Pathophysiology of Thromboembolic Stroke

Emer R. Mcgrath

Martin J. O’Donnell

Stroke is defined by the World Health Organization (WHO) as “rapidly developing clinical signs of focal (at times global) disturbance of cerebral function, lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin.”¹ This definition is conventionally considered to include ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Clinical presentations lasting <24 hours are defined as transient ischemic attacks (TIAs). Recently, there has been a proposal to change the definition of stroke and TIA to a tissue-based definition, that is, one based on the presence or absence of acute ischemia or hemorrhage on neuroimaging.

EPIDEMIOLOGY OF STROKE

Incidence and Prevalence of Stroke

Stroke is the leading cause of acquired adult disability worldwide and the second most common cause of death after cardiovascular disease.²^,³ The WHO estimates that 15 million people suffer a stroke each year, and of these, 5 million people are left with permanent disability.⁴ In the absence of further effective population-based interventions, a projected 18 million first-time strokes will occur in 2015, rising to 23 million first-time strokes in 2030.³ Typical estimates for stroke prevalence (the number of individuals living with a previous history of stroke) are approximately 500 per 100,000 people in developed countries. The estimated prevalence of stroke survivors worldwide was 62 million in 2005, and this is projected to increase to 67 million in 2015 and to 77 million in 2030.³

Stroke-Related Mortality

In 2005, there were an estimated 5.7 million deaths due to stroke, accounting for approximately 10% of total deaths worldwide. It is projected that 6.5 million stroke deaths will occur in 2015 and 7.8 million deaths in 2030. A small decrease in age-specific stroke mortality rates has been projected from 2005 to 2030, which is largely due to a decline in high-income countries. However, due to an increasingly ageing population worldwide, crude stroke mortality rates are actually projected to increase, from 89 per 100,000 in 2005 to an estimated 98 per 100,000 in 2030. The increase in stroke mortality will be most marked in developing countries, where increases in stroke incidence are most prominent.³

Socioeconomic Consequences of Stroke

Disease burden may be measured using disability-adjusted life years (DALYs). One DALY is 1 year of healthy life lost, due to premature death or living with a disability. The global burden of stroke is currently projected to rise from an estimated 38 million DALYs in 1990 to 61 million DALYs in 2020.⁴ Globally, stroke accounts for approximately 2% to 4% of total health care costs, while in high-income countries, stroke is responsible for more than 4% of direct health care budgets.⁵ The estimated direct and indirect cost of stroke in the United States for 2010 was $73.7 billion. The estimated mean lifetime cost of ischemic stroke in the United States is currently $140,048, encompassing immediate inpatient care, rehabilitation services, and follow-up care costs (including long-term care).⁶ A cost analysis study by Brown et al.⁷ estimated that the total cost of stroke for the United States from 2005 to 2050 will be US $2.2 trillion, based on 2005-dollar prices. The decline in case fatality of stroke reported in many high-income countries is expected to impact on health care resources in these countries, given the increased requirement for rehabilitation services and long-term care facilities.

Global Variation in the Burden of Stroke

Worldwide, stroke demonstrates significant geographical variations, in terms of incidence (and temporal trends), prevalence, case fatality, and case mix (i.e., stroke subtypes). A systematic review of population-based studies by Feigin et al. found that from 1970 to 2008 there was a 42% decrease in the incidence of stroke in high-income countries, compared to a more than 100% increase in the incidence of stroke in middle- and low-income countries. In addition, from 2000 to 2008, overall stroke incidence rates in low- to middle-income countries exceeded rates in high-income countries for the first time, by over 20% (117 per 100,000 and 94 per 100,000, respectively).⁸ In 2005, 87% of deaths due to stroke occurred in middle- and low-income countries. Moreover, this figure rose to 94% of global deaths due to stroke in those under the age of 70 years, where projected age-standardized death rates from stroke in people aged 30 to 69 years were higher for middle- and low-income countries than for high-income countries. For example, the age-standardized death rate for stroke in Nigeria was more than 120 per 100,000 people, compared to rates of approximately 20 per 100,000 people in the United Kingdom and <15 per 100,000 people in Canada. Finally, stroke mortality from 2005 to 2030 is predicted to increase by almost 33% in middle-income countries, from approximately 3 to 4 million deaths, while a small or negligible change is predicted for high-income countries.³ Therefore, regional variations in the burden of stroke are projected to become more marked in the coming decades. The determinants underlying these changes may include variations in the stages of the epidemiologic transition, differing access to
risk factor modification therapies, and availability of evidence-based acute stroke interventions (e.g., stroke units).

ETIOLOGY OF ISCHEMIC STROKE

Heterogeneity of Stroke

Unlike acute coronary syndrome, which is mostly due to large-vessel atherosclerosis, the underlying mechanisms for ischemic stroke are more heterogeneous. For each ischemic stroke subtype, thrombogenesis is the usual underlying pathophysiological mechanism, although the local factors responsible for development of thrombosis differ by ischemic stroke etiology.⁹ Ischemic stroke may be categorized into distinct etiological subtypes, including large vessel, small vessel, cardioembolism, mixed etiology, and cryptogenic.

Etiological Criteria for Ischemic Stroke

Stroke can be classified based on primary etiological mechanism into ischemic stroke and hemorrhagic stroke. In North America and Europe, approximately 85% to 90% of strokes are due to ischemia, with the remaining 13% occurring due to hemorrhage. In developing countries, a larger proportion of strokes are due to ICH.⁸ Within ischemic stroke, there are five subcategories based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system. The TOAST classification documents the pathophysiological mechanism of ischemic stroke based on clinical features and the results of investigations that include brain imaging (computed tomography [CT]/magnetic resonance imaging [MRI]), cardiac imaging (transthoracic and transesophageal echocardiography) and cardiac rhythm monitoring (e.g., Holter monitor), neurovascular imaging (duplex ultrasound, CT or MR angiography, and contrast angiography), and laboratory tests (Table 91.1). For secondary ischemic stroke prevention, the cornerstones of evidence-based therapy are lifestyle modification (e.g., smoking cessation), antiplatelet therapy, antihypertensive therapy, and statin therapy. Identification of certain ischemic stroke etiologies does inform additional evidence-based management approaches, most notably for atrial fibrillation (AF) (introduction of oral anticoagulant therapy) and significant carotid artery disease (carotid endarterectomy). The five categories in the TOAST classification system are (a) large-artery atherosclerosis, (b) cardioembolism, (c) small-artery occlusion or lacunar ischemic stroke, (d) stroke of other determined etiology, and (e) stroke of undetermined etiology ([i] two or more causes identified, [ii] negative evaluation, or [iii] incomplete evaluation).¹⁰ The etiology of hemorrhagic stroke can be due to primary ICH or SAH, with ICH often topographically subclassified into lobar and deep hemorrhage.

Large-Artery Atherosclerosis

Large-artery stroke is usually a consequence of atherosclerosis in the extracranial (carotid or vertebral) and/or intracranial arteries (e.g., middle cerebral or basilar artery), where plaque rupture and thrombus formation can result in local occlusion or distal occlusion due to artery-to-artery thromboembolism. Vascular locations that have a predilection for development of atherosclerosis include the arch of the aorta, the origin and bifurcation of the common carotid artery, the distal end of the internal carotid artery, the terminal segments of the vertebral arteries, the basilar artery, and less commonly, the middle cerebral and posterior cerebral arteries.¹¹^,¹² In large arteries, thrombosis typically occurs at the site of an atherosclerotic plaque, termed atherothrombosis. Ischemic stroke may result from atherothrombosis due to artery-to-artery thromboembolism or, less commonly, by acute occlusion with resultant hypoperfusion (e.g., watershed infarction).¹³^,¹⁴ Large-vessel atherosclerosis accounts for about 20% of all ischemic stroke in high-income countries and is predominantly extracranial in origin (e.g., carotid artery).¹⁵ Large-vessel disease is reported to be more common in parts of Asia, with an apparent predominance of intracranial artery stenosis (e.g., middle cerebral artery). For example, atherosclerosis of intracranial vessels has been reported to account for up to 33% to 50% of ischemic strokes in China and Thailand, based on some hospital-based registries.¹⁶^,¹⁷^,¹⁸ The factors underlying this global variation in the proportion, and location, of large-vessel disease are largely unexplained, but may relate to differences in risk factors profiles (e.g., smoking and hypertension) or underlying genetic susceptibility. From a management perspective, carotid artery stenosis is the most important source of large-vessel stroke to identify, as timely carotid endarterectomy dramatically reduces the risk of recurrent ischemic stroke in patients with recent minor ischemic stroke or TIA, based on the results of large randomized controlled trials. For large-vessel intracranial disease, a recent clinical trial (SAMMPRIS trial) did not report a benefit of endovascular stenting (plus aggressive medical management) over aggressive medical management alone; the trial was stopped early due to excess rate of stroke and death, within 30 days, in the endovascular group.

Table 91.1 Etiology of thromboembolic ischemic stroke

Etiological Mechanism

Frequency (%)

Large-artery atherosclerosis

˜20

Cardioembolism

˜20-30

Lacunar

˜20-30

Cryptogenic

15-40^a

^aDepending on the extent of etiological diagnostic workup.

Less common large-vessel mechanisms of ischemic stroke include arterial dissection,¹⁹ fibromuscular dysplasia,²⁰ Moyamoya disease, and large-vessel arteritis (e.g., Takayasu arteritis and giant cell arteritis) (see Chapter 100).¹¹ Arterial dissection, usually of the extracranial vessels, is the third leading cause of ischemic stroke in young people and can lead to ischemic stroke by either local occlusion or distal thromboembolism.¹⁹ Predisposing factors include direct trauma,²¹^,²² family history,²³ migraine,²⁴ and underlying arteriopathies, such as Moyamoya disease²⁵^,²⁶^,²⁷ or fibromuscular dysplasia.²⁸^,²⁹ Takayasu arteritis is a chronic granulomatous inflammatory condition of the aorta and its major branches. It occurs most commonly in Asia and is rare in Western Europe and North America. It predominantly affects the media and adventitia of the arterial wall, leading to stenosis or aneurysm formation.³⁰
Approximately 10% to 20% of patients with Takayasu arteritis will have a TIA or ischemic stroke.³¹

Cardioembolism

Cardioembolism is the mechanism responsible for approximately 20% to 30% of all ischemic strokes.¹⁵ There are a number of conditions that predispose to cardiac sources of emboli, which may originate from the venous system (paradoxical embolism), intracardiac (e.g., AF, left ventricular impairment) or postcardiac (aortic arch disease). Although the aortic arch is a large-vessel structure, it is conventionally included as a cardioembolic source, likely because it is usually identified on transesophageal echocardiography.

Paradoxical Embolism

Paradoxical emboli are proposed to occur when emboli that arise in the venous circulation, for example, from a deep vein thrombus, cross into the arterial circulation through a patent foramen ovale (PFO) or atrial septal defect, or through a pulmonary arteriovenous malformation (PAVM). Paradoxical embolism can be quite difficult to diagnose, and it is usually presumed, rather than confirmed, based on visualizing a right to left communication and/or shunt. PFO is common in the general population, present in about 20% of people. An association between PFO and ischemic stroke was first reported in younger patients (<55 years),³² but the association has also been reported in older adults more recently.³³^,³⁴^,³⁵^,³⁶^,³⁷ However, while case-control studies report a positive association between PFO and cryptogenic ischemic stroke (odds ratio [OR] 3.12; 95% confidence interval [CI] 1.98 to 5.10),³⁵ two prospective cohort studies have failed to demonstrate an independent association between PFO and an increased risk of stroke, after a mean follow-up of 5 years³⁸ and 7 years.³⁹ In addition, studies have failed to show that the presence of an isolated PFO is a risk factor for recurrent ischemic stroke. Diagnostic investigations include transthoracic echocardiogram, transesophageal echocardiogram (TEE), and transcranial Doppler with contrast.⁴⁰ TEE is the gold standard investigation for diagnosis of PFO and estimation of PFO size, with a specificity and sensitivity of 100% for color Doppler TEE and 100% and 89%, respectively, for contrast TEE.⁴¹ The optimal management strategy for patients with PFO and cryptogenic ischemic stroke remains controversial, due to difficulties in establishing a true causal relationship between PFO and ischemic stroke and a lack of randomized controlled trials delineating the best treatment options.⁴² Although some studies have suggested an adjunct role for thrombophilic disorders,⁴²^,⁴³^,⁴⁴^,⁴⁵ the role for thrombophilic testing also remains uncertain. In healthy individuals with PFO, primary prevention with antithrombotic therapy is not currently recommended. The American Stroke Association/American Heart Association (ASA/AHA) currently recommends antiplatelet therapy for patients with ischemic stroke or TIA and a PFO to prevent a recurrent event (class IIa, level B evidence). There are no randomized controlled trials comparing oral anticoagulation to antiplatelet therapy, other than a subgroup analysis of the WARSS trial, which did not find a difference in recurrence stroke rates between treatment groups. An emerging management approach has been PFO closure, which may be achieved by transcatheter device closure, percutaneous device-less closure, and surgical closure by open or thoracoscopic access.⁴⁷ However, the recently presented CLOSURE trial did not report a benefit from PFO closure in approximately 900 participants after ischemic stroke, who were randomized to receive PFO closure or usual medical care, but did report an associated increased risk of new AF in the closure group on follow-up.⁴⁸ Other randomized controlled trials, evaluating other approaches to PFO closure following ischemic stroke, are ongoing. Management challenges are faced in patients with large PFO, PFO associated with atrial septal aneurysm³³^,⁴⁹ or in younger patients with no other risk factor for ischemic stroke, especially in those who experience a recurrent episode of ischemic stroke despite antiplatelet therapy.

An atrial septal aneurysm is a protrusion of part of the atrial septum through the fossa ovalis into the right or left atrium or both,⁵⁰^,⁵¹ TEE is considered to be the investigation of choice for detection of atrial septal aneurysm.⁵² An atrial septal aneurysm is associated with an increased risk of ischemic stroke, especially in association with a PFO. A meta-analysis of case-control studies comparing patients with ischemic stroke to controls reported ORs of 1.83 for PFO, 2.35 for atrial septal aneurysm, and 4.96 for both PFO and atrial septal aneurysm, indicating a greater risk of stroke from the combination compared to either condition alone.⁵³ Other potential explanations for the increased risk of stroke associated with atrial septal aneurysm include a predisposition toward atrial arrhythmias, thrombus formation, and left atrial dysfunction.⁵¹^,⁵⁴^,⁵⁵^,⁵⁶

PAVMs, which are commonly congenital in origin, are abnormal connections between pulmonary arteries and veins. They are also associated with an increased risk of ischemic stroke,⁵⁷ and paradoxical embolism is considered to be the most likely underlying mechanism.⁵⁸ The reported incidence of stroke in studies of patients with PAVM has ranged from 2.6% to 25%.⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³ The gold standard for diagnosis of PAVM is pulmonary angiography, although less invasive techniques such as contrast and helical CT, magnetic resonance angiograms, and contrast echocardiography are also useful.⁶⁴ Treatment is recommended for patients with PAVMs who are symptomatic or who have feeding vessel diameters >3 mm. Embolotherapy is the current treatment of choice for PAVMs. Surgical resection is reserved for those who fail to respond to, or are unsuitable for, embolotherapy.⁶⁵

Intracardiac Sources of Thromboembolism

Left-sided cardiac sources of emboli include left atrial thrombus secondary to AF or flutter,⁶⁶^,⁶⁷^,⁶⁸ left ventricle (LV) thrombus subsequent to a transmural myocardial infarction (MI),⁶⁹^,⁷⁰ an old MI with akinetic segments of myocardium and ejection fraction ≤28%,⁷¹ cardiac tumors such as left atrial myxoma,⁷² and abnormalities of the mitral valve, both native and artificial.⁷³

AF is the most common cardiac arrhythmia and is a significant risk factor for stroke, associated with a fivefold increase in risk.⁷⁴ Irregular contractions of the atria lead to stasis of blood and an increased risk of thrombus formation, particularly in the left atrial appendage. This in turn predisposes to intracardiac thrombosis and, subsequently, ischemic stroke. In high-income countries, about 25% of all ischemic strokes and 36% of strokes in patients >80 years are due to AF.⁷⁵

AF may be categorized as valvular (mostly associated with mitral valve disease) or nonvalvular.⁷⁶ Aspirin reduces the risk of ischemic stroke by about 22%, the addition of clopidogrel reduces the risk of recurrent stroke by a further 18% (ACTIVE-A)
while anticoagulant therapy (warfarin; international normalized ratio [INR] 2 to 3) reduces the risk of ischemic stroke by 66% compared to control, and warfarin (INR 2 to 3) is superior to combination aspirin and clopidogrel (ACTIVE-W). Recently, large randomized controlled trials have reported on the effectiveness of novel anticoagulants (apixaban, dabigatran, and rivaroxaban), which all appear very promising as replacements for warfarin in patients with AF, see Chapter 92.⁷⁷

Other Cardiac Causes: Coronary heart disease is a known risk factor for ischemic stroke, mediated through a number of mechanisms. After an MI, mural thrombi, and subsequently cardioemboli, can arise due to the presence of left ventricular aneurysms, akinetic segments of left ventricular myocardium, or new-onset AF or flutter. A greater degree of myocardial injury and left ventricular dysfunction after anterior MI have been shown to increase the risk of stroke in the early postinfarct period.⁷⁸^,⁷⁹^,⁸⁰ The risk of mural thrombi, and therefore early stroke, is much greater after anterior wall MI rather than inferior wall MI.⁸¹^,⁸² The reported incidence of stroke in the first 2 weeks after MI ranges from 0.7% to 4.7%.⁷¹

Left ventricular hypertrophy (LVH) has also been associated with an increased risk of stroke both from electrocardiogram- and from echocardiogram-based studies, and this risk is independent of other risk factors. One proposed explanation for this association is that LVH can predispose to left atrial dilatation and in turn AF, largely medicated though the effect of hypertension.⁸³^,⁸⁴^,⁸⁵

Valvular Heart Disease: Valvular heart disease may be native (e.g., rheumatic) or prosthetic. Of native valvular disease, mitral stenosis has the strongest association with ischemic stroke,⁸⁶ and, less commonly, mitral annular calcification and mitral valve prolapse.⁸⁷ Mitral stenosis is commonly associated with AF, which further increases the risk of ischemic stroke. Rheumatic heart disease remains a common cause of mitral valve disease, and an important risk factor for cardioembolic ischemic stroke, in many regions of the world (e.g., Africa and India). Emboli can also arise from valvular vegetations consisting of fibrin and platelets in nonbacterial thrombotic endocarditis⁸⁸^,⁸⁹ and from infected valvular vegetations in infective endocarditis.⁹⁰ Patients with mechanical mitral and aortic valves, particularly mitral valves, have a sufficiently high risk of ischemic stroke that justifies indefinite oral anticoagulant therapy. In contrast, bioprosthetic valves require a finite course of antithrombotic therapy, usually 3 months after surgery, unless there is an alternative indication for indefinite therapy (e.g., AF).

Congestive heart failure (CHF) is an independent risk factor for stroke, associated with a twofold to threefold increase in the relative risk (RR) of stroke.⁷⁵^,⁹¹^,⁹²^,⁹³ Various mechanisms have been proposed to explain this association. Dysfunction of the LV in CHF can promote stasis of blood in the LV and left atrium (ejection fraction < 30%⁹⁴), thereby predisposing to thrombus generation and risk of cardioembolic stroke, while transient arrhythmias such as AF are more common in this patient population.⁹⁵ In South and Central America, Chagas disease (tropical parasitic disease Trypanosoma cruzi) is an important cause of dilated cardiomyopathy and risk factor for stroke, especially in younger patients.

Postcardiac sources: The prevalence of severe atheroma of the aortic arch (>4 to 5 mm) is approximately 30%, and its presence is associated with a fourfold increase in the risk of ischemic stroke and peripheral embolism.⁹⁶ Emboli can also arise from atherosclerotic plaques in the aortic arch, proximal to the left subclavian artery, and enter the cerebral circulation leading to an ischemic stroke.⁹⁷

Small-Vessel Disease

Approximately 20% to 30% of all ischemic strokes are due to lacunar infarcts.¹⁵ Lacunar infarcts occur due to occlusion of small deep penetrating arteries, such as the lenticulostriate branches of the anterior cerebral artery and middle cerebral artery. The terminal pathophysiological mechanism underlying small-artery occlusion is believed to be local thrombosis, secondary to microatheroma and lipohyalinosis. Microatheroma is thought to be the most common mechanism underlying symptomatic lacunar infarcts,⁹⁸ while lipohyalinosis is proposed to predominantly account for many asymptomatic lacunar infarcts, causing occlusion of very small penetrating arteries <200 µm in diameter.⁹⁹ A microatheroma is characterized by lipid-laden macrophages, cholesterol deposits, and subintimal fibroblast proliferation.¹⁰⁰ Lipohyalinosis is believed to be an intermediate stage between fibrinoid necrosis and microatheroma, having characteristics of both arterial (atheromatous lipid deposits) and arteriolar (hyalinization) disease.¹⁰¹ Fibrinoid necrosis typically occurs in the setting of malignant hypertension and affects cerebral, retinal, and renal arterioles and capillaries.¹⁰⁰ It is characterized histologically by intensely eosinophilic and finely granular deposits in the arteriolar wall.¹⁰² Other causes for small-artery occlusion include microemboli,¹⁰³ cholesterol emboli from atherosclerotic plaques,¹⁰⁴ polycythemia,¹⁰⁵ antiphospholipid antibodies,¹⁰⁶ amyloid angiopathy,¹⁰⁷ cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL),¹⁰⁸ Sneddon syndrome,¹⁰⁹ and various types of vasculitis.¹¹⁰

CADASIL is an uncommon inherited disorder that predominantly affects the small arteries of the brain, leading to an increased risk of early-onset strokes, typically lacunar infarcts, in the periventricular and basal ganglia regions. A study in Scotland estimated the prevalence at almost 2 per 100,000 adults, which is believed to be an underestimate.¹¹¹ Other clinical consequences include subcortical dementia, migraine with aura, and psychiatric symptoms.¹¹² It is caused by a mutation in the Notch3 gene on chromosome 19, which leads to the deposition of the ectodomain of the Notch3 receptor protein and granular eosinophilic material on vascular smooth muscle cells of arteries, resulting in their gradual degeneration.¹¹³ The degeneration of arterial vascular smooth muscle cells results in progressive fibrosis and luminal stenosis of small penetrating arteries in the brain, reduced blood flow, and subsequently, lacunar infarcts.¹¹⁴^,¹¹⁵ Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) has a similar pattern of early-onset cerebral ischemia to CADASIL and is due to a mutation in HTRA1.

Sneddon syndrome is a rare disorder characterized by cerebrovascular disease occurring in association with livedo reticularis, an ischemic dermatopathy of the skin, and the absence of an infection or collagen vascular disease.¹⁰⁹^,¹¹⁶ The definitive etiology is unknown, although it is thought to be autoimmune medicated.¹¹⁷ Hypertension is reported in approximately 60% of patients with Sneddon syndrome, while 35% are noted to have antiphospholipid antibodies.¹¹⁸ Previous neuropathological reports have noted multiple small infarcts, together with
smooth muscle cell hyperplasia and fibrotic occlusion of small- to medium-sized cerebral arteries, as well as occasional arterial thrombi. These findings suggest that the underlying pathogenesis for ischemic events in Sneddon syndrome is a noninflammatory arteriopathy affecting the small- to medium-sized cerebral arteries.¹⁰⁹^,¹¹⁹

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is an inherited progressive disorder due to mitochondrial dysfunction. It is characterized by early onset of stroke, typically before the age of 40.¹²⁰ The underlying pathophysiology for cerebrovascular events in MELAS has not been fully determined. MRI diffusion-weighted images in these individuals have demonstrated multiple hyperintense cortical laminar lesions, which do not follow the distribution of any single large artery.¹²⁰^,¹²¹ The mitochondrial angiopathy hypothesis suggests that the lesions are secondary to ischemia which is caused by mitochondrial and vascular dysfunction of cerebral small arteries.¹²⁰

Stroke of Other Determined Etiology

Other uncommon and rare causes of ischemic stroke are considered in the category of “stroke of other determined etiology,” according to the TOAST classification system. This category can include hematological disorders, hypercoagulable states, nonatherosclerotic vasculopathies, and arterial dissection.¹⁰ Cerebral venous sinus thrombosis accounts for <1% of ischemic strokes and typically affects younger people.⁴⁶^,¹²² The superior sagittal sinus, the transverse sinuses, and the cavernous sinuses are most commonly affected by thrombosis.¹⁰⁰ Venous thrombosis results in localized edema and venous infarction, which often becomes hemorrhagic, as well as raised intracranial pressure.¹²² Reported risk factors for cerebral venous sinus thrombosis include inherited prothrombotic states such as factor V Leiden (FVL) mutation¹²³ and prothrombin gene mutation 20210A (PT G20210A)¹²⁴; acquired prothrombotic states such as antiphospholipid antibodies,¹²⁵ pregnancy, and the puerperium¹²⁶; infections such as otitis, sinusitis, and mastoiditis¹²⁷; chronic inflammatory conditions such as Wegener granulomatosis and sarcoidosis¹²⁸; and trauma such as a head injury,¹²⁹ dehydration, and injury to the jugular veins or sinuses from neurosurgical procedures.¹²² MRI combined with MR venography is the most sensitive and specific diagnostic test.¹³⁰ A hyperintense signal from thrombosed sinuses on MRI together with corresponding absence of flow on MR venography confirms the diagnosis.¹²² AHA/ASA guidelines indicate that anticoagulation is probably effective for patients with acute cerebral vein thrombosis (class IIa; level of evidence B), although definitive clinical trials are lacking. In the absence of trial data to define the optimal duration of anticoagulation for acute cerebral vein thrombosis, it is recommended to administer anticoagulation for at least 3 months, followed by antiplatelet therapy (class IIa; level of evidence C).⁴⁶

Stroke of Undetermined Etiology

In some cases, the cause of stroke cannot be definitively determined and the stroke is classified as “stroke of undetermined etiology.” A stroke may be classified in this category when one of the following two conditions are met: (a) an extensive evaluation is negative, which includes large-vessel imaging and complete cardiovascular assessment, or (b) the diagnostic evaluation is incomplete.¹⁰ Clearly, the most important determinant of the proportion of patients labeled as cryptogenic is the extent of the diagnostic testing, which makes between-study comparisons of etiological case mix difficult.

Covert Stroke

Clinically overt stroke is considered to represent only a fraction of all episodes of cerebral infarction. The advent of contemporary MRI sequences has identified a large burden of subclinical cerebrovascular disease, which includes covert infarction, white matter hyperintensities, cerebral atrophy, and microbleeds. Moreover, the presence (pattern and burden) of covert stroke has been associated with an increased risk of cognitive decline, dementia, depression, vascular parkinsonism, and gait impairment.¹³¹^,¹³²^,¹³³^,¹³⁴^,¹³⁵^,¹³⁶ Previous studies report a twofold to fourfold increase in the risk of clinically overt stroke in the presence of covert cerebral infarcts, independent of other vascular risk factors.¹³⁵^,¹³⁶ Given their chronic clinical consequence, the term “covert” rather than “silent” has been adopted. A systematic review of eight population-based studies reported a prevalence of silent brain infarcts in the general elderly population of 8% to 28%.¹³² Previous studies indicate that the strongest risk factors associated with silent cerebral infarcts are age, hypertension, diabetes mellitus, and smoking.¹³²

TRADITIONAL RISK FACTORS FOR ISCHEMIC STROKE

Both ischemic and hemorrhagic stroke are strongly associated with a number of conventional risk factors, namely hypertension, smoking, diet, sedentary lifestyle, obesity, diabetes mellitus, and exercise. Many of these risk factors exert their effect through a number of intermediate mechanisms. For example, hypertension increases the risk of ICH, small-vessel disease, atherosclerosis, and AF.

The INTERSTROKE study, which included 6,000 participants from 22 countries, reported that 10 key risk factors were associated with 90% of the population-attributable risk (PAR) of ischemic stroke, namely hypertension, smoking, waist-to-hip ratio (WHR), diet, physical activity (PA) level, diabetes mellitus, alcohol intake, psychosocial stress and depression, cardiac causes such as AF, and ratio of apolipoprotein B (ApoB) to apolipoprotein A1 (ApoA1) (after adjustment for age and sex)¹³⁷ (Table 91.2). Since many of these risk factors are common and modifiable, these findings suggest that population-based programs, which target key risk factors, may have an enormous impact on the incidence of stroke.

Age

Age is the strongest independent risk factor for stroke. The incidence of stroke increases with age, with up to 75% of strokes occurring in individuals over the age of 65 in high-income countries.¹³⁸ For every 10 years above the age of 55, the risk of stroke more than doubles.⁴^,¹³⁹^,¹⁴⁰ A 5-year follow-up of a population-based cohort of over 4,000 people >65 years reported a hazard ratio (HR) of 1.74 per 10-year increase in age over 65.¹³⁸

Table 91.2 Traditional risk factors for ischemic stroke

Risk Factor

OR (99% CI)

Hypertension (self-reported history)

2.37 (2.00-2.79)

Current smoking^a

2.32 (1.91-2.81)

Diabetes mellitus

1.60 (1.29-1.99)

Ratio of ApoB to ApoA1

2.40 (1.86-3.11)

Obesity (waist-to-hip ratio)

1.69 (1.38-2.07)

Regular physical activity

0.68 (0.51-0.91)

Diet risk score

1.34 (1.09-1.65)

Alcohol consumption^a

1-30 drinks per month

0.79 (0.63-1.00)

>30 drinks per month

1.41 (1.09-1.82)

Psychosocial factors

Psychosocial stress

1.30 (1.04-1.62)

Depression

1.47 (1.19-1.83)

Odds ratios for waist-to-hip ratio and diet risk score are for the highest tertile compared to the lowest tertile.

^aComparator for current smoker and alcohol intake is never or former.

OR, odds ratio; CI, confidence interval; Apo, apolipoprotein.

From O’Donnell MJ, Xavier D, Lisheng L, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet 2010;376:112-123.

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