Stroke (Etiology, classification, and epidemiology)
INTRODUCTION
1.
2.
3.
The two broad categories of stroke, hemorrhage and ischemia, are diametrically opposite
conditions: hemorrhage is characterized by too much blood within closed cranial cavity, while
ischemia is characterized by too little blood to supply adequate amount of oxygen and
nutrients to part of brain.
Each of these categories can be divided into subtypes that have somewhat different causes,
clinical pictures, clinical courses, outcomes, and treatment strategies. As example,
intracranial hemorrhage can be caused by ICH, which involves bleeding directly into brain
tissue, and SAH, which involves bleeding into CSF that surrounds brain and spinal cord.
This topic will review classification of stroke. The clinical diagnosis of stroke subtypes and
overview of stroke evaluation are discussed separately.
DEFINITION
1. Stroke is classified into two major types.
A. Brain ischemia due to thrombosis, embolism, or systemic hypoperfusion
B. Brain hemorrhage due to ICH or SAH
2. A stroke is acute neurologic injury that occurs as result of one of these pathologic processes.
80% of strokes are due to ischemic cerebral infarction and 20% to brain hemorrhage.
3. An infarcted brain is pale initially. Within hours to days, gray matter becomes congested with
engorged, dilated blood vessels and minute petechial hemorrhages. When embolus blocking
major vessel migrates, lyses, or disperses within minutes to days, recirculation into infarcted
area can cause hemorrhagic infarction and may aggravate edema due to disruption of BBB.
4. A primary ICH damages brain directly at site of hemorrhage by compressing surrounding
tissue. Physicians must initially consider whether patient with suspected cerebrovascular
disease is experiencing symptoms and signs suggestive of ischemia or hemorrhage.
5. The great majority of ischemic strokes are caused by 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 brain of blood. Venous occlusion causes
back-up of fluid resulting in brain edema, and in addition it may cause both brain ischemia
and hemorrhage into brain.
BRAIN ISCHEMIA
1.
There are three main subtypes of brain ischemia.
A. Thrombosis generally refers to local in situ obstruction of artery. The obstruction may be
due to disease of arterial wall, such as arteriosclerosis, dissection, or fibromuscular
dysplasia; there may or may not be superimposed thrombosis.
B. Embolism refers to debris originating elsewhere that block artery to particular brain.
Since process is not local (as with thrombosis), local therapy only temporarily solves
problem; further events may occur if source of embolism is not identified and treated.
C. Systemic hypoperfusion is more general circulatory problem, manifesting itself in brain
and perhaps other organs.
2.
3.
4.
Blood disorders are uncommon primary cause of stroke. However, increased blood
coagulability can result in thrombus formation and subsequent cerebral embolism in
presence of endothelial lesion located in heart, aorta, or large arteries that supply brain.
TIA is defined clinically by temporary nature of associated neurologic symptoms, which last <
24 hours by 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.
Thrombosis
A. Thrombotic strokes are those in which pathologic process giving rise to thrombus
formation in artery produces stroke either by reduced blood flow distally (low flow) or
by embolic fragment that breaks off and travels to 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 causes,
outcomes, and treatments are different.
B. Large vessel disease
i.
Large vessels include both extracranial (CCA and ICA, VA) and intracranial arterial
system (Circle of Willis and proximal branches) (figure 1).
ii.
Intrinsic lesions in large extracranial and intracranial arteries cause symptoms by
reducing blood flow beyond obstructive lesions, and by serving as source of
intra-arterial emboli. At times combination of mechanisms is operant. Severe
stenosis promotes formation of thrombi which can break off and embolize, and the
reduced blood flow caused by vascular obstruction makes circulation less
competent at washing out and clearing these emboli.
iii.
iv.
v.
vi.
vii.
viii.
Pathologies affecting large extracranial vessels.
1. Atherosclerosis
2. Dissection
3. Takayasu arteritis
4. Giant cell arteritis
5. Fibromuscular dysplasia
Pathologies affecting large intracranial vessels.
1. Atherosclerosis
2. Dissection
3. Arteritis/vasculitis
4. Noninflammatory vasculopathy
5. Moyamoya syndrome
6. Vasoconstriction
Atherosclerosis is by far the most common cause of in situ local disease within
large extracranial and intracranial arteries that supply brain. White platelet-fibrin
and RBC-fibrin thrombi are often superimposed upon atherosclerotic lesions, or
they may develop without severe vascular disease in patients with hypercoagulable
states. Vasoconstriction (with migraine) is probably the next most common,
followed in frequency by arterial dissection (disorder much more common than
previously recognized) and traumatic occlusion. Fibromuscular dysplasia is
uncommon arteriopathy, while arteritis is frequently mentioned in differential
diagnosis, but it is extremely rare cause of thrombotic stroke.
Aortic disease is really form of proximal extracranial large vessel disease, but it is
often considered together with cardioembolic sources because of anatomic
proximity.
Identification of specific focal vascular lesion, including its nature, severity, and
localization, is important for treatment since local therapy is effective (surgery,
angioplasty, IA thrombolysis). It should be possible clinically in most patients to
determine whether local vascular disease is within anterior (carotid) or posterior
(vertebrobasilar) circulation and whether disorder affects large or penetrating
arteries.
Delivery of adequate blood through blocked or partially blocked artery depends
upon many factors, including BP, blood viscosity, and collateral flow. Local vascular
lesions also may throw off emboli, which can cause transient symptoms. In patients
with thrombosis, neurologic symptoms often fluctuate, remit, or progress in
stuttering fashion.
C.
Small vessel disease
i.
Small vessel disease affects intracerebral arterial system, specifically penetrating
arteries that arise from distal VA, BA, MCA, and circle of Willis.
1. Lipohyalinosis (lipid hyaline build-up distally) and fibrinoid degeneration
2. Atheroma formation at their origin or in parent large artery
ii.
The most common cause of obstruction of smaller arteries and arterioles that
penetrate at right angles to supply deeper structures within brain (basal ganglia,
internal capsule, thalamus, pons) is lipohyalinosis, ie, blockage of artery by medial
hypertrophy and lipid admixed with fibrinoid material in hypertrophied arterial wall.
A stroke due to obstruction of these vessels is referred to as lacunar stroke.
iii.
iv.
Lipohyalinosis is most often related to HTN, but aging may play role.
Microatheromas can also block these small penetrating arteries, as can plaques
within larger arteries that block or extend into orifices of branches.
Penetrating artery occlusions usually cause symptoms that develop during short
period of time, hours or at most few days, compared with large artery-related brain
ischemia, which can evolve over longer period.
5.
Embolism
A. Embolic strokes are divided into 4 categories (table 1).
i.
Those with known source that is cardiac
ii.
Those with possible cardiac or aortic source based upon TTE and/or TEE findings
iii.
Those with arterial source (artery to artery embolism)
iv.
Those with truly unknown source in which tests for embolic sources are negative
B. The symptoms depend upon region of brain rendered ischemic. The embolus suddenly
blocks recipient site so that onset of symptoms is abrupt and usually maximal at start.
Unlike thrombosis, multiple sites within different vascular territories may be affected
when source is heart or aorta. Treatment will depend upon source and composition of
embolus.
C.
D.
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 area of ischemia
that gave rise to symptoms. This process is often referred to as TIA due to embolism,
although it is more correctly termed embolic infarction or stroke in which symptoms
clear within 24 hours.
Cardioembolic strokes can be divided into those with known source and those with
possible cardiac or ascending aortic source based upon TTE/TEE findings.
E. High-risk cardiac source
i.
The diagnosis of embolic strokes with known cardiac source is generally agreed
upon by physicians (table 2).
1. Af
2. Rheumatic MV or AV disease
3. Bioprosthetic and mechanical heart valve
4. Atrial or ventricular thrombus
5. SSS
6.
7.
Sustained AF
Recent MI (within 1 month)
8.
9.
10.
11.
Chronic MI together with LVEF < 28%
Symptomatic CHF with LVEF < 30%
DCMP
Fibrous non-bacterial endocarditis as found in patients with SLE (Libman-Sacks
endocarditis), APS, and cancer (marantic endocarditis)
IE
Papillary fibroelastoma
Left atrial myxoma
CABG surgery
12.
13.
14.
15.
ii.
With CABG, incidence of post-operative neurologic sequelae is 2 to 6%, most of
which is due to stroke. Atheroemboli associated with ascending aortic
atherosclerosis is probably the most common cause.
F. Potential cardiac source
i.
Embolic strokes considered to have potential cardiac source (table 2) are ones in
which possible source is detected (usually) by UCG.
1. Mitral annular calcification
2. PFO
3. Atrial septal aneurysm ± PFO
4. Left ventricular aneurysm without thrombus
5. Isolated left atrial smoke on UCG (no MS or Af)
6. Complex atheroma in ascending aorta or proximal arch
ii.
In this group, association of cardiac or aortic lesion and rate of embolism is often
uncertain, since some of these lesions do not have high frequency of embolism and
are often incidental findings unrelated to stroke event. 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.
G. Aortic atherosclerosis
i.
In longitudinal population studies with non-selected patients, complex aortic
atherosclerosis does not appear to be associated with any increased primary
ii.
ischemic stroke risk. However, most studies evaluating secondary stroke risk have
found that complex aortic atherosclerosis is risk factor for recurrent stroke.
The range of findings is illustrated by following studies.
1.
2.
iii.
iv.
6.
A prospective case-control study examined frequency and thickness of
atherosclerotic plaques in ascending aorta and proximal arch in 250 patients
admitted to hospital with ischemic stroke and 250 consecutive controls, all
over age of 60 years. Atherosclerotic plaques ≥ 4 mm in thickness were found
in 14% of patients compared with 2% of controls, and OR 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 (RR 4.7).
In contrast, population-based study of 1135 subjects who had TEE found that
complex atherosclerotic plaque (> 4 mm with or without mobile debris) in
ascending and transverse aortic arch was not significant risk factor for
cryptogenic ischemic stroke or TIA after adjusting for age, gender, and other
clinical risk factors. However, there was association between complex aortic
plaque and non-cryptogenic stroke. The investigators concluded that complex
aortic arch debris is marker for presence of generalized atherosclerosis.
Methodologic differences are potential explanation for discrepant results of these
reports assessing 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, problem that may confound purely epidemiologic studies.
In author's opinion, there is no question that large protruding plaques in ascending
aorta and arch, particularly mobile plaques, are important cause of stroke.
Systemic hypoperfusion
A. 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 SCA or arrhythmia, or to reduced CO related to AMI, PE, pericardial effusion, or
bleeding. Hypoxemia may further reduce amount of oxygen carried to brain.
B. 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 HoTN such as pallor, sweating, tachycardia or severe bradycardia, and
low BP. The neurologic signs are typically bilateral, although they may be asymmetric
C.
when there is preexisting asymmetrical craniocerebral vascular occlusive disease.
The most severe ischemia may occur in border zone (watershed) region between 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 shoulders and thighs with sparing of
face, hands, and feet (pattern likened to "man-in-a-barrel").
7.
Blood disorder
A. Blood and coagulation disorders are uncommon primary cause of stroke and TIA, but
they should be considered in patients < 45, patients with history of clotting dysfunction,
and in patients with history of cryptogenic stroke.
i.
Sickle cell anemia
ii.
Polycythemia vera
iii.
Essential thrombocytosis
iv.
Heparin induced thrombocytopenia
v.
Protein C or S deficiency, acquired or congenital
vi.
Prothrombin gene mutation
vii.
Factor V Leiden (resistance to activated protein C)
viii.
Antithrombin III deficiency
ix.
Antiphospholipid syndrome
x.
Hyperhomocysteinemia
B. 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
DVT with paradoxical emboli.
C. Infectious and inflammatory disease such as pneumonia, UTI, IBD, HIV/AIDS, and
cancers result in rise in acute phase reactants such as fibrinogen, CRP, and coagulation
factors VII and VIII. In presence of endothelial cardiac or vascular lesion, this increase can
promote active thrombosis and embolism.
8.
TOAST classification
A. TOAST classification scheme for ischemic stroke is widely used and has good
inter-observer agreement. TOAST system (table 3) attempts to classify ischemic strokes
according to major pathophysiologic mechanisms that are recognized as cause of most
ischemic strokes (table 1). It assigns ischemic strokes to 5 subtypes based upon clinical
features and results of ancillary studies including brain imaging, neurovascular
evaluations, cardiac tests, and laboratory evaluations for prothrombotic state.
i.
Large artery atherosclerosis
ii.
Cardioembolism
iii.
Small vessel occlusion
iv.
Stroke of other determined etiology
v.
Stroke of undetermined etiology
B. The last subtype - stroke of undetermined etiology - involves cases where cause of
stroke cannot be determined with any degree of confidence, and by definition includes
those with two or more potential causes identified, those with negative evaluation, and
those with incomplete evaluation.
9.
SSS-TOAST and CCS classification
A. Since original TOAST classification scheme was developed in early 1990s, advances in
B.
stroke evaluation and diagnostic imaging have allowed more frequent identification of
potential vascular and cardiac causes of stroke. These advances could cause increasing
proportion of ischemic strokes to be classified as "undetermined" if strict definition of
this category (cases with two or more potential causes) is applied.
As result, evidenced-based modification of TOAST criteria called SSS-TOAST has been
developed. SSS-TOAST system divides each of original TOAST subtypes into 3
subcategories as "evident," "probable," or "possible" based upon weight of diagnostic
evidence as determined by pre-defined clinical and imaging criteria. In study that
compared original TOAST and SSS-TOAST criteria applied to series of 50 patients with
acute ischemic stroke, patients classified as "undetermined-unclassified" decreased for
TOAST and SSS-TOAST were 38 to 40 vs. 4%, and inter-examiner reliability for SSS-TOAST
was higher than for TOAST, although difference was not statistically significant.
C. In further refinement, automated version of SSS-TOAST called Causative Classification
System (CCS) was devised (table 4) to improve its usefulness and accuracy for stroke
subtyping. CCS is computerized algorithm that consists of questionnaire-style
classification scheme. CCS appears to have good inter-rater reliability among multiple
centers. It is available online at https://ccs.mgh.harvard.edu/ccs_title.php.
BRAIN HEMORRHAGE
1. There are two main subtypes of brain hemorrhage.
A.
B.
2.
Intracerebral hemorrhage refers to bleeding directly into brain parenchyma
Subarachnoid hemorrhage refers to bleeding into CSF within subarachnoid space that
surrounds brain
Intracerebral hemorrhage
A. Bleeding in ICH is usually derived from arterioles or small arteries. The bleeding is
directly into brain, forming 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 snowball rolling downhill. The
hematoma continues to grow until pressure surrounding it increases enough to limit its
spread or until hemorrhage decompresses itself by emptying into ventricular system or
into CSF on pial surface of the brain.
B. The most common causes of ICH are HTN, 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.
C. The earliest symptoms of ICH relate to dysfunction of portion of brain that contains
hemorrhage.
i.
Bleeding into right putamen and internal capsule region causes left limb motor
and/or sensory signs
ii.
iii.
3.
Bleeding into cerebellum causes difficulty walking
Bleeding into left temporal lobe presents as aphasia
D.
The neurologic symptoms usually increase gradually over minutes or 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.
E.
Headache, vomiting, and decreased level of consciousness develop if hematoma
becomes large enough to IICP or cause shifts in intracranial contents. These symptoms
are absent with small hemorrhages; the clinical presentation in this setting is that of
gradually progressing stroke.
F. ICH destroys brain tissue as it enlarges. The pressure created by blood and surrounding
brain edema is life-threatening; large hematomas have high mortality and morbidity.
The goal of treatment is to contain and limit the bleeding. Recurrences are unusual if the
causative disorder is controlled (hypertension or bleeding diathesis).
Subarachnoid hemorrhage
A. The two major causes of SAH are rupture of arterial aneurysms that lie at base of brain
and bleeding from vascular malformations that lie near pial surface. Bleeding diatheses,
trauma, amyloid angiopathy, and illicit drug use are less common.
B.
Rupture of aneurysm releases blood directly into CSF under arterial pressure. The blood
spreads quickly within CSF, rapidly IICP. Death or deep coma ensues if bleeding
continues. The bleeding usually lasts only few seconds but rebleeding is very common.
With causes of SAH other than aneurysm rupture, the bleeding is less abrupt and may
continue over longer period of time.
C.
Symptoms of SAH begin abruptly in contrast to more gradual onset of ICH. The sudden
increase in pressure causes cessation of activity (loss of memory or focus or knees
buckling). Headache is invariable symptom and is typically instantly severe and
widespread; the pain may radiate into neck or even down back into legs. Vomiting
occurs soon after onset. There are usually no important focal neurologic signs unless
bleeding occurs into 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.
D.
Approximately 30% of patients have minor hemorrhage manifested only by sudden and
severe headache (the so-called sentinel headache) that precedes major SAH. The
complaint of sudden onset of severe headache is sufficiently characteristic that minor
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% overall and 12% in
patients in whom headache was the only symptom.
E. The goal of treatment of SAH is to identify 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 CSF induces
vasoconstriction, which can be intense and severe. The treatment of SAH is discussed
separately.
EPIDEMIOLOGY
1.
2.
Data compiled by AHA show that proportion of all strokes due to ischemia, ICH and SAH is 87,
10, and 3%. Globally, incidence of stroke due to ischemia is 68%, while incidence of
hemorrhagic stroke (ICH and SAH combined) is 32%, reflecting higher incidence of
hemorrhagic stroke in low- and middle-income countries.
Worldwide, stroke is 2nd most common cause of mortality and 3rd most common cause of
disability. While incidence of stroke is decreasing in high-income countries, incidence is
increasing in low-income countries. The overall rate of stroke-related mortality is decreasing
in high and low income countries, but absolute number of people with stroke, stroke
survivors, stroke-related deaths, and the global burden of stroke-related disability is high.
3.
4.
5.
In the US, 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. There is a higher regional
incidence and prevalence of stroke and a higher stroke mortality rate in the southeastern US
(sometimes referred to as "stroke belt") than in rest of country.
Men have higher incidence of stroke than women at younger but not older ages, with
incidence reversed and higher for women by age 75 years and older.
Blacks and Hispanics have increased risk of stroke compared with whites in the US, as
illustrated by following observations.
A. Northern Manhattan Study reported that age-adjusted incidence of first ischemic stroke
among whites, Hispanics, and blacks was 88, 149, and 191 per 100,000. Among blacks
compared with whites, the relative rate of stroke attributed to intracranial
B.
C.
D.
atherosclerosis, extracranial atherosclerosis, lacunes, and cardioembolism was 5.85,
3.18, 3.09, and 1.58. Among Hispanics compared with whites, 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% more common, among blacks compared with whites. 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 non-Hispanic whites.
Stroke prevalence rates (age 18 and older) for blacks, whites, Asians, and American
Indian/Alaska natives are 3.9, 2.5, 1.5, and 5.9%.