Textbook of Stroke Medicine [3rd Edition] 9781108607643

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Textbook of Stroke Medicine [3rd Edition]
 9781108607643

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Table of contents :
Preface vii

List of contributors viii

Section I Etiology, pathophysiology and imaging

1 Neuropathology and pathophysiology of stroke Konstantin A. Hossmann Wolf-Dieter Heiss 1

2 Common causes of ischemic stroke Bo Norrving 28

3 Neuroradiology 40

(A) Imaging of acute ischemic and hemorrhagic stroke: CT, perfusion CT, CT angiography Patrik Michel 40

(B) Imaging of acute ischemic and hemorrhagic stroke: MRI and MR angiography Jens Fiehler 43

(c) Functional imaging in acute stroke, recovery and rehabilitation Wolf-Dieter Heiss 48

4 Ultrasound in acute ischemic stroke L?szl? Csiba 58

Section II Clinical epidemiology and risk factors

5 Basic epidemiology of stroke and risk assessment Jaakko Tuomilehto Markku M?h?nen Cinzia Sarti 77

6 Common risk factors and prevention Michael Brainin Yvonne Teuschl Karl Matz 89

7 Cardiac diseases relevant to stroke Claudia St?llberger Josef Finsterer 105

Section III Diagnostics and syndromes

8 Common stroke syndromes C?line Odier Patrik Michel 121

9 Less common stroke syndromes Wilfried Lang 135

10 Intracerebral hemorrhage Michael Brainin Raoul Eckhardt 154

11 Cerebral venous thrombosis Jobst Rudolf 165

12 Behavioral neurology of stroke Jos? M. Ferro Isabel P. Martins Lara Caeiro 178

13 Stroke and dementia Didier Leys Marta Altieri 194

14 Ischemic stroke in the young and in children Didier Leys Valeria Caso 203

Section IV Therapeutic strategies and neurorehabilitation

15 Stroke units and clinical assessment Risto O. Roine Markku Kaste 219

16 Acute therapies and interventions Richard O'Brien Thorsten Steiner Kennedy R. Lees 230

17 Management of acute ischemic stroke and its complications Natan M. Bornstein Eitan Auriel 243

18 Infections in stroke Achim Kaasch Harald Seifert 258

19 Secondary prevention Hans-Christoph Diener Greg W. Albers 272

20 Neurorehabilitation Sylvan J. Albert J?rg Kesselring 283

Index 307

Citation preview

Preface

This 3rd edition of our Textbook of Stroke Medicine contains mostly completely revised chapters and reflects the tremendous advances in our field since the first edition in 2010. It has been a fascinating challenge to update and renew the contents without extending the total length of the book. But following the developments in our field and the recommendations of many colleagues, we added two new chapters: “Cerebral Small-Vessel Disease” and “Intensive Care of Stroke.” The chapter on endovascular interventions has been elongated due to recent trials offering new treatment options. Over time, this volume has served well the purpose and expectations of our younger colleagues working in Stroke Medicine. Hopefully it will continue to do so. The book is focused on the “beginning specialist,” many of whom have come from all over the world to take the “Masters’ Degree in Stroke

Medicine” at the Danube University Krems in Austria, a program that has been set up by the European Stroke Organisation and has been endorsed by the World Stroke Organization since 2007. We want to thank all contributors for their efforts to update and supplement their chapters. We are very grateful that they have finished their tasks within an ambitious time plan in spite of many clinical and other duties in their academic lives. Our thanks also go to Susanne Tabernig, MD for providing excellent summaries for every chapter. We also thank our editors from Cambridge University Press, especially Emily Jones, who has been very patient with us and diligently provided guidance and help. Michael Brainin, MD Wolf-Dieter Heiss, MD

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Section 1 Chapter

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Etiology, Pathophysiology, and Imaging

Neuropathology and Pathophysiology of Stroke Konstantin-A. Hossmann and Wolf-Dieter Heiss

Neuropathology Vascular Origin of Cerebrovascular Disease In the latest edition of the International Classification of Diseases and Related Health Problems (ICD-­11) cere­brovascular diseases (CVD) are listed in the section of diseases of the nervous system [1]. However, they have their origin in the vessels supplying or draining the brain, and the knowledge of pathological changes occurring in the vessels and in the blood are essential for understanding the pathophysiology and therapy of the various types of CVD. Changes in the vessel wall lead to obstruction of blood flow; by interacting with blood constituents they may cause thrombosis and blockade of blood flow in this vessel. In addition to vascular stenosis or occlusion at the site of vascular changes, disruption of blood supply and consecutive infarcts can also be produced by emboli arising from vascular lesions situated proximally to otherwise healthy branches located more distal in the arterial tree or from a source located in the heart. At the site of occlusion, opportunity exists for thrombus to develop in anterograde fashion throughout the length of the vessel, but this event seems to occur only rarely. Changes in large arteries supplying the brain, including the aorta, are mainly caused by atherosclerosis. Middle-­sized and intracerebral arteries can also be affected by acute or chronic vascular diseases of inflammatory origin due to subacute to chronic infections, e.g. tuberculosis and lues or due to collagen ­disorders, e.g. giant cell arteritis, granulomatous angiitis of the CNS, panarteritis nodosa, and even more rarely systemic lupus erythematosus, Takayasu’s arteritis, Wegener granulomatosis, rheumatoid arteritis, Sjögren’s syndrome, Sneddon and Behçet’s disease. In some diseases affecting the vessels of the brain, the etiology and pathogenesis are still unclear, e.g. Moyamoya disease and fibromuscular dysplasia, but these disorders are characterized by typical locations of the vascular changes. Some arteriopathies are hereditary,

like CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), in some like cerebral amyloid angiopathy a degenerative cause is discussed. All these vascular disorders can cause obstruction, and lead to thrombosis and embolizations. Small vessels of the brain are affected by hyalinosis and fibrosis; this “small-­vessel disease” can cause lacunes and, if widespread, is the substrate for vascular cognitive impairment and vascular dementia. Atherosclerosis is the most widespread disorder lead­ ing to death and serious morbidity including stroke [2]. The basic pathologic lesion is the atheromatous plaque, the most commonly affected sites are the aorta, the coronary arteries, the carotid artery at its bifurcation, and the basilar artery. Arteriosclerosis, a more generic term describing hardening and thickening of the arteries, includes as additional types Mönkeberg’s sclerosis and is characterized by calcification in the tunica media and arteriolosclerosis with proliferative and hyaline changes affecting the arterioles. Atherosclerosis starts at young age, lesions accumulate and grow throughout life and become symptomatic and clinically evident when end organs are affected [3]. Atherosclerosis: atheromatous plaques, most commonly in the aorta, the coronary arteries, the bifurcation of the carotid artery and the basilar artery.

The initial lesion of atherosclerosis has been attributed to “fatty streaks” and the “intimal cell mass.” Those changes already occur in childhood and adolescence and do not necessarily correspond to the future sites of atherosclerotic plaques. Fatty streaks are focal areas of intra­cellular lipid collection in both macrophages and smooth muscle cells. Various concepts have been proposed to explain the progression of such precursor lesions to definite atherosclerosis [3, 4], most remarkable of which is the response-to-injury hypothesis postulating a cellular and molecular response to ­various atherogenic stimuli in the form of an inflammatory repair process [5]. This inflammation develops

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Section 1: Etiology, Pathophysiology, and Imaging

concurrently with the accumulation of minimally oxidized low density lipoproteins [6, 7], stimulates vascular smooth muscle cells (VSMCs), endothelial cells and macrophages [8], and as a result foam cells aggregate with an accumulation of oxidized LDL. In the further stages of artherosclerotic plaque development VSMCs migrate, proliferate, and synthesize extracellular matrix components on the luminal side of the vessel wall, forming the fibrous cap of the atherosclerotic lesion [9]. In this complex process of growth, progression, and finally rupture of an atherosclerotic plaque, a large number of matrix modulators, inflammatory mediators, growth factors, and vasoactive substances are involved. The complex interactions of these many factors are discussed in the special literature [6–10]. The fibrous cap of the atherosclerotic lesion covers the deep lipid core with a massive accumulation of extracellular lipids (atheromatous plaque), or fibroblasts and extracellular calcifications may contribute to a fibrocalcific lesion. Mediators from inflammatory cells at the thinnest portion of the cap surface of a vulnerable plaque – which is characterized by a larger lipid core and a thin fibrous cap – can lead to plaque disruption with formation of a thrombus or hematoma or even to total occlusion of the vessel. During the development of artherosclerosis the entire vessel can enlarge or constrict in size [11]. However, once the plaque covers >40% of the vessel wall, the artery no longer enlarges, and the lumen narrows as the plaque

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grows. In vulnerable plaques thrombosis forming on the disrupted lesion further narrows the vessel lumen and can lead to occlusion or be the origin of emboli. Less commonly, plaques have reduced collagen and elastin with a thin and weakened arterial wall, resulting in aneurysm formation which when ruptured may be the source of intracerebral hemorrhage (Figure 1.1). Injury hypothesis of progression to atherosclerosis: fatty streaks (focal areas of intra­cellular lipid collection) → inflammatory repair process with stimulation of vascular smooth muscle cells → atheromatous plaque.

Thromboembolism: Immediately after plaque rupture or erosion, subendothelial collagen, the lipid core, and procoagulants such as tissue factor and von Willebrand factor are exposed to circulating blood. Platelets rapidly adhere to the vessel wall through the platelet glycoproteins (GP) Ia/IIa and GP Ib/IX [12] with subsequent aggregation to this initial monolayer through linkage with fibrinogen and the exposed GP IIb/IIIa on activated platelets. As platelets are a source of nitrous oxide (NO), the resulting deficiency of bioactive NO, which is an effective vasodilator, contributes to the progression of thrombosis by augmenting platelet activation, enhancing VSMC proliferation and migration, and participating in neovascularization [13]. The activated platelets also release adenosine diphosphate (ADP) and thromboxane A2 with subsequent activation of the clotting cascade. The growing thrombus obstructs or even blocks the blood flow in

Figure 1.1  The stages of development of an atherosclerotic plaque. (1) LDL moves into the subendothelium and (2) is oxidized by macrophages and smooth muscle cells (SMC). (3) Release of growth factors and cytokines (4) attracts additional monocytes. (5) Macrophages and (6) foam cell accumulation and additional (7) SMC proliferation result in (8) growth of the plaque. (9) Fibrous cap degradation and plaque rupture (collagenases, elastases). (10) Thrombus formation. (Modified from Faxon et al. 2004 [6].)

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Chapter 1: Neuropathology and Pathophysiology of Stroke

the vessel. Atherosclerotic thrombi are also the source for embolisms, which are the primary pathophysiologic mechanism of ischemic strokes, especially from carotid artery disease or of cardiac origin. Rupture or erosion of atheromatous plaques → adhesion of platelets → thrombus → obstruction of blood flow and source of emboli.

Small-vessel disease usually affects the arterioles and is associated with hypertension. It is caused by subendothelial accumulation of a pathological protein, the hyaline, formed from mucopolysaccharides and matrix proteins. It leads to narrowing of the lumen or even occlusion of these small vessels. Often it is associated with fibrosis, which affects not only arterioles, but also other small vessels and capillaries and venules. Lipohyalinosis also weakens the vessel wall predisposing for the formation of “miliary aneurysms.” Small-­vessel disease results in two pathological conditions: status lacunaris (lacunar state) and status cribrosus (état criblé). Status lacunaris is characterized by small irregularly shaped infarcts due to occlusion of small vessels; it is the pathological substrate of lacunar strokes and vascular cognitive impairment and dementia. In status cribrosus small, round cavities develop around affected arteries due to disturbed supply of oxygen and metabolic substrate. These “criblures” together with miliary aneurysms are the sites of vessel rupture causing typical hypertonic intracerebral hemorrhages [14–17]. A second type of small-­vessel disease is characterized by the progressive accumulation of congophilic, βA4 immuno-­reactive, amyloid protein in the walls of small to medium-­sized arteries and arterioles. Cerebral amyloid angiopathy is a pathological hallmark of Alzheimer’s disease and also occurs in rare genetically transmitted diseases, e.g. CADASIL and Fabry disease [18]. For a more detailed discussion of the etiology and pathophysiology of the various specific vascular disorders see [19–21]. Small-vessel disease: subendothelial accumulation of hyaline in arterioles.

Types of Cerebrovascular Disease Numbers relating to the frequency of the different types of acute CVD are highly variable depending on the source of data. The most reliable numbers come from the in-­hospital assessment of stroke in the Framingham study determining the frequency of completed stroke: 60% were caused by atherothrombotic brain infarction, 25.1% by cerebral embolism, 5.4%

by subarachnoid hemorrhage, 8.3% by intracerebral hemorrhage, and 1.2% by undefined diseases. In addition, transient ischemic attacks accounted for 14.8% of the total cerebrovascular events [22]. Since the first Framingham reports, the rate of stroke death has declined by more than one-­third, but the relative frequency distribution of completed stroke is essentially the same [23]. Ischemic strokes result from a critical reduction of regional cerebral blood flow lasting beyond a critical duration, and are caused by atherothrombotic changes of the arteries supplying the brain or by emboli from sources in the heart, the aorta, or the large arteries. The pathological substrate of ischemic stroke is ischemic infarction of brain tissue, the location, extension, and shape of which depend on the size of the occluded ­vessel, the mechanism of arterial obstruction, and the compensatory capacity of the vascular bed (Figure 1.2). Occlusion of arteries supplying defined brain territories by atherothrombosis or embolizations lead to territorial infarcts of variable size: they may be large – e.g. the whole territory supplied by the middle cerebral artery – or small, if branches of large arteries are occluded or if compensatory collateral perfusion – e.g. via the circle of Willis or leptomeningeal anastomoses  – is efficient in reducing the area of critically reduced flow [15, 17]. In a smaller number of cases, infarcts can also develop at the borderzones between vascular territories, when several large arteries are stenotic and the perfusion in these “last meadows” cannot be constantly maintained above the critical threshold of morphological integrity [24]. Borderzone infarctions are a subtype of the low-­flow or hemodynamically induced infarctions, which are the result of critically reduced cerebral perfusion pressure in far-­downstream brain arteries. The more common low-­flow infarctions affect subcortical structures within a vascular bed with preserved but marginal irrigation [25]. Lacunar infarcts reflect disease of the vessels penetrating the brain to supply the capsule, the basal ganglia, thalamus, and paramedian regions of the brainstem [26]. Most often they are caused by lipohyalinosis of deep arteries (small-­vessel disease), less frequent causes are stenosis of the MCA stem and microembolization to penetrant arterial territories. Pathologically these lacunes are defined as small cystic trabeculated scars about 5 mm in diameter, but they are more often observed on magnetic resonance images where they are accepted as lacunes up to 1.5 cm diameter. The classic lacunar syndromes include pure motor, pure sensory, and sensorimotor syndromes,

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Figure 1.2  Topography of the most common types of cerebral infarcts: (1) anterior cerebral artery (left: total infarction, right: infarct of recurrent artery of Heubner); (2) anterior and middle cerebral arteries (left: with, right: without lenticulostriate arteries); (3) borderzone infarcts between anterior and middle cerebral arteries; (4) cystic infarcts (left: centrum ovale, right: caudate); (5) and (6) middle cerebral artery (5 left: total, right: cortical, 6 left: minimal, right: wedge-­shaped); (7) end-­artery and borderzone infarcts of the perforating branches of middle cerebral artery; (8) posterior cerebral artery (left: total, right: subtotal). (With permission, Zülch 1985 [15].)

sometimes ataxic hemiparesis, clumsy hand, dysarthria, and hemichorea/hemiballism, but higher cerebral functions are not involved. A new classification of stroke subtypes is mainly oriented on the most likely cause of stroke: atherosclerosis, small-­vessel disease, cardiac source, or other cause [27]. Territorial infarcts are caused by an occlusion of arteries supplying defined brain territories by atherothrombosis or embolizations. Borderzone infarcts develop at the borderzone between vascular territories and are the result of a critically reduced cerebral perfusion pressure (low-flow infarctions). Lacunar infarcts are mainly caused by small-­vessel disease.

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Hemorrhagic infarctions, i.e. “red infarcts” in contrast to the usual “pale infarcts,” are defined as ischemic infarcts in which varying amounts of blood cells are found within the necrotic tissue. The amount can range from a few petechial bleeds in the gray matter of cortex and basal ganglia to large hemorrhages involving the cortical and deep hemispheric regions. Hemorrhagic transformation frequently appears during the second and third phases of infarct evolution, when macrophages appear and new blood vessels are formed in

tissue consisting of neuronal ghosts and proliferating astrocytes. However, the only significant difference between “pale” and “red infarcts” is the intensity and extension of the hemorrhagic component, since in at least two-­thirds of all infarcts petechial hemorrhages are microscopically detectable. Macroscopically, red infarcts contain multifocal bleedings which are more or less confluent and predominate in cerebral cortex and basal ganglia which are richer in capillaries than the white matter [28]. If the hemorrhages become confluent intrainfarct hematomas might develop, and extensive edema may contribute to mass effects and lead to malignant infarction. The frequency of hemorrhagic infarctions (HIs) in anatomic studies ranged from 18% to 42% [29], with a high incidence (up to 85% of HIs) in cardioembolic stroke [30]. Mechanisms for hemorrhagic transformation are manifold and vary with regard to the intensity of bleeding. Petechial bleeding results from diapedesis rather than vascular rupture. In severe ischemic tissue vascular permeability is increased and endothelial tight junctions are ruptured. When blood circulation is spontaneously or therapeutically restored, blood can leak out of these damaged vessels. This can also happen with fragmentation and distal migration of an

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Chapter 1: Neuropathology and Pathophysiology of Stroke

embolus (usually of cardiac origin) in the damaged vascular bed, explaining delayed clinical worsening in some cases. For the hemorrhagic transformation also the collateral circulation might have an impact: in some instances reperfusion via pial networks may develop with the diminution of peri-­ischemic edema at borderzones of cortical infarcts. Risk of hemorrhage is significantly increased in large infarcts with mass effect supporting the importance of edema for tissue damage and the deleterious effect of late reperfusion. In some instances also the rupture of the vascular wall secondary to ischemia-induced endothelial necrosis might cause an intrainfarct hematoma. Vascular rupture can explain very early hemorrhagic infarcts and early intrainfarct hematoma (between 6 and 18 hours after stroke), whereas hemorrhagic transformation usually develops within 48 hours to 2 weeks. Hemorrhagic infarctions (HI) are defined as ischemic infarcts in which varying amounts of blood cells are found within the necrotic tissue. They are caused by leakage from damaged vessels, due to increased vascular permeability in ischemic tissue or vascular rupture secondary to ischemia.

Intracerebral hemorrhage (ICH) occurs as a result of bleeding from an arterial source directly into the brain parenchyma and accounts for 5–15% of all strokes [31, 32]. Hypertension is the leading risk factor, but in addition advanced age, race, and also cigarette smoking, alcohol consumption, and high serum cholesterol levels have been identified. In a number of instances ICH occurs in the absence of hypertension usually in atypical locations. These causes include small vascular malformations, vasculitis, brain tumors, and sympathomimetic drugs (e.g. cocaine). ICH may also be caused by cerebral amyloid angiopathy and rarely is elicited by acute changes in blood pressure, e.g. due to exposure to cold. The occurrence of ICH is also influenced by the increasing use of anti-­thrombotic and thrombolytic treatment of ischemic diseases of the brain, heart, and other organs [33, 34]. Spontaneous ICH occurs predominantly in the deep portions of the cerebral hemispheres (“typical ICH”) [35]. Its most common location is the putamen (35–50% of cases). The subcortical white matter is the second most frequent location (approximately 30%). Hemorrhages in the thalamus are found in 10–15%, in the pons in 5–12%, and in the cerebellum in 7% of cases [36]. Most ICHs originate from the rupture of small, deep arteries with diameters of 50–200 μm, which are affected by lipohyalinosis due to chronic hypertension.

These small vessel changes lead to weakening of the vessel wall and miliary micro-­aneurysm and consecutive small local bleedings, which might be followed by secondary ruptures of the enlarging hematoma in a cascade or avalanche fashion [37]. After active bleeding started it can continue for a number of hours with enlargement of hematoma that is frequently associated with clinical deterioration [38]. Putaminal hemorrhages originate from a lateral branch of the striate arteries at the posterior angle resulting in an ovoid mass pushing the insular cortex laterally and displacing or involving the internal capsule. From this initial putaminal-­claustral location a large hematoma may extend to the internal capsule and lateral ventricle, into the corona radiata, and into the temporal white matter. Putaminal ICHs are considered the typical hypertensive hemorrhages. Caudate hemorrhage, a less common form of bleeding from distal branches of lateral striate arteries, occurs in the head of the caudate nucleus. This bleeding early connects to the ventricle and usually involves the anterior limb of the internal capsule. Thalamic hemorrhages can involve most of this nucleus and extend into the third ventricle medially and the posterior limb of the internal capsule laterally. The hematoma may press on or even extend into the midbrain. Larger hematomas often reach the corona radiata and the parietal white matter. Lobar (white matter) hemorrhages originate at the cortico-­subcortical junction between gray and white matter and spread along the fiber bundles most commonly in the parietal and occipital lobes. The hematomas are close to the cortical surface and usually not in direct contact with deep hemisphere structures or the ventricular system. As atypical ICHs they are not necessarily correlated with hypertension. Cerebellar hemorrhages usually originate in the area of the dentate nucleus from rupture of distal branches of the superior cerebellar artery and extend into the hemispheric white matter and into the fourth ventricle. The pontine tegmentum is often compressed. A variant, the midline hematoma, originates from the cerebellar vermis, always communicates with the fourth ventricle, and frequently extends bilaterally into the pontine tegmentum. Pontine hemorrhages from bleeding of small paramedian basilar perforating branches cause medially placed hematomas involving the basis of the pons. A unilateral variety results from rupture of distal, long circumferential branches of the basilar artery.

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Section 1: Etiology, Pathophysiology, and Imaging

These hematomas usually communicate with the fourth ventricle, and extend laterally and ventrally into the pons. The frequency of recurrent ICHs in hypertensive patients is rather low (6%) [39]. Recurrence rate is higher with poor control of hypertension and also in hemorrhages due to other causes. In some instances multiple simultaneous ICHs may occur, but also in these cases the cause is another than hypertension. In ICHs, the local accumulation of blood destroys the parenchyma, displaces nervous structures, and dissects the tissue. At the bleeding sites fibrin globes are formed around accumulated platelets. After hours or days extracellular edema develops at the periphery of the hematoma. After 4–10 days the red blood cells begin to lyse, granulocytes and thereafter microglial cells arrive, and foamy macrophages are formed, which ingest debris and hemosiderin. Finally, the astrocytes at the periphery of the hematoma proliferate and turn into gemistocytes with eosinophylic cytoplasma. When the hematoma is removed, the astrocytes are replaced by glial fibrils. After that period – extending to months – the residue of the hematoma is a flat cavity with a reddish lining resulting from hemosiderin-­ laden macrophages [36]. Intracerebral hemorrhage (ICH) occurs as a result of bleeding from an arterial source directly into the brain parenchyma, predominantly in the deep portions of the cerebral hemispheres (typical ICH). Hypertension is the leading risk factor, and the most common location is the putamen.

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Cerebral venous thrombosis can develop from many causes and due to predisposing conditions. Cerebral venous thrombosis (CVT) is often multifactorial, when various risk factors and causes contribute to the development of this disorder [40]. The incidence of septic CVT has been reduced to less than 10% of cases, but septic cavernous sinus thrombosis is still a severe, however rare problem. Aseptic CVT occurs during puerperium and less frequently during pregnancy, but may also be related to use of oral contraceptives. Among the non-­infectious causes of CVT congenital thrombophilia, particularly prothrombin and factor V Leiden gene mutations, as well as anti-­thrombin, protein C, and protein S deficiencies must be considered. Other conditions with risk for CVT are malignancies, inflammatory diseases, and systemic lupus erythematosus. However, in 20–35% of CVT the etiology remains unknown. The fresh venous thrombus is rich in red blood cells and fibrin and poor in platelets. Later

on, it is replaced by fibrous tissue, occasionally with recanalization. The most common location of CVT is the superior sagittal sinus and the tributary veins. Whereas some thromboses, particularly of the lateral sinus, may have no pathological consequences for the brain tissue, occlusion of large cerebral veins usually leads to a venous infarct. These infarcts are located in the cortex and adjacent white matter and often are hemorrhagic. Thrombosis of the superior sagittal sinus may lead only to brain edema, but usually causes bilateral hemorrhagic infarcts in both hemispheres. These venous infarcts are different from arterial infarcts: cytotoxic edema is absent or mild, vasogenic edema is prominent, and hemorrhagic transformation or bleeding is usual. Despite this hemorrhagic component heparin is the treatment of choice. Cerebral venous thrombosis can lead to a venous infarct. Venous infarcts are different from arterial infarcts: cytotoxic edema is absent or mild, vasogenic edema is prominent, and hemorrhagic transformation or bleeding is usual.

Cellular Pathology of Ischemic Injury Acute interruption of cerebral blood flow causes a stereotyped sequel of cellular alterations which evolve over a protracted period of time and which depend on the topography, severity, and duration of ischemia [41]. Traditionally, these alterations have been studied by classical histological techniques, but recent developments in high resolution in vivo optical imaging such as multi-­photon laser scanning microscopy (MPM), optical coherence tomography (OCT), or photoacoustic imaging (PAI) have opened the way to correlate morphological alterations with functional disturbances [42]. The most sensitive brain cells are neurons, followed – in this order – by oligodendrocytes, astrocytes, and vascular cells. The most vulnerable brain regions are hippocampal subfield CA1, neocortical layers 3, 5, and 6, the outer segment of striate nucleus, and the Purkinje and basket cell layers of cerebellar cortex. If blood flow decreases below the threshold of energy metabolism, the primary pathology is necrosis of all cell elements, resulting in ischemic brain infarct. If ischemia is not severe enough to cause primary energy failure, or if it is of so short duration that energy metabolism recovers after reperfusion, a delayed type of cell injury may evolve which exhibits the morphological characteristics of necrosis, apoptosis, necroptosis, or other forms of programmed cell

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Chapter 1: Neuropathology and Pathophysiology of Stroke

death [43]. In the following, primary and delayed cell death will be described separately.

Primary Neuronal Cell Death In the core of the territory of an occluded brain artery the earliest sign of cellular injury is neuronal swelling or shrinkage, the cytoplasm exhibiting microvacuolation (MV), which ultrastructurally has been associated with mitochondrial swelling [44]. These changes are potentially reversible if blood flow is restored before mitochondrial membranes begin to rupture. One to two hours after the onset of ischemia, neurons undergo irreversible necrotic alterations (red neuron or ischemic cell change [ICC]). In conventional hematoxilin-­eosin stained brain sections such neurons are characterized by intensively stained eosinophilic cytoplasma, formation of triangular nuclear pyknosis, and direct contact with swollen astrocytes (Figure  1.3). Electron microscopically mitochondria exhibit flocculent densities, which

represent denaturated mitochondrial proteins. Ischemic cell change must be distinguished from artifactual dark neurons, which stain with all (acid or basic) dyes and are not surrounded by swollen astrocytes [45]. With ongoing ischemia, neurons gradually lose their stainability with hematoxilin, they become mildly eosinophilic, and, after 2–4 days, transform to ghost cells with hardly detectable pale outline. Interestingly, neurons with ischemic cell change are mainly located in the periphery and ghost cells in the center of the ischemic territory, which suggests that manifestation of ischemic cell change requires some residual or restored blood flow, whereas ghost cells may evolve in the absence of flow [41]. Primary ischemic cell death induced by focal ischemia is associated with reactive and secondary changes. The most prominent alteration during the initial 1–2 hours is perivascular and perineuronal astrocytic swelling, after 4–6 hours the blood–brain barrier

Light-microscopical characteristics of rat infarction Acute ischemic changes Control

sham surgery

swelling

shrinkage

4 hours

2 hours

Figure 1.3  Light-microscopical evolution of neuronal changes after experimental middle cerebral occlusion. (Modified with permission from Garcia et al. 1995 [168].)

Necrotic changes red neuron

1 day

ghost neuron

3 days

Dark neuron artifact

sham surgery

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Section 1: Etiology, Pathophysiology, and Imaging

Figure 1.4  Transformation of acute ischemic alterations into cystic infarct. Note pronounced inflammatory reaction prior to tissue cavitation. (Modified with permission from Petito 2005 [41].)

breaks down resulting in the formation of vasogenic edema, after 1–2 days inflammatory cells accumulate throughout the ischemic infarct, and within 1.5–3 months cystic transformation of the necrotic tissue occurs together with the development of a peri-­infarct astroglial scar (Figure 1.4).

Delayed Neuronal Death

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The prototype of delayed cell death is the slowly progressing injury of pyramidal neurons in CA1 sector of hippocampus after a brief episode of global ischemia [46]. In focal ischemia delayed neuronal death may occur in the periphery of cortical infarcts or in regions which have been reperfused before ischemic energy failure becomes irreversible. Cell death is also observed in distant brain regions, notably in substantia nigra and thalamus. The morphological appearance of neurons during the interval between ischemia and the manifestation of delayed cell death exhibits a continuum that ranges from necrosis to apoptosis with all possible combinations of cytoplasmic and nuclear morphology that are characteristic for the two types of cell death [47]. In its pure form, necrosis combines karyorhexis with massive swelling of endoplasmic reticulum and mitochondria, whereas in apoptosis mitochondria remain intact and

nuclear fragmentation with condensation of nuclear chromatin gives way to the development of apoptotic bodies. In hemorrhagic stroke lysed blood may induce ferroptosis, a particular form of iron-­dependent cell death, which is characterized by lethal accumulation of lipid reactive oxygen species (ROS) [48]. A widely used histochemical method for the visualization of apoptosis is terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-­ biotin nick-­ end labeling (TUNEL assay), which detects DNA strand breaks. However, as this method may also stain necrotic neurons, a clear differentiation is not possible [49]. A consistent ultrastructural finding in neurons undergoing delayed cell death is disaggregation of ribosomes, which reflects the inhibition of protein synthesis at the initiation step of translation [50]. Light microscopically, this change is equivalent to tigrolysis, visible in Nissl-­stained material that corresponds to the dissociation of ribosomes from the rough endoplasmic reticulum. Disturbances of protein synthesis and the associated endoplasmic reticulum stress are also responsible for cytosolic protein aggregation and the formation of stress granules [51]. In the hippocampus, stacks of accumulated endoplasmic reticulum may become visible, but in other areas this is not a prominent finding.

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Pathology of Neurovascular Unit The classical pathology of ischemic injury differentiates between the sensitivity of the various cell types of brain parenchyma with the neurons as the most vulnerable elements. The molecular analysis of injury evolution, however, suggests that ischemia initiates a coordinated multi-­compartmental response of brain cells and vessels, also referred to as the neurovascular unit [52]. This unit includes microvessels (endothelial cells, basal lamina matrix, astrocytic endfeet, pericytes, and circulating blood elements), the cell body and main processes of astrocytes, the nearby neurons together with their axons, and supporting cells, notably microglia and oligodendrocytes. It provides the framework for the bi-­ directional communication between neuron and supplying microvessel. Under physiological condition, the most prominent function is the neurovascular coupling for maintaining adequate supply of brain nutrients and clearance of waste products. Pathophysiological disturbances of microcirculation provoke bi-­directional responses, possibly mediated by alterations in the matrix of the vascular and non-­vascular compartments of the ischemic territory. Pericytes positioned between endothelial cells, astrocytes, and neurons assume a central role in this process and are critically involved in mechanisms of both injury and repair of the central nervous system [53]. Severe ischemia induces primary cell death due to necrosis of all cell elements. Not so severe or short-­ term ischemia induces delayed cell death with necrosis, apoptosis, or a combination of both. The neurovascular unit provides the conceptual framework for the propagation of injury from microvessels to neurons.

Repair Brain infarcts produced by focal ischemia are seemingly irresolvable in agreement with Cajal’s classical statement that in the adult brain “everything may die, nothing may be regenerated.” This dogma was reversed by the discovery of three permanently neurogenic regions, i.e. the subventricular zone (SVZ), the subgranular zone (SGZ), and the posterior perireticular (PPr) area, which provide lifelong supply of newly generated neurons to the hippocampus and olfactory bulb. After stroke, neurogenesis increases in these areas, and some of the newly formed cells migrate into the infarct penumbra, differentiate into oligodendrocytes and mature neurons, and survive for at least several

weeks [54]. Neurogenesis may also occur through the neurovascular unit. After ischemia pericytes strongly migrate into the peri-­infarct surrounding and contribute to tissue repair by controlling neurogenesis, angiogenesis, and blood–brain barrier function [55]. Ischemia-induced neurogenesis is enhanced by growth factors, nitric oxide, inflammation, non-­coding RNA, and various hormones and neurotransmitters, notably estradiol and dopamine, but it is repressed by activation of NMDA subtype of glutamate receptors. The functional consequences of spontaneous or drug-­ enhanced neurogenesis are modest, but optimism is building up for targeted interventions. Similarly, considerable expectations are placed on local or systemic transplantation of exogenous neural progenitor cells and on cerebral endothelial and bone marrow cells, particularly in combination with growth factors and/or strategies that permit recruitment of transplanted cells to the site of injury [56]. However, cell therapy carries the risk of tumorigenesis, and as major breakthroughs have not yet been achieved, further research is necessary to explore the actual potentials of stroke regenerative medicine [57]. Several brain regions may provide lifelong supply of newly generated neurons.

Pathophysiology The evolution of stroke is a highly intricate process which can be differentiated into two consecutive phases: a rather straightforward early “plumbing” problem that arises from the interruption of blood flow and brain energy supply, and a much more complex cascade of secondary events which depends on the interaction between metabolic and functional disturbances, on the one hand, and between hemodynamic and molecular alterations, on the other. As this complexity is differently depicted in different experimental stroke models, the technical particularities of these models must be understood before attempts are made to translate experimental insights to the clinical setting.

Animal Models of Stroke

According to the Framingham study, 65% of strokes that result from vascular occlusion present lesions in the territory of the middle cerebral artery, 2% in the anterior, and 9% in the posterior cerebral artery territories. The remaining lesions are located in brainstem, cerebellum, or in watershed or multiple regions. For each of these stroke types specific experimental models have been developed [58], but in accordance with

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10

the dominant clinical incidence middle cerebral artery occlusion models are preferentially used in experimental stroke research. Transorbital middle cerebral artery occlusion: This model was introduced for the production of stroke in monkeys [59], and later modified for use in cats, dogs, rabbits, and even rats. The procedure is technically demanding and requires microsurgical skills. The advantage of this approach is the possibility to expose the middle cerebral artery at its origin from the internal carotid artery without retracting parts of the brain. Vascular occlusion can thus be performed without the risk of brain trauma. On the other hand, removal of the eyeball is invasive and may evoke functional disturbances, which should not be ignored. Surgery may also cause generalized vasospasm, which may interfere with the collateral circulation and, hence, induce variations in infarct size. The procedure therefore requires extensive training before reproducible results can be expected. The occlusion of the middle cerebral artery at its origin interrupts blood flow to the total vascular territory, including the basal ganglia, which are supplied by the lenticulo-­striate arteries. These MCA branches are end-­ arteries, which in contrast to the cortical branches do not form collaterals with the adjacent vascular territories. As a consequence, the basal ganglia are consistently part of the infarct core, whereas the cerebral cortex exhibits a gradient of blood flow, which decreases from the peripheral towards the central parts of the vascular territory. Depending on the steepness of this gradient, a cortical core region with the lowest flow values in the lower temporal cortex is surrounded by a variably sized penumbra, which may extend up to the parasagittal cortex. Transcranial occlusion of the middle cerebral artery: Post- or retro-­ orbital transcranial approaches for middle cerebral artery occlusion are mainly used in rats and mice because in these species the main stem of the artery appears on the cortical surface rather close to its origin from the internal carotid artery [60]. Permanent occlusion is usually carried out by ligation or coagulation, and transient occlusion by clipping or lifting the vessel with a hook [61]. In contrast to transorbital middle cerebral artery occlusion, transcranial models do not produce ischemic injury in the basal ganglia because the lenticulo-­striate branches originate proximal to the occlusion site. Infarcts, therefore, are mainly located in the temporo-­parietal cortex with a gradient of declining flow values from

the peripheral to the central parts of the vascular territory. Filament occlusion of the middle cerebral artery: The presently most widely used procedure for middle cerebral artery occlusion in rats and mice is the intraluminal filament occlusion technique, first described by Koizumi [62]. A nylon suture with an acryl-­thickened tip is inserted into the common carotid artery and orthogradely advanced, until the tip is located at the origin of the middle cerebral artery. Modifications of the original technique include different thread types for isolated or combined vascular occlusion, adjustments of the tip size to the weight of the animal, poly-Llysine coating of the tip to prevent incomplete middle cerebral artery occlusion, or the use of guide-­sheaths to allow remote manipulation of the thread for occlusion during polygraphic recordings or magnetic resonance imaging. The placement of the suture at the origin of the middle cerebral artery obstructs blood supply to the total MCA-­supplying territory, including the basal ganglia. It may also reduce blood flow in the anterior and posterior cerebral arteries, particularly when the common carotid artery is ligated to facilitate the insertion of the thread. As this minimizes collateral blood supply from these territories, infarcts are very large and produce massive ischemic brain edema with a high mortality when experiments last for more than a few hours. For this reason, threads are frequently withdrawn after 1–2 hours following insertion. The resulting reperfusion salvages the peripheral parts of the MCA territory, and infarcts become smaller [63]. However, as the pathophysiology of transient middle cerebral artery occlusion differs from that of the clinically more relevant permanent occlusion models, the mechanisms of infarct evolution or the pharmacological responsiveness of the resulting lesions do not properly replicate that of clinical stroke [64]. Transient filament occlusion is also an inappropriate model for the investigation of spontaneous or thrombolysis-­induced reperfusion. Withdrawal of the intraluminal thread induces instantaneous reperfusion, whereas spontaneous or thrombolysis-­induced recanalization results in slowly progressing recirculation. As post-­ischemic recovery is greatly influenced by the dynamics of reperfusion, outcome and pharmacological responsiveness of experimental transient filament occlusion is also distinct from most clinical situations of reversible ischemia, where the onset of reperfusion is much less abrupt.

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Clot embolism of middle cerebral artery: Middle cerebral artery embolism with autologous blood clots is a clinically highly relevant but inherently variable stroke model, which requires careful preparation and placement of standardized clots to induce reproducible brain infarcts [65]. The most reliable procedure for clot preparation is thrombin-­induced clotting of autologous blood within calibrated tubings, which results in cylindrical clots that can be dissected in segments of equal length. Selection of either fibrin-­rich (white) or fibrin-­poor (red) segments influences the speed of spontaneous reperfusion and results in different outcome. Clots can also be produced in situ by microinjection of thrombin [66] or photochemically by ultraviolet illumination of the middle cerebral artery following injection of rose Bengal [67]. The main application of clot embolism is for the investigation of experimental thrombolysis. The drug most widely used is human recombinant tissue plasminogen activator [68], but the dose required in animals is much higher than in humans; this must be remembered when possible side-­effects such as t-­PA toxicity are investigated. The hemodynamic effect, in contrast, is similar despite the higher dose and adequately reproduces the slowly progressing recanalization observed under clinical conditions. A recent development of clinical stroke treatment and possibly the central challenge for future animal research is interventional thrombectomy [69, 70]. The animal most widely used for this research is the swine because the vessels are large enough to insert appropriate stent retriever devices, but as in this species the carotid access to the middle cerebral artery is impeded by a rete mirabile, clot embolism and retrieval is carried out via the internal maxillary or lingual artery [71]. Angiographic studies of this model confirm that clot retrieval by aspiration or removable stent devices results in immediate recanalization, but a detailed pathophysiological analysis of post-­ischemic reperfusion and of the metabolic-­functional recovery is not yet available. It has been suggested that the pathophysiology of thrombectomy can be replicated in small animals by technically simpler mechanical occlusion models, such as transient filament occlusion [72], but here again proper validation must be awaited. Various procedures for artery occlusion models, mostly middle cerebral artery occlusion models, were developed to study focal ischemia in animals.

Stroke Genetics Stroke is frequently the primary manifestation of a hereditary disorder [73]. The heritability of all ischemic strokes amounts to 37.9%, with differences between the various stroke subtypes (large vessel stroke 40.3%, small vessel stroke 16.1%, and cardioembolic stroke 32.6%). Early molecular genetic investigations relied on linkage studies or the examination of candidate genes, but with the advent of genome-­ wide association studies (GWAS) large numbers of single nucleotide polymorphisms (SNPs) are being examined in stroke patients [74]. These studies reveal an increasing number of genes involved in monogenic stroke syndromes or affecting the risk of common (sporadic) stroke. Examples of monogenic stroke syndromes are Cadasil (NOTCH3), Carasil or Maeda syndrome (HTRA1), Fabry disease, and MELAS. Genetic variants that affect the risk of common stroke are clearly related to different stroke subtypes and include the PTX2 and ZFHX3 genes which correlate with cardioembolic stroke in association with atrial fibrillation, or the HDAC9 and MMP12 genes which contribute to atherosclerosis-­associated large vessel stroke. So far, no variants have been associated with small vessel stroke, but there is evidence for genetic influences on intracerebral hemorrhage, involving the APP, COL4A1, and APOE genes [75]. An important newly evolving research field is pharmacogenetics which investigates the genetic influence on the individual responsiveness to stroke therapy. Examples are genetic differences in the metabolism of anti-­coagulants, notably dabigatran and clopidogrel, or of the fibrinolytic efficacy of rtPA. Such information is of substantial importance not only for individual drug selection and dosing, but also for decision-­making between alternative therapies, such as endovascular versus thrombolytic treatment [76].

Hemodynamics In the intact brain, cerebral blood flow is tightly coupled to the metabolic requirements of tissue (metabolic regulation), but remains essentially stable when blood perfusion pressure changes (autoregulation). An important requirement for metabolic regulation is the vasodilatory responsiveness of blood vessels to carbon dioxide (CO2 reactivity), which can be tested by the application of carbonic anhydrase inhibitors or CO2 ventilation. Under physiological conditions, blood flow doubles when arterial pCO2

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rises by about 30 mmHg, and is reduced by one-­third when pCO2 declines by 15 mmHg. The vascular response to CO2 depends mainly on the changes of extracellular pH, but it is also modulated by other factors such as prostanoids, nitric oxide, and neurogenic influences. Most of the energy generated by brain metabolism is used to cover the functional activity of the brain. As both are coupled locally to blood flow, regional alterations of flow and metabolism can be used for anatomical mapping of functional brain activity (neurovascular coupling). Autoregulation of cerebral blood flow is the remarkable capacity of the vascular system to adjust its resistance in such a way that blood flow is kept constant over a wide range of cerebral perfusion pressures (80–150 mmHg). The range of autoregulation is shifted to the right, i.e. to higher values, in patients with hypertension and to the left during hypercarbia. The mechanism of autoregulation is complex [77]. The dominating factor is a pressure-­sensitive direct myogenic response initiated by the activation of stretch-­sensitive cation channels of vascular smooth muscle. In addition, a flow-­sensitive indirect smooth muscle response is initiated by changes in the shear stress of endothelial cells, which result in activation of various signal transduction pathways. Other influences are mediated by metabolic and neurogenic factors, but these may be secondary effects of lesser significance. Metabolic regulation: cerebral blood flow is coupled to metabolic requirements of tissue by a vascular response to changes in CO2. Autoregulation: cerebral blood flow is kept constant over a wide range of cerebral perfusion pressures.

Disturbances of Flow Regulation

12

Focal cerebral ischemia is associated with tissue acidosis, which leads to vasoparalysis and, in consequence, to a severe disturbance of the metabolic regulation of blood flow. In the center of the ischemic territory, CO2 reactivity is abolished or even reversed, i.e. blood flow may decrease with increasing arterial pCO2. This paradoxical “steal” effect has been attributed to the rerouting of blood to adjacent non-­ischemic brain regions in which CO2 reactivity remains intact. Stroke also impairs autoregulation, but the disturbance is more severe at decreasing than at increasing blood pressure. This is explained by the fact that in the ischemic tissue a decrease of local brain perfusion

pressure cannot be compensated by further vasorelaxation, whereas an increase may shift the local perfusion pressure into the autoregulatory range and cause vasoconstriction. An alternative explanation is “false autoregulation” due to brain edema because the increase in local tissue pressure prevents the rise of tissue perfusion. Failure of cerebral autoregulation can be demonstrated in such instances by dehydrating the brain in order to reduce brain edema. When blood flow is progressively disturbed by gradual atherosclerotic obstruction of a brain artery, the local increase of vascular resistance is compensated by peripheral autoregulatory relaxation, provided the distal branches of the artery are not already fully dilated. The residual vasodilatory capacity is called hemodynamic reserve and can be evaluated by measuring the CO2 reactivity: the lower the flow response, the lesser the hemodynamic reserve and the greater the risk of brain ischemia [78]. After transient vascular obstruction, peripheral vasorelaxation persists for some time, which explains the phenomenon of post-­ ischemic hyperemia or luxury perfusion. During luxury perfusion, oxygen supply exceeds oxygen requirements of the tissue, as reflected by the appearance of red venous blood. With the cessation of tissue acidosis, vascular tone returns, and blood flow declines to or below normal. At longer recirculation times autoregulation  – but not CO2 reactivity – may recover, resulting in failure of metabolic regulation. This is one of the reasons why primary post-­ischemic recovery may be followed by delayed post-­ischemic hypoperfusion and secondary metabolic failure [79]. Disturbances of flow regulation through ischemia: tissue acidosis leads to vasorelaxation, CO2 reactivity is abolished or even reversed, and autoregulation is impaired.

Microcirculatory Disturbances

With the increasing understanding of the pathobiology of the neurovascular unit the importance of microcirculatory disturbances for the evolution of ischemic brain injury has been recognized [80]. Such disturbances develop at the capillary level within the first hour of focal ischemia and may persist even after full reversal of vascular occlusion (no-­reflow or incomplete microcirculatory reperfusion). The dominating pathology is the narrowing of the capillary lumen, induced by constriction or death of pericytes [81] and swelling of pericapillary astrocytic endfeet [82].

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Chapter 1: Neuropathology and Pathophysiology of Stroke

The capillaries are filled with aggregated red blood cells, leukocytes, and fibrin/platelet deposits, the high viscosity of which adds to the increased vascular resistance of the reduced capillary lumen. The mechanism of microcirculatory impairment is multifactorial. Pericytes constrict in response to the generation of reactive oxygen species (ROS), swelling of astrocytic endfeet is due to cytotoxic brain edema, and leukocyte adhesion to the vessel wall is part of the inflammatory response mediated by the generation of chemoattractants, cytokines, and chemokines. Finally, the activation of proteolytic enzymes contributes to the dismantlement of basal lamina and results in damage of the blood–brain barrier, an increase in interstitial tissue pressure, and the risk of hemorrhagic transformation. The impairment of microcirculation is equivalent to a reduction of nutritional blood flow. During permanent vascular occlusion, it aggravates the effect of primary ischemia, particularly in the borderzone of the infarct, and after transient vascular occlusion it may prevent adequate reoxygenation despite recanalization of the supplying artery. It is still unresolved to what extent microcirculatory impairment contributes to or originates from ischemic injury, but there is general consent that microvascular protection is a requirement for successful stroke treatment [83]. Focal brain ischemia is aggravated by microcirculatory disturbances, which may persist despite recanalization.

Collateral Circulation and Steal Phenomena The brain is protected against focal disturbances of blood flow by the collateral circulation, which provides a subsidiary network of vascular channels when principal conduits fail [84]. The most important intracranial collateral circuits are the circle of Willis at the base of the skull which provides low resist­ ance connections between the origins of the anterior, mid­dle and posterior cerebral arteries, and Heubner’s network of leptomeningeal anastomoses which connects the distal cortical branches of these arteries. The functional efficacy of the collaterals critically determines the severity of an ischemic lesion both during permanent and following transient vascular occlusion [85]. In contrast to this protective effect, collaterals may also divert blood from one brain region to another, depending on the magnitude and direction of the blood pressure gradients across the anastomotic connections

(for review, see [86]). The associated change of regional blood flow is called steal if it results in a decrease in flow, or inverse steal if it results in an improvement in flow. Inverse steal has also been referred to as the Robin Hood syndrome in analogy to the legendary hero who took from the rich and gave to the poor. Steals are not limited to a particular vascular territory and may affect both the extra- and intracerebral circulation. Examples of extracerebral steals are the subclavian, the occipital-­vertebral, and the ophthalmic steal syndrome. Intracerebral steal occurs across collateral pathways of brain, notably the circle of Willis and Heubner’s network of pial anastomoses. The pathophysiological importance of steal has been disputed, but as it depends on the individual hemodynamic situation, it may explain unintended effects when flow is manipulated by alterations of arterial pCO2 or vasoactive drugs. Most authors, therefore, do not recommend such manipulations for the treatment of stroke. “Steal”: decrease in focal blood flow when blood is diverted from one brain region to another by anastomotic channels; “inverse steal” if that results in an improvement in flow.

Concept of Ischemic Penumbra Opitz and Schneider [87] were the first to draw attention to the fact that an impairment of brain energy production induced by a reduction of blood flow affects the energy-­consuming processes in a sequential way: first, the functional activity of the brain is impaired; followed, at a more severe degree of hypoperfusion, by the suppression of the metabolic activity required to maintain its structural integrity. The concept of two different thresholds of blood flow for the preservation of functional and structural integrity was later refined by Symon et al. [88], who used a model of focal ischemia to produce a range of reduced flow levels. These studies revealed that EEG and evoked potentials are disturbed at substantially higher flow rates than the breakdown of the potassium gradient across the plasma membranes (“anoxic depolarization”). Since the breakdown of this gradient reflects the loss of cell viability, Symon et al. suggested that neurons located in the flow range between “electrical” and “membrane” failure are functionally silent, but structurally intact. In focal ischemia, this flow range corresponds to a crescent-­ shaped region intercalated between the necrotic tissue and the normal brain; it has been termed “penumbra” in analogy to the partly illuminated area around the

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complete shadow of the moon in full eclipse [89]. In metabolic terms it is the decline of blood flow below the level required to cover the functional but not the structural energy requirements of the brain.

Energy Requirements of Brain Tissue

14

A normal adult male’s brain containing about 130 billion neurons (21.5 billion in the neocortex) [90] comprises only 2% of total body mass, yet consumes at rest approximately 20% of the body’s total basal oxygen consumption and 16% of the cardiac blood output. The brain’s oxygen consumption is used almost entirely for the oxidative metabolism of glucose which in normal physiological conditions is the almost exclusive substrate for the brain’s energy metabolism [91] (Table 1.1). Glucose metabolized – and energy delivered  – to neuronal cell bodies is mainly to support cellular vegetative and house-­ keeping functions, e.g. axonal transport, biosynthesis of nucleid acids, proteins, lipids, as well as other energy-­consuming processes not related directly to the generation of action potentials. Therefore, the rate of glucose consumption of neuronal cell bodies is essentially unaffected by neuronal functional activation. Increases in glucose consumption (and regional blood flow) evoked by functional activation are confined to synapse-­rich regions, i.e. the neuropil, which contains axonal terminals, dendritic processes, and also the astrocytic processes that envelope the synapses. The magnitudes of these increases are linearly related to the frequency of action potentials in the afferent pathways, and increases in the projection zones occur regardless of whether the pathway is excitatory or inhibitory. Energy requirements of functional activation are due mostly to stimulation of the Na+K+-­ATPase activity to restore the ionic gradients across the cell membrane and the membrane potentials following spike activity, and are rather high compared to the basal energy demands of neuronal cell bodies [92]. In excitatory glutamatergic neurons, which account for 80% of the neurons in the mammalian cortex, glucose utilization during activation is mediated by astrozytes which consume glucose by anaerobic glycolysis to provide lactate to the neurons where it is used for oxidative metabolism [93] (Figure  1.5). Overall, 87% of the total energy consumed is required for signaling, mainly action potential propagation and post-­synaptic ion fluxes,

Table 1.1  Cerebral blood flow (CBF), oxygen utilization (CMRO2), and metabolic rates of glucose (CMRGIc) in man (approximated values)

Cortex

White matter

Global

CBF (ml/100 g/min)

65

21

47

CMRO2 (μmol/100 g/min)

230

80

160

CMRGlc (μmol/100 g/min)

40

20

32

and only 13% is expended in maintaining membrane resting potential [94]. The mechanisms by which neurotransmitters other than glutamate influence blood flow and energy metabolism in the brain are still poorly understood [95]. A normal adult male’s brain comprises only 2% of total body mass, yet consumes at rest approximately 20% of the body’s total basal oxygen consumption. Glucose is the almost exclusive substrate for the brain’s energy metabolism; 87% of the total energy consumed is required for signaling, mainly action potential propagation and post-­synaptic ion fluxes.

Viability Thresholds of Brain Ischemia The different amounts of energy required for the generation of membrane potential and the propagation of electrical activity are associated with different thresholds of blood flow that must be maintained to deliver the necessary amounts of oxygen and glucose from the blood to the brain. Functional activity – reflected by the amplitudes of spontaneous and evoked electrical activity – begins to decline at flow values below 50% of control and is completely suppressed at about 30% of control. In awake monkeys these values correspond to the progression of neurological injury from mild paresis at 22 ml/100g/min to complete paralysis at 8 ml/100g/min. Morphological damage evolves as soon as cell membranes depolarize (“terminal” depolarization) and occurs at flow values below 15–20% of control. Biochemically, functional suppression is associated with the inhibition of protein synthesis at about 50% and the development of lactacidosis at 30–40% of control, whereas membrane depolarization and morphological injury correspond to the breakdown of energy metabolism and the loss of ATP at about 18% of control (Figure 1.6).

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Glutamate-releasing presynaptic terminal

Astrocyte

Capillary

Glucose

Glycolysis

Lactate

Glucose

Oxidative phosphorylation Gln Glu

Gln Glu EAAT

K+ Na /K -ATPase +

Na +

Na

Postsynaptic site

Figure 1.5  Schematic representation of the mechanism for glutamate-­induced glycolysis in astrocytes during physiological activation. (With permission from the Human Frontier Science Program (HFSP) and Magistretti 2001 [169].)

+

+

lonotropic glutamate receptor NMDAR

Figure 1.6  Diagrammatic representation of viability thresholds of focal brain ischemia.

A detailed picture of the dynamics of injury evolution can be obtained by the simultaneous recording of local blood flow and spontaneous unit activity of cortical neurons [96] (Figures 1.7A, B). According to these measurements, unit activity disappears at a mean

value of 18 ml/100g/min, but the large variability of the functional thresholds of individual neurons (6–22 ml/100g/min) indicates differential vulnerability even within small cortical sectors. This explains the gradual development of neurological deficits, which may be

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16

Figure 1.7  A: Activity of a single neuron during graded ischemia before, during, and after reversible MCA occlusion. B: Recovery of neuronal function after a limited period of ischemia. C: Diagram of CBF thresholds required for the preservation of function and morphology of brain tissue. The activity of individual neurons is blocked when flow decreases below a certain threshold (dashed line) and returns when flow is raised again above this threshold. The fate of a single cell depends on the duration for which CBF is impaired below a certain level. The solid line separates structurally damaged from functionally impaired, but morphologically intact tissue, the “penumbra.” The dashed line distinguishes viable from functionally impaired tissue. (Modified from Heiss and Rosner 1983 [170].)

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Chapter 1: Neuropathology and Pathophysiology of Stroke

related to differences in single cell activity with regular or irregular discharges at flow levels above the threshold of membrane failure. Whereas neuronal function is impaired immediately when flow drops below this threshold, the development of irreversible morphological damage is time dependent. Based on unit recordings from a large number of neurons during and after ischemia of varying density and duration, it was possible to construct a discriminant curve representing the lowest residual blood flow and the longest duration of ischemia still permitting neuronal recovery (Figure  1.7C). These results broaden the concept of the ischemic penumbra: the tissue fate  – potential of recovery or irreversible damage – is determined not only by the level of residual flow, but also by the duration of the flow disturbance. Each level of decreased flow can, on average, be tolerated for a defined period of time; as a rule flow between 17 and 20 ml/100g/min can be tolerated for prolonged periods, whereas flow rates of 12 ml/100g/min lasting for 2–3 hours result in infarction. However, as lowflow perfusion is inhomogeneous, individual cells may become necrotic after shorter periods of time and at higher levels of mean residual flow. The ischemic penumbra is the range of perfusion between the flow threshold for preservation of function and the flow threshold for morphological integrity. It is characterized by the potential for functional recovery without morphological damage.

Imaging of Penumbra Based on the threshold concept of brain ischemia, the penumbra can be localized on quantitative flow images using empirically established flow thresholds. A more reliable approach is the imaging of threshold-­ dependent biochemical and/or functional disturbances and the demarcation of the mismatch between disturbances which occur only in the infarct core and others which also affect the penumbra [97]. Under experimental conditions the most accurate method for the precise localization of the infarct core is the loss of ATP on bioluminescent images of tissue ATP content (Figure 1.8). A biochemical marker of core plus penumbra is tissue acidosis or the inhibition of protein synthesis. The penumbra is the difference between the respective lesion areas. The reliability of this approach is supported by the precise co-­localization of gene transcripts that are selectively expressed in the penumbra, such as the stress protein Hsp70 or the documentation

of the gradual disappearance of the penumbra with increasing ischemia time [98]. Non-invasive imaging of the penumbra is possible using positron emission tomography (PET) or magnetic resonance imaging (MRI) [99]. Widely used PET parameters are the increase in oxygen extraction or the mismatch between reduced blood flow and the preservation of vitality markers, such as flumazenil binding to central benzodiazepine receptors [100]. An alternative PET approach is the use of hypoxia markers such as 18 F nitromidazol (F-­MISO) which is trapped in viable hypoxic but not in normoxic or necrotic tissue [101]. The best established MRI approach for penumbra imaging is the calculation of mismatch maps between the signal intensities of perfusion (PWI) and diffusionweighted images (DWI), but its reliability has been questioned [102]. An alternative method is quantitative mapping of the apparent diffusion coefficient (ADC) of water, which reveals a robust correlation with the biochemically characterized penumbra for ADC values between 90% and 77% of control [103]. Recently, MR stroke imaging has been performed by combining PWI, DWI, and pH-­weighted imaging (pHWI) where the mismatch between DWI and pHWI detects the penumbra, and that between PWI and pHWI the area of benign oligemia, i.e. a region in which flow reduction is not severe enough to cause metabolic disturbances [104]. Diffusion kurtosis imaging (DKI), an extension of diffusion imaging, demarcates the regions with stroke-­induced structural changes that provide information about acute and chronic alterations in the perilesional cortex [105]. Finally, new developments in non-­invasive molecular and optical imaging are of increasing interest for stroke research [106]. Using specific fluorescent probes and reporter gene technologies, these methods trace gene transcription and detect intracellular conjugates that reflect the metabolic status and/or bind to stroke markers. The number of molecules that can be identified by these methods rapidly expands and greatly facilitates the regional analysis of stroke injury. Non-invasive imaging of the penumbra is possible using positron emission tomography (PET) or magnetic resonance imaging (MRI).

Temporal Evolution of Stroke Focal brain ischemia produces brain infarction along two basically different pathophysiologies, depending on

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Figure 1.8  Biochemical imaging of infarct core, penumbra, and benign oligemia after experimental middle cerebral artery occlusion. The core is identified by ATP depletion, the penumbra by the mismatch between the suppression of protein synthesis and ATP depletion (top) or by the mismatch between tissue acidosis and ATP (bottom), and benign oligemia by the reduction of blood flow in the absence of biochemical alterations. (Modified from Hossmann and Mies 2007 [171].)

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the severity and duration of the primary flow reduction, on the one hand, and the dynamics of post-­ischemic recirculation, on the other. During permanent vascular occlusion, the central core of the ischemic infarct, i.e. the region in which blood flow declines below the threshold of cell viability, gradually expands into the penumbra (Figures 1.7 and 1.9). This expansion is not due to the progression of ischemia because the activation of collateral blood supply and spontaneous thrombolysis tend to improve blood flow over time. Infarct growth can be differentiated into three phases. During the acute phase tissue injury is the direct consequence of the ischemia-­induced energy failure and the resulting terminal depolarization of cell membranes. At flow values below the threshold of energy metabolism, this injury is established within a few minutes after the onset of ischemia. During the subsequent subacute phase, the infarct core expands into the peri-­infarct penumbra until, after 3–6 hours, core and penumbra merge. The reasons for this expansion are peri-­infarct spreading depressions and a multitude of cell biological disturbances, collectively referred to as molecular cell injury. Moreover, a late phase of injury evolves after several days to weeks after the onset of ischemia. During this phase secondary phenomena such as vasogenic edema, inflammation, and possibly programmed cell death may contribute to a further progression of injury. The largest increment of infarct volume occurs during the subacute phase in which the infarct core expands into the penumbra [107]. Using multiparametric

imaging techniques for the differentiation between core and penumbra, evidence could be provided that in small rodents submitted to permanent occlusion of the middle cerebral artery, the penumbra equals the volume of the infarct core at 1 hour ischemia, but after 3 hours more than 50% and between 6 and 8 hours almost all of the penumbra has disappeared and is now part of the irreversibly damaged infarct core [98]. In larger animals infarct core may be heterogeneous with multiple mini-­cores surrounded by multiple mini-­ penumbras, but also these lesions expand and eventually progress to a homogeneous defect with a similar time course [108]. After transient vascular occlusion stroke the pathophysiology of lesion growth is basically different. If blood flow is promptly restored within the first hour of ischemia, brain energy metabolism recovers throughout the ischemic territory including the infarct core. However, after a free interval of several hours or even days, a delayed type of neuronal death evolves in an area that roughly corresponds to the infarct core at the onset of ischemia. This injury differs from primary ischemic injury by the absence of major flow disturbances and, therefore, is mediated by molecular rather than hemodynamic variables, as during permanent ischemia. Finally, if transient vascular occlusion is gradually reversed as during spontaneous or thrombolytically induced recanalization, breakdown of energy metabolism in the infarct core does not recover because blood flow is too low or too inhomogeneous to resuscitate the brain within the revival time of the tissue. However, the

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Figure 1.9  Relationship between peri-­ infarct spreading depressions (above) and infarct growth (below) during permanent focal brain ischemia induced by occlusion of the middle cerebral artery in rat. The effect of spreading depressions on electrical brain activity (EEG) and blood flow (LDF) are monitored by DC recording of the cortical steady potential, and infarct growth by MR imaging of the apparent diffusion coefficient (ADC) of brain water.

improvement of flow stabilizes the penumbra and interrupts the growth of the infarct core as soon as reperfusion starts. During permanent vascular occlusion brain infarcts grow in three phases: • acute phase, within a few minutes after the onset of ischemia; terminal depolarization of cell membranes; • subacute phase, within 3–6 hours; molecular cell injury, the infarct core expands into the peri-infarct penumbra; • late phase, several days to weeks; vasogenic edema, inflammation, and possibly programmed cell death. After transient vascular occlusion quality of reperfusion determines outcome: • abrupt reperfusion restores core metabolism, but may cause delayed neuronal cell death; • gradual reperfusion does not restore core injury, but alleviates infarct growth.

Mechanisms of Injury Progression Spreading Depression A functional disturbance contributing to the growth of the infarct core into the penumbra zone is the generation of peri-­infarct spreading depression-­like depolarizations [109] (Figure 1.10). These depolarizations are initiated at the border of the infarct core and spread over the

entire ipsilateral hemisphere. During spreading depression the metabolic rate of the tissue markedly increases in response to the greatly enhanced energy demands of the activated ion exchange pumps [110]. In the healthy brain the associated increase of glucose and oxygen demands are coupled to a parallel increase of blood flow, but in the peri-­infarct penumbra this flow response is suppressed or even reversed [111]. As a result, a misrelationship arises between the increased metabolic workload and the low oxygen supply, leading to transient episodes of hypoxia and the stepwise increase in lactate during the passage of each depolarization. The pathogenic importance of peri-­infarct depolarizations for the progression of ischemic injury is supported by the linear relationship between the number of depolarizations and infarct volume. Correlation analysis of this relationship suggests that during the initial 3 hours of vascular occlusion each depolarization increases the infarct volume by more than 20%. This is probably one of the reasons that glutamate antagonists and other interventions, which inhibit the generation of spreading depolarizations, reduce the volume of brain infarcts [112]. Peri-infarct spreading depressions are depolarizations initiated at the border of the infarct core and may contribute to progression of ischemic injury.

Molecular Mechanisms In the borderzone of permanent focal ischemia or within the ischemic territory after transient vascular

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Figure 1.10  Schematic representation of molecular injury pathways leading to necrotic or apoptotic brain injury after focal brain ischemia. Injury pathways can be blocked at numerous sites, providing multiple approaches for the amelioration of both necrotic and apoptotic cell death.

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occlusion, cellular disturbances may evolve that cannot be explained by a lasting impairment of blood flow or energy metabolism. These disturbances are referred to as molecular injury, where the term “molecular” does not anticipate any particular injury pathway (for reviews, see [113, 114]). The molecular injury cascades (Figure 1.10) are interconnected in complex ways, which makes it difficult to predict their relative pathogenic importance in different ischemia models. In particular, molecular injury induced by transient focal ischemia is not equivalent to the alterations that occur in the core or the penumbra of permanent ischemia. Therefore, the relative contribution of the following injury mechanisms differs in different types of ischemia. Acidotoxicity: During ischemia oxygen depletion, the associated activation of anaerobic glycolysis causes an accumulation of lactic acid which depending on the severity of ischemia, blood glucose levels, and the degree of ATP hydrolysis results in a decline of intracellular pH to levels between 6.5 and below 6.0. As the severity of acidosis correlates with the severity of ischemic injury, it has been postulated that acidosis is neurotoxic. Evidence has also been provided that ASICs (acid-­sensing ion channels) are glutamate-­independent vehicles of calcium flux, and that blockade of ASICs attenuates stroke injury. This suggests that acidosis may induce calcium toxicity, and that this effect is the actual mechanism of acidotoxicity [115].

Excitotoxicity: Shortly after the onset of ischemia, excitatory and inhibitory neurotransmitters are released, resulting in the activation of their specific receptors. Among these neurotransmitters, particular attention has been attributed to glutamate, which under certain experimental conditions may produce excitotoxic cell death [116]. The activation of ionotropic glutamate receptors results in the inflow of calcium from the extracellular into the intracellular compartment, leading to mitochondrial calcium overload and the activation of calcium-­ dependent catabolic enzymes. The activation of metabotropic glutamate receptors induces the IP3-dependent signal transduction pathway, leading among others to the stress response of endoplasmic reticulum, and by induction of immediate-early-genes (IEG) to adaptive genomic expressions. At very high concentration, glutamate results in primary neuronal necrosis. However, following pharmacological inhibition of ionotropic glutamate receptors, an apoptotic injury mechanism evolves that may prevail under certain pathophysiological conditions. The importance of excitotoxicity for ischemic cell injury has been debated, but this does not invalidate the beneficial effect of glutamate antagonists for the treatment of focal ischemia. An explanation for this discrepancy is the above-­described pathogenic role of peri-­infarct depolarizations in infarct expansion. As glutamate antagonists inhibit the spread of these depolarizations, the resulting injury is also reduced.

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Calcium toxicity: In the intact cell, highly efficient calcium transport systems assure the maintenance of a steep calcium concentration gradient of approximately 1:10 000 between the extra- and the intracellular compartment on the one hand, and between the cytosol and the endoplasmic reticulum (ER) on the other. During ischemia, anoxic depolarization in combination with the activation of ionotropic glutamate and acid-­ sensing ion channels causes a sharp rise of cytosolic calcium [117]. At the onset of ischemia this rise is further enhanced by activation of metabotropic glutamate receptors which mediate the release of calcium from endoplasmic reticulum (ER), and after recovery from ischemia by activation of transient receptor potential (TRP) channels which perpetuate intracellular calcium overload despite the restoration of ion gradients (Ca2+ paradox) [118]. The changes in intracellular calcium activity are highly pathogenic. Prolonged elevation of cytosolic calcium causes mitochondrial dysfunction and induces catabolic changes, notably by activation of Ca2+-dependent effector proteins and enzymes such as endonucleases, phospholipases, protein kinases, and proteases that damage DNA, lipids, and proteins. The release of calcium from the ER evokes an ER stress response, which mediates a great number of ER-­ dependent secondary disturbances, notably inhibition of protein synthesis. Calcium-­dependent pathological events are therefore complex and contribute to a multitude of secondary molecular injury pathways. Free radicals: In brain regions with low or intermittent blood perfusion, reactive oxygen species (ROS) are formed which produce peroxidative injury of plasma membranes and intracellular organelles [119]. The reaction with nitric oxide leads to the formation of peroxynitrite, which also causes violent biochemical reactions. Secondary consequences of free radical reactions are the release of biologically active free fatty acids such as arachidonic acid, the induction of endoplasmic reticulum stress and mitochondrial disturbances, the initiation of an inflammatory response, breakdown of the blood–brain barrier, and fragmentation of DNA. The latter may induce apoptosis and thus enhance molecular injury pathways related to mitochondrial dysfunction. The therapeutic benefit of free radicals-­targeted therapies, however, is limited and has to await the discovery of novel, more efficient drugs [120]. Nitric oxide toxicity: Nitric oxide (NO) is a product of NO synthase (NOS) acting on argenin. There are

at least three isoforms of NOS: eNOS is constitutively expressed in endothelial cells, nNOS in neurons, and the inducible isoform iNOS mainly in macrophages. Pathophysiologically, NO has two opposing effects [121]. In endothelial cells the generation of NO leads to vascular dilation, an improvement of blood flow, and the alleviation of hypoxic injury, whereas in neurons it contributes to glutamate excitotoxicity and – by formation of peroxynitrite  – to free radical-­induced injury. The net effect of NO thus depends on the individual pathophysiological situation and is difficult to predict. Zinc toxicity: Zinc is an essential catalytic and structural element of numerous proteins and a secondary messenger, which is released from excitatory synapses during neuronal activation. Cytosolic zinc overload may promote mitochondrial dysfunction and generation of reactive oxygen species (ROS), activate signal transduction pathways such as MAP kinase, enhance calcium toxicity, and promote apoptosis [122]. However, at low concentration zinc may also exhibit neuroprotective properties, indicating that cells may possess a specific zinc set-­point by which too little or too much zinc can promote ischemic injury [123]. ER stress and inhibition of protein synthesis: A robust molecular marker for the evolution of ischemic injury is inhibition of protein synthesis, which persists throughout the interval from the onset of ischemia until cell death ensues [50]. It is initiated by a disturbance of the calcium homeostasis of the endoplasmic reticulum (ER), which results in ER stress and various cell biological abnormalities such as un- or misfolding of proteins, expression of stress proteins, and a global inhibition of the protein synthesizing machinery. The latter is due to the activation of protein kinase R (PKR), which causes phosphorylation and inactivation of the alpha subunit of eukaryotic initiation factor eIF2. This again leads to selective inhibition of polypeptide chain initiation, disaggregation of ribosomes, and inhibition of protein synthesis at the level of translation. To restore ER function un- or misfolded proteins must be refolded (by activation of the unfolded protein response, UPR) or degraded (by ER-­associated degradation, ERAD). Cells in which UPR and ERAD fail to restore ER function die by apoptosis [124]. Obviously, persistent inhibition of protein synthesis is incompatible with cell survival, but as the duration of inhibition does not correlate with the delay of cell death, other factors must also be involved.

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Mitochondrial disturbances: To mitigate metabolic or environmental stress, functional mitochondria are maintained by fission and fusion [125]. During ischemia, the concurrence of an increased cytosolic calcium activity with the generation of reactive oxygen species may lead to an increase in permeability of the inner mitochondrial membrane (mitochondrial permeability transition, MPT), which has been associated with the formation of a permeability transition pore (PTP). The PTP is a Ca2+-, ROS (reactive oxygen species), voltage-­dependent, and cyclosporine A–sensitive high-­conductance channel, located in the inner mitochondrial membrane. It is also a reversible fast Ca2+ release channel, facilitated by the mitochondrial matrix protein cyclophilin D [126]. The increase in permeability of the inner mitochondrial membrane has two pathophysiologically important consequences. The breakdown of the electrochemical gradient interferes with mitochondrial oxidative phosphorylation and, in consequence, with aerobic energy production. Furthermore, the equilibration of mitochondrial ion gradients causes swelling of the mitochondrial matrix, which eventually will cause disruption of the outer mitochondrial membrane and the release of pro-­apoptotic mitochondrial proteins into the cytosol (see below). Ischemia-­ induced mitochondrial disturbances thus contribute to delayed cell death both by impairment of the energy state and the activation of apoptotic injury pathways [127]. A large number of biochemical substrates, molecules, and mechanisms are involved in the progression of ischemic damage.

Apoptosis

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Apoptosis is an evolutionary conserved form of programmed cell death that in multicellular organisms matches cell proliferation to preserve tissue homeostasis [128]. It is an active process that requires intact energy metabolism and protein synthesis, and it is initiated essentially by two pathways: an extrinsic death receptor-­dependent route which is initiated by the activation of the Fas receptor, and an intrinsic pathway which depends on the mitochondrial release of pro-­apoptotic molecules such as apoptosis-­ inducing factor (AIF) and cytochrome C. Both pathways involve a series of enzymatic reactions and converge in the activation of caspase-­3, a cystine protease, which contributes to the execution of cell death. An end stage of this process is the ordered disassembly of the genome, resulting in a laddered

pattern of oligonucleosomal fragments as detected by electrophoresis or terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick end-­labeling (TUNEL). Although apoptosis is mainly involved in physiological cell death, it is widely assumed to contribute to the pathogenesis of diseases, including cerebral ischemia [129]. In the context of ischemic stroke, this is difficult to understand because in areas with primary cell death as in the ischemic core, the obvious reason is ischemia-­induced energy failure and tissue necrosis. In areas with secondary or delayed cell death, the dominating biochemical disturbance is irreversible suppression of protein synthesis, which is difficult to reconcile with the execution of an active form of programmed cell death. However, in experimental models of focal ischemia pro-­apoptotic pathways initiated by the activation of Toll-­like receptors 2 and 4, the NOTCH1 receptor, and the adiponectin receptor 1, as well as a multitude of other biochemical reactions that are reminiscent of apoptosis, such as the expression of p53, JNK, c-­jun, p38, cycline-­ dependent kinase 5, or caspase 3, have been documented, all of which correlate to some degree with the severity of ischemic injury. Conversely, the inhibition of apoptotic pathways by gene manipulation or pharmacological interventions reduces the volume of brain infarcts. Finally, the initiation of survival pathways such as kinase SIK2 and CREB coactivator TORC1, the unfolded protein response (UPR), the expression of HSP-­70 and NOGO-­A proteins, as well as a variety of neuroprotective reactions associated with inflammation and the activation of pericytes, tend to alleviate ischemic cell death. It has, therefore, been suggested that the outcome of brain ischemia is the result of a struggle between life and death pathways [130], and that the morphological manifestation of ischemic cell injury is a hybrid of necrosis and apoptosis, appearing on a continuum with the two forms of cell death at its poles [131]. Apoptosis, an active form of programmed cell death, may contribute to a certain extent to ischemic cell death.

Pre- and Postconditioning of Ischemic Injury The molecular signaling cascades initiated by brain ischemia are not solely destructive, but may also

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Chapter 1: Neuropathology and Pathophysiology of Stroke

exert a neuroprotective effect [132]. In fact, most of the above-­ described injury pathways including ischemia itself induce a transient state of increased ischemic tolerance, provided the initial injury remains subliminal for tissue destruction. Pharmacologically, such tolerance is also achieved with several inhalation anesthetics, notably isoflurane and halothane. The resulting neuroprotection is called “ischemic preconditioning” and can be differentiated into three phases: during the induction phase molecular sensors which respond to the preconditioning stimulus are activated by transcription factors; the transduction phase results in the amplification of the signal; and during the effector phase proteins with a protective impact are switched on [133]. The increase in ischemia tolerance appears 2–3 days after the preconditioning stimulus, and it vanishes after 1 week. An important preconditioning pathway is the upregulation of the hypoxia-­inducible factor 1 (HIF-­1) in astrocytes. HIF-­1 is a transcription factor that among others induces the expression of erythropoietin (EPO), which binds to the neuronal EPO receptor and which exhibits potent neuroprotective effects. Another putative mechanism is the endoplasmic reticulum stress response. Depletion of ER calcium stores causes accumulation of unfolded proteins in the ER lumen and induces the activation of two highly conserved stress responses: the ER overload response (EOR) and the unfolded protein response (UPR). EOR triggers activation of the transcription factor NF-­kappa B, and UPR causes suppression of the initiation of protein synthesis. As the latter contributes to delayed ischemic injury (see above), its reduction may have a neuroprotective effect. Evidence has also been provided that ischemic injury can be alleviated by repeated mechanical interruptions of blood reperfusion after a period of transient focal ischemia [134]. This phenomenon, termed “ischemic post­conditioning,” has been associated with the phosphorylation of several prosurvival protein kinases, such as extracellular signal-­regulated kinase (ERK), p38 mitogen-­activated protein kinase (MAPK), and Akt. The possibility to influence ischemic injury after the primary impact is challenging, but it remains to be shown for which kind of clinical situation this finding is of practical relevance. Short episodes of ischemia can improve the tolerance of brain tissue for subsequent blood flow disturbance.

Secondary Complications Ischemic Brain Edema Ischemia-associated brain edema is the volumetric accumulation of brain water that can be differentiated into two pathophysiologically different types: an early intracellular (cytotoxic) type, followed after some delay by a late extracellular (vasogenic) type of edema. The cytotoxic type of edema is threshold dependent. It is initiated at flow values of similar to 30% of control when stimulation of anaerobic metabolism causes an increase of osmotically active brain metabolites such as lactate and, hence, an osmotically obliged cell swelling. At flow values below 20% of control, anoxic depolarization and the increase in intracellular sodium results in the opening of voltage-­gated chloride channels which further enhances intracellular osmolality and cell swelling. Intracellular uptake of sodium is also associated with a coupled movement of water that is independent of an osmotic gradient and which is referred to as “anomalous osmosis.” In the absence of blood flow, cell swelling occurs at the expense of the extracellular fluid volume, causing shrinkage of the extracellular compartment, but no change in net water content. The shift of fluid is reflected by a decrease of the apparent diffusion coefficient of water (ADC), which is the reason for the increase of signal intensity in diffusion-­weighted MR imaging [103]. However, if some residual blood flow persists, water is taken up from the blood, and the net tissue water content increases. After vascular occlusion this increase starts within a few minutes after the onset of ischemia and causes a gradual increase in brain volume. With the evolution of tissue necrosis and the degradation of basal lamina, the blood–brain barrier breaks down [135], and after 4–6 hours blood serum begins to leak from the vessels into the brain. This disturbance initiates a vasogenic type of edema, which further enhances the water content of the tissue. Vasogenic edema reaches its peak at 1–2 days after the onset of ischemia and may cause an increase of tissue water by more than 100%. If brain infarcts are large, the volume increase of the edematous brain tissue may be so pronounced that transtentorial herniation results in compression of the midbrain. Under clinical conditions, this “malignant” form of brain infarction is the by far most dangerous complication of stroke and may require decompressive craniectomy [136].

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Another risk factor of vasogenic edema and the associated breakdown of the blood–brain barrier is hemorrhagic transformation of brain infarction, particularly in combination with thrombolytic therapy of stroke [137]. As barrier leakage starts 4–6 hours after onset of ischemia, the risk of bleeding sharply increases at this time. This is one of the reasons why thrombolytic therapy should not be delayed beyond this limit. Vasogenic edema, in contrast to the early cytotoxic type of edema, is iso-­osmotic and accumulates mainly in the extracellular compartment. This reverses the narrowing of the extracellular space and explains the “pseudonormalization” of the signal intensity observed in diffusion-­weighted MR imaging [138]. However, as the total tissue water content is increased at this time, the high signal intensity in T2-weighted images clearly differentiates this situation from a “real” recovery to normal. The formation of cytotoxic and, to a lesser extent, of vasogenic edema requires the passage of water through aquaporin channels located in the plasma membrane [139]. Inhibition of aquaporin water conductance may, therefore, reduce the severity of ischemic brain edema. Similarly, the inhibition of sodium transport across sodium channels has been suggested to reduce edema formation. However, as the driving force for the generation of edema is the gradient of osmotic and ionic concentration differences built up during ischemia, aquaporin and sodium channels may modulate the speed of edema generation, but not the final extent of tissue water accumulation. Their pathophysiological importance is, therefore, limited. Early cytotoxic edema is caused by osmotically induced cell swelling; the later vasogenic edema is iso-osmotic, caused by breakdown of the blood–brain barrier, and accumulates in the extracellular compartment.

Inflammation

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Brain infarcts evoke a strong inflammatory response, which is thought to contribute to the progression of ischemic brain injury (Figure 1.11). Gene expressions related to this response have, therefore, been extensively investigated to search for possible pharmacological targets (for review, see [140]). Inflammatory cytokines (interleukin [IL]-1β, IL-­6, IL-­10, and tumor necrosis factor-­ α [TNFα]) and chemokines (IL-­8, monocyte chemoattractant protein-­ 1 [MCP-­ 1], RANTES, and IP-­10), as well as adhesion molecules (ICAM1 and selectins), are upregulated and promote

recruitment and penetration of leukocytes across the blood–brain barrier. The inflammatory response of the ischemic tissue has been associated, among others, with the generation of free radicals in reperfused or critically hypoperfused brain tissue. The prostaglandin synthesizing enzyme cyclo-oxygenase-2 (COX-­2) and NF-­kappa B, a transcription factor that responds to oxidative stress, are also upregulated and may be neurotoxic, as suggested by the beneficial effect of COX-­2 inhibitors. Infarct reduction was also observed after genetic or pharmacological inhibition of matrix metalloproteinase (MMP)-9, but this effect has been disputed. A key player in the intracellular response to cytokines is the JAK (janus kinase)/STAT (signal transducer and activator of transcription) pathway, which induces alterations in the pattern of gene transcription. These changes are associated either with cell death or survival and suggest that inflammation may be both neurotoxic and neuroprotective [141]. Post-stroke inflammation is also triggered by so-­ called damage-­associated molecular pattern molecules (DAMPs), which are released by the ischemic brain tissue. These molecules include S100, heat shock, and chromatin-­associated proteins, as well as ATP, DNA, and RNA, and result in the orchestrated infiltration of the brain by immune cells [142]. Inflammatory reactions and the associated free radical-­ mediated processes are, therefore, important modulators of ischemic injury, but the influence on the final outcome is difficult to predict. Inflammatory reactions are important modulators of ischemic injury.

Therapeutic Window The difference between early and delayed ischemic injury and its association with different types of ischemia has important implications for the length of the therapeutic window for stroke treatment. During permanent vascular occlusion the irreversibly damaged infarct core rapidly expands into the potentially salvageable penumbra until  – between 3 and 6 hours – core and penumbra merge and the infarct reaches its final size. As tissue salvage is only possible as long as some viable penumbral tissue subsists, the therapeutic window closes at this time. However, the kinetic of infarct growth is asymptotic with the fastest growth rate shortly after the onset of ischemia. Therefore, most of the salvageable penumbra disappears long before the window closes;

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Chapter 1: Neuropathology and Pathophysiology of Stroke

NADPH oxidase iNOS

Activated astrocyte

ROS/NO

A

IL-1β TNF-α

BBB dysfunction

Neurotoxic microglia AP-1 NF-κB TSPO COX-2

P2×7

IL-1β TNF-α IL-6 IL-1β TNF-α

M1

TLR

apoptosis/ necrosis NADPH oxidase iNOS

Amyloid plaque

Inflammatory infiltration

Primed microglia

Amyloid-β aggregates

ROS

Neuron

ROS/NO

Phagocytosis

Neurotrophic factors TGF-β

N-APP

B

Surveying microglia

DR6

APP

Neuroprotective microglia

Figure 1.11  Components of the neurovascular unit (NVU), the “vicious cycle” of neuroinflammation, and the the dual – neurotoxic and neuroprotective – role of microglia. Contribution of peripheral immune cells (A) and of activated local microglia (B) to the inflammatory response and tissue damage. COX-­2, cyclooxygenase-­2; AP-­1, activator protein; NF-­kB, nuclear factor-­kB; iNOS, nitric oxide synthase; ROS, reactive oxygen species; NO, nitric oxide; TGF-­b, tumor growth factor-b. (With permission from Jacobs et al. 2012 [172].)

e.g. 1 hour after the onset of vascular occlusion about half of the ischemic territory is salvageable penumbra, but at 3 hours this portion declines to less than 10% [98]. This observation has led to the concept of the Golden Hour, which suggests that within the first hour of ischemia the potential of tissue rescue is much higher than after 3–6 hours, when the therapeutic window comes to its end [143]. After transient vascular occlusion, the dynamics of the therapeutic window are more complex. Depending on the quality of reperfusion, two patterns must be distinguished. If reperfusion is slowly restored as during spontaneous or pharmacologically induced

thrombolysis of clot embolism, the increase in blood perfusion pressure is too low to restore nutritional flow in the core tissue. But it improves the residual flow rate in the viable penumbra to such an extent that it decelerates the growth of the infarct core. In this scenario the therapeutic window – in particular for pharmacological treatment in combination with thrombolytic reperfusion  – matches that of permanent ischemia, i.e. 3–6 hours, with the greatest benefit during the first “golden hour” after the onset of ischemia. The second pattern refers to a pathophysiological situation in which vascular obstruction is abruptly released, as after transient mechanical occlusion or interventional

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Section 1: Etiology, Pathophysiology, and Imaging

thrombectomy. In this scenario the sudden restoration of full arterial perfusion pressure overcomes no-­reflow and salvages not only the penumbra, but potentially resuscitates also core tissue. At normal body temperature resuscitation of the infarct core is possible within the brain revival time of about 1 hour, but this recovery is followed by delayed neuronal death after a free “maturation” interval of up to several days. As tissue salvage is possible throughout this period, the therapeutic window after abruptly reversed ischemia is much longer than that of permanent or slowly reversed ischemia. Unfortunately, this difference has long been ignored in pre-­clinical stroke studies, where permanent and abruptly reversed transient ischemia were used indiscriminately to test the potentials of neuroprotective interventions. As a result, therapeutic windows of 6 hours or longer have been chosen for clinical trials, although the majority of stroke patients suffer from permanent or slowly reversed ischemia. This explains that most of these trials have failed [144]. However, with the advent of interventional thrombectomy, abrupt reversal of blood flow has become possible also under clinical conditions, opening a window of therapeutic opportunity that may extend well beyond the window of permanent or gradually reversed ischemia.

Clinical Translation

26

Experimental research has advanced our knowledge about brain physiology and pathophysiology of brain disorders, but the transfer of this knowledge into clinical application is difficult and often lacks behind. One of the reasons are differences between the brain of experimental animals and man with regard to evolutionary state (non-­gyrencephalic vs. gyrencephalic), anatomy (amount of gray vs. white matter), relative size, cellular density, blood supply, and metabolism (see Table 1.1). Additionally, experimental models in animals cannot be easily compared to complex human diseases often based on a different pathophysiology and affecting multimorbid patients. The other problem arises from the investigative procedures, which cannot be equally applied in animals and patients. This is especially true when pathophysiologic changes obtained by invasive procedures in animals, e.g. by analysis of tissue samples, by autoradiography, or by histology, should be related to the course of a disease, but cannot be assessed repeatedly and regionally. To facilitate the transfer of knowledge from experimental neuroscience to clinical neurology, it is necessary to develop

methods which can be equally applied in patients and animal models, and which are not invasive and can be performed repeatedly without affecting or harming the object. To this task of transferring experimental results into clinical application functional imaging modalities are successfully applied.

Positron Emission Tomography Positron emission tomography (PET) is still the only method allowing quantitative determination of various physiologic variables in the brain and was applied extensively for studies in patients with acute, subacute, or chronic stages of ischemic stroke (review in [100]). The introduction of scanners with high resolution (2.5–5 mm for human, 1 mm for animal application) made PET a tool for studying animal models and to compare repeat examinations of various variables from experiments to the course of disease in humans. The regional decrease of cerebral blood flow (CBF) can be directly observed in PET as in other studies (SPECT, PW-­MRI, PCT). However, already in early PET studies [145] preserved glucose consumption was observed in regions with decreased flow in the first hours after the ictus. Since the 1980s, PET with oxygen-­15 tracers became the gold standard for the evaluation of pathophysiologic changes in early ischemic stroke [146]. The quantitative measurement of CBF, CMRO2, OEF, and CBV permitted the independent assessment of perfusion and energy metabolism, and demonstrated the uncoupling of these usually closely related variables. Early PET studies in stroke have identified various tissue compartments within a brain territory compromised by ischemia [147–150]. Tissue with rCBF 22 ml/100 g/min) not primarily damaged by the lack of blood supply; luxury perfusion by flow increased above the metabolic demand; anaerobic glycolysis by a change in the ratio between glucose metabolism and oxygen utilization. It has to be kept in mind that the condition of the tissue is changing with time; the extent of the penumbra and its conversion into infarction is a dynamic process, and irreversible damage spreads from the core of ischemia to its border. However, PET has severe disadvantages limiting its routine application in patients with stroke: it is a complex methodology, requires multitracer application, and quantitative analysis necessitates arterial blood sampling. Sequential PET studies of CBF, CMRO2, and CMRGl before and repeatedly up to 24 hours after MCA occlusion

in cats could demonstrate the development and growth of irreversible ischemic damage [152]. Immediately after MCA occlusion CBF within the supplied territory dropped, but CMRO2 was less diminished and was pre­ served at an intermediate level. As a consequence, OEF was increased, indicating misery perfusion, i.e. penumbra tissue. With time, OEF was decreased, a process which started in the center and developed centrifugally to the borderline of the ischemic territory, indicating the conversion into irreversible damage and the growth of the MCA infarct. In experiments with transient MCA occlusion it could be demonstrated that an infarct did not develop when reperfusion was initiated to tissue with increased OEF. Comparable to patients with early thrombolysis reperfusion could salvage ischemic tissue in the condition of “penumbra” (Figure 1.12). Similar results were obtained in ischemia models of baboons.

CAT

HUMAN

CBF

CMRO2

OEF

Reperfusion

OEF

spontaneous course

rtPA treatment

CMRGlc

CBF

CMRGlc

Figure 1.12  Sequential PET images of CBF, CMRO2, and OEF of MCA occlusion in cats compared to images of patients after stroke. Left columns: In the right cat, the progressive decrease of CMRO2 and the reduction of OEF predict infarction and cannot benefit from reperfusion. Only if OEF is increased until start of reperfusion can it be salvaged (left cat). Middle columns: In the patient the areas with preserved OEF are not infarcted and can survive in spontaneous course (posterior part of ischemic cortex in left, anterior part in right patient as indicated on late MRI and CT). Right columns: In patients receiving rTPA treatment measurements of CMRO2 and OEF are not feasible, but flow determinations show the effect. If reperfusion occurs early enough and before tissue damage, tissue can be salvaged (left patient). If reperfusion is achieved too late, tissue cannot be salvaged despite hyperperfusion in some parts (right patient). Downloaded from https://www.cambridge.org/core. Access paid by the UCSF Library, on 10 Nov 2019 at 12:15:48, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1017/9781108659574.002

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Section 1: Etiology, Pathophysiology, and Imaging

The experimental findings from sequential studies and anecdotal clinical investigations at different time ­points after the attack [153] imply that the extent of the penumbra, i.e. of morphologically intact but functionally impaired tissue, depends on the time of measurement, relative to the onset of ischemia. The volume is large and the flow values are low if the penumbra is defined in the first hours of ischemia; at this point of time reperfusion strategies are most effective. The volume is small if defined later, limiting the efficacy of treatment. Positron emission tomography (PET) is the only quantitative method to reliably identify irreversible tissue damage and penumbra.

Prediction of Irreversible Tissue Damage

28

The prediction of the portion of irreversibly damaged tissue within the ischemic area early after the stroke is of utmost importance for the efficiency of treatment. Meticulous analyses of CBF and CMRO2 data indicated that CMRO2 below 65 μmol/100g/min predicted finally infarcted tissue, but also large portions with flow and oxygen utilization in the penumbra range were included in the final cortical-­subcortical infarcts. Determination of oxygen utilization additionally requires arterial blood sampling, which limits clinical applicability. These facts stress the need for a marker of neuronal integrity that can identify irreversibly damaged tissue irrespective of the time elapsed since the vascular attack, and irrespective of the variations in blood flow over time. Central benzodiazepine receptor (BZR) ligands can be used as markers of neuronal integrity as they bind to the GABA receptors abundant in cerebral cortex that are sensitive to ischemic damage. After successful testing in the cat MCA occlusion model, cortical binding of flumazenil (FMZ) was investigated in patients with acute ischemic stroke [154]. In all patients, defects in FMZ binding were closely related to areas with severely depressed oxygen consumption and predicted the size of the final infarcts, whereas preserved FMZ binding indicated intact cortex. Additionally, FMZ distribution within 2 minutes after tracer injection was highly correlated with CBF measured by H215O and therefore can be used as a relative flow tracer yielding reliable perfusion images. PET with FMZ therefore can be used as a non-­invasive procedure to image irreversible damage and critically

reduced perfusion (i.e. penumbra) in early ischemic stroke.

Surrogate Markers for Penumbra and Irreversible Damage PET remains the imaging gold standard for identification of the penumbra in stroke patients, but due to the complexity of the methodology, the limited access, the invasive and complicated procedures, and the exposure to radioactivity, PET cannot be applied in clinical routine. MR studies using diffusion and perfusion-­weighted imaging might provide a differentiation between the core and the penumbra: the early diffusion-­weighted imaging (DWI) lesion might define the ischemic core and adjacent critically hypoperfused tissue might be identified with perfusion-­weighted imaging [155]. Therefore, brain regions with hypoperfusion assessed by PWI but without restricted diffusion (PWI/DWI mismatch) were assumed to represent the penumbra. This surrogate definition of the penumbra has several uncertainties [156]: the initial diffusion lesion not only consists of irreversibly infarcted tissue; diffusion lesions may be reversed if blood flow is restored at an early time­point; critical perfused tissue (i.e. penumbra) cannot be clearly differentiated from tissue experiencing benign oligemia; the PWI abnormality often overestimated the amount of tissue at risk. These facts are further accentuated by methodological limitations: absolute or relative thresholds derived from PW-/DW-MRI are still not reliable in predicting the fate of ischemic tissue, and this is especially due to the difficulty to quantify perfusion by MRI [157]. Overall, the definition of the penumbra remains controversial and is suffering from lack of standardization of methodological approaches to imaging, post-­processing, and analysis, which restricts pooling of data and cross-­comparison of results across studies. A validation of PW-­ DW imaging results with quantitative measurements of flow values and oxygen consumption or FMZ uptake in the same patients early after stroke is necessary for the assessment of the accuracy of the applied signatures for predicting tissue outcome. Several studies were performed in order to validate mismatch as a surrogate of penumbra on PET-­ derived discrimination of irreversibly damaged, critically perfused “at risk” and oligemic “not at risk” tissue (review in [158]). The studies demonstrated that the

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Chapter 1: Neuropathology and Pathophysiology of Stroke

DWI lesion predicts more or less the finally infarcted tissue [159], but contains up to 25% false positive, i.e. surviving tissue. The inaccuracy in defining the penumbra with PW/ DWI mismatch is thought to be mainly related to PW data acquisition, since the parameters used to estimate perfusion are variable and somewhat arbitrary. As a consequence, perfusion lesion size differs markedly depending on the parameters calculated [160] and usually is overestimated and extends into considerable areas with non-­critical oligemia especially when short delays are used. Overall, PWI is unable to provide a reliable quantitative estimation of cerebal perfusion when compared to gold standards such as PET, SPECT, or Xe-­CT, and overestimated the size of the critically perfused tissue and therefore also the volume of critically perfused but salvageable tissue, i.e. the penumbra [161] (Figure 1.13). Of 13 patients showing considerable PW-­DWI mismatch, only eight had areas with elevated OEF typical for penumbra tissue, and these areas were always smaller on PW/DWI than on PET. Overall, the mismatch volume in PW/DWI as conventionally calculated does not reliably reflect misery perfusion, i.e. the penumbra as defined by PET. Recently, several methods have been proposed to improve the reliability of assessment of perfusion using MR methods [162], but they all need to be validated by quantitative measures. Therefore, PET validated and calibrated thresholds of the most predictive MR perfusion maps have to be implemented for optimal mismatch detection. Comparative PET MR studies detected the best threshold-independent PW maps as well as their optimal critical flow thresholds by comparative receiver operating characteristic (ROC) curve analysis (review in [158]). More advanced analytical procedures may help to identify more reliably the thresholds between critical and non-­critical hypoperfusion and to reduce the variance of determined values. In summary, the improved mismatch detection might be used for treatment stratification and standardization of post-­ processing in clinical trials.

Surrogate Markers for Treatment Efficiency The efficacy of treatment in ischemic stroke can only be proven by controlled randomized double-­ blind clinical trials. Since such controlled trials require large patients’ populations collected in many stroke centers and therefore usually take a long time and considerable

funds, surrogate markers are applied to predict potential therapeutic effects in small groups of patients. It has to be kept in mind that proven effects on surrogate markers always must be confirmed in controlled trials based on sufficient patients’ populations. In recent years identification of salvageable tissue by neuroimaging has gained much interest as a surrogate marker for treatment efficiency in stroke. The effect of the only approved conservative therapy for acute ischemic stroke was established also in imaging studies, in which reperfusion to penumbral tissue was followed by improvement in neurological deficits: reperfusion was significantly increased in rtPA treated patients compared to controls. The volume of tissue salvaged by reperfusion was established in a study in which CBF, as determined by H215O-PET within 3 hours of stroke onset, was compared with the volume of infarction determined on MRI 3 weeks after the ictus. This study demonstrated that a considerable portion of the critically hypoperfused tissue was probably salvaged by the reperfusion therapy [163]. The PW/DWI mismatch as the estimated zone of the penumbra has been proposed as a surrogate marker of efficacy of stroke treatment. Several groups reported results of serial PW/DWI in patients after intravenous or intra-­ arterial thrombolysis. Inhibition of lesion growth and even normalization of PWI [164] were seen with reperfusion after thrombolytic therapy and PW/DWI mismatch was proposed as an effective selection criterion for rTPA treatment of patients admitted more than 3 hours after onset of symptoms [165]. Several studies have included selection of patients for intravenous thrombolysis with PW/DWI mismatch: a meta-analysis of several mismatch-­based thrombolytic studies from the DIAS, DIAS-­2, DEDAS, EPITHET, and DEFUSE trials for delayed treatment showed an increased recanalization. However, this analysis did not confirm improvement of clinical outcome in delayed thrombolysis [166]. Even though these trials did not show an improvement of clinical outcome, they support the pathophysiological basis of mismatch-­ based treatment selection. The missing confirmation of a clinical benefit in the selection of patients for treatment by MRI profiles might be related to inappropriate definition of critically perfused and salvageable tissue. A more complex analysis of data might be required, including baseline DWI and PWI lesion volumes and coregistration of mismatch and infarct location [167].

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Section 1: Etiology, Pathophysiology, and Imaging

A

B

C

Figure 1.13  Left, A and B: Volumetric comparison of TTP (MRI) and OEF (PET) images in two patients measured in the chronic phase of stroke. In both patients a TTP delay of >4 seconds indicates a considerable mismatch volume (red contour on TTP images). The mismatch volumes were 473 cm3 for patient A and 199.7 cm3 for patient B. However, only patient B had a corresponding volume of penumbra (260 cm3). Right: Volumes of penumbra (black) and mismatch defined by TTP >4 (gray) in 13 patients: all 13 patients showed mismatch, only eight patients showed penumbra, which comprised 1–75% of the mismatch volume. (With permission from Sobesky et al. 2005 [161].)

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Chapter 1: Neuropathology and Pathophysiology of Stroke

Chapter Summary Atherosclerosis is the most widespread disorder leading to death and serious morbidity, including stroke. It develops over years from initial fatty streaks to atheromatous plaques with the risk of plaque disruption and formation of thrombus, from which emboli might originate. Lipohyalinosis affects small vessels, leading to lacunar stroke. The vascular lesions and emboli from the heart cause territorial infarcts, whereas borderzone infarcts are due to low perfusion in the peripheral parts of the vascular territories (last meadows). Ischemic infarcts may be converted into hemorrhagic infarctions by leakage of vessels, whereas intracerebral hemorrhages (5–15% of all strokes) result from rupture of arteries typically in deep portions of the hemispheres. Venous infarcts usually result from thrombosis of sinuses or veins and are often accompanied by edema, hemorrhagic transformation, and bleeding. Primary ischemic cell death is the result of severe ischemia; early signs are potentially reversible swelling or shrinkage; irreversible necrotic neurons have condensed acidophilic cytoplasm and pyknotic nuclei. Delayed neuronal death can occur after moderate or short-­term ischemia; it goes along with nuclear fragmentation and development of apoptotic bodies. The pathophysiology of ischemic cell damage was studied in a large number of animal models, which usually reflect only certain aspects of ischemia and cannot give a complete picture of ischemic stroke in man. From these experimental models principles of regulation of cerebral blood flow and flow thresholds for maintenance of function and morphology were deduced. As the energy requirement of the brain is very high, already mild decreases of blood supply lead to potentially reversible disturbance of function and, if the shortage is more severe and persists for certain periods, to irreversible morphological damage. Tissue perfused in the range between the thresholds of functional and morphological injury has been called the penumbra, a concept which has great importance for treatment. The ischemia-­induced energy failure triggers a complex cascade of electrophysiological disturbances, biochemical changes, and molecular dysfunction, which lead to progressive cell death and growth of infarction. The progression of ischemic injury is further boosted by inflammatory reactions and the development of early cytotoxic and later vasogenic brain edema. The translation of these experimental concepts into clinical application and management of stroke patients, however, is

difficult. It can be achieved in some instances by special functional imaging techniques, such as positron emission tomography, but requires further refinements to predict the outcome of neuroprotective interventions. Solid understanding of experimental and clinical stroke pathophysiology is, therefore, needed to improve the reliability of translational research.

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Chapter

2

Common Causes of Ischemic Stroke Bo Norrving

Introduction

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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: • large artery atherosclerosis in extracranial and large intracranial arteries • embolism from the heart • 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 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. Protruding aortic atheromas are frequently found in stroke patients.

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

Artery-to-artery embolism is considered the most common mechanism of TIA and ischemic stroke due to large artery atherosclerosis. Thrombosis at the site

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

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Chapter 2: Common Causes of Ischemic Stroke

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. Artery-to-artery embolism is considered the most common mechanism of TIA and ischemic stroke due to large artery atherosclerosis.

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]. Blood flow in the carotid artery is reduced if stenosis is more than 70%.

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. Cardiac disease is the most common cause of stroke overall.

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)

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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.

Atrial Fibrillation Non-valvular AF is by far the commonest major cardioembolic source, and an arrhythmia of considerable importance for ischemic stroke due to its prevalence in Table 2.1  Cardioembolic sources and risk of embolism

High risk

Low/Uncertain risk

I Atrial Atrial fibrillation

Patent foramen ovale

Sustained atrial flutter

Atrial septal aneurysm

Sick sinus syndrome

Atrial auto-contrast

Left atrial/atrial appendage thrombus Left atrial myxoma II Valvular Mitral stenosis

Mitral annulus calcification

Prosthetic valve

Mitral valve prolapse

Infective endocarditis

Fibro-elastoma

Non-infective endocarditis

Giant Lambl’s excrescences

III Ventricular

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Left ventricular thrombus

Akinetic/dyskinetic ventricular wall segment

Left ventricular myxoma

Subaortic hypertrophic cardiomyopathy

Recent anterior myocardial infarct

Congestive heart failure

Dilated cardiomyopathy Source: Modified from Ferro [21].

the population and the substantial increase in stroke risk. In the general population 5–6% of persons >65 years and 12% of persons >75 years have AF. Fifty-­ six percent of people with AF are over 75 years of age. Epidemiological studies have shown that non-valvular AF is associated with at least a 5-­fold increased risk of stroke. However, the individual risk of embolism in AF varies 20-­fold among AF patients, depending on age and other associated risk factors. To predict the future risk for embolism in AF risk stratification schemes (such as CHADS2 and CHADS-­ VASC) have been developed (see Chapter 24, Secondary Prevention). The proportion of ischemic strokes associated with AF increases with age, and in the highest age group >80 years about 40% of all strokes occur in patients with this arrhythmia [14]. AF is also seen in 20% of patients with TIA, with proportions increasing with age. The mean age of patients with stroke associated with AF is 79 years in European stroke registries, about 4 years higher than the average age of stroke in general. The importance of AF for ischemic stroke is likely to increase even further in the future because the prevalence of AF in the population is increasing (because persons with AF tend to live longer, and a larger proportion of people are reaching a higher age). Paroxysmal AF carries a risk for embolism similar to the average risk for chronic AF, which is of importance for therapeutic purposes. Paroxysmal AF after ischemic stroke appears to be undetected in a substantial proportion of patients. By subsequent use of Holter monitoring and other monitoring techniques new AF is detected in at least 5% of all patients with ischemic stroke who are initially in sinus rhythm [15]. Detection has been shown to improve with prolonged monitoring. Cardioembolic stroke accounts for 25–35% of all ischemic strokes. Non-­valvular atrial fibrillation is the commonest cause of cardioembolic stroke and carries at least a 5-­fold increased risk of stroke.

Prosthetic Heart Valves Mechanical prosthetic heart valves are well recognized for their propensity to produce thrombosis and embolism, whereas tissue prostheses appear to have a much lower risk. Long-­ term anti-­coagulant therapy with warfarin is standard practice for patients with mechanical prosthetic heart valves, but despite therapy embolism occurs at a rate of about 2% per year. Any type of prosthetic valve may be complicated by infective

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Chapter 2: Common Causes of Ischemic Stroke

endocarditis, which should be considered in patients who experience embolic events.

Endocarditis Infectious and non-­infectious endocarditis is covered in Chapter 10 (Less Common Stroke Syndromes).

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.

Dilated Cardiomyopathy Dilated cardiomyopathies are a well-­recognized cause of embolism, which may be due to the formation of intracardiac thrombus from severe ventricular dysfunction, AF, or endocarditis. In contrast, hypertrophic cardiomyopathies appear not to be associated with an increased risk of stroke per se.

Patent Foramen Ovale (PFO) and Atrial Septal Aneurysm (ASA) Patent foramen ovale (PFO) has been linked to ischemic stroke mainly in young adults, in whom frequencies for this cardiac finding of up to 40% are detected, about twice the rate in the general population [16, 17]. PFO is more commonly observed in patients with cryptogenic stroke than in those with a known cause, and this association appears to hold also for elderly patients [18]. PFO may cause stroke through paradoxical embolism, which requires the coexistence of thrombosis in lower limb, pelvic, or visceral veins

or pulmonary embolism, a cardiac right-to-left shunt, or cough or other Valsalva maneuver immediately preceding stroke onset. However, the exact mechanism by which PFO may cause stroke is still not clear, and evidence mainly comes indirectly from statistical associations. Concurrent venous thrombosis or pulmonary embolism is rarely detected even in patients with a high suspicion of paradoxical embolism. The long-­term risk of recurrent stroke from PFO was not well defined until recently, when several large clinical trials reported that the risk was about 1.3% per year, and reduced to about half by endovascular occlusion of the PFO [19]. Secondary prevention of PFO is further discussed in Chapter  24 (Secondary Prevention). Patent foramen ovale may cause strokes through paradoxical embolism.

Mitral Valve Prolapse Early studies proposed mitral valve prolapse to be the major cause of unexplained stroke in particular in young persons. However, revised diagnostic criteria and subsequent observational and case-­control studies have questioned the overall role of mitral valve prolapse as a cardioembolic source.

Clinical and Neuroimaging Features of Cardioembolic Ischemic Strokes Although cardioembolism may cause almost any clinical stroke syndrome, some features are statistically linked to this cause and are therefore characteristic (Box 2.2). However, it should be borne in mind that the positive predictive value of clinical features suggesting cardioembolism is very modest, at only about 50% [20, 21]. Conversely, some clinical and neuroimaging syndromes, such as a lacunar syndrome found on diffusion-­weighted magnetic resonance imaging (DWI) to be due to a single small infarct, are very unlikely to be due to cardioembolism. Traditionally it was thought that cardioembolic strokes almost always had a sudden onset of symptoms that were maximal from the beginning, but this doctrine has not stood the test of time. Exceptions with gradual and stuttering progressive courses are not rare, and may be due to distal migration of an embolus or early recurrence of embolism in the same vascular territory [22]. Strokes due to cardioembolism are usually more severe than average, probably because emboli from the heart tend

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Box 2.2  Features Suggestive of Cardioembolic Stroke Sudden onset of maximal deficit Decreased level of consciousness Rapid regression of initially massive symptoms (“spectacular shrinking deficit”) Supratentorial stroke syndromes of isolated motor or sensory dysphasia, or visual field defects Infratentorial ischemic stroke involving the cerebellum (posterior inferior cerebellar artery [PICA] or superior cerebellar artery [SCA] territories), top of the basilar Hemorrhagic transformation Neuroimaging finding of acute infarcts involving multiple vascular territories in the brain, or multiple levels of the posterior circulation

to be larger than emboli from arterial sources. However, cardioembolism may well cause TIAs, and the proportion of cardioembolic strokes preceded by TIA is similar to findings in other stroke subtypes. The risk of early hemorrhagic transformation (multifocal or in the form of secondary hematoma) is about twice as high in cardiac embolism compared to other stroke subtypes [23]. Hemorrhagic transformation has been thought to be due to leakage of blood through a vessel wall with ischemia-­induced increased permeability, but the process is likely to be much more complex. In patients with cardioembolism predictive factors of hemorrhagic transformation are decreased level of consciousness, high stroke severity, proximal occlusion, extensive early infarct signs in the MCA territory, and delayed recanalization [24]. Strokes due to cardioembolism are usually more severe than those from other causes and the risk of early hemorrhagic is about twice as high in cardiac embolism compared to other stroke subtypes.

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Some patients with a major cerebral hemispheric stroke syndrome due to distal internal carotid artery or proximal MCA occlusion may have rapid spontaneous improvement of neurological deficits, a phenomenon that has been labeled “spectacular shrinking deficit” [25]. This clinical syndrome is usually, but not exclusively, caused by cardioembolism. The rapid improvement is due to distal propagation, fragmentation, and subsequent spontaneous lysis of the embolus. Emboli from the heart may occlude the internal artery in the neck, but more commonly they occlude

one of the main intracranial vessels. In the anterior circulation cardioembolism and artery-to-artery embolism are the two major causes of full MCA infarcts due to proximal MCA occlusion as well as partial (pial territorial) MCA infarcts due to more distal occlusions. Large artery disease tends to be somewhat more common for anterior MCA infarcts, whereas cardioembolism is more common in posterior MCA lesions. Cardioembolism is also a recognized cause of the restricted cortical MCA syndrome of acute ischemic distal arm paresis, which may mimic peripheral radial or ulnar nerve lesion [26]. In the posterior circulation cardioembolism is no less frequent and tends to occur at characteristic “embolic” sites, common for embolism from cardiac and arterial sources. Cardioembolism is the cause of about a quarter of all lateral medullary infarcts, and about three-­quarters of cerebellar infarcts in the posterior inferior cerebellar artery (PICA) and superior cerebellar artery (SCA) territories, and distal basilar artery occlusions. Basilar artery occlusion presenting with sudden onset of severe brainstem symptoms is often due to cardioembolism [27]. Studies with DWI in patients with acute ischemic stroke have demonstrated that acute ischemic abnormalities involving multiple territories are much more common than previously thought; about 40% of all patients have scattered lesions in one vascular territory or multiple lesions in multiple vascular territories. As should be logically plausible, these ischemic lesion patterns have been associated with embolism from cardiac or large artery sources [28].

Small-Vessel Disease Infarcts due to small-­vessel disease of the brain were first recognized by French neurologists and neuropathologists in the nineteenth century, who also coined the term “lacune” from the autopsy finding of a small cavitation. However, the importance of lacunar infarcts as one of the main ischemic stroke subtypes was not clearly recognized until the investigations of C. Miller Fisher in the 1960s, who on the basis of careful clinicopathological observations laid the foundation for our pathological understanding of lacunar infarction. Lacunar infarcts are small (50% stenosis in arteries supplying the ischemic area, no major cardioembolic source, and no other specific cause identified. The recurrence stroke rate after ESUS is about 5% per year;

the best anti-­thrombotic regimen is currently under study in large clinical trials.

Chapter Summary The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification divides ischemic stroke into • atherothrombotic (30% of ischemic strokes, mostly emboli from the bifurcation of the carotid artery)

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• cardioembolic (25–35% of ischemic strokes, mostly due to atrial fibrillation [AF]) • small-vessel occlusion (25% of ischemic strokes, leading to lacunar infarcts) • other determined cause • and undetermined cause. Sometimes, overlapping causes can be identified. Large artery atherosclerosis is estimated to account for about 30% of all ischemic strokes. Large-­ vessel disease may cause ischemia through embolism (artery-to-artery embolism), reduction of blood flow (hemodynamic causes), or both (hemodynamically compromised brain regions appear to have a diminished capacity for wash-­out or clearance of small emboli). The clinical spectrum of large artery athero­ sclerosis ranges from asymptomatic arterial disease, TIA affecting the eye or the brain, and ische mic stroke of any severity in the anterior and posterior circulation. Cardioembolic stroke accounts for 25–35% of all ischemic strokes. The clinically most important cardioembolic source of cardioembolic stroke is non-­valvular AF followed by infective endocarditis, prosthetic heart valve, recent myocardial infarction, dilated cardiomyopathy, intracardiac tumors, and rheumatic mitral valve stenosis. Paroxysmal AF carries a risk for embolism similar to the average risk for chronic AF. Strokes due to cardioembolism are usually more severe than average and the risk of early hemorrhagic embolism is about twice as high in cardiac embolism compared to other stroke subtypes. In most series lacunar infarcts are thought to account for about one-­quarter of all ischemic strokes. Lacunar infarcts are small (125 cm/s EDV >40 cm/s ICA/CCA PSV ratio >2 Secondary: Delayed systolic flow acceleration in proximal MCA or TICA

ICA near ­occlusion or occlusion

Embolic signals in proximal MCA or TICA

Blunted, minimal, reverberating, or absent spectral Doppler waveforms in ICA (cont.)

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Table 5.3  (cont.)

Lesion location

TCD criteria (at least one present)

Basilar artery

Primary:

CD criteria

TIBI flow grades 0–4 at 73–100 mm

Extracranial findings may be normal or showing decreased VA velocities or VA occlusion

Secondary: Flow velocity increase in terminal VA and branches, MCAs, or PCommAs High-resistance flow signals in VA(s) Reversed flow direction in distal basilar artery (85 mm) Vertebral artery

Primary (intracranial VA occlusion): TIBI flow grades 0–4 at 40–75 mm

Extracranial findings may be normal (intracranial VA lesion) or showing decreased VA velocities or VA occlusion

Primary (extracranial VA occlusion) Absent, minimal, or reversed high-resistance flow signals in unilateral terminal VA Secondary: Embolic signals increased velocities or low pulsatility in contralateral VA

TICA – terminal internal carotid artery; TIBI – thrombolysis in brain infarction; ACommA – anterior communicating artery; PCommA – posterior communicating artery; CD – cervical duplex. Source: Reproduced with permission from Chernyshev et al. [16].

Emboli Monitoring and Acute Stroke

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TCD identifies microembolic signs (MES) in intracranial circulation. The ultrasound distinguishes signal characteristics through embolic materials – solid or gaseous – from erythrocyte flow velocity. Microembolic ­signals appear as signals of high intensity and short duration within the Doppler spectrum as a result of their different acoustic properties compared to the circulating blood. A microembolus signal is visible on transcranial Doppler registration of anterior cerebral artery (Figure 5.1). MES have been proven to represent solid or gaseous particles within the blood flow. They occur at random within the cardiac cycle and they can be acoustically identified by a characteristic “chirp” sound. Detection of MES can identify patients with stroke or transient ischemic attack (TIA) likely to be due to embolism. Potential applications of MES detection include determining the pathophysiology of cerebral ischemia, identifying patients at increased risk for stroke who may benefit from surgical and pharmacological intervention, assessing the effectiveness of novel anti-­platelet therapies and perioperative monitoring to prevent intra- and post-­operative stroke. The methodology includes simultaneous monitoring of both MCAs for at least 30 minutes, with fixed

transducers in order to reduce movement artifacts. With two possible embolic sources – cardiogenic and carotid plaque – the identification of MES contributes higher diagnosis accuracy and support for therapy decision-­making. MES detection, in addition, acts as a predictor for new cerebral ischemic event recurrence [17–21]. At present, monitoring of microembolisms is useful for patients with non-­defined AIS, and which is of probable cardio- or carotid-­embolic etiology. Simultaneous monitoring for MES in different vessels may help identify the active embolic source (cardiac? carotid?). Simultaneous monitoring above (i.e. MCA) and below (i.e. common carotid artery) an internal carotid artery (ICA) stenosis is another possible way of differentiating between artery-to-artery and cardiogenic embolism. The frequency of MES in acute stroke shows a wide range between 10% and 70%, probably due to different therapies, different criteria for MES detection, or different elapsed times after stroke. Some investigators used single registration, others serial measurements. The incidence of MES is maximal in the first week after stroke. The occurrence of MES showed more prevalence in completed stroke than in patients with TIA, and in symptomatic than asymptomatic hemispheres and a discrete subcortical or cortical pattern of

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Chapter 5: Ultrasound in Acute Ischemic Stroke

infarction on computed tomography (CT) compared with a hemodynamic or small-­vessel pattern. Some authors have demonstrated that MES occur predominantly in patients with large-­vessel territory stroke patterns and cases of artery-to-artery or cardiogenic embolism with persisting deficit. In contrast, MES are only occasionally detected in patients with small-­vessel infarctions. In addition, TCD monitoring may help to discriminate between different potential sources of embolism (i.e. artery-to-artery or cardioembolic strokes). Different types of emboli (i.e. cardiac or carotid) have different acoustic properties and ultrasonic characteristics, based on composition and size, which could permit differentiation. MES detection by TCD in CEA candidates may allow identification of a particularly high-­risk group of patients who merit an early intervention or, if this is not possible, more aggressive anti-­thrombotic therapy. The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis Study (CARESS) also revealed that the combination of clopidogrel and aspirin was associated with a marked reduction in MES, compared with aspirin alone (e.g. clopidogrel + aspirin versus aspirin) [22]. A meta-­ analysis confirmed the usefulness of MES detection by transcranial Doppler sonography. MES are a frequent finding in varying sources of arterial brain embolism and MES detection is useful for risk stratification in patients with carotid stenosis [23]. Recently, a meta-­ analysis has been published on the correlation between stroke or TIA and high MES count (eight studies with 1 400 patients), which reported stroke or TIA as an outcome along with high MES counts defined as positive. The sensitivity and specificity were 52% and 90%, respectively. At a median pre-­test probability of stroke of 3.1% a positive TCD test will increase an individual’s chance of future stroke to 14.4% and a negative TCD test will decrease it to 1.7% [24]. Numerous studies, including a prospective, observational one (ACES), proved that TCD can be used to identify patients who are at a higher risk of stroke and transient ischemic attack. The meta-­analyses of ACES with previous studies confirmed the association of embolic signals with future risk of ipsilateral stroke and TIA [25]. TCD identifies MES (microembolic signs) in intracranial circulation. Detection of MES can identify patients with stroke or TIA likely to be due to embolism, acts as a

predictor for new cerebral ischemic event recurrence, and can influence therapy.

Diagnostic Brain Perfusion Imaging in Stroke Patients The availability of new ultrasound contrast agents (UCAs) and the development of contrast-­ specific imaging modalities have established the application of ultrasound in stroke patients for visualization of brain perfusion deficits. The UCAs consist of micro­bubbles composed of a gas that is associated with various types of shells for stabilization. Because of their small size, they can pass through the microcirculation. There are interactions between ultrasound and microbubbles: at low ultrasound energies UCA microbubbles produce resonance, emitting ultrasound waves at multiples of the insonated fundamental frequency. The microbubbles (e.g. SonoVue) generate a non-­ linear response at low acoustic power without destruction, thus being particularly suitable for real-­ time imaging. Harmonic imaging differentiates echoes from microbubbles from those coming from tissue. The insonated tissue responds at the fundamental frequency, while resonating microbubbles cause scattering of multiples of the fundamental frequency  – the harmonic frequencies.

Real-Time Visualization of Middle Cerebral Artery Infarction Perfusion harmonic imaging after SonoVue bolus injection can be used in patients with acute stroke. In the early phase of acute ischemic stroke, bolus imaging after SonoVue injection is useful for analyzing cerebral perfusion deficits at the patient’s bedside. The ultrasound imaging data correlate well with the definite area of infarction and outcome after ischemic stroke. Ultrasound perfusion imaging (UPI) with SonoVue has allowed measurements not only in ischemic stroke but also in intracerebral hemorrhages, due to a characteristic reduction of contrast reaching the lesion. The real-­ time UPI can detect hemodynamic impairment in acute MCA occlusion and subsequent improvement following arterial recanalization. This offers the chance for bedside monitoring of the hemodynamic compromise (e.g. during the­ rapeutic interventions such as systemic or arterial thrombolysis [26–30]. A systematic review found 21 studies using CEUS to measure 20 cerebral perfusion

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and reproducibility. The accuracy of CEUS was compared with CT or MRI. The sensitivity and specificity of CEUS for the detection of cerebral ischemia ranged from 75% to 96% and from 60% to 100%, respectively. The authors conclude that, after ischemic stroke, CEUS may thus serve as an additional clinical tool for the bedside evaluation of brain tissue perfusion and response to recanalization therapy [31]. More efforts are needed to reduce operator dependency, and to improve automated attenuation assessment, optimization of UCA administration, and imaging. New ultrasound contrast agents (UCAs) that can pass through the microcirculation and the development of contrast-­specific imaging modalities make it possible to use ultrasound for the visualization of brain perfusion deficits.

Prognostic Value of Ultrasound in Acute Stroke

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During recent years, ultrasound has become an important non-­ invasive imaging technique for bedside monitoring of acute stroke therapy and prognosis. By providing valuable information on temporal patterns of recanalization, ultrasound monitoring may assist in the selection of patients for additional pharmacological or interventional treatment. Ultrasound also has an important prognostic role in acute stroke. A prospective, multicenter, randomized study confirmed that a normal MCA finding is predictive of a good functional outcome in more than two-­thirds of subjects. An occlusion of the main stem of the MCA within 6 hours after stroke was an independent predictor for poor outcome (p = 0.0006). Fifty percentage of patients with ultrasonographic diagnosis of branch occlusions and 63% with normal MCA had a good outcome [32]. The analysis of flow signal changes during thrombolysis acquired by TCD further confirmed the prognostic value of transcranial ultrasound. Acute arterial occlusion is a dynamic process since thrombus can propagate and break up, thereby changing the degree of arterial obstruction and affecting the correlation between TCD and angiography. A complete occlusion should not produce any detectable flow signals. However, in reality, some residual flow around the thrombus is often present. The Thrombolysis in Brain Ischemia (TIBI) flow-­grading system was developed to evaluate residual flow non-­ invasively and monitor thrombus dissolution in real time [33]:

• Grade 0: absent flow. • Grade 1: minimal flow. • Grade 2: blunted flow. • Grade 3: dampened flow. • Grade 4: stenotic flow. • Grade 5: normal flow. (TIBI 0 and 1 refer to proximal occlusion, TIBI 2 and 3 to distal occlusion, and TIBI 4 to recanalization.) Applying these criteria in acute stroke the TIBI classification correlates with initial stroke severity, clinical recovery, and mortality in patients treated with recombinant tissue plasminogen activator (rtPA). The grading system can also be used to analyze recanalization patterns. The waveform changes (0 → 5) correlate well with clinical improvement and a rapid arterial recanalization is associated with better short-­term improvement, whereas slow flow improvement and dampened flow signals are less favorable prognostic signs [33]. Even incomplete or minimal recanalization determined 24 hours after stroke onset results in more favorable outcome compared with persistent occlusion [33]. Reperfusion is important for prognosis. Both partial and full early reperfusion led to a lesser extent of neurological deficits irrespective of whether this occurred early or in the 6- to 24-­hour interval. Progressive deterioration after stroke due to cerebral edema, thrombus propagation, or hemodynamic impairment is closely linked to extra- and intracranial occlusive disease. Transcranial color-­coded duplex is also useful for the evaluation of combined i.v.–intra-­ arterial (i.a.) thrombolysis. Patients receiving combined i.v.–i.a. thrombolysis show greater improvement in flow signal and higher incidence of complete MCA recanalization compared with those receiving i.v. thrombolysis, especially when the MCA was occluded or had only minimal flow [34]. Patients with distal middle cerebral artery occlusion are twice as likely to have a good long-­term outcome as patients with proximal middle cerebral occlusion. Patients with no detectable residual flow signals as well as those with terminal internal carotid artery occlusions are least likely to respond early or long term. The distal MCA occlusions are more likely to recanalize with i.v. rtPA therapy; terminal ICA occlusions were the least likely to recanalize or have clinical recovery with i.v. rtPA compared with other occlusion locations [35]. The group of Alexandrov [36, 37] described the patterns of the speed of clot dissolution during continuous

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Chapter 5: Ultrasound in Acute Ischemic Stroke

TCD monitoring: sudden recanalization (abrupt normalization of flow velocity in a few seconds), stepwise recanalization as a progressive improvement in flow velocity lasting less than 30 minutes, and slow recanalization as a progressive improvement in flow velocity lasting more than 30 minutes. Sudden recanalization reflects rapid and complete restoration of flow, while stepwise and slow recanalization indicate proximal clot fragmentation, downstream embolization, and continued clot migration. Sudden recanalization was associated with a higher degree of neurological improvement and better long-­term outcome than stepwise or slow recanalization. A tandem internal carotid artery/middle cerebral artery occlusion independently predicted a poor response to thrombolysis in patients with a proximal MCA clot, but not in those with a distal MCA clot [38]. The transcranial color-coded consensus (TCCS) group elaborated a recommendation on how to use transcranial color-­coded duplex sonography for the assessment of intracranial arteries in clinical trials on acute stroke and developed a recanalization score based on objective hemodynamic criteria [39]. Ultrasound has an important prognostic role in acute stroke and can be used to monitor thrombus dissolution during thrombolysis.

Ultrasound Accelerated Thrombolysis During the last two decades, the transcranial Doppler has been used not only for diagnostic and prognostic purposes, but also for therapy. The ultrasound enhances the enzymatic thrombolysis, increasing the transport of t-­PA into the thrombus and improving the binding affinity, and provides a unique opportunity to detect the recanalization during and after t-­PA administration. The first observations were promising: continuous monitoring with 2 MHz TCD in combination with standard i.v. t-­PA therapy resulted in significantly higher recanalization rate or dramatic recovery than i.v. t-­PA therapy without TCD monitoring. In the CLOTBUST trial, complete recanalization or dramatic clinical recovery within 2 hours after the administration of a TPA bolus occurred in 49% of the target group as compared to 30% in the control group (p = 0.03) [40, 41]. An international, multicenter, prospective trial [42] has also been started to investigate the efficacy of combined therapy (i.v. t-­PA+TCD monitoring), but without positive results. A Cochrane analysis [43] urged further

investigations with sonothrombolysis, similarly to the statement of 2013 AHA/ASA guideline “the effectiveness of sonothrombolysis for treatment of patients with acute stroke not well established (Class IIb; Level of Evidence B)” [7]. Further investigations are necessary to verify the usefulness of sonothrombolysis in the acute stroke setting.

Right-to-Left Shunt Detection Right-to-left shunts, particularly a patent foramen ovale (PFO), are common in the general population, with a prevalence of 10–35% in various echocardiography and autopsy studies for PFO. The prevalence is even higher in cryptogenic stroke or TIA and especially in younger patients without an apparent etiology. Contrast-­enhanced TCD can be used for detecting the high-­intensity transient signals (HITS) passing through the MCA, thus indicating the presence of a right-to-left shunt. The results of contrast-­enhanced TCD have been compared with those of contrast-­ transesophageal echo and found to have a sensitivity and specificity of 68–100% and 67–100%, respectively [44]. Other studies with TCD and TEE proved the strength of TCD in PFO detection and right-to-left (RLS) quantification [45]. Advantages of TCD include ­calibrated Valsalva maneuver and the ability to change body positioning during the test. The TCD “bubble” test for right-to-left shunt is superior to transthoracic ­echocardiography, and possibly TEE. Recently a meta-­analysis and review analyzed the results of 35 studies with 3 000 patients. The authors concluded that the pooled sensitivity and specificity for TCD was 96.1% and 92.4%, whereas the respective measures for TTE were 45.1% and 99.6%. TCD is more sensitive but less specific compared to TTE for the detection of PFO in patients with cryptogenic cerebral ischemia. The overall diagnostic yield of TCD appears to outweigh that of TTE [46]. Contrast-enhanced TCD can also be used to identify patients with a patent foramen ovale.

Promising Ancillary Ultrasound Techniques for Acute Ischemic Stroke The invasive intracranial pressure (ICP) monitoring is not always possible. The repeated transport to an imaging center is difficult for instable, confused, or aphasic acute stroke

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patients (the CT(s) is (are) associated with radiation hazard), so the possibility of a bedside non-­invasive investigation is very attractive. The transcranial ultrasound is an easy technique for monitoring changes of the brain parenchyma (e.g. malignant middle cerebral infarction or intracerebral hemorrhage). The frequently investigated parameters are: • midline shift • arterial resistance • optic nerve sheath diameter. Despite important limitations related to sonography, these techniques could serve as screening tests in patients at risk for raised ICP, when invasive monitoring is impossible or associated with hazard.

Midline Shift A poor neurological outcome can be associated with a clinically significant midline shift of as little as 0.5 cm and a 2-­fold increase in mortality associated with greater than 1-­cm midline shift. Seidel et al. demonstrated the use and predictive value of ultrasonography for the measurement of midline shift [47]. The method measures the distance from the bilateral temporal bones to the midline third ventricle. Distance A is measured from the ipsilateral side, whereas distance B is from the contralateral side. You should also measure the full length from the ipsilateral to the contralateral temporal bone. Midline shift (MLS) = (distance A − distance B)/2. If the MLS is positive, this means that the MLS is away from the ipsilateral side. If the MLS is negative, the MLS is towards the ipsilateral side. Due to lack of bone window 15–20% of patients could not be investigated.

Arterial Resistance

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TCD can be used to provide a rough estimate for increased intracranial pressure or to rule out high ICP, but is not optimal for accurate invasive ICP monitors. Raised ICP can be measured by Gosling’s pulsatility index, which is a parameter of peripheral resistance, equal to the difference between the peak systolic velocity (PSV) and end-­diastolic velocity (ESV), divided by the mean velocity (MV). Pulsatility index (PI) = [PSV−EDV]/MV [48]. A formula has been developed for converting pulsatility index into ICP with a sensitivity of 89% and specificity of 92%. ICP = (10.93 × PI) − 1.28

A PI of >2.1 would correlate to an ICP >22 mmHg (clinically significant cut-­off for raised ICP), whereas normal pulsatility index (PI) is 20 mmHg). Rajajee et al. demonstrated that an ONSD of >4.8 mm corresponded to an ICP >20 mmHg with a sensitivity of 96% and a specificity of 94% [53]. Sonographic ONSD measurement is a quick modality, but also has limitations: tumors, inflammation, etc. can affect measurement. The ONSD measurement cannot replace invasive ICP monitoring, but can differentiate between normal and raised ICP. Therefore, it can potentially be used for screening purposes. The transcranial ultrasound is an easy technique for monitoring changes of the brain parenchyma (e.g. malignant middle cerebral infarction or intracerebral hemorrhage). Frequently investigated parameters are: midline shift, arterial resistance, and optic nerve sheath diameter. These techniques could serve as screening tests in patients at risk for raised intracranial presure, when invasive monitoring is impossible or associated with hazard.

Chapter Summary

Doppler ultrasonography is the primary non-­invasive test for evaluating carotid stenosis and dissection.

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Chapter 5: Ultrasound in Acute Ischemic Stroke

Eye bulb

Figure 5.4  B-mode ultrasound of eye and optic nerve sheath.

Symptomatic and asymptomatic carotid plaques and the degree of stenosis can be analyzed with ultrasonography by examining the echogenicity of the structures and the velocity of the blood flow. An estimation of the degree of internal carotid artery (ICA) stenosis solely based on diameter or area reduction is not reliable. Commonly used methods to characterize stenosis are peak systolic velocities (PSV) and ratios of flow velocities. Most studies consider carotid stenosis of 60% or greater to be clinically important. Transcranial Doppler (TCD) has been shown to provide diagnostic and prognostic information that determines patient management decisions in multiple cerebrovascular conditions and periprocedural/surgical monitoring (see Table 5.2). With transcranial color-­coded duplex sonography (TCCD), using low frequencies to penetrate the skull, most intracranial stenoses and occlusions can be detected by combining velocity analysis with other parameters. With the use of echo-­contrast enhancing agents (ECE), the sensitivity and specificity can be increased and the diagnostic confidence of contrast-­ enhanced TCCD for intracranial vessel occlusion can reach that of magnetic resonance angiography.

A practical algorithm has been published for urgent bedside neurovascular ultrasound examination with carotid/vertebral duplex and transcranial Doppler in patients with acute stroke (see Table 5.3). TCD also identifies microembolic signs (MES) in intracranial circulation. Detection of MES can identify patients with stroke or TIA likely to be due to embolism, acts as a predictor for new cerebral ischemic event recurrence, and can influence therapy. New ultrasound contrast agents (UCAs) that can pass through the microcirculation and the development of contrast-­specific imaging modalities make it possible to use ultrasound for the visualization of brain perfusion deficits (e.g. acute MCA occlusion and subsequent improvement following arterial recanalization). Ultrasound has an important prognostic role in acute stroke and can be used to monitor thrombus dissolution during thrombolysis. Contrast-enhanced TCD can also be used to identify patients with a patent foramen ovale. The transcranial ultrasound is an easy technique for monitoring changes of the brain parenchyma (e.g. malignant middle cerebral infarction or intracerebral hemorrhage). Frequently investigated parameters are midline shift, arterial resistance, and optic nerve sheath diameter. These techniques could serve as screening tests in patients at risk for raised intracranial presure, when invasive monitoring is impossible or associated with hazard.

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5. 6.

Brinjikji W, Rabinstein AA, Lanzino G, et al. Ultrasound characteristics of symptomatic carotid plaques: a systematic review and meta-analysis. Cerebrovasc Dis 2015; 40(3–4):165–74. Silver B. Carotid ultrasound. http://emedicine .medscape.com/article/1155193-overview. Updated: 15 December 2008. Liu CH, Chang CH, Chang TY, et al. Carotid artery stenting improves cerebral hemodynamics regardless of the flow direction of ophthalmic artery. Angiology 2015; 66(2):180–6. Grant EG, Benson CB, Moneta GL, et al. Carotid artery stenosis: grayscale and Doppler ultrasound diagnosis – Society of Radiologists in Ultrasound consensus conference. Ultrasound Q 2003; 19(4):190–8. Nadalo LA, Walters MC. Carotid artery, stenosis: imaging. http://emedicine.medscape.com/ article/417524-overview. von Reutern GM, Goertler MW, Bornstein NM, et al. Grading carotid stenosis using ultrasonic methods. Stroke 2012; 43(3): 916–21.

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22. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005; 111(17):2233–40. 23. Ritter MA, Dittrich R, Thoenissen N, Ringelstein EB, Nabavi DG. Prevalence and prognostic impact of microembolic signals in arterial sources of embolism. A systematic review of the literature. J Neurol 2008; 255(7):953–61. 24. Best LM, Webb AC, Gurusamy KS, Cheng SF, Richards T. Transcranial Doppler ultrasound detection of microemboli as a predictor of cerebral events in patients with symptomatic and asymptomatic carotid disease: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg 2016; 52(5):565–80. 25. Markus HS, King A, Shipley M, et al. Asymptomatic embolisation for prediction of stroke in the Asymptomatic Carotid Emboli Study (ACES): a prospective observational study. Lancet Neurol 2010; 9(7):663–71. 26. Artemis D, Alonso A, Hennerici MG, Meairs S, Kern R. Real-time ultrasound perfusion imaging in acute stroke: assessment of cerebral perfusion deficits related to arterial recanalization. Ultrasound Med Biol 2013; 39(5):745–52. 27. Della Martina A, Meyer-Wiethe K, Allemann E, Seidel G. Ultrasound contrast agents for brain perfusion imaging and ischemic stroke therapy. J Neuroimaging 2005; 15(3):217–32. 28. Seidel G, Meyer-Wiethe K. Acute stroke: perfusion imaging. Front Neurol Neurosci 2006; 21:127–39. 29. Meairs S, Kern R. Intracranial perfusion imaging with ultrasound. Front Neurol Neurosci 2015; 36:57–70. 30. Seidel G, Meyer-Wiethe K, Berdien G, et al. Ultrasound perfusion imaging in acute middle cerebral artery infarction predicts outcome. Stroke 2004; 35:1107–11. 31. Vinke EJ, Kortenbout AJ, Eyding J, et al. Potential of contrast-­enhanced ultrasound as a bedside monitoring technique in cerebral perfusion: a systematic review. Ultrasound Med Biol 2017; 43(12):2751–7. 32. Allendoerfer J, Goertler M, Reutern GM. Prognostic relevance of ultra-­early Doppler sonography in acute ischaemic stroke: a prospective multicentre study. Lancet Neurol 2006; 5(10):835–40. 33. Demchuk AM, Burgin WS, Christou I, et al. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke 2001; 32(1):89–93. 34. Baracchini C, Manara R, Ermani M, Meneghetti G. The quest for early predictors of stroke evolution: can TCD be a guiding light? Stroke 2000; 31:2942–7.

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35. Perren F, Loulidi J, Graves R, et al. Combined IV– intraarterial thrombolysis: a color-­coded duplex pilot study. Neurology 2006; 67:324–6. 36. Saqqur M, Uchino K, Demchuk AM, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke 2007; 38(3):948–54. 37. Alexandrov AV, Burgin SW, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-­term improvement. Circulation 2001; 103:2897–902. 38. Rubiera M, Ribo M, Delgado-Mederos R, et al. Tandem internal carotid artery/middle cerebral artery occlusion: an independent predictor of poor outcome after systemic thrombolysis. Stroke 2006; 37:2301–5. 39. Nedelmann M et al. and the TCCS Consensus Group. Consensus recommendations for transcranial color-­ coded duplex sonography for the assessment of intracranial arteries in clinical trials on acute stroke. Stroke 2009; 40(10):3238–44. 40. Alexandrov AV, Molina CA, Grotta JC, et al. For the CLOTBUST investigators: ultrasound-­enhanced thrombolysis for acute ischemic stroke. N Engl J Med 2004; 351:2170–8. 41. Barlinn K, Tsivgoulis G, Barreto AD, et al. Outcomes following sonothrombolysis in severe acute ischemic stroke: subgroup analysis of the CLOTBUST trial. Int J Stroke 2014; 9(8):1006–10. 42. Schellinger PD, Alexandrov AV, Barreto AD, et al. CLOTBUSTER investigators. Combined lysis of thrombus with ultrasound and systemic tissue plasminogen activator for emergent revascularization in acute ischemic stroke (CLOTBUST-­ER): design and methodology of a multinational phase 3 trial. Int J Stroke 2015; 10(7):1141–8. 43. Ricci S, Dinia L, Del Sette M, et al. Sonothrombolysis for acute ischaemic stroke (review) . The Cochrane Library 2012, Issue 10, 1–35. 44. Droste DW, Silling K, Stypmann J, et al. Contrast transcranial Doppler ultrasound in the detection of

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right-to-left shunts: time window and threshold in microbubble numbers. Stroke 2000; 31(7):1640–5. Belvis R, Leta RG, Marti-Fabregas J, et al. Almost perfect concordance between simultaneous transcranial Doppler and transesophageal echocardiography in the quantification of right-to-left shunts. J Neuroimaging 2006; 16(2):133–8. Katsanos AH, Psaltopoulou T, Sergentanis TN, et al. Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: a systematic review and diagnostic test accuracy metaanalysis. Ann Neurol 2016; 79(4):625–35. Seidel G, Gerriets T, Kaps M, Missler U. Dislocation of the third ventricle due to space-­occupying stroke evaluated by transcranial duplex sonography. J Neuroimaging 1996; 6(4):227–30. Bellner J, Romner B, Reinstrup P, et al. Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure (ICP). Surg Neurol 2004; 62(1):45–51. Lau VI, Arntfield RT. Point-of-care transcranial Doppler by intensivists. Crit Ultrasound J 2017; 9(1):21. Siebler M. Neuroorbital ultrasound. In Csiba L and Baracchini C, eds. Manual of Neurosonology. Cambridge University Press; 2016: 300–5. Ohle R, McIsaac SM, Woo MY, Perry JJ. Sonography of the optic nerve sheath diameter for detection of raised intracranial pressure compared to computed tomography: a systematic review and meta-analysis. J Ultrasound Med 2015; 34(7):1285–94. Khan MN, Shallwani H, Khan MU, Shamim MS. Noninvasive monitoring intracranial pressure – a review of available modalities. Surgical Neurology International 2017; 8:51. Rajajee V, Vanaman M, Fletcher JJ, Jacobs TL. Optic nerve ultrasound for the detection of raised intracranial pressure. Neurocrit Care 2011; 15(3):506–15.

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Section 2 Chapter

6

Clinical Epidemiology and Risk Factors

Basic Epidemiology of Stroke and Risk Assessment Jaakko Tuomilehto and Yvonne Teuschl

Definition of Stroke Epidemiological studies are dealing with populationlevel assessments of disease occurrence and determinants of health and disease. It is important to define the disease in a standardized way and using methods that are suitable for large population examinations. Therefore, the definition of a disease may differ to some extent from that used in individuals in clinical medicine where it is possible to apply more detailed and expensive diagnostic tools. It has been agreed that for epidemiological purposes stroke is primarily defined by clinical findings and symptoms [1]: rapidly developed signs of focal (or global) disturbance of cerebral function lasting more than 24 hours (unless interrupted by surgery or death), with no apparent cause other than a vascular origin. This approach may be supplemented with neuroimaging, but even with advanced imaging techniques the diagnosis is based on clinical signs. Therefore, precise definitions of clinical signs are needed. WHO definitions are [1]: Definite focal signs: • unilateral or bilateral motor impairment (including dyscoordination) • unilateral or bilateral sensory impairment • aphasis/dysphasis (non-­fluent speech) • hemianopia (half-­sided impairment of visual fields) • diplopia • forced gaze (conjugate deviation) • dysphagia of acute onset • apraxia of acute onset • ataxia of acute onset • perception deficit of acute onset. Not acceptable as sole evidence of focal dysfunction, although strokes can present in this way, these signs are not specific and cannot therefore be accepted as definite evidence of stroke: • dizziness, vertigo • localized headache

• • • • •

blurred vision of both eyes dysarthria (slurred speech) impaired cognitive function (including confusion) impaired consciousness seizures.

Neuroimaging studies are needed for classification of stroke by subtypes: subarachnoid hemorrhage, intracerebral hemorrhage, and brain infarction (necrosis). Although there may be large variations in stroke subtype distributions between populations, thrombotic and embolic strokes are responsible for about 80–85% of all strokes in the Indo-­European populations, and as low as 65% in some Asian populations. Subarachnoid hemorrhage represents 5–10% of all strokes, and may often occur in middle-­aged people [2], while both intracerebral and especially thrombotic and embolic stroke events increase markedly with age. This classic WHO definition is mainly clinical and does not account for recent advances in science and diagnostic technology. Therefore, the Stroke Council of the American Heart Association/American Stroke Association developed an expert consensus document for an updated definition of stroke in 2013 [3] that attempted to take into account advances in basic science, neuropathology, and neuroimaging of the central nervous system (Box 6.1). Central nervous system infarction was defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The aim of this updated definition of stroke was to incorporate clinical and tissue criteria that may be used in clinical practice, research, and public health aspects.

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Box 6.1  Updated Definition of Stroke According to the Expert Consensus Statement of the American Heart Association/American Stroke Association Definition of Stroke The term “stroke” should be broadly used to include all of the following: Definition of CNS infarction: CNS infarction is 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 excluded. (Note: CNS infarction includes hemorrhagic infarctions, types I and II; see “Hemorrhagic Infarction.”) Definition of ischemic stroke: An episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. (Note: evidence of CNS infarction is defined above.) Definition of silent CNS infarction: imaging or neuropathological evidence of CNS infarction, without a history of acute neurological dysfunction attributable to the lesion. Definition of intracerebral hemorrhage: A focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma. (Note: intracerebral hemorrhage includes parenchymal hemorrhages after CNS infarction, types I and II – see “Hemorrhagic Infarction.”) Definition of stroke caused by intracerebral hemorrhage: rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain CNS indicates

central nervous system parenchyma or ventricular system that is not caused by trauma. Definition of silent cerebral hemorrhage: a focal collection of chronic blood products within the brain parenchyma, subarachnoid space, or ventricular system on neuroimaging or neuropathological examination that is not caused by trauma and without a history of acute neurological dysfunction attributable to the lesion. Definition of subarachnoid hemorrhage: bleeding into the subarachnoid space (the space between the arachnoid membrane and the pia mater of the brain or spinal cord). Definition of stroke caused by subarachnoid hemorrhage: rapidly developing signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space (the space between the arachnoid membrane and the pia mater of the brain or spinal cord), which is not caused by trauma. Definition of stroke caused by cerebral venous thrombosis: infarction or hemorrhage in the brain, spinal cord, or retina because of thrombosis of a cerebral venous structure. Symptoms or signs caused by reversible edema without infarction or hemorrhage do not qualify as stroke. Definition of stroke, not otherwise specified: an episode of acute neurological dysfunction presumed to be caused by ischemia or hemorrhage, persisting ≥24 hours or until death, but without sufficient evidence to be classified as one of the above. Source: Sacco et al. [3].

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For ischemic stroke, further subtypes have been proposed, since prognosis, recurrence rate, and management of acute phase vary by subtype. In the Oxfordshire Community Stroke Project Subtype Classification (OCPS) four clinically identifiable subgroups of cerebral infarction were defined [4]. Of the patients 17% had large anterior circulation infarcts with both cortical and subcortical involvement (total anterior circulation infarcts, TACI), 34% had more restricted and predominantly cortical infarcts (partial anterior circulation infarcts, PACI), 24% had infarcts clearly associated with the vertebrobasilar arterial territory (posterior circulation infarcts, POCI), and

25% had infarcts confined to the territory of the deep perforating arteries (lacunar infarcts, LACI). Other criteria called TOAST (Trial of ORG 10172 in Acute Stroke Treatment) propose five subtypes: large artery atherosclerosis, cardioembolism, small artery occlusion, stroke of other determined cause, and stroke of undetermined cause [5].

The Scope of the Problem Stroke is the second leading cause of death worldwide in the adult population, the first being coronary heart disease [6]. Stroke is an increasing problem in low- and

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Chapter 6: Basic Epidemiology of Stroke and Risk Assessment

middle-­income countries where over 80% of all stroke deaths occur [2, 6–11]. Stroke is the second leading cause of disease burden (as measured in disability-­ adjusted life years [DALYs]) after coronary heart disease in 2016 [12]. It caused about 4.4 million deaths worldwide in 1990, 5.4 million in 1999, 5.7 million in 2004, and 5.5 million in 2016, with two-­thirds of these deaths occurring in less-­developed countries [6, 8–10, 13]. In 2010, globally the highest burden of stroke was found among people living in low- and middle-­income countries. DALYs due to stroke were 62.67 per million person-­years in high-­income countries, corresponding to 4.5% of the total DALYs, the estimate for low-andmiddle-income countries was 9.35 per million person-­ years corresponding to 6.3% of the total DALYs in the human population [10]. The burden of stroke is particularly high in Eastern Europe, North Asia, Central Africa, and the South Pacific with a 10-­fold difference in stroke mortality and morbidity rates between the most affected and least affected countries [10, 11]. The Stroke Experts Panel of the Global Burden of Disease (GBD) group has also reported estimates for ischemic and hemorrhagic stroke in all ages for 188 countries during 1990 to 2013 [14]. In 2013, there were globally almost 25.7 million stroke survivors (71% with IS), 6.5 million deaths from stroke (51% died from IS), 113 million DALYs due to stroke (58% due to IS), and 10.3 million new strokes (67% IS). During 1990 to 2013, there were statistically significant reductions in the incidence, mortality, and DALY rates of ischemic stroke. For hemorrhagic stroke there were statistically non-­significant increases in the incidence and prevalence, and decrea­ses in the mortality and DALY rates (Figure 6.1). There was a significant increase in the absolute number of DALYs due to ischemic stroke, and of deaths from ischemic and hemorrhagic strokes, survivors, and incident events for both ischemic and hemorrhagic stroke (Table 6.1). The preponderance of the burden of stroke continued to reside in developing countries, comprising 75.2% of deaths from stroke and 81.0% of stroke-­related DALYs. The recent estimate indicated that in the USA the cost of stroke (direct and indirect costs together) was $73.7 billion [3] in 2010. The rapid increase in life expectancy in most parts of the world has a major effect on the burden of stroke, since stroke is a disease of older people. Even though the stroke risk in the middle-­aged and young-­old population has significantly decreased in many countries, the onset of the disease might have moved to older ages.

Therefore, the overall burden measured by incidence, prevalence, and DALYs related to stroke globally has not changed much during the last decade [14].

Occurrence of Stroke: Incidence, Prevalence, Mortality, and Case Fatality Although stroke is considered as a major public health problem, data are still limited to epidemiology of stroke besides mortality statistics. There are several measures to describe the occurrence of stroke from an epidemiological (and to some extent also clinical) perspective. These are: the incidence (or event rate), prevalence, mortality, and case fatality (reverse of survival). The incidence means the number of first stroke events (either non-­fatal or fatal) per population during a certain time period, for instance events/ 100 000 population/year. While it is useful to know the incidence (occurrence of first stroke events), in most populations data may be available on mortality from stroke only, but not on non-­fatal events. The case fatality at the stroke event is usually determined as the proportion of deaths occurring during the first 4 weeks after the onset of a stroke event, but can be presented for any other time period as well. It gives information about the severity of stroke and may also reflect the efficacy of early management of acute stroke. The relative frequency of different subtypes of stroke varies among ethnic groups and populations. This variation is mostly due to genetic differences, but also due to differences in lifestyle and risk factor profiles.

Mortality Since cause-­specific mortality data are routinely collected in all high-­income countries and also in many low- and middle-­income countries nationwide, stroke mortality data are available in a large proportion of the world’s population. However, the coverage and accuracy of stroke mortality varies among countries. In some countries validation studies have been carried out using standard methodology [1]. Data from many countries show that stroke mortality rates have declined over recent decades, most notably in Japan, Australia, North America, and Western Europe [15]. Mortality from stroke was highest in the world in Finland in the 1970s, together with Japan [15–19], but reduced dramatically in these countries over the past decades.

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Age-adjusted incidence per 100 000 people

Age-adjusted DALYS per 100 000 people

140

1 500

1 000

500

0

1990

2005

60

40

20

0

100 80 60 40 20

1990

2005

2013

1990

2005

2013

350 Age-adjusted prevalence per 100 000 people

Age-adjusted mortality per 100 000 people

80

HS

120

0

2013

IS

1990

2005

2013

300 250 200 150 100 50 0

Figure 6.1  Age-adjusted DALYs, mortality, incidence, and prevalence rates of ischemic (IS, blue) and hemorrhagic (HS, red) strokes per 100 000 people (with 95% uncertainty intervals) in 1990, 2005, and 2013. (From Feigin et al. 2015 [14] with permission from S Karger AG, Basel.)

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The geographic differences in stroke mortality among countries are huge. The highest rate was found in Russia and several other countries from the previous Soviet Union [11]. Also China, Mongolia, countries from the Middle East and North Africa, Brazil, the Caribbean region, and the Pacific islands have high incidence of ischemic stroke. The lowest rate was seen in the Seychelles and Switzerland. Most of the low mortality countries were found in Western Europe, North and Central America, Japan, Australia, and New Zealand (Figure 6.2). Mortality rates were 2-­fold higher in developing countries than in developed

countries. In 2013, there were approximately 5.6 million deaths from stroke globally; ischemic and hemorrhagic strokes had an equal share of these deaths [14]. The highest ischemic stroke mortality rates (124–174 per 100 000 person-­years) were observed in Russia and Kazakhstan, with the lowest (at or below 25 per 100 000 person-­years) seen in Western Europe and North and Central America, a 7-­fold difference [14].

Incidence The incidence gives the rate of new cases of stroke within a time period (usually per year) in a specified

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Chapter 6: Basic Epidemiology of Stroke and Risk Assessment

Table 6.1  Absolute number of DALY, death, incident, and prevalent cases of ischemic (IS) and hemorrhagic stroke (HS) (with 95% uncertainty intervals) in the world 1990 and 2013

IS

HS

Metric

1990

2013

DALYs

34 155 606 (29 592 196–38 325 866)

47 424 681 (40 537 540–52 211 800)

Deaths

2 182 865 (1 923 290–2 430 872)

3 272 924 (2 812 654–3 592 562)

Incidence

4 309 356 (4 118 103–4 531 909)

6 892 857 (6 549 814–7 352 226)

Prevalence

10 045 202 (9 643 525–10 453 439)

18 305 491 (17 767 372–18 920 736)

DALYs

55 953 376 (49 881 127–62 161 971)

65 454 194 (59 497 415–74 654 738)

Deaths

2 401 930.40 (2 109 380.2–2 669 117.5)

3 173 951 (2 885 717–3 719 684)

Incidence

1 886 345 (181 6991–1 976 659)

3 366 175 (3 199 978–3 543 213)

Prevalence

3 891 158 (3 769 541–4 019 014)

7 363 457 (7 139 691–7 616 146)

Source: Feigin et al. 2015 [14], with permission from S Karger AG, Basel.

population. The incidence depends on the effect of risk factors that are causing the disease. There are few incidence studies with validated data from stroke registers or other sources. The highest rate was found in Russia and also several other countries from the previous Soviet Union are among the top 20. Also China, Mongolia, countries from the Middle East and North Africa, Brazil, the Caribbean region, and the Pacific islands have a high incidence of ischemic stroke. The GBD Stroke Panel Experts Group has presented data on incidence and mortality of stroke for all countries to assess the burden of ischemic and hemorrhagic stroke between regions and over time [14]. The analysis was based on 119 studies, 58 in high-­income and 61 in low-­ income countries. They used a GBD analytic technique (DisMod-­MR) [21] to calculate the country-­specific incidence for 1990 and 2010. The highest incidence rate for ischemic stroke was found in Russia and also several other countries from the previous Soviet Union and Balkans were among the top. Also China, Mongolia, countries from the Middle East and North Africa, Brazil, the Caribbean region, and the Pacific islands have high incidence of ischemic stroke. The incidence of stroke has declined sharply in Finland during the last decades [17], and in 1998 it was 241/100 000, not far from other Western industrialized countries, after a steady fall of about 3% per year throughout the years studied. Other countries that already had comparatively low stroke incidence rates in the 1980s, for example New Zealand [22], the USA [23], or Denmark [24], have reported no further fall in stroke incidence, while an increase in the incidence of stroke has been observed in Eastern Europe and Russia [2, 9, 10, 25–27]. In Shanghai, China, almost no decline in incidence of stroke but a clear decline in stroke mortality was reported [28]. Central and Eastern European

countries have the highest incidence and mortality rates through Europe. The improvements in stroke prevention and treatment in Central and Eastern European countries did not completely reach the quality para­ meters present in Western European countries [29]. Incidence studies from Greece [30] and Bulgaria [31] confirm the findings from mortality statistics showing the populations in the Balkan region have a very high risk of stroke. Geographic comparisons of stroke incidence are useful for identifying populations at high risk and developing hypotheses for prevention of stroke. The differences observed between countries in mortality rates, and even more in incidence rates, are, however, difficult to interpret, as they largely depend on the study design, the accuracy of the data collection, and the time point when the measurements were made.

Prevalence Prevalence means the proportion of people in the population who have the disease at a particular time point. In the case of stroke, the prevalence shows the number of stroke survivors in the population. It therefore means the number of incident cases minus people deceased in stroke attack. The prevalence is more difficult to estimate than the incidence or mortality, since the number of stroke survivors living in the target population needs to be known, and this cannot be derived from routine statistics of hospital admissions (a usual source for incidence) or death register (the source for mortality). Both the incidence and mortality vary over time and geographically depending on many factors such as age, socioeconomic status, lifestyles, comorbidities, and health services. Thus, the prevalence is a result from many medical and non-­medical

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A

B Figure 6.2  Age-standardized annual mortality rates (per 100 000) of ischemic stroke (A) and hemorrhagic stroke (B) in 2013. There is large geographical variation in stroke burden, with the highest stroke mortality rates in developing countries. (From Feigin et al. 2015 [20], with permission from S Karger AG, Basel.)

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factors. Nevertheless, the GBD Stroke Panel Experts Group estimated prevalence of stroke during 1990 to 2013 [32]. Among adults aged 20–64 years, the global prevalence of hemorrhagic stroke in 2013 was 3.7 million and the prevalence of ischemic stroke was 7.3 million (Table  6.2). Globally, the number of people with prevalent hemorrhagic stroke increased from 2.0 million in 1990 to 3.7 million in 2013, and the number

of those with prevalent ischemic stroke from 3.8 million to 7.3 million. In 2013, of people living with hemorrhagic stroke 2.7 million lived in developing countries and 1.1 million in developed countries; and of people living with ischemic stroke 3.2 million lived in developing countries and 4.0 million in developed countries. The prevalence per 100 000 population for hemorrhagic stroke increased

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1990 2013

1990 2013

1990 2013

1990 2013

1990 2013

Developed

Global

IS Developing

Developed

Global

Prevalence

3 801 396 7 258 216

2 076 621 4 044 107

1 724 774 3 241 108

1 980 830 3 725 085

530 589 1 059 315

1 450 240 2 665 770

95% UI

3 660 560–3 957 700 6 996 272–7 569 403

1 954 109–2 206 981 3 869 281–4 238 562

1 632 729–1 810 733 3 033 261–3 446 309

1 918 964–2 056 065 3 548 098–3 871 018

490 269–574 953 983 851–1 138 970

1 391 277–1 510 464 2 521 485–2 789 120

Source: Krishnamurthi et al. [32], with permission from S Karger AG, Basel.

1990 2013

HS Developing

Year

321 560 435 972

95 635 79 564

225 925 356 408

857 927 1 047 735

140 931 111 795

716 996 935 939

Death

259 801–370 056 354 018–504 656

78 800–112 305 68 651–96 978

181 026–266 063 280 551–414 875

761 615–955 263 945 087–1 184 192

119 814–160 849 98 625–129 473

636 079–797 977 839 444–1 060 482

95% UI

Table 6.2  Prevalent cases, deaths and DALYS in those aged 20–64 years between 1990 and 2013 in developing and developed countries

DALYs

10 730 563 14 733 144

3 157 115 2 965 492

7 573 447 11 769 652

30 528 067 36 696 295

4 839 572 3 861 930

25 688 495 32 834 364

95% UI

8 685 007–12 392 179 12 209 576–17 011 339

2 664 748–3 664 830 2 551 752–3 520 588

6 058 331–8 960 467 9 345 527–13 601 182

27 119 019–33 944 576 33 011 678–41 372 106

4 165 098–5 492 067 3 426 825–4 432 344

22 803 083–28 597 621 29 352 075–37 133 284

Chapter 6: Basic Epidemiology of Stroke and Risk Assessment

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Section 2: Clinical Epidemiology and Risk Factors

from 75 to 130 in developed countries and from 72 to 81 in developing countries during 1990 to 2013. The increases for ischemic stroke prevalence per 100 000 population were from 292 to 497 in developed and from 86 to 97 in developing countries, respectively.

Case Fatality The case fatality indicates the proportion of people who died in acute stroke attack. It reflects the severity of the underlying disease or efficacy of the management of acute stroke, or both. Before the era of thrombolysis or thrombectomy no proven life-­saving clinical treatment for acute stroke was available; therefore, the case fatality mainly reflected the disease severity. It can be calculated in various ways: within a defined time period, e.g. 1-­day, 1-­week, 4-­week, 1-year period, etc., or in relation to the management of stroke, e.g. out-­of hospital, in-­ hospital, before thrombolysis, after thrombolysis, etc. The overall case fatality (the proportion of deaths among all strokes) varies markedly among populations, even within a country, and is roughly 20% within the first month, and subsequently increases by around 5% each year after the acute stroke event. The large variation in case fatality of stroke was demonstrated well in the WHO Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) Stroke Study: among men the case fatality of stroke ranged from 12% in northern Sweden to 53% in Moscow, Russia [25]. Overall, the case fatality was high in all Eastern European countries. In women, the difference in case fatality of stroke between populations was larger than in men, ranging from 16% in Kuopio, Finland to 57% in Moscow. The INTERSTROKE study has shown that stroke case fatality and functional outcome is dependent on the case mix presenting in different global regions on the one hand, but also on the access to stroke management services, such as CT scanning, stroke unit treatment, and anti-­platelet therapy on the other [33]. Good functional outcome (modified Rankin Scale 0–3) is achievable in 90% of stroke victims in high-­ income countries compared to 78% in low-­income or middle-­income countries [33].

Trends in Stroke Event Rates, Case Fatality, and Mortality of Stroke 116

In the WHO MONICA Stroke Study stroke event rates, case fatality, and mortality (obtained from both the

register and in routine mortality statistics) [34] of stroke event rates declined in 9 of 14 populations in men and 8 of 14 populations in women. In men, the case fatality of stroke declined in seven populations, increased in eight, and fluctuated only slightly in two. Among women, a decline in case fatality was seen in eight populations, no obvious change was seen in three, and an increase was observed in three. The trends in case fatality were statistically significant among men in only two populations with declining trends and in two with increasing trends. Among women, there was a significant downward trend in four populations. Of the 14 populations, stroke mortality declined in 8 populations among men and 10 populations among women. Thus, stroke trends have not been uniform among countries. Stroke mortality increased in all the Eastern European populations except in Warsaw, Poland. In Beijing, China and in the nine Western European populations, stroke mortality declined. Effects of changes in incidence and improved survival on the downward trend in stroke mortality are not easy to quantify and compare, due to the difficulty of measuring accurately the incidence of stroke. In the WHO MONICA Stroke Study populations, changes in stroke mortality, whether declining or increasing, were principally attributable to changes in case fatality rather than changes in event rates (i.e. incidence of stroke) [34]. Since only limited advances in acute stroke care took place during that time, it is likely that the natural history of stroke events has changed and they have become less severe. Effects of risk factor changes on stroke mortality have obviously been important, such as reduced blood pressure levels, smoking, and dietary changes (especially lower salt intake), but actual data on these issues are limited. The analysis by the GBD Stroke Panel Experts Group showed that globally there were significant increases in absolute numbers and prevalence of both hemorrhagic and ischemic stroke for people aged 20–64 years [32]. There was a 20% decline in the number of total stroke deaths in this age group in developed countries, but a 37% increase in developing countries (Figure 6.3). Death rates for all strokes declined significantly from 47 to 39 per 100 000 population per year from 1990 to 2013 in developing countries and from 33 to 24 per 100 000 population per year in developed countries. Regarding stroke subtypes, for hemorrhagic stroke mortality there was a significant decrease for adults aged 20–64 only in developed countries from 20 to 14 per 100 000 population per year between 1990

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Chapter 6: Basic Epidemiology of Stroke and Risk Assessment

Figure 6.3  Percentage change from 1990 to 2013 in total stroke mortality by Global Burden of Disease region in the age group 60–64. Significant declines on mortality were seen in the high-­income regions of Asia Pacific and other developed regions of the world, whereas increases in mortality were seen in African regions and Oceania. (From Krishnamurthi et al. 2015 [32] with permission from S Karger AG, Basel.)

and 2013, but no significant change was detected in ischemic stroke mortality. Globally, there was a 24% increase in total DALYs with a 20% and 37% increase in hemorrhagic stroke and ischemic stroke numbers, respectively. After the WHO MONICA Stroke Study no formal multinational comparison of stroke incidence has been organized. There are, however, data from many countries. Feigin at al. carried out a systematic review of published stroke incidence studies from 1970 to 2008 [2]. They found adequate data from 47 centers in 28 countries. Over the four decades, age-­adjusted stroke incidence rates in high-­income countries decreased by 42% (from 163 per 100 000 person-­years in 1970–1979 to 94 per 100 000 person-­years in 2000–2008; p = 0.0004), whereas in low- to middle-­income countries the stroke incidence rates more than doubled (52 per 100 000 and 117 per 100 000 person-­years, respectively; p