large artery atherosclerosis

These advances could cause an increasing proportion of ischemic strokes to be classified as

As a result, an evidenced-based modification of the TOAST criteria called SSS-TOAST was

There are two main subtypes of brain hemorrhage [2]:

Intracerebral hemorrhage — Bleeding in ICH is usually derived from arterioles or small

Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28 percent, and

INFORMATION FOR PATIENTS

• Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion

• Thrombosis generally refers to local in situ obstruction of an artery. The obstruction

• Systemic hypoperfusion is a more general circulatory problem, manifesting itself in the

System (CCS) ( table 4) is an automated version of the SSS-TOAST. (See 'Classification

● Brain hemorrhage – There are two main subtypes of brain hemorrhage:

● Epidemiology – Globally, ischemia accounts for 62 percent, intracerebral hemorrhage 28

Use of UpToDate is subject to the Terms of Use.

1. Caplan LR. Intracranial branch atheromatous disease: a neglected, understudied, and

23. Caplan LR. Intracerebral haemorrhage. Lancet 1992; 339:656.

Pathophysiologic ischemic stroke classification

Large vessel atherothrombotic stroke

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

Origin of the common carotid artery

Posterior cerebral artery stem

Origin of the major branches of the basilar-vertebral arteries

Small vessel (lacunar) stroke

Less frequently proximal atherothrombotic occlusion

Least likely embolic occlusion

Most common locations

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