Introduction

This chapter focuses on the major causes of ischemic stroke. Common and less common stroke syndromes are described in Chapters 9 and 10.

Ischemic stroke is not a single disease, but a heterogeneous condition with several very different pathophysiological mechanisms. Identification of the underlying cause is important for several reasons. It helps to group patients into specific subtypes for the study of different aspects of prognosis, which may be used for planning and information purposes. It also helps for selecting patients for some specific therapies such as thrombectomy, and for specific secondary preventive purposes. Identification of the mechanism of ischemic stroke should therefore be part of the routine diagnostic workup in clinical practice.

Ischemic stroke is generally caused by one of three pathogenic mechanisms:

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  large artery atherosclerosis in extracranial and large intracranial arteries

  
  
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  embolism from the heart

  
  
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  intracranial small-vessel disease (lacunar infarcts).

These three types account for about 75% of all ischemic strokes (Figure 2.1). In about 20% of patients no clear cause of ischemic stroke can be identified despite appropriate investigations; this is labeled cryptogenic stroke. About 5% of all ischemic strokes result from more uncommon causes. These frequencies relate to ischemic stroke aggregating all age groups: in younger patients with stroke the pathogenic spectrum is much different, with arterial dissection as the most common single cause in patients <45 years of age (Chapter 10, Less Common Stroke Syndromes).

Figure 2.1 Graphic illustration of the major causes of ischemic stroke.

As described in Chapter 9 (Common Stroke Syndromes), there are several classification schemes for ischemic stroke based on the underlying pathophysiology. The most widely used is the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, which divides ischemic stroke into atherothrombotic, cardioembolic, small-vessel occlusion, other determined cause, and undetermined cause [1]. The last category comprises both truly cryptogenic strokes, ischemic strokes that are “undetermined” because of incomplete investigation, and strokes that are “undetermined” because multiple possible causes coexist in the same patient. In a further development of the TOAST classification the “undetermined cause” category has been subdivided, and definitions of subtypes have been further refined, taking more recent advances in diagnostic tools into account [2, 3]. A computerized algorithm of this classification has been developed, and further defines categories into evident, probable, and possible based on the level of diagnostic support (Box 2.1). Although these classification schemes were developed for use in clinical trials, they also form a useful framework for identifying causes of stroke in clinical practice.

Large Artery Atherosclerosis

Atherosclerosis of the major vessels supplying the brain is an important mechanism in ischemic stroke. Although the common occurrence of atherosclerosis in the region of the carotid bifurcation was observed early in the twentieth century, and the mechanism of distal embolization in causing strokes was proposed, it was widely assumed that most cerebral ischemic strokes were caused by in situ middle cerebral artery (MCA) thrombosis. The full implications of extracranial atherosclerosis for ischemic stroke were not recognized until the mid twentieth century with the advent of the diagnostic techniques of catheter angiography and later ultrasound, the links with clinical syndromes, and the therapeutic implications of carotid surgery for carotid bifurcation disease.

Large-vessel disease may cause ischemia through embolism (artery-to-artery embolism) or reduction of blood flow (hemodynamic causes). Emboli from large-vessel disease are usually platelet aggregates or thrombus formed on atherosclerotic plaques. Atherosclerotic debris and cholesterol crystals may also contribute. In many patients carotid or vertebral artery occlusion occurs without symptoms because good collateral supply is provided through the circle of Willis, the external carotid artery, and cortical pial anastomoses. Patients with stroke often have generalized atherosclerosis in other vascular beds. About one-quarter of patients with transient ischemic attack (TIA) or stroke have a history of a symptomatic coronary event, and an additional 25–50% have asymptomatic coronary plaques, stenoses, or silent myocardial infarcts [4, 5]. Although coronary heart disease is somewhat more prevalent in patients with large atherosclerosis of the cervical arteries, it is commonly present also in patients with other stroke subtypes.

Prevalence of Large Atherosclerosis: Extra- and Intracranial

Symptomatic atherosclerosis is most common at the bifurcation of the common carotid artery into the external and internal carotid arteries (Figure 2.2). Other common extracranial sites are the aortic arch, the proximal subclavian arteries, and the vertebral artery origins. Severe carotid stenosis (50–99%) is present in 10–15% of patients with anterior circulation ischemic strokes, with proportions increasing with age. The proportions are similar in patients with transient ischemic attacks (TIAs). Intracranial atherosclerosis, in white populations less common than extracranial, most often affects the carotid siphon, the intracranial vertebral arteries as they penetrate the dura, and the basilar artery. Severe atherosclerosis in the proximal MCA is rarer; in whites MCA occlusion is usually the result of embolism from the heart or a proximal arterial site. Overall, large artery atherosclerosis is estimated to account for about 30% of all ischemic strokes.

Figure 2.2 An extracranial carotid stenosis (degree of stenosis 67%) as visualized by MR angiography (left) and digital subtraction angiography (right).

(Courtesy of Dr. Mats Cronqvist.)

However, the pattern of atherosclerosis is widely different in other populations. Intracranial atherosclerosis appears to be much more common in the Asian and African American population (Figure 2.3). Intracranial large artery disease has long been a relatively neglected disorder because of a research focus on the more accessible extracranial carotid artery occlusive disease lesions. However, intracranial large artery disease appears to be the most common stroke subtype worldwide [6, 7]. In Chinese and Japanese populations intracranial atherosclerosis accounts for up to half of all strokes, and in Korean studies up to a quarter. The underlying causes of racial differences in the distribution of extracranial and intracranial occlusive disease are not fully understood: they are presumably related to differences in risk-factor patterns, but findings from different regions do not show a consistent pattern. Genetical factors may also contribute.

Figure 2.3 Stenosis of the middle cerebral artery visualized by MR angiography (left) and digital subtraction angiography (right).

(Courtesy of Dr. Mats Cronqvist.)

Large Artery Atherosclerosis in the Aortic Arch

The link between atherosclerosis of the aortic arch and ischemic stroke was not clearly recognized until the early 1990s when autopsy studies revealed a high prevalence of such lesions in particular in patients with cryptogenic strokes [8]. At that time examination of the aortic arch was not part of the routine echocardiographic examination. Protruding aortic atheromas (>4–5 mm) have been found to be three to nine times more common in stroke patients than in healthy controls. Later studies have established that aortic arch atheroma is clearly associated with ischemic stroke, possibly both by serving as a source of emboli and by being a marker of generalized large artery atherosclerosis including cerebral vessels. In stroke patients thick or complex aortic atheromas are associated with advanced age, carotid stenosis, coronary heart disease, atrial fibrillation (AF), diabetes, and smoking. For the long-term prognosis, the characteristics of thickness over 4–5 mm, ulceration, non-calcified plaque, and presence of mobile components are associated with a 1.6–4.3 times increased risk of recurrent stroke.

Mechanisms of Cerebral Ischemia Resulting from Extracranial and Intracranial Large Artery Atherosclerosis

Artery-to-artery embolism is considered the most common mechanism of TIA and ischemic stroke due to large artery atherosclerosis. Thrombosis at the site of an atherosclerotic lesion is due to interplay between the vessel wall lesion, blood cells, and plasma factors. Severe stenosis alters blood flow characteristics, and turbulence replaces laminar flow when the degree of stenosis exceeds about 70%. Platelets are activated when exposed to abnormal or denuded endothelium in the region of an atheromatous plaque. Plaque hemorrhage may contribute to thrombus formation, similar to the mechanisms in coronary artery disease. Plaque instability appears to be a dynamic phenomenon [9], and may explain the observation that the risk of recurrent ischemic events is highest early after a TIA and is much lower from 1 to 3 months and onwards [10, 11]. Plaque instability is characterized by a thin fibrous cap, large lipid core, reduced smooth muscle content, and a high macrophage density. Complicating thrombosis occurs mainly when the thrombogenic center of the plaque is exposed to flowing blood.

Reduction of blood flow in the carotid artery is not affected until the degree of stenosis approaches 70%, corresponding to a luminal diameter of less than 1.5 mm. However, the degree of carotid stenosis correlates poorly with intracranial hemodynamic alterations because of the variability of the collateral circulation. Embolic and hemodynamic causes of ischemic stroke and TIA are not mutually exclusive mechanisms. Ultrasound studies with transcranial Doppler have documented the frequent occurrence of microembolic signals not associated with apparent clinical symptoms in patients with symptomatic ischemic vascular disease of the brain. Hemodynamically compromised brain regions appear to have a diminished capacity for wash-out or clearance of small emboli which are more likely to cause infarcts in low-flow areas [12].

Clinical Features of Large Artery Atherosclerosis

Large artery atherosclerosis is a prototype of stroke mechanism that may cause almost any clinical stroke syndrome. Furthermore, some degree of atherosclerosis in brain-supplying arteries is present in most patients with ischemic stroke, raising the issue of determining the likely cause if multiple potential causes are identified. The clinical spectrum of large artery atherosclerosis ranges from asymptomatic arterial disease, TIA affecting the eye or the brain, and ischemic stroke of any severity in the anterior and posterior circulation. Less common clinical syndromes due to large artery atherosclerosis, e.g. those due to hemodynamic causes, are detailed in Chapter 10.

Cardioembolic Stroke

Cardioembolic stroke accounts for 25–35% of all ischemic strokes, making cardiac disease the most common major cause of stroke overall – a practical point often forgotten. Non-valvular AF is the commonest cause of cardioembolic stroke. The heart is of particular importance in ischemic stroke for other reasons also: cardiac disorders (in particular coronary heart disease) frequently coexist in patients with stroke and are important long-term prognostic determinants. Whereas recurrent stroke is the most common vascular event during the first few years after a first stroke, with time an increasing proportion of new vascular events are due to coronary heart disease.

Proportion of All Strokes due to Cardioembolic Stroke

The proportion of strokes associated with cardioembolic strokes increases sharply with age, mainly because of the epidemiological characteristics in the population of AF, the single most common major cardioembolic source.

In some cases of cardioembolic stroke the association may be coincidental. This is certainly true for several of the minor cardioembolic sources (see below), for which findings from case-control studies show divergent results. As technology advances further more cardiac conditions that may constitute potential causes of stroke are detected. It is also true for AF, which is associated with several other stroke risk factors, and is very common in the general population. However, the finding that anti-coagulant therapy reduces the risk of ischemic stroke by about 60% in patients with AF suggests that the majority of strokes associated with AF are the result of cardiac embolism. An autopsy study of patients with stroke dying within 30 days showed that 70% of patients with a diagnosis of cardioembolic stroke in this study (based on cardiac conditions that may produce emboli in the heart or through the heart) were found to have intracardiac thrombi, which were of similar composition to persistent emboli detected in the major intracerebral arteries [13].

Cardioembolic Sources: Major and Minor

There are several cardiac disorders that may constitute a source of embolus, but not all sources pose equal threats. They are commonly divided by origin in the heart (atrial, valvular, ventricular) and potential for embolism (high risk versus low or uncertain risk, or major versus minor) (Table 2.1). The clinically most important cardioembolic sources are non-rheumatic AF, infective endocarditis, prosthetic heart valve, recent myocardial infarction, dilated cardiomyopathy, intracardiac tumors, rheumatic mitral valve stenosis, and patent foramen ovale.

Recent Anterior Myocardial Infarct

Ischemic stroke may occur in close temporal proximity (hours, days, weeks) to an acute myocardial infarct, suggesting a cause-and-effect relationship due to embolism. Left ventricular mural thrombi have been diagnosed by echocardiography in up to 20% of patients with large anterior infarcts, but the frequency has not been well determined in the current era of much more active anti-thrombotic drug treatments and endovascular procedures in the acute phase of coronary heart disease. Studies have reported a frequency of about 5% for ischemic stroke during the first few weeks after myocardial infarction. After this period the stroke risk appears to be much lower, and is probably related to the presence of shared risk factors for coronary heart disease and ischemic stroke in the vast majority of these patients.

Five percent of ischemic strokes are related to a myocardial infarct.

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Related posts:

Chapter 8 – Cardiac Diseases Relevant to Stroke Chapter 7 – Common Risk Factors and Prevention Chapter 16 – Stroke and Dementia Chapter 19 – Acute Therapies for Stroke Chapter 22 – Management of Acute Ischemic Stroke and its Late Complications Chapter 21 – Intensive Care of Stroke

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