Stroke

Stroke is the second leading cause of mortality worldwide and a leading cause of acquired adult disability. Primary stroke subtypes include ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Each stroke subtype has differing etiologies, outcomes, and management strategies. In the past 30 years, there have been major advances in the diagnosis (emergence of widely available neuroimaging) and treatment of acute stroke. In addition, there is increased awareness of the importance of covert stroke (stroke on neuroimaging without a history of acute clinical stroke). This chapter provides an overview of stroke, with a primary focus on ischemic stroke, which is the most common cause of stroke worldwide.

Definition

Stroke is defined by the World Health Organization (WHO) as “rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting 24 hours or longer or leading to death with no apparent cause other than that of vascular origin.” This definition is conventionally considered to include ischemic stroke, ICH, and SAH. However, due to advances in our knowledge about the nature, timing, and clinical presentation of stroke and its mimics, as well as significant advances in neuroimaging, in 2013 the American Heart Association (AHA)/American Stroke Association (ASA) proposed an updated definition of central nervous system (CNS) infarction (including hemorrhagic infarction) defined as “brain, spinal cord, or retinal cell death attributable to ischemia, based on: (1) pathological, imaging, or other objective evidence of cerebral, spinal cord, or retinal focal ischemic injury in a defined vascular distribution; or (2) clinical evidence of cerebral, spinal cord, or retinal focal ischemic injury based on symptoms persisting ≥24 hours or until death, and other etiologies have been excluded.” According to the AHA/ASA, “a transient ischemic attack (TIA) is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”

Epidemiology

Frequency

The WHO estimates that approximately 14 million people suffer a stroke each year, and of these, more than five million die and another five million people are left permanently disabled. Although age-specific stroke mortality rates worldwide have declined between 1990 and 2016, predominantly due to a decline in high-income countries, the reduction in age-standardized stroke incidence rates has been far less over that time period, indicating that the global burden of stroke remains high. Indeed, the estimated global lifetime risk of stroke among those aged 25 years or older increased from 22.8% in 1990 to 25% in 2016, and the incidence of stroke in some lower-income regions (e.g., east Asia and Southern sub-Saharan Africa) increased between 1990 and 2016. Worldwide, stroke shows significant geographical variation, in terms of incidence (and temporal trends), case fatality, and case mix (i.e., stroke subtypes). Overall, because of the aging population and population growth, the absolute numbers of individuals with prevalent stroke, stroke-related mortality, and global stroke-related disability remain high and continue to increase.

Traditional Risk Factors for Stroke

Both ischemic stroke and ICH are associated with several potentially modifiable risk factors, including hypertension, diabetes mellitus, smoking, poor diet, and physical inactivity. The INTERSTROKE study, which included 6000 participants from 22 countries, reported that 10 key risk factors are associated with 90% of the population-attributable risk (PAR) of ischemic stroke, namely hypertension, smoking, waist-to-hip ratio, diet, physical activity level, diabetes mellitus, alcohol intake, psychosocial stress/depression, and cardiac causes such as atrial fibrillation and ratio of apolipoprotein B to apolipoprotein A1 ( Table 144.1 ). Of these risk factors, five were associated with 80% of the PAR for all stroke (hypertension, smoking, abdominal obesity, physical inactivity, and diet), and each was an important risk factor for both ischemic and hemorrhagic stroke. Thus a large proportion of stroke is potentially preventable through population-based interventions aimed at modifying these risk factors. Hypertension is the strongest risk factor for both ischemic stroke and ICH and, arguably, the most modifiable through lifestyle intervention (e.g., reducing salt intake) and use of antihypertensive medications.

Table 144.1

Traditional Risk Factors for Ischemic Stroke

Reprinted with permission from Elsevier. O’Donnell MJ, Xavier D, Liu 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.

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 Apo A1	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)

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

a Comparator for current smoker and alcohol intake is never or former

Pathobiology

Stroke can be classified into ischemic stroke ( Fig. 144.1 ) and hemorrhagic stroke. Hemorrhagic stroke is further subtyped into ICH ( Fig. 144.2 ) and SAH. In North America and Europe, approximately 87% of strokes are due to ischemia, with the remaining 13% due to hemorrhage.

Figure 144.1, COMPUTED TOMOGRAPHY OF BRAIN WITH RIGHT INTRACEREBRAL HEMORRHAGE.

Figure 144.2, COMPUTED TOMOGRAPHY OF BRAIN WITH LEFT HEMISPHERIC ISCHEMIC STROKE.

Etiological Classification of Ischemic Stroke

Unlike acute coronary syndrome, which is primarily due to large vessel atherosclerosis (see Chapter 145 ), the underlying mechanisms for ischemic stroke are more heterogeneous. The most used etiological classification is the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system which focuses on the pathophysiological mechanism of ischemic stroke and is based on clinical features and the results of diagnostic investigations (brain imaging, cardiac investigations, and neurovascular imaging). The five etiological subcategories in the TOAST classification system include large-artery stroke, cardioembolism, small-artery occlusion (or lacunar ischemic stroke), stroke of other determined etiology, and stroke of undetermined etiology.

Large Artery Stroke

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), with plaque rupture and thrombus formation. Ischemic stroke may result from artery-to-artery thromboembolism with distal occlusion or, less commonly, by acute occlusion with resultant hypoperfusion (e.g., watershed infarction). Large vessel atherosclerosis accounts for approximately 20% of all ischemic stroke in high-income countries and is predominantly extracranial in origin. Intracranial atherosclerosis has been reported to account for up to 33% to 50% of ischemic strokes in parts of Asia (e.g., China and Thailand), but it is a much less common cause of acute stroke in North America and Europe. Arterial dissection, the third leading cause of ischemic stroke in young people, can lead to ischemic stroke by either local occlusion or distal thromboembolism. Predisposing factors for dissection include trauma and underlying collagen vascular disorders, such as fibromuscular dysplasia and Ehlers-Danlos syndrome. Less common large vessel mechanisms of ischemic stroke include moyamoya disease, Fabry disease, and large vessel arteritis (e.g., Takayasu arteritis and giant cell arteritis).

Cardioembolism

Approximately 14% to 30% of all ischemic strokes are caused by cardioembolism, with marked regional variation (see Chapter 14 ). Several conditions predispose to cardioembolism, originating from the venous system (paradoxical embolism), intracardiac (e.g., atrial fibrillation), or postcardiac (aortic arch disease).

Precardiac

Paradoxical emboli occur when emboli that arise in the venous circulation (e.g., from a deep vein thrombus) cross into the arterial circulation through a patent foramen ovale (PFO), atrial septal defect (ASD), or a pulmonary arteriovenous malformation (AVM). A PFO is found in up to 20% of the general population. Several observational studies have reported an association between first ischemic stroke and PFO, particularly in younger patients, and percutaneous PFO closure reduces the risk of recurrent stroke in patients younger than 60 years of age, indicating that PFO is a risk factor for recurrent ischemic stroke. Atrial septal aneurysm, a protrusion of part of the atrial septum through the fossa ovalis into the right or left atria, is associated with an increased risk of ischemic stroke, particularly when it occurs simultaneously with a PFO.

Intracardiac

Left-sided cardiac sources of emboli include left atrial thrombus secondary to atrial fibrillation or flutter (see Chapter 146 ), left ventricle thrombus after a transmural myocardial infarction (see Chapter 145 ), akinetic segments of myocardium with a low ejection fraction in the setting of an old myocardial infarction, cardiac tumors such as left atrial myxoma, and abnormalities of the mitral valve (both native and artificial). Atrial fibrillation or flutter is a significant risk factor for stroke, associated with a fivefold increase in risk. In North America and Europe, approximately 25% of all ischemic strokes are attributed to atrial fibrillation, a proportion that increases with older age (see Chapter 147 ). After acute myocardial infarction, mural thrombi can arise in the presence of left ventricular aneurysms, akinetic segments of left ventricular myocardium or new-onset atrial fibrillation or flutter. Congestive heart failure is an independent risk factor for stroke and is associated with a twofold to threefold increase in the relative risk of ischemic stroke. Valvular heart disease can involve both native (e.g., rheumatic heart disease) and prosthetic heart valves. Of native valvular disease, mitral stenosis has the strongest association with ischemic stroke; mitral annular calcification and mitral valve prolapse have weaker associations. Mitral stenosis is also commonly associated with atrial fibrillation, further increasing the risk of ischemic stroke. Emboli can also arise from valvular vegetations in nonbacterial thrombotic endocarditis or infective endocarditis. Mechanical mitral and aortic valves are associated with a sufficiently high risk for ischemic stroke that indefinite oral anticoagulant therapy is indicated. Rheumatic heart disease still accounts for half of all cases of endocarditis in some regions of the world (e.g., India and Africa). Several epidemiological studies have shown a link between ischemic stroke and Trypanosoma cruzi infection (Chagas disease) in South America.

Postcardiac

Atherosclerotic plaques in the aortic arch proximal to the left subclavian artery can be postcardiac sources of emboli, either atheromatous debris or platelet emboli, which then enter the cerebral circulation resulting in ischemic stroke. Severe aortic arch atheromas (>4 mm in diameter) are associated with a fourfold increase in the risk of ischemic stroke and peripheral embolism. Although anatomically a large vessel source, aortic arch disease is usually included in cardiac causes of ischemic stroke because it is typically identified via transesophageal echocardiography.

Small Vessel Disease

Approximately 20% of all ischemic strokes are due to lacunar or small vessel infarcts. Lacunar infarcts are the result of occlusion of small, deep penetrating arteries, such as the lenticulostriate branches of the anterior cerebral and middle cerebral arteries. The terminal pathophysiological mechanism underlying small artery occlusion is believed to be local thrombosis secondary to microatheroma (lipid laden macrophages, cholesterol deposits, and subintimal fibroblast proliferation) and lipohyalinosis (the intermediate stage between fibrinoid necrosis and microatheroma, which has characteristics of both arterial atheromatous lipid deposits and arteriolar hyalinization disease). Growing evidence supports a concept that damage to the glycocalyx by factors such as hyperglycemia, hypertension, and smoking contributes to vascular endothelial damage (see Chapter 142 ). Other causes of small artery occlusion include microemboli from atherosclerotic plaques, polycythemia vera (see Chapter 70 ), antiphospholipid antibodies (see Chapter 139 ), amyloid angiopathy (see Chapter 93 ), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), Sneddon syndrome, and various types of small vessel arteritis. The combination of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is an inherited progressive disorder characterized by mitochondrial dysfunction and early onset of stroke, typically before the age of 40. The mitochondrial angiopathy hypothesis suggests that the lesions are secondary to ischemia which is caused by mitochondrial and vascular dysfunction of cerebral small arteries.

Ischemic Stroke of Other Determined Etiology

Cerebral Venous Sinus Thrombosis

Cerebral venous sinus thrombosis accounts for less than 1% of ischemic strokes and typically affects younger people. The superior sagittal, transverse, and cavernous sinuses are those most commonly affected by thrombosis. Venous thrombosis results in localized edema and venous infarction, which often becomes hemorrhagic and may raise intracranial pressure (ICP). Reported risk factors for cerebral venous sinus thrombosis include inherited thrombophilia (see Chapter 138 ); acquired prothrombotic states such as antiphospholipid syndrome (see Chapter 139 ), pregnancy and the puerperium (see Chapter 141 ) and hypercoagulability of malignancy; infections such as otitis, sinusitis, and mastoiditis; chronic inflammatory conditions such as granulomatosis with polyangiitis and sarcoidosis; and trauma such as a head injury, dehydration, and injury to the jugular veins or sinuses during neurosurgical procedures.

Intracerebral Hemorrhage

ICH accounts for approximately 10% to 15% of all strokes (a larger proportion is reported in middle- and low-income countries) and can be classified as either primary or secondary, depending on the underlying cause. Primary ICH accounts for approximately 80% to 90% of cases and is the result of spontaneous rupture of small intracerebral blood vessels, usually damaged by chronic hypertension (and other vascular risk factors) or amyloid angiopathy. Antithrombotic therapy, particularly anticoagulant therapy, is an important risk factor for ICH (see Chapter 143 ). Secondary ICH occurs as a result of vascular abnormalities (ruptured saccular aneurysm, AVM), tumors (e.g., cavernous angioma, intracerebral neoplasm), impaired coagulation (e.g., due to use of oral anticoagulants or bleeding disorders such as hemophilia [see Chapter 134 ] or von Willebrand disease [see Chapter 133 ]), hemorrhagic transformation of ischemic stroke, septic emboli, vasculitis, moyamoya disease, and alcohol or illicit drug use (e.g., cocaine, amphetamines).

Subarachnoid Hemorrhage

SAH refers to bleeding within the subarachnoid space, which is the space between the arachnoid and pia mater. It accounts for approximately 3% to 5% of all strokes and is mostly caused by rupture of an intracranial aneurysm (approximately 80% to 85% of cases). Idiopathic nonaneurysmal perimesencephalic hemorrhage accounts for approximately 10% of cases, while the remaining 5% are due to rare causes such as inflammatory lesions of cerebral arteries (e.g., mycotic aneurysm, polyarteritis nodosa, primary angiitis), noninflammatory lesions of intracerebral vessels (e.g., arterial dissection, cerebral AVMs, cerebral amyloid angiopathy, cerebral venous thrombosis, moyamoya disease), vascular lesions of the spinal cord (saccular aneurysm of the spinal artery, spinal AVM), coagulopathy (e.g., hemophilia, von Willebrand disease), sickle cell disease (see Chapters 42 and 43 ), tumors (e.g., malignant glioma), trauma, and drug use (e.g., cocaine, anticoagulants and sympathomimetic agents).

Covert Stroke

Clinically overt stroke is considered to represent only a fraction of all episodes of cerebral infarction. The advent of contemporary magnetic resonance imaging (MRI) sequences has identified a large burden of subclinical cerebrovascular disease, which includes covert infarction, white matter hyperintensities, enlarged perivascular spaces, cerebral atrophy, and microbleeds. Covert stroke is common; for example, a systematic review of eight population-based studies reported a prevalence of silent brain infarcts in an older population of 8% to 28%. Moreover, covert stroke has been associated with an increased risk of cognitive decline, dementia, depression, and gait impairment. (See box on What Is Cryptogenic Ischemic Stroke? )

What is Cryptogenic Ischemic Stroke?

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 is met: (1) an extensive evaluation is negative, which includes large vessel imaging and complete cardiovascular assessment; or (2) the diagnostic evaluation is incomplete. The most important determinant of the proportion of patients labeled as having cryptogenic stroke is the extent of the etiological diagnostic testing, including transesophageal echocardiography. In studies where an extensive etiological work-up was undertaken, the proportion of patients designated as having cryptogenic stroke is small (5%–15%). In older patients with complete evaluation, paroxysmal atrial fibrillation is suspected to be the most common underlying cause of ischemic stroke in older adults with “cryptogenic” ischemic stroke.

Hematological Disorders and Ischemic Stroke

Inherited Thrombophilia

In general, studies have reported either no association or a modest association between inherited thrombophilia and ischemic stroke (see Chapter 138 ). Meta-analyses of observational studies have failed to demonstrate a significant association between the factor V Leiden mutation and ischemic stroke in adults, although some small case-control studies have reported an increased risk of ischemic stroke in those with the factor V Leiden mutation using oral contraceptives. Two large prospective population studies, the Physicians’ Health Study and the Cardiovascular Health Study, failed to demonstrate a significant association between the prothrombin gene mutation G20210A and ischemic stroke risk, although a large meta-analysis of 19 case control studies reported a modest association. There is no prospective evidence to definitively support an association between protein C, protein S, or antithrombin deficiency and ischemic stroke risk in adults.

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