textbook-of-stroke-medicine.pdf

This page intentionally left blank Textbook of Stroke Medicine Textbook of Stroke Medicine Edited by Michael Brainin MD FESO FAHA Center of Clinical Neurosciences, Danube University, Krems, Austria Wolf-Dieter Heiss MD Max Planck Institute for Neurological Research, Cologne, Germany Editorial Assistant Susanne Heiss MD CAMBRIDGE UNIVERSITY PRESS Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore, São Paulo, Delhi, Dubai, Tokyo Cambridge University Press The Edinburgh Building, Cambridge CB2 8RU, UK Published in the United States of America by Cambridge University Press, New York www.cambridge.org Information on this title: www.cambridge.org/9780521518260 © Cambridge University Press 2010 This publication is in copyright. Subject to statutory exception and to the provision of relevant collective licensing agreements, no reproduction of any part may take place without the written permission of Cambridge University Press. First published in print format 2009 ISBN-13 978-0-511-69119-5 eBook (NetLibrary) ISBN-13 978-0-521-51826-0 Hardback Cambridge University Press has no responsibility for the persistence or accuracy of urls for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate. Every effort has been made in preparing this publication to provide accurate and up-to-date information which is in accord with accepted standards and practice at the time of publication. Although case histories are drawn from actual cases, every effort has been made to disguise the identities of the individuals involved. Nevertheless, the authors, editors and publishers can make no warranties that the information contained herein is totally free from error, not least because clinical standards are constantly changing through research and regulation. The authors, editors and publishers therefore disclaim all liability for direct or consequential damages resulting from the use of material contained in this publication. Readers are strongly advised to pay careful attention to information provided by the manufacturer of any drugs or equipment that they plan to use. 11 Cerebral venous thrombosis 165 CT angiography 40 Jobst Rudolf Patrik Michel (B) Imaging of acute ischemic and 12 Behavioral neurology of stroke 178 hemorrhagic stroke: MRI and MR José M. Hossmann 8 Common stroke syndromes 121 and Wolf-Dieter Heiss Céline Odier and Patrik Michel 2 Common causes of ischemic stroke 28 9 Less common stroke syndromes 135 Bo Norrving Wilfried Lang 3 Neuroradiology 40 10 Intracerebral hemorrhage 154 (A) Imaging of acute ischemic and Michael Brainin and Raoul Eckhardt hemorrhagic stroke: CT. Roine and Markku Kaste 5 Basic epidemiology of stroke and risk assessment 77 16 Acute therapies and interventions 230 Jaakko Tuomilehto. perfusion CT. Ferro. Thorsten Steiner and Cinzia Sarti and Kennedy R. Lees 6 Common risk factors and prevention 89 17 Management of acute ischemic stroke Michael Brainin.Contents Preface vii List of contributors viii Section I – Etiology. pathophysiology 7 Cardiac diseases relevant to stroke 105 Claudia Stöllberger and Josef Finsterer and imaging 1 Neuropathology and pathophysiology of stroke 1 Section III – Diagnostics and syndromes Konstantin A. 14 Ischemic stroke in the young recovery and rehabilitation 48 and in children 203 Wolf-Dieter Heiss Didier Leys and Valeria Caso 4 Ultrasound in acute ischemic stroke 58 László Csiba Section IV – Therapeutic strategies Section II – Clinical epidemiology and neurorehabilitation and risk factors 15 Stroke units and clinical assessment 219 Risto O. Bornstein and Eitan Auriel v . Markku Mähönen Richard O’Brien. Yvonne Teuschl and its complications 243 and Karl Matz Natan M. Martins and Lara Caeiro angiography 43 13 Stroke and dementia 194 Jens Fiehler Didier Leys and Marta Altieri (c) Functional imaging in acute stroke. Isabel P. Albers Index 307 vi . Albert and Jürg Kesselring 19 Secondary prevention 272 Hans-Christoph Diener and Greg W. Contents 18 Infections in stroke 258 20 Neurorehabilitation 283 Achim Kaasch and Harald Seifert Sylvan J. This book has been stroke care. the pathological. Thus. tion. In places this leads to some differences of opinion in the approach to particular Michael Brainin patients or conditions. or medical doctors entering the field of specialized The development of this textbook has been trig- stroke care. e. Finally. they were handled from different topological or didac- ists”. important issues. in addi. e. we would like to thank Dr Susanne Heiss physiological and anatomical background is included for her expert editorial assistance and her diligent and where necessary. shaped by the experiences of the lecturers – most of The textbook leads the reader through the many them also leading authors for our chapters – and the causes of stroke. we hope to satisfy the needs of students tried to keep the clinical aspects to the fore. giving and young doctors from many different countries. The book benefits from the experi. relative weight to those chapters that cover clinically both within and outside Europe. on genetics or rarer forms of diseases. thereby providing Thanks also to Nick Dunton and his team at Cambridge expert coverage of the various topics by international University Press for their help and patience. as Editors we have tried not Wolf-Dieter Heiss vii .g.Preface This book is designed to improve the teaching and to interfere with the individual character of each learning of stroke medicine in postgraduate educa. goes into much greater depth. and describing Stroke Organisation and has been endorsed by the the more technical facets and settings of modern World Stroke Organization.g. Therefore the text contains what is gered by the “European Master in Stroke Medicine considered essential for this readership but. ence of many specialized authors. however. It is targeted at “beginning special. chapter. leaving only duplicate presentations when tional programs. and the feedback of our students during several runs of this practical management of the stroke patient. Programme” held at Danube University in Austria. either medical students with a deeper interest tic aspects. its typical manifestations. the coverage This program has been fostered by the European of less frequent causes of stroke. authorities in the field. We have course. expert help in summarizing the chapters’ contents. patho. University Medical School. Rome. Landesklinikum Donauregion Tulln. Italy Tulln. Tel-Aviv. Germany Marta Altieri MD PhD Raoul Eckhardt MD Department of Neurology. University of Perugia. Hospital de Santa Maria and Wolf-Dieter Heiss MD Instituto de Medicina Molecular. Department of Neurology. Danube University. Klinik und Poliklinik für Neuroradiologische Tel-Aviv. Portugal Department of Neurology. Italy Society. Lara Caeiro PhD Vienna. Germany Center of Clinical Neurosciences. Austria Department of Neurosciences. Natan M. Department of Neurology. . Ferro MD PhD Eitan Auriel MD Department of Neurosciences. Lisbon. Department of Neurology. Hungary Sylvan J. Department of Internal Medicine. Rehabilitation Centre. Hospital de Santa Maria and Instituto Souraski Medical Center. Neurorehabilitation. de Medicina Molecular. Max Planck Institute for Neurological Research. Max Planck Institute for Neurological Research. Stanford. Josef Finsterer MD PhD Krems. Contributors Gregory W. CA. Israel Diagnostik und Intervention. Albers MD László Csiba MD PhD DSc Department of Neurology. Jens Fiehler MD Souraski Medical Center. Michael Brainin MD FESO FAHA Diagnostikzentrum Universitaetsklinikum Eppendorf. University of Essen. University of Lisbon. Albert MD Hans-Christoph Diener MD PhD FAHA Department of Neurology and Department of Neurology. Bornstein MD Lisbon. Israel University of Lisbon. Valens. Austria José M. Germany Valeria Caso MD PhD Konstantin A. Klaus-Joachim-Zülch-Laboratories of the Max Planck viii Perugia. Hamburg. Stanford University Medical Center. Austria Department of Neurology. USA Debrecen. Portugal Cologne. “Sapienza” University. Hossmann MD PhD Stroke Unit. Hospital Rudolfsstiftung. Switzerland Essen. Cologne. Didier Leys MD PhD General Hospital “Papageorgiou”. Markku Mähönen Helsinki. Greece Department of Neurology. Jobst Rudolf MD Western Infirmary. Division of Cardiovascular and Medical Sciences. University of Cologne. Switzerland Universitaire Vaudois. Finland National Institute of Health and Welfare. Helsinki. Switzerland Neurologische Abteilung. University of Glasgow. Germany ix . University Hospital. Centre Hospitalier Valens. Krems. Kennedy R. Finland Western Infirmary. University of Lausanne. Lausanne. Roine MD PhD Vienna. Helsinki. Centre Hospitalier Universitaire Vaudois. Turku University Hospital. KH der Barmherzigen Brüder Wien. UK Department of Neurology. Portugal Thorsten Steiner MD PhD MME Karl Matz MD Department of Neurology. University Lille II. UK Jürg Kesselring MD Department of Neurology and Neurorehabilitation. Germany Department of Neurology. Department of Chronic Disease Prevention. Wilfried Lang MD Lausanne. Richard O’Brien MBChB MRCP Helsinki University Central Hospital. Céline Odier MD Rehabilitation Centre. Glasgow. University of Heidelberg. Martins MD PhD Department of Neurosciences. University of Cologne. Bo Norrving MD PhD FESO Cologne. Danube University. Center of Clinical Neurosciences. Austria Heidelberg. Lille. Glasgow. Germany Neurology Service. Neurology Service. Risto O. Harald Seifert MD Hospital de Santa Maria and Instituto Institute for Medical Immunology and Hygiene. Germany Lisbon. Finland. Sweden Markku Kaste MD PhD FAHA FESO Department of Neurology. Austria Department of Neurology. France University of Helsinki. Achim J. Finland Isabel P. University of Helsinki. Finland Division of Cardiovascular and Medical Sciences. Kaasch MD University of Lausanne. Helsinki. Lees MD Turku. Department of Public Health. Switzerland Immunology and Hygiene. Thessaloniki. List of contributors Patrik Michel MD Faculty of Medicine of the University of Cologne. University of Helsinki. Cinzia Sarti CHU Hopital Roger Salengro. Lund. Institute for Medical Microbiology. Department of Public Health. Cologne. de Medicina Molecular. University of Lisbon. University of Glasgow. University of Helsinki. Hospital Rudolfsstiftung. South Ostrobothnia Central Hospital. Vienna. Finland. Finland Center of Clinical Neurosciences. Department of Public Health. Austria Helsinki. Yvonne Teuschl PhD Seinäjoki. Austria x . Krems. Danube University. List of contributors Claudia Stöllberger MD Jaakko Tuomilehto MD PhD Second Medical Department. the opportunity exists for thrombus to calcification in the tunica media and arteriolosclerosis develop in anterograde fashion throughout the length with proliferative and hyaline changes affecting the of the vessel. granulomatous angiitis of the CNS. or due to colla. Various concepts but these disorders are characterized by typical have been proposed to explain the progression of such locations of the vascular changes. Some arteriopathies precursor lesions to definite atherosclerosis [1. knowledge of pathological changes occur. 2]. Atherosclerosis starts at a young age. The basic pathological lesion is the atheroma- stenosis or occlusion at the site of vascular changes. such as CADASIL (cerebral autosomal most remarkable of which is the response-to-injury 1 . tous plaque. lesions situated proximally to otherwise healthy a more generic term describing hardening and branches located more distal in the arterial tree or thickening of the arteries. obstruction of blood flow. Small vessels of the brain are affected by ring in the vessels and in the blood is essential for hyalinosis and fibrosis. tions. for vascular cognitive impairment and vascular peutic strategies. areas of intracellular lipid collection in both macro- e. lesions accumulate and grow throughout life and including the aorta. cation of the carotid artery and the basilar artery. by interacting with blood Atherosclerosis is the most widespread disorder constituents they may cause thrombosis and blockade leading to death and serious morbidity including of blood flow in this vessel.g. become symptomatic and clinically evident when sclerosis. obstruction. and the basilar artery. Wegener granulomatosis. is the substrate types of CVD and for the planning of efficient thera. and in some such as cerebral cerebrovascular disease amyloid angiopathy a degenerative cause has been All cerebrovascular diseases (CVD) have their origin suggested. At the site of type Mönkeberg’s sclerosis and is characterized by occlusion. rheumatoid arterii. Hossmann and Wolf-Dieter Heiss The vascular origin of dominant arteriopathy with subcortical infarcts and leukoencephalopathy). are mainly caused by athero.g. most com- of inflammatory origin due to subacute to chronic monly in the aorta. Takayasu’s attributed to the “fatty streaks” and the “intimal cell arteriitis. In addition to vascular stroke. the coronary arteries. Those changes occur in childhood and adoles- tis. e.g. Section 1 Etiology. or Sneddon and Behcet’s cence and do not necessarily correspond to the future disease. and lead to thrombosis and emboliza- Therefore. arterioles. but this event seems to occur only rarely. panarteritis nodosa. also be affected by acute or chronic vascular diseases Atherosclerosis: atheromatous plaques. In some diseases affecting the vessels of the sites of atherosclerotic plaques. Fatty streaks are focal brain the etiology and pathogenesis are still unclear. Arteriosclerosis. the carotid artery at can also be produced by emboli arising from vascular its bifurcation. e. tuberculosis and lues. and the most commonly affected sites are disruption of blood supply and consecutive infarcts the aorta. the coronary arteries. the are hereditary. phages and smooth muscle cells. Sjögren’s syndrome. and Changes in large arteries supplying the brain. Middle-sized and intracerebral arteries can end organs are affected [1]. mass”. Changes in the vessel wall lead to dementia. giant cell arteriitis. moyamoya disease and fibromuscular dysplasia. and even The initial lesion of atherosclerosis has been more rarely systemic lupus erythematosus. if widespread. this “small-vessel disease” understanding the pathophysiology of the various can cause lacunes and. the bifur- infections. pathophysiology and imaging Chapter 1 Neuropathology and pathophysiology of stroke Konstantin A. includes as an additional from a source located in the heart. gen disorders. All these vascular disorders can cause in the vessels supplying or draining the brain. proliferate. During the development of (NO). inflammatory mediators.1. (5) Macrophages and (6) foam cell accumulation and additional (7) SMC proliferation result in (8) growth of the plaque. Less commonly. exposed to circulating blood. progression and finally rupture of of vascular smooth muscle cells ! atheromatous an atherosclerotic plaque a large number of matrix plaque. (3) Release of growth factors and cytokines (4) attracts additional monocytes. In this complex tion) ! inflammatory repair process with stimulation process of growth. resulting in aneurysm forma- a result foam cells aggregate with an accumulation of tion which when ruptured may be the source of intra- oxidized LDL. endothelial cells and macrophages. Platelets rapidly adhere cific lesion.1). This fibrous cap covers the Immediately after plaque rupture or erosion. (1) LDL moves into the subendothelium and (2) is oxidized by macrophages and smooth muscle cells (SMC). As platelets are a source of nitrous oxide total occlusion of the vessel. endothelial collagen. pathophysiology and imaging Figure 1. plaque development VSMCs migrate. growth factors and vasoactive substances are involved. This inflam. Mediators from inflammatory cells at the to the vessel wall through the platelet glycoproteins thinnest portion of the cap surface of a vulnerable (GP) Ia/IIa and GP Ib/IX [8] with subsequent aggre- plaque – which is characterized by a larger lipid core gation to this initial monolayer through linkage with and a thin fibrous cap – can lead to plaque disruption fibrinogen and the exposed GP IIb/IIIa on activated with formation of a thrombus or hematoma or even to platelets. plaques and stimulates vascular smooth muscle cells have reduced collagen and elastin with a thin and (VSMCs). modulators. sub- deep lipid core with a massive accumulation of extra. and synthesize extracellular matrix components on the Injury hypothesis of progression to atherosclerosis: luminal side of the vessel wall. 5]. [5]. . and as weakened arterial wall. (9) Fibrous cap degradation and plaque rupture (collagenases. the resulting deficiency of bioactive NO. Section 1: Etiology. and the response to various atherogenic stimuli in the form lumen narrows as the plaque grows. sion or be the origin of emboli. forming the fibrous fatty streaks (focal areas of intra-cellular lipid collec- cap of the atherosclerotic lesion [6].) hypothesis postulating a cellular and molecular of the vessel area. The stages of development of an atherosclerotic plaque. However. plaques thrombosis forming on the disrupted lesion mation develops concurrently with the accumulation further narrows the vessel lumen and can lead to occlu- of minimally oxidized low-density lipoproteins [4. once the plaque enlarges to >40% sion of thrombosis by augmenting platelet activation. In vulnerable of an inflammatory repair process [3]. the artery no longer enlarges. (10) Thrombus formation. In the further stages of atherosclerotic cerebral hemorrhage (Figure 1. which 2 atherosclerosis the entire vessel can enlarge or constrict is an effective vasodilator. contributes to the progres- in size [7]. the lipid core and procoagulants cellular lipids (atheromatous plaque) or fibroblasts and such as tissue factor and von Willebrand factor are extracellular calcifications may contribute to a fibrocal. elastases). (Modified from Faxon et al. The complex interactions of these many factors are discussed in the Thromboembolism specialist literature [4–6]. Rupture or erosion of atheromatous plaques ! they are caused by atherothrombotic changes of the adhesion of platelets ! thrombus ! obstruction arteries supplying the brain or by emboli from of blood flow and source of emboli. Athero. if the critical blood flow reduction lasts beyond a critical duration. These “criblures” together with miliary aneurysms are Borderzone infarctions are a subtype of the low-flow the sites of vessel rupture causing typical hypertonic or hemodynamically induced infarctions which are intracerebral hemorrhages [10–13].4% by subarachnoid hemorrhage.g. diseases.8% of the total cere- which are the primary pathophysiological mechan. In status cribrosus small several large arteries are stenotic and the perfusion in round cavities develop around affected arteries due to these “last meadows” cannot be maintained above disturbed supply of oxygen and metabolic substrate. In a smaller number of cases infarcts can also develop strate of lacunar strokes and vascular cognitive at the borderzones between vascular territories. 8. In addition. brovascular events [15]. Often bed. especially from carotid Ischemic strokes are caused by a critical reduction artery disease or of cardiac origin. infarctions affect subcortical structures within a vas- cular bed but with marginal irrigation [17]. thal- diseases amus and paramedian regions of the brain stem [18].3% the clotting cascade. isms of ischemic strokes. It leads to narrowing of the tion and the compensatory capacity of the vascular lumen or even occlusion of these small vessels. Small-vessel disease usually affects the arterioles The pathological substrate of ischemic stroke is ische- and is associated with hypertension. the hyaline. via the circle of Willis or status cribrosus (state criblé). but also other small vessels and capillaries leads to territorial infarcts of variable size: they might and venules. Small-vessel disease results in two patho. 5. less frequent causes are on the source of data. and shape of these infarcts depend on the size of the tein. of large arteries are occluded or if compensatory logical conditions: status lacunaris (lacunar state) and collateral perfusion – e. The most reliable numbers stenosis of the MCA stem and microembolization to 3 come from the in-hospital assessment of stroke in penetrant arterial territories. 25.2). of regional cerebral blood flow and. Pathologically these . the aorta or the large arteries. formed from mucopolysaccharides occluded vessel. if branches aneurysms”. the critical threshold during special exertion [16]. The activated of complete stroke: 60% were caused by athero- platelets also release adenosine diphosphate (ADP) thrombotic brain infarction. It is caused by mic infarction of brain tissue. Lipohyalinosis also weakens the vessel be large – e. the whole territory supplied by the wall. Status lacunaris is char.2% by undefined or even blocks the blood flow in the vessel.1% by cerebral and thromboxane A2 with subsequent activation of emboli. it is the pathological sub. the more common low-flow of hyaline in arterioles. the mechanism of arterial obstruc- and matrix proteins. occlusion of small vessels. when impairment and dementia. Numbers relating to the frequency of the different Most often they are caused by lipohyalinosis of deep types of acute CVD are highly variable depending arteries (small-vessel disease). Borderzone infarcts are located in cortical areas between the territories of Small-vessel disease: subendothelial accumulation major cerebral arteries. extension subendothelial accumulation of a pathological pro. Chapter 1: Neuropathology and pathophysiology of stroke enhancing VSMC proliferation and migration. Occlusion of arteries supplying defined brain it is associated with fibrosis. the location. isolated transient ischemic sclerotic thrombi are also the source of embolisms. leptomeningeal anastomoses – is efficient in reducing acterized by small irregularly shaped infarcts due to the area of critically reduced flow [12. 13] (Figure 1. certain vulnerable brain areas. predisposing it to the formation of “miliary middle cerebral artery (MCA) – or small. Lacunar Types of acute cerebrovascular infarcts reflect disease of the vessels penetrating the brain to supply the capsule. and the Framingham study determining the frequency participating in neovascularization [9].g. sources in the heart. The growing thrombus obstructs by intracerebral hemorrhage and 1. which affects not only territories by atherothrombosis or embolizations arterioles. attacks (TIAs) accounted for 14. The etiology the result of critically reduced cerebral perfusion and pathophysiology of the various specific vascular pressure in far-downstream brain arteries that leads disorders are discussed in specialist articles and to a reduced cerebral blood flow and oxygen supply in handbooks [14]. the basal ganglia. i. pathophysiology and imaging a b c d e Figure 1. Macro- tions are not involved. In severe ischemic tissue are found within the necrotic tissue. scopically red infarcts contain multifocal bleedings which are more or less confluent and predominate in Territorial infarcts are caused by an occlusion of cerebral cortex and basal ganglia which are richer arteries supplying defined brain territories by athero. where they formed in tissue consisting of neuronal ghosts and are accepted as lacunes up to 1. clumsy hand. However. If the thrombosis or embolizations. but they are more often when macrophages appear and new blood vessels are observed on magnetic resonance images. Section 1: Etiology. manifold and vary with regard to the intensity of trast to the usual “pale infarcts”. in capillaries than the white matter [19]. The amount can vascular permeability is increased and endothelial range from a few petechial bleeds in the gray matter tight junctions are ruptured. (a) Total territorial infarct due to defective collateral supply. (e) Lacunar infarctions due to small-vessel disease. but higher cerebral func. frequency of hemorrhagic infarctions (HIs) in anatomic Lacunar infarcts are mainly caused by small.e.) lacunes are defined as small cystic trabeculated scars during the second and third phase of infarct evolution. can leak out of these damaged vessels. This can also Hemorrhagic transformation frequently appears happen with fragmentation and distal migration of an . sometimes intensity and extension of the hemorrhagic compo- ataxic hemiparesis. meningeal anastomosis supply peripheral zones. pure difference between “pale” and “red infarcts” is the sensory. The flow infarctions). bleeding. dence (up to 85% of HIs) in cardioembolic stroke [21]. dysarthria and nent. about 5 mm in diameter. hemorrhages become confluent intrainfarct hematomas Borderzone infarcts develop at the borderzone might develop. Petechial bleeding results from diapedesis mic infarcts in which varying amounts of blood cells rather than vascular rupture. hemorrhages are microscopically detectable. studies ranged from 18 to 42% [20]. and sensorimotor syndromes. (c) Territorial infarct in center of supply area. (d) Borderzone infarction in watershed areas due to stenotic lesions in arteries supplying neighboring areas. Various types and sizes of infarcts due to different hemodynamic patterns. since in at least two-thirds of all infarcts petechial hemichorea/hemiballism. (b) Core infarct. the only significant classic lacunar syndromes include pure motor. blood 4 involving the cortical and deep hemispheric regions. are defined as ische.2. with a high inci- vessel disease. and extensive edema may contribute between vascular territories and are the result of a critically reduced cerebral perfusion pressure (low to mass effects and lead to malignant infarction. (Modified from Zülch [13].5 cm diameter. due to branch occlusion. Mechanisms for hemorrhagic transformation are Hemorrhagic infarctions. “red infarcts” in con. When blood circulation of cortex and basal ganglia to large hemorrhages is spontaneously or therapeutically restored. The proliferating astrocytes. cocaine). area of the dentate nucleus from rupture of distal Spontaneous ICH occurs predominantly in the branches of the superior cerebellar artery and extend deep portions of the cerebral hemispheres (“typical into the hemispheric white matter and into the fourth ICH”). Larger hematomas often reach the corona serum cholesterol levels. Most ICHs originate from the rupture of small. Vascular rupture can branch of the striate arteries at the posterior angle. This bleeding soon connects to the ventricle and usually Intracerebral hemorrhage (ICH) occurs as a result involves the anterior limb of the internal capsule. large hematoma may extend to the internal capsule and lateral ventricle.g. a less common form of caused by leakage from damaged vessels. cells are found within the necrotic tissue. usually in atypical locations. 30%). from the cerebellar vermis. The pontine tegmentum is often com- (35–50% of cases). Hypertension is the leading risk and the posterior limb of the internal capsule laterally. In a radiata and the parietal white matter. occurs in the head of the caudate nucleus. but in addition old age and race. due to exposure to structures or the ventricular system. of bleeding from an arterial source directly into the Thalamic hemorrhages can involve most of this brain parenchyma and accounts for 5–15% of all nucleus and extend into the third ventricle medially strokes [22. which might be followed by secondary ruptures of rhage is significantly increased in large infarcts. Risk of hemor. at borderzones of cortical infarcts. due to increased vascular permeability in ischemic tissue bleeding from distal branches of lateral striate arter- or vascular rupture secondary to ischemia. The causes the cortico-subcortical junction between gray and include small vascular malformations. The subcortical white matter is pressed. Its most common location is the putamen ventricle. alcohol consumption and high midbrain. . white matter and spread along the fiber bundles brain tumors and sympathomimetic drugs (e. most commonly in the parietal and occipital lobes.g. 25]. 5 in the pons in 5–12% and in the cerebellum in 7% erally into the pontine tegmentum. originates the second most frequent location (approx. From this initial putaminal-claustral location a develops within 48 hours to 2 weeks. Cerebellar hemorrhages usually originate in the heart and other organs [24. In some instances hematoma. They are Caudate hemorrhage. the temporal white matter. vascular bed. For the hemorrhagic transformation the which are affected by lipohyalinosis due to chronic collateral circulation might also have an impact: in hypertension. some cases. These small-vessel changes lead to some instances reperfusion via pial networks may weakening of the vessel wall and miliary micro- develop with the diminution of peri-ischemic edema aneurysm and consecutive small local bleedings. A variant. As atypical cold. explaining delayed clinical worsening in deep arteries with diameters of 50 to 200 mm. and also The hematoma my press on or even extend into the cigarette smoking. 23]. ies. After active bleeding starts it can con- for tissue damage and the deleterious effect of late tinue for a number of hours with enlargement of reperfusion when edema resolves. number of instances ICH occurs in the absence of Lobar (white matter) hemorrhages originate at hypertension. Putaminal ICHs were mic infarcts in which varying amounts of blood considered the typical hypertensive hemorrhages. have been identified. into the corona radiata and into Hemorrhagic infarctions (HI) are defined as ische. the midline hematoma. with the enlarging hematoma in a cascade or avalanche mass effect supporting the importance of edema fashion [27]. with the fourth ventricle and frequently extends bilat. hypertension. always communicates Hemorrhages in the thalamus are found in 10–15%. The occurrence of ICH is also influenced by ICHs they are not necessarily correlated with the increasing use of antithrombotic and throm. explain very early hemorrhagic infarcts and early resulting in an ovoid mass pushing the insular cortex intrainfarct hematoma (between 6 and 18 hours after laterally and displacing or involving the internal cap- stroke). e. which is frequently associated with clinical also the rupture of the vascular wall secondary to deterioration [28]. whereas hemorrhagic transformation usually sule. vasculitis. ICH may also be caused by cerebral amyloid The hematomas are close to the cortical surface and angiopathy and rarely damage is elicited by acute usually not in direct contact with deep hemisphere changes in blood pressure. Chapter 1: Neuropathology and pathophysiology of stroke embolus (usually of cardiac origin) in the damaged [26]. ischemia-induced endothelial necrosis might cause Putaminal hemorrhages originate from a lateral an intrainfarct hematoma. bolytic treatment of ischemic diseases of the brain. factor. contribute to the development of this disorder [30]. but septic cavernous sinus energy metabolism. of all cell elements. and prothrombin mutation. edema is prominent. Despite this hemorrhagic cytoplasm. These venous infarcts are different from arterial which ingest debris and hemosiderin. Later on. a infection causes of CVT are congenital thrombophilia. the component heparin is the treatment of choice. and hemorrhagic transformation liferate and turn into gemistocytes with eosinophilic or bleeding is usual. Thrombi of the cerebral veins and sinuses can develop followed – in this order – by oligodendrocytes. After hours the cortex and adjacent white matter and often are or days extracellular edema develops at the periphery hemorrhagic. astrocytes are replaced by glial fibrils. systemic lupus erythematodes. neocortical multifactorial. cytes and vascular cells. inflammatory diseases and hematomas usually communicate with the fourth ven. Other conditions with risk for circumferential branches of the basilar artery. The recurrence cells and fibrin and poor in platelets. severity and duration of ischemia Cerebral venous thrombosis [31. granulocytes and thereafter micro. particularly prothrombin gene and factor V Leiden median basilar perforating branches cause medially mutations. Section 1: Etiology. The most vulnerable brain ditions. In some zation. astro- from many causes and because of predisposing con. pathophysiology and imaging Pontine hemorrhages from bleeding of small para. occlusion of cerebral veins usually dissects the tissue. the primary pathology is necrosis thrombosis is still a severe. protein C and protein S deficiencies A unilateral variety results from rupture of distal long must be considered. when various risk factors and causes layers 3. After that Cerebral venous thrombosis can lead to a venous period – extending to months – the residue of the infarct. Intracerebral hemorrhage (ICH) occurs as a result of bleeding from an arterial source directly into the brain parenchyma. the outer segment of striate nucleus. vasogenic astrocytes at the periphery of the hematoma pro. Whereas some thromboses. the local accumulation of blood destroys lateral sinus. and hemorrhagic trans- formation or bleeding is usual. However. displaces nervous structures and for the brain tissue. These CVT are malignancies. Acute occlusion of a major brain artery causes a Hypertension is the leading risk factor. These infarcts are located in are formed around collections of platelets. may have no pathological consequences the parenchyma. The frequency of recurrent of ICHs in hyperten. also in these cases the cause is other than hypertension. or if it is of so short duration that 6 to use of oral contraceptives. delayed type of cell death may evolve which exhibits . If blood flow decreases below the threshold of less than 10% of cases. When the hematoma is removed. in 20–35% tricle and extend laterally and ventrally into the pons. but usually causes cells begin to lyse. genic edema is prominent. it is rate is higher with poor control of hypertension and replaced by fibrous tissue. 5 and 6. Venous infarcts are different from arterial hematoma is a flat cavity with a reddish lining infarcts: cytotoxic edema is absent or mild. At the bleeding sites fibrin globes leads to a venous infarct. of CVT the etiology remains unknown. Cellular pathology of ischemic stroke tions of the cerebral hemispheres (typical ICH). energy metabolism recovers after reperfusion. The most common location of CVT is the instances multiple simultaneous ICHs may occur. vaso- resulting from hemosiderin-laden macrophages [26]. Finally. antithrombin. Thrombosis of the superior sagittal sinus of the hematoma. Among the non. Cerebral venous thrombosis (CVT) is often regions are hippocampal subfield CA1. but superior sagittal sinus and the tributary veins. resulting in ischemic brain infarct. The fresh venous thrombus is rich in red blood sive patients is rather low (6%) [29]. stereotyped sequel of morphological alterations which evolve over a protracted period and which depend on the topography. but may also be related energy failure. predominantly in the deep por. Aseptic CVT occurs during puerperium and less If ischemia is not severe enough to cause primary frequently during pregnancy. and the most common location is the putamen. as well as placed hematomas involving the basis of the pons. problem. glial cells arrive and foamy macrophages are formed. the infarcts: cytotoxic edema is absent or mild. After 4 to 10 days the red blood might lead only to brain edema. however rare. bilateral hemorrhagic infarcts in both hemispheres. occasionally with recanali- also in hemorrhages due to other causes. 32]. The most sensitive brain cells are neurons. and the Purkinje and basket cell layers of cerebellar The incidence of septic CVT has been reduced to cortex. particularly of the In ICHs. astrocytes. apop. Inter- undergo irreversible necrotic changes (red neuron or estingly. neurons which stain with all (acid or base) dyes and ion (MV). neurons ghost cells with a hardly detectable pale outline. Light-microscopical evolution of neuronal changes after Acute ischemic changes experimental middle cerebral occlusion. the cytoplasm exhibiting microvacuolat. characterized by con- tosis or a combination of both. neurons gradually lose are potentially reversible if blood flow is restored their stainability with hematoxylin. densed acidophilic cytoplasm. (Modified from Garcia et al. In the following. which ultrastructurally has been associated are not surrounded by swollen astrocytes (Figure 1. These changes With ongoing ischemia. with mitochondrial swelling [33].3. After 2–4 hours. transform into One to two hours after the onset of ischemia. Chapter 1: Neuropathology and pathophysiology of stroke the morphological characteristics of necrosis. ische- mic cell change with incrustrations appears. Ischemic cell the earliest sign of cellular injury is neuronal swelling change must be distinguished from artifactual dark or shrinkage. Electronmicroscopically mitochondria exhibit flocculent densities which represent denatu- Cellular pathology of ischemic stroke rated mitochondrial proteins. mildly eosinophilic and. formation of triangular primary and delayed cell death will be described nuclear pyknosis and direct contact with swollen separately.3). which Primary ischemic cell death has been associated with formaldehyde pigments de- In the core of the territory of an occluded brain artery posited after fixation in the perikaryon.) Control swelling shrinkage sham surgery 4 hours 2 hours Necrotic changes red neuron ghost neuron Dark neuron artifact 1 day 3 days sham surgery 7 . within 4 days. neurons with ischemic cell change are mainly Light microscopical characteristics of rat brain infarction Figure 1. ischemic cell change (ICC)). they become before mitochondrial membranes begin to rupture. [94]. global ischemia [34]. The most notable alteration during the ini. (Modified from Petito [32]. resulting in the formation of vasogenic with all possible combinations of cytoplasmic and edema.4. Transformation of acute ischemic alterations into cystic infarct. Section 1: Etiology. The morphological appearance of neurons during tial 1–2 hours is perivascular and perineuronal astro. after 4–6 hours the blood–brain barrier continuum that ranges from necrosis to apoptosis breaks down. ischemia is associated with reactive and secondary notably in the substantia nigra and thalamus.5 days Lipid-laden macrophages and necrosis Cavitation with sparing of outer cortical layer subacute infarct cystic infarct Figure 1. the interval between ischemia and cell death exhibits a cytic swelling. apoptosis mitochondria remain intact and nuclear fragmentation with condensation of nuclear chroma- tin gives way to the development of apoptotic bodies Delayed neuronal death (Figure 1. after 1–2 days inflammatory cells accumulate nuclear morphology that are characteristic of the throughout the ischemic infarct. In focal ischemia delayed neur- festation of ischemic cell change requires some onal death may occur in the periphery of cortical residual or restored blood flow. whereas ghost cells infarcts or in regions which have been reperfused may evolve in the absence of flow [32]. A frequently used histochemical 8 The prototype of delayed cell death is the slowly method for the visualization of apoptosis is terminal progressing injury of pyramidal neurons in the CA1 deoxyribonucleotidyl transferase (TdT)-mediated . necrosis 3 months cystic transformation of the necrotic tissue combines karyorrhexis with massive swelling of endo- occurs together with the development of a peri-infarct plasmic reticulum and mitochondria. changes. and within 1. Note pronounced inflammatory reaction prior to tissue cavitation. In its pure form. Primary ischemic cell death induced by focal Cell death is also observed in distant brain regions. which suggests that mani. pathophysiology and imaging Inflammation and cavitation of ischemic infarction Necrotic neurons.) located in the periphery and ghost cells in the center sector of the hippocampus after a brief episode of of the ischemic territory. whereas in astroglial scar.5 days 1.5 to two types of cell death [35]. before ischemic energy failure becomes irreversible. ghosts and PMN leukocytes Necrotic neurons and PMN leukocytes 1.4). sized penumbra which may extend up to the para- Not so severe or short-term ischemia induces delayed cell death with necrosis. the for cytosolic protein aggregation and the formation basal ganglia are consistently part of the infarct core of stress granules [38].or retro-orbital transcranial approaches for middle cerebral artery occlusion are mainly used in rats and mice because in these species the main stem Pathophysiology of stroke of the artery appears on the cortical surface rather close to its origin from the internal carotid artery [40]. A nylon later modified for use in cats. territory. anterior and 9% in the posterior cerebral artery terri. variations in infarct size. this situation is reflected by the of the vascular territory. branches are end-arteries which. preferential use of middle cerebral artery occlusion Filament occlusion of the middle cerebral artery: models. requires extensive training before reproducible results A consistent ultrastructural finding in neurons can be expected. The advantage of this advanced. Disturb. visible in Nissl-stained material. the currently most widely used procedure for Transorbital middle cerebral artery occlusion: middle cerebral artery occlusion in rats and mice this model was introduced in the seventies for is the intraluminal filament occlusion technique. in contrast to the ances of protein synthesis and the associated endo. cause generalized vasospasm which may interfere which detects DNA strand breaks. this change is equivalent to plied by the lenticulo-striate arteries. and first described by Koizumi et al. poro-parietal cortex with a gradient of declining or in watershed or multiple regions. or the use of 9 ances which should not be ignored. dogs. In the hippocampus. Depending on the steepness of this gradient. On the other hand. the production of stroke in monkeys [39]. As a consequence. Transcranial occlusion of the middle cerebral artery: post. Surgery may also guide-sheaths to allow remote manipulation of the . removal of the poly-L-lysine coating of the tip to prevent incom- eyeball is invasive and may evoke functional disturb. finding. which reflects the inhibition of protein origin interrupts blood flow to the total vascular synthesis at the initiation step of translation [37]. However. of brain trauma. therefore. plete middle cerebral artery occlusion. a cor- tical core region with the lowest flow values in the Severe ischemia induces primary cell death due to lower temporal cortex is surrounded by a variably necrosis of all cell elements. undergoing delayed cell death is disaggregation of The occlusion of the middle cerebral artery at its ribosomes. Modifications of the cerebral artery at its origin from the internal carotid original technique include different thread types artery without retracting parts of the brain. These MCA tigrolysis. adjust- occlusion can thus be performed without the risk ments of the tip size to the weight of the animal. a clear dif. are mainly located in the tem- tories. induce method may also stain necrotic neurons. cortical branches. In experimental flow values from the peripheral to the central parts stroke research. as this with the collateral circulation and. hence. rabbits and even suture with an acryl-thickened tip is inserted into rats. combination of both. stacks whereas the cerebral cortex exhibits a gradient of of accumulated endoplasmic reticulum may become blood flow which decreases from the peripheral visible but in other areas this is not a prominent towards the central parts of the vascular territory. including the basal ganglia which are sup- Light-microscopically. the rest are located in brainstem or cerebellum. The procedure therefore ferentiation is not possible [36]. Infarcts. [41]. In Animal models of focal ischemia contrast to transorbital middle cerebral artery occlu- According to the Framingham study. 65% of strokes sion. Vascular for isolated or combined vascular occlusion. until the tip is located at the origin of approach is the possibility of exposing the middle the middle cerebral artery. do not form collaterals with the plasmic reticulum stress are also responsible adjacent vascular territories. Chapter 1: Neuropathology and pathophysiology of stroke biotin-16-dUTP nick-end labeling (TUNEL assay). 2% in the branches originate proximal to the occlusion site. apoptosis or a sagittal cortex. The procedure is technically demanding and the common carotid artery and orthogradely requires microsurgical skills. transcranial models do not produce ischemic that result from vascular occlusion present lesions in injury in the basal ganglia because the lenticulo-striate the territory of the middle cerebral artery. namic effect. were developed to study focal ischemia in animals. in The most reliable procedure for clot preparation patients with hypertension and to the left during is thrombin-induced clotting. Clot embolism of middle cerebral artery: Autoregulation of cerebral blood flow is the middle cerebral artery embolism with autologous remarkable capacity of the vascular system to adjust blood clots is a clinically highly relevant but also its resistance in such a way that blood flow is kept inherently variable stroke model which requires constant over a wide range of cerebral perfusion careful preparation and placement of standardized pressures (80–150 mmHg). infarcts become smaller [42]. It may also reduce blood flow in plasminogen activator (rt-PA) but the dose required the anterior and posterior cerebral arteries. The range of autoregula- clots to induce reproducible brain infarcts [43]. Selection of either fibrin-rich (white) the direct effect of blood pressure variations on the or fibrin-poor (red) segments influences the speed myogenic tone of vessel walls. i. outcome and 30 mmHg and is reduced by approximately 35% pharmacological responsiveness of transient filament when CO2 falls to 25 mmHg. conditions. Under physiological conditions. is similar despite the infarcts are very large and produce massive ischemic higher dose and adequately reproduces the slowly brain edema with a high mortality when experiments progressing recanalization observed under clinical last for more than a few hours. CO2 ventilation. The hemody- izes collateral blood supply from these territories. The resulting reperfusion salvages Various procedures for artery occlusion models. to higher values. the peripheral parts of the MCA territory. The placement of the suture at the origin of The main application of clot embolism is for the the middle cerebral artery obstructs blood supply investigation of experimental thrombolysis. hypercarbia. tion is shifted to the right. of cerebral vessels. (metabolic regulation) but the flow rate remains Transient filament occlusion is also an inappro. and mostly middle cerebral artery occlusion models. nitric oxide and neurogenic influences. . threads are frequently withdrawn 1–2 hours fol- lowing insertion. such as t-PA toxicity are investigated. particu. However.e. For this reason. cerebral blood flow is tightly logical responsiveness of the resulting lesions are coupled to the metabolic requirements of tissue comparable. following injection of rose Bengal [45]. The vascular response occlusion is distinct from most clinical situations of to CO2 depends mainly on changes in extracellular reversible ischemia where the onset of ischemia is pH. Withdrawal of the ment for metabolic regulation is the CO2 reactivity intraluminal thread induces instantaneous reperfu. the patho. which can be tested by the sion whereas spontaneous or thrombolysis-induced application of carbonic anhydrase inhibitors or recanalization results in slowly progressing recircula. in animals is much higher than in humans. in contrast. and neither the Regulation of blood flow mechanisms of infarct evolution nor the pharmaco. The to the whole MCA-supplied territory. As post-ischemic recovery is greatly influenced blood flow doubles when CO2 rises by about by the dynamics of reperfusion. Other influences are of spontaneous reperfusion and results in different mediated by metabolic and neurogenic factors but outcomes. essentially constant despite alterations in blood priate model for the investigation of spontaneous or pressure (autoregulation). by UV illumination of the middle cerebral artery netic resonance recordings. physiology of transient MCA occlusion differs basic- ally from that of the clinically more relevant permanent occlusion models. but it is also modulated by other factors such as much less abrupt. In the intact brain. tion. Section 1: Etiology. prostanoids. which results in cylin. As this minim. including drug most widely used is human recombinant tissue the basal ganglia. which larly when the common carotid artery is ligated to must be remembered when possible side effects facilitate the insertion of the thread. pathophysiology and imaging thread for occlusion during polygraphic or mag. Clots can also be produced in situ by these may be secondary and are not of great 10 microinjection of thrombin [44] or photochemically significance. An important require- thrombolysis-induced reperfusion. The myogenic theory of autoregulation drical clots that can be dissected into segments of suggests that changes in vessel diameter are caused by equal length. This is one of the brain’s oxygen consumption is almost entirely for the reasons why primary post-ischemic recovery may be oxidative metabolism of glucose. in conse. During and therefore sufficient blood supply to the brain luxury perfusion. Stroke also impairs autoregulation but the dis.g. Subsequently. depending constant over a wide range of cerebral perfusion on the magnitude and direction of the blood pressure pressures. blood circulation. With the cessation of tissue (21. In the center of the ischemic territory. biosynthesis of nucleic acids. Failure of cerebral autoregulation can be demon- strated in such instances by dehydrating the brain in order to reduce brain edema. The in failure of metabolic regulation. The pathophysiological importance of steal has been turbance is more severe with decreasing than with disputed but as it depends on the individual hemody- increasing blood pressure. in an improvement in flow. yet consumes at rest approxi- declines to or below normal. and cause vasoconstriction. ritory and may affect both the extra. Most authors. Examples of extracerebral steals are the flow may decrease with increasing arterial pCO2. tion is impaired.and intracerebral CO2 reactivity is abolished or even reversed. resulting tion supplied by 16% of the cardiac blood output. mately 20% of the body’s total basal oxygen consump- lation.5 billion in the neocortex) [49] comprises only 2% acidosis. which in normal followed by delayed post-ischemic hypoxia and physiological conditions is the almost exclusive secondary metabolic failure [47]. This is explained by the namic situation it may explain unintended effects fact that a decrease of local brain perfusion pressure when flow is manipulated by alterations of arterial cannot be compensated by further reduction of vas. quence. male’s brain containing approx. as reflected by the appear. i. vascular tone returns. e. substrate for the brain’s energy metabolism [50] Disturbances of flow regulation through ischemia: (Table 1. metabolized in neuronal cell bodies is mainly to sup- ity is abolished or even reversed and autoregula.1). Chapter 1: Neuropathology and pathophysiology of stroke Metabolic regulation: cerebral blood flow is coupled to metabolic requirements of tissue by a Anastomotic steal phenomena vascular response to CO2. notably the circle of regions in which CO2 reactivity remains intact. to a severe disturbance of the regulation of Steals are not limited to a particular vascular ter- blood flow [46]. therefore. Inverse steal Disturbances of flow regulation has also been referred to as the Robin Hood syn- Focal cerebral ischemia is associated with tissue drome in analogy to the legendary hero who took acidosis which leads to vasorelaxation and. An alternative explan- ation is “false autoregulation” due to brain edema “Steal”: decrease in flow in a region because blood is diverted from one brain region to another by which causes an increase in local tissue pressure that anastomotic channels. CO2 reactiv. 130 billion neurons ance of red venous blood. from the rich and gave to the poor. vasorelaxation persists Energy requirements of brain tissue for some time. which explains the phenomenon of The energy demand of the nervous tissue is very high post-ischemic hyperemia or luxury perfusion. the occipital-vertebral and the ophthalmic paradoxical “steal” effect has been attributed to the steal syndrome. Intracerebral steals occur across col- rerouting of blood to adjacent non-ischemic brain lateral pathways of the brain. Willis and Heubner’s network of pial anastomoses. autoregu. “inverse steal” if that results precludes a rise of the actual tissue perfusion pressure. pCO2 or vasoactive drugs. and blood flow of total body mass. This subclavian. 11 . but not CO2 reactivity. oxygen supply exceeds the oxygen must be maintained consistently. It must be kept in mind that the glucose tissue acidosis leads to vasorelaxation.e. The connection of ischemic and non-ischemic vascu- lar territories by anastomotic channels may divert Autoregulation: cerebral blood flow is kept blood from one brain region to another. may recover. axonal transport. gradients across the anastomotic connections (for review see Toole and McGraw [48]). do cular resistance whereas an increase may shift the not recommend such manipulations for the treatment local perfusion pressure into the autoregulatory range of stroke. The concept of ischemic penumbra After transient ischemia. port cellular vegetative and house-keeping functions. A normal adult requirements of the tissue. 87% of the total energy consumed is required by signaling. Overall. and only 13% is expended in maintaining Energy metabolism by functional activation is membrane resting potential [53] (Figure 1. account for 80% of the neurons in the mammalian neuropil which contains axonal terminals. oxygen utilization and energy metabolism in the brain are still not under- metabolic rates of glucose in man (approximate values). cell membrane and the membrane potentials that Therefore the rate of glucose consumption of neur. 87% of the action potentials in the afferent pathways. increases in the projection zones occur regardless of mainly action potential propagation and postsynaptic whether the pathway is excitatory or inhibitory. glucose utilization during activation is medi- processes. Cortex White matter Global A normal adult male’s brain comprises only 2% CBF 65 21 47 of total body mass. Section 1: Etiology. Cerebral blood flow. mainly CMRGlc 40 20 32 action potential propagation and postsynaptic ion (mol/100 g/min) fluxes. (a) Schematic representation of the mechanism for glutamate-induced glycolysis in astrocytes during physiological 12 activation [95]. The magnitudes of these vide lactate to the neurons where lactate is further increases are linearly related to the frequency of oxidatively phosphorylated [52]. i. due mostly to stimulation of the NaþKþ-ATPase The mechanisms by which neurotransmitters other than glutamate influence blood flow and Table 1. . as well as other energy-consuming activity to restore the ionic gradients across the processes not related directly to action potentials. tion (and regional blood flow) evoked by functional In excitatory glutamanergic neurons. and total energy consumed is required by signaling.1. pathophysiology and imaging proteins. stood [54].5). (Figure 1. Increases in glucose consump. and also the astrocytic processes that ated by astrocytes which by anaerobic glycolysis pro- envelop the synapses. were degraded by the spike activity and is rather high onal cell bodies is essentially unaffected by neuronal compared to the demand of neuronal cell bodies [51] functional activation. yet consumes at rest approxi- (ml/100 g/min) mately 20% of the body’s total basal oxygen con- CMRO2 230 80 160 sumption.K ATPase 3% presynaptic Ca Na+ 47% action-potential propagation lonotropic glutamate receptor Postsynaptic site NMDAR Figure 1.5). Glucose is the almost exclusive substrate (mol/100 g/min) for the brain’s energy metabolism. (b) Distribution of energy expenditure in rat cortex at a mean spike rate of 4 Hz: most energy is required for activity. 96]. lipids. ion fluxes.5.e. dendritic cortex. which activation are confined to synapse-rich regions. only 13% is used for maintenance of resting potential for both neurons and glial cells [53. Glutamate-releasing Astrocyte Capillary presynaptic terminal Glucose 34% postsynaptic ion fluxes Glycolysis Lactate 10% neuronal resting Oxidative Glucose potential phosphorylation Gln Glu Gln 3% glial resting potential Glu K+ 3% glutamate recycling + 2+ EAAT Na+ Na+. As a rule used penumbra” [55]. be tolerated for a defined period. on onal function is impaired and a lower threshold average. damage) is determined not only by the level of logical integrity.7). A more Spontaneous neuronal activity as well as EPs were direct approach is the imaging of threshold-dependent restored when blood flow was re-established above biochemical disturbances and demarcating the mis- the critical values. synthesis. between 17 and 20 ml/100 g/min can be tolerated for phological damage occur – was called the “ischemic prolonged but yet undefined periods. permitting neuronal recovery (Figure 1. . related to altered single-cell activity with grouped or the penumbra can be localized on quantitative flow regular discharges at flow levels above the threshold. In larger ischemic areas this final step is the respective lesion areas. It is characterized by the potential for disappeared at approximately 18 ml/100 g/min. in some instances critical.7). bra [59] (Figure 1. These mation (signals) lead to different thresholds of energy results broaden the concept of the ischemic penum- consumption and consequently blood flow required bra: the potential for recovery (or irreversible for preservation of neuronal function and morpho. function and the flow threshold for morphological and the spontaneous activity of cortical neurons integrity. It starts at low flow values (below 10 ml/ loss of ATP on bioluminescent images of tissue ATP 100 g/min) after short duration of ischemia with content. disturbance. The penumbra is the difference between ization. ischemic monkeys gradually developing a neuro. approach is supported by the precise co-localization tial. flow rates of 12 ml/100 for functional recovery without morphological g/min lasting for 2–3 hours lead to large infarcts. The interaction of severity and duration of ische. individual cells may become necrotic after shorter established at a sufficient level and within a certain periods and at higher levels of residual flow. Under experimental conditions opment of irreversible morphological damage is time. such as the stress protein hsp70 was studied by simultaneous recordings of cortical or the documentation of the gradual disappearance neuronal activity and local blood flow. flow below which irreversible membrane failure and mor. The reliability of this indicated by depolarization of the cortical DC poten. However. leading to delayed neuronal death in vulnerable brain logical deficit progressing from mild paresis at regions [58]. images using established flow thresholds. match between disturbances which occur only in the Whereas neuronal function is impaired immedi. time window [56. Concurrently the electrocorticogram and the evolved The ischemic penumbra is the range of perfusion between the flow threshold for preservation of potentials (EPs) were abolished at 15–20 ml/100 g/min. it is characterized by the potential in many experimental models. but damage. but not detrimental. The range of perfusion between residual flow but also by the duration of the flow those limits – a blood flow level below which neur. Based on of the penumbra with increasing ischemia time [60] 13 recordings from a considerable number of neurons (Figure 1. 57].6). indicating loss of bra is tissue acidosis or the inhibition of protein membrane function and leading to anoxic depolar. This explains the gradual development of Imaging of penumbra neurological deficits. provided that local blood flow can be re. The functional recovery without morphological large variability of the functional thresholds of damage. Each level of decreased flow can. 22 ml/100 g/min to complete paralysis at 8 ml/100 g/min. infarct core and others which also affect the penum- ately when flow drops below the threshold. Chapter 1: Neuropathology and pathophysiology of stroke Flow thresholds for preservation during and after ischemia of varying degree and duration it was possible to construct a discriminant of function and morphological integrity curve representing the worst possible constellation of The different energy requirements for maintenance residual blood flow and duration of ischemia still of membrane function and for propagation of infor. which might additionally be Based on the threshold concept of brain ischemia. The functional threshold was demonstrated in flow disturbance may trigger dynamic processes. A biochemical marker of core plus penum- leakage of Kþout of cell bodies. individual neurons (6–22 ml/100 g/min) indicates selective vulnerability even within small cortical sectors. of gene transcripts that are selectively expressed in mia in the development of irreversible cell damage the penumbra. the devel. the most reliable way to localize the infarct core is the dependent. Non-invasive imaging of the penumbra is possible The best-established NMR approach for penumbra using positron emission tomography (PET) or mag. Diagram of cerebral blood flow (CBF) threshold. alterations suppression of EEG and EP cessation of single cell activity 10 membrane failure single cell necrosis infarction 0 0 30 60 90 120 min 4 5 6 24 48 h time Blood flow Protein synthesis ATP penumbra core Blood flow Tissue pH ATP penumbra core Figure 1. imaging is the calculation of mismatch maps between netic resonance imaging (NMR). An alternative ficient (ADC) of water. hypoxic but not in normoxic or necrotic tissue [62].6. pathophysiology and imaging 50 Figure 1. The core is identified by ATP depletion and 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) (Hossmann and Mies [59]). has been questioned [63]. An alternative method is vation of vitality markers. 40 CBF (ml/100 g/min) normal function viable tissue 30 “penumbra” functional impairment 20 biochem. Widely used PET the signal intensities of perfusion (PWI) and parameters are the increase in oxygen extraction or the diffusion-weighted images (DWI). Biochemical imaging of infarct core and penumbra after experimental middle cerebral artery occlusion. which reveals a robust correl- PET approach is the use of hypoxia markers such as ation with the biochemically characterized penumbra 14 18F-nitromidazol (F-MISO). which is trapped in viable for ADC values between 90% and 77% of control [64]. such as flumazenil binding quantitative mapping of the apparent diffusion coef- to central benzodiazepine receptors [61]. but its reliability mismatch between reduced blood flow and the preser.7. Section 1: Etiology. Recently MR stroke imaging has been performed by . after 3 hours more (pHWI). During the of glucose and oxygen demands is coupled to a paral- subsequent subacute phase. where the mismatch between DWI and than 50% and between 6 and 8 hours almost all of pHW detects the penumbra. This is probably one of the reasons that core and penumbra. As a result. after 4–6 hours. Using multiparametric depolarization increases the infarct volume by more imaging techniques for the differentiation between than 20%. new developments in non-invasive the most important mediators of infarct progression molecular imaging are of increasing interest for will be discussed. Chapter 1: Neuropathology and pathophysiology of stroke combining PWI. edema. and that between PWI the penumbra has disappeared and is now part of the and pHWI the area of benign oligemia [65]. At flow values below the threshold energy demands of the activated ion-exchange of energy metabolism this injury is established within pumps. However. stroke research [66]. The reasons for this reversed [67]. During this phase secondary The pathogenic importance of peri-infarct depo- phenomena such as vasogenic edema. like depolarizations. molecular analysis of stroke injury. penumbra this flow response is suppressed or even core and penumbra merge. Non-invasive imaging of the penumbra is possible  delayed phase. a delayed and the stepwise increase in lactate during the passage phase of injury evolves which may last for several of each depolarization. cell injury. This growth is A functional disturbance contributing to the growth not due to the progression of ischemia because the of the infarct core into the penumbra zone is activation of collateral blood supply and spontaneous the generation of peri-infarct spreading depression- thrombolysis tend to improve blood flow over time. several days to weeks. Progression of ischemic injury With the advent of non-invasive imaging evidence has Peri-infarct spreading depression been provided that brain infarcts grow. The largest increment of infarct volume occurs Correlation analysis of this relationship suggests that during the subacute phase in which the infarct core during the initial 3 hours of vascular occlusion each expands into the penumbra. In the healthy brain the associated increase a few minutes after the onset of ischemia. days or even weeks. In the following. Finally. the infarct core expands lel increase of blood flow but in the peri-infarct into the peri-infarct penumbra until. inflammation and possibly programmed cell death. vasogenic using positron emission tomography (PET) or mag- netic resonance imaging (NMR). During the acute phase tissue injury is the over the entire ipsilateral hemisphere. the number of depolarizations and infarct volume. within 4–6 hours. leading to transient episodes of hypoxia referred to as molecular cell injury. the infarct core expands into the peri- infarct penumbra. During spread- direct consequence of the ischemia-induced energy ing depression the metabolic rate of the tissue mark- failure and the resulting terminal depolarization of edly increases in response to the greatly enhanced cell membranes. DWI and pH-weighted imaging as the infarct core [60]. Finally. a misrelationship arises expansion are peri-infarct spreading depressions and between the increased metabolic workload and the low a multitude of cell biological disturbances. inflammation larizations for the progression of ischemic injury is and possibly programmed cell death may contribute supported by the linear relationship between to a further progression of injury. collectively oxygen supply. within a few minutes after the onset status and/or bind to stroke markers. irreversibly damaged infarct core. These depolarizations are Infarct progression can be differentiated into three initiated at the border of the infarct core and spread phases. . terminal depolarization of cell of molecules that can be identified by these methods membranes. rapidly expands and greatly facilitates the regional  subacute phase. evidence could be provided that glutamate antagonists reduce the volume of brain 1 hour after occlusion of the middle cerebral artery infarcts because these drugs are potent inhibitors of 15 the penumbra is still approximately of the same size spreading depression. These methods make use of contrast probes that trace gene transcription or of Brain infarcts grow in three phases: intracellular conjugates that reflect the metabolic  acute phase. The number of ischemia. As the severity of acidosis correlates with the “molecular” does not anticipate any particular injury severity of ischemic injury. Section 1: Etiology.8) Acidotoxicity: during ischemia oxygen depletion In the border zone of permanent focal ischemia or and the associated activation of anaerobic glycolysis in the ischemic territory after transient vascular cause an accumulation of lactic acid which. and Spreading depression K+ Glu Na+ CYTOTOXIC EDEMA Signal transduction Glu DAG Gene expression Glu IP3 ER STRESS RESPONSE Protein synthesis inhibition EXCITOTOXICITY Stress protein expression Glu CALCIUM OVERLOAD MITOCHONDRIAL PERMEABILITY TRANSITION Ca2+ Ca2+ Energy failure Permeability Cytochrome C Glu transition release NECROSIS Enzyme induction Caspase 3 Membrane damage FREE RADICALS NAD depletion (ROS. cellular disturbances may evolve that on the severity of ischemia.8) are interconnected in complex ways. where the term 6.0. providing multiple approaches for the amelioration of both necrotic and apoptotic tissue injury. evidence has been (Figure 1. results in a decline flow or energy metabolism. focal ischemia is not equivalent to the alterations that occur in the core or the penumbra of permanent ischemia. depending occlusion. Schematic representation of molecular injury pathways leading to mitochondrial failure and the endoplasmic reticulum 16 stress response. blood glucose levels cannot be explained by a lasting impairment of blood and the degree of ATP hydrolysis. pathogenic importance in different ischemia models. the relative contribution of the Molecular mechanisms of injury following injury mechanisms differs in different types of ischemia. Recently. These disturbances are of intracellular pH to levels between 6. it has been postulated that pathway (Figure 1.8. The molecular injury cascades acidosis is neurotoxic. .8).5 and below referred to as molecular injury. pathophysiology and imaging Peri-infarct spreading depressions are depolariza. tions initiated at the border of the infarct core and In particular. Therefore. NO) APOPTOSIS Leukocyte Inflammation infiltration mediators DNA damage INFLAMMATION PARP Microglia activation Figure 1. provided that ASICs (acid-sensing ion channels) are which makes it difficult to predict their relative glutamate-independent vehicles of calcium flux. progression (Figure 1. molecular injury induced by transient may contribute to progression of ischemic injury. Injury pathways can be blocked at numerous sites. and the intracellu. Calcium-dependent pathological events are extracellular into the intracellular compartment. notably inhibition of protein receptors results in the inflow of calcium from the synthesis. intracellular calcium activity are highly pathogenic: and that this effect is the actual mechanism of acido. The latter may induce ischemic cell injury has been debated. Excitotoxicity: shortly after the onset of ischemia. species (ROS) are formed which produce peroxida- way. prolonged elevation of cytosolic calcium causes mito- toxicity [68]. calcium from endoplasmic reticulum (ER). nNOS in neurons a steep calcium concentration gradient of approxi. of NO synthase (NOS) acting on argenin. As glutamate antagonists NXY-059 [73]. Among these neurotransmitters. activation of calcium-dependent catabolic enzymes. The changes in suggests that acidosis may induce calcium toxicity. flow and the alleviation of hypoxic injury. highly efficient least three isoforms of NOS: eNOS is constitutively calcium transport systems ensure the maintenance of expressed in endothelial cells. explanation for this discrepancy is the above. At the onset of ischemia this induced injury. There are at Calcium toxicity: in the intact cell. An The therapeutic benefit of free radical scavengers. phages. as recently documented by the described pathogenic role of peri-infarct depolariza. is limited. therapeutic failure of the free-radical-trapping agent tions in infarct expansion. inhibit the spread of these depolarizations. to the formation of peroxynitrate. This of ion gradients (Ca2þparadox) [71]. chondrial dysfunction and induces catabolic changes. In endothelial cells the generation of NO cytosol and the endoplasmic reticulum (ER) on the leads to vascular dilatation. the induction of mitochondrial disturbances conditions. organelles [72]. Pathophysiologically. therefore complex and contribute to a multitude of leading to mitochondrial calcium overload and the secondary molecular injury pathways. The net effect of NO thus depends rise is further enhanced by activation of metabotropic on the individual pathophysiological situation and glutamate receptors which mediate the release of is difficult to predict. During ischemia anoxic depolarization in com. an improvement of blood other. and after Zinc toxicity: zinc is an essential catalytic and recovery from ischemia by activation of transient structural element of numerous proteins and a sec- receptor potential (TRP) channels which perpetuate ondary messenger which is released from excitatory 17 intracellular calcium overload despite the restoration synapses during neuronal activation. Chapter 1: Neuropathology and pathophysiology of stroke that blockade of ASICs attenuates stroke injury. notably by activation of Ca2þ-dependent effector excitatory and inhibitory neurotransmitters are proteins and enzymes such as endonucleases. the induction of endoplasmic reticulum that may prevail under certain pathophysiological stress. Free radicals: in brain regions with low or The activation of metabotropic glutamate receptors intermittent blood perfusion. however. glutamate results in violent biochemical reactions. The release of lar attention has been attributed to glutamate. reactive oxygen induces the IP3-dependent signal transduction path. and the inducible isoform iNOS mainly in macro- mately 1:10 000 between the extra. Cytosolic zinc . which also causes sions. The reaction with nitric oxide leads early genes (IEG) to adaptive genomic expres. damage DNA. at high concentrations is known to produce excito. NO has two opposing lar compartment on the one hand. resulting in the activation of their specific phospholipases. lipids and proteins. protein kinases and proteases that receptors. whereas bination with the activation of ionotropic glutamate in neurons it contributes to glutamate excitotoxicity and acid-sensing ion channels causes a sharp rise of and – by formation of peroxynitrate – to free-radical- cytosolic calcium [70]. The importance of excitotoxicity for and fragmentation of DNA. leading inter alia to the stress response of tive injury of plasma membranes and intracellular endoplasmic reticulum. but this does apoptosis and thus enhance molecular injury not invalidate the beneficial effect of glutamate pathways related to mitochondrial dysfunction. which mediates a great number of ER-dependent toxicity [69]. which calcium from the ER evokes an ER stress response. However. and between the effects [74]. antagonists for the treatment of focal ischemia. At high concentration. the Nitric oxide toxicity: nitric oxide (NO) is a product resulting injury is also reduced. particu. released. an apoptotic injury mechanism evolves donic acid. following quences of free radical reactions are the release pharmacological inhibition of ionotropic glutamate of biologically active free fatty acids such as arachi- receptors. and by induction of immediate. Secondary conse- primary neuronal necrosis. The activation of ionotropic glutamate secondary disturbances. other factors are also involved. inter alia. tigated in the search for possible pharmacological ition of polypeptidepol chain initiation. persistent inhibition of protein synthesis is metalloproteinase (MMP)-9. in consequence. the modulators of ischemic injury but the influence on adenine nucleotide translocator (ANT). Obvi. activate signal transduction pathways such as protein with aerobic energy production. MPT). molecules and mechanisms are involved in the by the ischemia-induced release of calcium stores progression of ischemic damage. therefore. ally will cause disruption of the outer mitochondrial protective properties. It is initiated A large number of biochemical substrates. The former stress. radical-mediated processes are. These changes are associated with either cell in permeability of the inner mitochondrial membrane death or survival and suggest that inflammation (mitochondrial permeability transition. D and other molecules. has been associated with the formation of a permeabil. therefore. and SUMOylation (i. as the interval disputed. indicating that cells may possess membrane and the release of pro-apoptotic mito- a specific zinc set-point by which too little or too chondrial proteins (see below). between onset of ischemia and cell death greatly A key player in the intracellular response to cyto- varies. Furthermore. kines is the JAK (janus kinase)/STAT (signal trans- Mitochondrial disturbances: the concurrence of an ducer and activator of transcription) pathway. throughout the interval from the onset of ischemia until the manifestation of cell death [37]. with the generation Other consequences of ER stress are ubiquination of free radicals in reperfused or critically hypoper- and trapping of proteins which are crucial for cellular fused brain tissue. The of ischemic injury. The PTP is thought to con. expression of stress proteins Inflammation and a global inhibition of the protein-synthesizing Brain infarcts evoke a strong inflammatory response machinery [76]. has been associated. SUMO).e. cyclophilin the final outcome is difficult to predict. as suggested by the beneficial effect of COX-2 translation arrest because protein aggregates include inhibitors. conjugation with the enzyme cyclooxygenase-2 (COX-2) and NF-kappa small ubiquitin-like modifier. . important sist of a voltage-dependent anion channel (VADC). been extensively inves- initiation factor eIF2. are strongly upregulated and may be neuro- is presumably the reason for the irreversibility of toxic. This again leads to selective inhib. which persists ways [78]. which increased cytosolic calcium activity with the gener. Inflammatory reactions and the associated free- ity transition pore (PTP). pathophysiology and imaging overload may promote mitochondrial dysfunction breakdown of the electrochemical gradient interferes and generation of reactive oxygen species (ROS). induces alterations in the pattern of gene transcrip- ation of reactive oxygen species leads to the increase tion. of ribosomes and inhibition of protein synthesis at the The inflammatory response of the ischemic tissue level of translation. a transcription factor that responds to oxidative suppression of most transcription factors. which causes phosphorylation ischemic brain injury. Infarct reduction was also observed after components of the translation complex [77]. the kinase C or enhance glutamate toxicity by inhibiting equilibration of mitochondrial ion gradients causes GABAA channels and blocking excitatory amino acid swelling of the mitochondrial matrix. mitochondrial disturbances thus contribute to Inhibition of protein synthesis: a robust molecular delayed cell death both by impairment of the energy marker for the progression of ischemic injury is state and by the activation of apoptotic injury path- inhibition of protein synthesis. Section 1: Etiology. genetic or pharmacological inhibition of matrix ously. which results in ER stress and various cell biological abnormalities such as misfolding of proteins. which causes B. Ischemia-induced much zinc can promote ischemic injury [75]. The prostaglandin-synthesizing function. which may be both neurotoxic and neuroprotective [80]. but this effect has been incompatible with cell survival but. The latter is due to the activation of which is thought to contribute to the progression of protein kinase R (PKR). with mitochondrial respiration and. which eventu- transporters. Gene expressions related to and inactivation of the alpha subunit of eukaryotic this response have. disaggregation targets (for review see Rothwell and Luheshi [79]). The increase in permeability 18 of the inner mitochondrial membrane has two Inflammatory reactions are important modulators pathophysiologically important consequences. However. zinc may also exhibit neuro. from the endoplasmic reticulum (ER). and it is further enhances the water content of the tissue. Inhibition of aquaporin ization and equilibration of ion gradients across the water conductance may. approx. It is an active process that requires intact disturbance initiates a vasogenic type of edema which energy metabolism and protein synthesis. which is the Early cytotoxic edema is caused by osmotically reason for the increase in signal intensity in diffusion. The shift of fluid is reflected by a decrease in the apparent diffusion coefficient of water. the volume increase of the edematous brain cing factor (AIF) and cytochrome c. in the activation of caspase 3. Similarly. therefore. anoxic depolar- plasma membrane [84]. cell swelling occurs porin channels may modulate the speed of edema at the expense of the extracellular fluid volume. in contrast to the early cyto. followed after some delay by a late vaso- increased at this time. is isoosmotic and accumulates (TdT)-mediated biotin-16-dUTP nick-end labeling mainly in the extracellular compartment. generation but not the final extent of tissue water leading to the shrinkage of the extracellular compart- accumulation. An endstage brain infarction is by far the most dangerous compli. but not to a change in the net water content. tration differences built up during ischemia. induced cell swelling. However. Their pathophysiological importance ment. This (TUNEL). caused by breakdown of the blood– blood flow persists. occlusion this increase starts within a few minutes after the onset of ischemia and causes a gradual increase in brain volume. an osmotically obliged cell swelling. brain barrier. aqua- In the absence of blood flow. The intracellular ition of sodium transport across sodium channels uptake of sodium is also associated with a coupled has been suggested to reduce edema formation. as the total tissue water content is toxic type. resulting in a laddered pattern of oligonu- craniectomy [82]. Both pathways tissue may be so pronounced that transtentorial involve a series of enzymatic reactions and converge herniation results in compression of the midbrain. 19 . the later vasogenic edema weighted MR imaging [64]. reduce the sever- cell membranes further enhance intracellular osmol- ity of ischemic brain edema. also vasogenic edema requires the passage ality and. However. initiated essentially by two pathways: an extrinsic Vasogenic edema reaches its peak at 1–2 days after death receptor-dependent route. cleosomal fragments as detected by electropho- Vasogenic edema. is. to a lesser metabolism causes an increase of brain tissue osmol- extent. It is initiated at flow values of situation from a “real” recovery to normal. as the driving force for the generation of gradient and which is referred to as “anomalous edema is the gradient of osmotic and ionic concen- osmosis”. this “malignant” form of contributes to the execution of cell death. Chapter 1: Neuropathology and pathophysiology of stroke Brain edema reverses the narrowing of the extracellular space and explains the “pseudonormalization” of the signal Ischemic brain edema can be differentiated into two intensity observed in diffusion-weighted MR imaging pathophysiologically different types: an early cyto- [83]. This stasis. and after 4–6 hours serum proteins matches cell proliferation to preserve tissue homeo- begin to leak from the blood into the brain. water is taken up from the blood. of water through aquaporin channels located in the At flow values below 20% of control. the blood–brain barrier grammed cell death that in multicellular organisms breaks down [81]. movement of water that is independent of an osmotic However. After MCA compartment. the high signal intensity genic type of edema. Apoptosis With the evolution of tissue necrosis and the deg. Apoptosis is an evolutionarily conserved form of pro- radation of basal lamina. the inhib- ality and the associated cell swelling. of this process is the ordered disassembly of the cation of stroke and an indication for decompressive genome. limited. If brain infarcts are of pro-apoptotic molecules such as apoptosis indu- large. 30% of control when stimulation of anaerobic The formation of cytotoxic and. a cystine protease which Under clinical conditions. hence. and an intrinsic the onset of ischemia and may cause an increase of pathway which depends on the mitochondrial release tissue water by more than 100%. if some residual is isoosmotic. resis or terminal deoxyribonucleotidyl transferase toxic type of edema. and accumulates in the extracellular and the net tissue water content increases. therefore. The cytotoxic type of edema is in T2-weighted images clearly differentiates this threshold-dependent. It has. mic cell death. ischemia induces a ischemia are not solely destructive but may also multitude of biochemical reactions that are reminis. appearing on a continuum with the tioning stimulus are activated by transcription two forms of cell death at its poles [86] (Figure 1. it is widely assumed to contribute to death. most of the cent of apoptosis. above-described injury pathways including ischemia c-jun. provided the initial injury remains sub- injury. such as the expression of p53. Conversely. may contribute to a certain extent to ische- the pathogenesis of diseases. However.9. exert a neuroprotective effect.and postconditioning with delayed injury protein synthesis is irreversibly The molecular signaling cascades initiated by brain suppressed (Figure 1. an active form of programmed cell logical cell death. This effect is called manipulation or pharmacological interventions reduces “ischemic preconditioning” and can be differenti- the volume of brain infarcts. factors. and in regions Ischemic pre. In the context of stroke this is difficult to understand because in areas with primary cell death the obvious cause is energy failure. therefore. Although apoptosis is mainly involved in physio. Non–NMDA APOPTOSIS NUCLEAR MORPHOLOGY NECROSIS Adult. The matrix shows possible combinations between nuclear and cytoplasmic morphologies near or at the terminal stages of degeneration [35]. all itself induce a transient state of increased ischemic of which correlate to some degree with the severity of tolerance. The concept of the apoptosis–necrosis continuum of neuronal cell death. NMDA APOPTOSIS MORPHOLOGY CYTOPLASMIC NECROSIS Figure 1. p38. including cerebral ische. inhibition of these reactions by gene liminal for tissue destruction. mia [85]. Section 1: Etiology. cycline-dependent kinase 5 or caspase 3.9). Apoptosis. pathophysiology and imaging Newborn. the transduction phase results in the . been ated into three phases: during the induction phase suggested that ischemic cell death is a hybrid of necrosis molecular sensors which respond to the precondi- 20 and apoptosis. In fact. JNK.9). p38 mitogen-activated protein kinase Experimental research has advanced our knowledge (MAPK) and Akt. This is especially true when die. particularly in unfolded protein response (UPR). major breakthroughs have synthesis. Recently. This phenomenon. relative size. e. regulation of the hypoxia-inducible factor 1 (HIF-1) Ischemia-induced neurogenesis is enhanced by in astrocytes. genic regions. has been associ. inflammation. to the course of a disease. One of the reasons is the differences between the brains of experimental animals and man with Short episodes of ischemia can improve the toler. To facilitate the transfer 21 generated neurons to the hippocampus and olfactory of knowledge from experimental neuroscience to . but it is repressed by activation exhibits potent neuroprotective effects. the subventricular zone (SVZ). in agreement with Cajal’s classic tigative procedures.1). but cannot be assessed lar (PPr) area. ance of brain tissue for subsequent blood flow gyrencephalic). cellular density. i. and it slowly mature neurons. Depletion of ER calcium stores causes accu. Neurogenesis may also occur within cerebral An important preconditioning pathway is the up. EOR triggers acti. Another puta. nitric oxide. which cannot be equally applied statement that in the adult brain “everything may in animals and patients. [89]. Several brain regions may provide lifelong supply of newly generated neurons. which provide lifelong supply of newly repeatedly and regionally. Translation of experimental ated with the phosphorylation of several prosurvival protein kinases. respect to evolutionary state (non-gyrencephalic vs. bid patients. by analysis of tissue samples. matter). The possibility of influencing about brain physiology and the pathophysiology of ischemic injury after the primary impact is challen. The other problem arises from the inves- ingly irresolvable. induces the activation of two highly conserved stress considerable expectations are placed on the trans- responses. should be related subgranular zone (SGZ) and the posterior perireticu. of the NMDA subtype of glutamate receptors.e. As the latter contributes to delayed ische. differentiate into glia and days after the preconditioning stimulus. This dogma was pathophysiological changes obtained by invasive pro- reversed by the discovery of three permanently neuro. termed “ischemic postconditioning”. not yet been achieved. experi- mental models in animals cannot be easily compared Regeneration of ischemic injury to complex human diseases often affecting multimor- Brain infarcts produced by focal ischemia are seem. anatomy (amount of gray vs. neurogenesis increases in these phase proteins with a protective impact are switched areas. The increase in ischemia tolerance appears 2–3 to the infarct penumbra. Chapter 1: Neuropathology and pathophysiology of stroke amplification of the signal. evidence has been provided that ische- mic injury can also be alleviated by repeated mechan. the ER overload response (EOR) and the plantation of neural progenitor cells. and during the effector bulb. such as extracellular signal-regulated concepts to clinical stroke kinase (ERK). brain disorders. and survive for at least several weeks disappears after 1 week. behind. cedures in animals. but the transfer of this knowledge ging but it remains to be shown for which kind of into clinical application is difficult and often lags clinical situation this finding is of practical relevance. Similarly. blood supply and metabolism (see Table 1. but this finding is debated. cortex.g. sary to explore the actual potentials of stroke regen- roprotective effect. additionally. combination with growth factors and/or strategies vation of the transcription factor NF-kappa B. However. ous hormones and neurotransmitters. After stroke. ical interruptions of blood reperfusion after a period of transient focal ischemia [88]. the by autoradiography or by histology. and some of the newly formed cells migrate on [87]. erative medicine. and vari- alia induces the expression of erythropoietin (EPO). and further research is neces- mic injury (see above) its reduction may have a neu. nothing may be regenerated”. white disturbance. The tive mechanism is the endoplasmic reticulum stress functional consequences of spontaneous or drug- response. and that permit recruitment of transplanted cells to the UPR causes a suppression of the initiation of protein site of injury. notably estra- which binds to the neuronal EPO receptor and which diol and dopamine. HIF-1 is a transcription factor that inter growth factors. enhanced neurogenesis are modest but optimism mulation of unfolded proteins in the ER lumen and is increasing for targeted interventions. range were included in the final cortical–subcortical Sequential PET studies of CBF. which MCA occlusion in cats could demonstrate the devel. but preserved ous variables from experiments to the course of dis. indicating the conversion into performed repeatedly without affecting or harming irreversible damage and the growth of the MCA infarct. OEF and CBV permitted the Positron emission tomography (PET) is the only quantitative method to reliably identify irreversible independent assessment of perfusion and energy tissue damage and penumbra. To this task of transferring experimental In experiments with transient MCA occlusion it could results into clinical application. In the 1980s. i. Positron emission tomography (PET) is still the Comparable to patients with early thrombolysis. The introduction of scanners with high ous tissue compartments within an ischemic territory: resolution (2. These facts stress the need opment and growth of irreversible ischemic damage.5 to 5 mm for human. Late CT or MRI often showed these with flow and oxygen utilization in the penumbra regions as morphologically intact.e. early ischemic stroke [91]. for a marker of neuronal integrity that can identify Immediately after MCA occlusion CBF within the irreversibly damaged tissue irrespective of the time supplied territory dropped. With time. but also large portions normal 40–50%). change in the ratio between glucose metabolism and even in early PET studies [90] preserved glucose con. However. metabolism. limits clinical applicability. and demonstrated the uncoupling of these usually closely related variables. Determination of oxygen utilization add- CMRGlc before and repeatedly up to 24 hours after itionally requires arterial blood sampling. by decreased flow. Central benzodiazepine receptor (BZR) ligands ing misery perfusion. PW-MRI. PCT). stroke: it is a complex methodology. can be used as markers of neuronal integrity as they . were obtained in ischemia models of baboons.e. reperfusion was initiated to tissue with increased OEF. and quantitative analysis necessi- for the evaluation of pathophysiological changes in tates arterial blood sampling. perfusion” and served as a definition for the penum. However. requires multi- PET with oxygen-15 tracers became the gold standard tracer application. 22 level. sion. oxygen utilization above a critical threshold. only method allowing quantitative determination of reperfusion could salvage ischemic tissue in the various physiological variables in the brain and was condition of “penumbra” (Figure 1. The regional decrease of cerebral by increased OEF.10). The quantitative measure- ment of CBF. penumbra tissue. PET has severe disadvan- sumption was observed in regions with decreased tages limiting its routine application in patients with flow in the first hours after the ictus. functional imaging be demonstrated that an infarct did not develop when modalities are successfully applied. indicat. i. 1 mm for animal irreversible damage by decreased flow and oxygen application) made PET a tool for studying animal consumption below critical thresholds. These studies provided data on flow and metabolic variables Prediction of irreversible predicting final infarction on late CTs (rCBF less than 12 ml/(100 g min). oxygen utilization. subacute or chronic stages of ischemic stroke (review In conclusion. and which are not invasive and can be ischemic territory. Section 1: Etiology. this pattern was coined “misery of utmost importance for the efficiency of treatment. PET permits the definition of vari- in Heiss [61]). Relatively preserved CMRO2 indicated The prediction of the portion of irreversibly damaged maintained neuronal function in regions with tissue within the ischemic area early after the stroke is severely reduced CBF. penumbra. anaerobic glycolysis by a in other studies (SPECT. pathophysiology and imaging clinical neurology it is necessary to develop methods OEF was decreased. which is characterized by increased oxygen cated that CMRO2 below 65 mmol/(100 g min) pre- extraction fraction (up to more than 80% from the dicted finally infarcted tissue. a process which started in the center which can be equally applied in patients and animal and developed centrifugally to the borderline of the models. CMRO2 less than 65 mmol/ tissue damage (100 g min)). CMRO2 and infarcts. misery perfu- models and to compare repeat examinations of vari. the object. Similar results applied extensively for studies in patients with acute. OEF was increased. luxury perfusion by flow increased blood flow (CBF) can be directly observed in PET as above the metabolic demand. As a consequence. CMRO2. expressed ease in humans. but CMRO2 was less elapsed since the vascular attack and irrespective of diminished and was preserved at an intermediate the variations in blood flow over time. Meticulous analyses of CBF and CMRO2 data indi- bra. the progressive decrease of CMRO2 and the reduction of OEF predicts final infarction. Sequential PET images of CBF. infarcts. irreversible necrotic neurons have permit a reliable estimation of critically decreased condensed acidophilic cytoplasm and pyknotic blood flow [93]. tissue can be salvaged (left cat and left patient in lower part of figure).e. Additionally. edema. tissue cannot be salvaged (right cat.10. PET with FMZ therefore can be age of vessels. hemorrhagic transformation and bleeding. Lipohyalinosis affects final infarcts. whereas intracerebral hemorrhages (5–15% of all strokes) result from rupture of arteries used as non-invasive procedure to image irreversible typically in deep portions of the hemispheres. match by PW-DW-MRI. nuclei. defects in FMZ binding were to atheromatous plaques with the potential for closely related to areas with severely depressed plaque disruption and formation of thrombus. FMZ distribution lesions and emboli from the heart cause territorial within 2 min after tracer injection was highly correl. It develops over years from initial fatty streaks [92]. This method yields sinuses or veins and are often accompanied by more reliable results than the determination of mis. damage and critically reduced perfusion (i. Chapter 1: Neuropathology and pathophysiology of stroke Figure 1. If reperfusion is achieved after this therapeutic window. Ischemic infarcts may be used as a relative flow tracer yielding reliable be converted into hemorrhagic infarctions by leak- perfusion images. in the patient the area with preserved OEF is finally not infarcted (outside area indicated on late MRI). In all patients. After successful testing in the cat MCA occlusion Atherosclerosis is the most widespread disorder model. penum- Venous infarcts usually result from thrombosis of bra) in early ischemic stroke. whereas preserved FMZ binding indi. cortical binding of flumazenil (FMZ) was leading to death and serious morbidity including investigated in patients with acute ischemic stroke stroke. leading to lacunar stroke. from oxygen consumption and predicted the size of the which emboli might originate. Primary ischemic cell death is the result of severe sion signal overestimate the volume of final infarct. where changes in the diffu. Delayed neuronal death can occur after 23 . CMRO2 and OEF of permanent MCA occlusion in a cat compared to images of a patient 12 hours after stroke: in the cat. The vascular cated intact cortex. whereas borderzone infarcts are due to low ated with CBF measured by H215O and therefore can perfusion in the last meadows. If reperfusion occurs before OEF is reduced. small vessels. early signs are potentially reversible swell- and changes in kinetics of Gd distribution do not ing or shrinkage. right patient). ischemia. bind to the GABA receptors abundant in cerebral Chapter Summary cortex that are sensitive to ischemic damage. and Computed Tomography. 316:1371–5. and Management. if hypertension. Pathophysiology. Blackwell Science. Nature Med 2002. clinical and tomographic 3. and outcome. Brain 1963. A case-control study. et al. Weir B. Rajamani K. range between these two thresholds was called the 12. treatment. Fisher M. Rossrussell RW. Nitric oxide insufficiency. Fisher M. features. 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Use of 2002. Phelps ME. An energy budget for signaling 89. brain injury. Simon RP. et al. Ho KL. Chapter 1: Neuropathology and pathophysiology of stroke 80. Bottger S. Magistretti PJ. Strasbourg: HFSP Workshop XI. Evolution of apparent cerebrovascular disease. et al. Biochem Soc Trans 2006. Thijs VN. Stroke 1995. 22:637–44. early in the twentieth century. Identification of the “undetermined” because multiple possible causes underlying cause is important for several reasons. and strokes that are pathophysiological mechanisms.1). Less common stroke syndromes). In about 20% of patients no clear cause of ischemic stroke can be identified Large artery atherosclerosis despite appropriate investigations. and the mechanism trum is much different. taking more recent It also helps for selecting patients for some specific advances in diagnostic tools into account [2]. this is labeled cryp. Ischemic stroke is not a single disease but a het. and undetermined cause [1]. In a further development It helps to group patients into specific subtypes for of the TOAST classification the “undetermined cause” the study of different aspects of prognosis. which category has been subdivided. probable. These three types account for about 75% of all ischemic strokes (Figure 2. and undeter-  intracranial small-vessel disease (lacunar infarcts). A computerized algorithm of this classification has dary preventive measures currently available. and definitions of sub- may be used for planning and information purposes. classification schemes were developed for use in clin- Cerebral infarction is generally caused by one of ical trials. there are several classification schemes for of extracranial atherosclerosis for ischemic stroke ischemic stroke based on the underlying pathophy. it was widely assumed that most cerebral (Chapter 9. small-vessel occlusion. other determined cause. other determined stroke. which divides ischemic stroke into atherothrombotic. they also form a useful framework for three pathogenic mechanisms: identifying causes of stroke in clinical practice. with arterial dissection as the of distal embolization in causing strokes was pro- most common single cause in patients <45 years of age posed. Atherosclerosis of the major vessels supplying the togenic stroke. Chapter 2 Common causes of ischemic stroke Bo Norrving Introduction in Acute Stroke (TOAST) classification. coexist in the same patient. which are among the most effective secon. and further defines categories fication of the mechanism of ischemic stroke should into evident. cardioembolic.  large artery atherosclerosis in extracranial and large intracranial arteries The TOAST classification divides ischemic stroke  embolism from the heart into atherothrombotic. These frequencies Although the common occurrence of atherosclerosis relate to ischemic stroke aggregating all age groups: in the region of the carotid bifurcation was observed in younger patients with stroke the pathogenic spec. cardio- This chapter focuses on the major causes of ischemic embolic. ischemic strokes were caused by in situ middle cere- As described in Chapter 8 (Common stroke syn. were not recognized until the mid-twentieth century 28 siology. types have been further refined. mined cause. small-vessel occlusion. About 5% of all ischemic strokes result brain is an important mechanism in ischemic stroke. Common and less common stroke syndromes cause. from more uncommon causes. Identi. and possible based on the level therefore be part of the routine diagnostic workup in of diagnostic support (Table 2.1). therapies. ischemic strokes that are “undetermined” because of erogeneous condition with several very different incomplete investigation. bral artery (MCA) thrombosis. The most widely used is the Trial of Organon with the advent of the diagnostic techniques of . The full implications dromes). been developed [3]. The latter are described in Chapters 8 and 9. category comprises both truly cryptogenic strokes. Although these clinical practice. Large-vessel disease may cause ischemia through embolism or reduction of blood flow. the intracranial vertebral sclerosis in other vascular beds. Other common large-vessel disease are usually platelet aggregates or extracranial sites are the aortic arch. it is strokes. Causative Classification System for Ischemic Graphic illustration of Stroke (CCS) [3]. and an additional 25–50% is rarer.2). affects the carotid siphon. Severe carotid stenosis (50–99%) is pre- tribute. . the major causes of ischemic stroke. and the basilar patients with TIA or stroke have a history of a symp. catheter angiography and later ultrasound. Emboli from external and internal carotid arteries. in Caucasian popu- anastomoses. Table 2. Prevalence of large atherosclerosis: cations of carotid surgery for carotid bifurcation disease. Severe atherosclerosis in the proximal MCA tomatic coronary event. About one-quarter of arteries as they penetrate the dura.1. the links with clinical syndromes. most often Patients with stroke often have generalized athero. large artery atherosclerosis is heart disease is somewhat more prevalent in patients estimated to account for about 30% of all ischemic 29 with large atherosclerosis of the cervical arteries. In many patients carotid or vertebral artery sent in 10–15% of patients with anterior circulation occlusion occurs without symptoms because good ischemic strokes. Intracranial atherosclerosis. the proximal thrombus formed on atherosclerotic plaques. The proportions are similar in patients with Willis. and the vertebral artery origins sclerotic debris and cholesterol crystals may also con. Although coronary arterial site. subclavian arteries. Large artery atherosclerosis Evident – probable – possible Cardio-aortic embolism Evident – probable – possible Small artery occlusion Evident – probable – possible Other causes Evident – probable – possible Undetermined causes unknown – cryptogenic embolism unknown – other cryptogenic unknown – incomplete evaluation unclassified commonly present also in patients with other stroke subtypes.and intracranial Large-vessel disease may cause ischemia through Symptomatic atherosclerosis is most common at the embolism (artery-to-artery embolism) or reduction of bifurcation of the common carotid artery into the blood flow (hemodynamic causes). artery. stenoses or result of embolism from the heart or a proximal silent myocardial infarcts [4. lations less common than extracranial. 5]. (Figure 2. Athero. with proportions increasing with collateral supply is provided through the circle of age. the external carotid artery and cortical pial TIAs. extra.1. Chapter 2: Common causes of ischemic stroke Figure 2. and the therapeutic impli. Overall. in Caucasians MCA occlusion is usually the have asymptomatic coronary plaques. the char- acteristics of thickness over 4–5 mm. carotid stenosis. Later studies have established that aortic arch atheroma is clearly associated with ische- mic stroke. non- calcified plaque and presence of mobile components are associated with a 1. Figure 2. intracranial large factors.3 times increased risk of recurrent stroke. and may explain the observation findings from different regions do not show a con. pathophysiology and imaging with cryptogenic strokes [7]. Intracranial athero. similar to the mechanisms in coronary artery sive disease are not fully understood: they are presum. early after a TIA and is much lower from 1–3 months and onwards [9. disease. Severe stenosis alters blood flow characteris- artery disease appears to be the most common stroke tics. diabetes and smoking. In Chinese and Japanese degree of stenosis exceeds about 70%. The underlying causes of racial differences in Plaque hemorrhage may contribute to thrombus for- the distribution of extracranial and intracranial occlu. atrial fibrillation. reduced smooth muscle content.6–4. For the long-term prognosis. Thrombosis at tively neglected disorder because of a research focus the site of an atherosclerotic lesion is due to interplay on the more accessible extracranial carotid artery between the vessel wall lesion. mation. Plaque instability appears to be a dynamic ably related to differences in risk-factor patterns but phenomenon [8]. that the risk of recurrent ischemic events is highest sistent pattern. 10]. and turbulence replaces laminar flow when the subtype worldwide [6]. possibly both by serving as a source of emboli and by being a marker of generalized large artery atherosclerosis including cerebral vessels.) Mechanisms of cerebral ischemia However. coronary heart disease.3). intracranial large artery atherosclerosis sclerosis appears to be much more common in the Artery-to-artery embolism is considered the most Asian and African-American population (Figure 2. At that time examin- ation of the aortic arch was not part of the routine echocardiographic examination. An extracranial carotid stenosis (degree of stenosis Protruding aortic atheromas are frequently found 67%) as visualized by MR angiography (left) and digital subtraction in stroke patients. ulceration. Plaque instability is character- Large artery atherosclerosis ized by a thin fibrous cap. Complicating thrombosis occurs mainly when the The link between atherosclerosis of the aortic arch thrombogenic center of the plaque is exposed to and ischemic stroke was not clearly recognized until flowing blood. (Courtesy Dr Mats Cronqvist. and in Korean studies up to a endothelium in the region of an atheromatous plaque. In stroke patients thick or complex aortic atheromas are associated with advanced age. 30 the early 1990s when autopsy studies revealed a high Reduction of blood flow in the carotid artery is prevalence of such lesions in particular in patients not affected until the degree of stenosis approaches . Platelets are populations intracranial atherosclerosis accounts for activated when exposed to abnormal or denuded up to half of all strokes. large lipid core.2. quarter. Protruding aortic atheromas (>4–5 mm) have been found to be 3–9 times more common in stroke patients than in healthy controls. the pattern of atherosclerosis is widely resulting from extracranial and different in other populations. blood cells and plasma occlusive disease lesions. due to large artery atherosclerosis. Section 1: Etiology. common mechanism of TIA and ischemic stroke Intracranial large artery disease has long been a rela. and a high macrophage dens- in the aortic arch ity. However. angiography (right). Blood flow in the carotid artery is reduced if sten- osis is more than 70%. Embolic and hemodynamic causes of point often forgotten. determining the likely cause if multiple potential In some cases of cardioembolic stroke the associ- causes are identified. some degree of atheroscler. corresponding to a luminal diameter of less than Cardioembolic stroke 1. However. This is certainly true for artery atherosclerosis ranges from asymptomatic several of the minor cardioembolic sources (see arterial disease. disease.5 mm. Furthermore. Clinical features of large artery Proportion of all strokes due atherosclerosis to cardioembolic stroke Large artery atherosclerosis is a prototype of stroke The proportion of strokes associated with cardio- mechanism that may cause almost any clinical stroke embolic strokes increases sharply with age. for which findings from case-control studies and ischemic stroke of any severity in the anterior show divergent results. Hemodynami- determinants. which is associated with several . As technology advances fur- and posterior circulation. Chapter 2: Common causes of ischemic stroke Figure 2. Less common clinical syn.3. below). the single most patients with ischemic stroke. ther more cardiac conditions that may constitute dromes due to large artery atherosclerosis. making cardiac disease the most ations because of the variability of the collateral common major cause of stroke overall – a practical circulation. Ultrasound studies with transcranial heart is of particular importance in ischemic stroke Doppler have documented the frequent occurrence for other reasons also: cardiac disorders (in particular of microembolic signals not associated with apparent coronary heart disease) frequently co-exist in patients clinical symptoms in patients with symptomatic with stroke and are important long-term prognostic ischemic vascular disease of the brain.g. because of the epidemiological characteristics in the osis in brain-supplying arteries is present in most population of atrial fibrillation. (Courtesy Dr Mats Cronqvist. The mechanisms. are detailed in Chapter 9. e. Cardiac disease is the most common cause of stroke overall. TIA affecting the eye or the brain.) 70%. raising the issue of common major cardioembolic source. Non-valvular atrial fibrillation ischemic stroke and TIA are not mutually exclusive is the commonest cause of cardioembolic stroke. It is also true 31 due to hemodynamic causes. with time an increasing proportion small emboli which are more likely to cause infarcts of new vascular events are due to coronary heart in low-flow areas [11]. The clinical spectrum of large ation may be coincidental. Whereas recurrent stroke is the most cally compromised brain regions appear to have a common vascular event during the first few years diminished capacity for wash-out or clearance of after a first stroke. those potential causes of stroke are detected. Stenosis of the middle cerebral artery visualized by MR angiography (left) and digital subtraction angiography (right). mainly syndrome. for atrial fibrillation. the degree of carotid stenosis cor- Cardioembolic stroke accounts for 25–35% of all relates poorly with intracranial hemodynamic alter- ischemic strokes. hypertension of AF for ischemic stroke is likely to increase even 32 (1 point). prosthetic heart valve. and in the highest age rillation patients. ventricular) and potential III Ventricular for embolism (high risk versus low or uncertain risk. recent myocardial infarc. age (1 point). European stroke registries. cardiomyopathy tion. dilated cardiomyopathy. Left ventricular myxoma Subaortic hypertrophic itis. this score takes the average age of stroke in general. They are commonly divided by origin endocarditis in the heart (atrial. depending on age and other asso. the individual risk The proportion of ischemic strokes associated of embolism in AF varies 20-fold among atrial fib. The importance congestive heart failure (1 point). fibrillation is associated with at least a five-fold increased risk of stroke. or major versus minor) (Table 2. In the general mary prevention setting.2. However. stroke due to its prevalence in the population and CHADS2 and other scores mainly refer to the pri- the substantial increase in stroke risk. infective endocard. Of the many schemes available. The mean age of embolism in AF risk stratification schemes have patients with stroke associated with AF is 79 years in been developed. and an arrhythmia of considerable importance for ischemic corresponds to 1. 1 point the population is increasing (because persons with AF . pathophysiology and imaging other stroke risk factors. the finding that anti- coagulant therapy reduces the risk of ischemic stroke High risk Low/uncertain risk by about 60% in patients with atrial fibrillation I Atrial suggests that the majority of strokes associated with atrial fibrillation are the result of cardiac embolism. (Modified from Ferro [21].4% annual stroke risk [13]. Epidemi- Atrial fibrillation carries at least a five-fold increased ological studies have shown that non-valvular atrial risk of stroke. valvular. Cardioembolic sources and risk of embolism. diabetes (1 point) and prior further in the future because the prevalence of AF in stroke and TIA (2 points) into account. people with AF are over 75 years of age.) general population. group >80 years about 40% of all strokes occur in ciated risk factors. To predict the future risk for patients with this arrhythmia [14].2). appendage thrombus cardiac thrombi. Atrial fibrillation Patent foramen ovale A recent autopsy study of patients with stroke dying Sustained atrial flutter Atrial septal aneurysm within 30 days showed that 70% of patients with a Sick sinus syndrome Atrial auto-contrast diagnosis of cardioembolic stroke in this study (based on cardiac conditions that may produce emboli in the Left atrial/atrial heart or through the heart) were found to have intra. Fifty-six percent of egories of very high risk. The clinically Left ventricular Akinetic/dyskinetic thrombus ventricular wall segment most important cardioembolic sources are non- rheumatic atrial fibrillation (AF). about 4 years higher than CHADS2 score is best validated. Infective endocarditis Fibroelastoma tute a source of embolus. myocardial infarct Dilated cardiomyopathy Atrial fibrillation Non-valvular atrial fibrillation (AF) is by far the commonest major cardioembolic source. Section 1: Etiology. Mitral stenosis Mitral annulus calcification Prosthetic valve Mitral valve prolapse Cardioembolic sources: major and minor There are several cardiac disorders that may consti. which were of similar composition Left atrial myxoma to persistent emboli detected in the major intracereb- II Valvular ral arteries [12]. Patients in whom cerebral population 5–6% of persons >65 years and 12% of embolism has occurred generally fall into the cat- persons >75 years have AF. intracardiac tumors Recent anterior Congestive heart failure and rheumatic mitral valve stenosis. with AF increases with age. However. and is very common in the Table 2. but not all sources pose Non-infective Giant Lambl’s excrescences equal threats. intracardiac thrombus from severe ventricular dys- which is of importance for therapeutic purposes. Any type of of thrombosis in lower limb. Concurrent venous thrombosis or pul- in Chapter 9 (Less common stroke syndromes). atrial fibrillation or endocarditis. pelvic or visceral veins prosthetic valve may be complicated by infective or pulmonary embolism. due to embolism. Par. However. Endocarditis and evidence mainly comes indirectly from statistical Infectious and non-infectious endocarditis is covered associations. tricular arrhythmias. preceding stroke onset. a cardiac right-to-left shunt. suggesting a cause-and-effect relationship stroke from PFO has not been precisely determined. Besides paradoxical embolism PFO may be linked Recent anterior myocardial infarct to stroke through causing a propensity for supraven- Ischemic stroke may occur in close temporal prox. 17]. but the recurrence. which may be due to the formation of embolism similar to the average risk for chronic AF. but despite therapy embolism paradoxical embolism. Long-term anticoagulant therapy cause. PFO is more commonly observed in patients embolism. monary embolism is rarely detected even in patients with a high suspicion of paradoxical embolism. Studies have reported a frequency of about 5% for ischemic Patent foramen ovale may cause strokes through stroke during the first few weeks after myocardial paradoxical embolism. Left ventricular mural thrombi it appears that mainly the coexistence of PFO and have been diagnosed by echocardiography in up to ASA is associated with a clearly increased risk of 20% of patients with large anterior infarcts. Patent foramen ovale (PFO) has been linked to ische- mic stroke mainly in young adults. endocarditis. Chapter 2: Common causes of ischemic stroke tend to live longer. By subsequent use of Holter monitoring and other monitoring techniques new AF is detected in at least Patent foramen ovale (PFO) and atrial 5% of all patients with ischemic stroke who are ini- septal aneurysm tially in sinus rhythm [15]. The long-term risk of recurrent infarct. Mechanical prosthetic heart valves are well recognized about twice the rate in the general population for their propensity to produce thrombosis and [16. and through thrombus from a imity (hours. which requires the coexistence occurs at a rate of about 2% per year. days. revised diagnostic criteria and subsequent observational and case–control stud- Five percent of ischemic strokes are related to a ies have questioned the overall role of mitral valve 33 myocardial infarct. After this period the stroke risk appears Mitral valve prolapse to be much lower. PFO may cause stroke through prosthetic heart valves. function. infarction. PFO has also been linked to migraine frequency has not been well determined in the cur. young persons. be associated with an increased risk of stroke per se. However. and a larger proportion of people Dilated cardiomyopathy are reaching a higher age). but recent studies have not confirmed this treatments and endovascular procedures in the acute association [19]. Dilated cardiomyopathies are a well-recognized cause Paroxysmal atrial fibrillation carries a risk for of embolism. weeks) to an acute myocardial coexisting ASA. and this association appears to hold also for is standard practice for patients with mechanical elderly patients [18]. (which increases the risk of stroke in young rent era of much more active antithrombotic drug adults). In con- oxysmal AF after ischemic stroke appears to be trast. hypertrophic cardiomyopathies appear not to undetected in a substantial proportion of patients. whereas tissue prostheses appear to have with cryptogenic stroke than in those with a known a much lower risk. the exact mechan- ism by which PFO may cause stroke is still not clear. phase of coronary heart disease. . prolapse as a cardioembolic source. and is probably related to the Early studies proposed mitral valve prolapse to be the presence of shared risk factors for coronary heart disease and ischemic stroke in the vast majority of major cause of unexplained stroke in particular in these patients. which should be considered in patients or cough or other Valsalva maneuver immediately who experience embolic events. in whom frequen- Prosthetic heart valves cies for this cardiac finding of up to 40% are detected. but this doctrine has not stood the test of time. In the anterior emboli from arterial sources.3. levels of the posterior circulation toms that were maximal from the beginning. common for embolism complex. or visual field defects gesting cardioembolism is very modest. fragmentation and subsequent embolus or early recurrence of embolism in the same spontaneous lysis of the embolus.4). sensory dysphasia. but more commonly they occlude because emboli from the heart tend to be larger than one of the main intracranial vessels. probably artery in the neck. Exceptions with gradual and stuttering progressive courses are cardioembolism. and may be due to distal migration of an distal propagation. high stroke severity. at only about Infratentorial ischemic stroke involving the cerebellum 50% [20. Section 1: Etiology. about 40% of . it should be borne in mind that Supratentorial stroke syndromes of isolated motor or the positive predictive value of clinical features sug. Large artery disease tends to Strokes due to cardioembolism are usually more be somewhat more common for anterior MCA severe than those from other causes. infarcts. Basilar Some patients with a major cerebral hemispheric artery occlusion presenting with sudden onset of stroke syndrome due to distal internal carotid artery severe brainstem symptoms is often due to cardioem- or proximal middle cerebral artery occlusion may bolism [27]. about twice as high in cardiac embolism compared to which may mimic peripheral radial or ulnar nerve other stroke subtypes [23].3). However. caused by more common than previously thought. Conversely. cardioembo. or multiple strokes almost always had a sudden onset of symp. factors of hemorrhagic transformation are decreased Cardioembolism is the cause of about a quarter level of consciousness. extensive early infarct signs in the MCA ters of cerebellar infarcts in the PICA and SCA terri- territory and delayed recanalization [24]. The rapid improvement is due to not rare. a phenomenon that has been labeled mic stroke have demonstrated that acute ischemic 34 “spectacular shrinking deficit” [25]. tories. top-of-the basilar imaging syndromes. ation has been thought to be due to leakage of blood In the posterior circulation cardioembolism is through a vessel wall with ischemic-induced increased no less frequent and tends to occur at charac- permeability. In patients with cardioembolism predictive from cardiac and arterial sources (Figure 2. Clinical and neuroimaging features Sudden onset of maximal deficit of cardioembolic ischemic strokes Although cardioembolism may cause almost any clin. and distal basilar artery occlusions. Hemorrhagic transformation are very unlikely to be due to cardioembolism. proximal of all lateral medullary infarcts. lesion [26]. some features are statistically Rapid regression of initially massive symptoms linked to this cause and are therefore characteristic (“spectacular shrinking deficit”) (Table 2. Cardioembolism is also The risk of early hemorrhagic transformation a recognized cause of the restricted cortical MCA (multifocal or in the form of secondary hematoma) is syndrome of acute ischemic distal arm paresis. partial (pial territorial) MCA infarcts due to more distal occlusions. Features suggestive of cardioembolic stroke. circulation cardioembolism and artery-to-artery lism may well cause TIAs. Hemorrhagic transform. Strokes due to cardioembolism Emboli from the heart may occlude the internal are usually more severe than average. but the process is likely to be much more teristic “embolic” sites. Neuroimaging finding of acute infarcts involving Traditionally it was thought that cardioembolic multiple vascular territories in the brain. vascular territory [22]. 21]. This clinical abnormalities involving multiple territories are much syndrome is usually. but not exclusively. whereas cardioembolism is more common in posterior MCA lesions. have rapid spontaneous improvement of neurological Studies with dw-MRI in patients with acute ische- deficits. pathophysiology and imaging Table 2. Decreased level of consciousness ical stroke syndrome. such as a lacunar syndrome found on dw-MRI to be due to a single small infarct. However. and about three-quar- occlusion. and the proportion of embolism are the two major causes of full MCA cardioembolic strokes preceded by TIA is similar to infarcts due to proximal MCA occlusion as well as findings in other stroke subtypes. some clinical and neuro- (PICA or SCA territories). these ische. who also coined the term acteristics of lacunar infarcts are based on quite few “lacune” from the autopsy finding of a small cavitation. Diagnosis and Management. However. Cambridge MA: Blackwell Science 1996). observations. hypertension. Posterior Circulation Disease. all patients have scattered lesions in one vascular Lacunar infarcts are small (<15 mm diameter) sub- territory or multiple lesions in multiple vascular ter. The arterial pathology is characterized by intracranial atherosclerosis (in situ atheroma either at the mouth or along the length Small-vessel disease of the penetrating vessel) and segmental arterial disor- Infarcts due to small-vessel disease of the brain were first ganization or lipohyalinosis secondary to the effects of recognized by French neurologists and neuropatholo. 1960s. Clinical Findings. In the current the main ischemic stroke subtypes was not clearly recog. Chapter 2: Common causes of ischemic stroke Figure 2. cortical infarcts that result from occlusion of a single ritories. (From Caplan LR.4. partly due to the difficulties in obtaining However. sule. Lacunar infarcts are usu- mic lesion patterns have been associated with ally located in the basal ganglia. penetrating arteries. corona radiate and the brainstem. the detailed microvascular char- gists in the nineteenth century.5). . internal cap- embolism from cardiac or large artery sources [28]. Main emboli recipient sites in the posterior circulation. thalamus. the importance of lacunar infarcts as one of adequate and timely autopsy specimens. era of better blood-pressure control lipohyalinosis nized until the investigations of C. Miller Fisher in the appears to have become rarer [29]. As should be logically plausible. who on the basis of careful clinico-pathological observations laid the foundation for our pathological Lacunar infarcts result from occlusion of single 35 understanding of lacunar infarction. penetrating artery (Figure 2. Face.e. disease. Bendikt’s syndrome. Classic lacunar syndromes When symptomatic. pathophysiology and imaging Clinical features Lacunar infarcts cause stroke. Section 1: Etiology. portion similar to cardioembolic stroke and infarcts The classic lacunar syndromes are further detailed due to large-vessel atherosclerosis. arm and leg involvement are characteristic of the first three syndromes. small-vessel occlusion. disease of the parent vessel (basilar branch occlusion) . dysarthria–clumsy hand syndrome. Occlusion of a branch artery at its origin by the small arteries of the brain (see Chapter 9). a pro. gender. penetrating artery. presumably most often due to occlusion of a small nant arteriopathy with subcortical infarcts and leuken. pure motor hemiplegia plus sixth demonstrated that the vascular risk-factor profile is nerve palsies) and isolated cranial nerve palsies (most not specific for lacunar infarction. In particular. About half of these patients go Figure 2. Sometimes patients present with a burst of dramatic TIAs with dense hemiparesis for 5–15 min- utes alternating with normal function – the “capsular warning syndrome”. caused by occlusion of single penetrating arteries. horizontal gaze palsy. Lacunar infarcts are also part infarct in the brainstem (visualized only by MRI). (Courtesy Professor Stig Holtås. though the mechanism is likely to 36 cephalopathy (CADASIL). Diffusion-weighted MRI of a lacunar infarct in the on to develop a lacunar infarct within the first 1–2 internal capsule. hypertension.) days. when they occur at strategic sites where descending and ascending long tracts are concentrated in their course subcortically or in the brainstem. five of which are well recognized: pure motor hemiparesis. Preceding TIAs occur in about 25% of all cases. limited. Descriptions include movement disorders smoking. Lacunar infarcts are formed on a risk-factor profile but the clinicopathological evidence for this is more that comprises age. and ataxic hemiparesis. Initial progression of the neurological def- icit is observed in up to 40% of all cases. The exact mechanisms of the progression for about one-quarter of all ischemic strokes. Patients with lacunar in Chapter 8. previous TIA and possibly ischemic heart such as chorea. hypertension was initially Brainstem syndromes (such as internuclear ophthal- thought to be a prerequisite for the development of moplegia. The most important clinical feature is the absence of cognitive symptoms or signs and visual field defects. pure sens- ory stroke. later studies have Claude’s syndrome. This is likely to be indirectly linked to the fact that cardioembolic sources Other clinical presentations of lacunar infarcts become more prevalent with age and consequently Several other rarer clinical syndromes may also be patients with cardiac embolism tend to be older. give rise to acute stroke symptoms. making Prevalence and risk factors lacunar infarct the most common subtype of progres- In most series lacunar infarcts are thought to account sive stroke. i. lacunar infarcts are associated with clinical “lacunar” syndromes. hemibalismus and asterixis. but is largely similar often third nerve palsies) may be caused by a micro- to other stroke types [30]. of the clinical spectrum of cerebral autosomal domi. However. dystonia. despite routine antiplatelet and even heparin therapies. diabetes.5. infarcts are on average a few years younger than patients with ischemic stroke in general. usually only shortly before the infarct occurs. sensorimotor stroke. are unclear [31]. a genetic disease affecting vary. Chapter 2: Common causes of ischemic stroke appears to occur more commonly in the posterior clinical and neuroimaging features that are compat- circulation than in the anterior circulation. of which are “lacunar”) are at least five times as common as symptomatic ones. which can be an incidental lacunar infarcts. MRI studies of the general population ual patient data from randomized controlled trials of have disclosed that most lacunar infarcts do not carotid surgery. Silent brain infarcts (95% infarct as defined by CT criteria [37]. of such ‘cryptogenic’ strokes are less than 5 mm in diameter. A causative rather than coinci- affect the long motor and sensory tracts in the sub. whether these mostly emboli from the bifurcation of the carotid findings are purely coincidental or represent the cause artery) 37 of the infarct is not clear. the identification of a potential 35]. survivors are classified as cryptogenic stroke. carotid artery ultrasound. cognitive decline and dementia [33]. Silent lacunar infarcts but large artery or cardiac causes of stroke are not Lacunar infarcts cause clinical symptoms when they always coincidental. In the acute stage the diameter should be less ones in cryptogenic stroke patients and for identifying than 15 mm. embolic source [36]. Chapter Summary Multiple overlapping causes of ischemic stroke The Trial of Organon in Acute Stroke (TOAST) classifi- In some patients multiple overlapping causes of ische. cation divides ischemic stroke into  atherothrombotic (30% of ischemic strokes. where ible with lacunar infarction may have associated find- the mechanism is more often in situ disease in pene.e. For example. linked to their clinical presentation. with dw-MRI may stem from unrecognized cardiac embolism in in no less than one-third of patients lesion patterns of younger patients. However. 4% of all stroke patients had small artery dis- tion of vasa vasorum to the peripheral nerve outside ease coexisting with large artery disease or a cardiac the brainstem is probably incorrect [32]. viduals. but it is a matter of debate which strokes should be labeled Specificity of the clinical lacunar syndromes cryptogenic – what level of evidence is needed for Studies have shown that the majority of patients with accepting a finding or risk factor as the “cause”? Such lacunar syndromes have dw-MRI findings suggestive of debate has surrounded PFO. Previous reports show that 20–25% of stroke than symptomatic ones. In one cranial nerve syndromes were usually caused by affec. but may extend up to 20 mm in some patients at high risk of recurrence would be clinically cases. ings of large artery atherosclerosis or a cardioembolic trating vessels. In such cases. and have been shown Cryptogenic ischemic stroke to increase the risk of vascular events (including Patients experiencing a TIA/stroke frequently have no stroke). The cause of stroke in such patients is difficult to establish on an individual basis. dental role of an ipsilateral carotid stenosis (70–99%) cortical areas. determined etiology after standard diagnostic evalu- Silent lacunar infarcts are five times more frequent ation. Because multiple small embolic infarcts are present underlying cause also relates to how far the diagnostic in a proportion of all patients presenting with a lacunar evaluations are pursued. is indirectly suggested by a pooled analysis of individ- However. patients with . mic stroke are identified. The infarct size shrinks by at least half from the most useful but are currently not available. ECG and cardiac detected by long-term rhythm monitoring in 23% of monitoring to detect atrial fibrillation should also be such patients in a recent study [38]. i. acute to the chronic stage. which showed that surgery was also produce acute stroke symptoms but are clinically beneficial in a subgroup of patients with a lacunar unrecognized or “silent”. Intermittent fibrillation was syndrome. and most late lacunar infarcts Many. if not most. that the imaged ischemic abnormal. study. and from subclinical aortic and multiple ischemic areas in the cortex or subcortex are large artery atherothrombotic embolism in older indi- seen. for distinguishing incidental PFOs from pathogenic ing artery. finding or possibly an underlying mechanism: methods ity is compatible with the territory of a single perforat. However. The old doctrine that isolated vascular source (most commonly atrial fibrillation). part of clinical routine in such patients. suggesting embolism as the underlying cause [34. 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Identification of embolic stroke patterns by 23. treatment may be started in the scanner while of CT and perfusion CT (PCT) in different ischemic the patient is undergoing PCT and CTA. hypoattenuation (hypodensity) is very specific and PCT examinations usually consist of two predictive for irreversible ischemia. CT scanning is initiated 7 seconds after injec- perfusion pressure with increased MCV and therefore tion of 50 ml of isoosmolar iodinated contrast mate- represents potentially salvageable tissue [1]. 3]. 4].1. arachnoid hemorrhage. The lowest of these eight false-negative NCCT in the subacute stage of ischemic cerebral CT sections usually cuts through the mid- stroke. For each edema without hypoattenuation indicates low series. The 40 . Patrik Michel The latter is preferable as it is quantitative and allows accurate identification of the ischemic Non-contrast CT (NCCT) penumbra [5]. Focal image acquisition and processing usually overlap. “fogging effect” relates to the potential disappearance Multidetector-array technology currently allows the of hypoattenuation from approximately day 7 for up acquisition of data from four adjacent 5–10 mm to 2 months after the acute stroke. and regional cerebral blood flow Non-contrast CT (NCCT) is highly accurate for iden. and is considered sufficient to a non-contrast baseline cerebral CT is immediately select patients for intravenous thrombolysis with followed by PCT. with a total of about 15 minutes from the start identifying acute intracerebral hemorrhage and sub. the other slices cover most of Prognosis in thrombolysed and non-thrombolysed the supratentorial brain. Then. Similarly. whereas early 40-second series separated by 5 minutes. or endovascular treatment and a contrast-enhanced CT of the brain are per- within 6 hours. mean tran- early ischemic signs [3. (rCBF). If the patient fulfils arachnoid hemorrhage. to the end of the examination. The approximate sensitivity NCCT. center of the large superior sagittal venous sinus. However. but quite insensitive for which is completely absent in a reference pixel at the detecting acute ischemia. but quite insensitive for criteria for intravenous thrombolysis based on the detecting acute ischemia. It may result in sections for each series. patients benefit from early the central volume principle to create parametric maps intravenous and intra-arterial thrombolysis despite of regional cerebral blood volume (rCBV). iv-RTP within 4. The rial into an antecubital vein using a power injector. helical CT scanner. CT  as dynamic perfusion CT with first-pass ANGIOGRAPHY bolus-tracking methodology. a CTA of the head and neck. tive estimation of the partial size averaging effect. Chapter 3 Neuroradiology PART A: IMAGING OF ACUTE Perfusion CT (PCT) ISCHEMIC AND HEMORRHAGIC PCT with iodinated contrast may be used in two ways:  as a slow-infusion/whole-brain technique STROKE: CT. patients is worse if there are clear early ischemic signs The perfusion CT data are analyzed according to on NCCT [2. The rCBV map is calculated from a quantita- tifying acute intracerebral hemorrhage and sub. NCCT can be performed in less than a minute with a In a patient with suspected acute ischemic stroke. It is a highly accurate method for formed. brain and hippocampi. stroke subtypes is depicted in Figure 3. PERFUSION CT.5 hours. sit time (MTT). (C) mean transit time.2D).0 ml/100 g represents separate reversible from irreversible ischemia [10. but this comparison still needs to be performed in acute stroke patients. 11] the rCBV threshold: pixels belong to the infarct core if and result in high inter-observer agreement [11].2. PCT has an overall sensitivity 100% of about 75% for ischemic stroke. and * 75% a high specificity for ischemia [7. ial curve. displayed in red (Figure 3. hemispheric hypoperfusion contralateral to the aura PCT data are from the ASTRAL registry. above 85% for non-lacunar supratentorial infarcts (Figure 3. and focal on non-contrast CT (NCCT) in territorial (continuous line) and lacunar hypoperfusion is rare [18]. which is sometimes still present after the resolution of the patients’ sym- 3h 12h 24h 7days ptoms [17]. 11 14]. also in white matter [9]. can then be displayed graphically (Figure 3. Threshold maps [6]. and (D) core infarct maps according to a threshold 41 model (Wintermark. MTT is the most sensitive measure for decreased Total ischemic area (penumbra and infarct) is blood flow but overestimates ischemia. tissue with low likelihood of survival (infarct core) is chymal time–concentration curves by a reference arter. PCT also « fogging » predicts mass effect in the MCA territory [15]. and for acute ischemic stroke [12]. symptoms is found [19]. occasional poorly delimited subacute phase on NCCT.1. Approximate likelihood of detecting ischemic stroke with epileptic seizures has been described. 2. rCBF is more defined as cerebral pixels with a greater than 145% specific in identifying salvageable tissue. and red: low likelihood of survival (infarct). found on awakening with aphasia and right hemiparesis. 8].1. Comparison of PCT with PET in healthy controls 50% shows that quantitative measures of blood flow are accurate [16]. Chapter 3: Neuroradiology MTT maps result from a deconvolution of the paren. A 77-year-old patient. the rCBF values can be calculated Raw maps of PCT images may be interpreted in from the rCBV and MTT values for each pixel using a non-quantitative way by comparing the different the following equation: rCBF ¼ rCBV/MTT. CBF CBV MTT A B C D (ml/100g/min) (ml/100g) (sec) Figure 3. .2A–C). and to the The 64-slice CT scanners allowing for eight or penumbra if the rCBV value is superior to the thresh. and rCBV is prolongation of MTT compared with the correspon. Finally. the rCBV value is inferior to the threshold. more brain slices have increased the detection rate old.1). NIHSS ¼ 20. The dotted line indicates approximate sensitivity of perfusion CT in non-lacunar supratentorial strokes. the most specific parameter for irreversibly damaged ding region in the contralateral cerebral hemisphere tissue [7. The maps parameters given in Table 3. In (D). PCT also shows brain perfusion alterations in about 25% of patients with TIAs. Within this selected area. which is now similar to that of DWI [13]. Ann Neurol 2002 [10]). green: reversible ischemia (penumbra). * indicates the fogging effect observed in the migrainous patients. Perfusion CT maps depicting (A) regional cerebral blood flow. (B) regional cerebral blood volume. Salvageable penumbra is displayed in green. During the aura of (dashed line) infarcts. Focal hyperperfusion in relationship Figure 3. dictor of outcome in this group [21]. It has these patients. rCBV and rCBF in case of Cerebral and cervical CT angiography is performed ischemia (comparison with contralateral homologous region). (B) CT angiography with occlusion of the middle cerebral artery (white arrow). and a high in predicting the clinical status and outcome [21]. and an acquisition delay of about 15 seconds. showing a small. This suggests encephalitis. . Perfusion CT (PCT) has an overall sensitivity of about 75% for ischemic stroke. Same patient as in Figure 3. Data acquisition Healthy parenchyma ¼ ¼ ¼ is performed from the origin of the aortic arch branch Penumbra "" # ¼ or " vessels to the circle of Willis and reconstructed as Infarct """ ## # maximum-intensity projections (MIP) (Figure 3. Lower row: (D) plain CT at 24 hours with a small left basal ganglion bleed (dotted arrow). a lacunar stroke. PCT predictors of treatment response are not yet established. The patient was then given intravenous thrombolysis with rTPA at 13 hours after going to bed and 2. above 85% for acute advanced functional imaging performs better non-lacunar supratentorial infarcts. As compared to standard imaging [3]. small PCT. The presence or absence of a large-vessel occlu- cortical stroke [12] or a stroke-imitating condition sion before thrombolysis was not a significant pre- (migraine.3E) and three-dimensional reconstructions (Figure 3. one might suspect were patient age and the total ischemia volume on a posterior fossa stroke. using intravenous administration of 50 ml of iodinated MTT rCBF rCBV contrast material at a rate of 3 ml per second. venous thrombosis. Acute recanaliza. partially hemorrhagic lesion. thrombolysis may be particularly effective tion treatments might be inappropriate in some of if an initial large-vessel occlusion is present. and (C) perfusion CT with threshold maps. specificity for ischemia.5 hours after awaking (approved study protocol with informed consent from 42 family).2. Upper row: imaging at 12 hours after going to bed: (A) plain CT.3B). rity in the acute stage. and do so better in left-sided infarctions [20]. Figure 3. Alterations of MTT. (E) CT angiography with repermeabilization. Section 1: Etiology. pathophysiology and imaging Overall. In a series of 75 patients [22]. and (F) diffusion-weighted MRI at 5 days. that i. conversion syndrome).1. been shown that thrombolysis saves salvageable tissue Baseline PCT volumes correlate with stroke seve. the best CT angiography Table 3.3. Todd’s paralysis. in the absence of an abnormality on PCT predictors for dependency (mRS > 2) at 3 months in a patient with stroke symptoms. as identified by PCT [23].v. whether ische- limited availability. more difficult patient monitoring. MR angiography (MRA) and con- hibits frequent use of PCT and CTA. and the longer time combining diffusion and perfusion-weighted MRI required for scanning [34]. A few pilot studies have considered its containing metastases may sometimes give false- predictive value [10. If threshold models are with higher risk of vascular malformations. 29]. Adding CTA can be useful in patients source images and DWI [28.) should probably receive neither within a few minutes.and CT-based of hematoma growth and poorer clinical outcome. Intracranial hemorrhage (ICH) can be diagnosed between PCT-MTT and PWI-TTP. The linear relationship between contrast concen. without stroke patients. or renal failure.and MR-based perfusion and arterial imaging including PCT [37]. Multiparametric stroke imaging pace-maker incompatibility. with moderate cooperation. indicate that there is no ischemia are feasible in the emergency setting. such as patients with ICH the site of arterial occlusion in acute ischemic outside the perforator (deep) localizations. the PCT core correlates well with DWI and PCT total ischemia with PWI-MTT [10. Practical aspects of acute stroke MRI MRA is probably more specific in diagnosing cervical Magnetic resonance imaging (MRI) can be used as artery dissections [33]. mic or hemorrhagic. 43 information about brain perfusion. PART B: IMAGING OF ACUTE tration and signal intensity is an important advantage ISCHEMIC AND HEMORRHAGIC of CT perfusion imaging over gadolinium-based MR perfusion imaging. 13]. Clot (ICH) is present on NCCT from its onset in virtually burden scores and collateral circulation [25] can all patients. Significant correlation has been demonstrated between PCT-CBV and DWI. Iodinated contrast ventional MR sequences such as fluid-attenuated can occasionally be associated with allergy. and the easy monitoring of patients. With regard to around the hematoma but rather point to edema information about brain perfusion. These drawbacks are counterbalanced by the availability of CT in most emergency rooms. thus providing a pathophysiological basis for rational . Whereas CTA better identifies arterial calcifications. metric MRI approach lies in the characterization of PCT appears to be at least equivalent to MRI for the lesion extension and of the stroke mechanism. One main advantage of adding iodinated contrast in ICH is that contrast extravasation (“leakage”) is an independent predictor Comparison of MR. with simi- Hyperintensity in acute intracranial hemorrhage lar accuracy compared to DSA and MRA [24]. and between CTA with NCCT. The advantage of a multipara- iodinated contrast agents nor gadolinium [36]. Adding CTA is debated. ANGIOGRAPHY Both CTA and MRA detect significant stenosis Jens Fiehler and vascular malformations quite reliably [24. It may constitute a target for aggressive antihypertensive acute stroke imaging or hemostatic therapy. PCT appears at least formation. Chapter 3: Neuroradiology CTA has been shown to identify the site of arterial CT and intracranial hemorrhage occlusion in acute ischemic stroke patients. the sole modality for the emergency imaging of patients with suspected acute stroke. used. 21]. hypertension. and of younger age. 32]. but its value for predicting positive results. but is probably treatment response remains insufficiently known [26]. Exposure to radiation pro- (DWI and PWI). Valid criticisms of MR imaging include its cost. Short acquisition times reduce motion arti- facts and enable the study of acute stroke patients easy accessibility. Both CT. 27–30]. Intraparenchymal calcifications or melanin- be assessed. although this seems to occur as the primary imaging modality in major stroke rarely [35]. equivalent to MRI [13. allowing a more quantitative STROKE: MRI AND MR estimation of cerebral blood flow [31]. useful in patients with higher risk of vascular malforma- CT angiography (CTA) has been shown to identify tions underlying the ICH. hyperthy- inversion recovery (FLAIR) is increasingly utilized roidism. Various radiological methods. its centers. Fast image reconstruc- Patients with known severe renal failure (creatinine tion makes the results of MRA or PWI available clearance <30 ml/min. Most patients with more and intracerebral hemorrhage proximal occlusions on MRA reveal a considerable Measurement of transverse relaxation times that char- lesion growth and a poor outcome [39]. The penumbra in acute stroke patients has been Multiparametric MRI (using a combination of defined as brain tissue with loss of electrical activity and diffusion. cell may be harmed [45. the anatomic location and time from of the vessel occlusion. 50]. 46]. traditional PWI > DWI mismatch [51]. A likely factor in these shortcomings is that the same degree of perfusion impairment might Magnetic resonance angiography (MRA) have a different impact on the tissue depending on In contrast to PWI. It is widely accepted that extension of recovery (FLAIR) can provide a characterization of the lesion in acute stroke as delimited in perfusion- the extension of the lesion and of the underlying weighted MRI (PWI) beyond the corresponding mechanism in acute stroke. The size of the thrombus – stroke onset. Both the volume and chronic hemorrhage. Another way to improve diagnostic accuracy is the use of multi- Perfusion-weighted imaging (PWI) variate prediction models that integrate all available imaging parameters into one prediction model [52]. increased oxygen extraction fraction in the presence However. the hypointense vessel sign in T2*-weighted of a perfusion deficit. such base- increase caused by slow-moving spins between two line MRI findings can identify subgroups that are likely diffusion-sensitizing magnetic field gradients. This PWI > DWI mismatch has been used. In a recent prospective study it has through the capillary bed and reflect several aspects been shown that MRI is more effective than plain CT of cerebral perfusion such as cerebral blood volume for detection of acute ischemia. Especially for DWI is based on the additional signal intensity stroke patients treated 3–6 hours after onset. However. and because of noted overesti- above normal ranges (cell lysis and necrosis). MRA directly reveals the location patient age. Without acterize the signal loss caused by local susceptibilities MRA available signal intensity changes within vessels (T20 ) is sensitive to changes of the local concentration (“vessel signs”) in conventional MRI sequences can be of deoxy-Hb in brain tissue as a direct indicator of an helpful in diagnosing the site of vessel occlusion.and perfusion-weighted MRI (DWI and potential recovery after timely recanalization of the PWI)). 42]. related to the site of vessel occlusion in MRA – is an important determinant of vessel recanalization rates and cannot be derived from diffusion or perfusion- Susceptibility-weighted imaging weighted imaging alone. ICH. and T20 lesions exceeding the MRI and the hyperintense vessel sign in FLAIR do not dimensions of the corresponding ADC lesion were a independently predict recanalization. and “pseudonormaliza. validated Diffusion-weighted imaging (DWI) and refined in several studies [42–44]. lesion boundary in diffusion-weighted imaging (DWI) is indicative of the penumbra [41. at follow-up imaging. it should be the preferred and the severity of the initial perfusion deficit are test for accurate diagnosis of patients with suspected associated with the growth of the initial DWI lesion acute stroke [38]. for example in . mation of the extent of infarction seen at follow- up [49. and can detect acute and flow and the mean transit time. or clinical more specific predictor of infarct growth than the outcome [40]. imaging may still be normal. MR angiography (MRA) and conventional MR sequences such as fluid-attenuated inversion occluded artery. pathophysiology and imaging decision-making. 48] on the grounds that the PWI lesion cannot tion” after 1–10 days (increased extracellular water discriminate reliably between benign oligemia and content ¼ vasogenic edema) followed by a further rise true penumbra. DWI to benefit from reperfusion therapies and can poten- signal intensity in acute stroke reveals a typical tially identify subgroups that are unlikely to benefit or sequel of an early decrease (minutes to <1 hour. the PWI > DWI depolarization and cytotoxic edema) when T2w mismatch concept has also been challenged [47. Section 1: Etiology. and the mismatch concept In the future such information might be most bene- 44 PWI maps are derived from the signal intensity ficial in patients where the decision whether or not change caused by the passage of contrast agent to treat with thrombolysis is difficult. and distribu. 55]. Kim EY. Regional blood flow (rCBF) is more specific MRI only. 2004. On DWI SDHs early decrease of signal intensity in acute stroke when appear hyperintense and on T2*-weighted images T2w imaging may still be normal. and that MRI in fact may be superior [53]. A mismatch of DWI to SDHs [56]. patients. Subdural stroke: MRI hematomas (SDHs) and subarachnoid hemorrhages The advantage of a multiparametric MRI approach (SAHs) can be identified reliably by using appropriate lies in the characterization of the lesion extension MRI techniques. . ASPECT Perfusion CT (PCT) has an overall sensitivity overview of NINDS. Imaging of acute ischemic and hemorrhagic stroke: CT Non-contrast CT (NCCT) is highly accurate for identifying acute intracerebral hemorrhage and subarachnoid hemorrhage. the cerebral microbleeds (CMBs). though). Levine S. Radiology 2005. In the hyperacute setting SDHs are and of the stroke mechanism. imaging nulls the effect of cerebrospinal fluid. CT sign of brain (hypodensity) is very specific and predictive for irre- swelling without concomitant parenchymal versible ischemia. Hill MD. Canada. Adding CTA is probably useful in patients with lation/antiaggregation therapy or after thrombolytic higher risk of vascular malformations underlying the ICH. With the brain parenchyma diagnosed in T2*-weighted regard to information about brain perfusion. Hyperintensity in acute intracranial hemorrhage CMBs are associated with a higher risk of a clinically (ICH) is present on NCCT from its onset in virtually all relevant intracerebral hemorrhage after anticoagu. NCCT is considered sufficient hypoattenuation: comparison with diffusion. within 6 hours. above 85% for Symposium. Threshold maps rhages. ECASS. et al. bral blood volume (rCBV) is the most specific param- especially for the detection of small chronic hemor. and ATLANTIS. For the evaluation of intracranial hemorrhage Mean transit time (MTT) is the most sensitive (ICH) clinicians have traditionally relied on CT. The best imaging sequences for and PWI in the extension of the ischemic lesion is MRI-based SAH detection are FLAIR and proton indicative of the penumbra (this concept has also density-weighted images [57]. with similar accuracy compared to DSA and MRA. the site of arterial occlusion in acute ischemic stroke Current data do not support the hypothesis that patients. Recent studies suggest that this is not the in identifying salvageable tissue. Ryoo JW. but quite insensitive for detecting acute ischemia. SDHs Diffusion-weighted imaging (DWI) reveals a typical are best appreciated on this sequence. been challenged. and regional cere- case. Focal hypoattenuation References 1. The presence of mixed ance angiography (MRA) directly reveals the loca- signal intensity within the SDH may indicate the tion of the vessel occlusion.5 hours or endovascular treatment 235(3):992–48. and a high speci- risk of bleeding complications.and to select patients for intravenous thrombolysis with perfusion-weighted MR imaging. ficity for ischemia. TAST 45 of about 75% for ischemic stroke. eter for irreversibly damaged tissue. number. Since FLAIR physiological basis for rational decision-making. iv-RTP within 4. Perfusion-weighted imaging (PWI) reflects several aspects of cerebral presence of blood with different ages and MRI may perfusion such as cerebral blood volume and flow emerge as a tool in selecting the therapeutic approach and the mean transit time. Magnetic reson- they tend to be hypointense. history as well as the location. in measure for decreased blood flow but overestimates fear of missing or misdiagnosing an ICH by utilizing ischemia. Na DG. 2. therapy in stroke patients. Chapter 3: Neuroradiology a patient arriving after >3 h or with known elevated non-lacunar supratentorial infarcts. Cerebral microbleeds. PCT MRI should be interpreted in the light of the patient’s appears at least equivalent to MRI. Whistler. thus providing a patho- best demonstrated on FLAIR sequences. CT angiography (CTA) has been shown to identify tion of the lesions and associated imaging findings. von Kummer R. et al. sub- dural hematomas and subarachnoid hemorrhages Chapter Summary can be identified reliably by using appropriate MRI techniques (fluid attenuated inversion recovery (FLAIR) and proton density-weighted images). CMBs in separate reversible from irreversible ischemia. and thus do not support the general exclusion of patients from therapy Imaging of acute ischemic and hemorrhagic based on the presence of CMBs [54. 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Hacke W. Schwark C. et al. 7:299–309. 50:729–40. Radiology 30. Liu Y. Boulanger JM. Fiehler J. Thomalla G. perfusion-weighted imaging: MR imaging in acute improvement or recovery of neurological deficits stroke patients without vessel recanalization. 57. Albers GW. RECOVERY demonstrate recruiting and compensatory mecha- AND REHABILITATION nisms in the functional network responsible for Wolf-Dieter Heiss complete or partial recovery of disturbed functions. pathways may be accompanied by the development 248:979–986. 38:2738–44. Banno T. Mayer TE. Surgical treatment of their reorganization in the recovery after focal chronic subdural hematoma based on intrahematomal brain damage is the domain of functional imaging membrane structure on MRI. especially the Radiology 2002. Fiehler J. et al. (eventually with follow-up). Only a few studies have been performed applying Role of functional imaging this last and most complete design together with extensive testing for the evaluation of the quality of in stroke patients performance finally achieved. Starkman S. of different strategies to deal with the new functional- 52. Section 1: Etiology. Kucinski T. Bruckmann H. cerebral cortex. Gass A. 1:122–30. Saver JL. disturbed interaction in functional networks and of Matsumoto T. Kidwell CS. comparing location and extent to deficit and outcome 96:684–9. JAMA task. discussion 618–19. Medele R. they before thromboLysis (BRASIL): pooled analysis of T2*-weighted magnetic resonance imaging data from change over time and thereby are related to the course 570 patients. Fiehler J. The observed patterns 55. Dijkhuizen RM. anatomical situation at the behavioral level. in long-term recovery. the sprouting of fibers from surviving neurons physiological heterogeneity of infarction risk in acute and the formation of new synapses could play a role human ischaemic stroke using MRI. pathophysiology and imaging growth in hyperacute stroke? Comparative study tissue damage. Since destroyed tissue usually S. Bleeding risk analysis in stroke imaging the dynamics of the development of the lesion. can be achieved only by reactivation of functionally Am J Neuroradiol 2005. Comparison of MRI and CT for within the functional network involved in a special detection of acute intracerebral hemorrhage. and also the type and Hjort N. Wegener the functional network. and therefore functional imaging tools can be 2004. magnetic resonance imaging. Fitting T. Fiehler J. Siemonsen S. after stroke) to IN ACUTE STROKE.g. Detection of hyperacute disturbed function and altered brain activity studies subarachnoid hemorrhage of the brain by using can be designed in several ways: measurement at rest. Wu O. Naumann D. These compensatory mecha- 129:2384–93. Knab R. localized brain damage. Tissue at risk is overestimated in cannot be replaced in the adult human brain. disturbed but morphologically preserved areas or 51. T20 imaging predicts infarct growth beyond the acute diffusion-weighted functional network. Wiesmann M. Stroke 2007. J Neurosurg 2002. Hill MD. Derex L. Christensen S. and of the non-affected elements of 50. Hjort N. Chalela JA. by recruitment of alternative pathways within the Finsterbusch J. recovery depends on the adaptive between relative and quantitative measurements. Additio- Kucinski T. Brain 2006. flow or metabolism at rest and during activation Demchuk AM. 143:613–18. and measure- PART C: FUNCTIONAL IMAGING ment at rest and during activation tasks early and later in the course of disease (e. measurement during activation tasks. 223:361–70. 26:815–19. Acta Neurochir (Wien) modalities such as PET and functional magnetic 2001. This activation of alternative imaging lesion in acute stroke. and the recovery of a deficit. Schoder V. depend on the site. et al. Mase M. applied successfully for studying physiological corre- 54. 48 The functional deficit after a focal brain lesion is A large amount of data has been collected over determined by the localization and the extent of the the past years with functional imaging of changes in . et al. et al. The visualization of 56. Yamada K. et al. Horn P. Int J Stroke 2006. Tanikawa M. comparing changes in activation patterns to functional performance. resonance imaging (fMRI). the extent. Yousry I. Summers P. Characterizing nally. nisms are expressed in altered patterns of blood 53. Yamashita N. Cerebral microbleeds: old leaks and new lates of plasticity and recovery noninvasively after haemorrhages. et al. Radiology 2008. For the analysis of the relationship between Hamann GF. plasticity of the undamaged brain. 292:1823–30. of CMRO2 as a measure of brain function. and (iv) a lumped constant correcting a specific state. an on-site cyclotron is necessary. as introduced for autoradiographic fractions (OEFs) into images of CMRO2 as given by experimental studies by Sokoloff et al. The cerebral metabolic rate for (123 seconds). FDG is transported across the Functional activation studies as they are used blood–brain barrier and into brain cells. e. the FDG method has been employed metabolic scans. repeat studies can be activation studies using positron performed [10. the increase in oxygen consumption is remains quite stable between 30 and 50 minutes considerably delayed. Whereas it is well docu- fructose-6-phosphate analog.g. Mapping of neuronal activity O-labeled molecular oxygen. Because of imum of 12 doses of 15O labeled tracers.g. task or stimulus in comparison to for the differing behavior in brain of FDG and the resting condition. Various PET methods have been developed for emission tomography (PET) determining the cerebral metabolic rate for oxygen The energy demand of the brain is very high and (CMRO2). is phosphorylated by hexokinase. which is converted into water by carbonic tional networks and of their reorganization in the recovery after focal brain damage is the domain of anhydrase in the lungs. Like glucose. two assumptions. the time to metabolic equilibrium Almost all commonly applied methods for the (20–40 min) must be taken into consideration. leading to a decreased oxygen after intravenous tracer injection. consumption. 11]. because of the short biological The principle of functional and half-life of the radiotracers. multiple intercalated scans. if required. can quantify changes activity concentration measured with PET during in CBF and CMRGlc accompanying different acti- this steady-state period. and. and does not diffuse mented that increases in blood flow and glucose out of the cells in significant amounts. this glucose (CMRGlc) can be quantified with PET using and other methodological complexities limit the use 2-[18F]fluoro-2-deoxyglucose (FDG) and a modifi. Because 15O has a short half-life by Reivich et al. e. The distri. Due to the radioactivity of the necessary tracers. Applica- cation of the three-compartment model equation tion of this method for detection of penumbra tissue developed for autoradiography by Sokoloff et al. (ii) the concentration–time vation states of brain tissue. FDG-6. Typical measuring times range between 40 seconds and 2 minutes. and color-coded maps can be glucose. The regional values of course of tracer in arterial plasma. Using (i) the local radio. administered either directly by intravenous bolus injection or by the inhalation of 15O-labeled carbon The visualization of disturbed interaction in func- dioxide. (iii) plasma glucose CBF or CMRGlc represent the brain activity due to concentration. local for positron emission tomography (PET) in humans OEF and local CBF. PET detects and. assuming a close association between energy metab- phosphate cannot be metabolized to its respective olism and blood flow. Using 15O-labeled water function after stroke [1–6]. CMRGlc can be computed pixel by pixel analyzed or correlated to morphological images. or two doses of 18F-labeled tracers. concentration–time curves in arterial plasma and brain. Chapter 3: Neuroradiology activation patterns related to recovery of disturbed of diffusible tracer exchange. CBF can be estimated from functional imaging modalities such as PET and steady-state distribution or from the radioactivity functional magnetic resonance imaging (fMRI). The resulting pseudocolor-coded images reflect all activation studies with PET are limited to a max- effects on cerebral glucose metabolism. All require the con- in the brain can be primarily achieved by quantitation current estimation or paired measurement of CBF of the regional cerebral metabolic rate for glucose in order to convert the measured oxygen extraction (rCMRGlc). where it now rely primarily on the hemodynamic response. Especially for studies of glucose in many PET studies. 12 flow its robustness with regard to procedure and model scans. [7] and adapted the product of arterial oxygen concentration. [8]. thus permitting extraction fraction (OEF) during activation [13]. consumption are closely coupled during neuronal bution of the radioactivity accumulated in the brain activation. [7]. as 49 quantitative imaging of CBF are based on the principle well as the time interval between measurements . using continuous [11] or single-breath relies almost entirely on the oxidative metabolism of inhalation [12] of air containing trace amounts of 15 glucose (see Chapter 1). according to an optimized operational equation [9]. However. is described in Chapter 1. 11C. Approxi. and the activation paradigm must be magnetic properties of oxygenated and deoxygenated restricted to passive movement or imagination of hemoglobin. The diverging experimental con- (BOLD) signal. This means that mainly the different studies extremely difficult. tical representations and complex fiber tracts. O2 to the tissue (CMRO2) and on the cerebral blood PET used to quantify the regional concentration of volume (CBV) [15]. 18F) which are characterized by a unique in brain function. niques. pathophysiology and imaging required for isotope decay (HT for 18F 108 min. Typical in-plane resolution (full width at half-maximum) is Motor and somatosensory deficits <5 mm. 3D data accumulation and reconstruction Motor function may be impaired by damage to a permits imaging of the brain in any selected plane widely distributed network.g. State-of-the-art PET scanners are (TMS). There are some advantages of PET. labeled probe molecule. using CT-like algorithms and reliable scatter and attenuation corrections. Color-coded maps of different activation states of the involvement of deep gray structures. the basal brain tissue can be analyzed or coregistered to ganglia. Section 1: Etiology. equipped with thousands of detectors arranged in up to 24 rings. e. the associ- and quantify changes in cerebral blood flow (CBF) ation of lesions in cortical areas and in fiber tracts and and cerebral metabolic rate of glucose (CMRGlc). radioactive tracers can be used to detect recovery depends on the site of the lesion. simultaneously scanning 47 slices of Functional MRI (fMRI) detects changes in brain function by measuring differences in magnetic <5 mm thickness. involving multiple cor- or view. two 511 keV (kilo electron volt) photons that are better signal-to-noise ratio. which can be superimposed on the decay scheme. it has lost so much and more flexible experimental set-ups. Pseudocolor-coded tomographic properties of hemoglobin depending on the blood images of the radioactivity distribution are then oxygen level. for oxygenated arterial blood (CBF). activated and reference values – which support its limated (convergent) detectors facing each other. color-coded to produce fMRI images that map changes 15 O.e.g. As fMRI does not involve ionizing radiation atomic nucleus. termed the blood-oxygen-level-dependent motor performance. and might help 50 amount of deoxyhemoglobin in small blood vessels explain the lack of a clear concept of “neuronal plas- is recorded. 13N. which gives an estimate of changes in ditions make the interpretation and comparison of oxygen availability [14]. This results in a spatial resolution of particle of the mass of an electron. the annihilation of the two oppositely charged par. The magnitude of these changes these tracers relies on the labeling of the compounds in signal intensity relative to the resting conditions is with short-lived cyclotron-produced radioisotopes (e. altered metabolism and blood flow and the patterns of activation after stimuli or during motor tasks are manifold and reflect the site and extent of the lesion. is emitted from a fMRI of 1–3 mm with a temporal resolution of approx. it has become energy that it combines with an electron. however – ticles by the emission at an angle of 180  0. and in combination with special stimulating tech- ized directly to the straight line between these coin. better quantitation. ticity” applicable to recovery from motor stroke . i. The degree of motor impairment and the potential for In PET. Following emission from the 10 sec. The patterns of morphological images. imaging (fMRI) patients cannot carry out complex or even simple fMRI measures signals that depend on the differential motor tasks. the origin of the photons can be local. fewer artifacts. continued use especially in complex clinical situations Therefore. reconstructed from the many projected coincidence counts by a computer. subjects. which depends on the flow of well. With severe motor impairment. using pairs of uncol. Functional magnetic resonance but they are also dependent on the paradigm of stimulus or task. A positron. and allows more rapid signal acquisition mately 1–3 mm from its origin. resulting in the dominant technique for functional imaging. actual recorded as coincident events. the positron takes a path marked by and thus is also used without limitation in healthy multiple collisions with ambient electrons. a positively charged anatomical image.5 of physiologically specific measures. on the outflow of 15 O 2 min). such as transcranial magnetic stimulation cidence detectors. thalamus and brainstem. also seen in premotor and insular cortex. 5. the systems of the paretic and non-paretic limb. or use of collateral pathways in the activity was found [21]. In addition to stronger intensity. ipsilateral sphere actually inhibits the generation of a voluntary activation of motor cortex is consistently found to be movement by the paretic hand [23]. These results indicate that recruitment of ipsilateral cortices During recovery from hemiparesis. It was also shown that fMRI or PET studies involving active or passive the over-activation observed a few weeks after a movements. (ipsilateral) to be a compensatory cortical process related to the premotor cortex. an effect probably parallel processing. this anterior parts of the insula/frontal operculum. The areas included mechanisms appearing even late in the course frontal and parietal cortices. stantial changes in the activity of the proprioceptive bral cortex. spheric reorganization of motor networks during ment of entirely new motor networks” [2]. 6. These fMRI studies demonstrate that increasing corticospinal damage leads to a shift in the pattern of activation from the primary to the secondary motor system. a widespread network of neurons was stroke diminishes over time. and sometimes the basal (Figure 3. A recent review con. Newly (Figure 3. . Reco- unaffected hand (as in normal subjects) were accom.5) [22]. by which an reorganization. reflecting spatial extent of activation in motor cortex was an interhemispheric shift of attention to propriocep- enlarged. a variety of mechanisms including perilesional motor Similar results were obtained by fMRI. very from infarction is also accompanied by sub- panied mainly by activation of the contralateral cere. In most recovery from hemiparesis. or possibly the develop. use of motor pathways in subcortical evolution of the activation in the sensorimotor cortex structures. It is of importance that the unaffected hemi- undamaged hemisphere can be observed.4). Chapter 3: Neuroradiology Figure 3. Brain activity for hand grip compared to rest for individual subjects with corticospinal damage. This effect of stronger for movement of the paretic fingers after transcallosal inhibition can be reduced by repetitive recovery from stroke. hemispheric reorganization of motor networks Task-oriented arm training increased activation takes place. In particular.4. whereas movements of the transcranial magnetic stimulation (rTMS) [24]. bilateral networks [19]. 16–18]). a dynamic bi- plays a role in recovery. lesion of the contralateral primary motor cortex. (Modified from Ward [5].) (reviews in [2. suggesting compensatory activated in both hemispheres. suggesting a dynamic bihemi- contralateral hemisphere. supplementary motor area (SMA). and activation on the ipsilateral side was tive stimuli associated with recovery [25]. Ipsilateral cortical recruitment seems ganglia and cerebellum. suggesting an improved functional brain reorganiza- cluded that “motor recovery after stroke depends on tion in the bilateral sensory and motor systems [20]. and process of compensatory recruitment will persist if the bilateral inferior parietal cortices are often activated primary motor cortex is permanently damaged. These results suggest that sensorimotor learned movements after focal cortical injury are functions are represented in extended. use of collateral pathways in the ipsilateral from early contralesional activity to late ipsilateral hemisphere. fMRI and PET studies can display the bilaterally in the inferior parietal area. variable. which is dependent on the intensity of rehabilitative Whereas changes in both the damaged and the training. represented over larger cortical territories. in premotor compensatory cortical processes and show the 51 areas and in the contralateral sensorimotor cortex. importance of transcallosal inhibition. outcome Post-stroke aphasia studies reveal that this strategy is significantly less Studies of glucose metabolism in aphasia after stroke effective than repair of the speech-relevant network have shown metabolic disturbances in the ipsilateral in adults.5. and their improvement was differ- in patients with a poor outcome of post-stroke apha. In addition. and by less than 5% in the left deactivation of temporo-parietal cortex is regularly Broca area. (From Calautti C. et al. Therefore. That the quality of recovery is mainly hemisphere caused by the lesion and contralateral dependent on undamaged portions of the language hemisphere caused by functional deactivation (dia. In right-handed individuals on homologous right hemisphere areas [28] can be with language dominance in the left hemisphere. network in the left hemisphere and to a lesser extent schisis) (review in [26]). supramarginal gyrus and lateral and transverse blood flow in 10 normal controls by more than 10% superior temporal gyrus are the most frequently and relative to resting condition in both upper temporal consistently impaired. patients with an eventual good recovery improved substantially and activated the right inferior predominantly activated structures in the ipsilateral frontal gyrus and the right superior temporal 52 hemisphere. indi. Left hemisphere is shown on the left of the standard MRI templates. Section 1: Etiology. Decrease of initial bilateral overactivation to activation restricted to the primary sensorimotor cortex in the affected and primary motor cortex in the unaffected hemisphere. considerably in several tests.) left-hemispheric centers are impaired [27]. temporal infarcts cating significant cell loss caused by the ischemic showed only little improvement. Although the brain recruits right. stroke (Figure 3. which is probably responsible for the aphasic 23 aphasic patients grouped according to the site of symptoms. Activation PET studies were by rCMRGlc in speech-relevant brain regions early performed in the subacute stage approximately after stroke is predictive of the eventual outcome 2 weeks after the stroke and repeated 6 weeks later. Stroke 2001. 32:2534–42. These differences episode outside the ischemic core. of aphasia. related network. In patients with gyrus of both sides and in the lower part of the central aphasia attributable to purely subcortical strokes gyrus of the left side. metabolism in the showed different patterns of activation in the acute hemisphere outside the infarct was significantly less and chronic phase. ent: whereas subcortical and frontal infarcts improved sia than in those with good language recovery. The three groups of aphasic patients hood of the infarct. The functional disturbance as measured the MRI/CT lesion.6): the subcortical and frontal groups mance. pathophysiology and imaging Figure 3. the in improvement of speech deficits were reflected in functionality of the network was reduced in patients different patterns of activation in the course after with an eventual poor outcome. Overactivation in the primary and secondary motor area in five patients compared with normal controls 7 and 31 weeks after left capsular stroke during right thumb-index tapping. by 5–10% in planum temporale and Heschl is related to the severity of aphasia. in particular the angular post-stroke aphasia [29]. This test procedure was applied to found. gyrus (STG) at baseline and regained regional left hemispheric regions for speech-processing when the . the deduced from an activation study in the course after left temporo-parietal region. Repeating words activated gyrus. where not only functional deactivation On matched MRIs regions of interest were defined in (diaschisis) but also neuronal loss may contribute to 14 identified structures of the bilateral language- metabolic and perfusional changes in the neighbor. during task perfor. and the degree of impairment gyri. currents in discrete brain areas which. the left temporal areas are reactivated correlating to better recovery of language function. The effect of rTMS was accompa- (rTMS) with activated imaging nied by a prolongation of reaction time latencies to rTMS is a non-invasive procedure to create electric verbal stimuli. (From Heiss et al. Increases in rela- the right STG at follow-up. PET activation studies [38]: at rest. but increased ipsilaterally outside the coil and in the contralateral homologous transcranial magnetic stimulation area (Figure 3.) STG activation at follow-up. During verb generation. can lead to residual language performance can be investigated by 53 transient increases and decreases in excitability of combining rTMS with functional imaging. Activation patterns in patients with left hemispheric stroke 2 and 8 weeks after stroke. non-fluent aphasia patients piracetam.7). rTMS decreased blood flow ipsilaterally and contralaterally. the triangular part of the left inferior frontal speech areas. In a randomized controlled study speech fMRI in chronic. [29]. PET. In the case of subcortical and frontal infarction. Collateral ipsila- stroke have shown metabolic disturbances in the teral as well as transcallosal contralateral inhibition ipsilateral hemisphere caused by the lesion and contralateral hemisphere caused by functional can be demonstrated by simultaneous rTMS and deactivation (diaschisis). intensity and duration. while the left Broca area and supplementary motor areas at higher-frequency stimulation (5–20 Hz) leads to an baseline and the precentral gyrus bilaterally as well as increase in cortical excitability [36]. This right hemisphere over-activation may in a Cochrane Review [34]. TMS studies with blockade of this con- gyrus and the left posterior temporal gyrus [35]. These results were confirmed in comparable gous language regions during overt propositional studies [30–32].6. which improved performance in a large indicated over-activation of right language homo- multi-center trial [33] and was identified as effective logues. e. rCBF was decreased during rTMS Combination of repetitive ipsilaterally under the coil. it activated 5 Hz) can suppress excitability of the cortex. tralateral over-activation by series of 1 Hz rTMS [37] have reported improved picture-naming ability in Studies of glucose metabolism in aphasia after chronic non-fluent aphasia patients. Low frequencies of rTMS (below improved only in word comprehension. but could not reactivate the tive cerebral blood volume in contralateral homolo- left STG. which was preted as a result of decreased transcallosal inhibition reflected in increased activation in the left temporal due to damage of the specialized and lateralized gyrus. depending The role of activation in the right hemisphere for on frequency. .g. The temporal group the affected cortex. Chapter 3: Neuroradiology Figure 3. improved performance in represent a maladaptive strategy and can be inter- aphasia tests for spontaneous speech. developing brain damage the language function ency tasks than patients with effects of rTMS only can be completely shifted to the right hemisphere. Image (A) shows inferior frontal gyrus activation during simple verb generation. even complete. The coil position is shown in the 3D rendering. Effect of repetitive transcranial magnetic stimulation on activation pattern by verb generation. Section 1: Etiology.) In patients in whom verb generation activated pre.7. This The activation studies in the course of recovery approach might open a new therapeutic strategy for of post-stroke aphasia suggest various mechanisms post-stroke aphasia. In some patients with slowly These patients had lower performance in verbal flu. for the compensation of the lesion within the functional network. compensation. [38]. (Modified from Thiel et al. a hierarchy for effective recovery might PET. recovery can only be achieved by restoration of the original activation pattern after small brain damage outside primary centers. Image (B) clearly shows the decreased activation on the left (blue arrow) and increased activity on the right side (yellow arrow) during rTMS interference. reduction of transcallosal inhibition causes . studies [39]. which dominantly the right inferior frontal gyrus. over the left IFG.  If primary functional centers are damaged. suggesting a less effective compen- In most instances the disinhibition of homotopic satory potential of right-sided network areas. Counteraction by rTMS of contralateral active be deduced: areas might open a new therapeutic strategy for post-stroke aphasia. Chapter Summary reduction of collateral inhibition leads to activation of areas around the lesion The visualization of disturbed interaction in func- (intrahemispheric compensation).g. functional imaging modalities such as PET and fMRI. These areas contralateral to the lesion impairs the capacity results indicate a potential for rTMS in the treatment for recovery – a mechanism which might be counter- of post-stroke aphasia. residual language performance can be investigated geneity of patients included in different imaging by combining rTMS with functional imaging. acted by rTMS of these contralateral active areas. e. pathophysiology and imaging Figure 3. this is usually not as efficient as intrahemispheric response could be blocked by rTMS over this region. Despite differences among the The role of activation in the right hemisphere for activation and stimulation paradigms and the hetero. activation of contralateral homotopic areas. tional networks and of their reorganization in the recovery after focal brain damage is the domain of 54  If the ipsilateral network is severely damaged.  Best. the measurement of local cerebral glucose utilization in man. a widespread network of neurons 1998. Pawlik G. 24:453–8. 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Estimation of local cerebral glucose utilization by Activation studies in the course of recovery of post. can be investigated by combining rTMS with functional fMRI measures signals that depend on the imaging. cortical recruitment seems to be a compensatory cor- tical process related to the lesion of the contralateral 5. Heiss stimulation (rTMS) with activated imaging WD. Functional imaging correlates from hemiparesis. The (14 C)-deoxyglucose Studies of glucose metabolism in aphasia after stroke method for the measurement of local cerebral glucose have shown metabolic disturbances in the ipsilateral utilization: theory. The regional values of lead to transient increases (with higher frequencies) CBF or CMRGlc represent the brain activity due to and decreases (with lower frequencies) in excitability a specific state. 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Herscovitch 25. 2001. and unaffected hemisphere after unilateral cortical stroke. Price CJ. 24:P62–3. Diener HC. Martin WRW. Cerebrovasc 30. Krakauer JW. Kracht LW. 93:95–105. Schumacher B. Baker EH. Kobayashi M. Schwarz M. et al. Thiel A. chronic aphasia after TMS to part of right Broca’s area: 39. Seekins of transcallosal disinhibition in language networks. 57 . Wienhard K. Wagner R. J Physiol Paris 2006. recovery from aphasia. 26:1122–7. Improved picture naming in J Cereb Blood Flow Metab 2006. H. Huber W. Chapter 3: Neuroradiology 37. Martin PI. activation studies of word processing in the 38. Functional an open-protocol study. Brain Lang 2005. Zahn R. et al. Nicholas M. Naeser MA. Direct demonstration 99:370–85. Gairing S. and contralateral vasculature. poster- present and negative predictive values (NPV) means ior or ipsi. ultrasound results Positive predictive value ð%Þ must be compared to the established gold standards. the color of the . The results of non-invasive tests (e. Extracranial ultrasound invasive test indicates the absence of disease but the gold standard is positive. By convention. ultrasound) can be highly variable. A true-positive result indi. in acute stroke negative results can be used to calculate sensitivity The most important diagnostic question in ultrasono- and specificity. true negatives þ false positives To calculate these statistics. while the non- invasive study is positive. ¼  100 true negatives þ false negatives positive result means that the gold standard is nega- tive.and intracranial vessel(s) is/are correctly diagnose disease. Sensitivity is the ability of a test to graphy is which extra. often providing ambiguous results. performed. Note that clinically silent sten- number of positive results obtained by the gold otic processes might also influence the cerebral standard. surgery or autopsy findings. It can be calculated by stenotic or occluded and can it/they be responsible for dividing the number of true-positive tests by the total the clinical symptoms. Specificity is the ability to diagnose the absence Because of the interactions between extra. A true-negative true negatives result indicates that both tests are negative.and intra- of disease and is calculated by dividing the true cranial hemodynamics. indicating the presence of disease. True-positive and true. based on the incidence of with the brightness-mode (B-mode) technique and disease in the patient population.g. Negative predictive value ð%Þ cates that both tests are positive. circulation. both extracranial and intracra- negative by the total number of negative results nial ultrasound techniques should be performed in obtained by the gold standard. A false-negative result occurs when the non. Because the sometimes color flow information is superimposed on 58 patient population referred to the ultrasound lab is the grayscale image. indicating the absence of disease. calcula. These results are not very specific and imaging and spectral analysis. true positives Sensitivity ð%Þ ¼  100 Although other parameters can be reviewed. true positives usually angiography. Chapter 4 Ultrasound in acute ischemic stroke László Csiba Introduction diverse. that disease is not present. high levels of sensitivity and specificity help to make the diagnosis optimal. and true positives by the total number of tests Carotid ultrasonography consists of two steps. clinically silent stenoses should ive value (PPV) or likelihood means that disease is be detected by careful investigation of anterior. acute stroke. The positive predict. Images are produced can be highly variable. true positives þ false negatives tion of overall accuracy. A false. Similarly. sensitivity and specificity as true negatives well as positive and negative predictive values are Specificity ð%Þ ¼  100 useful to the clinician who is managing the patient. The ¼  100 true positives þ false positives simplest statistic compares the outcome of each test as either positive or negative. Overall accuracy can be Doppler ultrasonography is the primary non- calculated by dividing the number of true negatives invasive test for evaluating carotid stenosis. blood  peak systolic velocities (PSV) and end diastolic velocity increases to maintain volume flow. Vertebral hyperechoic and moderately stenotic. high-resistance vessel) on spectral analysis. Even in normal conditions.e.  maximal systolic flow velocity within the ICA Note the carotid bifurcation. The be a satisfactory index of plaque instability. An important general rule for ultra. When a small degree of stenosis is present. spectral analysis and find the highest velocity or fre- atic and asymptomatic carotid plaques are different. age. An object that a smaller caliber. such flow can be seen around the carotid bulb. CCA and its major branches. the structures and the velocity of the blood flow. The vertebral artery runs perpendicular to basis of the waveform and spectral analysis of the vertebral processes. Symptomatic plaques are more likely to be hypoechoic the sonographer should assess the vertebral circulation. Symptomatic and asymptomatic carotid plaques and the degree of stenosis can be analyzed with Flow of blood is even. sive test for evaluating carotid stenosis. branch coming off. After assessment of the anterior circulation. sex. With even greater stenosis. vertebral body processes appear as hypoechoic trans- The degree of stenosis is better measured on the verse bars. The sonographic characteristics of symptom. 59 diastolic endpoints in between those of external and hypertension. smaller The stroke risk depends on more than the degree caliber than the jugular vein and systolic peak and of carotid artery narrowing (cardiac diseases. Most .e. Perform plaques. and  maximal systolic flow velocity of the nonaffected color may be used at this point to identify flow within ICA. look for plaques. Plaques with irregular surface and/or (i. artery) and often helps identify the area of highest sound is the greater the degree of stenosis. while ICA is often posterolateral to rebounds very little of the pulse is hypoechoic. the C4–C6 segment is accessible. the artery and potential areas of high velocity. identification of vessels (especially the vertebral osis or occlusion. velocities The extracranial ultrasound procedure starts with  ratios ICA/CCA maximal systolic flow velocity the CCA. When no stenosis is present. with the fastest flow in the ultrasonography by examining the echogenicity of middle and the slowest at the edges of the vessel. shows positive “temporal tap” (i. The echogenicity of an object on internal carotid arteries on spectral analysis. internal carotid artery (ICA) and external within the ICA stenosis carotid artery (ECA). undulations in wave- Soft plaques present a higher embolic risk than hard form with tapping of the temporal artery). CCA can be identified by pulsatile walls. tion of stenosis solely based on this criterion is not the resistance decreases significantly. Degree of stenosis the flow can become turbulent [1]. that is independent of direction or velocity of flow and gives an angiographic-like picture of an artery. Chapter 4: Ultrasound in acute ischemic stroke pulsating artery is red. the blood flow becomes disturbed and loses its laminar quality. Some sonographers characterize the degree of sten- In normal hemodynamics. as vessel length osis based on diameter or area reduction but estima- increases so does resistance. especially the ICA. and highly stenotic while asymptomatic plaques are Usually. the higher velocity. With increasing radius. ECA has virtually no diastolic flow is hyperechoic. Evaluation of arteries can be identified with a probe parallel to the the surface of the plaque has not been demonstrated to carotid: angle the probe laterally and inferiorly. Commonly used methods: As vessel diameter (and area) decreases. quency. Doppler ultrasonography is the primary noninva- Blood flow can be laminar. disturbed or turbulent. reliable. blood flow is laminar. An object ECA and ECA may have a superior thyroid artery that reflects much of the signal. such as calcified plaque. ECA heterogeneous echogenicity are more likely to embolize. smoking and plaque structure). Power Doppler provides color imaging of arterial occlusion [1]. ECA has the image determines its brightness. Color non-affected CCA imaging and power Doppler may be used but may  ICA/ICA not necessarily provide additional information. at least two or three spectral  maximal systolic flow velocity within the analyses of each vessel should be obtained. Use of color flow Doppler enables the more rapid Spectral (velocity) analysis is essential to identify sten. reduces scan time and may help in diagnosis the velocity. stenosis attempt to characterize the nature of the plaque. In a case of a suspected stenosis ations in which cardiovascular factors (e. With stenosis .  <50% stenosis: ICA PSV <125 cm/s and plaque  ICA waveforms may have a high-resistance or intimal thickening. segments proximal and distal to a stenosis have to be analyzed. veloci. and no flow is seen A severe carotid stenosis is shown in Figure 4. narrowing. power and color Doppler ultrasound. on spectral. poor not only the intrastenotic but also the flow from vessel ejection fraction) limit the increase in velocity [1].) studies consider carotid stenosis of 60% or greater to flow fail. (Courtesy of L.  Normal: ICA PSV <125 cm/s. When possible.  >70% stenosis to near occlusion: ICA PSV  Long-segment ICA stenosis may not have high >230 cm/s and visible plaque and lumen end-diastolic velocity. This equals a ties may actually drop as mechanisms that maintain peak systolic velocity over 125 cm/s. configuration in ipsilateral ICA lesions. laboratories should perform their own correlations with angiographic measurements Doppler ultrasonography associated with stenosis for quality control.  Near occlusion: a markedly narrowed lumen on  Imaging can be used to downgrade stenosis in the c-Doppler ultrasound. The stenosis ranges vary from laboratory to  70% stenoses ICA=CCA : > 4:0: laboratory. If normal flow signals are present before and < 50% stenoses ICA=CCA : < 2:0: behind the suspected lesion significant stenosis can be 50  69% stenoses ICA=CCA : 2:04:0: excluded. Duplex color-Doppler ultrasound. Ratios may be particularly helpful in situ- be clinically important.  Total occlusion: no detectable patent lumen is seen on grayscale ultrasound. configuration in ipsilateral distal ICA lesions. greater to be clinically important. pathophysiology and imaging Figure 4. Most studies consider carotid stenosis of 60% or 60 With stenosis over 90% (near occlusion). Section 1: Etiology. A consensus statement of the Society might result in false positive/negative results: of Radiologists in Ultrasound recommended the  Ipsilateral CCA-to-ICA flow ratios may not be following criteria for estimating stenosis [2]: valid in the setting of contralateral ICA occlusion.  Velocities supersede imaging in grading stenosis.g. CCA lesions. setting of turbulence caused by kinking [3]. More than 300 cm/s systolic velocity could be measured in the stenotic area depicted by the color mode.  50–69% stenosis: ICA PSV is 125–230 cm/s and  ICA waveforms may be dampened in ipsilateral plaque is visible.1. no plaque or  CCA waveforms may have a high-resistance intimal thickening.1. Oláh. be seen in over 50% of stenoses. Chapter 4: Ultrasound in acute ischemic stroke over 90% (near occlusion). measurements are performed. depending on gender 61 and longitudinal image using the B. increases in the a reversed (extra ! intracranial) flow could be intimal-medial thickness (IMT) of the carotid artery detected in the ophthalmic artery. can Society of Echocardiography and the Society for Vascular Medicine for measuring IMT: (1) use end- diastolic images for IMT measurements. For each 0. bedside. CCA IMT greater than firmed by ultrasound contrast agents. most common locations of atherosclerotic stenosis. Diagnosis of severe Ratios (maximal systolic flow velocity within the stenosis is based on hemodynamic parameters (meas- ICA stenosis/maximal systolic flow velocity within ured by pre-. CCA has been correlated directly with successful A high grade of subclavian stenosis (>50%) treatment with drugs that lower serum low-density results in increased flow velocities and a turbulent lipoprotein levels. the risk the ophthalmic origin (ICA has low flow velocities increased approximately 30%. and the diagnosis can be con- of cardiovascular disease [4].1 [5]. can be detected within the carotid artery can be measured. high-grade stenosis are difficult. velocities may actually of the ultrasound system. Ultrasound diagnosis of intracranial ICA stenosis and occlusion stenosis and occlusion Mild stenoses (<50%) can be estimated by measure. The levels of evidence of the Euro- the intimal-medial thickness (IMT) of the carotid pean Federation of Neurological Societies are shown artery are associated with an increased risk of myo. to account for changes Raised flow velocities and spectral broadening can in distending pressure. and a higher pulsatility but preserved diastolic The following method is suggested by the Ameri. In high-grade subclavian stenosis an alternating With ultrasound.90 mm were Using duplex ultrasound a proximal ICA occlu- associated with a progressively increased risk of car. 0.and poststenotic Doppler spec- the non-affected CCA) may be particularly helpful trum analysis). artery is a simple. the risk increased by approximately 27%. velocity). ancillary method in sus- pected ICA stenosis or occlusion (equally severe upper and lower extremity paresis). especially its origin. A distal extracranial Treatment with lipid-lowering drugs has been VA occlusion may cause a stump signal or a high shown to decrease the intimal thickness of the carotid pulsatile flow signal with almost absent end-diastolic artery. Decrease in the thickness of the intima of the flow component. cardial infarction and stroke.87 mm and ICA IMT greater than 0.55 mm increase in ICA IMT.g. Diagnosis is frequently reached through . in situations in which cardiovascular factors Investigation of flow direction in the ophthalmic (e. Intracranial disease corresponds to approximately ment of area and/or diameter in the cross-sectional 8–10% of acute ischemic stroke. sion (proximal to the origin of the ophthalmic diovascular events. (3) avoid use of a and subclavian arteries single upper limit of normal for IMT because the The origin of the vertebral artery (VA) is one of the measure varies with age. or even a retrograde flow. particularly when serial but is difficult to investigate. Increases in the ipsilateral VA. no color-mode signal and no Doppler flow) CCA IMT. (2) categor. the intimal-medial thickness of flow.20 mm increase in artery. intra. can be distinguished from the ICA occlusion distal to For each 0. and (4) incorp. Area measurements in drop as mechanisms that maintain flow fail. Extracranial vertebral ization of plaque presence and IMT. sex and race. in Table 4. orate lumen measurement.and color-mode and race. In a case of hemodynamically significant ICA stenosis or occlu- IMT measurement sion (proximal to the origin of the ophthalmic artery) In the Cardiovascular Health Study. flow. were associated with an increased risk of myocardial Occlusion results in a complete absence of color- infarction and stroke in older adults without a history flow signal in ICA. poor ejection fraction) limit the increase in velocity. 75–3. between 50% and 60% of studied vessels in 62  The angle correction should only be applied to unenhanced TCCS but reached 80–90% after velocity measurements when the sample volume intravenous contrast administration. Section 1: Etiology. because of the insufficient acoustic signal is absent in one segment.1. level B patients with cerebrovascular disease Transcranial Doppler is very useful for monitoring arterial reperfusion after thrombolysis of acute class II. level A disease. Domains Class and level Ultrasonography is the non-invasive screening technique indicated for the study of vessels class IV.  The mean velocity analysis is not enough to  The accuracy of ultrasound for detecting identify intracranial vessel abnormalities.5 MHz). spectral analysis specificity and only 4% of examinations are and knowledge of extracranial circulation. The duplex mode of  Intracranial stenosis: local increase in the peak TCCD enables sampling of vessels and Doppler meas. segmental elevations. Transcranial color-coded duplex sonography  Flow velocities in the arterial as well as in the (TCCD) combines the imaging of intracranial vessels venous system are higher in women than in men. The power TCCD does not for intracranial vessel occlusion is similar to that display information on the flow direction. pathophysiology and imaging Table 4.2. level A circulating emboli Asymptomatic embolization is common in acute stroke. be combined with other parameters such as  The use of Levovist increases the sensitivity and asymmetry. and parenchymal structures. least 2 cm length. systolic flow velocities. To penetrate the skull. . whereas the pulsatility TCCD uses low frequencies (1. particularly in patients with carotid artery class II. TCD is the only imaging technique that allows detection of class II. It must intracranial stenosis is summarized in Table 4. of magnetic resonance angiography.  Either flow velocities (frequency-based TCCD) or  After application of echo-contrast enhancing the integrated power of the reflected signal (power agents (ECE) the diagnostic confidence of TCCD TCCD) can be coded. level A Even in asymptomatic patients.  About 15% of patients cannot be examined by  The intracranial vessel is occluded if the color TCCD. visualized. In this group the presence of embolic signals has been shown to predict the combined stroke and transient ischemic attack (TIA) risk and more recently the risk of stroke alone arteriography. level A treated with intravenous thrombolysis may improve both early recanalization and clinical outcome The presence of embolic signals with carotid stenosis predicts early recurrent stroke risk class II. and decrease with age. inconclusive because of insufficient bone windows. limit the spatial resolution. TCD is an ancillary diagnosis tool with can be located in a straight vessel segment of at good sensitivity and specificity. while other vessels window. which index increases. disturbances with low frequency and high- General characteristics of the investigation [6–10]: intensity Doppler signals.  Flow velocities are determined by spectral  In an acute stroke study the ability of duplex Doppler sonography using the color Doppler ultrasound to diagnose main stem arterial image as a guide to the correct positioning of the occlusions within the anterior circulation was Doppler sample volume. level B MCA occlusions Clinical studies have suggested that continuous TCD monitoring in patients with acute MCA occlusion class II. GCPP involved in causing symptoms of carotid stenosis Transcranial Doppler (TCD) is useful for screening for intracranial stenosis and occlusion in class II. post-stenotic flow urements of angle-corrected blood-flow velocities. Highlights of the guidelines of the European Federation of Neurological Societies [5]. Identification rates decline with and parenchymal structures can be correctly advancing age. TCCS TCCS is possibly useful (Type C. and enabling assessment of appropriate tests of diagnostic accuracy. conventional angiography. or non-imaging TCD is unclear (Type U).2. The relative value of TCD compared with MR angiography or CT angiography remains to be determined (Type U). Highlights of the American Academy of Neurology recommendations [7]. CT scanning. Class II–III). and where test is applied in blinded evaluation. test/predictor unproven. (CE)-TCCS may provide information in patients with ischemic cerebrovascular disease and aneurysmal enhanced TCCS SAH (Type B. Class IV: any design where test is not applied in blinded fashion OR evidence provided by expert opinion or descriptive case series. using a “gold standard” to define cases. BA 55–81 96 TCD is probably useful (Type B. Cerebral  Complete occlusion 50 100 thrombolysis  Partial occlusion 100 76  Recanalization 91 93 TCD is probably useful for monitoring thrombolysis of acute MCA occlusions (Type B. Type A: established as useful/predictive or not useful/predictive for the given condition in the specified population. Class II–IV). More data are needed to assess the frequency of monitoring for clot dissolution and enhanced recanalization and to influence therapy (Type U). where test is applied in blinded evaluation. Type U: data inadequate or conflicting. Class I: evidence provided by prospective study in broad spectrum of persons with suspected condition. Sensitivity (%) Specificity (%) Intracranial  Anterior circulation 70–90 90–95 steno-occlusive  Posterior circulation occlusion 50–80 80–96 disease  MCA 85–95 90–98  ICA. Class II-IV). More data are needed to show if it has value vs. Cerebral TCD monitoring is probably useful for the detection of cerebral microembolic signals in a variety of microemboli cardiovascular/cerebrovascular disorders/procedures (Type B. Class III) for the evaluation and monitoring of space-occupying ischemic MCA infarctions. 63 . Type B: probably useful/predictive or not useful/predictive for the given condition in the specified population. Class III: evidence provided by retrospective study where either persons with established condition or controls are of narrow spectrum. Chapter 4: Ultrasound in acute ischemic stroke Table 4. Data are insufficient to recommend replacement of conventional angiography with TCD (Type U). Its clinical utility vs. Type C: possibly useful/predictive or not useful/predictive for the given condition in the specified population. VA. Class II–III) for the evaluation of occlusive lesions of intracranial arteries in the basal cisterns (especially the ICA siphon and MCA). Data do not support the use detection of this TCD technique for diagnosis or monitoring response to antithrombotic therapy in ischemic cerebrovascular disease (Type U). given current knowledge. CT and MRI scanning and if its use affects clinical outcomes (Type U). Class II: evidence provided by prospective study in narrow spectrum of persons with suspected condition or well-designed retrospective study of broad spectrum of persons with suspected condition (by “gold standard”) compared to broad spectrum of controls where test is applied in blinded evaluation and enabling assessment of appropriate tests of diagnostic accuracy. Contrast. will result in a status of the ICA. Section 1: Etiology. extending more than 30 cm/s.g. turbulence and asymmetry into mild. at least 30 to the occlusion. if an of the MCA.3. Occlusions distal to the PICA origin will result in mild MCA occlusion to moderate flow alterations of the extracranial VA. cm/s flow velocity difference between the right and left sides. the proximal Stenosis and occlusion in posterior and distal vessel segments should also be evaluated. no more imaging is needed. e. Vertebral MCA stenosis stenoses can be diagnosed by flow velocity. A1↑ Posterior cerebral artery 100 145 distal PCA post-stenotic fp ipsilateral M1-MCA↑ Basilar artery 100 140 distal BA/PCA post-stenotic fp VA/proximal BA pre-stenotic fp Vertebral artery  90 120 distal VA/BA post-stenotic fp VA extracranial pre-stenotic fp Fp: flow pattern. ↑ increased velocity as collateral sign. A proximal PCA occlu- sion can be diagnosed by absent flow signal. pathophysiology and imaging Table 4.and post-stenotic flow patterns. and differences diagnosis of ACA stenosis and occlusion [9]. profile Stenoses of the M1-MCA can be graded according to disturbances. and pre. . may also be useful. ocity. ACA stenosis and occlusion  The investigation should start on the presumably Clinical symptoms (contralateral lower leg paresis) non-affected side (road map ! clinical can suggest ACA stenosis or occlusion. The presence of collaterals and reduced flow with low velocities and a marked bilat- delayed flow acceleration on TCD usually eral asymmetry. Modified from Baumgartner et al. If there is a proximal M1-MCA occlusion no highly specific identification of a normal flow signal is seen. In distal M1-MCA occlusion by using eTCCD in a patient with sufficient bone a reduced flow velocity is present with variable pulsa- windows. [9]. mainly on their relation to the origin of the PICA (proximal or distal). Alter- reduced flow signals in vessel segments proximal ation of flow velocities and turbulence. Flow signals in VA occlusion strongly MCA segments should be insonated [7–9].  A correctly performed TCD investigation also Distal MCA occlusion. flow velocity. In occlusions of the middle part intracranial arterial status. [8] and Valdueza et al.  If a pathological finding is present. Therefore. indicates a hemodynamically significant lesion (>80% ICA stenosis or occlusion). Ultrasound grading of intracranial stenosis. Altered vel- symptoms).3. the presence of turbulence or missing ACA and  The sonographer looks for a focal velocity rise in a ipsilateral increased MCA flow velocities can help the circumscribed vessel segment. Velocity values for mild and severe stenosis are given moderate and high-grade stenoses and all detectable in Table 4. of a relevant M2-MCA provides valuable information about the vascular branch or more than one M2 branch. depend on the site of the occlusion.  Occlusions are characterized by missing color and circulation Again the typical clinical symptoms of vertebrobasilar Doppler flow signals at the site of the occlusion or insufficiency should orient the sonographer. Stenosis 50% 50–80% 80% Middle cerebral artery 155 cm/s 220 distal M1/M2-MCA post-stenotic fp A1-ACA and/or P1/P2-PCA↑ Anterior cerebral artery 120 155 A2-ACA post-stenotic fp ipsilateral M1-MCA and/or contralat. a small orthograde flow with increased experienced sonographer detects no abnormalities pulsatility may be present.  The diagnostic strength of eTCCD can be the reduced. between the affected and non-affected sides. 64 Depending on the location of the occlusion. the mainly depending on its diameter and its former rele- Doppler spectrum may be completely absent or vance in the posterior circulation [9]. tility depending on the presence of a temporal branch. urgent TCD studies can Emboli monitoring and acute stroke be completed and interpreted quickly at the bedside. assess collateral supply. nial Doppler in patients with acute stroke. find the worst residual flow signal. TCD identifies microembolic signs (MES) in intra- The expanded fast-track protocol for combined cranial circulation. the insonation Transforaminal and transtemporal insonation allows begins with the non-affected side. The non-invasive vascular ultrasound evalu- arteries [9]. the sensitivity neurological deficits. apparently normal VA and ation (NVUE) in patients with acute ischemic stroke proximal BA velocities are not sufficient to exclude has a high yield and accuracy in diagnosing lesions top of the basilar occlusion. The ultrasound distinguishes carotid and transcranial ultrasound testing in acute signal characteristics through embolic materials – cerebral ischemia is shown in Table 4. examination Recently. with artery. MES have been proven . as a result of their different acoustic properties com. The most distal segment of the basilar artery insonation starting at the mid-M1-MCA depth may be better insonated transtemporally. Chapter 4: Ultrasound in acute ischemic stroke Basilar artery stenosis and occlusion arterial territory. using low frequencies to penetrate the that an urgent angiogram will show any acute skull. for ultrasound screening criteria for LAIT are shown in example. amenable to interventional treatment (LAIT). confidence of eTCCD for intracranial vessel In summary. enhancement (Table 4. a practical algorithm has been published ination with carotid/vertebral duplex and transcra- for urgent bedside neurovascular ultrasound examin. The waveforms and alization of the distal part of the basilar artery appears systolic flow acceleration are compared to the non- to be difficult even using echo-enhancing agents.4. This is followed the investigation of the total length of the basilar by locating the MCA on the affected side. bedside ultrasound in acute stroke occlusion can reach that of magnetic resonance may identify thrombus presence. and monitor recanalization and Fast-track neurovascular ultrasound reocclusion. affected side. a practical algorithm has been published for urgent bedside neurovascular ultrasound exam- Recently. The However. For example. location(s). this is followed by proximal MCA and A proximal BA occlusion will always result in pre- ICA bifurcation assessment (range 60–70 mm) stenotic flow alterations of both extracranial vertebral [11. with a completely With transcranial color-coded duplex sonography normal spectral TCD. 12]. 65 mined by the clinical localization of ischemic pared to the circulating blood. Below. Occlusions are difficult to assess and diagnostic the distal MCA segments are insonated (range certainty depends on the site of the occlusion. With the use of echo. sity and short duration within the Doppler spectrum The choice of fast-track insonation steps is deter. If a normal MCA flow is found. there is less than 5% chance (TCCD). helps to determine the ischemic nature of acute focal contrast enhancing agents (ECE).2). arterial obstructions located in the proximal MCA The highlights of the recommendation of the and ICAs. but the visu- range. 12]. Therefore. we solid or gaseous – from erythrocyte flow velocity. if patients present with middle cerebral artery symptoms. as this cannot exclude the presence of. most intracranial stenoses and occlusions obstruction [12]. ation with carotid/vertebral duplex and transcranial Doppler in patients with acute stroke [11.5. Using such a protocol. 40–50 mm). a fragmented thrombus. ultrasound should Table 4. always be used together with other diagnostic tools such TCD has the highest sensitivity (>90%) for acute as CTA. can be detected by combining velocity analysis While TCD demonstration of an arterial occlusion with other parameters. or DSA in presumed BA pathology. usually 50–58 mm. 12]. a normal TCD result would and specificity can be increased and the diagnostic support a lacunar mechanism.2). determine thrombus angiography. However. MRA. TCD has modest sensitivity (55–60%) for American Academy of Neurology [7] summarize posterior circulation lesions if performed without the accuracy of TCD in intracranial steno-occlusive transcranial color-coded duplex imaging or contrast disorders (Table 4. highlight the most important details of the algorithm Microembolic signals appear as signals of high inten- [11. Evaluate and compare waveform shapes and systolic flow acceleration. Start with TCD because acute occlusion responsible for the neurological deficit is likely to be located intracranially. Start on the affected side by locating CCA using longitudinal B-mode plane. In patients with concomitant chest pain. identifying patients at increased risk for cycle and they can be acoustically identified by a stroke who may benefit from surgical and pharmaco- characteristic “chirp” sound. If time permits or in patients with pure motor or sensory deficits. Fast-track neurovascular ultrasound examination (Chernyshev et al. If time permits or in patients with pure motor or sensory deficits. pathophysiology and imaging Table 4. . color or power mode. If short on time. Fast-track insonation steps follow clinical localization of patient symptoms. Use portable devices with bright display overcoming room light. increase the depth to 62 mm. They occur at random within the cardiac ischemia. Stand behind patient headrest. 2. 5. Document if ICA (or CCA) has a lesion on B-mode and corresponding disturbances on flow images. PCA. Apply color or power modes and spectral Doppler to identify flow in intratransverse VA segments.and postoperative stroke. Start on the affected side in transverse B-mode planes followed by color or power-mode sweep from proximal to distal carotid segments. evaluate CCA as close to the origin as possible. 4. Start suboccipital insonation at 75 mm (VA junction) and identify BA flow at 80–100 mm. B. perform transverse and longitudinal scanning of the arteries on the non-affected side. find the terminal VA (40–80 mm) on the non-affected side for comparison and evaluate the terminal VA on the affected side at similar depths. Identify CCA and its bifurcation on B-mode and flow-carrying lumens. Check flow direction and pulsatility in the OA at depths 40–50 mm followed by ICA siphon at depths 55–65 mm. examine cervical portion of the vertebral arteries (longitudinal B-mode. perform bilateral duplex examination of the CCA. evaluate BA (depth 80–100 mm) and terminal VA (40–80 mm). If time permits. reduce the depth to trace the MCA stem or identify the worst residual flow signal. 4. Potential applications of MES detection toring to prevent intra. M2 30–45 mm) and velocity for comparison with the affected side. Perform similar examination on other side. 3. [11]). 3. ICA and external carotid artery. 3. or M2 MCA. Detection of MES can logical intervention.4. Perform angle-corrected spectral velocity measurements in the mid-to-distal CCA. ICA and external carotid artery as described above. STEP 2: Vertebral/carotid duplex ultrasound 1. 2. Clinical diagnosis of cerebral ischemia in the posterior circulation STEP 1: Transcranial Doppler 1. Follow VA course to its origin and obtain Doppler spectra. to represent solid or gaseous particles within the include determining the pathophysiology of cerebral blood flow. 2. 3. spectral Doppler) on the affected side. evaluate both MCAs and ACAs (60–75 mm) for possible compensatory velocity increase as an indirect sign of basilar artery obstruction. If no signals detected. Search for possible flow diversion to the ACA. begin insonation on the non-affected side to establish the temporal window. If an anterograde flow signal is found. start on the affected side: first assess MCA at 50 mm. Section 1: Etiology. Extracranial carotid/vertebral duplex may reveal an additional lesion often responsible for intracranial flow disturbance. Clinical diagnosis of cerebral ischemia in the anterior circulation STEP 1: Transcranial Doppler 1. assessing the effectiveness of 66 identify patients with stroke or TIA likely to be due novel antiplatelet therapies and perioperative moni- to embolism. If time permits. A. 4. Continue on the affected side (transorbital window). If time permits. and turn transducer downward to visualize shadows from transverse processes of midcervical vertebrae. 2 If abnormal signals present at 75–100 mm. Continue with transtemporal examination to identify PCA (55–75 mm) and possible collateral flow through the posterior communicating artery (check both sides). If time permits. STEP 2: Carotid/vertebral duplex 1. normal MCA waveform (M1 depth 45–65 mm. 4. [11]). Chapter 4: Ultrasound in acute ischemic stroke Table 4. reverberating. B-mode evidence of a lesion in ICA  CCA. or M2 Increased resistance in ipsilateral TICA Embolic. filling through ACommA or collateral flow through Flow imaging evidence of no flow or PcommA residual lumen Reversed OA Delayed systolic flow acceleration in or blunted ipsilateral MCA. or: Flow imaging evidence of residual lumen or no flow 67 . MFV > 20 cm/s Secondary: ICA > 50% stenosis PSV > 125 cm/s EDV > 40 cm/s ICA/CCA PSV ratio > 2 Embolic signals in unilateral MCA ICA near-occlusion or occlusion Normal OA direction due to retrograde filling of Blunted. disturbed flow at stenosis Nonharmonic and harmonic covibrations (bruit or pure musical tones) TICA Primary: TIBI grades 0–4 at 60–70 mm Decreased ICA velocity unilateral to lesion or normal extracranial findings Increased velocities suggest anterior cross-filling or collateral flow in posterior communicating artery Secondary: Embolic signals in unilateral MCA Blunted unilateral MCA. minimal. Lesion location TCD criteria (at least one present) CD criteria M1/M2 MCA Primary: TIBI grades 0–4 (absent. minimal.5. Extracranial findings may be normal or may dampened. or absent siphon spectral Doppler waveforms in ICA Tandem ICA/MCA Primary: stenosis/occlusion TIBI grades 0–4 and: B-mode evidence of a lesion in ICA  CCA. or stenotic) at depths <45 mm (M2) show decreased ICA velocity on the side of and 45–65 mm (M1) the lesion Secondary: Flow diversion to ACA. Ultrasound screening criteria for lesions amenable for intervention (Chernyshev et al. signals in MCA Turbulence. MFV > 20 cm/s Proximal ICA Primary: Increased flow velocities suggest anterior cross. PCA. blunted. 5. (cont. with fixed trans. . [11]. minimal. TIBI – thrombolysis in brain infarction. MCA. or absent spectral Doppler waveforms in ICA Basilar artery Primary: 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. or unilateral PComma or: Reversed unilateral DA ICA > 50% stenosis PSV > 125 cm/s EDV > 40 cm/s ICA/CCA PSV ratio > 2 Secondary: Delayed systolic flow acceleration in proximal ICA near-occlusion or occlusion MCA or TICA Embolic signals in proximal MCA or TICA Blunted. in addition. 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. PCommA – posterior communicating artery. reverberating. 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. MES detection. pathophysiology and imaging Table 4. acts as a predictor two possible embolic sources – cardiogenic and carotid for new cerebral ischemic event recurrence [13–16]. With making. CD – cervical duplex. diagnosis accuracy and support for therapy decision- 68 ducers in order to reduce movement artifacts. The methodology includes simultaneous monitoring plaque – the identification of MES contributes higher of both MCAs for at least 30 minutes. Reproduced with permission from Chernyshev et al. Section 1: Etiology. ACommA – anterior communicating artery. minimal. MCAs.) Lesion location TCD criteria (at least one present) CD criteria Increased velocities in contralateral ACA. Simultaneous monitoring above new cerebral ischemic event recurrence and can (i. stroke patterns and cases of artery-to-artery or car. stroke. while resonating microbub- strokes). The incidence of MES is maximal in of ultrasound in stroke patients for visualization of the first week after stroke. culation. Detec- tion of MES can identify patients with stroke or TIA vessels may help identify the active embolic source likely to be due to embolism. thus being particularly suitable for real- small-vessel infarctions. emitting ultra- Some authors have demonstrated that MES occur sound waves at multiples of the insonated fundamen- predominantly in patients with large-vessel territory tal frequency. cardiac or bles cause scattering of multiples of the fundamental carotid) have different acoustic properties and ultra. MES are a frequent finding a characteristic reduction of contrast reaching the 69 in varying sources of arterial brain embolism and lesion. In contrast.e. compared with aspirin alone (e. which could permit differentiation. bolus Emboli in Symptomatic Carotid Stenosis Study imaging after SonoVue injection is useful for analyz- (CARESS) also revealed that the combination of clo.g. an internal carotid artery (ICA) stenosis is another possible way of differentiating between artery-to- artery and cardiogenic embolism. is of probable cardio. if this Perfusion harmonic imaging after SonoVue bolus is not possible. Simultaneous monitoring for MES in different TCD identifies MES in intracranial circulation. others serial imaging modalities have established the application measurements. echoes from microbubbles from those coming from criminate between different potential sources of tissue. Chapter 4: Ultrasound in acute ischemic stroke At present. microbubbles produce resonance. common carotid artery) influence therapy decision-making. based on composition and size. apy. injection can be used in patients with acute stroke. definite area of infarction and outcome after ischemic clopidogrel þ aspirin versus aspirin) [17]. The Clopidogrel and Aspirin for Reduction of In the early phase of acute ischemic stroke. The occurrence of MES brain perfusion deficits. and which patients with carotid stenosis [18]. Because of asymptomatic hemispheres and a discrete subcortical their small size. or different elapsed times after stroke. nonlinear response at low acoustic power without MES are only occasionally detected in patients with destruction. SonoVue) generate a diogenic embolism with persisting deficit. Real-time visualization of middle MES detection by TCD in CEA candidates may allow identification of a particularly high-risk group cerebral artery infarction of patients who merit an early intervention or.e. sonic characteristics. Some (UCAs) and the development of contrast-specific investigators used single registration. The new microbubbles (e.e. The insonated tissue responds at the funda- embolism (i. they can pass through the microcir- or cortical pattern of infarction on computed tomo. The UCAs consist of micro- showed more prevalence in completed stroke than bubbles composed of a gas that is associated with in patients with TIA. pidogrel and aspirin was associated with a marked The ultrasound imaging data correlate well with the reduction in MES. artery-to-artery or cardioembolic mental frequency. more aggressive antithrombotic ther. Ultrasound perfusion imaging with SonoVue A recent meta-analysis confirmed the usefulness has allowed measurements not only in ischemic of microembolic signs (MES) detection by transcra. Diagnostic brain perfusion imaging The frequency of MES in acute stroke shows a wide range between 10% and 70%. Harmonic imaging differentiates In addition. ing cerebral perfusion deficits at the patient’s bedside.e. There are interactions between ultrasound graphy (CT) compared with a hemodynamic or and microbubbles: at low ultrasound energies UCA small-vessel pattern. acts as a predictor for (cardiac? carotid?). monitoring of microembolisms is MES detection is useful for risk stratification in useful for patients with non-defined AIS. due to nial Doppler sonography. The availability of new ultrasound contrast agents tion.g. frequency – the harmonic frequencies. MCA) and below (i. . time imaging. and in symptomatic than various types of shells for stabilization. Different types of emboli (i. probably due to in stroke patients different therapies. TCD monitoring may help to dis.or carotid-embolic etiology. different criteria for MES detec. stroke but also in intracerebral hemorrhages. ultrasound findings remai. pass through the microcirculation and the develop- The grading system can be used also to analyze reca- ment of contrast-specific imaging modalities make it possible to use ultrasound for the visualization of nalization patterns. toring of acute stroke therapy and prognosis. Patients with no detectable residual flow signals as well A complete occlusion should not produce any as those with terminal internal carotid artery occlusions detectable flow signals. downstream embolization and continued clot .v. rt-PA compared with other occlusion locations [27]. in reality.a. ultrasound monitoring may assist in of neurological deficits irrespective of whether this the selection of patients for additional pharmacological occurred early or in the 6. some are least likely to respond early or long term. toring: sudden recanalization (abrupt normalization of  Grade 2: blunted flow. ment in flow signal and higher incidence of The analysis of flow signal changes during throm. CT scan results. TIBI complete restoration of flow. The distal residual flow around the thrombus is often present. receiving i. speed of clot dissolution during continuous TCD moni-  Grade 1: minimal flow. sive improvement in flow velocity lasting more than 30 min. Section 1: Etiology. flow non-invasively and monitor thrombus dissol. Prognostic value of ultrasound whereas slow flow improvement and dampened flow signals are less favorable prognostic signs [24]. pathophysiology and imaging In spite of continuous effort. brain perfusion deficits. terminal ICA occlusions were the least grading system was developed to evaluate residual likely to recanalize or have clinical recovery with i. thrombolysis. rt-PA therapy. ution in real time [24]: Alexandrov et al. in acute stroke Even incomplete or minimal recanalization deter- During recent years. while stepwise and 70 2 and 3 to distal occlusion and TIBI 4 to slow recanalization indicate proximal clot fragmen- recanalization. between TCD and angiography. as a progressive improvement in flow velocity lasting  Grade 4: stenotic flow.) thrombolysis. Transcranial color-coded duplex is in more than two-thirds of subjects. Patients receiving com- and preexisting risk factors.a. less than 30 min.v. outcome compared with persistent occlusion [25]. or hemodynamic multicenter.and intracranial MCA finding is predictive of a good functional outcome occlusive disease. bined i. or interventional treatment. stepwise recanalization  Grade 3: dampened flow. Ultrasound also has an Progressive deterioration after stroke due to cere- important prognostic role in acute stroke.) tation. thereby changing the degree are twice as likely to have a good long-term outcome as of arterial obstruction and affecting the correlation patients with proximal middle cerebral occlusion. neurological deficit on admission. After adjustment for also useful for the evaluation of combined i.–i. perfusion imaging in Applying these criteria in acute stroke the TIBI acute stroke is still in the experimental phase [19–22]. especially when the MCA nostic value of transcranial ultrasound. The Thrombolysis in Brain Ischemia (TIBI) flow.v. complete MCA recanalization compared with those bolysis acquired by TCD further confirmed the prog. thrombolysis show greater improve- ned the only independent predictor of outcomes [23].v. flow velocity in a few seconds). However. The waveform changes (0 ! 5) correlate well with clinical improvement and a rapid arterial recanalization is associated with better short-term improvement.to 24-hour interval. randomized study confirmed that a normal impairment is closely linked to extra. Acute arterial was occluded or had only minimal flow [26]. thrombus propagation.v. and slow recanalization as a progres-  Grade 5: normal flow. classification correlates with initial stroke severity. bral edema.–intra- age. MCA occlusions are more likely to recanalize with i. occlusion is a dynamic process since thrombus can Patients with distal middle cerebral artery occlusion propagate and break up. Sudden recanalization reflects rapid and (TIBI 0 and 1 refer to proximal occlusion. [28] described the patterns of the  Grade 0: absent flow. By Reperfusion is important for prognosis. mined 24 h after stroke onset results in more favorable ant non-invasive imaging technique for bedside moni. Both providing valuable information on temporal patterns partial and full early reperfusion led to a lesser extent of recanalization. arterial (i. ultrasound has become an import. clinical recovery and mortality in patients treated with New ultrasound contrast agents (UCAs) that can recombinant tissue plasminogen activator (rt-PA). A prospective. Arterial recanalization can be enhanced by combi- ning t-PA with ultrasound. previ.  seconds of breath holding cific phospholipid molecules that. the MCA velocity in response to 30 s breath-holding ial recanalization. Recent studies evaluated Ultrasound has an important prognostic role in the effects of administration of microbubbles on the acute stroke and can be used to monitor thrombus initial MCA recanalization during systemic thromboly- dissolution during thrombolysis. Although these microbubbles. Vasomotor reactivity domly assigned to receive continuous TCD monitoring Vasomotor reactivity describes the ability of the cere- or placebo in addition to intravenous t-PA. Chapter 4: Ultrasound in acute ischemic stroke migration. temic thrombolysis. and even further with Continuous monitoring with 2 MHz TCD in com- gaseous microbubbles. Sudden recanalization was associated with through the circulation. As the bubbles approach and a higher degree of neurological improvement and permeate through the thrombus.v. Another widely used agent is i. Measuring vasomotor increase in the rate of intracerebral hemorrhage [30]. significantly higher recanalization rate or dramatic recovery than i. nanobubbles carry gas showed that impaired vasomotor reactivity can help . the phospholipid A tandem internal carotid artery/middle cerebral shell breaks up and releases gas. which increase the surface bination with standard i. were originally designed to improve MFVend  MFVbaseline BHI ¼ conventional ultrasound images. unique opportunity to detect the recanalization during and after t-PA administration. The result is bubble- artery occlusion independently predicted a poor induced cavitation with fluid jets that erode the throm- response to thrombolysis in patients with a proximal bus surface. nostic and prognostic purposes. sis and continuous 2 MHz pulsed-wave TCD monitor- ing.v.15 mg/kg). 126 patients were ran. Others [33] evaluated BHI in different studies and 71 When injected intravenously. when exposed to mechanical agitation. [32] described a simple measurement of microbubbles showed signs of further enhancing arter. Only 4. Newer-generation bubbles use spe. t-PA therapy results in area for the thrombolytic action of t-PA. the recanalization or dramatic clinical recovery within 2 h changes in cerebral blood flow (velocity in TCD stud- after the administration of a TPA bolus occurred in ies) in response to such stimuli can be studied by 49% of the target group as compared to 30% in the TCD. Upon encoun- recanalization. facilitation of throm. ultrasound and gaseous Markus et al.v. Complete bral circulation to respond to vasomotor stimuli.8% of patients vasomotor reactivity. ultra- increasing the transport of t-PA into the thrombus sound-alone treatment should not be substituted for and improving the binding affinity. MFVbaseline bolysis is now emerging as a new treatment application 100 for this technology. increases the surface area for thrombolytic action and accelerates lysis of clots [12]. acetazolamide (0. The complete recanalization rate was significantly Ultrasound accelerated thrombolysis higher in the t-PAþultrasoundþmicrobubbles group (55%) than in the t-PA/ultrasound (41%) and t-PA and microbubbles (24%) groups [31] with no increase in sICH after sys- Transcranial Doppler can be used not only for diag. they can be detected better long-term outcome than stepwise or slow and activated by the ultrasound energy. combining t-PA. but not in those with a distal MCA clot [29]. tering an ultrasound pressure wave. (MFV: mean flow velocity). but also for therapy. reactivity requires standard experimental conditions. arrange themselves in nanobub. ness of ultrasound in facilitating thrombolysis. Recently. These results showed the positive effects of 2 MHz CO2 results in vasodilatation and increased cere- continuous TCD monitoring in acute stroke. t-PA therapy without TCD monitor- ing. bles with a consistent 1–2 µm (or even less) diameter. CO2 is a widely used agent to measure cerebral control group (P ¼ 0.03). and termed it the breath-holding index (BHI): ously known as diagnostic microbubbles or gaseous microspheres. and provides a t-PA treatment. this erosion MCA clot. with no bral blood flow velocity. developed symptomatic intracerebral hemorrhage. In the presence of t-PA. Although recent observations support the useful- The ultrasound enhances the enzymatic thrombolysis. In the CLOTBUST trial. is seen on grayscale ultrasound.  70% stenoses ICA/CCA: >4.0. To penetrate the skull. and the diagnosis can be confirmed by ultra- sound contrast agents. respectively [34]. blood flow is laminar. The results of contrast. power and color Doppler ology. When The duplex mode of TCCD enables sampling no stenosis is present. The sonographic characteristics of symptomatic Transcranial color-coded duplex sonography (TCCD) and asymptomatic carotid plaques are different: combines the imaging of intracranial vessels and symptomatic plaques are more likely to be hypo. detecting the high-intensity transient signals (HITS)  Ratios of the maximal systolic flow velocity within passing through the MCA. Decreased important general rule for ultrasound is the greater vasomotor reactivity suggests failure of collateral flow the degree of stenosis.  50–69% stenosis: ICA PSV is 125–230 cm/s Right-to-left shunt detection and plaque is visible. while asymptomatic uses low frequencies (1. Some patients cannot be exam- The degree of stenosis is better measured on the ined because of an insufficient acoustic window. to approximately 8–10% of acute ischemic stroke.0.  Peak systolic velocities:  Normal: ICA PSV <125 cm/s. the carotid artery can be measured. The prevalence  Total occlusion: no detectable patent lumen is even higher in cryptogenic stroke or TIA and espe. infarction and stroke. the intimal-medial thickness of value in the diagnostic workup of stroke patients. Contrast-enhanced TCD can be used for ultrasound. parenchymal structures. which limit the plaques are hyperechoic and moderately stenotic. the ICA stenosis divided by the maximal systolic ence of a right-to-left shunt. Occlusion results in a complete absence of color-flow signal in Chapter Summary ICA. Various studies using differ. Right-to-left shunts. An corrected blood-flow velocities.  Near occlusion: a markedly narrowed lumen with a prevalence of 10–35% in various echocardi- on c-Doppler ultrasound.75–3. to adapt to the stenosis. Doppler ultrasonography is the primary non-invasive Intracranial stenosis and occlusion corresponds test for evaluating carotid stenosis. flow velocity within the non-affected CCA: enhanced TCD have been compared with those of  <50% stenoses ICA/CCA: <2. sensitivity and specificity of 68–100% and 67–100%. the flow becomes turbulent. osis or occlusion (proximal to the origin of the oph- thalmic artery) a reversed (extra ! intracranial) flow can be detected in the ophthalmic artery. TCCD echoic and highly stenotic. contrast-transesophageal echo and found to have a  50–69% stenoses ICA/CCA: 2.g. Another study with TCD and TEE Ratios may be particularly helpful in situations in proved the strength of TCD in PFO detection and which cardiovascular factors (e. spatial resolution. In case of hemodynamically significant ICA sten- tify patients with a patent foramen ovale.0–4. Mean velocity . Section 1: Etiology. basis of the waveform and spectral analysis. are common in the general population. 30% risk of stroke with ultrasonography are: over 2 years. motor reactivity have demonstrated a remarkable Commonly used methods to estimate stenosis ipsilateral event rate of approx. no plaque or The changes in cerebral blood flow in response to intimal thickening. greater to be clinically important.  <50% stenosis: ICA PSV <125 cm/s and plaque or intimal thickening. ovale (PFO). thus indicating the pres. poor ejection frac- right-to-left (RLS) quantification [35]. and no flow cially in younger patients without an apparent eti. tion) limit the increase in velocity. vasomotor stimuli can be studied by TCD. particularly a patent foramen  >70% stenosis to near occlusion: ICA PSV >230 cm/s and visible lumen narrowing. TCD has an established clinical With ultrasound. Contrast-enhanced TCD can also be used to iden. the higher the velocity.5 MHz).0. pathophysiology and imaging to identify patients at higher risk of stroke. Most studies consider carotid stenosis of 60% or ent provocative measures for assessing cerebral vaso. In conclusion. ography and autopsy studies for PFO. Increases in the TCD is also an evolving ultrasound method with intimal-medial thickness (IMT) of the carotid artery are associated with an increased risk of myocardial increasing therapeutic potential. With of vessels and Doppler measurements of angle- 72 greater stenosis. is seen on spectral. MES Chaves PH. Assessment transcranial dissolution during thrombolysis. provides a unique opportunity to detect recanaliza- spectral analysis and knowledge of extracranial cir. which could permit differentiation. Tegeler CH. improvement and dampened flow signals are less favorable prognostic signs. Feldman E. if this is not 2003. increasing the transport of t-PA into the abnormalities. Eur J Neurol acute stroke is still in the experimental phase. 2002. Detection of MES can identify patients with stroke or TIA likely to be due to embol. References 1. 8. but also for 9. Alexandrov AV. ultrasound and gaseous microbubbles. Brainin M. Irimiaa P. circulation lesions if performed without transcranial color-coded duplex imaging or contrast enhance- ment.e. Sloan MA. Different types of emboli (i. imaging http://emedicine. Cao JJ. media thickness. Chabriate H. Valdueza JM. TCD monitoring Society of Radiologists in Ultrasound consensus conference. . 9:1–8. examination with carotid/vertebral duplex and trans. intracranial circulation. 108(2):166–70. Carotid artery. 246(8):637–47. acts as a predictor for new stenosis: grayscale and Doppler ultrasound diagnosis – cerebral ischemic event recurrence. Stuttgart: 73 Thieme. therapy. 2008. Zipper SG. The changes in cerebral blood flow in response lished for urgent bedside neurovascular ultrasound to vasomotor stimuli can be studied by TCD. New ultrasound contrast agents (UCAs) that can Bogousslavsky J. acute stroke and can be used to monitor thrombus Caplan LR. in addition. Ultrasound Q 2003. possible to use ultrasound for the visualization of 6. car.com/article/ diac or carotid) have different acoustic properties 417524-imaging. whereas slow flow 62:1468–81. artery-to-artery or cardio. C-reactive protein. Roehl JE. It must be combined with other par. Chapter 4: Ultrasound in acute ischemic stroke analysis is not enough to identify intracranial vessel thrombolysis. The waveform Doppler ultrasonography report of the therapeutics changes correlate well with clinical improvement and technology assessment subcommittee of the and a rapid arterial recanalization is associated with American Academy of Neurology. and incidence of ischemic stroke in the tification of a particularly high-risk group of patients elderly: the Cardiovascular Health Study. Eur J Neurol 2006. and ultrasonic characteristics. generation bubbles permeate through the thrombus cranial vessel occlusion is similar to that of magnetic and erode the thrombus surface. thrombus and improving the binding affinity. Decreased vasomotor reactivity suggests failure of cranial Doppler in patients with acute stroke. Manolio TA.medscape. based on composition 4. Ultrasound has an important prognostic role in 7. 2. tion during and after t-PA administration. Arterial culation. et al. With a completely normal spectral TCD. Benson CB. Klingebiel R. Silver B. Kuller LH. diagnostic and prognostic purposes. 3. Moneta GL. more aggressive antithrombotic therapy. Grant EG. better short-term improvement. Contrast-enhanced TCD can also be used to iden- TCD has modest sensitivity (55–60%) for posterior tify patients with a patent foramen ovale. http://emedicine. Newer- with ECE the diagnostic confidence of TCCD for intra. 19(4):190–8. But perfusion imaging in colour-coded duplex sonography-a review.com/article/ TCD identifies microembolic signs (MES) in the 1155193-overview. et al. Neurology 2004. may help to discriminate between different potential sources of embolism (i. carotid intima- detection by TCD in CEA candidates may allow iden. Nadalo LA. stenosis: embolic strokes). TCD has collateral flow to adapt to a stenosis and can help the highest sensitivity (>90%) for acute arterial identify patients at higher risk of stroke. and ameters such as asymmetry. segmental elevations. Stolz E. et al. Thach C. Psaty BM. Recently. The use of echo-contrast enhancing agents recanalization can be further enhanced by combining (ECE) increases the sensitivity and specificity and t-PA. surface area for the thrombolytic action of t-PA. Clinical application of transcranial brain perfusion deficits. there is less than 5% chance that an urgent angiogram will show any acute obstruction. guideline on neuroimaging in acute stroke. J Neurol 1999. Masdeu JC. which increases the resonance angiography. Baumgartner RW. Asenbaumb S. Circulation who merit an early intervention or. obstructions located in the proximal MCA and ICAs. 13:1271–83. Report of ment of contrast-specific imaging modalities make it an EFNS task force.medscape. EFNS pass through the microcirculation and the develop. Schreiber SJ. 5. Transcranial color-coded duplex Transcranial Doppler can be used not only for sonography. and size. et al. a practical algorithm has been pub. Walters MC. Updated: 15 Dec 2008.e. Spencer MP. Carotid artery ism and. possible. 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Stroke 2000; 31:1640–5. 75 Section 2 Clinical epidemiology and risk factors Chapter 5 Basic epidemiology of stroke and risk assessment Jaakko Tuomilehto, Markku Mähönen and Cinzia Sarti Neuroimaging studies are needed for classification Definition of stroke of stroke by subtypes: subarachnoid hemorrhage, In epidemiological studies, stroke is defined by clin- intracerebral hemorrhage and brain infarction ical findings and symptoms [1]: rapidly developed (necrosis). Although there may be large variations in signs of focal (or global) disturbance of cerebral func- stroke subtype distributions between populations, tion lasting more than 24 hours (unless interrupted by thrombotic and embolic strokes are responsible for surgery or death), with no apparent cause other than a about 80–85% of all strokes in the Indo-European vascular origin. This approach is supplemented with populations, and as low as 65% in some Asian popu- neuroimaging but even with advanced imaging lations. Subarachnoid hemorrhage represents 5–10% techniques the diagnosis is based on clinical signs. of all strokes, and occurs more often in younger Therefore, precise definitions of clinical signs are subjects, while both intracerebral and especially needed. WHO definitions are [1]: thrombotic and embolic stroke increase markedly Definite focal signs: with age.  unilateral or bilateral motor impairment (including dyscoordination)  unilateral or bilateral sensory impairment The scope of the problem  aphasis/dysphasis (non-fluent speech) Stroke is the second leading cause of death worldwide  hemianopia (half-sided impairment of visual in the adult population, the first being coronary heart fields) disease [2]. Of note, stroke is an increasing problem  diplopia in developing countries, 87% of stroke deaths occur-  forced gaze (conjugate deviation) ring in low- and middle-income countries [2–4].  dysphagia of acute onset Stroke is the fourth leading cause of disease burden  apraxia of acute onset (as measured in disability-adjusted life years [DALYs])  ataxia of acute onset after heart disease, HIV/AIDS and unipolar depres-  perception deficit of acute onset. sive disorders [2]. In the 1990s, it caused about 4.4 million deaths worldwide in 1990 and 5.4 million Not acceptable as sole evidence of focal in 1999, with two-thirds of these deaths occurring in dysfunction: less-developed countries [5, 6]. While in high-income  dizziness, vertigo countries 9.9% of all deaths could be attributed  localized headache to stroke, in low-and-middle-income countries this  blurred vision of both eyes proportion was 9.5%, almost equal; because the total  dysarthria (slurred speech) number of deaths in low- and middle-income coun-  impaired cognitive function (including confusion) tries is much greater than in high-income countries,  impaired consciousness globally the highest burden of stroke is among people  seizures. living in low- and middle-income countries. DALYs due to stroke were 62.67 per million person-years (Although strokes can present in this way, these in high-income countries, corresponding to 4.5% of signs are not specific and cannot therefore be the total DALYs, when the corresponding estimate for accepted as definite evidence of stroke.) low-and-middle-income countries was 9.35 per 77 Section 2: Clinical epidemiology and risk factors Men 35–74, period 1968–1994 Women 35–74, period 1968–1994 Poland Poland Hungary Yugoslavia (form.) Yugoslavia (form.) Romania Bulgaria Hungary Romania Mauritius Mauritius Cuba Czechoslovakia (form) Czechoslovakia (form) Cuba Bulgaria Argentina Argentina Greece Denmark Mexico Venezuela Denmark Mexico Venezuela Greece Chile Uruguay Uruguay Chile Sweden Sweden Trinidad and Tobago Trinidad and Tobago The Netherlands United Kingdom Norway The Netherlands Portugal Norway Finland Portugal United Kingdom Austria New Zealand Finland Italy Italy Austria New Zealand Ireland Germany (form. Fed.) Germany (form. Fed.) Canada Spain USA Israel Belgium Canada Ireland Belgium Spain Switzerland Switzerland USA Israel France France Australia Australia Japan Japan –8 –4 0 4 8 –8 –4 0 4 8 % % Figure 5.1. Annual percentage change in mortality from stroke in men (left) and women (right) aged 35–74 years in selected countries during the entire study period, 1968–1994. (Source and copyright, see reference 3.) million person-years, and this translated to 6.3% of A comparison of routinely collected stroke the total DALYs. mortality data from many countries shows that, in general, mortality rates have declined over recent decades, most notably in Japan, Australia, North Incidence, mortality and case fatality America and Western Europe [7] (Figure 5.1). There are several issues related to the occurrence of Mortality from stroke was highest in the world in stroke that are important from an epidemiological Finland in the 1970s, together with Japan. (and clinical) perspective. While it would be useful There are few studies with validated data from to know the incidence (occurrence of first stroke stroke registers or other sources. The incidence of events), in most populations data may be available stroke has declined sharply in Finland during the on mortality from stroke only, but not on non-fatal last decades [8], and in 1998 it was 241/100 000, not events. The case fatality at the stroke event, usually far from other Western industrialized countries, determined as the proportion of deaths occurring after a steady fall of about 3% per year throughout during the first 4 weeks after the onset of stroke event, the 15 years studied. Mortality from stroke declined gives information about the severity of stroke and even more steeply, around 4% per year, with a may also reflect the efficacy of early management of standardized mortality rate in 1998 of 50/100 000 acute stroke. The relative frequency of different sub- among men and 30/100 000 among women [8]. types of stroke varies among populations, and in Other countries that already had comparatively particular among different ethnic groups. This vari- lower stroke incidence rates in the 1980s, for 78 ation may be in part due to genetic differences or due example New Zealand [9], the USA [10], or to differences in risk-factor profiles. Denmark [11], have reported no fall in stroke Chapter 5: Basic epidemiology of stroke and risk assessment incidence, while an increase in the incidence in the nine western European populations, stroke of stroke has been observed in Eastern Europe and mortality declined. Russia [6, 7, 12]. In Shanghai, China, almost no Changes in incidence and improved survival on decline in incidence of stroke but a clear decline in the downward trend in stroke mortality are not easy stroke mortality was reported [13]. The differences to quantify, due to the difficulty of measuring accu- observed between countries in mortality rates, and rately the incidence of stroke. The MONICA Stroke even more in incidence rates, are, however, difficult Study, for example, compared stroke incidence (or to interpret, as they depend largely on the study more precisely attack rate, which included various design, the accuracy of the data collection, and the proportions of recurrent strokes), mortality and case time point when the measurements were made. fatality in 14 populations aged 35–64 years (mostly The overall case fatality (the proportion of deaths located in Europe except two – one in China and one among all strokes) is roughly 20% within the first in Novosibirsk in Asian Russia). The study confirmed month, and increases around 5% per year. There is, the above observed trends in stroke incidence and however, a large variation in case fatality of stroke mortality, and reported a large geographical variation among populations; in the WHO Monitoring of also in case fatality. In most populations, changes Trends and Determinants in Cardiovascular Disease in stroke mortality, whether declining or increasing, (MONICA) Stroke Study among men, the case fata- were principally attributable to changes in case fatality lity of stroke ranged from 12% in northern Sweden rather than changes in event rates [7]. to 53% in Moscow in Russia [14]. Overall, the case fatality was high in all eastern European countries. In many epidemiological studies strokes have been defined without confirmation by neuroimaging. In women, the difference in case fatality of stroke Definitions by clinical means alone can be impre- between populations was larger than in men, ranging cise and sometimes misleading. Robust data have from 16% in Kuopio to 57% in Moscow. shown that the overall case fatality is roughly 20% within the first month and increases about 5% per year. Large variations occur between countries. On Trends in stroke event rates, case fatality a global scale, stroke is the second most frequent cause of mortality world-wide and a leading cause and mortality of stroke of disability. It is especially prevalent in low- and Table 5.1 shows the trends, separately for each middle-income countries. MONICA population, in stroke event rates, case fatal- ity and mortality of stroke, both in the register and in routine mortality statistics. Stroke event rates declined Risk factors in nine of 14 populations in men and eight of Stroke has a multifactorial origin and a plethora of 14 populations in women. In men, the case fatality putative and confirmed risk factors have been listed of stroke declined in seven populations, increased and tested in various types of studies. The assessment in eight, and fluctuated only slightly in two. Among of the global epidemiology is severely hindered by the women, a decline in case fatality was seen in eight lack of any kind of data on stroke occurrence and risk populations, no obvious change was seen in three, and factors in most populations in the world. Although an increase was observed in three. The trends in case over 65% of all deaths due to stroke occur in develop- fatality were statistically significant among men in ing countries, studies of stroke epidemiology in these only two populations with declining trends and in populations hardly exist. two with increasing trends. Among women, there The American Heart Association Stroke Council’s was a significant downward trend in four populations. Scientific Statement Oversight Committee guideline Within each population, the CIs for the case fatality has provided an overview of the evidence on various trends were larger than those for the trends in stroke established and potential stroke risk factors and pro- event rates. Of the 14 populations, stroke mortality posed recommendations for the reduction of stroke declined in eight populations among men and risk [15]. The committee used systematic literature 10 populations among women. Stroke mortality reviews published during 2001 to January 2005, refer- increased in all the eastern European populations ence to previously published guidelines, personal files 79 except in Warsaw, Poland. In Beijing, China and and expert opinions to summarize existing evidence 1. Age standardized stroke attack rate. % Mortality Rate per 100 000 First 3 Years Last 3 Years First 3 Years Last 3 Years First 3 Years Last 3 Years Men CHN-BEI 248 241 27 26 67 63 (234–264) (226–255) (24–29) (23–29) (59–75) (56–71) CEN-ELO 218 160 16 20 34 31 (197–241) (143–179) (12–20) (15–25) (26–44) (24–40) FIN-KUO 572 510 19 16 72 50 (340–407) (292–340) (16–23) (13–20) (58–88) (30–63) FIN-NKA 258 257 22 20 60 51 (254–325) (226–290) (17–28) (15–25) (53–89) (38–68) FIN-TUL 236 228 23 17 54 37 (209–267) (201–257) (18–29) (12–21) (41–70) (27–50) ITA-FR 129 121 35 24 45 29 (120–139) (112–130) (32–39) (21–27) (41–52) (25–34) LTU-KAU 309 347 23 24 60 54 (234–335) (322–374) (19–25) (21–27) (58–83) (72–97) POL-WAR 171 171 52 40 89 69 (166–188) (166–187) (47–57) (35–44) (77–101) (50–79) RUS-MOC 270 216 32 53 86 111 (241–302) (190–245) (26–37) (45–59) (70–105) (93–153) RUS-MOI 249 237 38 51 96 122 (231–269) (220–259) (34–42) (43–55) (54–108) (110–135) RUS-NOI 438 449 27 35 122 190 (382–500) (409–500) (21–33) (30–40) (93–159) (132–192) SWE-GOT 129 149 17 18 22 27 (115–145) (133–165) (13–21) (14–22) (17–27) (21–34) SWE-NSW 221 219 16 12 35 26 (205–230) (203–235) (12–19) (10–15) (29–42) (21–33) YUG-NOS 222 211 37 41 82 87 (109–248) (100–238) (31–42) (36–47) (58–98) (74–100) Women CHN-BEI 175 182 30 27 64 50 (163–188) (160–195) (27–34) (24–31) (47–81) (43–58) DEM-ELO 90 90 19 22 20 19 80 (95–114) (77–104) (14–25) (15–28) (14–28) (13–26) . Population Attack Rate per 100 000 Case Fatality. case fatality and mortality in the WHO MONICA Stroke Study populations [14]. Section 2: Clinical epidemiology and risk factors Table 5. . migraine headache. infection. documented or less well-documented).) Population Attack Rate per 100 000 Case Fatality. diabetes. modifiable. inflammation and to cigarette smoke. exposure phospholipase. % Mortality Rate per 100 000 First 3 Years Last 3 Years First 3 Years Last 3 Years First 3 Years Last 3 Years FIN-KUO 139 130 27 16 48 21 (167–213) (113–140) (22–32) (11–21) (38–61) (14–30) FIN-NKA 124 117 23 20 29 23 (103–148) (97–140) (16–31) (13–27) (19–41) (15–34) FIN-TUL 117 108 24 24 29 27 (90–137) (91–128) (17–31) (17–31) (20–30) (18–37) ITA-FRI 68 50 42 31 26 18 (57–70) (53–65) (37–47) (26–36) (22–30) (15–22) LTU-KAU 154 152 24 26 35 46 (139–170) (166–190) (19–23) (22–30) (23–44) (38–55) POL-WAR 90 93 54 44 49 40 (79–101) (83–104) (48–60) (38–49) (40–56) (38–47) RUS-MOC 146 94 39 47 53 44 (120–165) (79–110) (31–44) (30–55) (43–65) (35–55) RUS-MOI 135 107 30 57 52 61 (122–145) (29–118) (35–44) (52–68) (45–60) (54–60) RUS-MOI 341 391 25 23 87 82 (303–383) (352–433) (20–31) (18–27) (58–109) (65–106) SWE-GOT 71 72 24 25 17 18 (61–82) (65–84) (17–30) (18–32) (12–23) (13–24) SWE-MSW 119 136 21 17 25 23 (107–132) (123–150) (17–25) (13–20) (20–31) (18–20) YUG-NOS 114 127 49 42 55 53 (99–132) (112–144) (40–65) (35–48) (44–67) (43–64) Note: Values in parentheses are 95% CIs. include the metabolic syndrome. This paper represents probably the most thor- tain other cardiac conditions. poor diet. Less well- for modification (non-modifiable. hyperhomocysteinemia. dyslipidemia. alcohol abuse. oral contraceptive use. sex. hypercoagulability. postmenopausal prevention of stroke. Chapter 5: Basic epidemiology of stroke and risk assessment Table 5. ethnicity and genetic factors. sickle-cell disease. atrial fibrillation and cer. physical inactivity and first stroke were classified according to their potential obesity and central body fat distribution. or documented or potentially modifiable risk factors potentially modifiable) and strength of evidence (well.1. elevated lipoprotein-associated modifiable risk factors include hypertension. Risk factors or risk markers for a hormone therapy. carotid ough assessment of the prediction and potential for the 81 artery stenosis. Non-modifiable drug abuse. on standard criteria. Well-documented and elevated lipoprotein(a). sleep-disordered risk factors include age. low birth weight. (cont. race/ breathing. and (v) scoring within compared with European Americans. tions and diseases that have importance as risk factors consuming 0. 5 to 15 g/day). (iii) familial in the Women’s Health Study [32]. 20] and some Hispanic Americans [21. in men within the age range of 45–84 years [18. blood pressure themselves cannot be modified. diabetes. the corresponding proportions were 35% and 52%. 22] (iv) modest alcohol consumption (men. responding relative risks were 0. and 0. >30 g alcohol/day in risk factor for stroke [29. it is particularly important to pay [34]. Thus. (ii) a body mass index clear ethnic group differences exist. almost 60% of ischemic stroke cases could advances in genetic research are taking place and have be attributed to hypertension. Stroke is a common and the burden of stroke that may be attributed to disease in both men and women. A low-risk healthy lifestyle interpret. was associated that the stroke risk in such individuals could not be with 52% to 76% lower risk of total stroke mortality modified. Low-risk lifestyle was not significantly rence of risk factors for stroke. (ii) genetic associated with risk of hemorrhagic stroke. in the analysis of the data from the Health decade after age 55 years [16. while the age relation of intracerebral Health Study the impact on stroke risk of a combi- hemorrhage is less steep and the peak age of SAH nation of healthy lifestyle characteristics was evaluated incidence is around 45–55 years. In the Women’s Health Study. Low birth weight is another (>15 g alcohol/day in women. and who had none of these factors. 5 to have higher stroke incidence and mortality rates as 30 g/day. In them. There are several well-documented medical condi. it does not mean <120/80 mmHg.5 to 1. women. it is well known that intracerebral bleed. 17]. had 71% lower risk of ischemic stroke Brainin et al. some general observations compared with women with the least healthy lifestyle are made on lifestyle factors. men) [33]. low birth weight.19 for ischemic stroke compared with women ing is more common in oriental populations. In this chapter.20 Both paternal and maternal history of stroke are for ischemic stroke. the cor- SAH most common in Finland and Sweden [7. Stamler et al. smoking. and their relative import. five low-risk factors had a relative risk of 0. respectively. a low-risk healthy lifestyle that is associated ance for stroke incidence or recurrence is reported. Among men. Among women. Women with all mortality does not follow any ethnic patterns [23]. found that a low-risk lifestyle. seems to be beneficial in the prevention of ischemic racial or ethnic factors.21 for total Nevertheless. (iii) 30 min/day of moderate activity. and among men familial aggregation. with a reduced risk of multiple chronic diseases also Among the non-modifiable risk factors old age. Other studies have sharing of environmental/lifestyle factors associated also evaluated joint effects of multiple lifestyle-related with stroke and (iv) the interaction between genetic risk profiles on stroke risk. 47% of total and associated with an increased stroke risk [24–26]. Diet and other lifestyle factors were updated from self- Racial or ethnic specific stroke risk is difficult to reported questionnaires. cans [18. African Ameri- <25 kg/m2. 30]. These are described in the next chapter by healthy diet. rapid dam study. but it is more common these unhealthy lifestyle choices was calculated [31]. the risk of stroke doubles for each successive Recently.5 drinks a day. defined as never smoking. exercising  4 times a week. In individuals In the WHO MONICA Project. continuous monitoring of stroke events was . Although these risk factors defined as cholesterol <200 mg/dl. 19]. This is also true for Professionals Follow-up Study and from the Nurses’ ischemic stroke. [32]. In the German EPIC Pots- and environmental effects [26–28]. While within a country such as the USA was defined as: (i) not smoking. nor was it susceptibility to these risk factors. having a BMI <22 kg/m2. repeated popu- 82 with non-modifiable risk factors. globally stroke the top 40% of a healthy diet score. Currently. stroke. women with the attention to the control of modifiable risk factors. healthiest lifestyle score. hypercholes- resulted in the identification of genes associated with terolemia. Section 2: Clinical epidemiology and risk factors Non-modifiable risk factors of stroke Overall lifestyle patterns Age is probably the most important determinant of and stroke risk stroke. It is 54% of ischemic stroke cases were attributable to lack not necessarily “stroke genes” that are behind this of adherence to a low-risk lifestyle. cular disease in general. 24]. and some. and following a for stroke. times genetic susceptibility play a role. as it is for cardiovas. and heavy alcohol consumption stroke and its subtypes. and not smoking. nisms may contribute to it such as (i) familial occur. prevention focused lation surveys of cardiovascular risk factors and on the modifiable ones is particularly important.31 for total and 0. but one or more of the mecha. all with a score of 4 or greater. of all referrals with suspected TIA (p < 0. patients with probable or definite TIA (p < 0. and 31. serum cholesterol and BMI with a very high risk of suffering a lasting stroke as systolic blood pressure into a risk score explained opposed to those whose TIA lasted only a few only a small additional fraction of the variation in minutes. have developed and validated a addition. or 10-year stroke with a score of 5. but it is certainly not possible to make any use of in the Oxford Vascular Study population-based cohort such information for the individual risk assessment. On Hospital-based and population-based cohort studies the other hand. Prediction of stroke in patients with TIA Prediction of stroke in the Ischemic stroke is often preceded by early symptoms. while have reported 7-day risks of stroke of up to 10% plenty of risk prediction scores for coronary heart [39–43]. lifestyle background. stroke. This imbalance is mainly of stroke after TIA or minor stroke have been due to the fact that most prospective studies of cardio- developed [39–42. it is robust enough to be used in routine stroke rates was considered.006). The Framingham Stroke Profile (FSP) 6. Stroke authors concluded that the risk of stroke during the trends were compared with trends in individual risk 7 days after TIA seems to be highly predictable. Combining trends in daily who suffered a TIA lasting longer than 1 hour carry cigarette smoking. A six-point score pointed out that the major risk factors for coronary derived (age [ >60 years ¼ 1]. A 3–4-year time they call for further validations and refinements of lag between changes in risk factors and change in this score. In women. gender. association in men. Population-level trends clinical practice to identify high-risk individuals in in systolic blood pressure showed a strong association European populations who need emergency investi- with stroke event trends in women. five-. A substantial international vascular disease have been carried out in the middle- variation exists as to how patients with suspected TIA aged populations (men) in whom coronary heart are managed in the acute phase.4% in 274 (73%) captured by such tools. 12. of symptoms in min [  60 ¼2. Patients systolic blood pressure. The reason why one person gets a ance without weakness ¼ 1. ethnicity and geography are incompletely of 5 or greater: 7-day risk was 0. Models with predictors for long-term risk disease have been developed. 38]. 38% of the variation in stroke event trends was explained by changes in Transient ischemic attacks carry a high risk of early recurrence especially within the first days. Some risk-assessment tools are patients with a score less than 5. general population i. 44–46].0001).1% in 66 (18%) gender-specific and give one-. is not clear. other ¼ 0]. In Rothwell et al. Simple risk scores to assess high versus stroke event trends. and in For stroke risk-assessment tools. 95% of factors stratified by non-modifiable factors such as strokes occurred in 101 (27%) patients with a score age. speech disturb. only a few such attempts exist. blood pressure [systolic heart disease. <10 ¼ 0]) Variations in genetic factors or interactions between was highly predictive of 7-day risk of stroke in lifestyle-related factors may provide some answers. Chapter 5: Basic epidemiology of stroke and risk assessment conducted in 35–64-year-old people over a 7–13-year appointment. complex inter- the hospital-based weekly TIA clinic-referred cohort actions of risk factors and the effects of certain risk (p ¼ 0. The risk of Various multivariable models can be generated to esti- stroke after a TIA attack has been underestimated for mate a person’s risk for stroke in the populations many years due to issues in study designs [37. 14 (7. but there was no gation and treatment. The period in 15 populations in nine countries. type 2  140 mmHg and/or diastolic 90 mmHg ¼ 1]. diabetes and certain types of cancer all share the same ical features [unilateral weakness ¼ 2. In the hospital-referred clinic cohort.e.5%) uses a Cox proportional-hazards model with risk 83 patients had a stroke before their scheduled factors as covariates and points calculated according . In the suspected TIA cohort. and duration stroke and another one type 2 diabetes etc. While factors and their combinations [35]. where prospective studies have been carried out.4% in 35 (9%) with a score of risk estimates. a transient ischemic attack (TIA) [36]. many risk prediction models have included simple risk score to predict stroke during the first mostly biological risk factors. peripheral vascular disease. low stroke risk in TIA patients are clinically useful. disease is a more common outcome than stroke. clin. It has been repeatedly 7 days after a TIA attack [47]. 10–59 ¼ 1.0001). Framingham stroke risk profile. Points 0 þ1 þ2 þ3 þ4 þ5 þ6 þ7 þ8 þ9 þ10 Men Age.2. modified [49]. mmHg History of diabetes No Yes Cigarette smoking No Yes Cardiovascular disease No Yes Atrial fibrillation No Yes Left ventricular hypertrophy No Yes on electrocardiogram . mmHg Treated systolic blood 97–105 106–112 113–117 118–123 124–129 130–135 136–142 143–150 151–161 162–176 177–205 pressure. mmHg Treated systolic blood 95–106 107–113 114–119 120–125 126–131 132–139 140–148 149–160 161–204 205–216 pressure. years 54–56 57–59 60–62 63–65 66–68 69–72 73–75 76–78 79–81 82–84 85 Untreated systolic blood 97–105 106–115 116–125 126–135 136–145 146–155 156–165 166–175 176–185 186–195 196–205 pressure. mmHg History of diabetes No Yes Cigarette smoking No Yes Cardiovascular disease No Yes Atrial fibrillation No Yes Left ventricular hypertrophy No Yes on electrocardiogram Women Age. years 54–56 57–59 60–62 63–64 65–67 68–70 71–73 74–76 77–78 79–81 82–84 Untreated systolic blood 95–106 107–118 119–130 131–143 144–155 156–167 168–180 181–192 193–204 205–216 pressure.84 Table 5. strong to suggest that the control of the established probably causal risk factors for ischemic heart disease: risk factors for stroke will result in prevention of a raised apoB/apoA1 ratio. but unfortunately we do or duration of exposure to the risk factor)? not have such a simple risk-assessment tool for stroke. a practical way to Trends and Determinants in Cardiovascular Disease consider the causal significance of a risk factor for (MONICA) stroke study compared the stroke inci- ischemic stroke [57]: dence (or more precisely attack rate). It is independent of other risk factors that may interact widely used. It is especially prevalent in low. based on the well-known middle-income countries. multiple variable regression analysis to be pendent stroke predictors are shown in Table 5. Techniques such as meta-analysis will help. not be allocated disproportionately to emerging novel smoking and diabetes. However. simple risk assessment tools  Is the temporal relation correct (exposure to the that have been developed for instance for type 2 risk factor occurred before the stroke)? diabetes [53] might be useful since they do not require  Is there a dose–response relation (increasing risk or any laboratory testing. On a global scale. but its validity among various subgroups with the risk factor or be a confounding risk other than the Framingham cohort has not been factor? adequately studied. Nevertheless risk-prediction tools  Is the association strong? based on clinical data have been developed [51. the contribution of any single Chapter Summary gene towards ischemic stroke is likely to be modest and to apply in selected patients only and in combin. and many other Stroke risk assessment leans on risk profiles in a dietary factors. This avenue risk of stroke? in risk assessment needs to be further pursued in order to identify people at risk of stroke as early as possible.  Is the association biologically plausible? Yet it is not difficult to design such given the large  Is the association epidemiologically plausible? number of prospective studies using stroke as the  Is there evidence that reducing exposure to the risk outcome. and also to atrial fibrillation risk factors that may account for up to only 20% of all and valvular heart disease (cardiogenic and embolic strokes at the expense of researching the determinants ischemic stroke) [56]. their causal role remains to be proven. A recent review indicated that of the relatively few established causal factors that about 10% to 20% of atherosclerotic ischemic strokes account for up to 80% of all strokes.2. obesity.g. and also in case factor and ischemic stroke shown by means of . they can many populations. The WHO Monitoring of Bradford Hill criteria on causality. Therefore. The Framingham Stroke Profile is widely used but has so far not been validated in life. While the importance of genes predisposing to stroke cannot be denied [58]. Chapter 5: Basic epidemiology of stroke and risk assessment to the weight of the model coefficients [48–50]. resources should be attributed to high blood pressure. and  Is there evidence from experiments in humans? case fatality in 14 populations aged 35–64 years. New risk factors for stroke but only if the original studies were done properly As many as 60% to 80% of ischemic stroke events can and were comparable. 52]. only be considered as cross-sectional in a particular population. [57].  Is the association consistent from study to study? In a clinical setting. dyslipidemia. it is very important to under- stand the inferences that can be drawn from various studies. by RCTs) leads to a reduction in the predicted the stroke incidence well [55]. Inde. stroke is the second most frequent ation with environmental factors or via other epistatic cause of mortality world-wide and a leading cause (gene–gene or gene–environmental) effects. very large number of stroke events and premature psychosocial stress and low fruit and vegetable intake deaths. In both men and women the FINDRISC factor (e. Therefore. physical inactivity. The study confirmed the large geographical variation  Is the association between exposure to the risk 85 in stroke incidence and mortality.and Hankey proposed. It needs to be pointed out that certain issues such as smoking and alcohol drinking. and if such experiments would appear. The evidence is can probably be attributed to recently established. can never be properly tested in real population. of disability. mortality. Similar tools have been now severity of stroke associated with increasing dose developed for dementia [54]. of stroke varies among populations. However. physical inactivity. 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Targets of primary stroke prevention can Five low-risk lifestyle factors with a high potential to prevent stroke: be the entire population or high-risk – but stroke-  non-smoking free – individuals partly suffering from disorders  moderate activity  30 min/day such as hypertension or diabetes mellitus.5. the Nurses’ shown cigarette smoking to be an independent risk Health Study (71 243 women) and the Health Profes. 89 Persons with low-risk lifestyle (all five low-risk smokers differed between stroke types.4 million to 6. body mass index < 25 kg/m2 adjusted for age. Lifestyle modifications have a high potential to tion is to lower stroke risk attributed to these factors prevent at low cost and low risk the development of through education. The strategy in primary preven. 95% CI 1. was found to be associated with a reduction in Smoking is a well-documented preventable risk ischemic stroke (RR 0. smoking. 95% CI 0. high cholesterol.6 (95% CI 2. low-normal body mass index. Smoking is a leading cause of burden of disease.3. moderate activity Smoking causes changes in blood pressure and weight.1–0. lowered by controlling and treating the underlying disorder. Thus.6) [8].3–2. The total number of low-risk tionship was identified ranging from RR 2. Yvonne Teuschl and Karl Matz The aim of primary prevention is to reduce the risk lifestyle factors) had a decreased risk of stroke of first-ever stroke in asymptomatic people. overweight at low risk for all five factors. and dietary factors.9).2–0. In tobacco will rise from 5. 4–7].  30 min/day.3 factors for vascular diseases: high blood pressure.5 (1–14 factors was associated with a significantly reduced cigarettes/day) to RR 3. Lifestyle factors Stroke prevalence has been associated with individual lifestyle factors (e. only 2% of women and 4% of men were alcohol consumption.g. A dose–response rela- women 5–15 g/day). Chapter 6 Common risk factors and prevention Michael Brainin.4 million in this study. risk of total and ischemic stroke in men and women. healthy lifestyle. was RR 2.g. Healthy lifestyle in general was considered in one Projections estimate the mortality attributed to large prospective cohort study of healthy women. Seven compared to persons fulfilling none of the low-risk factors are regarded as potentially modifiable risk lifestyle factors. diet. blood pressure and obesity stroke risk and modest alcohol consumption (men 5–30 g/day.4) and RR 0.6) [1]. moder.4–1. dyslipidemia. Using factor of stroke.5) for women and men respectively. Large observational studies have the data of two large cohort studies. factor for stroke in both men and women [e. alcohol consumption) in several studies. lifestyle changes and medication. lifestyle components non-smoking. healthy diet.3 million in 2030 [3]. Stroke risk for smokers as compared to non. of these deaths are caused by cardiovascular diseases ate alcohol consumption. Nearly one-third from smoking.  healthy diet  body mass index < 25 kg/m2  modest alcohol consumption. body mass Cigarette smoking index (BMI). sionals Follow-up Study (43 685 men).8 (25 cigarettes/day) [8]. Chiuve et al. regular exercise and healthy and 8% by cerebrovascular diseases [3]. physical inactivity. A meta-analysis of 22 studies indicates an overall [2] defined a low-risk lifestyle score based on the five risk increase for stroke (RR 1. being highest . 5 (95% CI 2.9) [15].4 (95% CI 1–1. times higher (OR.6 mm (SD  2.3) for light smokers a meta-analysis total stroke risk was 1. 95% CI 1. women not using oral contraceptives and 3.3 (95% CI 0.9 (95% CI 1.2 (95% CI 0.7) for women.2 (OR.6–2.1–7. Nevertheless passive for former smokers compared to never smokers was smoking was associated with a greater progression 1.1 (OR. Never smokers exposed to in current smokers [5]. the effects of other risk factors. 2.2–16.4) higher for icians’ Health Study [13] and the Women’s Health non-smoking women using oral contraceptives. for men and women respectively. In the Oslo study. how- current smokers was 43.9–15.7.4 (95% CI 0.0) for smoking ation of ICH risk and smoking in men and women.3.2) and 1.8 (95% CI 0.1 (95% CI 0. The age and risk factors adjusted RR were 2. An interaction between cases of first-ever SAH found an increased risk of smoking and the use of oral contraceptives was noted SAH as high as 7.6) for past smokers compared to Study stroke risk had decreased 5 years after quitting never smokers.3) in former smokers [8]. and OR 4.3) for two longitudinal studies and was higher than blood pressure of other participants. level. cessation is only modest. hypertension and BMI.5–3. increased stroke risk (RR 1.4).3 (95% contraceptives had a 7. p ¼ 0. exposure was 1. In a Japanese cohort relative tobacco smoke had in the period of 3 years a mean risk for stroke mortality had declined 2–4 years after increase of intimal media thickness (IMT) of the smoking cessation by 27% and after 10–15 years it carotid artery of 31. 1. oral contraceptives had an increased risk of ischemic Association of smoking and intracerebral hemor.8) [16]. Several behavioral and 90 mental tobacco smoke exposure.7–2.1–1. relative risk of stroke found for the highest level of cerebral hemorrhages (OR 0.1 increased risk analysis studying the risk factors for ICH found an (95% CI 1.2) for light smokers [11]. In the Framingham 1.07) [10]. nearly 2-fold for ischemic stroke (OR 1.2) and no clear relationship for intra.0–4.3–1. Compared to non-smoking women not for heavy smokers (>20 cigarettes/day).6 (95% CI 2. Smoking is a well-established risk factor for ischemic Smoking may have additive effects and potentiate stroke [8]. due to its addictive effect the success in smoking a few studies investigated stroke risk due to environ. 95% CI 0.1–1 ciga. and 0. using oral contraceptives had a 2.5–3.3.5–1. the Phys.5).0) [8].1) and 2.9–1.6–2. smokers (20 cigarettes/day). stroke OR 1. non-smoking women rhages (ICH) is less well established.1–3. Section 2: Clinical epidemiology and risk factors for subarachnoid hemorrhages (OR 2.5).8 (95% CI 0. risk nearly disappeared after 2 years and relative risk rette based on urine cotinine. A meta-analysis of pharmacological therapies are available to assist 16 studies of variable design and quality suggests that smokers in quitting and their effects are the subject .2 higher risk (95% CI 3.1.1 (95% 95% CI 1. The risk for hemor- smoked [12].1 Study [14].1–1. exposed to smoke.66 (95% CI 2. smoking to the level of non-smokers [4]. rhagic stroke was 1.7–2. 95% CI 0. found a positive dose-dependent associ.6–1. Only ever.2 using oral contraceptives. One meta.0) compared to was decreased by 52% and no longer differed from 25. a achnoid hemorrhages (SAH) found a relative risk of large cohort study. but the absolute difference was larger for non- control studies [9].8 (adjusted OR.2–1. of aneurysmal SAH adjusted for other risk factors Similar effects were found for BMI and blood glucose such as family history. an odds ratio of 3.9. In a study including young and smokers than for smokers. Two large prospective studies.3) for seven case. 12 studies) for ever having observed for hemorrhagic stroke. In and 2. Another between fatal stroke cases and other men were only population-based case-controlled study including 432 found for non-smokers [17]. A similar but weaker synergistic effect was 1. blood pressure of fatal stroke cases 1.64–5. In the Non-smokers exposed to tobacco smoke were Nurses’ Health Study total and ischemic stroke excess estimated to absorb only the equivalent of 0.8) for smoking women using oral con- CI 1. but smoking women using oral adjusted relative risk for current smokers of 1.5–2.9 mm (SD  2. smoking women not using (95% CI 2.6. A meta-analysis focusing only on subar. This may suggest a lower middle-aged patients (18–49 years) and with the risk tolerance for high blood pressure in smokers [17].9–4.7) while it was 2.6 (95% CI 1. Differences in BMI and blood glucose level the OR was 3.1–4.0 mm (SD  1.7–8.9.1) CI 1.9 (95% CI 1. 95% CI 1.4–7. 95% CI 3.7) Smoking cessation reduces stroke risk rapidly. The mean increase of IMT for The benefits of quitting smoking are evident. The 95% CI 1. 95% CI spousal cigarette smoking is associated with an 2.7–5.6–5.010) for non-smokers not people who had never smoked [7].5) for heavy traceptives [19].1).2) in atherosclerosis [15].2 (95% CI (<20 cigarettes/day). 13 studies) and an adjusted relative risk of [18]. A positive linear rela.1–3. but benefits overcome the harmful effect of alcohol at light-moderate alcohol consump.7) than for men (RR 0. even when alcohol consumption was other- of similar efficacy to nicotine replacements [21].9) Alcohol consumption and ischemic stroke (RR 1. Comparing the type of alcoholic beverage consumed. increases the risk of ischemic and total nicotine receptor partial agonist varenicline was also stroke [32. and moderate consumption (12– A high body mass index (BMI 25) is associated with 24 g/day) with a reduction in ischemic stroke (RR an increased risk of stroke in men [38.6–4.9-fold for subarachnoid (RR 2. 95% CI 1.2) and hemorrhagic stroke (RR 2. 41]. drinking and light-drinking hypertensive subjects. 95% CI drinking increase the risk of atrial fibrillation. The wise light. a major 1.2) and nortriptyline (OR wine seems to be associated with the lowest ischemic 2.9. as well as the risk of coronary heart disease and Reducing excessive alcohol intake was found to stroke [25].6–3.96). 0. Especially the flavonoids of transdermal patches. 40.0. 25].8 mmHg in four tional studies found for a consumption of more than randomized controlled intervention studies [36].7. 95% CI 1. Ischemic stroke rate increases in a tionship was found between alcohol consumption dose-dependent manner with body mass index (BMI) and hemorrhagic stroke [25.6) were increased significantly hemorrhages and nearly 2-fold for ischemic in hypertensive heavy drinkers compared to non- stroke.8–1) [26].83.8–2. blood pressure and the risk of hypertension. The relative risk [38. The antidepressants bupro.91) and ischemic stroke (RR 0. Even passive smoking was associated with increased risk for stroke. In a 26-year Japanese prospective cohort ive but have to be intensive [24]. 39] and 0. risk factor of stroke [37]. The relationship between hemorrhagic reduction for total stroke for light alcohol drinking stroke and BMI is less clear. women [40.75–0. 95% CI or more than three drinks/day) and episodic heavy 1. .5) attrib- Excessive alcohol drinking increases all-cause mortal. 1. 44].67–0. as well as the risk of coronary heart disease 26]. Psychosocial intervention such as behavioral jects stroke risk was increased significantly by heavy therapy.57–0. reduce systolic blood pressure by 3.4. 95% CI 0. 41. 43]. 95% CI 0. thereby Currently not enough evidence has been found for the increasing stroke risk. In hypertensive sub- [23]. The relationship between alcohol and overall and ischemic stroke risk was described as J-shaped [25.1.g.1) and to a lesser extent ischemic stroke risk Stroke risk for smokers is 2. pion (OR 1.72. Chapter 6: Common risk factors and prevention of a number of Cochrane reviews (e. study hemorrhagic stroke risk (RR 3. however. mass index [38.7. whereas others found an increased risk of The apparently positive effect of light to moderate hemorrhagic stroke for people with elevated body 91 alcohol consumption is still under discussion. 60 g of ethanol/day (approximately six drinks) an Heavy long-term alcohol consumption (>36 g/day increased risk of ischemic stroke (RR 1. ity. tion. 95% CI 1. inhalers. Their effect seems. uted to heavy drinking were not significant [34]. 95% CI 1. 95% CI 0. found to be more effective in 12 months abstinence Heavy alcohol intake and binge drinking increase when compared to a placebo or to bupropion [22]. 26]. The pattern of cessation.6–0.2) [26]. Obesity 95% CI 0. 95% CI 1. 95% CI 0.91) [26]. All Beneficial effects on lipids and hemostatic factors forms of nicotine replacement therapy (nicotine gum.2. 95% CI 0.7–2. influence of BMI on hemorrhagic stroke risk [39. 41–45]. binge pendent of their antidepressant effect and they are drinking. Excessive alcohol drinking increases all-cause mor- tality. effect at light-moderate alcohol consumption levels.9.5–1.1–9.4) are also successful for smoking stroke and vascular risk [29–31]. [20–24]). this seems to be especially true efficacy of cannabinoid type 1 receptor antagonists for hemorrhagic stroke [33–35].6. to be inde. drinking seems to influence the vascular risk. whereas for non-hypertensive persons the increased risks of hemorrhagic stroke (RR 1. self-help or telephone counseling are effect. have been reported [27].80.3–2.7. drinking. Some studies found no (<12 g/day) seems to be larger for women (RR 0. This suggests that benefits overcome the harmful and stroke. nasal spray.5–3. Light alcohol consumption (<12 g/day) was associated with a reduction in all stroke (RR 0.7) [20]. A meta-analysis including 35 observa. tablets) are red wine have been presumed to be involved in pre- effective in increasing abstinence from smoking (RR venting the formation of atherosclerotic plaques [28].3. 95% CI 0.6–1.8. moder. Study results on the blood pressure by 3. However. 47]. 58]. However. CI 0. The Global Burden 92 pared with low activity (RR 0. This may be explained by differ- the effect of body mass without eliminating it [38– ent definitions of physical activity and levels of activ- 40. abdominal sion and better short-term outcome [52]. leisure-based physical activity (2 to 5 ratio) has been suggested to be a better indicator for hours per week) has been independently associated stroke risk than overall body mass (measured by with a reduced severity of ischemic stroke at admis- BMI).3. Poor dietary habits contribute to the development of in a meta-analysis high and moderate activity signifi. 47].4–0.7. Increas. hypertension and dyslipidemia.8) and hemorrhagic stroke (RR 0. Physical activity decreases body weight physically highly active individuals had a lower risk of and blood pressure. and those physically active during leisure time had a decreased risk for ischemic (RR 0.g.5–0.4 mmHg and diastolic may also reduce stroke risk [56]. Overall only a or mediated through blood pressure. Nevertheless it is still under discussion ity. 95% CI 0. 95% ratio) is associated with an increased risk of stroke. Com- risk [48]. have shown the protective effect of regular physical The favorable effect of physical activity is at least activity for stroke in women and men.8–1. 95% CI 0. 95% CI 0.g. tional physical activity. active at work had a decreased risk for ischemic (RR ing the intensity of psychological intervention 0. Only a few studies investigated Dietary factors the effect of activity on hemorrhagic stroke.7–0. the definitions of activity No randomized controlled trial has tested the levels and activity types vary considerably and the effect of weight reduction in obese adults on stroke amount of activity is generally self-assessed. 46. 95% CI 0. in a meta-analysis systolic blood muting physical activity (walking or cycling to work) pressure was reduced by 4.7. inconsistent (a meta-analysis distinguishing between Combined interventions including dietary and leisure and occupational physical activity found a exercise strategies with cognitive-behavioral therapy protective effect of both activity types) [59]. between stroke risk and different levels of activity [e.9. diabetes and dyslipidemia.6. and increases HDL serum choles- stroke and lower stroke mortality than those with low terol. Additionally physically more active people were ately active individuals had a lower risk of stroke. of total disability-adjusted life years (DALYs) lost are .1–0. stroke for high versus low activity (RR 0. People were the most successful for weight loss [50]. 58]. 95% CI 0.9. found to be more often non-smokers [e. 54–56].0). other stroke risk factors such as obesity. Adjusting no difference between moderate and high physical for these confounding risk factors often attenuates activity [e. Obesity (high body mass index or high waist-to-hip 95% CI 0. adiposity was found to be associated with increased Some studies found a dose–response relationship stroke rate [41. 95% CI 0. Even when accounting for BMI. 42.g.9) and for moderate versus low activity (RR 0.1) [51]. 57. 61].8. partly mediated through beneficial effects on other analysis of 18 cohort and five case–control studies. others found a U-shaped relationship or hypertension. 44. diabetes. activity (RR 0. risk factors. Obesity is associated with an increased risk of 53. diabetes and few studies have evaluated the influence of occupa- cholesterol levels. plasma tissue and glucose tolerance [60. cantly decreased hemorrhagic stroke risk when com.7–0. There is not enough evidence for the type and Physical inactivity intensity of fitness training protecting best against Several prospective longitudinal population studies stroke.1) [51].6–1. Additionally there may be different metabolic whether obesity is an independent risk factor of stroke effects of different types of exercise.1 kg [49]. 95% CI 0.4% RR 0.7–0.9) and hemorrhagic stroke (RR 0. Section 2: Clinical epidemiology and risk factors Abdominal adiposity (measured by waist-to-hip Additionally.9 and of Disease study 2000 estimates that in Europe 4. No randomized controlled trial has stud- ied the effect of regular controlled exercises on stroke risk. resulted in greater weight reduction [50].7.7–0.8).6 mmHg for an average weight influence of the type of activity on stroke risk are loss of 5. Similarly. probably mediated through beneficial A similar relationship was found in ischemic effects on other risk factors. In a meta.8. compared with those who were inactive (RR 0. Regular physical activity has a protective effect for stroke.8).9) [51]. used the individual consumed fish at least once per month (RR 0.8) compared to people eating fewer tolic and diastolic blood pressure were reduced by than three servings. found strong evidence for the respectively by 7% and 3% in women and by 4% and benefit of low sodium intake [75]. The DASH diet stroke.0) for the quintile benefits of fish intake indicates that for modest fish with the highest intake of a DASH-style diet com- consumption (1–2 servings/week) the benefits of fish pared to the quintile with the lowest intake of a 93 intake exceed the potential risks. tion. Participants were 5% in men for each increment of one serving of fruits randomized to one of three sodium intake levels and and vegetables per day [65]. An evaluation of all risks and adjusted RR of 0. Different foods and nutrients found that any fish consumption had greater relative have been suggested to influence stroke risk via sev.52–0. Dietary calcium.0 mmHg respectively for a median both ischemic and hemorrhagic stroke [64]. Women with a dietary pattern guish between stroke subtypes. Chapter 6: Common risk factors and prevention attributed to low fruit and vegetable intake and high consumption should limit some fish species with another 7. people with very DASH-style diet [79]. engaged in more physical activity and ity and may thus prevent or delay hypertension [78]. This association is at least partly mediated by the In large epidemiological studies. inflammation risk. Observational studies found an association insulin resistance. how- pressure.0). Potassium intake can attenuate salt sensitiv- non-smokers.69 fat and cholesterol) or a control diet (a typical (95% CI 0. decreasing platelet aggregation. a randomized controlled study includ- 38 683 men ischemic and total stroke risk were reduced ing 412 participants. In the reduction of 74 mmol/day or 4.g. high fruit and well-studied positive relationship between salt intake vegetable intake was associated in a dose-dependent and blood pressure [73]. The Dietary Approaches to Stop Hypertension Health Professionals’ Follow-up Study including (DASH) trial. A quantitative analysis of in dietary habits therefore have high potential for fish consumption and stroke risk including six studies reducing stroke risk.1 mmHg and diastolic blood pres- per day had a decreased relative risk of stroke RR 0. decreasing blood dence of stroke in prospective cohort studies. This effect was significant for 2. Different nutrients and aliments cannot be seen Ecological studies raised the concern that high fish independently of each other and thus the effect of consumption may increase the risk of hemorrhagic different diets has been investigated. and decreasing inflammation. and this effect increased linearly with an tamination in fish. Fung et al. 68]. Another concern was more similar to the DASH diet had a lower relative raised on the negative effect of methyl mercury con. In American diet). Combining both studies either the DASH diet (rich in vegetables and fruits the quintile with the highest intake of fruits and vege.8% to overweight and obesity [62]. especially from dairy sources and The consumption of oily fish or n3 fatty acids dietary magnesium have been found to be inversely has been suggested to decrease the risk of vascular associated with blood pressure and with lower inci- disease by lowering serum lipids. more highly educated [e. but no association for hemorrhagic Study to classify individuals’ alimentation according stroke [69]. Generally. A Mediterranean-style diet rich .7 sure by 2.7–0. Epidemiological studies found an inverse relation- lar disease but not stroke [66]. endothelial function and oxidation [63]. and low in dairy fat products.g. between sodium intake and stroke mortality [72]. to the DASH-style diet. intake was associated with a reduction in cardiovascu. eral mechanisms. However.7–1. 95% information on food intake of the Nurses’ Health CI 0. 65. A meta-analysis of eight cohort studies sug. vascular reactivity.0 mmHg and 1. by influencing blood pressure. 77]. Changes high mercury levels [70]. persons with ship between intake of potassium and risk of stroke higher fruit and vegetable intake were more likely to be [76. platelet func. (see above) was associated with a significant decrease gested a lower risk of ischemic stroke in people who in blood pressure [75].7 mmHg. stroke risk. Both sodium reduction and the a meta-analysis of seven cohort studies whole grain DASH diet reduced blood pressure significantly. 67.8 (95% CI 0.7. A reduction in salt intake in fashion with decreased risk of stroke. several studies did not distin. A meta-analysis hypertensive persons (median urinary sodium reduc- including nine cohort studies found that persons tion by 78 mmol/day or 4.4 g urinary sodium Nurses’ Health study including 75 596 women and the [74]. risk reduction than no fish consumption [71].5–1. In normotensive individuals sys- (95% CI 0.92) compared to the lowest quintile. and total and saturated tables had a decreased relative risk of stroke RR 0.6 g/day) reduced systolic eating more than five servings of fruit or vegetables blood pressure by 5. improving ever. the evidence is only moderate [63]. e. olive oil. coronary risks. A meta-analysis of randomized . trial including 10 101 postmenopausal women with coronary heart disease or multiple risk factors for coronary heart disease no effect of raloxifene on the Postmenopausal estrogen risk of coronary events or stroke incidence was found. The Multiple Outcomes of Mozaffarian suggest that a diet low in sodium. with RR for overall and Diseases and pathological conditions ischemic stroke respectively of 1. high Raloxifene Evaluation (MORE) trial including 7705 in potassium. 85]. beneficial effect of postmenopausal hormone therapy for the prevention of cardiovascular diseases and Hormone replacement therapy is associated with an increased risk of stroke. and fatty fish has the highest all effect on cardiovascular events (including stroke) potential to reduce stroke risk [63].2 (95% CI 1. Worldwide.5) and ischemic stroke RR of 1.2–0. whole osteoporotic postmenopausal women found no over- grains.1 (95% CI 1. 30–40% and 20–30% for the age gallbladder disease and dementia.2) and 1. vegetables and grain did not result in a and osteoporosis without increased risk of breast reduced incidence of coronary events and stroke [81]. tolic BP by 40–50%. Lowering BP substantially reduces stroke and rectal cancer after 4 or 5 years of treatment [82. cereal fiber.5% of deaths are attributed to high 1. A Cochrane systematic review came to the [90]).0–1. stroke.1–1.4) [82]. fruits. canola oil. about 54% of CI 1.6) for women using hormone replacement ther.4. 95% replacement therapy CI 1.2) [88]. In the Raloxifene Use for The Heart (RUTH) and fatty fish has the highest potential to reduce stroke risk. and rich in fruits and vegetables. cereal fiber. Two meta-analyses suggest that hor.4) [89]. heart and stroke risk increases with every 10 mmHg of sys- attack. whole grains. 95% CI Starting at a BP of 115/75 mmHg. However.3 (95% CI strokes and 13.0–1. stroke (after 3 years of use). fish. cancer. an increased intake and they may therefore prevent cardiovascular risk of fruits.4. This has been attributed to a protective effect (RR 1. However.9) and cardiovascular events in a subset of A diet low in sodium. domized controlled trial including 48 835 women SERMs have estrogen-agonist effects on bone and with dietary interventions consisting of total fat lipid metabolism but not in the breasts and uterus. 94 fits are that it reduces the risks of fracture and colo. To date few studies have investigated the effect Reviewing the current evidence Ding and of SERMs on stroke risk. stroke in primary prevention trials (RR 1.1–1. a meta-analysis of nine observa- tional studies indicated an increased risk of stroke – especially of ischemic stroke – in women using hor- mone replacement therapy.9) [84].0–2.3 (95% able risk factor for stroke. increases steeply in an approximately log-linear rela- mone therapy (estrogen alone or with progesterone) tionship with BP [91]. apy [83]. Age attenuates this relationship increases the risks of venous thromboembolism.5. 95% CI 1. breast cancer. but a decreased risk of stroke (RR 0. high in potassium. able to bind directly to estrogen receptors [86]. blood pressure (systolic blood pressure >115 mmHg. 95% CI 1. High blood pressure (BP >115/75 mmHg) is same conclusion and found hormone replacement strongly and directly related to vascular and overall therapy to be associated with an increased risk of mortality without evidence of any threshold [91]. a ran.4–2. [87]. Another meta-analysis Hypertension including 28 randomized controlled trials found a Elevated blood pressure is the best-documented treat- significant increase in total stroke RR of 1.1–1. but the risk of fatal stroke was increased (RR 1.1–1. 60–69 and 70 respectively [92]. groups <60. and the only bene. therapy lacking the steroid structure of estrogens but tion of coronary heart disease [80]. 95% CI 0.7) and ischemic stroke risk of estrogen and thus research has focused on the (RR 1. Section 2: Clinical epidemiology and risk factors in a-linolenic acid. stroke mortality risk 1.4. Selective estrogen receptor modulators (SERM) vegetables and whole grains and low in saturated fat are a class of drugs used for hormone replacement has been found to be successful in secondary preven. A meta-analysis (nine trials) investi- Until menopause women generally suffer from a gating the risk of ischemic stroke in tamoxifen treat- lower rate of vascular diseases. including ischemic ment for breast cancer found an increase of overall stroke. reduction to 20% of energy intake. and rich in women with increased cardiovascular risk at baseline fruits and vegetables.8. BP to 140/85 mmHg or below [93].0) and As a consequence guidelines recommend lowering stroke mortality (RR 0.7. these data suggests a risk reduction of 31% for every The Hypertension in the Very Elderly Trial 10 mmHg reduction of systolic BP [92]. macrovascular events.0) or non- treatment [93]. controlled studies – the Action to Control Cardiovas- A meta-analysis comparing the effect of b. Compared to the standard glucose control whether it is isolated systolic hypertension or not has group. diuretics and/or b-adrenergic receptor blockers) the 103]. 95% CI 1.0) [101]. patients. 95% CI 0. 95% CI 0.8–1. in non-fatal stroke rate (RR 0. No differences in major option for initial and subsequent antihypertensive macrovascular events (RR 0. especially diabetic persons with cardiovascular diseases or at high in central BP. A meta-regression of or older than 65 years) [100]. Chapter 6: Common risk factors and prevention controlled trials comparing antihypertensive drugs to found no evidence for the advantage of a specific placebo showed an overall stroke risk reduction of antihypertensive drug class according to age (younger 30% when BP was lowered.4–1. the analysis did intensive blood glucose control on major vascular not account for it. A recent meta-analysis found on the risk of major microvascular events – 95 including 31 trials with more than 190 000 participants especially on nephropathy (RR 0. trol. Due to the association between events. 95% CI 0.5–1. an effect of intensive glucose control was only been shown to be beneficial [99]. At the same time the overall death rate was higher ences in the effect of BP-lowering drugs in older for the intensive control group (1. In macro. despite reporting different amounts of ation study (ADVANCE) [106] – found no effect of BP reduction for different drugs. Lowering BP reduces patients (see below) [94]. one might expect differ. 95% CI 0. The ADVANCE trial included more than 11 000 tension (systolic blood pressure >140 mmHg and dia. To compare the effect of the different classes of blood pressure lowering drugs (angiotensin-converting Diabetes mellitus enzyme (ACE) inhibitors.1.2. AR1 blockers and a-blockers) suggests a small On the other hand. However. provide sive drug class was found to be superior in reducing new evidence for a possible advantage of tight glucose stroke risk [92. The benefit (HYVET).8–1. 95% CI 0.8–1. 96]. Maintaining the target glucose level reduced the Blood Pressure Lowering Treatment Trialists’ risk of microvascular complication but not the risk of (BPLTT) Collaboration performed a large meta. Additionally the prevalence of systolic hyper.0) . cular Risk in Diabetes Study (ACCORD) [105] and blockers to other hypertensive drugs suggests that the Action in Diabetes and Vascular Disease: Preterax the relative risk of stroke is 16% higher for b-blockers and Diamicron Modified Release Controlled Evalu- [98]. only when fasting blood glucose was elevated [104].6. 95. tors. There is insufficient evidence from randomized trials angiotensin-receptor blockers (ARBs). The ACCORD study included more than 10 000 b-blockers may reflect lesser BP reduction. fatal stroke rate (RR 1.5).5) were found for As the strength in the association between BP and intensive as compared to standard blood glucose con- stroke risk attenuates with age. patients with type 2 diabetes with a history of major stolic blood pressure <90 mmHg) increases with age.9. No antihyperten. tory of diabetes showed an increased risk of stroke tensive drugs (calcium-channel blockers. preferable to achieve these targets [93]. findings from a small prospective cohort study.9. the inferiority of trials. calcium antagonists. 96]. A meta-analysis comparing control in diabetic subjects.or microvascular disease and another vascular elderly subjects controlling hypertension regardless of risk factor. and they may still be considered an risk for cardiovascular disease. Participants with a his- “old” (diuretics and/or b-blockers) with “new” hyper. the Northern Manhattan Study (NOMAS). The antihyperten- sive treatment should be more aggressive in diabetic Elevated blood pressure is the best-documented treatable risk factor for stroke.0–1. How- analysis including 29 randomized trials and more ever. Both studies were partly secondary prevention BP reduction and stroke incidence. two recent large randomized benefit of calcium-channel blockers [97]. a randomized controlled trial. than 160 000 participants [95. showed that of BP reduction suggested by the results of clinical even hypertensive patients older than 80 years benefit trials is therefore consistent with the relationship from blood pressure lowering therapy by a reduction found in cohort studies. including stroke [103]. ACE inhibi. A combination of two or stroke risk by 31% for every 10 mmHg systolic BP more antihypertensive agents is often necessary and reduction. and thiazide that improving glucose control reduces stroke [102. 9. blood cholesterol and stroke mortality was weak.2).9) [114]. was found to be nega- Statin therapy reducing LDL cholesterol on average by tively associated with total and ischemic stroke inci- 1.3) did spective studies analyzed the influence of blood not differ between statin and non-statin treatment.7% to 2. . Similarly. RR 0. found similar results [115]: stroke incidence was sig- terol level in ischemic stroke but negatively for intra. However. In both trials hypoglycemia occurred more different age classes. No 6%–39%) and major vascular events by 22% (95% CI such relationship was found for hemorrhagic stroke. both stroke types but stronger in hemorrhagic stroke. esterol and stroke incidence [113]. Hypertension and diabetes accounted for by an association between total choles- are highly correlated and diabetic persons have an terol and blood pressure. RR 0. The effect of statins was clearly associated stroke incidence [111]. For hemorrhagic stroke the increased prevalence of hypertension [107].9. 26 randomized trials of statins including more than 95 000 patients. lipoprotein (HDL).0 mmol/l was found to reduce stroke by 24% (95% CI dence in several prospective cohort studies [112]. 95% CI cholesterol on vascular mortality by distinguishing 0. the numbers were only 78 compared to between total serum cholesterol level and overall 84 patients. sex and vascular risk factors can modify the stroke was decreased (eleven trials. A meta-analysis of 61 observational pro. 110]. from 2.6%. In a review of betic and non-diabetic persons was not significant. the incidence of non-hemorrhagic Age. In prospective cohort studies stroke risk was review including 42 trials assessing statin therapy found to be positively associated with serum choles. However.4% to 2. 95% CI relationship between blood cholesterol and vascular 0.7–1.1%.9). Overall the association between total to the standard therapy group. statin therapy reduced stroke trials found a clear positive effect of cholesterol- risk by 33% in diabetic and by 24% in non-diabetic lowering statin (3-hydroxy-3-methylglutaryl coen- participants in the lipid-lowering arm of the ASCOT zyme A (HMG-CoA) reductase inhibitors) therapy study [110].8. however. 95% CI cerebral hemorrhages [112]. for higher blood pressure levels the relation- an increased blood triglyceride concentration and ship was negative.8. 95% CI 0.7–0.7% (OR 0. stroke rate was reduced by 15.7–0. 13%–30%) in 5963 diabetic participants. Similarly. The difference between the effects in dia. the incidence of stroke was reduced There is insufficient evidence that improving from 3. These relationships are similar for reduced HDL cholesterol concentration. the incidence of hemorrhagic 96 mortality. In diabetic patients blood pressure should dependent on blood pressure. The relationship between total for all cardiovascular events regardless of the drug blood cholesterol and stroke mortality is highly used [94].1). for every 10% decrease in LDL cholesterol relationships for ischemic and intracerebral hemor. 95% CI 0. This was In contrast to the partly inconsistent findings comparable to risk reduction in non-diabetic partici. For systolic blood pres- be lowered to below 130/80 mmHg [92]. sex and different levels of blood frequently in the intensive control group as compared pressure [112]. This might be due to different with LDL. glucose control reduces stroke. stroke (eleven trials. nificantly decreased by statin therapy (RR 0. the incidence of hemorrhagic stroke was not higher in the statins Dyslipidemia group than in the control group (OR 0. in contrast. Treatment with tionship between low-density lipoprotein (LDL) chol- statins reduces LDL cholesterol and stroke risk simi. weakly positive in middle age (40–59) and may be emia and hypertension. a In addition to an increased stroke risk subjects positive association was only found in the age group with type 2 diabetes have an increased prevalence of 45–59. on the incidence of ischemic stroke.9.8–1. Section 2: Clinical epidemiology and risk factors but not on major macrovascular events (RR 0. 0. High-density larly to results seen in non-diabetic persons [109. A more recent rhages. from epidemiological studies.7– Older epidemiological studies found no relationship 1. hyperlipid. Contrary to what might be expected from observational studies.9). Lowering association was negative and only found for older blood pressure has been shown to decrease the risk participants (70–79). total and LDL cholesterol concentrations do not differ Insufficient data are available to identify a rela- from the general population [108]. Treatment of This was mainly due to a reduction in non-fatal diabetic patients with statins reduced the risk of stroke by 24–33%.8. 95% CI 0. randomized controlled pants [109].8–0. sure levels below 145 mmHg this association was Dyslipidemia in type 2 diabetes is characterized by positive. For ischemic stroke this association was other stroke risk factors such as obesity. stroke. Risk stratification should be such as age. Taking all lipid.9) for more intensive statin 2050 [121]. 0.3% per year and those for the high-risk class from were statins [119].1% among persons younger than 55 years to analysis of seven partly secondary prevention trials 9% among persons older than 80 years. from 0. and was not used to determine whether patients should be given related to LDL cholesterol levels [118].8–0.2 mmol/l for the Strokes associated with AF generally have a higher more and less intensive statin regimes. The threshold for a final cholesterol as powerful identification element. This effect of atorvastin was independent of ance potential benefits and risks of chronic anti- other factors influencing intracerebral hemorrhage. Despite some clear benefit of anticoagulants 97 6. schemes to stratify stroke risk in patients with atrial mary stroke prevention were niacin.8% in statins com.7–1.2 mmol/l and between 2. Atrial fibrillation (AF) is a strong independent risk Because of the linear relationship between risk factor for ischemic stroke [120]. for those older Cholesterol Levels (SPARCL) showed an increased than 75 years without prior stroke or TIA the stroke risk for recurrent hemorrhagic stroke in patients rate ranged from 3. In a A review comparing 12 stratification schemes found meta-analysis including 38 primary and secondary substantial differences between them [125].3% non-statin drugs). (OR 0.0 mmol/l [119]. The effect of statin treatment on bleeding effect of cholesterol-lowering statin therapy on the risk remains unclear. This makes risk level that could clearly separate between risk reduc. a more atrial fibrillation (AF) increases with age. ever. patients being categorized as at low risk. including 629 patients with intracerebral hemorrhages studied the effect of statin treatment before the event. ranging intensive statin therapy might be indicated. For non-statin drugs no significant 2. thrombotic therapy.3–7. age and the Stroke Prevention with Aggressive Reduction in presence of other stroke risk factors. At the same time the cholesterol-lowering 77% being at high risk [125].6.9% per year. between risk stratification schemes probably contrib- pared to 8. 95% CI 0. sex and blood pressure. respectively.1.8. assessment in primary prevention even more diffi- tion and no risk reduction was 232 mg/dl or cult. Chapter 6: Common risk factors and prevention The event rate for hemorrhagic stroke was not Randomized controlled trials found a clear positive reported. 95% CI 0. The effect ent schemes to classify individual stroke risk in a of diet (seven trials) was strongest. fibrillation have been proposed and tested [125].5% vs.48). aspirin. Intensive therapy found a significant excess of ele. in patients with atrial fibrillation they are still . Using eleven differ- effect on stroke incidence was found [119]. OR 1. 95% CI 0. or nothing. fibrate. This is not caused only by the aging therapy compared to less intensive therapy [117]. treated with high-dose atorvastin (n ¼ 55 vs. mortality and poorer functional outcome [122.8. ute to confusion and the inconsistent use of anti- lowering therapies together a strong correlation was coagulant treatment. 2.0) and myocardial infarction A long-term increase in AF has been projected until (OR 0. AF is therefore artery disease found a significant reduction of stroke primarily a risk factor in the older population. In the Framingham Study the risk of ischemic stroke vated aminotransferase levels compared to less inten.4%. 123]. oral anticoagulation.2% to 5. A prospective cohort study incidence of ischemic stroke. All stratification schemes found between stroke incidence and final cholesterol include the occurrence of a previous stroke or TIA level (r2 ¼ 0.5% per year to 7.2% per year [124]. 33 for Risk assessment is particularly important to bal- placebo). How- sive therapy (1. These differences effect was highest for statins (21. Atrial fibrillation 90-day mortality or functional independency [116].4). was nearly 5-fold for subjects with AF [120]. The prevalence of reduction in stroke and LDL cholesterol level.11). it is almost 4% including more than 29 000 patients with coronary for persons older than 60 years [121]. and 11 to p ¼ 0. stroke risk is highly variable in patients with On the other hand the secondary prevention trial atrial fibrillation and depends on sex. Several Among other lipid-lowering therapies used in pri.1 and 3. 95% CI 2.6 and of obesity in the Western world. the most effective in reducing stroke risk 2. gemfibrozil.1. No effect of statins was found on 30-day mortality.3–1. population but probably also by a higher prevalence The LDL levels achieved varied between 1. clo. but highly variable common test cohort resulted in 7% to 42% of the and therefore insignificant (OR 0. bezafibrate and lifestyle modifications. A meta. Observed stroke prevention trials using different lipid-lowering rates for the low stroke risk class ranged from 0% to therapies. The WASPO Diseases and pathological conditions (Warfarin vs. receive long-term anticoagulation with a target INR valvular AF [128]. relatively by 64% (95% CI 49%–74%).  Elevated blood pressure is the best-documented 98 genarians) [132] and BAFTA (Birmingham Atrial treatable risk factor for stroke. 127]. this was independ- ent of the use of warfarin [131]. Major extracranial Five low-risk lifestyle factors with a high potential to bleeding events and intracranial hemorrhages were prevent stroke: rare and therefore risk estimates are imprecise.6. Section 2: Clinical epidemiology and risk factors underused. responds to an absolute risk reduction of 0.0. 0. Intracranial hemorrhages were rare but slightly whole grains. 95% CI 18%–52%) [128]. [130]. with or without AF. relative risk of passive smoking for stroke can ing patients with non-valvular atrial fibrillation and be as high as 1. For primary prevention this cor.46 vs.8% per year. are stroke. However. How. The in stroke risk [128]. A permanent AF [134]. high in 60%) in a cohort of persons with non-valvular AF potassium. cereal fiber. which is markedly decreased warfarin (target INR 2.3) [129]. and rich in fruits and vegetables. adjusted-dose Atrial fibrillation is a strong independent risk factor for ischemic stroke. 1. this corres- ponds to an absolute risk reduction of 2. But an increased risk of intracranial hemorrhages of OR benefits overcome the harmful effect of alcohol 2. 2. partly because of a high perceived risk of showed that warfarin was safe and effective in older bleeding and fears about being responsible for hem. the results of these even better indicator for stroke risk than overall randomized trials have been found to translate well body mass (as measured by BMI).2–3.5 (95% CI 0. 95% CI highest potential to reduce stroke risk. Stroke risk for patients with paroxysmal or per- Stroke risk in patients with AF is markedly sistent AF is comparable to the risk in patients with decreased by the use of oral anticoagulation. Lowering BP Fibrillation Treatment of the Aged) [133] trials .1. reduced risk of thromboembolism (95% CI 39%–  Healthy diet – a diet low in sodium. In direct comparison adjusted-dose warfarin proved to be more effective than anti-platelet Chapter Summary therapy at reducing stroke (relative risk reduction 39%. should risk by 22% (95% CI 6%–35%) in patients with non. A recent Cochrane review includ. as well as anticoagulants compared to antiplatelet therapy and the risk of coronary heart disease and stroke. Patients with rheumatic mitral meta-analysis of 29 randomized trials including more valve disease with AF are at high risk of systemic than 28 000 participants with at least 3 months’ embolism and therapy with oral anticoagulation follow-up showed that antiplatelet agents compared (target INR 2–3) is recommended [135].23 per 100 person-years).0 (95% CI 1. individuals.9-fold for subarachnoid hemorrhages and 2-fold for ischemic stroke. increases with older age. Abdominal adiposity (as measured by waist-to-hip ratio) has been suggested to be an generally not included. into clinical practice. and fatty fish has the higher for warfarin (adjusted hazard ratio 2.  Non-smoking – stroke risk for smokers increases ever. but there is no clear nial hemorrhage was less than the absolute reduction relationship for intracerebral hemorrhages.0–3. the increase in absolute risk of major extracra. Compared to the control group.2–3. hypertension and dyslipidemia. stroke and hemorrhages. orrhages [126. Warfarin therapy compared to  Moderate activity 30 min/day – regular physical no treatment or aspirin was associated with a 51% activity has a protective effect for stroke. no history of stroke or TIA found a risk reduction of  Modest alcohol consumption – excessive alcohol ischemic stroke of OR 0.4–0. however.0) reduced stroke risk by oral anticoagulation. Aspirin for Stroke Prevention in Octo. Patients with to a placebo or no treatment reduced relative stroke a prosthetic heart valve.7% in pri- mary prevention. with index is associated with an increased risk of the highest risk of AF. The risk These five lifestyle modifications contribute to of non-intracranial major hemorrhages was not the reduction of other stroke risk factors such as increased [130]. based on the prosthesis type [136].7) for oral drinking increases all-cause mortality. because participants of clinical trials are usually  Body mass index <25 kg/m2 – a high body mass highly selected and especially very old persons. There have been concerns at light-moderate alcohol consumption. The risk of major hemorrhages diabetes. 0. Ann Intern Med 1993. Walker M. Risk in Communities (ARIC) Study. absolute risk reduction of 0. trials that improving glucose control reduces 298:789–94. Hankey G.  Atrial fibrillation (AF. Kase CS. 259:1025–9. Primary prevention of stroke by 279:119–24. 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Society for Cardiovascular Angiography and 131. 104 . BAFTA): a randomised 69:546–54. et al. Pearce LA. Hylek EM. Kanu C. Salem DN. CD006186. Stroke Risk in Atrial Fibrillation Working Group. 128. 290:2685–92. Pearce LA. Age Ageing 2007. 146:857–67. RA. 25:1734–40. Rothbart RM. Hart RG. associated hemorrhage: the anticoagulation and risk Valentin A. Go AS. Stroke Prevention in Atrial Fibrillation 126. et al. Munteis E. Warfarin versus aspirin for stroke 124. Portner R. 54:1231–6. 125. of the impact of atrial fibrillation on the risk of early 36:151–6. Radley DC. Stafford RS. Bussey HI. atrial fibrillation: incidence and predictors during Stroke 2008. prevention in an elderly community population with Independent predictors of stroke in patients with atrial atrial fibrillation (the Birmingham Atrial Fibrillation fibrillation: a systematic review. Henault LE. Rodríguez-Campello A. Henault LE. J Neurol 2006. Lip GY. 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Hylek EM. et al. et al. D. 39:1901–10. Heart J 2004. et al. 35:183–7. Aguilar MI. Stroke with intermittent stroke in patients with nonvalvular atrial fibrillation. et al. Freed MD. Ann Intern Force on Practice Guidelines. Carabello BA. Chang Y. Downes T. Hauch O. Fitzmaurice 253:1484–9. 126:457S–82S. Age and the risk of warfarin. Meta-analysis: Faxon DP. Section 2: Clinical epidemiology and risk factors 122. reported use of anticoagulation therapy in nonvalvular Horstkotte D. 41:56–61. 1990 to 2002. 134. Slany J. ACC/AHA 2006 patients with non-valvular atrial fibrillation and no guidelines for the management of patients with history of stroke or transient ischemic attacks. Jensvold NG. prosthetic: the Seventh ACCP Conference on 127. Treatment of the Aged Study. Hart R. Martinek-Bregel M. Circulation 2006. versus aspirin for stroke prevention in octogenarians Martínez-Rodríguez JE. Stroke patients with atrial factors in atrial fibrillation study. et al. Gross CP. Gomis M. 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Approximately 85% of the individuals atrial fibrillation with AF are between 65 and 85 years of age [1]. ive methods of detecting AF in stroke patients  Brady. Another Rhythm disturbances study found that the combined use of Holter and Atrial fibrillation serial electrocardiograms within the first 3 days gave a better rate of AF detection (14%) than serial electro- AF is a cardiac arrhythmia. such as palpitations. Effect- (LVHT). have a 17-fold  In embolic stroke. identifying par- transient left ventricular dysfunction.6%. Among all ischemic strokes 17–31% occur ventricular hypertrabeculation/non-compaction because of embolic complications of AF [3–5]. to as Takotsubo syndrome (TTS). rheumatic AF have a 5-fold increased risk of stroke endocarditis. coronary heart disease or dilatative cardiomyopathy (dCMP). from a itional 6–8% after negative Holter monitoring [6]. also referred oxysmal AF in stroke patients is still a challenge. stroke are at high risk of suffering recurrent strokes. and influence the irrespective of whether AF is permanent or clinical course and rehabilitation.and tachyarrhythmias may compromise are warranted since patients with AF after ischemic cerebral blood flow. Interestingly. Thus. cardiac diseases may be the Whereas diagnosis of permanent AF is easily feasible consequence of the stroke. 24–72 hours detected AF in 4.  Cardiac diseases may coexist. cause skin irritation. whereas patients with non- cause of embolism. defined by the absence of cardiograms alone (11%) [8]. fre- quent supraventricular ectopic beats (>70 during a 24-hour Holter) were predictors of AF [7]. Compared to patients with sinus Cardiac diseases can be relevant to stroke in different rhythm. Apart Detection of paroxysmal AF is impeded by the from hemodynamic consequences due to the loss of available monitoring devices. this chapter aims to focus A further study applied 7-day event recording at on the most frequent and controversially discussed 0. A review comprising five studies analyzed the diag-  Congenital abnormalities such as patent foramen nostic yield of monitoring devices to detect paroxys- ovale (PFO) or atrial septal aneurysm (ASA) may mal AF in 736 stroke patients: Holter monitoring over implicate paradoxical embolism. whereas 4-day or Several diseases may coexist in a single patient. left ventricular aneurysm or left [2].1). such as atrial fibrillation (AF). with an initial negative Holter [7]. Diagnosing paroxysmal atrial fibrillation  In some instances. The electrodes may 105 atrial contraction and symptoms. 7-day event loop recorders detected AF in an add- such as coronary heart disease and AF. such as stroke-induced from the 12-lead electrocardiogram. such as paroxysmal. Chapter 7 Cardiac diseases relevant to stroke Claudia Stöllberger and Josef Finsterer Introduction AF may lead to embolic stroke or peripheral or mes- enteric embolism. pragmatic point of view. 3. particularly mitral stenosis. patients with AF due to rheumatic heart respects: disease. making it difficult to wear . cardiac diseases may be the increased risk of stroke. AF is a common arrhythmia and its preva- lence increases with age up to 9% at age 80–89 years Future developments for detection of paroxysmal (Figure 7. Ongoing studies are 106 However. paroxysmal atrial fibrillation in patients with stroke. and their time of onset and duration (Figure 7.1. them for long periods.2).2. Event loop recorders miss asymptomatic AF because they rely on the patient’s recognition of symptoms. Ongoing stud- ies are evaluating the use of this implantable loop recorder for the diagnosis of paroxysmal AF in patients with stroke. Improved methods for detecting AF are currently being evaluated in pilot trials. . The Reveal XT (Medtronic Inc. such as a 30-day cardiac event monitoring belt in the EMBRACE study or the Reveal XT [9]. there are several concerns about the ratio. the device is able to detect AF episodes.) is an implantable event- triggered recorder which detects and monitors atrial and ventricular tachycardias. The Reveal XT (Medtronic Inc. Using a special algorithm. Section 2: Clinical epidemiology and risk factors 800 000 250 000 700 000 200 000 600 000 Estimated AF patients 500 000 Austrian Population 150 000 Estimated total AF patients Estimated male AF patients 400 000 Estimated female AF patients Total Austrian Population Male Austrian Population 100 000 300 000 Female Austrian Population 200 000 50 000 100 000 0 0 4 9 4 20 9 25 4 9 35 4 40 8 4 50 9 55 4 60 9 65 4 9 75 4 9 an –84 e 0– 5– –1 –1 –2 –2 –3 –3 –4 –4 –5 –5 –6 –6 –7 –7 or m 10 15 30 45 70 85 80 d Age (years) Figure 7.) is an implantable device anticoagulation (OAC) to prevent strokes in AF [10]. Left atrial appendage occlusion for stroke prevention in atrial fibrillation Surgical or percutaneous closure of the left atrial appendage (LAA) is considered an alternative to oral Figure 7. recording the cardiac rhythm for up to 3 years. Prevalence of atrial fibrillation according to age ranges in the Austrian population according to an estimation for the US population [1]. evaluating these implantable loop recorders for the diagnosis of nale and safety of LAA occlusion. are supported by the low long-term efficacy of RFA. have to be considered. ever. LAA elim.5%. There are concerns. closed LAA. The RFA catheter. The LAA myocardium wall. with no recent embolism by transesophageal echo. and during a follow-up of 58 months The targets of RFA are myocardial sleeves near the LAA thrombus did not predict stroke/embolism [11]. . RFA can only be performed successfully when with stagnant blood flow. 107 disease [14]. formation (Figure 7. the role in hemodynamic and body fluid regulation. and ischemic and heart failure and thirst-perception [12]. These considerations global warming and the obesity epidemic. how- has a higher distensibility than the left atrial myocar. Even if technical improvements lead to a more including pericardial tamponade and life-threatening effective LAA occlusion. The LAA is a valvular heart disease leading to structural abnormal- place of secretion of atrial natriuretic peptide (ANP). There is no evidence that embolism in AF exclu. junction of the pulmonary veins with the left atrium The LAA has properties which may impede the and autonomic ganglia in the left atrial posterior completion of the occlusion. however. all located epicardially.3). LAA targets of RFA are not well defined. is considerably high [14]. is introduced into the left atrium and thus radio- dium. Incomplete LAA closure creates a pouch Thus. whether RFA is a safe cardiography. ities such as atrial myocardial fibrosis. only 2. potential further side-effects atrio-esophageal fistula. AF results from elimination may impede physiological regulation of long-standing arterial hypertension.3. frequency energy is delivered from the endocardial possibly leading to leakage of a primarily completely surface with the aim of creating transmural lesions. Progressive dilatation of the LAA occurs in AF. The LAA plays an important Since AF is not only an electrical problem. Therefore the rate of procedural complications. the prevalence of LAA thrombi was and effective therapy to prevent strokes. In view of regions and that AF may recur. Since RFA does ANP contributes to physiological control of lipid not abolish myocardial fibrosis it can be expected that mobilization in humans so LAA elimination might ectopic activity may arise from other non-ablated promote development of obesity [13]. This jet was not visible at PLAATO implantation but was only detected after 24 months. which enhances thrombus affecting the epicardial side of the left atrial wall. When prospectively Radiofrequency catheter ablation (RFA) of AF is a investigating clinically stable outpatients with AF and recently proposed interventional method to cure AF. Chapter 7: Cardiac diseases relevant to stroke Figure 7. Transesophageal echocardiographic picture of the left atrium and left atrial appendage with a percutaneously implanted left atrial appendage occluder (PLAATO device) showing a small jet by color Doppler sonography (arrow) between the PLAATO device and the left atrial appendage wall. Ablation of atrial fibrillation for stroke prevention sively derives from LAA thrombi. ination is a highly questionable procedure for stroke especially in permanent AF and structural heart prevention. or tachycardia.1.or tachycardia is given in Table 7. and low risk of embolism. alcohol withdrawal. It has also been empha- sized that recurrent AF is more frequently clinically patients with suggestive symptoms. however. Assessment of vital signs The prevalence of AF.or tachycardia is observed in a stroke Tachycardia is defined as a heart rate >100 beats per patient. Practical approach to stroke patients with brady. Thus. the initial diagnostic steps are very similar minute. the proportion of AF patients who might profit from RFA is much lower Registration of a 12-lead electrocardiogram than the proportion of those who might not. Non-cardiac tiate between cardiac and non-cardiac causes. and becomes symptomatic only when the create new potential sources of arterial embolism.1. Furthermore. valvular heart  At present it is uncertain how long this embolic disease. D-dimer. Patients with AF have a 5-fold (non-rheumatic AF) to 17-fold increased risk of stroke (embolism due to or AF. thyroid function tests) due to endocardial lesions. The success rate of RFA is low when the patient is over 65 years [15]. electrolyte disturbances  The majority of AF patients are too old for RFA. and it is at present unknown whether these shunts are clinically relevant Bradycardia is defined as a heart rate <50 beats per in terms of paradoxical embolism. Performing a standard electrocardiogram enables one to diagnose more precisely the type of bradycardia as Atrial fibrillation (AF) may lead to embolic stroke. The electroenceph- silent after than before RFA [16]. increases with advan. monary embolism. Cardiac symptoms may erroneously be interpreted as epileptic causes of tachycardia are the same as for bradycardia. tachycardia may be caused and aim to assess the clinical severity and to differen. by non-cardiac and cardiac causes. and disorders such as hypothyroidism. Measurement of blood pressure cing age (Figure 7. Holter monitoring to detect recurrent and the clinical consequences range from palpitations episodes of brady. and increased parasympathetic tone. risk persists after the procedure. which is a potentially life-threatening situation [18]. causes of tachycardia in stroke patients comprise gested practical approach to stroke patients with fever. Bradycardia and tachycardia Tachycardia If brady. OAC for at least 3 months is usually recommended to prevent thrombus forma. hypothermia. and degenerative primary electrical disease. Thus.or tachycardia causes symptoms such as spasm. mia and to assess whether QT prolongation is present. Assessment of current and previous medication tion on the ablation lines [14]. increases the risk of stroke periprocedurally Blood tests (electrolytes. pain. . Furthermore. Non-cardiac causes following reasons: comprise side-effects of drugs. Like bradycardia. broncho- Brady. sinus bradycardia.1) [1]. performed so far is 50–63 years [14]. hyperthyroidism. C-reactive protein. light-headedness. sinus arrest. blood cell count. Bradycardia may be due to We doubt that RFA prevents stroke in AF for the cardiac and non-cardiac causes. is uncertain whether OAC can be stopped at all after RFA. acute or chronic coronary heart disease. hypovolemia. pul- brady. anemia. and to look for signs of acute myocardial ische- rheumatic heart disease). These previously treated with beta-blocking agents. the  Candidates for RFA belong to a subgroup with a brain may be involved in cardiovascular regulation. side-effects of drugs and rebound in patients dizziness. Section 2: Clinical epidemiology and risk factors The mean age of patients in whom RFA has been Table 7. A sug. Measurement of the QT interval according to Bazett’s Possible candidates for RFA tend to have a low risk formula: QTc ¼ QT/√RR of embolic stroke since they are under 65 years and Registration of the body temperature mostly have AF without cardiovascular diseases. however. RFA may minute. Thus. the transseptal puncture during Bradycardia RFA creates interatrial shunts. RFA. rate drops significantly. spells or fainting. the insular cortex is assumed to play a role in rhythm  The RFA procedure itself may increase the control [17]. atrioventricular block.or tachycardia may be useful in to sudden cardiac death. As a consequence it alogram is usually normal in these patients. Cardiac causes of bradycardia include embolic risk. 108 seizures. such as antiarrhythmic drugs class IA and results stress the importance for the neurologist to be III. . is found in up to 33% of patients with ischemic stroke [21]. most probably due to common of a bad prognosis due to heart and renal failure [25]. 20]. diabetes mellitus. especially the insular region [17. When caring for stroke patients in the acute or QT prolongation in stroke may be due to cardiovascular rehabilitation phase. 30–40% of patients. antihistamines.torsades. as a prolongation of the QT interval on the electro. disease. Cardiovascular diseases induce a higher susceptibility to drug-induced prolongation of the QT interval. Degeneration into ven. sion. In acute stroke patients without a history or signs of coronary heart and stroke disease. but also influences the prognosis of patients surviving tions. light-headedness. The triggering factors should be screened and. but rather 109 disease and stroke. with QT prolongation associated with bradycardia biomarkers which are found to be highly specific for because it entails the risk of torsades de pointes [18]. and hypercholes- These symptoms may erroneously be interpreted terolemia. either myocardial infarction or angina pec- toris. Torsades de pointes however. a stroke. ischemia should entail rhythm monitoring and cardi- maker should be strongly considered. Chapter 7: Cardiac diseases relevant to stroke Brady. because Coexistence of coronary heart disease stress testing might be indicated.org). it is necessary to be aware of comorbidity. obtained from the internet (www. Special care should be taken with patients measuring serum levels of troponin T or troponin I. T-wave If QT prolongation is observed in a stroke patient. Stroke patients with normal troponin levels but signs and symptoms suggestive of myocardial ischemia Coronary heart disease should also be referred to the cardiologist.or tachycardia causes symptoms such atherosclerotic risk factors such as arterial hyperten- as dizziness. Most of these drugs block a specific potassium channel There is a frequent coexistence of coronary heart disease and stroke. atherosclerotic risk factors. 19]. myocardial necrosis [24]. elevated troponin levels are not There is a frequent coexistence of coronary heart indicators of silent coronary heart disease. concomitant administration of different QT-prolonging drugs and Diagnosis of coronary heart disease bradycardia. Two-thirds of the myocardial infarctions in that study cardiogram. In addition to the congenital long QT syndrome cardiac causes than of recurrent stroke [21. aware of cardiac symptoms of stroke patients and for depressants. smoking. is not only a frequent finding at autopsy are often self-limited and are associated with palpita. Elevated troponin levels in In these patients the heart rate should be raised to stroke patients with signs or symptoms of myocardial >80 beats per minute and implantation of a pace. An autopsy study of patients with fatal QT prolongation stroke found coronary plaques in 72%. concomitant drug intake and metabolic clinical symptoms of myocardial ischemia such as disturbances. however. graphic abnormalities such as ST-depression. abnormalities or newly developing Q-waves [20]. QT prolongation may be associated with were clinically silent [22]. dizziness or syncope. including coronary angio- Stroke is associated with QT prolongation in graphy and percutaneous coronary intervention. if possible. or electrocardio- cerebral region. detection of myocardial injury can be improved by corrected. Coronary heart disease. Stroke is another condition associated in stroke patients with QT prolongation in 30–40% of patients [19. Correctable factors include hypokalemia. These many drugs. are known to prolong the QT interval. A history of symptomatic coronary heart as epileptic seizures. ological consultation regarding further therapeutic and diagnostic measures. torsades de pointes tachycardia. Five-year follow-up studies have shown that tricular fibrillation and sudden cardiac death can survivors of ischemic stroke are more likely to die of occur. 23]. but may also originate from ischemic chest pain or exertional dyspnea. neuroleptics and anti. spells or fainting. the cardiologist to develop cardioprotective measures Information about QT-prolonging drugs can be for stroke patients. coronary sten- Prolongation of ventricular repolarization manifests osis in 38% and myocardial infarction in 41% [22]. most probably due to common substantially involved in ventricular repolarization. antibiotics. the microorganism 110 Between onset of the symptoms and diagnosis a mean involved. surgeons have frequently been reluctant to operate on infective endocarditis patients with acute stroke because of concerns about cerebral bleeding compli- Valvular heart disease cations because of anticoagulation during the cardio- pulmonary bypass. imaging studies Antibiotic therapy is the main measure in therapy for to look for left ventricular thrombi. The risk of stroke in infective transthoracic echocardiography. peutic management. This is due neurological condition. generalized weakness and fatigue. endocarditis has to be considered as a differen- of embolism tial diagnosis in all stroke patients. The therapy should be planned tory and microbiological investigations. delay in surgical Infective endocarditis and stroke intervention can lead to the death of patients who Ischemic and hemorrhagic strokes occur in 10 to 23% might have benefited from surgery [35]. most probably due to changes in the ation of antibiotic therapy. Native valves as well as prosthetic was achieved in 70% of the survivors and secondary valves may be affected by endocarditis. Myocardial infarction as a cause Thus. valve prosthesis and ventricular thrombi may still be detected in patients vegetation to confirm or exclude the diagnosis after myocardial infarction. left visualization of the valves. The incidence of left ventricular protein are found or if the patient is febrile. . 31]. event of infective endocarditis in a stroke patient the neurologist. increase if laboratory signs such as elevated blood ysm in the chronic phase of a large. complete neurological recovery valve [30. echocardiography is necessary because of its better taneous coronary interventions [28]. leukocytosis or elevated C-reactive wall infarction [27]. 33]. within 1 week after the initiation of antibiotic therapy graphic signs of previous myocardial infarction. worse prognosis than patients with native valves Based on these findings we recommend that in the [32. However. Embolic events such as stroke are frequently the cause of hospital admission in these patients [29].4). The suspicion of endocarditis should myocardial infarction or due to a ventricular aneur. diac surgery may be necessary. should be performed endocarditis has been shown to decrease rapidly in all stroke patients with a history or electrocardio. cardiac tricular aneurysms can be a cause of embolic stroke. especially if revasculariza. which now stroke and suspected endocarditis transesophageal comprises intensive anticoagulant therapy and percu. and symptoms Cardiogenic embolism from a left ventricular throm. However. mainly anterior sedimentation rate. the response to antibiotic therapy and the interval of 31 days has been reported [34]. if there are large vegetations or destruction of the valves leading to heart failure car- Acute or subacute myocardial infarction and ven. preferentially infective endocarditis. prolonged flu-like disease. leading to cerebral hemorrhage due to cardiac surgery occurred stroke. microbiologist and cardiac Diagnosis of infective endocarditis surgeon should discuss together the optimal thera- Despite the availability of echocardiography. tion in the acute phase has not been performed or was Therapy of infective endocarditis unsuccessful or if the myocardial infarction affected large parts of the left ventricle. [29]. In the past. Among ive study of patients with infective endocarditis and patients with endocarditis and stroke. a recent retrospect- the period of untreated infection [29–31]. Although of patients with endocarditis and cluster during no prospective data are available. considerable with consideration of the clinical course. Thus. cardiologist. Blood thrombi early after myocardial infarction has declined cultures should be taken in these patients before initi- in recent years. Section 2: Clinical epidemiology and risk factors Troponin positivity may also indicate myocardial to the unspecific symptoms of endocarditis such as involvement in neuromuscular disease [26]. However. labora. suggestive of endocarditis should be asked for at bus may occur as a complication of acute or subacute admission. In most of the cases with acute therapy of myocardial infarction. the mitral valve stroke undergoing cardiac surgery has shown that seems to be more frequently affected than the aortic mortality was 18%. delay occurs until infective endocarditis is diagnosed. the echocardiographic findings. (Figure 7. Stroke patients with prosthetic valves have a less frequently than was previously thought [36]. After heart valve surgery patients are at increased risk of thromboembolism. Once the pulmon- ischemic stroke is similar to that in the general popu. However. as in patients stroke patients if laboratory signs of inflammation after valve repair. mitral repair is not always tech. than in the mitral position [37]. Long-term follow-up In utero. due to either thrombus forma. left atrial lation [38]. This is followed by anatomical especially when the left atrium is already enlarged closure of the septum primum and septum secun- before surgery. VE ¼ vegetation. pressure increases and allows functional closure of nically feasible. the closure is incom- plete. Approximately 20% of patients with an aortic mic stroke as well as bleeding. especially after are present. In about 25% of humans. Chapter 7: Cardiac diseases relevant to stroke Figure 7.4. dum. mitral valve surgery. the embolic risk is lower in patients with when the right atrial pressure exceeds the left atrial bioprostheses than with mechanical prostheses. pressure. LV ¼ left ventricle. Transesophageal echocardiographic picture (left) and autopsy specimen (right) of a patient with embolic stroke and aortic valve endocarditis. the type of factor for stroke in patients with mitral prostheses. within 15 years after valve replacement [37]. the foramen ovale. embolic risk with mitral than with aortic valve tion on the artificial valve. infective endocarditis or replacement [37]. and patent foramen ovale (PFO) remains as a Bioprosthesis flap-like opening. LA ¼ left atrium. MV ¼ mitral valve. AO ¼ aortic valve. Patients with a mechanical valve prosthesis and thesis) and the affected valve (mitral versus aortic poorly controlled OAC are at increased risk of ische- valve). 40]. including cerebral or mitral valve prosthesis have an embolic stroke bleeding [39. AF may develop. Valve repair Valve repair is nowadays the preferred surgical cor. Pros. Furthermore. permitting right-to-left shunting Generally. the foramen ovale serves as a physiological studies have shown that after mitral repair. ary circulation is established after birth. The embolic risk varies according to the type of function has been identified as an additional risk surgery (repair versus replacement). especially of the mitral valve. and increase embolic risk. neces- must be considered as a differential diagnosis in all sitating reoperation [39]. the risk of conduit for right-to-left shunting. replaced valve (bioprosthesis versus mechanical pros. and AF may develop postoperatively. Stroke after heart valve surgery Mechanical valve prosthesis After heart valve surgery patients are at increased risk Patients with mechanical prostheses have a higher of thromboembolism. Preoperative left ventricular dys- AF. Strokes occur in 10 to 23% of patients with endo. A disadvantage of carditis. Patent foramen ovale rection of mitral regurgitation. Endocarditis bioprostheses is their propensity to degenerate. Transesophageal echocardiography (TEE) 111 theses in the aortic position have a lower embolic risk is considered the method of choice for diagnosing . In one observational study of population [42–44].77) and intraobserver (k ¼ 0. presence of venous warfarin or aspirin [44]. 49]. Section 2: Clinical epidemiology and risk factors Table 7. the incidence of recur- assumed to be the pathomechanism. subjects from the general population with PFO have diac defect which will permit right-to-left shunting. uncertain how many strokes in PFO patients are due There are indications that paradoxical embolism to paradoxical embolism and how to treat paradoxical 112 is enhanced by right atrial structures such as Chiari’s embolism. an increased risk of ischemic stroke has been studied Screening especially for venous thromboembolism by two prospective cohort studies.2. In a further prospective randomized study. 3 [78] (1993) 42 V 0–90 60 Calf. These congenital on these issues are urgently needed. Paradoxical embolism has been patients treated with aspirin.82) variability in flow pattern into adult life and direct the blood from the diagnosis [41]. .2). patients with PFO meet the criteria for the diagnosis the recurrence rate of stroke was the same in those of paradoxical embolism. % thrombosis. The question of whether thrombosis or pulmonary embolism and an intracar. D ¼ duplex sonography. However. which unani- has been performed only rarely. Delays in venous diagnostic evaluation increased risk of recurrent stroke. R ¼ radioisotope venography. Overall. ND ¼ data not given. with or without PFO in those treated with either lism without a cardiac source. although there is considerable interobserver remnants may maintain an embryonic right atrial (k ¼ 0. only rent stroke was higher in patients with than without few of the reported cases of cryptogenic stroke in PFO [47]. it is may account for negative or confusing results. 8 Iliac. Furthermore. 13 Popliteal.67 20 Pelvic. 3 Iliac. the inferior vena cava preferentially toward the inter- atrial septum [45. PFO. 2 Femoral. 46]. MRV ¼ magnetic resonance venography. Paradoxical embolism PFO does not manifest clinically. it has for venous thromboembolism early after stroke not been demonstrated that patients with PFO are at (Table 7. Results from randomized clinical trials network or Eustachian valves. but several retro. 1 [79] (1993) 13 V 0–28 0 0 [80] (1994) 17 R ND 35 ND [81] (1994) 16 V or D ND 31 ND [82] (1994) 27 V or D ND 11 ND [83] (1994) 18 V 1–300 11 ND [84] (1997) 53 V 1–15 9 ND [85] (2004) 46 MRV 2  0. which are: systemic embo. n [77] (1991) 23 V 2–210 26 Femoral. The results of mously found that PFO was not a risk factor for these studies highlight the importance of searching future cerebrovascular events [48. Author (year) Patients Technique Days between event Prevalence of Location of and investigation thrombosis. 9 Notes: V ¼ venography. Stroke risk and PFO spective and case–control studies in patients with It is uncertain whether the recurrence rate of stroke in cryptogenic stroke found that the prevalence of patients with cryptogenic stroke is dependent on the PFO is 30–46% and thus higher than in the general presence of a PFO. Studies investigating the venous system in suspected paradoxical embolism. also been reported. carcinoid or lymphoma population-based studies [44. The prevalence of atria. there spective clinical study [58]. During an lead to arterial embolism. stroke in patients with suspected paradoxical embol- dCMP is frequently associated with cardiac rhythm ism. Similarly to PFO. is 1–2% and depends on the echocar- [59]. with dCMP developed a stroke [54]. hypereosinophilic syndrome. The cause of rCMP may be idiopathic or rCMP diographic criteria. interobserver may be a cardiac manifestation of amyloidosis. Due to the [59. the efficacy cardiographically if the atrial septum appears abnor. 47–49]. who all had benefits from OAC [55]. The etiology of ASA is unknown. Among 846 In patients with cryptogenic stroke the prevalence patients with ischemic stroke dCMP was found in of patent foramen ovale is 30–46%. It is uncertain Restrictive cardiomyopathy (rCMP) is diagnosed whether strokes in ASA are due to paradoxical echocardiographically if there is enlargement of both embolism or other mechanisms. sarcoidosis.74) variability sclerodermia. Whether rCMP is asso- accepted diagnostic criteria would facilitate research ciated with an increased risk of ischemic stroke is into ASA. Gaucher’s disease. Given the tion. The Interventional PFO closure might even create new prevalence of intra-atrial thrombi in patients with cardiac sources for embolism. Development of uniformly morbidity and mortality [60]. of OAC for dCMP has never been proved in a pro- mally redundant and mobile. ASA has been found to be closely associated with hyperoxaluria. Fabry’s cryptogenic stroke in retrospective and case–control disease. Although OAC is recommended for sec- Atrial septal aneurysm ondary stroke prevention in patients with dCMP and An atrial septal aneurysm (ASA) is diagnosed echo. but patients 19%. Furthermore. cystinosis. Whether dCMP without AF is associated with an potential risks and costs associated with PFO closure. Compared to dCMP.45) and intraobserver (k ¼ 0. and normal coronary angiography [52]. such as two patients with dCMP from cardiac involvement in Duchenne muscular dys- trophy [56]. studies. but failed to be identified as a risk factor reactive arthritis. 60]. normal systolic function and wall thickness and ASA. (k ¼ 0. Werner’s syndrome. but single cases with rCMP have been Atrial septal aneurysm has been found to be closely described who developed an ischemic stroke [61]. patients with rCMP rarity of ASA it will be difficult to perform ade- are assumed to have a worse prognosis regarding quately powered studies. Thrombus formation dCMP is estimated to be 20–25% and the prevalence may occur on the left side of the occlusion device and of intraventricular thrombi 50% [53]. are no uniform echocardiographic criteria for this abnormality. Strauss syndrome. Noonan’s syndrome. associated with cryptogenic stroke but is not a risk In a study of 15 patients with amyloidosis 60% 113 factor for future stroke. unknown. 57]. three . no randomized trial examining the abnormalities and intraventricular thrombus forma- efficacy of PFO device closure exists [50]. Single with PFO are not at increased risk of recurrent cases with dCMP who developed ischemic stroke have stroke. Unfortunately. various for future stroke in prospective randomized or neuromuscular disorders. or embolism is regarded as being increased. hemochromatosis. Chapter 7: Cardiac diseases relevant to stroke Patent foramen closure and risk Dilatative cardiomyopathy of recurrent stroke Dilatative cardiomyopathy (dCMP) is a cardiac con- dition characterized by dilatation of the cardiac Surgical or interventional closure of PFO is increas- cavities (LVEDD >57 mm). increased risk of stroke or embolism is under debate. developed an arterial thromboembolic event. intracardiac thrombus formation [53. as assessed by echocardiography in the general a restrictive filling pattern (deceleration time <150 ms) population. Churg- in diagnosing ASA is high [41]. especially in patients with observational period of 31 months 5% of the patients coagulopathies [51]. it would be prudent to await the results of diligently At least in patients with dCMP and documented designed randomized clinical trials before recom- intracardiac thrombus formation the risk of stroke mending this unproven procedure. ASA Restrictive cardiomyopathy is frequently associated with PFO. pseudoxanthoma elasticum. reduced systolic function ingly performed as a measure to prevent recurrent (FS <25%). However. LVHT is most fre- vated. non-compaction ally and electrophysiologically in patients with normal Left ventricular hypertrabeculation/noncompaction coronary arteries [63]. diagnosed on echocardiography. alcohol withdrawal. Section 2: Clinical epidemiology and risk factors of whom had an ischemic stroke and two transitory myopathy [67]. severe knee background of LVHT it does not seem to represent a joint pain. Coronary angiography shows no stenoses of quently located in the apex of the left ventricle and the coronary arteries. exists that LVHT is most easily phosphokinase and troponin might be slightly ele. in LVHT [71]. Cardiac enzymes such as creatine sus. tracheostomy. although there is no consensus about the echo- segments: the non-affected ventricular segments show cardiographic criteria to define LVHT [70]. . Initially. cerebral stroke or in rCMP patients [59]. overexertion. syncope. Reversible (Figure 7. maline myopathy. The cause and pathogenesis over the lateral wall. the ECG shows ST elevation. Takotsubo syndrome Takotsubo syndrome (TTS). Consen- hyper-contractility. amyotrophic lateral sclerosis. Most probably these embolic systolic function. intestinal perforation. ing myocardium or possibly the result of myocarditis. which develops frequently cardioembolic events. TTS is clinically characterized (LVHT) is characterized by a meshwork of inter- by sudden onset of anginal chest pain. Transthoracic echocardiographic parasternal long axis view (left) and apical four-chamber view (right) showing left ventricular hypertrabeculation/non-compaction involving the posterobasal and lateral wall (left). ventricular attempt to compensate for an insufficiently contract- tachycardia. but usually spares the middle of TTS are unknown.5. 69]. icity [66]. TTS results in significantly reduced ischemic attacks [62]. 65]. distinct from the normal compacted myocardium which may persist for months [64. LVHT is frequently physical or emotional stress and catecholamine tox. lined with endocardium. pneumothorax. events have their source in the enlarged left atrium which may give rise to thrombus formation and lastly and are aggravated by AF. distinct cardiomyopathy but is rather the result of an subarachnoidal hemorrhage. which which constitutes a spongy myocardial layer clearly turns into negative T-waves a few hours or days later. transient ischemic attack have been only rarely reported during a TTS episode [68. also known as apical Left ventricular hypertrabeculation/ ballooning. pulmonary embolism. lymphoma. dyspnea or woven myocardial strings. however.5) [70]. However. anesthesia. Because of the heterogeneous genetic plasmapheresis. and metabolic LVHT is associated with neuromuscular disorders 114 Figure 7. is a reversible neuromyocardial failure which resembles acute myocardial infarction clinic. and wall motion abnormalities. The noncompacted to compacted akinesia or hypokinesia affects most frequently the layer ratio required to fulfill the diagnostic criteria is left ventricular apex but rarely also the midventricular >2. associated with heart failure and systolic dysfunction. but it may be triggered by and basal parts of the septum. TTS has been described in association with which have been also identified as prognostic factors pheochromocytoma. we QT prolongation: stroke is associated with QT regard it as not justified to generally propose OAC for prolongation in 30–40% of patients. So far there region. Patients with right atrial pressure exceeds the left atrial pressure. which is associated with palpitations. or both. dial fibrosis is unknown. and paroxy- No consensus has been reached so far as to somal AF can be diagnosed with 24–72-hour Holter whether LVHT is associated with an increased risk monitoring or 7-day event loop recorders. the type of replaced valve (bioprosth- esis versus mechanical prosthesis) and the affected valve (mitral versus aortic valve). especially the insular region. disease and stroke. QT prolongation is no evidence for a general clotting defect in LVHT may be associated with torsades de pointes tachy- patents requiring OAC [70]. Endo. AF have a 5-fold (non-rheumatic AF) to 17-fold In patients with cryptogenic stroke the prevalence of 115 . Endomyocardial fibrosis is a rare disease in European Coronary heart disease countries and is more prevalent in women than in There is a frequent coexistence of coronary heart men. Systolic performance is disease should lead to cardiological consultation for normal or only slightly depressed despite severe further therapeutic and diagnostic measures. to prevent strokes in AF. Chapter Summary Patent foramen ovale (PFO) Rhythm disturbances In about 25% of humans the foramen ovale remains Atrial fibrillation (AF) may lead to embolic stroke open. unless there is concomitant AF. Diagnosis of permanent AF is feasible is the one most frequently associated with LVHT [73]. permitting right-to-left shunting when the or peripheral or mesenteric embolism. Diagnosis of infective endocarditis is difficult. Clinically. but may also be due to the affected brain any other established indication of OAC. and left ventricular fractional shortening matched Brady. QT prolongation in stroke may be due to cardiovascular comorbidity. atherosclerotic risk factors. Among tial diagnosis in all stroke patients if laboratory signs these is one who developed multiple ischemic strokes of inflammation are present. spells or fainting. Among all NMDs. Suspected coronary heart erately increased heart size. Acute or subacute myocardial obliteration of the right or left ventricle [75]. LVHT patients. ment is the treatment of choice.or tachycardia causes symptoms such controls was found [70]. dizzi- ness or syncope. ing coronary angiography and percutaneous coron- tation. sex. atrioventricular valve regurgi. Barth syndrome heart disease). Degeneration into ventricular Endomyocardial fibrosis fibrillation and sudden cardiac death can occur. In a retrospective study of as dizziness. replacement). most probably due to common ized by severe congestive heart failure with only mod. 104 patients with LVHT stroke was found on imaging These symptoms may erroneously be interpreted studies in 16% of them [74]. with appreciable postoperative improvement and a 10-year survival of Valvular heart disease Ischemic and hemorrhagic strokes occur in 10 to 23% approximately 70% [75]. Though stroke/embolism as epileptic seizures. light-headedness. from the 12-lead electrocardiogram. endomyocardial fibrosis is character. cause of embolic stroke. The embolic risk varies cerebral infarctions from endomyocardial fibrosis according to the type of surgery (repair versus associated with hypereosinophilic syndrome [76]. Chapter 7: Cardiac diseases relevant to stroke (NMDs) in up to 82% of the cases. In a study on 62 patients percutaneous closure of the left atrial appendage is with LVHT no increased risk of these patients considered as an alternative to oral anticoagulation developing stroke/embolism as compared with age. endocarditis has to be considered as a differen- reported who developed an ischemic stroke. Whether there is a generally of patients with endocarditis. in association with endomyocardial fibrosis from After heart valve surgery patients are at increased schistosomiasis and one with multiple cerebellar and risk of thromboembolism. but single patients have been Thus. cardia. Surgical or of stroke/embolism or not. infarction and ventricular aneurysms can also be a cardial resection with atrioventricular valve replace. 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Rohr-Le Floch J. . sophageal echography or repeated 24-hour cardiac anterior choroidal (AChA). involvement) and by interpretation of imaging abnor. interventions by localizing the stroke (anterior versus In this chapter. it would lead to intracranial branches. and posterior circulation infarcts (POCI). gates the PCA territory. posterior cerebral artery (PCA) comes from the Fourth. while the proximal recognize and treat complications related to a specific PCA originating from the basilar artery is hypo. but of fusing the basal ganglia. A modification of it neuroimaging. localization helps to The anterior circulation refers to the part of the brain direct the subsequent work-up. it also allows the clinician to anticipate. such as large fluctuations in the lacunar aplastic. per- occurred in the territory distal to the stenosis. such as transe. There are five main etiology is suspected. This variant of the circle of sion from cerebellar edema. but is ably changed over the last decade. making the correct diagnosis means The anterior circulation can be subdivided into choosing the appropriate secondary prevention. If a cardioembolic perfused by the carotid arteries. such as cognitive-behavioral lacunar infarcts (LACI). during hospitalization. The greater diffi- dromes is still very important for several reasons. Section 3 Diagnostics and syndromes Chapter 8 Common stroke syndromes Céline Odier and Patrik Michel Introduction Several classifications for stroke territory. if a lacunar etiology and middle cerebral (MCA) arteries. carotid artery.or stroke type. via a large PCoA. PRES. watershed. it enables diagnosis. However. criteria and seems more accurate [2]. for instance. the cardiac investigation may remain uals.1). etc. With advances in partially outdated (Table 8. may be appropriate candidates for acute endovascular recanalization. the parts of internal capsule. total anterior circulation presentations which are easily misdiagnosed. method defines four subtypes of strokes according to anxiety. In some individ- is presumed. anterior cerebral (ACA) rhythm recording. 4]. subtypes. endar. . we will discuss classic presenta- posterior circulation or cortical versus subcortical tions of anterior circulation. localization of the lesion has become (SS-TOAST) adds a variety of clinical and radiological easier. published computer algorithm. distal: ophthalmic. The Oxfordshire exclusion of stroke imitators (migraine. In two systems. 2–10% according to different authors [3. and hemorrhagic strokes and try malities. and the deep perforating artery system. Finally. the leptomeningeal artery system vascu- the presence of a significant carotid stenosis. clinical recognition of stroke syn. in the acute phase. the adjacent white matter and the terectomy may be very effective if the recent stroke AChA. and recognition of rare clinical presentation attributed to a vascular territory: manifestations of stroke. culty in using it has been improved by a recently First. Each subtype of stroke may benefit from to identify clinical clues which can improve the intravenous thrombolysis for example. posterior communicating (PCoA). epilepsy. the centrum semiovale and 121 limited effectiveness if another territory is involved. it contributes to the planning of acute (PACI). the limited. partial anterior circulation infarcts Second. most frequently used for stroke mechanism. In contrast. psychogenic. Willis is also known as a fetal origin of the PCA. lacunar. which are from proximal to more intensive cardiac investigations. but only some diagnosis. posterior circulation.). Anterior circulation syndromes Third. such as proximal intracranial occlusion. infarcts (TACI). In these cases. the anterior circulation irri- “capsular warning syndrome” or brainstem compres. larizing the cortex. The TOAST classification [1] is The approach to neurovascular disease has consider. mechan- ism and etiology exist. the Sylvian artery. precentral. Small-vessel disease occlusion and is associated with a rather unfavorable prognosis. The visual of two of the three MCA territories (deep. and ipsilateral conjugated rior) M2 division of the MCA manifests itself clinic- eye and head deviation (the patient looks at his/her ally with contralateral isolated brachiofacial paresis. suggests a thrombus in a distal depending on the site of the occlusion. the extent of part of the MCA trunk. infarction presents contralateral hemiparesis. aphasia. Large-vessel disease suggests an M1 occlusion with or without carotid 2. in right lesions. A bilateral ptosis has also been described as an part. (proximal M2 segment). Large infarcts are defined as involvement or in the ACA territory should be suspected. malignant MCA infarct [5]. MCA territory infarcts A complete superficial MCA infarct. anterior patients at risk enables the medical team to propose a parietal. from Jacques Dubois.1. when vigi- lance decreases and initial signs worsen. An infarct of the superior (sometimes called ante- hypesthesia. a linguist and anatomist tinues. lead to quite variable severity of the stroke and of concomitant ischemia in the internal capsule (AChA) prognosis. Undetermined or multiple possible etiologies and transtentorial herniation. anosognosia. hemianopsia. hemicraniectomy for selected patients. superior field deficit may be a contralateral homonymous hemi- and inferior divisions) and “malignant MCA stroke” anopia or a quadrantanopsia. Particularly in younger people. Other etiology intracranial pressure and subsequent subfacial. angular and temporal arter. a patient with an acute complete MCA sion but often less pronounced or rapidly improving. with important variations in their territories. less severe. the M2 segment. The patient is usually awake or presents mild partial brachiofacial sensitive loss (mainly tactile and drowsiness or agitation. an of the lower limbs are less involved than the face and occlusion of the same artery at the same place may arms. confusion and monotone language of illness). Cognitive deficits are similar to an M1 occlu- Clinically. leading to ipsilateral corticospinal ment after the bifurcation into superior and inferior signs. respectively. the leptomeningeal arteries. including the insular notch). Early recognition of frontal. mostly in a right arise from the M3 segments and are named orbito. imminent sign of temporal herniation. a treatment ies. The deviation of the head as complete or near complete MCA territory infarc. gual apraxia in the case of left infarcts and various contralateral multimodal hemineglect (visual. lesion). Broca aphasia) frequently associated with buccolin- ideomotor apraxia. bellar tentorium. The artery is subdivided into the M1 segment. particularly with a right discriminative modalities). the etiology. degrees of multimodal hemineglect. ticulostriated arteries. . visual. New cortical symptoms may occur because of infarction of ACA or Middle cerebral artery (MCA) PCA arteries. motor. and the eyes is more transitory and the sensitive deficit is tion with ensuing mass effect from brain edema. which has proved highly effective if performed within The MCA territory is the one most frequently 48 hours and before those signs occur [6]. affected by acute strokes. uncal 5. In the case of a right lesion. hemi. spatial. Visual fields are usually spared. transient conjugate ipsilat- infarct. own body) and confusional state are seen. Cognitive signs are always present: in the case eral eye and head deviation and aphasia (aphemia or of a left lesion. and the M3 segment. sparing the len- can be subtle or a devastating clinical syndrome. prefrontal. leading to an ipsilateral fixed mydriasis and the contra- from which start the deep perforating lenticulostriate lateral cerebral peduncle is compressed against the cere- arteries. leading to high 4. anosodiaphoria (indifference to illness). anosognosia (denial anosodiaphoria. central sulcus. As collateral networks are highly variable. Motor and sensitive functions work. malignant 3. The clinical deterior- ation occurs typically within 48–72 hours. known as When the herniation of the medial temporal lobe con- Jacobus Sylvius (1489–1555). such as Babinski’s sign and paresis (Kernohan divisions. which become compressed against inter- The middle cerebral artery (MCA) is also designated hemispheric falx and cerebellar tentorium. If leg involvement is important and persistent. 122 sensitive. auditive). corresponding to the seg. Cardioembolism stroke with brain edema may develop. Stroke categories according to the TOAST asomatognosia (lack of awareness of a part of one’s classification. and the collateral arterial net. posterior parietal. in Paris. This picture 1. Section 3: Diagnostics and syndromes Table 8. The M4 segments. at the bifurcation of the artery ischemia. the uncus compresses the third cranial nerve. and most of the time global. Involvement of the corpus callosum can produce The centrum ovale receives its blood supply from the callosal disconnection syndrome. in contrast with larger and multiple infarcts. signs include proportional hemiparesis. ipsilateral conjugated degree the inferior posterior and retrolenticular part eye and head deviation (the patient looks at his/her of the internal capsule. which are the dominant part of the picture. the presen. the tail of the caudate nucleus. except in the case of deafferentation of the cortex the contralateral leg are also described. confusional state. which presents ideomotor apraxia. and occasionally abnormal in ischemia of the deep perforating arteries and the movements in the case of involvement of basal ganglia. which supplies the (M3 or M4) can produce highly circumscribed infarcts caudate head. anterior communicating artery (ACoA)). motor hemineglect and transcortical Both small and larger lesions may occur in the motor aphasia. Clinical function. may develop. named hallucination. grasping. the posterior corona the case of a right lesion. similar symptoms. contralateral multimodal radiata. Symptoms of an acute complete MCA infarction: contralateral hemiparesis. MCA is mostly lipohyalinosis and local arteriolo- ACA infarcts cause weakness predominantly of the sclerosis. border-zone area between the deep (leptomeningeal) and superficial (meningeal) arteries from hemody- namic mechanisms (see below). hypophonia. phia. upper limb. in the case of a left lesion. Therefore. hemi- sonal variants. Small infarcts (less than tion from the right hemisphere to cognitive center in 1. Wernicke’s aphasia or conduction aphasia The ACA is subdivided into the A1 segment (before the are observed and with a right lesion. aphasia. hemianopsia. the lateral geniculate body and the beginning 123 hemineglect. the genu and anterior arm of the internal accompanied by specific neurological deficits and is capsule and the supero-anterior putamen. less and subsequent herniation. leading to high intracranial pressure times called posterior) M2 division of the MCA. delusions and amusia may be present. Infarctions of the lower arterial segments show tation includes contralateral homonymous hemian. Sphincter dys- by interruption of subcortical cortical pathways. Clinically less important are . Cortical signs are absent or motor area). raH. dysarthria. Anterior choroidal artery (AChA) The boundaries of the territory supplied by the AChA The MCA territory is the one most frequently affected are still controversial [7]. Malignant stroke with brain edema of the optic radiations. followed by constructional and clothing dyspraxia. and in part of the lenticular nucleus. hemihypesthe. transcortical motor aphasia and behavioral dis- territory can therefore produce severe deficits with a turbances (with involvement of the supplementary very small-volume lesion. it is restricted to the deficits are often less proportional than in pontine left hand. Both the len- most of the time related to embolism. anterograde amnesia. mutism. Sensory hemisyndromes affecting mainly minor. the A2 segment (after the ACoA). behavioral changes. mild or transient brachiofacial paresis and cognitive disturbances. opsia or upper quadrantanopsia. then A3 segments. spatial dis. left posterior temporal branch and suggests strongly a The clinical presentation of ACA infarcts includes cardioembolic mechanism. Ischemia in their glect. probably reflecting interper- by acute strokes. frequent than superior division infarction. The artery vascularizes to a variable hypesthesia. agra- or internal capsule lacunes. Chapter 8: Common stroke syndromes In the presence of an infarct of the inferior (some. hemineglect. secondary to medullary perforating arteries coming principally interruption of the connection of physical informa- from leptomeningeal arteries. tactile anomia (inability to name objects placed Etiology in the deep perforator territories of the into the left palm) and the alien-hand syndrome.5 cm) usually present as lacunar syndromes but the left hemisphere. and behavioral disturbances are particularly frequent sia. motor hemine- glia and parts of the internal capsule. but not the complete picture. the medial lenticulostriate arteries. and gives rise to the Involvement of one of the leptomeningeal branches recurrent artery of Heubner (raH). For example. particularly in the elderly. With a Anterior cerebral artery (ACA) left lesion. The A1 segment has deep perforating arteries. orientation. an ticulostriate arteries and the raH are particularly vulner- isolated Wernicke’s aphasia occurs with occlusion of the able during aneurysm surgery of the ACoA. plus. weakness predominantly of the distal lower limb and The lenticulostriate arteries vascularize the basal gan. distal lower limb and to a lesser degree of the which are embolic from an arterial or cardiac source. to a lesser degree of the upper limb. lesion). with a classic subacute two. true rotatory or artery occlusion or branch retinal artery occlusion). The manifestations of acute internal carotid occlusion are quite variable. showing concomitant signs of all anter. hiccup. hypesthesia and upper quadrantanopsia or contra- lateral versus ipsilateral hemianopsia (in the case of Embolic occlusion of the ICA. watershed stroke. initial decreased 124 up including detailed ophthalmological examination. It may even be asymptomatic. sub. A rare but specific visual field defect less severe. enter the cranium through the foramen Lacunar syndrome within AChA territory causes magnum. level of consciousness and amnesia should be actively carotid imaging and a search for Horton’s arteritis. with a classic subacute two-phase pre- is a homonymous defect in the upper and lower sentation or even asymptomatic. A rarer but typical presentation of AChA ential branches as well as four cerebellar arteries. which manifests as a choreic or a lacunar syndrome: pure motor or sensorimotor hemi. drunken-type gait. jargon speech and seman. before are more frequent in the posterior circulation. respectively) concomitant signs of all anterior circulation arter- without cognitive disturbances. in the apophysis of the sixth to the second cervical vertebra. thalamic region. ent (amaurosis fugax) or persistent (central retinal Past diplopia. The two vertebral arteries leave the tic paraphasic errors) with left infarct. There exist numerous individual variations. the clinically most important being the fetal origin of Internal carotid artery (ICA) the PCAs from the carotid arteries (via the PCoA). decreased and leg weakness more severe and persist. basilar circulation. tentorium. showing lateral geniculate body or optic tract. the upper extremity. coarse tremor-like abnormal movement of variable paresis and less frequently a pure sensory deficit or an frequency and several minutes duration. AchA infarct subclavian arteries. usually leads to anterior circulation strokes severe stroke. parts of hemodynamic stress such as hypotension can lead to a midbrain (substantia nigra. a progressive atherosclerotic occlusion Similarly. searched for in the history of stroke patients. depending on the collateral status Clinical clues to differentiate posterior from and preexisting carotid stenosis. and choroid plexus. and infarcts is the triad of contralateral severe hemipar. circulation. hippocampus. and phase presentation. Consciousness is usually more posterior circulation stroke and should be recognized. then splits into two PCAs at the level of the cerebellar esis. headache is more frequent in the posterior is usually less severe. . uncus. either proximally or distally. mostly of ataxic hemiparesis syndrome. Retinal ischemia quadrants with sparing of a horizontal sector [8]. (BA). The BA gives several paramedian and circumfer- paresis. crossed motor or sensory symptoms. cognitive signs occur in AChA infarcts fugax) or persistent. secondarily to involvement of thalamocortical path- ways. optic tract. migraine [10]. an individual can present a In the majority of patients. either proximally or distally. Embolic occlusion of the ICA. It typically occurs when an A rarer but typical presentation of AChA infarcts orthostatic stress leads to a hypoperfusion of the brain is the triad of contralateral severe hemiparesis. and join together to form the basilar artery most frequently pure motor or sensorimotor hemi. usually leads to severe stroke. pass through transverse foramina may therefore imitate incomplete MCA strokes. from carotid emboli may be transient (amaurosis Rarely. in contrast with ies. [9] secondary to carotid severe stenosis. is typically ipsilateral to the infarct. including hemineglect and constructional apraxia with right lesion and thalamic aphasia (fluent Posterior circulation syndromes language with relatively preserved comprehension The posterior circulation is also called the vertebro- and repetition but anomia. Important clinical symptoms and signs point to a ior circulation arteries. the presentation is a limb-shaking TIA. tilt of the vision. A progressive atherosclerotic occlusion is usually MCA infarction. hemihypesthesia and upper quadrantanopsia. hemi. In rare situations. Section 3: Diagnostics and syndromes variable contributions to the vascular supply of the In the case of a chronic ICA stenosis or occlusion. may have features of primary headaches such as Retinal ischemia from carotid emboli may be transi. Preceding TIAs and strokes in the days and hours ent than in isolated proximal MCA occlusion. bilateral or It often occurs in isolation and requires urgent work. cerebral peduncle). In contrast. linear vertigo. amygdala. and is usually accompanied by a marked hori. and hemianopia from thalamic or hemispheric PCA zontal or horizonto-rotatory nystagmus. However. there is “wrong-way eye deviation” if compared to a simultaneous damage to the long sensory and motor hemispheric lesion in the MCA territory. which supplies the inferior cerebellum and 125 sisting of myosis. mild ptosis of of skew deviation (downward displacement of the axis the upper and lower eyelid. it should be underlined lesion). Chapter 8: Common stroke syndromes On exam. and proximal PCA occlusion may mimic MCA overcome with oculovestibular reflexes (“doll’s eyes infarction. the side of the lesion and head tilt to the side of the An ocular tilt reaction is characterized by the triad lesion). and hemifacial anhydrosis. ior circulation stroke: preceding TIAs and strokes in A nystagmus of central origin may be recognized the days and hours before the infarct. The former is due to the nuclei (such as in internuclear ophthalmoplegia). oblongata and the upper cervical cord. it is due to a paresis of one or several rounding the carotid artery. acute unilateral torsion towards the side of the lesion and head tilt to deafness. dissection. deviated toward the hemiparesis (brainstem ment with fixation. PPRF. The latter structure may also . ipsilateral dorsolateral brainstem. In the latter situation. headache.e. the absence of nausea despite clear-cut gaze or a conjugate gaze paresis with the eyes nystagmus with primary gaze. the side of the lesion. cognitive drome) leads to an ipsilateral deviation of the eyes. PICA. a disconjugate gaze strongly suggests a eyelid. If the eyes are deviated toward the hemiparesis. the eyes cannot tracts that cross in the caudal parts of the brainstem. cerebellar and sensitive signs are less spe- nucleus or its intra-axial fascicle (cranial nerves III. and the Another visual sign is Horner’s syndrome. The ocular tilt reaction may be caused by peripheral lesion of the inferior cerebellar artery (PICA) vestibular apparatus or the central vestibular connec. or ment of the ocular axis. and acute unilateral deafness (with or without (for saccades: parapontine reticular formation. by its direction (vertical. be directed to the other side because the command Truncular ataxia is quite characteristic of brainstem centers allowing this action are damaged in the pons lesions. mild ptosis of the upper and lower the dorsolateral medulla. especially if downgaze palsy is also present. The vertebral arteries give origin to two arteries tions including vestibular nuclei. cerebellar and of the globe ipsilateral to the lesion). this eye deviation cannot be ones. It may occur as a fixed misalign. a vertical gaze paresis (dorsal mesencepha- that a medullary or a cerebellar stroke can mimic a lic lesion). truncular ataxia. and for pursuit: parts of the nucleus of the VI) or the Despite these clinical clues. but may also occur due to a carotid deviation of the eyes as part of the ocular tilt reaction. con. A lateral medullary lesion (Wallenberg syn. It occurs with an brainstem lesion. cific in brainstem lesions. nystagmus. be associated with a caudal paramedian thalamic Clinical symptoms and signs that point to a poster- infarct. bilateral supply of the brainstem by one midline artery Gaze paresis may also be conjugate in brainstem (the BA). nerves and fascicles that produce ipsilateral signs and i. such as in vertical skew thalamic lesion. ischemia. orbital muscles as a result of an infarct of a single Motor. conjugate ocular sensitive signs. from ischemia to the cerebral peduncles. somnolence and early anisocoria. vertigo) suggests ischemia in the AICA territory. before joining to form the basilar artery: the anterior and the medial longitudinal fascicle (MLF) up to the spinal artery. lacunar brainstem midbrain (parts of the nucleus of the VI). and hemifacial anhy- drosis). multidirectional gaze-evoked typically ipsilateral to the infarct. ocular tilt reaction (triad of peripheral nystagmus and that vestibular ischemia skew deviation. and its lack of improve. early anisocoria or vertical A vertical gaze paresis (upwards. the peripheral sympathetic fibers sur- Alternatively. conjugate ocular torsion towards from AICA may result in a peripheral vestibular lesion. but the presence of bilateral IV or VI). vestibulocerebellum. Horner’s syndrome (myosis. The latter is caused by ischemia of cranial lesions. a disconjugate or pendular). signs and eye deviation from thalamic involvement. which supplies the medial medulla interstitial nucleus of Cajal. hemiparesis results maneuver”). Visual tilt of the environment towards the side of the lesion is frequently associated The vertebral artery (VA) and the posterior and may result in “upside-down vision”. bilateral or crossed motor. upper cervical. downwards. or from connections in between these or crossed signs is suggestive. Contrarily to infarcts may be indistinguishable from supratentorial most supratentorial infarcts. posterior circulation stroke is both) points to a dorsal mesencephalic lesion and may more probable than carotid territory stroke. however. or gaze palsy are present. If somnolence. contra. which can mimic a and contralateral thermoalgesic sensory deficit (spi- vestibular neuronitis. severe gait ataxia and ocular/truncular cending sympathetic tract). ventilation. ipsilateral ataxia and Horner’s syndrome. vestibular absence of an inferior cerebellar lesion cannot be nerve or labyrinthine artery). Section 3: Diagnostics and syndromes receive direct (long circumferential) branches from the case. and the VIIIth cranial nerve. This maneuver should not be applied in patients with AICA territory stroke can present as an isolated ver- suspected vertebral artery dissection. after Adolf ynx and vocal cord weakness and facial thermoalgesic Wallenberg (1862–1946). Occasionally. apnea) and finally cardio- medullary stroke (or Babinski-Nageotte syndrome). the laby- ipsilateral ataxia (inferior cerebellar peduncle). leading to contralateral motor and all- is the most common of those three syndromes and modalities sensory deficits. tigo or isolated cerebellar syndrome. the patient develops paresthesia in the shoulder. respiratory arrest. no motor recognized in their territory: the medial medullary responses. palatal and vocal cord weakness (ambiguous nucleus). lateral lemniscal sensory loss (medial lemniscus) and The hemimedullary syndrome is very rare and ipsilateral tongue paresis (nucleus of hypoglossal includes Wallenberg’s presentation with Déjerine’s nerve and tract). tions are the hearing loss and the peripheral-type tion-changing. a German neurologist. Major variations nausea. vertebral artery. Hiccup is cult unless certain cranial nerve deficits are present. (hypertension. but the main clinical distinc- nystagmus. More rarely. is occluded. ipsilateral tongue. nuclei or fascicle). In the first The SCA syndrome includes ipsilateral limb and gait . deficit. Isolated inferior cerebellar infarcts usually have a good outcome. superficial respiratory pattern. One clue which can help to make nothalamic tract). horizontal ipsilateral gaze reflex with the head thrust (Halmagyi) maneuver. and the hemi. Wallenberg’s syndrome includes ipsilat- eral thermoalgesic facial deficit (spinal trigeminal nucleus and tract). the presence or vomiting and nystagmus (vestibular nuclei. Dorsolateral medullary stroke (or Wallenberg syn- drome) is the most common brainstem syndrome the latter being usually the case if the vertebral artery of vertebral artery involvement. bradycardia. nausea. the dorsolateral medul. ipsilateral facial hypesthesia (trigeminal sent with vertigo. and preservation of the vestibulo-ocular facial palsy. ipsilat. dysar- ipsipulsion. ipsilateral deafness with determined clinically. Cushing’s triad lary stroke (or Wallenberg syndrome). vomiting. dysphagia. ipsilateral ataxia. A deceptive appearance of PICA stroke is thria (middle cerebellar peduncle and cerebellum) the isolated vertigo presentation. ipsilateral Inferior cerebellar lesions in the PICA territory peripheral-type facial palsy (facial nucleus or fascicle without involvement of the dorsolateral medulla pre. and may be refractory to treatment. nystagmus. nystagmus. phar- is named the Wallenberg syndrome. However. unreactive. the antero-inferior cerebellum. With transtentorial herniation. The medial medullary stroke is a rare stroke lethargy and coma are accompanied by central hyper- syndrome and classically includes contralateral hemi. dysphonia due to The AICA vascularizes the dorsolateral inferior pons. ocular and truncular of the extent of cerebellar supply by the three cerebel- ipsipulsion (vestibular nuclei) and ipsilateral Horner’s lar arteries may make localization to the AICA diffi- sign (descending sympathetic tract). of VII). tinnitus (cochlear nerve or cochlear artery). a post-infarct edema can provoke brainstem The superior cerebellar artery (SCA) compression. or transtentorial (upward) herniation. It is frequently misdiagnosed as the correct diagnosis is the presence of an unusual Wallenberg syndrome. Three classic clinical syndromes are neck stiffness up to opisthotonos. ipsilateral Horner’s syndrome (des- eral limb ataxia. palsy or dysphagia are also present. but the territory is 126 subsequent hydrocephalus and tonsillar (downward) regularly involved in distal basilar artery occlusion. Wallenberg syndrome and an infarct in the inferior cerebellum stroke can be seen in isolation or together. obstruction of the fourth ventricle with An isolated SCA syndrome is rare. which will be purely horizontal or direc. severe rinth. vomiting. small and unreactive pupils. ataxic then stroke (or Déjerine syndrome). common. the cochlea. The laterodorsal medullary stroke syndrome. contralateral thermoalgesic deficit The anterior inferior cerebellar artery (AICA) (spinothalamic tract). position pupils and decerebration. If a The classic AICA syndrome includes vertigo with Wallenberg’s syndrome is present. mid- paresis sparing the face (corticospinal tract). in the case of large PICA infarcts. upward gaze paralysis. pebrae superioris. or i. corresponding to circum. arm – medial) [12]. Collier sign (upper eyelid from the cerebellar arteries. Its territory can be subdivided into three parts ness and communication. and also include cending sympathetic tract). to light because of interruption of the afferent limb of eral lesions. origin of vertebral arteries (which can lead to artery- scribed lesions and precise deficits (see Table 8. basilar artery ischemia can help to provide aggressive form abnormal movements or palatal myoclonus therapy by i. can be found in Table 8. Other classic midbrain syndromes Involvement of the tegmentum implies more sensory. The anteromedial terri. and horizontal gaze palsy. the pupillary reflex. Chapter 8: Common stroke syndromes ataxia and important dysarthria. Other which will become paretic [14]. Nuclear reflecting the topographical orientation of the fibers palsy is recognizable by bilateral upgaze paresis and (leg – lateral. on a ventro-dorsal level [11]. Therefore. Distal basilar territory stroke usually leads to mid- tory receives its blood supply from the paramedian brain ischemia and is therefore characterized by arteries. such as paresthesias. In ventral paramedian retraction). and small pupils with diminished reaction lesions. Nystagmus (middle are nonspecific. in the case of penetrator occlusions of lacunar origin Atherosclerosis and embolism are the two major or can be devastating when the artery itself is acutely mechanisms of basilar artery stroke and occlusion. occluded. skew deviation. thrombolysis before a cata- (superior cerebellar peduncle interrupting the denta. the motor deficit is mild and can pre. and/or superior cerebellar peduncle. careful exami- and vascularizes the pons. dysarthria. sleep abnormalities. bilateral face palsy. the anterolateral territory from the short ocular manifestations. the mesencephalon and the nation of voluntary up. Given its and low NIHSS on admission were independent close relationship to the distal basilar artery. and contralateral thermoalgesic sensory as well as pseudoseizures with tonic spasm of the side deficit (spinothalamic tract) may be present. Rapid identification of signs have been described. Con- The basilar artery (BA) sciousness and vertical gaze are usually spared unless The BA lies on the ventral surface of the brainstem the midbrain is involved. prodromes are mentioned above. Severe pontine strokes are characterized by a locked-in syndrome that involves quadriplegia. part of the BA. such as disorders of reflex circumferential arteries (or anterolateral arteries) and voluntary vertical gaze. while paramedian infarcts and the central nucleus innervates both levator pal- involve the medial part of the medial lemniscus.2. About half of individuals present premonitory signs and the midpart of the BA [17].2) to-artery embolism). the intracranial part of the VA. (“herald”) hemiparesis or dizziness. Hypersomnolence or coma cranial nerves and oculomotor deficits.and downgaze in a seemingly middle and upper cerebellum through the AICA and comatose patient may establish preserved conscious- SCA. Small midbrain lesions may result dominate in the leg (crural dominant hemiparesis). Embolic clots may and symptoms. More specific lum and vermis). hemiparesis is the most severe. in nuclear or fascicular third nerve palsies. in Table 8.2. In anterolat. between the union of VA and AICA. it has been shown that vessel recanalization contralateral deafness (lateral lemniscus). superior cerebel. ipsilateral Horner’s syndrome (des. disorder and the dorsolateral territory from the long circum. strophic picture of a locked-in syndrome or coma. Dorsolateral lesions bilateral ptosis as the medial subnucleus of the III often involve the spinothalamic tract and lateral part innervates the contralateral superior rectus muscle of the medial lemniscus. strokes are very frequently embolic (from an arterial Less severe pontine stroke syndromes are listed or cardiac source). such as ipsilateral chorei.a. of convergence with pseudosixth palsy in the presence ferential arteries (or posterolateral arteries) as well as of hyperconvergence. SCA predictors of favorable outcome [15]. arise from vertebral or basilar atherosclerosis or from 127 tebral or basilar artery is the cause. especially if atherosclerosis of the ver. Some symptoms aortic or cardiac sources. usually requires extension of the ischemia into the Stroke severity in the BA territory is highly vari. contralateral fourth palsy pathological laughter (“fou rire prodromique”) [13] (IV nucleus).v. thalamic territory as part of the “top of the basilar able: it can present with isolated neurological deficits syndrome” [16]. and partial Indeed. Different eponym syndromes have been Common sites of atherothrombotic stenosis are the described in the literature. Occlusion of the basilar artery mostly results in where thrombus frequently extends into the caudal a devastating stroke with severe disability or death. torubral pathway). They are a regular cause of . Contralateral pain and temperature sympathetic fibers. X. Déjerine’s Nageotte syndrome and Opalsi’s syndromes distal vertebral and proximal BA occlusions. lid lag Raymond Ventral caudal VI Corticospinal tract Abduction palsy and crossed hemiplegia pons Millard. Hemimedullary Combination of Wallenberg’s.a. X. tegmental VII. retraction nystagmus. XI Corticospinal tract below Ipsilateral hemiplegia with Wallenberg syndrome the pyramid syndrome Babinski.2. corticospinal. . Horner’s. XI palsy. deficit and olivocerebellar tracts Déjerine Medial XII Corticospinal. X. lemniscus Ipsilateral tongue palsy. and spinothalamic sensory loss spinothalamic tracts Wallenberg Medulla. Selected brainstem syndromes with their eponyms.v. Eponym Site Cranial Tracts Signs nerves Weber Base of III Corticospinal Oculomotor palsy with crossed hemiplegia midbrain Claude Midbrain III Red nucleus and Oculomotor palsy with contralateral tegmentum brachium conjunctivum cerebellar ataxia and tremor Benedikt Midbrain III Red nucleus Oculomotor palsy. contralateral abnormal tegmentum movements Nothnagel Midbrain Unilateral Superior cerebellar Oculomotor palsy. Lateral spinothalamic Ipsi V. eyelid retraction. Corticospinal tract. ipsilateral cerebellar tectum or peduncles ataxia bilateral III Parinaud Dorsal midbrain Paralysis of upward gaze. IX. ipsilateral gaze palsy) Marie-Foix Lateral caudal Middle cerebellar Ipsilateral ataxia. contralateral hemiparesis pons (AICA) peduncle. IX. Gubler medial pons (fascicles) contralateral hemiplegia Foville Caudal VI nucleus. medial pons INO) Raymond. contralateral all Cestan pons VI nucleus) medial lemniscus sensory modalities deficit (contralateral (corticospinal tract) hemiparesis. XI tract. Another less common cause of BA strokes is the Rapid identification of basilar artery ischemia can help dolichoectasic basilar or vertebral arteries. or i. descending ataxia. Rostral dorsal (PPRF and Spinothalamic tract and Ataxia with “rubral” tremor. 128 been documented in up to 10% and are related to the thrombolysis before a catastrophic picture develops. PPRF lemniscus. and the presence of vascular risk factors and an increased risk predominant cause of distal BA occlusions. spino. VI Corticospinal tract Abduction and peripheral facial palsy. contralateral medullary median hemiplegia and lemniscal sensory loss syndrome Opalski Submedullary V. MLF contralateral hemiparesis (and hypesthesia. They have to provide timely aggressive therapy by i. medial Gaze and peripheral facial palsy. Section 3: Diagnostics and syndromes Table 8. light-near dissociation. cerebellar tegmentum IX. for lacunar stroke [18]. Caudal ventral VII. lateral Spinal V. basal segments. Cambridge: Cambridge University Press. 2001: 461. supply. and imitator”. Motor symptoms are infrequent and minor [19] and are mostly related to laterothalamic edema affecting the posterior internal capsule or to ischemia of the cerebral peduncles. hypesthesia and hemianopsia. basilar artery (2). ganglia and brainstem nuclei.e. basilar syndrome” causes headaches.1. a patient may present severe contralateral hemiplegia. metamorphosia. central  the thalamogeniculate (or inferolateral) artery visual loss and decreased level of consciousness. palinopsia. Caplan L. Lastly. cortical PCA branch occlusion causes diverse cortical lesions in the superficial PCA territory. Only blood Sensory symptoms (visual loss. variable parts of the thalamus and posterior hemispheric terri- tory. spatial disorientation (topographag- nosia). which may also include dyschro. posterior communicating an MCA stroke as mentioned above. Rarer The thalamus is essentially fed by the posterior causes include dissections. Its vascularization is subdivided into four prosopagnosia [16]. posterior cerebral segment P1 (3). and the anterior thalamus (via the PCoA) may stem toms are infrequent and minor. Chapter 8: Common stroke syndromes The posterior cerebral artery (PCA) The PCA is subdivided into four segments with associ- ated clinical presentation. eds. including upper midbrain. leading to variable clinical presentations and prognosis. Sensory symptoms are quite common in PCA infarcts and are usually related to laterothalamic involvement. Bilateral PCA infarcts are typical of the “top of the thalamogeniculate artery (8). mimicking Figure 8. Occlusions of the P2 (or postcommunal) segment before the branching of the thalamogeniculate arteries provoke ischemic lesions in the lateral thalamus and the hemispheric PCA territory. all of which can cause headaches. Source: Barth et al. posterior choroidal artery (9). segments). paramedian arteries (7). In the latter situ- ation. cortical and subcortical strokes in the anterior or ocular apraxia or poor hand–eye coordination and posterior circulation and is also called “the great optic ataxia or apraxia of gaze). . For example. postero-inferior temporal and variable part of the posterior parietal lobes. segment P2 (4). Percheron reported that the The thalamus paramedian arteries may arise from a unique P1 seg- The thalamus is a centrally situated structure with ment or from a vascular arcade connecting both P1 129 extensive reciprocal connections with the cortex. matopsia. visual agnosia or alexia-without agraphia with a left lesion. artery (5). The “top of the from the carotid system. Therefore it can mimic tanognosia or incapacity to see a scene as a whole. hemianopsia) are going to the lateral geniculate body (via the AChA) quite common in PCA infarcts. Balint syndrome (asimul. fetal origin of PCA and circulation via branches from the PCA (P1 and P2 migrainous stroke. from cardiac sources. Carotid artery (1).  the paramedian arteries The source of PCA strokes is embolic in the majority  the posterior choroidal artery (PChA). the PCoA and the PChA. while motor symp. An occlusion of the proximal segment (P1 or precommunal) usually causes a total PCA infarction. and proximal verteb- robasilar and aortic atherothrombotic disease. The syndrome of bilateral PCA territories correlated with the organization of the strokes must be distinguished from PRES (posterior thalamic nuclei [20] (Figure 8. including the occipital. Stroke Syndromes. i. amusia. tuberothalamic artery (6). of cases. in: Bogousslavsky J. basilar syndrome”.1): reversible encephalopathy syndrome) and venous  the tuberothalamic (or polar) artery thrombosis. central visual There are inter-individual variations in thalamic loss and decreased level of consciousness. part of the lateral and medial mic pathway. With unilateral infarction. mild contralateral hemiparesis The paramedian arteries arise from the P1 seg- or clumsiness. The inferior and middle rami include temporospatial disorientation. emotional the superior ramus irrigates a variable extent of thal- unconcern. apathy and even loss of psychic self- The thalamogeniculate (or inferolateral) arteries activation associated with amnesia similar to Korsakoff are a group of 5–10 arteries arising from the P2 syndrome. slight transient tively preserved syntax. speech with grammatically correct phrases. bucco. named the thalamic pain nucleus. This picture of amnesia and behavioral segment of the PCA. hemiparesis and thalamic astasia. ior. apathy. They also irrigate posterior portions “mid-line split”. toward the side contralateral to the lesion in the arising from the P2 segment of the PCA. phonological and impairment. while the medial branches supply the medial observed only with concomitant lesion of the anterior geniculate body and the inferior branches the rostral nucleus. named amus but mostly the dorsomedial nucleus. geniculate body. They to result from interruption of the dentatorubrothala. The aphasia. Individuals present a disorganized laminar nuclei and internal medullary lamina. It may be associated with chor. resembling those found after ation with facial paresis for emotional movement. but with Infarctions also tend to involve the medial midbrain. The principal branches supply disturbances is recognized as a “thalamic dementia”. and lateral dorsal and lateral deficit. and affective changes. severe persistent amnestic syndrome is nuclei. acalculia with preservation of reading evidently more severe. and a unique behavioral pattern. cerebellar stroke [21]. the posterior parts of the intra- Individuals describe paresthesias without objective laminar nuclei. Bilateral involvement is prehension. lack of spontaneity. hemibody side with vasomotor disturbances and lothalamic tract. Thalamic astasia Hypophonia and dysarthria can be associated. which have usually The classic features consist of a triad with an initial been discussed previously. an inferolateral infarct. personality changes. vertical gaze abnormalities and cognitive with reduced fluency. anomia. with sensory modalities. perseveration. Pseudoradicular sensory deficit is also sugges. is characterized by a reduced verbal fluency. Sensory deficits are heterogeneous. while judgment. amygdalofugal pathway. or a posterior nuclei. decreased level of consciousness with or without fluc- facial or limb apraxia and thalamic aphasia can occur tuations. Subsequent to. intrusions of unrelated themes. 130 tive of a thalamic involvement. involving one or several [20]. named adynamic aphasia tralateral hemihypesthesia. Behavioral disturbances are infrequent in infero- Infarction results in anterograde amnesia (mostly lateral stroke and include soft executive dysfunction reversible if unilateral). as well as the laterodorsal metry is obvious in language versus visual-spatial nucleus. The “thalamic hand”. supply the pulvinar. Cognitive and behavioral disturbances ment of the PCA. and ventral part of the internal medullary lamina. and is absence of significant motor deficit and is thought subdivided into medial and lateral branches. parts of midbrain an abrupt stopping of the deficit on the midline of the and probably the subthalamic nucleus. which become more obvious after the semantic paraphasia. impairment. resolution of the somnolence. euphoria. particularly in the cheiro-oral region. Visual-spatial disturbances are present mostly of personality changes with disinhibited behav- with a right lesion. the intra- palipsychism [21]. is flexed. a left–right asym- and lateral pulvinar. impulsivity. the lesion. pronated is absent in about a third of the population. contralateral hemisensory loss with mild . defined by a subjective sensation of of medial temporal structures. is characterized by disequilibrium backwards or The fourth territory is irrigated by the PChA. comprehension and repetition. automatic-voluntary dissoci. [20]. Cognitive disturbances consist and repetition. irrigate parts of the midbrain and the pons. decreased optokinetic nystagmus contralaterally to or rarely in the acute phase of. ventral pole of the medial dorsal nucleus syndrome of Déjerine-Roussy. perseveration and paraphasic errors but with a rela- eoathetoid movements. syndrome is characterized by visual field defects. rostral part of the ventrolateral choreoathetoid movements. impaired com. Section 3: Diagnostics and syndromes The tuberothalamic (or polar) artery arises from some individuals develop paroxysmal stimulus- the PCoA and irrigates the anterior nuclei. hemiataxia. the ventral sensitive. in which and the thumb is buried beneath the other fingers case the paramedian arteries vascularize its territory. mamil. The clinical presentation can include con. mis. With a left lesion. It described by Foix and Hillemand. severe and refractory pain in the affected anterior nucleus. the ventrolateral nucleus and the ventroposterior However. The clinical trunk. pure motor hemiparesis with internuclear ophthalmoplegia. increasing age. a homonymous visual related to a lesion in the ventroposterior nucleus of defect in the upper and lower quadrants sparing a the thalamus. treated with intravenous thrombolysis whenever pos- Five main classical lacunar syndromes are sible. The deficit wedge-shaped sectoranopsia. male gender. a lacunar stroke in a “jerky dystonic unsteady hand”. are most frequently due to an infarct in the internal superior or inferior. per. facial sonality changes. it has to be repeated that lect was associated with right pulvinar lesions. is usually proportional. syndromes.  pure motor hemiparesis Although lacunar infarcts have better recovery  pure sensory stroke and lower mortality rate during the first year. No specific behav. they are part of the spectrum of small-vessel disease. Hemichorea- than 1. Dysarthria–clumsy hand syndrome is due most involvement. non-lacunar strokes and small intracerebral hemor- rhages may present as lacunar syndromes.g. Similarly. in the event of pulvinar pons. including ataxia. Other mechanisms include microatheromas. disturbances [25]. . and rarely from the paramedian AChA [22]. etic movements. microbleeds. On the other hand. amnesia. but some spatial neg. pure Lacunar stroke syndromes motor hemiparesis with transient subcortical aphasia. and infarct in the subthalamic nucleus.5 cm in diameter occurring in perforator terri- hemiballismus is a classic presentation of a lacunar tories. underlining Ischemia in the thalamus can mimic cortical and the need for appropriate neuroimaging of all patients subcortical strokes in the anterior or posterior cir- suspected of stroke. dys. microembolism. vasculitis. horizontal sector is highly characteristic of vascular Sensorimotor stroke may result from a lesion of the lesions in the lateral geniculate body irrigated by the internal capsule. 24–48 hours after onset or can fluctuate considerably. culation. the phenomenon is called “capsular warning are considered to be of lacunar origin. smoking. decreased level of consciousness. myoclonus and chorea. resulting usually from a lacune in the mated that only one of five lacunes is symptomatic. internal capsule. About half of these fluctuating patients Lacunes result most frequently from occlusion of a will end with a lacunar stroke within 24–48 hours. Some individuals. They include isolated dysarthria. of the time to a lacunar infarct in the basis pontis. arm and leg ive of a lateral geniculate body lesion irrigated by the to the same extent. About 20% of all strokes function. In the acute setting. The single penetrating artery from lipohyalinosis within pathogenesis is not clear but seems to be rather electro- the artery. corona radiata or basis pontis. and a homonymous horizontal capsule. hyper- to elevation of perfusion pressure.2. develop delayed contralateral hyperkin. clinical features. and less frequently the corona radiata. specific location may lead to different lacunar stroke ioral disturbance is described. paresis. Visual field Pure motor hemiparesis and ataxic hemiparesis deficits include homonymous quadrantanopsia. a syndrome named the cerebral peduncle. physiological. rubral tremor. Therefore. which is highly suggest. and coronary artery If a severe hemiplegia alternates repeatedly with normal disease are also risk factors. Depending on the location there can be additional symptoms (e. and transcortical aphasia. Together with leukoaraiosis. Chapter 8: Common stroke syndromes hemiparesis. as overall they respond as well as do patients with recognized: other stroke subtypes. given its stereotyped fluctuations. They often progress during the first but diabetes. isolated ataxia and hemichorea-hemiballismus [24]. but lesions in the “hypertensive” (deep) intracerebral hemorrhages. coagulable states or genetic disease (CADASIL) and are individuals with presumed lacunar strokes should be present in up to a third of patients [23]. basal ganglia may also cause it. Pure sensory stroke is usually PChA. cognitive Many other lacunar syndromes have been impairment.  sensorimotor stroke small-vessel disease carries a high risk of vascular  dysarthria–clumsy hand syndrome death. recurrent stroke and development of cognitive 131  ataxic hemiparesis. Lacunes are defined as small subcortical infarcts less and many of the syndromes in Table 8. isolated third nerve palsy. previous lacunar TIA or stroke. less frequently to a lesion in the internal capsule or tonia. involving face. and the occlusion of the penetrator orifice from a large plaque absence of response to antithrombotic medication and in the mother artery. described. hemiataxia. and it is esti- syndrome”. pain). Ischemic lacunar strokes have some characteristic This disease is tightly related to chronic hypertension. plus. and in the case of a tricle respectively. Section 3: Diagnostics and syndromes Lacunes are small subcortical infarcts less than 1. ovale. The classic subacute two-phase presentation. hemodynamic failure. a Chapter Summary combination of these mechanisms has been proposed [27]: hypoperfusion due to severe arterial stenosis or Anterior circulation syndromes occlusion would impair the reserve of brain areas The anterior circulation refers to the part of the becoming more susceptible to the effect of microemboli. Internal carotid artery (ICA) Clinical presentation of WS infarction is hetero. Posterior infarction .  pure sensory stroke Infratentorially. of all strokes. Signs and symptoms may be bilateral in the signs of all anterior circulation arteries.5 is classically associated with Balint’s syndrome cm in diameter occurring in perforator territories. of paucity of blood supply [29] and in the lumbosacral segments due to the high concentration of neurons and higher metabolic demands [30]. If Five main classic lacunar syndromes are recognized: an arterial pathology is present. Middle cerebral artery (MCA) WS infarcts have been studied best in the anterior The MCA territory is the one most frequently affected circulation in relationship to severe stenosis or occlu. as a chain-like (or rosary-like) pattern in this deep Infarctions of the lower arterial segments show territory. ipsilateral conjugated eye and head deviation from the prefrontal or parieto-occipital cortex down (the patient looks at his/her lesion). the extent of ischemia. strokes. Incomplete leading to high intracranial pressure and subsequent IWS strokes may appear as a small single lesion or herniation. contralateral multimodal hemineglect. depending on the sion of the ICA. They involve the junction of distal regions The clinical presentation is heterogeneous and of two arterial systems. Watershed infarcts (WS) Watershed (or borderzone) infarcts represent about 5% Watershed (or borderzone) infarcts involve the junction of distal regions of two arterial systems. Two typical patterns are observed: site of the occlusion. onset can be less abrupt than in embolic strokes and can fluctuate  pure motor hemiparesis with changes of blood pressure and body position. and low flow with stagnation of blood would increase clot formation and decrease wash-out of emboli. case of a left lesion. A progressive case of systemic hypotension or unilateral in the case atherosclerotic occlusion is usually less severe. transient (amaurosis fugax) or persistent (central retinal 132 the “man-in-the-barrel” with proximal weakness of artery occlusion or branch retinal artery occlusion). anterior–posterior orientation in the centrum semi. Recently. optic ataxia and ocular apraxia). There is better evidence that IWS stroke. or embolic occlusion of an intracerebral artery are implicated. MCA territory infarcts can be subtle or a devastating clinical syndrome. geneous and depends on the location of ischemic usually leads to severe stroke. hemian- Strokes appear radiologically as wedges extending opsia. brain perfused by the carotid arteries. aphasia. either proximally or distally. in the to the frontal and occipital horns of the lateral ven. has an association with hemodynamic failure rather than with embolic mechanisms. or even asymp- tomatic. The IWS area is situated in an right lesion. but not the complete picture (e. Embolic occlusion of the ICA. showing concomitant changes. and the collateral arterial network. the cortical WS (CWS) and the internal WS (IWS) etiology. by acute strokes. with a of unilateral carotid severe stenosis or occlusion. Pathophysiologically. upper and lower limbs. contralateral hemiparesis. Malignant stroke with brain edema may develop. ovale and along the lateral ventricle [28]. similar symptoms. hemihypesthesia. ACA and PCA territories.  sensorimotor stroke The watershed area in the upper spinal cord is  dysarthria–clumsy hand syndrome thought to be on the thoracic level T4 to T6 because  ataxic hemiparesis. tight stenosis (or occlusion) of a cervical or intracranial artery [26]. (asimultagnosia. systemic depends on the location of ischemic changes. isolated brachiofacial paresis with or without visual particularly rosary-like infarction in the centrum semi- field symptoms).g. The CWS area is located superficially in the Symptoms of an acute complete MCA infarction: cortex between the MCA. Retinal ischemia from carotid emboli may be classic picture of a bilateral deep anterior IWS stroke. is rare. WS strokes are not well investigated. gaze paresis (dorsal mesencephalic lesion).  sensorimotor stroke 65(4):561–4. Neurology 1996. cerebellar and sensitive signs. They often progress during the first Cerebrovasc Dis 2000. Tanghe HL. Grandin CB. 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Chapter 9 Less common stroke syndromes Wilfried Lang Introduction Boundary-zone infarcts This chapter deals with focal brain ischemia. profound and elsewhere. either The evidence that at least some boundary-zone TIA or ischemic stroke. as a result of The first part focuses on an uncommon mechanism cardiac arrest or cardiac surgery) sometimes causes of focal brain ischemia. usually ciated clinical syndromes. between the supply territories of the MCA and the However. in the corona radiate and centrum semiovale. The clinical features include mon clinical presentations of focal brain ischemia are visual disorientation and agnosia. Brachiofacial hypoesthesia is frequent. uncommon causes of TIA Hemianopia is the most common symptom in and ischemic stroke are presented together with asso. with macular sparing and predominating in the lower quadrant. some impaired sensation of the same distribu- circle of Willis is incomplete or diseased. lesions manifest as either low flow isolated word-finding difficulty or transcortical sens- ory aphasia (impaired comprehension but preserved Ischemic strokes and transient ischemic word repetition and speech output). This chapter is divided into three parts. The boundary are caused by embolic and acute. flow – anterior circulation Anterior boundary-zone infarction is recognized Most ischemic strokes and transient ischemic attacks in severe carotid stenosis or occlusion. Secondly. which is low flow. Mechanisms tion and transcortical motor aphasia (intact compre- to compensate for the reduction of blood flow are hension and repetition with impaired speech output). more than the arm and sparing the collateral circulation is compromised because the face. in some patients severe stenosis or occlu. vasodilatation by autoregulation and an increase of which may be preceded by mutism if in the dominant the oxygen extraction fraction. relatively prolonged hypotension (e. unilateral posterior boundary-zone infarction. and amnesia. mechanisms and infarcts are caused by low flow rather than acute clinical syndromes of brain hemorrhage are described arterial occlusion is that a sudden. The clinical features are contralateral weak- critical reduction of blood flow. There is an internal or subcortical boundary zone ularly vulnerable to any fall in perfusion pressure. parieto-occipital regions. In the non- dominant hemisphere contralateral hemispatial neg- attacks caused by low cerebral lect and anosognosia are usually found. branches from the MCA trunk and the medullary 135 . Most TIA infarction bilaterally in the posterior boundary zones and ischemic strokes are caused by embolism or in between the supply territories of the middle cerebral situ artery occlusion. This lies between blood pressure may cause transient or permanent the supply areas of the lenticulostriate perforating focal ischemia. In Uncommon mechanism of stroke: the dominant hemisphere. lateral Under these circumstances a small drop in systemic and/or above the lateral ventricle. In the third part. Hemodynamic causes of focal artery (MCA) and the posterior cerebral artery in the brain ischemia are less common. If the vascular bed hemisphere. uncom.g. in situ (usually zone is located in the frontoparasagittal region. is maximally dilated the supplied brain is partic. thrombotic) occlusion of an artery in the brain. anterior cerebral artery in the frontoparasagittal sion of carotid or vertebral arteries may cause a region. orthostatic dysregulation.g.g. Objects appear bleached and a brief visual loss A sudden and profound hypotension sometimes may follow. irrevers-  with exercise. The symptoms usually point towards a seizure. This symptom has been related to retinal causes boundary-zone infarction. ies during head rotation. followed by tinnitus. concomitant disorder of  on standing up very quickly. lation in Moyamoya disease. osteophytes or degenerative characterized by 30–60 sec episodes of repetitive changes resulting from cervical spondylosis may be jerking movements of contralateral arm and/or leg the cause of compression. perhaps. ated with severe large artery disease with exhausted posterior cerebral arteries. leading to a slowly progressive.1).g.) but embolism from heart is also possible Ischemic strokes and transient ischemic  during operative hypotension  if the patient has recently been started on or attacks caused by low cerebral flow. Rotational vertebral artery occlusion (RVAO) and stroke Rotational vertebral artery occlusion (RVAO) is Limb-shaking TIA caused by mechanical compression of vertebral arter- A transient ischemic attack which is typically associ. even if postural uncompensated. The labyrinth is predominantly supplied shows no somatotopic spread of movement activity by the internal auditory artery. hyperventi. e. reduced blood flow from the 136 endarterectomy or extracranial–intracranial bypass vertebral artery would result in ischemia. palpitations. e. e. Further  during Valsalva maneuver (but embolism is typical findings are neovascularization of the retina another possibility) and iris (rubeosis iris) [2]. The vertebral artery is usu- ated with severe large artery disease with exhausted ally compressed at the atlantoaxial C1–C2 level. increased the dose of any drug likely to cause posterior circulation hypotension. Ischemic ophthal- toms start under certain circumstances [1]: mopathy is a specific. within this internal boundary zone. Quite  immediately after a heavy meal characteristic is the history of a gradual. which is usually a (no Jacksonian march) and usually has a low branch of the anterior inferior cerebellar artery frequency (about 3 Hz). occasionally with bouts of  in very hot weather obscuration. to low flow. coughing or hyperventilation ible damage of the retinal neuronal layer. Approxi- (Figure 9. progressive loss of visual acuity.g. middle (e. of an already marginal perfusion. As AICA usually takes off the basilar artery shaking disappears with revascularization. claudication: an increase in the metabolic demand A fall in cerebral perfusion pressure as a cause of during exposure to bright light cannot be met because focal brain ischemia should be suspected if the symp. carotid at its lower portion. usually causing lacunar or partial anterior circulation syndrome. Most RVAO patients and has been described with carotid occlusion but exhibit an ipsilateral stenosis or vessel malformation also with stenosis of intracranial vessels. with a mixed downbeat torsional and horizontal beat- like activity and are often misdiagnosed as focal ing nystagmus which may spontaneously reverse dir- seizures.  during a clinically obvious episode of cardiac dysrhythmia (chest pain. Infarction can occur hemodynamic reserve is “limb-shaking TIA”. Section 3: Diagnostics and syndromes perforating arteries which arise from the cortical A transient ischemic attack which is typically associ- branches of the MCA and the anterior and. limb shaking ection [3]. In contrast to seizure activity. etc. critically reduced perfusion pressure hypotension cannot be demonstrated in the clinic due to internal carotid artery occlusive disease. in Ischemic ophthalmopathy association with severe carotid disease and sometimes Another symptom of low flow is monocular transient an obvious hemodynamic precipitating cause. It is Tendinous insertions. Video-oculography showed that RVAO is associated sion. or by carotid compres. mately 50% of RVAO patients treated conservatively . retinal ischemia occurring when looking into bright light. the (con- shaking TIA” is elicited in situations which dispose tralateral) dominant vertebral artery is compressed. “Limb bral artery. It is reported that limb (AICA). hemodynamic reserve is “limb shaking TIA”. hypoplasia) and a contralateral dominant verte- cerebral artery or anterior cerebral artery. The leading symptom is vertigo. With ispilateral head rotation. The leading symptom consciousness. With vertebrobasilar ischemia. 137 ischemia [5]. In a large series. suffered from infarction or residual neurological def. Limb-shaking TIA. diplopia or blurred vision be caused by compression of the vestibular nerve as (Figure 9. The right internal carotid artery (ICA) was occluded. Among 116 patients with unilat- immediately after the fall despite being uninjured. only other sensation. eral steal as shown by ultrasonography none had Not a single patient in the New England Medical symptoms of brain ischemia [7]. is vertigo. par. vertigo or occlusion are asymptomatic. A 55-year- old woman with risk factors (metabolic syndrome.8%) had objective signs of and is not induced by a change of posture or move. The patient may be unable to rise coolness of the arm. brachial ischemia such as aching after exercise or ment of the head.2). Territory of the ICA was supplied from the left ICA via the anterior communicating artery. arteries [6]. the symptom was considered to be focal epileptic. Rotational vertebral artery occlusion (RVAO) is In “drop attacks” a sudden loss of postural tone caused by mechanical compression of vertebral causes a fall to the ground without loss of arteries during head rotation. smoking) presented with a limb shaking of the left leg when standing. Perfusion MR showed reduction of blood flow in the anterior territory of the right middle cerebral artery and the right anterior cerebral artery. falls are usually preceded by and associated with icits [4].1. A “drop attack” has been described in a caused by close contact with intracranial vessels. sudden able to significant subclavian or innominate artery . patient with parasagittal motor cortex/subcortex ticularly the posterior inferior cerebellar artery ischemia in the territory of both anterior cerebral (PICA). Drop attack and vertebrobasilar ischemia Subclavian steal syndrome and hemodynamic effects “Drop attacks” are episodes of sudden loss of postural of proximal vertebral artery disease tone which cause the subject to fall to the ground Most patients with subclavian artery stenosis or without apparent loss of consciousness. Occlusion was presumably acute. There was no collateral blood flow from the posterior communicating artery. Initially. Brief episodes of rotational vertigo can also symptoms such as vertigo. Among more than Center Posterior Circulation Registry had a drop 400 patients with posterior circulation TIAs or ische- attack as the only symptom of posterior circulation mic stroke only two had symptoms (TIAs) attribut. followed by tinnitus. Chapter 9: Less common stroke syndromes Figure 9. The attack occurs without warning 15 out of 324 patients (4. In sickle-cell anemia. blurred vision. hematocrit as found in polycythemia vera. .2. Causes of stenosis or occlusion of the verte- red cell deformability (sickle-cell anemia. blurred vision. particularly in the stenosis or occlusion of the proximal vertebral artery. Associated symptoms vertigo. increase in cell a difference of blood pressure between the two arms counts (e. blood pressure and hemorrheological diplopia.g. occasionally with cause of cerebral ischemia. Drop attack. Binswanger’s disease or large than to have hemodynamic effects: among 407 artery (territorial) infarction. Stenosis of the basilar artery proximal to the AICA (anterior inferior cerebellar artery) was assumed to be the cause of these drop attacks. hemodynamic effects considered to be the cause of Plasma hyperviscosity syndrome is a clinical entity cerebral ischemia. weakness and sudden falling without losing consciousness. Only in 13 of 80 were the development of moyamoya. Episodes were particularly frequent after reduction of elevated blood pressure. and decreased drome. in diseases such as polycythemia vera. vertigo (sensation of being turned around). paresthesias. flow and/or increased coagulability may be the cause decreased vision or oszillopsia. spherocytosis. Different ischemic patterns Severe stenosis or occlusion of the proximal verte. disease [8]. lethargy. This may cause Circulation Registry 80 of 407 patients had severe damage in the microcirculation. sweating.g. diplopia. such as lacunar infarction. with hematological disease (e. Waldenstrom’s macro- A difference in the wrist or the antecubital pulses and globulinemia or paraproteinemia). as have been Cerebral blood flow is diminished with high reported by bowlers or baseball pitchers. Section 3: Diagnostics and syndromes Figure 9. Abnormal changes of blood plasma are brief and may be elicited by exercise of the arm. was also found. paresthesias. blood vessels. such as headache. Symptoms Most patients with subclavian artery stenosis or are often unspecific. Takayashu disease and hemoglobinopathies) lead to a hyperviscous state [9]. vertigo. of focal brain ischemia. In 45 of the 80 (56%) embolization was the most likely But large-artery occlusive disease. Twelve of these 13 patients had with mucous membrane bleeding. temporal arteritis or mechanical trauma. dizziness or occlusion are asymptomatic. nitus. decreased vision or oszillopsia. Symptoms which have been associated Hyperviscosity and low flow with decreased anterograde flow or retrograde flow Blood flow in the brain is determined by the size of in the vertebral artery are episodes with dizziness. patients in the New England Medical Center Posterior deformability of red cells is decreased. The attacks factors of the blood. An 82-year-old woman with insulin-dependent diabetes mellitus suffered from recurrent short episodes with nausea. Low may include episodes with dizziness. boundary zones between major arterial territories. have been described. Symptoms disappeared after stent-PTA of the stenosis. headache. bral artery are: arteriosclerosis. ery- are reliable signs which indicate subclavian steal syn- throcytosis or hyperleukotic leukemias). bral artery is more likely to be a cause of embolism boundary infarction. and occasionally seizures. blurred vision or tinnitus. dizziness. tin- artery [8]. 138 severe bilateral occlusive disease of the vertebral visual loss. hemiplegic TIAs is limited in time and lasts about such as headache. blurred vision or tinnitus.3. it has been suggested that an atheroma in the MCA may cause a high-grade obstruction at the origin of stroke of the single lenticulostriate artery [10] (Figure 9. 24–48 hours. It is assumed that the occlusion of a single perforating artery (lenticulostriate artery) was the cause of the lacunar infarct. He was unable to walk. The risk of developing a lacunar infarct sias. dizziness or vertigo. This infarct typically presents Sudden cortical blindness is a rare symptom of TIA or with “pure motor hemiparesis”.3). is about 40% within the next few days. Symptoms are often unspecific. arm and leg. The visual field defects may be . Abnormal changes of blood plasma lead to a stereotypic transient ischemic attacks with “pure hyperviscous state and cerebral blood flow can motor hemiparesis” (“lacunar TIAs”). This burst of be diminished. Alterna- Uncommon clinical presentations tively. A 65-year-old with hypercholesterolemia was referred to the hospital because of a sudden weakness of left face. The next day he suffered a lacunar stroke in the internal capsule with persisting pure motor hemiparesis. Capsular warning sign. He was dysarthric. The capsular warning syndrome A small infarct in the internal capsule is considered to be caused by the occlusion of a single lenticulostriate Bilateral blindness: “top of the basilar artery which arises from the mainstem of the middle artery” cerebral artery (MCA). Symptoms disappeared after about 10 minutes but over the next 5 hours he had four further identical episodes lasting for several minutes. In situ small- vessel disease (microatheroma or lipohyalinosis) is considered to be the most likely mechanism. The term “capsular stroke and has been explained by an occlusion of the warning syndrome” describes the phenomenon in “top of the basilar artery” at the origin of the posterior 139 which the infarct may be preceded by repetitive. paresthe. Chapter 9: Less common stroke syndromes perforating lenticulostriate arteries main branches MCA occlusion of a perforator Figure 9. cerebral arteries [11]. Other symptoms which we consciously experience (“autobiographic of bilateral ischemia in the territory of the PCA may episodes”). This so-called blind sight is probably cerebral arteries. responded to verbal commands and was partially oriented. response to light was reduced. A 65-year-old patient with known Parkinson’s disease and vascular risk factors (diabetes mellitus.4). The cognitive system representing this 140 be: memory loss. Although without conscious visual perception he was able to unconsciously prevent himself from bumping into objects when walking. Symptoms may be cases of persistent amnesia. Personal (autobiographical) memories depend on ism from the heart or the proximal vertebrobasilar the ability to encode. There was no weakness of the limbs. On admission he was awake. and agitated delirium. “Blind sight”. which is composed of the superior colliculi and their Amnesia projections to peristriate cortex (Figure 9. In by questions about recent personal history or more .4. He reported not seeing anything with either eye. tical blindness is present. It can be tested and retrograde amnesia. Embol. quite asymmetric and variable. The primary visual cortex of each side was damaged. patients may retain some ability to avoid bumping into objects and may blink Bilateral blindness can be due to occlusion of the basilar artery at the bifurcation to the posterior to visual threat. explained by some sparing of the visual cortex and by preservation of the so-called second visual system. the mesial temporal lobe was described [8]. usually involving both anterograde ability is termed episodic memory. CCT showed a bilateral infarction in the territory of the posterior cerebral artery with hemorrhage on the right side. hypertension. store and retrieve information artery is the cause of this sign [12]. When showing him different numbers of fingers he mentioned not seeing the fingers but his performance of rating the number of presented fingers was much above chance. Pupils were mid-dilated. Section 3: Diagnostics and syndromes Figure 9. Even when severe cor. obesity and smoking) suddenly lost muscle tone and consciousness. bilateral infarction of transient (TIA) or persisting. fornix. artery which branches from the posterior cerebral artery rograde amnesia. language disturbance. Depending stimuli on the site of the lesion. After regaining consciousness. symptoms or can be demonstrated with brain imaging. If amnesia is the leading clinical the only symptom of acute stroke.and downgaze palsy or skew deviation) artery (parts of the thalamus). disorientation to time. Further. Embolism from the illusions or hallucinations). A disorder of from an occlusion of a single thalamic-subthalamic the system underlying episodic memory causes ante. or person. Infarcts in the anterior and dorsomedial memory impairment thalamus can produce severe memory deficits which  clinical features developing over a short time and are almost always accompanied by other neurological tending to fluctuate over the course of a day. The arterial blood supply of the (PCA). Recall of the following symptoms and signs: memories is mainly based on two processes. Patients can be hypersomnolent or comatose as anatomical structures subserving episodic memory if being in an anoxic or metabolic coma without local- has many sources. increased or decreased psychomotor found to be the cause of bilateral infarcts. Input from this system is Reduced vigilance or coma necessary to ensure that the multimodal information from the environment which is processed and as the leading symptom integrated in the neocortical association areas Bilateral paramedian thalamic infarction can result becomes memorable and retrievable.  bilateral infarcts of the medio-basal temporal lobe  bilateral thalamic infarcts and  subarachnoid hemorrhage from aneurysm of the Agitation and delirium as the presenting anterior communicating artery. posterior cerebral and neuropsychological deficits may become apparent. disturb visuo-spatial memories. syndromes which cause amnesia: Coma is frequently found in basilar artery occlusion. posterior communicating combined up.and perirhinal cortex. artery and the anterior communicating artery (basal disturbance of vertical gaze function (upgaze palsy. incoherent speech more. recognition of familiarity or  disorganized thinking as indicated by irrelevant or conscious recollection may be more disturbed. ento. place. disturbances of sleep– heart or proximal vertebrobasilar artery is typically wake cycle. activity. additional of the fornix). But here.  reduced ability to maintain attention to external ments that something is familiar and the conscious stimuli and to appropriately shift attention to new recollection of an episode with all attributes. antly verbal amnesia whereas right-sided lesions may perceptual disturbances (misinterpretations.  symptoms such as reduced level of consciousness. symptom Memory defects can follow unilateral or bilateral According to the American Psychiatric Association infarcts of the medio-basal temporal lobe but are more (1987) delirium is defined as a clinical symptom with common with left-sided and bilateral lesions. parahippocampus. mammillary bodies). nucleus anterior thalami. left-sided infarcts are known to cause predomin. neurological signs such as ophthalmoplegia and bilateral There are three uncommon but relevant stroke extensor plantar reflexes indicate brainstem ischemia. judge. particularly the anterior cerebral izable neurological signs. mamillothalamic tracts and Amnesia can be caused by temporal lobe or thalamic infarcts. cingulate gyrus. neglect or executive Agitation and/or delirium may be the leading or 141 dysfunctions. the basolateral limbic circuit (dorso-medial thalamic nucleus and amygdala) and the basal forebrain. artery (hippocampus and parahippocampal gyrus). Chapter 9: Less common stroke syndromes systematically by presenting a list of words and by symptom TIA or stroke has to be distinguished from testing free recall of them after a few minutes. TIA and stroke are anatomical structures underlying episodic memory either accompanied by other neuropsychological are the Papez circle (hippocampus. and neuropsychological symptoms such as attentional deficits. forebrain and fornix). It is uncommon . The transient global amnesia (TGA). Coma is more frequently found in patients with acute anterior choroidal artery (anterior hippocampus and occlusion of the basilar artery in whom ischemia involves adjacent cortex) and posterior choroidal artery (parts the bilateral pontine tegmentum. focal hemorrhage or ischemia in the mesencephalon. The . Akinesia or involuntary movements cranial nerve palsy without any sensory or motor Acute hypokinetic or hyperkinetic movement dis- deficits may indicate a focal brainstem ischemia. Contralateral akinesia/hypokinesia. Acute akinesia or hypokinesia of the contralateral 142 lomotor nerve [14]. (b) bilateral motor and/or sensory deficits or (c) disorders of conjugate eye movements. In five patients a focal ischemic lesion in the stroke. facial nerve underlying white matter have been found to be most and even of the vestibular part of the vestibuloco- frequently associated with agitation and delirium. Rarely. A patient suffered from a large infarction in the territory of the right anterior cerebral artery (ACA). Section 3: Diagnostics and syndromes Figure 9. the mesencephalon had an isolated palsy of the ocu. and may not be considered a clinical manifestation of palsy. With movements of the right finger an activation in the intact left supplementary motor area (SMA) preceding the onset of movement by more than 1 second was shown [17]. chlear nerve is caused by focal hemorrhage or ische- mia in the pons [16]. Right palsy of the trochlear nerve has been described with hemisphere infarcts that include the hippocampus. The patient participated in an experiment with measurements of magnetic fields of the brain preceding spontaneous movements of the right index finger. amygdala.5. Thömke et al.5). trigeminal. In a retrospective analysis. tiple) together with contralateral motor or sensory deficit. Stroke in the brainstem is typically indicated by (a) Focal brainstem ischemia may cause isolated cra- ipsilateral cranial nerve (III–XII) palsy (single or mul. Ischemia may be caused by low Isolated cranial nerves flow in boundary zones. entorhinal and perirhinal cortex and their Isolated palsy of the abducens. 19 of 661 stroke mesencephalon was causal for the deficit. Isolated patients (3%) presented with delirium [13]. His left arm was spontaneously not used but showed forced grasping reflexes to visual and tactile stimuli. orders are an uncommon but sometimes the leading Two out of 22 patients with focal ischemic lesions in symptom of stroke. [15] studied 29 part of the body is found after ischemic lesions of the patients with diabetes mellitus and oculomotor nerve medial part of the frontal lobe [17] (Figure 9. nial nerve palsy. Usually. systemic lupus . Cerebral embolism from infected valves is the involves frontal cortex. Bilateral lesions of the mesial aneurysms are often assumed to be the cause of cere- frontal cortex are known to cause severe akinetic states. cirrhosis. bral hemorrhage. Stroke manifestations of systemic disease Endocarditis of various origins typically causes Infective and non-infective endocarditis: multi-territorial multi-territorial infarctions. Small and large multi-territorial infarction is a radiographic sign in NBTE [27]. other cerebro- body. encephalo- Uncommon causes of stroke pathy rather than focal deficits may be the initial and associated clinical syndromes clinical presentation. especially mucin-producing Akinesia can be caused by lesions in the medial adenocarcinomas (particularly pancreatic carcinoma frontal lobe. Response to hemorrhage include hemorrhagic transformation of external stimuli helps to distinguish motor hypokinesia/ the ischemic infarction. More common mechanisms of visual or tactile clues (“forced grasping”). Lesions of vascular complications include intracranial hemor- the right SMA are associated with hypokinesia/akinesia rhage and subarachnoid hemorrhage [22]. rheumatic heart disease. It is char- reported acute involuntary movement disorder in acute acterized by the accumulation of sterile platelet and stroke. Mycotic of the left part of the body. face þ arm þ leg). these symptoms are transient. Besides brain and retinal ischemia. central mechanism of neurological injury in patients The SMA receives excitatory input from the ventro. rheumatological diseases mon in focal brain ischemia for isolated movements such as lupus (where it is referred to as Lipman-Sacks such as extension of fingers and hand or movements endocarditis). gastrointestinal diseases such as of the tongue to be the only symptom (Figure 9. Non-infective endocarditis is termed non- Hemichorea-hemiballism is the most frequently bacterial thrombotic endocarditis (NBTE). Chapter 9: Less common stroke syndromes supplementary motor area (SMA) is the medial part coagulase-negative Staphylococcus or Enterococcus) of the premotor cortex and is supplied by the anterior or. But mycotic aneurysms are found in less than served or even exaggerated ability to respond to external 3% of hemorrhages. Inflammatory vasculopathies and connective tissue 143 tions caused by bacterial (Staphylococcus aureus. Typically either one part suffer from stroke [25]. vessels. face þ arm. basal ganglia and thalamus. AIDS. arm. A significant proportion of or several parts of the body are involved (face. disease: a chronic and multisystemic disease The vast majority of endocarditis is secondary to infec. and severe systemic illness. Embolic debris from lateral thalamus. infected valves typically lodges in the distal branches sphere cause a lack of spontaneous speech (transcortical of the middle cerebral artery [20]. of focal attention. It has classically been described after an acute fibrin aggregates on the heart valves to form small small deep infarct in the subthalamic nucleus [18]. Lesions of the SMA in the left hemi. and concurrent antithrombotic neglect syndrome which is characterized by a reduction medication use [23]. pattern of ischemic stroke Endocarditis of the heart and its valves in particular Inflammatory vasculopathies and connective tissue can be classified into infective and non-infective types. including leg.6). Thus. with infective endocarditis. Focal paresis Although only less than 2% of patients with cancer Weakness of one side of the body is the most frequent have NBTE. They are thought to develop after Typically there is a marked contrast between the paucity septic microembolism to the vaso vasorum of cerebral or absence of spontaneous movements and the pre. Over 50% of patients motor aphasia) with preserved comprehension and had infarcts involving more than one arterial territory repetition and a hypokinesia/akinesia of contralateral [21]. and non-small-cell lung cancer) and hematological malignancies (lymphoma and leukemia [24]). It is more uncom. Aspergillus) organisms cerebral artery. patients with NBTE have other disorders. up to 50% of these patients with NBTE symptom of TIA or stroke. fungal (Candida. vegetations. septic endarteritis and non- akinesia from motor neglect. disease are Takayashu’s arteritis. Motor (hemi-) neglect aneurysmal arterial erosion at the site of the previous may be an isolated symptom but is mainly part of a embolic occlusion. It is part of a neuronal loop which [19]. rarely. About 50% of NBTE cases occur in asso- ciation with cancer. such as burns or sepsis [26]. temporalis medio A. Section 3: Diagnostics and syndromes P A. Sneddon syndrome. A. Wegener’s granulomatosis).gyri angularis Ramus parietalis aris aris 1 A. cerebri post. Figure 9. thies and connective tissue disease. A 95-year-old woman suffered from slurred speech. ant. tempo A. and paraneoplastic vasculi- drome. Behcet disease. carotis interna A. ophthalmica A. There was a shift of the tongue to the left side. erythematosus (SLE). A. primary systemic vasculitis tis. Warlow et al. cerebelli sup.praerolandica A. (R. antiphospholipid antibody syn. which may in general indicate inflammatory vasculopa- 144 Churg-Strauss syndrome. Focal paresis.cerebr A. Diffusion-weighted imaging showed a small cortical lesion in the frontal operculum which was most likely caused by a cardiac embolism because of atrial fibrillation. cerebelli inf. communicans post. [1] have summarized clinical clues (classic polyarteritis nodosa. primary angiitis of with TIA and stroke but also with encephalopathy: . the central nervous system. Patients may present Sjögren syndrome. microscopic polyangiitis.6. double-stranded DNA and other manifestations of disease such as deep venous antineutrophil cytoplasmic antibodies (ANCA). arthropathy. Diplopia and arteries may be found in MR angiography. which may cause stroke. which causes with a pathologically and virologically verified disease infarction of the optic nerve. The titer must be  when there is diagnostic suspicion. There is a delay usually develop late in the course of disease. temic lupus erythematosus are uncommon but not rare and will be presented in more detail. weight loss. skin rash. intracranial vessels. recurrent miscarriage. cranial arteritis or Horton’s disease. headache. It may also involve have no history of zoster rash or chicken pox. symptoms of polymyalgia rheumatica. which may signs and findings (for review: Nagel et al. some patients may involving small vessels may represent florid or healed even have no pleocytosis. Most patients with giant cell arteritis have can be diagnosed because of the following symptoms.1 months (range between same Giant cell arteritis involves the ophthalmic. malaise. Most patients such as weight loss. be clinically silent but may present with stroke and toms. Among those diseases. The antiphospholipid syn-  anemia and leukocytosis in the routine blood drome cannot be diagnosed on the basis of a raised screening tests single titer of antibody in the serum. by virus and bacterial infection especially in the night. migraine-like headache. livedo reticularis. or hemolytic anemia. particularly the extradural verte. Headache.6/ Intracranial vasculopathies caused 100 000 for those aged between 50 and 59 years to 44. (3) Varicella zoster virus as the cause much more often causes a generalized subacute or of stroke can be proven by examinations of the chronic encephalopathy than focal ischemic or hem. giant cell arteritis and sys. A high proportion of patients also have  younger patient in most cases (an exception being antiphospholipid antibodies. Chapter 9: Less common stroke syndromes  preceding or accompanying systemic features non-bacterial thrombotic embolism). and VZV-DNA in 30%. thrombocytopenia. precede the headache. pure small artery disease Systemic lupus erythematosus is a chronic auto. Inflammatory vasculopathies require special diag- nostic tests. cardiac valvular vegetations. of stroke averaging 4. The annual incidence increases with age from 2. renal failure and nuclear factor is highly sensitive but not specific. which seem to be par- giant cell arteritis) ticularly associated with cardiac valvular vegetations  a raised ESR and C-reactive protein and arterial thrombosis. fatigue and malaise or arthralgia Varicella zoster virus (VZV) vasculopathy may often and jaw claudication are the predominating symp. Giant cell arteritis is also known as temporal arteritis. specified substantially raised on several occasions and must be immunological tests such as raised serum associated not only with ischemic stroke but also with antiphospholipid.6/100 000 for those older than 80 years. zoster rash. (2) Angiographic evidence of narrowing in cerebral bral arteries. have circulating antinuclear antibodies. in 37% and a mixed vascular pathology in most immune disease affecting mainly young women. There was pure brainstem ischemia. Specific antibodies (anti- vasculitic lesions. particularly ophthalmic-distribution Ischemic symptoms of the retina and the brain zoster or a history of chicken pox. located in the temporal region. A raised anti- livedo reticularis. But between the onset of zoster/chicken pox and the onset stroke may even be the first indication of disease. posterior day and 2. In vascular ophthalmoplegia may develop but are mainly caused studies 70% had vasculopathies. A raised ESR (over 50 or even (1) About two-thirds of patients have a history of 100 mm in the first hour) is also indicative. Different patterns of by necrosis of the extraocular muscles and not by vascular lesions have been found. large artery disease in 13%. fever Double-stranded DNA and anti-Sm antibodies are  lack of any other obvious or more common cause much more specific but are found in less than half of stroke of cases. It patients (50%). cerebrospinal fluid: 67% of patients have a pleocytosis orrhagic cerebral episodes. Large artery occlusions can be VZV-IgG) with proven intrathecal synthesis were 145 explained in some patients by cardiac sources (NBTE: found in 93% of patients. [28]). Intimal proliferation (>5 white blood cells/mm3). .5 years). thrombosis. But about one-third of patients ciliary and central retinal arteries. Thus. Varicella zoster virus vasculopathy fever. With tuberculous meningitis. The cerebrospinal fluid shows mild to moderate pleocytosis with white blood cells up to 300/mm3. meningeal infections Ischemic stroke complicates chronic meningeal infec- tions which cause inflammation and thrombosis of arteries and veins on the surface of the brain. Different vascular territories may be involved depending on the spatial extent of the men- ingeal infection. definite diagnosis of syphilitic meningovasculitis. The primary infection with a syphilitic lesion in the Pleocytosis in the CSF together with specific anti- mucosa may have been months to years ago. size of ischemic infarcts is small. incomplete downgaze palsy.7). vasculopathies. contraversive ocular tilt reaction (tendency to fall of an obstruction of the basal cisterns. Usually. Chronic bacterial.7. the antigen. Other mechanisms small or middle-large vessels. dizziness. the glucose is reduced with Patients may present with signs of meningeal subacute infections and protein is elevated as a sign (meningo-encephalitic) inflammation such as head- of the disturbed circulation of the cerebrospinal fluid. . (Ziehl–Neelsen). MR shows a vascular lesion in the well. is mainly involved. feeling sick. culture. Infected vessels and their vasa 146 vasorum together with lymphocytic infiltration cause Viral and bacterial infections can cause specific a slow progression of stenosis leading to occlusion. The patient presented with meninges such as lesion of cranial nerves or the following signs: awake but apathic. development of hydrocephalus as a consequence complete upgaze palsy. Section 3: Diagnostics and syndromes A negative result for both VZV DNA and anti-VZV- IgG antibody in CSF can reliably exclude the diagno- sis of VZV vasculopathy. change of Infection with tuberculosis can be proven by cytology personality. Tuberculous meningitis has to be considered as a clinical syndrome when one of the following criteria accompanies ischemic stroke [29]:  medical history with manifestation of tuberculosis in the lungs or in a different organ (this manifestation may have been many decades ago)  one or more symptoms indicating chronic meningeal infection such as headache or subfebrile temperature preceding stroke  other signs indicating a process in the basal Figure 9. There was a minimal hemiparesis shown up by a tendency to In addition there may be more unspecific signs as pronate with the right arm. to the right side and skew deviation). Syphilitic bodies in the serum can be taken as evidence of a meningovasculitis presents with an obliteration of likely syphilitic meningovasculitis. infection is predominantly located at the base of the brain and vasculitis causes thrombosis in the large intracranial arteries and terri- torial infarction. territory of the left thalamic-subthalamic artery. decreased episodic memory. Meningovascular syphilis. ache. drowsiness or myalgia. sleep disorder. Pupils were reactive to light. The territory of the middle cerebral artery luetica with aortic dissection and endocarditis. rarely are large arteries of stroke associated with syphilis are mesaaortitis involved. show up the basal meningitis. Documentation of the intrathecal Syphilitic meningovasculitis may be the first clinical production of specific antibodies is required for a presentation of an infection with Treponema pallidum. This lesion was caused by meningovascular syphilis proved by intrathecal Contrast-enhanced magnetic resonance imaging may production of specific antibodies (FTA-Abs) and mild pleocytosis. detection of DNA (PCR) or Ischemic stroke can be preceded by TIA. such as loss of appetite. There may be lesions of the cranial nerves because of the associated men- Syphilitic meningovasculitis ingitis (Figure 9. disturbed converge of eyes. apathy and deficits of episodic memory. ations of the arteriolar wall [30]. picion of multiple sclerosis. angiokeratomy corporis diffusum. is an X-linked paresis. With lysosomal storage disorder. endothelial and smooth muscle cells. hemiplegic and prolonged aura is high. ataxic hemi. such a constellation may lead to a false sus- disorders associated with their own clinical and radio.8. Fabry disease and MELAS (mitochondrial risk factors. WMHs are characteristically located in the white CADASIL matter of the anterior temporal lobe and the external Genetic and pathological research suggests that the capsule as early as in the third decade [31]. White matter hyperintensities (WMHs) are characteristically located in the white matter of the anterior temporal lobe and the external capsule.) Hereditary causes of stroke (single gene multiple lacunar lesions and extensive white matter hyperintensities (WMHs). abnormalities with SVD in the absence of vascular pathy). Further evidence comes logical presentation. Two-thirds of patients present with Fabry’s disease. The patients Microangiopathy or small-vessel disease (SVD) is are mainly young and present with a variety of 147 the morphological presentation of the disease with symptoms and signs which are caused by deposition . Alpha-galactosidase defi- increasing load of subcortical white matter lesion. CADASIL. In CADASIL. which is unusual for other small-vessel diseases. which may be accompan- disorders) and their clinical presentation ied by evidence of microbleeds (MBs).4% in female stroke patients [32]. Chapter 9: Less common stroke syndromes Figure 9. particularly in younger patients. sensory but the frequency of attacks with basilar. stroke becomes manifest in the Fabry disease course of disease. and focal or generalized frequency of Fabry disease. A first hint for CADASIL (cerebral autosomal dominant arteriopa. especially in younger patients. At a mean age of 41 years. Location accumulation of the ectodomain of the NOTCH 3 of WMHs and age of onset are unusual for other protein is associated with severe ultrastructural alter. Twenty percent of patients have aged 18 to 55 years showed a rare but not negligible severe mood disorders. mainly in vascular dementia with deficits of executive functions.9% in male seizures have been observed in about 8% of patients. Not infre- encephalopathy lactic acidosis and stroke) are genetic quently. ciency leads to accumulation of glycolipids.8). from the distribution of WMHs. (Courtesy of Professor Franz Fazekas. The earliest clinical CADASIL is a rare genetic disorder causing small- manifestation of CADASIL is migraine with aura at a vessel disease and multiple white matter lesions in mean age of 28 years. The aura may be visual or young adults. pure sensory or sensory motor stroke. SVDs (Figure 9. also Anderson-Fabry’s disease or lacunar syndromes such as pure motor. A more recent and attentional and memory deficits develops (mean study of 721 sufferers from acute cryptogenic stroke age of 50 years). University of Graz. Extensive morphological abnormalities are found in CADASIL despite the absence of vascular risk factors. and 2. CADASIL is the presence of extensive morphological thy with subcortical infarcts and leukoencephalo. which was 4. vessel ectasia (particular encoding gene. indicating dysfunc- angiokeratomas (mainly in the bathing-trunk area) tion of the respiratory chain.9. have been reported with this muta- and stroke. and larger vessels. which could be a consequence ADC. posterior cerebral artery and middle cerebral artery. The most likely origin of stroke- acidosis and stroke) like episodes is a sudden metabolic failure with loss of function and transient or persistent cellular MELAS is a mitochondrial disorder that causes damage. cardiomyopathy in combinations. stroke-like syndromes in young patients. myopathy and episodes of headache and seizure or vomiting occur. observed and there appears to be a predisposition for MELAS-related brain lesions appear bright on infarction to occur in the vertebrobasilar system. embolism from the heart. appears to be a hyperintense signal of correct diagnosis comes from the fact that MELAS the pulvinar thalami on T1-weighted images [33]. In this patient. corneal dystrophy. sometimes within relatively short intervals of days to weeks [35]. . small fiber neuropathy with burn. Many different phenotypes. MELAS is associated with a mitochondrial DNA ing pain and paresthesias in hands and feet. Clinically silent or appear to be most frequent (Figure 9. alone or basilar artery). Sudden like syndromes. diffusion-weighted imaging with reduced diffusity Vascular ectasia up to the megadolichobasilar artery on corresponding ADC maps and are thus frequently has also been reported. cognitive decline. MELAS. with transient or per. and hypohydrosis.) of glycolipids in the tissue: skin manifestation with Blood lactate levels are elevated. other sites. aphasia or hemiparesis. however. the two vascular territories. Besides increased levels of Fabry disease presents with a variety of symptoms. Posterior parietal and occipital locations of microvascular calcification. occurring as early as the teenage years. MR spectroscopy including stroke. tion (hearing impairment. and rarely by have a tendency to slowly progress or to reoccur at intracranial hemorrhage. MELAS is a mitochondrial disorder causing stroke- 148 manent hemianopia. Up lesions usually tend to cross the known borders of the to one-quarter of patients with Fabry disease may vascular territories of the brain and have a variable show this abnormality. MELAS-related brain lesions appear bright on diffusion- weighted imaging (right-hand picture). The lesions manifest strokes. Section 3: Diagnostics and syndromes Figure 9. (Courtesy of Professor Franz Fazekas. Most commonly. of the left hemisphere are involved.9). renal point mutation at position 3243 within the tRNA dysfunction or failure. or epilepsy). A hint towards the ity. lactacidosis. A hint towards the correct diagnosis is that MELAS lesions usually tend to cross the known borders of the vascular territories of the brain. University of Graz. mistaken for acute infarction [34]. may also serve to demonstrate increased lactate in the brain parenchyma and cerebral lesions as well MELAS (mitochondrial encephalopathy lactic as in the CSF [36]. caused by occlusion of small vessels or by extasia of which would be quite unusual for infarction. are may also subside without remaining signal changes. The most specific abnormal. progres- The early presence of incidental WMHs has been sive external ophthalmoplegia. both cortical and subcortical. lactate in the CSF during the attack. red-ragged fibers. Sub. and the annual incidence of vertebral artery dissection 1. In some patients. The vertebral artery is most mobile and susceptible to mechanical injury at the C1/C2 level. near the C2/C3 vertebral level. sternocleidomastoid muscles). suggesting that some dissections are Collet Sicard syndrome. Subadventitial dissections may cause arterial  ischemic stroke (46%) dilatation (aneurysms).5 per 100 000 [39]. Predisposing factors for CAD are trauma (mild or trivial. Most patients with dissections are between 30 and 50 years of age. XII). and extends superiorly for a vari- able distance. XI. of Innsbruck. ology but range from 1 in 5. There was a prominent coiling of the internal carotid artery in the area of dissection. Marfan syndrome).) intimal dissections are more likely to cause luminal stenosis. no com. recent infection or drugs (cocaine). arteriopathies (e. Ehlers Danlos syndrome. relevant narrowing of the lumen. X. Extracranial ICA dissection typically occurs about 2 cm distal to the bifurcation. The absence of  pulsatile tinnitus alone when carotid dissection an external elastic lamina and a thin adventitia makes spreads distally to the base of the skull (2%) intracranial arteries prone to subadventitial dissection  partial Horner’s syndrome as a result of damage to and subsequent subarachnoid hemorrhage. University the result of a primary intramedial hematoma. fibro- muscular dysplasia. .  unusual and sharp pain in the face or in the neck ary to luminal narrowing or occlusion or embolism on the side ipsilateral to ICA dissection (21%) from thrombus within the true lumen.10.5% in 1200 consecutive first stroke patients. SAH is the sympathetic nerve fibers around the dissected reported in about one-fifth of intracranial ICA dissec. migraine. Some weeks later he was admitted to a neurological department and presented with right- found connective tissue disorders in one-fourth of sided glossopharyngeal and spinal accessory nerve lesions patients with cervical artery dissections after chiro.85 million manipulations ipsilateral headache. problems with swallowing and tongue to as many as 1 in 20 000 manipulations. particularly the hypoglossus (XII). Saver and Easton [42] summarized symptoms and as a result of nerve compression (3%) at the base 149 signs of ICA dissection: of the skull (Figure 9.10). carotid artery.g. (moderate paresis of the upper portion of the trapezius and the practic manipulations [40]. (IX. Mechanisms of ischemic  TIA (30%) stroke are either hemodynamic compromise second. hypoglossus and recurrent nerve palsies. Chapter 9: Less common stroke syndromes Arterial dissection: uncommon clinical presentations Bogousslavsky et al. Estimates of dissection risk after chiroprac- Figure 9. Under the age of 45 the incidence of cervical artery dissection (CAD) is much higher at 10–25% and CAD is the second leading cause of stroke in younger adults [38]. The combination munication between the true and the false lumen can of lower cranial nerve palsies (IX to XII) is commonly referred to as be demonstrated. One study movements and dysarthria (hoarseness). major. iatrogenic). ICA (32%) and tions and in more than half of intracranial vertebral  ipsilateral palsies of one or more cranial nerves artery dissections [41]. A 60-year-old man noticed right-sided neck pain. The annual incidence of cervical internal carotid artery dissection was found to be 3. and the mean age is appro- ximately 40 years. (Courtesy of Dr Michael Spiegel. [37] found an incidence of arterial dissection of 2.5 per 100 000 in those older than 20 years. Collet Sicard syndrome in dissection of the internal tic manipulation vary widely with the study method. MRI showed a dissection of the right internal carotid artery in Arterial dissections usually arise from an intimal its very distal extracranial section with a prominent subadventitial tear that allows the development of an intramural wall hematoma and expansion of the vessel diameter but without hematoma (false lumen). An subclavian. but not entirely. involuntary movements. It  ischemic stroke (75%) is mainly familial or congenital but can be caused  TIA (25%) by various disorders (meningeal or nasopharyngeal  head or neck pain (75%) infection. arterial wall. (orbital.5%) [45].6%). 7.  prolonged aura (lasting longer than 1 hour but eral hypoplasia of the internal carotid arteries”. The pattern of collat- erals looks like a puff of smoke (moyamoya in Japanese) Cervical artery dissection is the second leading in the basal ganglia region on the cerebral angiogram. It may progress after diagnosis. Aura can be classified into: Moyamoya  typical aura with visual. hemiparesthetic. a generalized  rarely: cervical nerve root lesions (C5 and C6) as fibromuscular dysplasia. ischemic stroke by embolism. drugs such as cocaine). Moyamoya is defined by a pattern of severe 150 stenosis or occlusion of one or more often of both With migrainous infarction the symptoms associ- internal carotid arteries with additional involvement ated with the typical aura are not fully reversible after . spinal. The vascular reserve capacity is exhausted and ischemia Aortic arch dissection can cause generalized brain can be provoked by conditions which induce vasodi- hypoxemia and low-flow infarction as a result of latation. stroke. found in Japanese Symptoms and sign of extracranial vertebral dis. ethmoidal or transdural). vasculitis.  migraine with acute aura onset. develops gradually over 5–20 several centimeters. cognitive impairment. dissection extends  syncope Moyamoya is characterized by stenosis/occlusion of both internal carotid arteries and a network of  hypotension collaterals (“haze”).  diminished. Moyamoya is mostly. epileptic  sudden and severe anterior chest pain and/or seizures (7. [43] have reported that dissec. It is mostly. sickle-cell disease or neurofi- caused by ischemia or pressure from the bulging bromatosis. The mechanism of brain ischemia is low flow. cause of stroke in young adults. ies and may cause occlusion with low flow or TIA and seizure and. Small collaterals develop from the lenticulostriate. but not exclusively. hemorrhage (21.4%). mia and infarction. Children present with recurrent focal cerebral ische- Dissection may spread out into the major neck arter. such as hyperventilation. headache. Section 3: Diagnostics and syndromes Baumgartner et al. interscapular pain which may move as the headache. tions causing ischemic events are more often associ. tha- ated with occlusion and stenosis greater than 80% and lamoperforating and pial arteries at the base of the brain. The annual incidence in section are [42]: Japan has been calculated to be 0. 63. blood pressure in the arms and sometimes legs  acute aortic regurgitation and cardiac failure  simultaneous or sequential ischemia in carotid. and other East Asian subjects. aphasic The first report of a patient was published in 1957 by or hemiparetic (hemiplegic) symptoms and signs Takeuchi and Shimizu [44] with the diagnosis “bilat. occasionally. acute aortic regurgitation or myocardial infarction. coronary and other aura is defined as a neurological symptom which is aortic branches if the dissection extends over localizable in the brain. minutes and lasts less than 1 hour. that dissections that do not cause ischemic events are from leptomeningeal collaterals of the posterior cerebral more often associated with Horner’s syndrome and artery or from branches of the external cerebral artery lower cranial nerve palsies. of the circle of Willis. Clues for the diagnosis Adults can present with either focal brain ischemia of aortic dissection are [1]: (TIA. cipitated by infection in the upper respiratory airway. unequal or absent arterial pulses and found in Japan. cognitive impairment.35/100 000 persons. irradiation. vertebral. and are often pre- systemic hypotension caused by cardiac tamponade.g. trauma. This less than 7 days with normal brain imaging) was a 29-year-old man who had been suffering from  basilar aura visual disturbance and hemiconvulsive seizures since  migraine aura without headache the age of 10 years. Migraine and stroke The prevalence of migraine with aura is about 4%.6%) or others (e. – Tuberculous meningitis (inflammation and  An uncommon mechanism of brain ischemia: thrombosis of arteries and veins on the sur- low flow. lesion of cranial nerves or deve- reduction of blood flow. double-stranded DNA. ally. The following criteria have to be fulfilled: increase of cell counts (e.g. akinesia. resulting in a multi-territorial pattern of stroke. dizziness or vertigo. such as after car. as well as isolated appropriate investigations (particularly other cranial nerve palsy. diac arrest or cardiac surgery. rotational vertebral artery occlusion and arteriopathy with subcortical infarcts and leu- “drop attacks”. blurred vision or tinnitus. within 7 days or/and neuroimaging demonstrates paresthesias. In some patients severe stenosis or occlusion of symptoms indicating chronic meningeal carotid or vertebral arteries may cause a critical infection. of the heart. cific antibodies in the serum. shaking TIA”. particularly ophthalmic- deficits. Chapter 9: Less common stroke syndromes 7 days and/or there is an infarct on brain imaging. or with exercise. monocular transient retinal ische. such  Uncommon causes of stroke as CADASIL. more often causes a generalized subacute or ent monocular blindness in a few patients.g. Diagnosis: history of A migrainous stroke only rarely causes persisting zoster rash. agitation and delirium. with hematological disease (e. A sudden and profound hypotension antigen. characteristic clinical syndrome in the absence of no – Varicella zoster virus (VZV) vasculopathy more likely causes of stroke [1]. but a positive statement to describe a bodies can frequently be found. ischemic infarction in the relevant area  Uncommon clinical presentations of stroke  other causes of infarction have been ruled out by – Include sudden cortical blindness. A migrainous stroke often results in a homonym. on standing up very Diagnosis: intrathecal production of specific quickly. Systemic lupus erythematodes been observed in the retinal circulation during transi. coughing or hyperventila. MR angiographic evidence of narrowing in cerebral arteries.g. giant cell ous hemianopia and rarely causes persisting and arteritis. giant cell arteritis infarction of the optic nerve “Vasospasm” is often postulated and is said to have can develop. antibodies or pleocytosis in the CSF with spe- tion. – CADASIL (cerebral autosomal dominant mia. In demonstrated and it is not clear why it occurs. A raised antinuclear factor. chronic encephalopathy than focal ischemic A migrainous stroke should never be a diagnosis of or hemorrhagic cerebral episodes. Syndromes of low flow may include “limb. may present with stroke. causing unspecific neurological deficits are not completely reversible symptoms such as headache. pleocytosis and anti-VZV- Chapter Summary IgG and VZV DNA in the cerebrospinal fluid. or which may mimic migraine such as lead to cerebral embolism from the valves arterial dissection). paraneoplastic vasculitis). Arterial occlusion has rarely been arteritis nodosa. Usu- start under certain circumstances. sickle cell migraine with neurological aura anemia) lead to a hyperviscous state and cerebral  the present attack is typical of previous attacks. – Inflammatory vasculopathies (e. MELAS or antiphospholipid – Infective or non-infective endocarditis can syndrome. poly- severe disability. distribution zoster or a history of chicken pox. desperation when no other cause of ischemic stroke anti-Sm antibodies or antiphospholipid anti- can be found. a drop in systemic blood lopment of hydrocephalus. sometimes causes boundary-zone infarction.g. but blood flow can be diminished. the size of ischemic infarcts is small. polycythemia vera) and  patient has previously fulfilled criteria for decreased red cell deformability (e. culture. A fall – Syphilitic meningovasculitis presents with in cerebral perfusion pressure as a cause of focal an obliteration of small or middle-large brain ischemia should be suspected if the symptoms vessels. detection of DNA (PCR) or ischemia. systemic lupus erythematodes. causes which are associated with migraine. paraproteinemia). cytology (Ziehl– pressure may cause transient or permanent focal Neelsen). 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Moya-moya. dizzi. costs and due to the fact that conventional Due to the primary ischemic lesions rapidly turning T1-weighted and T2-weighted MRI pulse sequences hemorrhagic. cerebellum and from the increasing incidence of anticoagulation- pons). rhagic infarcts is probably higher than was previously However. By contrast. (See Chapter 3 for a hemorrhages into the brain but are not yet applicable 154 detailed discussion of imaging. Thus. some “new” aspects of hemorrhages and are often lethal events. Often hemorrhages extending into lobes or ganglia. and thus can be rated as a “complication” of therapy. the first hours after onset [3]. At many centers non. including . thalamus. It is also enough only a history of elevated blood pressure is well known that hemorrhages into the thalamic region known. rarely a feeling of unsteadiness. the consequences are downward herniation of ting. Typical warning signs have been discussed among clinicians and researchers.2). recent studies have impressively shown that thought (for classification of secondary hemorrhages blood-sensitive gradient echo (GRE) sequences are as see Table 10. New MRI techniques. While in many cases it is elderly patients. Chapter 10 Intracerebral hemorrhage Michael Brainin and Raoul Eckhardt Hemorrhages into the brain occur unexpectedly More recently. and has been described in cases of large days or weeks before the onset of a stroke. This is well known in bral hemorrhage (ICH). but such symptoms do not classic textbooks of neuropathology as “Wühlblutung” have localizing value such as in ischemia. are not known. particularly in and other cardiac diseases. it comes “out of the tend to rupture into the ventricles after some hours or blue”. associated ICH in elderly people with atrial fibrillation rhages that occur in lobar regions. an ischemic infarct turning into time. hypertension most commonly occurs in deep brain Another issue arising from clinical practice comes structures (e.g. primary intracerebral hemor. reaching a total volume (such as more than 60 ml The fact that many parenchymal hemorrhages within one cerebral hemisphere) that cannot be com. are commonly related to cerebral often not evident whether anticoagulation (especially amyloid angiopathy but might also be associated with when within the therapeutic range) is the cause of ICH hypertension (Table 10. Thus. a given time-constrained window has been designed Primary intracerebral hemorrhage associated with as a therapeutic intervention [4]. putamen.) for routine use [5]. 2]. where (the bleeding that penetrates or forces itself into the stroke-like warning signs (transient attacks) can occur parenchyma). efforts to inhibit this process by early artificial clot- acity. MRI has not been favored due to its higher a secondary hemorrhage is visible upon first imaging. a chance to restrict blood volume in the the medial temporal lobe and compression of the brain has been seen and prevention of growth within brainstem. the true incidence of secondary hemor- are not sensitive to blood in the hyperacute stage.1). owing coagulation therapy resulting from insufficient protec- to its widespread availability and rapid acquisition tion of the brain. Then. for most patients. it contrast CT is the imaging modality of choice for might equally often be considered a failure of anti- the assessment of intracerebral hemorrhage. and this is manifested as a dramatic clinical event the most decisive prognostic component and when with sudden deterioration and herniation signs. The volume of the hemorrhage into the brain is days. one being the fact that hemorrhages can grow within ness or a tingling sensation can precede an intracere. Genetic tests or markers of primary accurate as CT for the detection of intraparenchymal hemorrhage would in the future be helpful in making hemorrhage and far superior to CT for the detection important distinctions between primary and secondary of chronic hemorrhage [1. have a tendency to “grow” has led to therapeutic pensated by intracranial compartmental reserve cap. Overall. which is mostly reported as time course and pathophysiology of ICH [6]. has a clear age-dependent space-occupying effect incidence rate. varying prog. one further chapter in this Lobar 528 (34. dent prognostic factors of 30-day mortality were Today. Most population-based registries report an incidence of 10 per 100 000 per year. In the cere- ent echo sequences have also been found quite fre. A number of European and North American N (%) guidelines have been published in recent years with Putaminal/thalamic 704 (45. and. reasons for this decline are not known.3) book is dedicated to treatment aspects. patients with ICH represent a growing ICH volume. a volume of over 60 ml carries a quently and their clinical significance as risk factors unfavorable prognosis and is seen for deep hemor- has not been fully determined. This risk might cases do not survive the first month [12–14]. treatment or imaging [6–8]. but this One multivariate analysis showed that indepen- has not yet been confirmed in controlled studies. trained to manage not only ischemic strokes but also It is worth noting that in one study a decreased ICH because of their differing risks. of hemorrhagic injury and provide insights into the Early mortality. and slightly less often for lobar bleeding markers of vascular risk factors or in patients already (71%). referring to these.7) a focus on management. it is reasonable to assume that a decline in rates as well as severity of magnetic resonance spectroscopy and diffusion tensor arterial hypertension has significantly contributed to imaging. decisive prognostic component. Smaller bleedings show better prognosis and having suffered an ICH. also be increased in anticoagulation patients. occupying effect Parenchymal hematoma type 1 (PH-1) Incidence and prevalence rates Hematoma in up to 30% of infarct region with some ICH. which in most European countries are not treated on stroke units but on neurosurgical wards or wards with extensive neurointensive care. A decrease of rates has been reported over time Source: Adapted from Kidwell CS. Distribution by site of 1539 cases of ICH from therefore ICH patients often require a different inten- the Austrian Stroke Registry seen at stroke units between 2003 and 2007. Therefore here Cerebellar 72 (4. Stroke physicians and stroke nurses should be presence of intraventricular blood [15].8) Subarachnoid hemorrhages are not covered in this chapter as they are mainly caused by rupture of cere- Miscellaneous 177 (11. typical warning signs are not known. bral hemispheres. from several regions of the world. the reader is referred to textbooks of neuro- Hemorrhagic infarction type 1 (HI-1) intensive or neurosurgical care. sity of observation and separate management. Chapter 10: Intracerebral hemorrhage Table 10. Table 10.5) bral aneurysms. and for in a setting of a neurological/neurosurgical . Petechiae along the margins of the infarct Intracerebral hemorrhage (ICH) comes “out of the blue sky”. CT classification of hemorrhagic transformation.2. Lancet Neurol 2008. and might signal an less early mortality. workload on any stroke emergency ward or stroke age over 80 years. occurring slightly earlier in life than Parenchymal hematoma type 2 (PH-2) ischemic attacks. 30-day mortality. up to 50% of all ICH increased risk of further hemorrhage. Pontine 58 (3. The Hemorrhagic infarction type 2 (HI-2) volume of the hemorrhage (>60 ml) is the most Petechiae within the infarct region without space. like ischemic stroke.1. mortality rate was seen when such patients are cared 155 nosis and high proportion of complications. While the exact 7:256–67 [2]. Wintermark M. might have importance in the understanding the declining rate of ICH [9–11].7) the focus is limited to clinical aspects and diagnosis. infratentorial origin of ICH and unit. and largely depends on bleeding volume. is higher than in ischemic stroke Silent hemorrhages seen on blood-sensitive gradi. They might be relevant rhage (93%). Glasgow Coma Score on admission. and Dense hematoma in more than 30% of infarct region with variations exist towards higher rates in some popula- substantial space-occupying effect tions. For this. series or uncontrolled experiences reported from Other risk factors for ICH in addition to old age. 23] confirmed the role of smoking as a risk factor for ICH.06 (95% CI 1. however. Monogenic disorders associated with spontaneously While elevated cholesterol levels play a less signifi- occurring ICH are not known. alcohol. the overall [21] the relative risk of ICH was reduced by 76% 3-month mortality seen in this cohort was 19%. 26]. 95% CI 0. and the 1-year mortality rates were 52% and spontaneous intracerebral hemorrhage and the fre- 69%. several large clinical trials. Both the Physi- better neurological and functional prognoses than the cians’ Health Study and the Women’s Health Study survivors of ischemic stroke [19].90). [22.67 (95% CI 1.34–1. respectively. whole. Defining the more complex 29%. other regions or countries [18]. in autopsy of patients with ICH.93). P ¼ genetics of sporadic ICH. P ¼ 0. The causative role of hypertension is supported could be attributed to a large difference in survival by the high frequency of left ventricular hypertrophy during the first 30 days. age over 80 risk was 2. In the PROGRESS trial Though not controlled or randomized. acute stroke unit in patients with primary intracranial hemorrhage [17]: 56 patients were allocated to an Hypertension. Section 3: Diagnostics and syndromes intensive care unit compared to treatment in general sporadic ICH. While investigations of genetic rence (adjusted HR 0. In one series of bleeding. Genetic screening and counseling might ICH. They are likely to generate novel intensive care units (ICU) [16]. But some disorders convey an increased very low levels of cholesterol have been questionable risk of ICH. and have more frequent microscopic factors in increasing the risk of ICH. will probably 0.82. The 30-day mortality rate was 39% in the acute stroke cholesterol and drugs unit. ICH survivors treated with statins require defining multiple common genetic variants after discharge did not have a higher risk of recur- with weaker effects. inferences made from observational data show 156 limited to candidate gene polymorphisms. 629 ICH patients the effect of statin use was investi- pathy. such as hereditary cerebral amyloid angio. insights into cerebral bleeding risks and strategies for One randomized trial investigated the effect of an prevention [20].96) and early mortality is up to 50% within the first month. infratentorial origin of ICH and presence of Several studies document an increased risk of ICH intraventricular blood. smoking. hypertension and ethnicity include cigarette smoking It is generally believed that ICH survivors have and excessive alcohol consumption.04–6. No genetic markers cant role in ICH than in ischemia. risk factors for sporadic ICH have thus far been Thus. the reduced mortality after quency has been estimated to be between 70 and primary intracranial hemorrhage seen in a stroke unit 80%. Thus. that statin use prior to ICH does not influence mor- genome association studies are being undertaken in tality or functional outcome and statin use following . The role of hyper- This is corroborated by another finding from the tension and the beneficial effect of antihypertensive Austrian Stroke Registry reporting on 1539 cases of treatment with regard to risk of ICH were verified in ICH treated on stroke units between 2003 and 2007. For men smoking 20 cigarettes or more the The incidence of ICH is 10 per 100 000 per year. relative risk of ICH was 2.08–3. acute stroke unit and 65 to a general medical ward. Conversely. in relation to regular alcohol consumption and that spontaneous ICH can also be triggered by binge drinking [24]. CADASIL and collagen type IV A1-associated gated.84) or mortality (46% versus 45%.66). compared with 63% in the general medical Hypertension is the most common risk factor for wards. Statins were used by 149/629 (24%) before vasculopathy. statin use and/or exist to date.99. and in comparison with the placebo-treated group after far lower than expected when compared to any other 4 years of follow-up. Glasgow Coma Score on admission. years. for women smoking 15 cigarettes or more the relative Factors determining prognosis are ICH volume. Risk factors Anticoagulation increases the risk of ICH 8 to 11 times compared to patients of similar age who Genetics of spontaneous ICH are not on anticoagulation [25. P ¼ 0. There was no effect of pre-ICH statin use on be reasonable for pedigrees of patients with some very the rates of functional independence (28% versus rare and selected cases. excessive alcohol con- ‘false’ aneurysms. Etiology It was C. trauma. which are associated with specific gradual development of ICH and can probably be underlying diseases. including sinus thrombosis. catheter angiography is Cerebral amyloid angiopathy (CAA) required and might need to be repeated if the results CAA refers to the deposition of amyloid proteins into were initially negative owing to the mass effect of the the cerebral vessel walls with degenerative changes. thalamo- antiplatelets. Thus deep basal ganglia bleed. patients include lipohyalinosis and media hyper- Secondary ICH may be caused by aneurysms. supplying the area of the dentate nucleus are often Underlying vascular lesions are more common in involved. where one or more hypointense rings bility should be kept in mind in young patients in show due to hemosiderin from a previous bleeding. neoplasms. Chapter 10: Intracerebral hemorrhage ICH is not associated with an increased risk of ICH hemorrhage can be considered to support an indica- recurrence [27]. of GRE MRI. They have been described in detail elsewhere [26. Brain tumors. In the cerebellum the arterioles thrombosis. 28]. however. whereas lobar bleedings are often seen in The main histological findings in vessels of ICH elderly patients with CAA [30. perforating and basilar artery rami and pontem are vasculitis. ruptures at the periphery of the enlarging characteristic flow voids can be seen in the brain hematoma. The lenticulostriate. Previous Intracerebral hemorrhages (ICH) are classified into primary (80–85%. vasculitis and various ary (15–20%) causes. Cavernous mal- A variety of illicit drugs. in some cases. also increase the sion and cerebral amyloid angiopathy) and second- risk of ICH. results from rupture of lipohyalinoic arteries followed More than 50% of primary ICH events are associated by secondary arterial ruptures at the periphery of the with hypertension. Hereditary forms of CAA are known but CAA is most logical calcifications. Small-vessel disease The ‘miliary aneurysms’ described by Charcot and Hypertension is the most common risk factor for Bouchard in the small penetrating vessels of patients spontaneous ICH. and 30% are found in association enlarging hematoma in a cascade or avalanche fash- with cerebral amyloid angiopathy (CAA). 29]. are known to cause ICH and this possi. lipohyalinoic arteries followed by secondary arterial With an underlying arteriovenous malformation. disease. 31]. This observation of mechanical disruption Intracerebral hemorrhages predominantly occur and tearing of smaller vessels might account for the at certain locations. presence of subarachnoid blood. such as amphetamine formation can usually be reliably diagnosed by means and cocaine. on the impression of irregularity of the penetrating vessels due to their intramural blood accumulation denoting penetration. trophy. cigarette smoking. anticoagulation. are important causes of ICH. whom other causes such as arteriovenous malforma- tion or trauma have been excluded [26. coagulopathies. parenchyma on MRI. such as thrombolytics. leakage and intima destruction. hematoma. This deposition is seen in the . study of two brains that hypertensive ICH most likely mary (80–85%) and secondary (15–20%) causes. M. considered the most relevant neuropathological cor- ings are often found in patients with hypertensive relate for the ‘growing’ properties of hemorrhages. Findings from imaging such as patho. ion [26]. Further risk factors include old with intracerebral bleeding have been shown to be age. as well as elongation of the deep penetrating arteriovenous malformations. arterioles of the brain. the rami of the superior and posterior infe- patients with intracerebral hemorrhages located in rior cerebellar arteries. mainly associated with hyperten- medications. Fisher who concluded from the detailed Intracerebral hemorrhage (ICH) is classified into pri. tion for direct catheter angiography. vasculopathies. and larger hematomas are more com- Hypertensive ICH most likely results from rupture of monly associated with arteriovenous malformations. The aneurysmal feature was based sumption. lobar lesions. commonly sporadic and related to amyloid b (Ab) 157 vessel abnormalities or an unusual location of peptide deposition. and illicit drugs such as amphetamine and cocaine. CT angiography or MR angiog- raphy might reveal the underlying vascular lesion. oral anticoagulants. moyamoya disease or sinus venous affected most often. differing only in amount and distribution. Gradient echo meninges. lytic therapy. rently being tested as a tool for direct diagnosis but tions. but The biological and neuropathological interaction also old. get- INR >3. Mounting extravasation of blood [35]. and. The results of only confirmed to have a 62% accuracy. “possible” diagnostic categories. Whereas the “defin. deposition seem to be an avenue for clinical therapy 4432 of whom were people with cerebrovascular dis- options for amyloid-associated progressive cognitive eases. the “probable” category includes at least non-traumatic intracerebral hemorrhage (ICH). cognitive decline was correspond to hemosiderin-laden macrophages adja- independent of other Alzheimer-related pathological cent to small vessels and are indicative of previous criteria. less commonly. Microbleeds were seen in 83% (95% CI 71–90) of out any other definite cause for this hemorrhage. so far no peripheral blood markers for CAA or gers for CAA production and deposition are not well CAA-related risk of ICH have been found. of hemorrhage when on antithrombotic or thrombo- lant. the results of two large CAA-associated hemorrhages account for the studies did not show an increased risk of hemorrhage 158 second largest group of hemorrhages after hyperten. head injury. One study several case reports and small series suggest that showed that patients with CAA deposits more often patients with microbleeds might be at increased risk have cerebral hemorrhages associated with anticoagu. rising to 34% (95% CI 31–36) in people with ischemic ite” category is based on neuropathological workup of stroke. Whereas the “probable” cases Microbleeds have been suggested as markers of a have an accuracy of 100%. neoplasm or other ting older. 43]. such as neurofibrillary tangles. and less MRI can be useful to detect silent hemorrhages in often in capillaries and veins. in patients with microbleeds who were treated with sive bleedings and their rate depends on the case mix intravenous tissue plasminogen activator [42. MRI visualizes acute and chronic hematomas. including current anticoagulation treatment with an Hypertension. flip angle. and to 60% (95% CI 57–64) in people with the brain. two acute or chronic lobar hemorrhagic lesions with. elderly. 34]. only some understood. of elderly people at one stroke unit.0. antiplatelet or thrombolysis treatment [33. slice gap and slice thickness were found as The “Boston criteria” proposed for the clinical well as inconsistent definitions of microbleed size diagnosis of CAA-ICH include “definite”. Overlaps with Alzheimer’s typical (cortical) areas and thus help to determine disease are known and therefore old age and positive the diagnosis of CAA. ICH cases with recurrent ICH [36]. Significant variations in MRI magnet strength. cerebral autosomal disease that can mimic such a condition. “probable” (44% chose a diameter of 5 mm). Pathological studies have a major focus of research. that are not detected on CT. The criteria dominant arteriopathy with silent infarcts and leu- for “possible” CAAH are a single lobar hemorrhage in koaraiosis (CADASIL) have been identified as a person older than 55 years and no other obvious important risk factors for microbleeds [37–39]. Its overlaps with dementia are recognized though also less well understood. Amyloid PET imaging is cur- ApoE E4 allele are major risk factors for both condi. 41]. By contrast. of 70 years. cause of this bleed [31]. Microbleeds have a erative diseases of the brain as well as in elderly hypointense appearance on MRI and are usually patients with a high risk of parenchymal bleeding is smaller than 5–10 mm. stroke. Although the metabolism and pathological trig. One review [36] included evidence shows that drugs able to inhibit amyloid 53 case series studies involving 9073 participants. In elderly persons over the age of 90 years it is present in 50% of individuals and in AD patients it is present Microbleeds in over 80% of all neuropathological cases. CAA is now recognized as a major cause hereditary forms can be diagnosed from blood or of non-hypertensive lobar cerebral hemorrhage in the other tissue samples [34]. the possible category was bleeding-prone angiopathy [40. In one rare hereditary form shown that microbleeds seen with GRE MRI usually with excessive CAA deposits. cerebral amyloid angiopathy. Section 3: Diagnostics and syndromes walls of small arteries and arterioles of the lepto. clinically non-apparent cerebral microbleeds between amyloid b (Ab) deposition in primary degen. cerebral and cerebellar cortices. The authors found (with or without supporting neuropathology) and a 5% prevalence of microbleeds in healthy adults. decline [32]. Cerebral amyloid angiopathy (CAA) refers to the deposition of amyloid proteins into the cerebral CAA is a frequent finding particularly over the age vessel walls with degenerative changes. . A pattern of multiple hemorrhages with. Noting such a progression is vital and confirmed as a common finding in patients with contrasts with ischemic strokes. If the hemorrhage spreads from the putamen appearing as convergent downward gaze (the patient into the thalamic region. about 4% in hemorrhage extending into the deep frontal white the pons. It can be a prominent sign in in parallel with a decrease in motor function. been considered satisfactory [45]. whereas bleeding into the thalamus causes a nosis on clinical grounds alone to differentiate distinct and total hemisensory loss and dense between ischemic and hemorrhagic stroke have not hemiplegia. 34% either of frontal lobar hemorrhage or of a putaminal in a lobar location. can be visualized on MRI. This is the case when sudden. or in pontine Clinical presentation of spontaneous ICH depends on hemorrhages extending over the midline. The pupil which is smaller lamic. bilateral abrupt but gradual and can be seen occurring over localizing signs appear and loss of consciousness is several hours. a hemiparetic patient with a sensorimotor hemipar- microbleeds are considered to bear prognostic signifi. strokes that remain stable can be reliably considered dicts the risk of future symptomatic intracerebral to be caused by ischemia and therefore do not need hemorrhage in patients with lobar hemorrhage and confirmation with neuroimaging. rhages. All attempts to make a probabilistic diag. although patients 159 progressive deterioration of consciousness is seen in with cerebellar hemorrhages almost always vomit . They both present with sudden onset of sensorimotor out an underlying cause and restricted to lobar hemiparesis of varying degree and can both be asso- regions in an elderly patient is highly indicative of a ciated with additional hemispheric symptoms such as diagnosis of cerebral amyloid angiopathy according aphasia or neglect. esis. this invariably denotes involvement of one hemisphere. This is a sign 45% in the putaminal region and in the thalamus. Such an ICH can rupture into the subthalamic structures. and. Vomiting is a frequent sign of ICH but can also Usually transition into drowsiness and stupor occurs indicate ischemic stroke. progression is not the ventricles. This is the case in large putaminal or thalamic hema- Clinical syndromes tomas that rupture into the ventricles. and 11% were not classifiable (Table 10. also no medical rationale to restrict imaging to young patients or to patients with some other demographic Old. In general. clinically non-apparent cerebral microbleeds or clinical feature. A particularly noteworthy opinion at some centers that “typical” hemiparetic finding is that the total number of microbleeds pre. thalamic hemorrhage can be Putaminal hemorrhages are the most frequent accompanied by a conjugate spasm of both eyes. in patients with intracerebral hemorrhage small or medium-sized putaminal bleedings also tend due to hypertensive disease. site and size. There they are most to remain stable. ones. hemorrhages such as contrast. Therefore. hemiparesis and a gradual decrease of alertness. tored closely because of the likelihood of rupture into turing and coma. giving rise to sudden pos. More often. matter. the area of the basal ganglia and deep white matter of when present. and. microbleeds are most to remain stable after the first few days and cannot be commonly found in deep and infratentorial regions. they are called putaminotha. distinguished from ischemic infarcts in the basal gan- although hypertension can also contribute to lobar glia and capsular region on clinical grounds alone. showing an increase of sensorimotor the rule. consciousness can occur within minutes after onset. Then they show a large volume extending over denotes the hemispheric side of the bleeding. and have been suggested ICH can also occur extremely abruptly and loss of as markers of a bleeding-prone angiopathy. Chapter 10: Intracerebral hemorrhage Although there are still many studies ongoing. Such cases have to be moni- lateral or third ventricles. By occurs in the first hours or days. looks at his/her nose tip). 5% in the cerebellum. most of which tend cerebral amyloid angiopathy. If no deterioration or progression commonly found in lobar brain regions [32]. Conjugate eye deviation to the side of the bleeding In our series of 1539 ICH cases we have located signals extension into the frontal lobe. This contradicts the prevailing to the Boston Criteria.1). clinical investigation as well Contralateral limb weakness and hemisensory as neuroimaging are both important for a reliable symptoms are typical of mid-sized putaminal hemor- diagnosis. If a posterior fossa hemorrhage. In contrast. microbleeds. there is probable cerebral amyloid angiopathy [44]. this can give rise to suspicion of a growing cance for any future bleeding event and have been hematoma. The most frequent putaminal Evacuation of the hematoma can also become neces. headache is also not hematoma. Many patients unless it is very severe and then indicates rupturing with posterior fossa hemorrhage show severe impair. and sudden posturing and coma to a a cardinal symptom of ICH. The estimated blood volume is 60 ml. Figure 10. on site and size. in cerebrospinal fluid space.1. Section 3: Diagnostics and syndromes early in the clinical course. Progressive sary after some days. it is not a reliable sign with in large hematomas and has no localizing value either localizing or etiological value. CT: large putaminothalamic hemorrhage with to ischemic infarction). Close observation of vital apparent.3. 160 .2. hemorrhages show a sudden onset. rupture into lateral and third ventricles. MRI: subacute thalamic hemorrhage with gradient echo (GRE) sequence (left). In patients with loss of ment of sitting balance and ataxia that can be pro. deterioration of consciousness points to a growing Contrasting with lay beliefs. Headache can occur rupture of the bleeding into the lateral or third Figure 10. consciousness meningeal irritation must not be nounced ipsilaterally. as deterioration can be sudden Clinical presentation of spontaneous ICH depends or progressive over the first few days after onset. CT: small putaminal hemorrhage (possibly secondary Figure 10. parameters is crucial. liver disease. but not reliable. CT: left shows only one larger intracerebral hematoma.1–10. Vomiting and headache are frequent. Hemorrhage growth was significantly associated with clinical deterioration [46]. rhage expansion include initial hematoma volume. . MRI: coronal slice though lateral ventricles (T2 weighted) showing extensive lacunar infarctions and widespread leukoaraiosis. signs. See Figures 10. The frequency of increased bleed- ing is high. occurred in 26% of 103 patients within 4 hours after the first symptoms. Predictors of hemor- Figure 10. Chapter 10: Intracerebral hemorrhage ventricle.5. though the frequency diminishes with time from onset of symptoms. defined as a 33% increase of hematoma volume on CT. though it might not be clear in all cases whether growth of volume is due to rebleeding or continuous bleeding. whereas on MRI additional multiple punctuate hematomas are seen 161 indicative of amyloid encephalopathy. showed that “growth”. Complications An increase in the bleeding volume is an early com- plication of ICH. Enlargement of ICH is also seen when observation periods are extended up to 48 hours. Figure 10.6. Brott et al.6. Figure 10. early presentation.4. The transverse horizontal slice (GRE) shows multiple punctuate hemorrhages within the putamen and central white matter indicative of advanced vascular (hypertensive) encephalopathy. Another 12% had growth within the following 20 hours. irregular shape. MRI: lobar hematoma in the left temporal lobe. Imaging (non-contrast CT) [50]. Wintermark M. coagulopathies. Lancet Neurol 2006. Early hemorrhage growth in factors: ICH volume. Lo EH. antiplatelets. trauma. amyloid proteins into the cerebral vessel walls with lar extension. Frequent complications are an increase of the Vomiting and headache are frequent. hyperglycemia. primary ICH typically in basal ganglia) most likely orrhage (IVH) and the 30-day mortality rate was results from rupture of lipohyalinoic arteries followed reported as 43% for patients with ICH and IVH by secondary arterial ruptures at the periphery of the compared with 9% in patients with isolated IVH enlarging hematoma. hydrocephalus and edema. Incidence: 10 per 100 000 per year. haemorrhage. sion. and presence of intraventricular blood). Conjugate eye deviation to the side of the perihematomal ischemia is small and has no great bleeding signals extension into the frontal lobe. Ortega-Aznar A. decisive prognostic component. may interact with symptoms such as aphasia or neglect. Becker K. Tomsick T. Shrinking of the hematoma due to clot retraction Clinical presentation of spontaneous ICH leads to an accumulation of serum in the early phase depends on site and size. intraventricular hemorrhage. and the utility of CT angiography. Brott T. deterioration of consciousness points to a growing hematoma. et al. Hernández- Guillamon M. 7:256–67. 28:1–5. Broderick J. Tirschwell D. ity: up to 50% within the first month (prognostic Sauerbeck L. 3. Glasgow Coma Score on admis. 5:53–63. association with cerebral amyloid angiopathy. of the medial temporal lobe and compression of the 2. age over 80 years. The References volume of the hemorrhage into the brain is the most 1. MMP-9-positive . Thirty percent are found in [48]. moyamoya disease or subacute phase and may increase up to 14 days [49]. intraventricular hemorrhage. Early mortal. Kidwell CS. Furthermore. signs with neither localizing or etiological value. infratentorial origin of ICH. hydrocephalus and edema. anticoagulation and 162 illicit drugs such as amphetamine and cocaine. Chapter Summary Intracerebral hemorrhage (ICH) comes “out of the blue sky”. Cere- chymal origin of ICH. hemostasis. Further risk factors: old age. typical warning signs are not known. 20%) causes. Barsan W. Several rupture of the bleeding into the lateral or third ven- studies in spontaneous ICH suggest that the role of tricle. vasculitis. a clinical importance [54]. Factors released onset of sensorimotor hemiparesis of varying degree from activated platelets at the site of bleeding. factor. Kothari R. within one cerebral hemisphere leads to herniation Int J Stroke 2008. Hoff JT. Imaging of intracranial brainstem. excessive alcohol consumption. patients with intracerebral hemorrhage. Lancet Neurol 2008. sinus venous thrombosis. alcohol use and hypo- Etiology: intracerebral hemorrhage (ICH) is clas- fibrinogenima [47]. Thrombin and several serum proteins were is necessary to differentiate ischemic infarcts from found to be involved in the inflammatory reaction hemorrhage. Putaminal hemorrhages show a sudden of the perihematomal zone [51. Complications are due to increase of the bleed- ing. Tuhrim et al. sified into primary (80 to 85%) and secondary (15 to Between 36% and 50% of patients with spon. blood and total volumes are predictors of outcome typically lobar bleedings) refers to the deposition of in patients with spontaneous ICH and intraventricu. arterio-venous malformations. 5. oral anticoagulants. Secondary ICH may be caused by aneurysms. 52]. 4. hydrocephalus was found degenerative changes. Mechanisms of brain injury Risk factors: hypertension is the most common risk after intracerebral haemorrhage. Keep RF. 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Tomsick T. 98:985–992. the deep veins that drain traditionally assumed. and that its prognosis is much the basal ganglia and other deep subcortical structures better than is generally accepted. as the transverse sinus. epileptic seizures or disturbances of of vasoconstriction or vasodilatation. In contrast to veins. It superficial veins can be identified in the majority of has been estimated that annually about five to eight patients: the upper anastomotic vein of Trolard. often with the diag. CVT was con. there is no mind in stroke cases that present with a fluctuating possibility of influencing venous blood flow by means course. cases of CVT are identified among stroke patients of which drains into the superior sagittal sinus. the petrose or the spectrum of clinical symptoms and the often subacute lateral sinus. diameter and topography of these veins vary all stroke patients. headache. The variety of verse and sigmoid sinuses. Cerebral veins do not possess diagnosis in the pre-angiograph era was usually made valves and therefore allow blood flow in both direc- post-mortem. However. but be the cause of an acute stroke in approximately 1% of number. In contrast. Galen and the straight sinus. provided that the do not possess the diversity of the superficial venous diagnosis is suspected. the incidence of CVT is among individual patients. The cerebral venous system consists of two distinct sinusitis. i. This is the main reason why even larger throm- niques allow the diagnosis of CVT at an early stage botic venous occlusions may remain clinically silent and document that CVT is more frequent than was for a long time. the respective neuroimaging network. namely otitis. CVT has a favorable prognosis. finally reaching the vena clinical signs and symptoms renders the diagnosis cava via the jugular veins. two major not known. Diagnosis is still lum and brainstem is drained from the posterior fossa frequently overlooked or delayed due to the wide by veins reaching the vein of Galen. However. as population-based studies are lacking. tions. Septic CVT is observed as a complication of Anatomy bacterial infections of the visceral cranium. With timely therapeutic intervention. and the tertiary care hospitals [1]. with Cerebral veins have a peculiar anatomy. The 165 groups – the superficial and the deep cerebral veins – infectious agents reach the cerebral sinuses ascending . thrombosis of the inner cerebral veins as well as septic CVT remain severe diseases with high mortality rates. mastoiditis and bacterial meningitis. The superficial veins of the brain that drain the cortex and Acute thrombosis of the cerebral sinuses and veins the underlying white matter form a network of anas- (cerebral venous thrombosis. The basal veins of Rosenthal and the internal examinations are performed in a timely manner. which drains into sidered a severe. Chapter 11 Cerebral venous thrombosis Jobst Rudolf Introduction which eventually drain into the cerebral sinuses. cerebral veins drain into the great cerebral vein of and therapy is initiated early. the level of consciousness. Blood supply to the cerebel- of CVT a challenge to the physician. almost inevitably fatal disease. Etiology CVT may be due to infectious and non-infectious causes. [2]. CVT) is considered to tomoses that drain into the cortical sinuses.e. However. Historically. lower anastomotic vein of Labbé. are formed by duplication of the dura mater and are It is important to keep the diagnosis of CVT in fixed to the osseous cranial structures. Thus. the cerebral sinuses or lingering disease onset. as they do an overall mortality rate of about 8% in recent studies not follow the arteries as in other parts of the body. modern neuroimaging tech. and from there the trans- nosis being clinically suspected only. However. 14]. and administration of acetazolamide induces – in contrast to arterial thrombosis – a significant Hormonal replacement therapy increase of rCBF [5]. the auto- Drugs regulation of cerebral perfusion is nearly fully main- Oral contraceptives tained. 4. Injury to sinuses or jugular vein. Regional cerebral blood hemoglobinuria flow (rCBF) is not significantly impaired. primary and secondary thromboses in many ways: venous thrombosis does Thrombocythemia not manifest acutely. often fluctuating process. jugular catheterization Genetic prothrombotic conditions Neurosurgical procedures Antithrombin III deficiency Lumbar puncture Protein C and protein S deficiency Miscellaneous Factor V Leiden mutation Dehydration. colitis ulcerosa) Adamantiadis-Behçet syndrome Hematological conditions Pathophysiology Venous thrombosis of the CNS differs from arterial Polycythemia. Aseptic CVT may be caused by the same causes as extracranial throm- Inflammatory bowel disease (Crohn’s disease.1. including paroxysmal nocturnal cesses occur concurrently. Systemic lupus erythematosus Septic CVT may be caused by bacterial infections of Wegener’s granulomatosis the visceral cranium. mastoiditis Sarcoidosis and bacterial meningitis. Section 3: Diagnostics and syndromes Table 11.g. However. . e.1). Potential causes of and risk factors associated with cerebral venous thrombosis [3. especially in children Prothrombin AG20210 mutation Cancer Mutations in the methylenetetrahydrofolate reductase (MTHFR) gene Acquired prothrombotic states Nephrotic syndrome via the draining veins of the face. Otitis.g. In venous congestion. as arterial thrombosis does. Leukemia but is a subacute. trauma 166 logical signs and symptoms may be observed in CVT Head injury even after weeks. disturb- Steroids ances of neuronal functional metabolism are tolerated Cytotoxic drugs (e. Meningitis all of them resembling those of extracranial thrombosis Systemic infectious disease (Table 11. sinusitis. Inflammatory disease in spite of a thorough diagnostic workup [2–4].1). in which endogenous pro-thrombotic and fibrinolytic pro- Anemia. otitis. sinusitis Aseptic CVT may stem from a variety of causes. or following local inflammation that destroys Homocysteinemia osseous structures that separate the infectious focus from the brain. the sinuses or the Antiphospholipid antibodies ear. Clinical signs and symptoms of septic Pregnancy CVT comprise signs of systemic infection and of Puerperium meningitis. bosis (see Table 11. Septic CVT remains a rare disease with Infections high mortality in spite of modern therapeutic surgical and medical approaches (see below for details). asparaginase) for a much longer time than in arterial occlusion. mastoiditis. the cause of CVT remains unknown in approximately 15–20% of all patients. and full recovery from severe focal and generalized neuro- Mechanical causes. Thus. With cortical CVT. . papilledema. perium. but their localizing value by the diapedesis of erythrocytes through the endo. Motor symptoms may initially present as a re-opened by endogenous fibrinolysis will result in a monoparesis that gradually develops into a full-blown lowering of venous and capillary pressure. extension of the thrombosis into the large sinuses is intense and diffuse headache was either the first the exception. both cases secondary generalization is often observed. cerebral venous thrombosis may neurological signs or focal seizures. straight failure of collateral venous drainage will result in the sinus. Focal neurological signs may be observed in 30–50% physiological point of view. tions may be impaired. a condition exception to this rule is CVT in pregnancy and puer. 8]. 3. 6. extended thrombosis of cortical sinuses will result in symptoms and signs of general- Clinical features ized brain dysfunction (headache and other signs of Abrupt occlusion of a cerebral artery results in the increased intracranial pressure. sinuses usually leads to bilateral symptoms. reflected by coma and disturbances of ation of focal or generalized brain dysfunction. due to the excellent collateralization of thelial membrane. 6. Furthermore. (any degree from somnolence to deep coma) may be present in 30–50% of patients. immedi. with signs and symptoms different from that of deep Cavernous sinus thrombosis may be unilateral. but CVT. while due to ischemia of the brain tissue perfused by this isolated cortical venous thrombosis will result in focal artery. trigem- venous structures involved. The onset of or systemic infection. 8]. precede the manifestation of other symptoms and a percentage significantly higher than in cerebral signs by days or even weeks. remain clinically silent. as long as venous drainage is The rare thromboses of the inner cerebral veins maintained by collateral veins or sinuses. pond to territories of cerebral arteries. 6. and septic CVT will show findings other than the good collateralization between the cavernous aseptic thrombosis. the heparin or low-molecular-weight heparin (LMWH) is intensity of focal signs and symptoms may fluctuate that preventing the re-occlusion of veins and sinuses over time. psychotic symptoms are observed in 20–25% [2. and acute delirium or Hemorrhages are frequent in CVT. allows inversion of venous drainage in the case of bosis. following the increase of the venous cerebral veins and the lack of venous valves that and capillary transmural pressure after venous throm. In general. usually associated with poor outcome [9]. As a rule. is limited. 8]. and aphasia or apraxia may be ate anticoagulation results in clinical amelioration observed. of CVT [2. as well as the paranasal sinuses or other structures of the nausea. with the characteristic combination of ocular chemo- Clinical features of CVT differ according to the sis. Thrombosis of the cavernous sinus may present bosis may present within minutes or hours [7]. etc. 6. higher cortical func- in the presence of hemorrhage due to CVT. painful ophthalmoplegia. 3. a percentage much higher than in ral bleeding. 3. 3. impairment of the acute manifestation of focal neurological symptoms level of consciousness.) will result in a severe dysfunction of the gradual. Cortical CVT will present inal dysfunction. present as simple partial seizures with post-ictal intracerebral hematoma in CVT is atypically localized limb paresis or as complex partial seizures. The most common epileptic seizures is observed in 40–50% of all cases form of intracranial hematoma in CVT is intracereb. Seizures in CVT may noid hemorrhage may be observed. In contrast. Acute appearance of arterial thrombosis or embolism. Most cases of cavernous sinus throm- (> 70%) or the most common (75–90%) symptom bosis are due to ascending infection from the orbita. where signs and symptoms of venous throm. Headache. (veins of Rosenthal. Eventually. while In most prospective clinical series [2. generalized seizures). and its incidence may reach 40–50% [3. and – occasionally – papilledema. Chapter 11: Cerebral venous thrombosis Intracranial hemorrhage is often observed in headache in CVT is subacute over hours and may CVT. The rationale for anticoagulant therapy with localized thrombotic occlusion. An eye movements and pupillary reflexes. visual loss or sixth nerve palsy. arterial thrombosis of the brain. Impairment of the level of consciousness without increase in hematoma volume. diencephalon. but subdural and – rarely – subarach. these bleedings are caused of CVT patients [2. and in in cortical and subcortical regions that do not corres. great vein of Galen. 6]. eye protrusion. of cortical venous thrombosis. even hemiparesis. 8]. is viscerocranium and are accompanied by signs of local 167 due to increased intracranial pressure. fluctuating or progressive clinical manifest. From a patho. Unenhanced cranial computed tomography scan showing an atypical right temporal hemorrhagic venous infarction 168 Cerebral computed tomography (CCT) is widely in a patient with isolated cortical venous thrombosis. malignancies and known pro-thrombotic states. bacterial infection. However.2). the more difficult is the diagnosis of CVT. and is always accom. Thus. the diagnosis of CVT presents a challenge to the clinical physician. and in patients with first-ever headache in combination with seizures of subtle focal signs.1). Headache is the most common and formed before and after the intravenous application frequently the first symptom of CVT. CT venography may increase the panied by symptoms and signs of systemic infection. Thus. Aseptic thrombosis of the cavernous sinus leading to painful uni. impairment of in CVT are often nonspecific and may consist of one the level of consciousness and psychotic symptoms or more of the following: localized or diffuse brain can occur. diagnostic yield of CCT in CVT [9]. The less distinct the clinical presentation is. pregnancy and puerper- ium. CVT may be suspected in the presence of headache and other signs of intracranial hypertension. the main indication of extremely high. in stroke with unusual presentation. alone or in combination with epileptic seizures and fluctuating neurological signs. Septic CVT is accompanied by symptoms of sys- However.g. The thrombotic occlusion of an isolated Diagnostic workup cortical vein may present as a thread-like hyperdense Owing to the multitude of clinical manifestations as structure on no-contrast CCT (“cord sign”). edema. but its mortality remains graphically proven CVT.or bilateral ophthalmoplegia has to be differentiated from the Tolosa-Hunt syndrome. After well as etiologies.or oligosymptomatic cases of CVT may be difficult to diagnose. hemorrhagic infarctions or hematomas (Figure 11. otitis. present – are highly suggestive of CVT (Figures 11. cord sign. The differential diagnosis of aseptic CVT com- prises benign intracranial hypertension. The pres- ence of CVT has to be suspected in young stroke patients. Computed tomography Figure 11. but also all forms of intracranial hypertension due to neoplastic diseases. CVT may be mistaken for meningo-encephalitis. Epileptic of iodinated contrast media.1. focal neurological signs. focal hypodensities that do not comply with Septic thrombosis of other sinuses is found as a the boundaries of cerebral arterial territories. in painful stroke. mas. mono. Note the available and is feasible in critically ill patients. bacterial meningitis). CCT findings seizures. see Table 11. However. .g. Where available.1 and 11. toiditis. Section 3: Diagnostics and syndromes Symptoms of CVT are manifold: they may remain CCT is often the first neuroimaging technique clinically silent as long as venous drainage is still applied to patients with CVT and should be per- maintained.1). especially if conditions are present that may favor thrombogen- esis (e. there are two CCT findings that – if temic infection. CCT may be Septic CVT accounts for about 5% of all cases of entirely normal in up to 25% of patients with angio- cerebral thrombosis. CCT in CVT is to rule out other conditions that may mimic or be confounded with CVT. In patients with signs and symptoms of systemic infection. atypical complication of bacterial infection (e. the 11. . brain edema.2. Cranial computed tomography in a patient with thrombosis of the straight sinus: the straight sinus presents as a hyperintense thread (cord sign) in non-enhanced CCT (left image). are highly suggestive tri-planar MRI in sagittal. Figure sign is found in up to 20% of CVT cases only. Figure 11. underlying parenchymal alterations. axial and coronal T1 and of CVT. in analogy to the design Magnetic resonance imaging of the Greek capital letter Delta [D]).3. T2* and FLAIR sequences in combination with Figure 11. and the non-enhancing intravenous thrombus may be discriminated as a triangle (“empty triangle” or “Delta-sign”. Chapter 11: Cerebral venous thrombosis intravenous application of iodinated contrast media. The main indication is to rule out the dura mater of the sinuses will show a distinct other conditions. Magnetic resonance imaging (T1-weighted images after intravenous injection of paramagnetic contrast media) in a patient 169 with thrombosis of the superior sagittal. while after intravenous injection of iodinated contrast media the surrounding sinus structures show a distinct enhancement surrounding the thrombus (right image). a thread-like hyperdense structure on MRI and MRV to obtain images in various planes no-contrast CCT and a ‘Delta-sign’. such as T2. facilitates the visualization of the different cerebral shaped non-enhanced structure showing after sinuses. a triangle. enhancement. Other findings are nonspecific. It is important to obtain – at least initially – application of contrast media.3) and magnetic resonance venography (MRV) are Delta-sign has been described in 15–45% of CVT extremely sensitive in detecting CVT as well as the patients [10]. The ability of A ‘cord sign’. straight and right transverse sinus. While the cord Cerebral magnetic resonance imaging (MRI. the hypoplasia of a MRI and MRV allow direct imaging of the thrombus. indicating the presence of deoxyhemoglobin remains restricted to those patients where the clinical in erythrocytes of the thrombus. Initially bosis. DSA is now- adays restricted to patients where other neuroima- tense signal on both T1. Figure 11. MRI and MRV are non-invasive neuroima. Owing to the high peri-procedural risk. and recanalization may occur with the re-appearance Other diagnostic findings of flow void signaling. associated with a [14. but MRI and MRV are highly sensitive in detecting CVT.4.4). inal flow void and a strongly hypointense signal on T2 Thus. However.g. the interpretation of DSA (as of MRV weighted hypointense signal of deoxyhemoglobin and or CT venography) may be complicated by the pres- intracellular methemoglobin with flow voids [10. However. MRI and MRV are – in most cases – requires extensive laboratory exams as well as other unable to detect isolated cortical venous thrombosis. 170 . As differential diagnosis of CVT ging techniques and may easily be repeated for comprises a large number of diseases. or the (days 1–5).and hyperintense on T2-weighted images. workup in patients with the final diagnosis of CVT ease. auxiliary testing: lumbar puncture. Section 3: Diagnostics and syndromes MRV. sinus aplasia or hypoplasia and not to mistake the T2. ence of anatomical variations. Digital subtraction angiography in a patient with isolated thrombosis of the right inferior anastomotic vein of Labbe (right). and normal contrast media (Figure 11. the role of DSA in the diagnosis of CVT images. the thrombus becomes hypointense on T1. After 2 weeks. 11]. digital subtraction angiography (DSA) thrombosis may be suspected if the D-dimers. e. During the second suspicion cannot be corroborated by other neuroima- week after clot formation. elevated D-dimers just indicate active structures after intra-arterial injection of iodinated thrombosis (anywhere in the body). in order to minimize confusion of CVT with peri-procedural risk of death or stroke of about 1%. red blood cells are des. and deoxyhemoglobin is metabolized into methemoglobin. diagnostic follow-up and re-evaluation of the course of the dis. transverse sinus [13]. Acute Until recently. phase of aseptic CVT are nonspecific: mild leukocy- tosis. ging techniques are not feasible. ging techniques. the dilatation of venous collaterals. EEG and trans- cranial Doppler ultrasound are often performed.g. elevated erythrocyte sedimentation rate and Digital subtraction angiography CRP are the most common abnormalities. in contrast to physiological imaging of the cerebral vein findings of the contralateral hemisphere (left). troyed. Partial or total recanalization is The diagnosis of CVT is based on the detection of observed within 4–5 months after thrombosis venous thrombosis by the neuroimaging techniques [10–12]. are found to be ele- documenting the partial filling of cerebral venous vated. Often. a has been the gold standard for the diagnosis of CVT.and T2-weighted images. They allow direct imaging of the thrombus. the Most routine laboratory findings in the acute signal intensity depends on clot age. DSA is an values for D-dimers do not exclude acute CVT invasive diagnostic procedure. described above. the only findings that indicate the presence of CVT. and the thrombus yields a hyperin. Furthermore. fibrinogen degradation product. However. e. indirect signs of throm- whose signal intensity depends on clot age. 15]. most findings are nonspecific. thrombotic material gives an isointense regional prolongation of venous transition time are signal on T1 images instead of the normal intralum. acute CVT include increased CSF pressure. ized slowing. a mild pleocytosis and elevated CSF protein in about 50% Anticoagulation of patients. Normal values for D-dimers do not exclude acute CVT. followed by the initiation of anticoagulant treatment and the treat- ment of underlying causes. especially bacterial Other laboratory markers for acute thrombosis infections. However. Societies published evidence-based guidelines on the their diagnostic value in the acute phase of CVT is treatment of CVT [1]. following sections. these findings are nonspecific The rationale for immediate anticoagulation therapy and do not allow the diagnosis of CVT. However.2) should be per. a thorough therapy in acute CVT is also addressed in the recent thrombophilia screening (Table 11. The diagnos. prevention of herniation As the clinical features of CVT may be mistaken initiation of anticoagulant treatment for those of meningo-encephalitis. Prothrombin AG20210 mutation Lumbar puncture is necessary to exclude or FV-Leiden mutation confirm infectious meningo-encephalitis in septic CVT. The Anti-beta2-GP IgG and IgM antibodies treatment priority in the acute phase is to stabilize Anti-prothrombin IgG and IgM antibodies the patient and to prevent herniation. thrombin-antithrombin (TAT) and In 2006. include PAI-1. and testing is not widely available.2. lumbar puncture is treatment of underlying causes. APC resistance Laboratory parameters and CSF findings in aseptic Mutations in the MTHFR gene CVT are nonspecific. and are in danger of Lupus anticoagulant dying within hours from cerebral herniation. Chapter 11: Cerebral venous thrombosis Table 11. However. the European Federation of Neurological plasmin-antiplasmin (PAP) complexes. but – if that is not feasible at a American Heart Association/American Stroke Asso- certain institution – at least patients with recurrent ciation [16]. Transcranial duplex sonography may disclose an Protein S elevation in venous flow velocities in patients with Protein C severe CVT. CSF findings in terial infections. Anticardiolipin IgG and IgM antibodies Impaired consciousness and cerebral hemorrhage on admission are associated with a poor outcome. However. especially bac- often performed in these patients. or even focal or generalized epileptic Genetic prothrombotic conditions discharges. The question of anticoagulation After the diagnosis of acute CVT. Homocysteine Vitamin B12 Therapy Folic acid Patients with acute CVT may present with signs and symptoms of acutely increased intracranial pressure Inflammatory diseases or extended venous infarctions. in patients with definite and acute CVT is to stop pro- tic value of lumbar puncture in CVT patients is the thrombotic processes and allow endogenous fibrino- exclusion of definite infectious meningo-encephalitis lysis to recanalize the occluded veins and sinuses. Suggested thrombophilia screening in patients EEG in CVT patients may show focal or general- with cerebral venous thrombosis. Thrombophilia screening should be per- Factor VIII formed especially in patients with recurrent throm- Acquired prothrombotic conditions boembolic events. EEG findings may be physio- Antithrombin III logical in up to 25% of patients. 171 (or its diagnosis in septic CVT). guidelines issued by the Council on Stroke of the formed in all patients. which are outlined in the under debate. thromboembolic events or those with a positive Acute management: family history of such disease should be referred to a stabilization of the patient specialized center for a hematological workup. concern has been raised about the possible . subcutaneous LMWH poses the question of patient coagulation treatment compared with those not receiv. particularly in critical ill patients. one-third were treated (dose: body-weight-adjusted 90 anti-Xa units twice daily). treatment with vitamin K antagonists neously twice daily in a body-weight-adjusted total should be stopped and antiplatelets (e. the anticoagula- out reaching statistical significance. dose-adjusted intravenous significant reduction in the pooled relative risk of heparin therapy (therapeutic goal: doubling of acti- death or dependency [17]. extracerebral venous thromboembolism found a rhagic venous infarction. The advantage of dose-adjusted intravenous heparin minated after inclusion of 10 patients in each group. LMWH include the subcutaneous instead of intraven- pared anticoagulant treatment with dose-adjusted ous route of administration. Other advantages of small randomized controlled trials [6. Whether acid 100 mg qid) should be given for at least another treatment with full-dose UFH or subcutaneously 6 months [16]. As recanalization of considered safe and probably effective in CVT. both UFH and LMWH are tion with vitamin K antagonists. with LMWH). Immediate anticoagulation is recommended. may be the as an interim analysis documented a beneficial effect fact that the activated partial thromboplastin time of heparin treatment on morbidity and mortality. If no underlying disease is is the doubling of activated partial thromboplastin identified that justifies the continuation of oral anti- time (aPTT). A minority of patients received either low-dose LMWH antiplatelet treatment or no anti. Section 3: Diagnostics and syndromes dangers of anticoagulation in the presence of hemor. therapy. 16].g. and occluded cerebral veins is observed until 5 months immediate anticoagulation is recommended even in after diagnosis [12]. while LMWH is administered subcuta. coagulation. more advantage of a short half-life and the possibility of than 80% of the enrolled patients with CVT were antagonization with protamin. Long-term treatment of CVT – as of other forms coagulants at all. has stabilized [1. vated partial thromboplastin time (aPTT)) has the In the recently published ISCVT study [2]. but no differences in treatment tion with vitamin K antagonists aiming at an INR of safety or efficacy were observed between patients on 2. In uncomplicated treated with anticoagulation (two-thirds of patients CVT cases. with.0 is recommended after the patient’s condition UFH or LMWH. oral clear. Therefore. There are insufficient data to Based on the results of these studies. hemorrhage occurred in either treatment group. LMWH should be preferred over heparin received dose-adjusted UFH. The issue has been addressed in two bleeding complications [18]. if complications occur or surgical interven- poor outcome of 38% with LMWH treatment. and no new symptomatic cerebral over heparin in uncomplicated CVT cases [1]. tion becomes necessary. anticoagulation may be given for 3 months if CVT 172 analysis which compared the efficacy of fixed-dose was secondary to a transient risk factor. with placebo treatment [6]. There was a non-significant trend of venous thrombosis – with intravenous UFH or towards favorable outcome in patients under anti. compliance. it is suggested that effective anti- the presence of hemorrhagic venous infarcts [1. . and for 6–12 subcutaneous LMWH versus adjusted-dose UFH for months if it was idiopathic [19]. Both studies were tory effect of heparin may be immediately antagonized criticized for inadequately small sample size [8] or with protamin.0–3. as direct comparisons are lacking. Following current guidelines. In coagulation treatment for acute CVT showed a non. A meta. meta-analyses determine the optimal duration of oral anticoagula- and observational data. The normalizes within 1–2 h after discontinuation of the second study documented a relative risk reduction for infusion. acetylsalicylic dose of 180 (2  90) anti-Xa units per day. a switch to oral anticoagula- ing anticoagulation. which increases the unfractionated heparin (UFH [8]) or weight-adjusted mobility of patients. 8] that com. In addition. for LMWH. coagulation should be performed for about 6 months When using intravenous UFH. the therapeutic goal after diagnosis of CVT. and the lack of a need for labora- LMWH (nadroparin 90 anti-Xa units/kg BW bid) tory monitoring and subsequent dose adjustments. in the presence of hemorrhagic venous infarcts. even A meta-analysis of the studies on immediate anti. while such an antidote is not available baseline imbalance favoring the placebo group [6]. and for the Patients with intracranial hemorrhage were included reasons mentioned above. The first study was ter. found in up to 40% of all superiority for LMWH and significantly fewer major CVT patients [2]. critically ill patients. Alternatively. and in analogy to applied LMWH is equally effective for CVT is not patients with extracerebral venous thrombosis. 16]. LMWH should be preferred in both studies. 0) is recommended. heterozy. leading to a possible bias in outcome patients with CVT and a “mild” hereditary thrombo.g. V Leiden mutation. and this risk seems to be especially high in performed cautiously in order to avoid over-sedation. some patients lation treatment. treatment and assessment coagulation is recommended for 6–12 months in were non-blind. Severe headache may require treat- show a distinct deterioration of their clinical condi- ment with opioids. because they do not have a relevant impact on venous outflow. with pos. the decision on the duration of anticoagulant therapy must be based on individual Thrombolysis is not recommended in current guidelines. philia such as protein C and S deficiency. haloperi- has the potential to provide faster restitution of dine). ondansetron. dosage. Headache is the main symptom of CVT. However. management of signs and symptoms (e. route (systemic or local). However. In addition. A potential publication bias in the For the treatment of headaches. complications. granisetron). hereditary and precipitating factors predisposing to CVT as well as on the potential bleeding risks of long- term oral anticoagulation. as the patients’ bleeding risk may be increased due to the concomitant anticoagu- Despite immediate anticoagulation. paracetamol current published work has been assumed. intracranial hemorrhage. In general. homozygous factor lysis may be a therapeutic option in selected cases. first- of a poor clinical outcome [2]. Acetylsalicylic Thrombolysis acid should be avoided. oral anti. such causes of deterioration have been ruled out. idiopathic objectively documented extracerebral and method of administration (repeated bolus or venous thrombosis [19]. patients presenting with focal neurological signs and Concomitant nausea requires parenteral anti- reduction of the level of consciousness. Long-term treatment should be con. thrombo- as antithrombin-III deficiency. local thrombolysis in patients with CVT.g. and positive effects of both systemic the patient’s level of consciousness. but dose titration should be tion.g. nausea and agitation peutic goal: INR 2. optimal substance mended in patients with two or more episodes of (urokinase or rt-PA). the use of either systemic or local thrombolysis in this disorder [20. ingly. of controlled data. nial pressure.0–3. The recent emetic treatment with metoclopramide. For long-term treatment of CVT. underlying causes as the most important predictors If sedation of agitated patients is required. may cause The duration of effective anticoagulation considerable agitation.g. systematic reviews of thrombolysis therefore their use should be restricted to necessary in CVT do not show sufficient evidence to support diagnostic or therapeutic interventions. . assessment [14]. If patients sidered for patients with a “severe” hereditary throm. sedation of agitated patients. Current guidelines [1] state that there is insuffi- gous factor V Leiden or prothrombin G20210A cient evidence to support the use of either systemic or mutations. should be preferred over acetylsalicylic acid 173 sible under-reporting of cases with poor outcome and because of the patients’ bleeding risk. Mild to moderate headache in CVT patients should be treated with paracetamol. in the absence bolus plus infusion) are not known. “Indefinite” anticoagulation is recom. levopromazine. chlorpromazine) or thrombosis of the deep venous system apart from HT3 antagonists (e. Regular follow-up visits Symptomatic therapy should be performed after termination of anticoagu- Symptomatic treatment of acute CVT comprises anal- lation and patients should be informed about early gesia.g. and should be treated accord- depends on CVT etiology. deteriorate despite adequate anticoagulation and other bophilia which carries a high risk of recurrence. Thrombolytic therapy choice drugs are major neuroleptics (e. Chapter 11: Cerebral venous thrombosis According to current guidelines [1]. minor neu- ISCVT study identified coma on admission and roleptics (e. It has to be kept in and local thrombolytic treatment of CST have been mind that other sedative drugs (e. benzodiazepines) reported from case reports and small uncontrolled impair the evaluation of the course of the disease and series. a switch to oral anticoagulation with vitamin K antagonists (thera. or two or more thrombophilic possibly in those without hemorrhagic infarction or conditions. headache) indicating a pos- epileptic seizures and treatment of elevated intracra- sible relapse. Pain. 21]. responds to improved venous drainage after anti- terally administered antiepileptic drugs (phenytoin.6% [2. Late seizures are more of increased intracranial pressure. 174 in patients with focal sensory deficits and focal Steroids are not recommended. remains unclear. Prophylactic treat. minor brain recurrence and status epilepticus is extremely high. but threatened vision due levels within a short time. antiepileptic therapy may pressure. Therefore. in CVT. In some patients with lumbar punc- valproic acid. as the risk of seizure 50% of all patients with CVT. removal should be performed. osmotic diuretics (e. since their efficacy is unproven and their be tapered off gradually after the acute stage. acetazolamide might be ment with antiepileptic drugs may be an option required. whereas in patients recommended for treatment of elevated intracranial without these risk factors.g. This intervention is usually followed by a CVT. lumbar puncture with sufficient CSF acid and levetiracetam. logical deficits and no focal parenchymal lesions on In the case of severe brain swelling. shunting.e. However. prolonged fore be used with caution only. patients with isolated intracranial treatment should follow the general rules for the hypertension). acetazolamide sion CT/MRI as significant predictors of early should be considered in patients not responding to symptomatic seizures [22]. swelling (e. Osmodiuretics common in patients with early symptomatic seizures may thus reduce venous drainage and should there- than in those patients with none. e. i.g. mannitol) and – after admission to an ICU – lepsy is low. A hemorrhagic lesion diuretic drugs are not as quickly eliminated from in the acute brain scan was the strongest predictor of the intracerebral circulation as in other conditions post-acute seizures [22]. Thus. effective drug plasma levels herniation) needs no other treatment than anticoagu- should be achieved as soon as possible. deteriorate despite CSF removal and acetazolamide peutic option for those patients. .g. head In spite of the high incidence of epileptic seizures elevation to 30 . In single epileptic therapy may be an option in patients with patients with impending herniation due to unilateral focal neurological deficits and focal parenchymal hemispheric lesion. promote the thrombotic process [1. promote the thrombotic process. However. These findings suggest lumbar puncture. but evidence is anecdotal [24]. decompressive hemicraniectomy lesions on admission CT/MRI. Steroids cannot be generally lesion on admission CCT or MRI. shunting procedures (lumbo-peritoneal is not warranted when there are no focal neuro. ture with CSF removal. Volume restriction treatment with AED for 1 year may be reasonable should be avoided. optic nerve fenestration) are recommended. 23]. and the presence of focal edema or infarcts on admis. anti-edema brain scan (e. administration may be harmful. In these patients. If visual function continues to that prophylactic treatment with AED may be a thera. lation. treatment of raised intracranial pressure. with reported incidence rates between 5% moderate controlled hyperventilation with a target and 10. coagulation may be started 24 hours after CSF ness of a prophylactic use of AEDs in patients with removal. Section 3: Diagnostics and syndromes Epileptic seizures Elevated intracranial pressure All CVT patients presenting with seizures should Localized or diffuse brain edema is observed in about receive antiepileptic treatment. the risk of residual epi. glycerol or in the acute phase of CVT.g. valproic to papilledema. osmo- occurring within the first year. as steroids may Current guidelines [1] state that prophylactic anti. 22] and the vast majority of late seizures pCO2 of 30–35 mmHg. Increased intracranial pressure in most cases Epileptic seizures should be treated with paren. coagulation. as anticoagulation improves venous drainage to first-line antiepileptic drugs (AEDs) in CVT patients a degree that effectively reduces intracranial pressure. Although controlled data are lacking. as they may edema or infarcts on admission CT/MRI. as dehydration may further for patients with early seizures and a hemorrhagic increase blood viscosity. not resulting in midline shift or uncal For the same reason. One study identified focal sensory deficits rapid improvement of headache and visual function. are those that can be administered parenterally and In patients with the clinical signs of isolated intra- allow a dosage that reaches therapeutic plasma drug cranial hypertension only. levetiracetam). but that the optimal can be life-saving and even allow a good functional duration of treatment for patients with seizures recovery. anti- There are insufficient data regarding the effective. whereas treatment therapy. phenytoin. should adhere to the principles outlined for aseptic and the manifestation of other (extracerebral) throm- CVT. 14]. but also in order to prevent the recurrence of intra. recurrence of CVT is rarely observed. Fatalities after the acute phase are predominantly eclampsia. most often dehydra- vital and functional prognosis of CVT is much better tion. malig- diagnosed. Infectious CVT requires immediate broad antibiotic Recurrent CVT may be difficult to diagnose. 20% Recurrence of cerebral venous intraventricular bleedings). As pregnancy and puerperium are conditions that favor the manifestation of CVT. it seems feasible to repeat MR venography Until the results of microbiological cultures are avail- in CVT patients after 4–6 months. This should be pointed out to patients recovering Infectious CVT requires immediate broad antibiotic from CVT. neonates. A new parenchymal Manifestation of CVT in neonates seems to be associ- lesion is present in one-third of patients who deterior- ated with maternal risk factors (hypertension. Therefore. age and male sex. In the acute phase of CVT. Deterioration after admission CVT in older children resemble those of adult CVT in occurs in about 23% of patients. gestational or chronic diabetes mellitus). as established in the ISCVT cohort. otitis. outcome.) should be given. unless a prothrombotic disorder has been prognosis are the presence of CNS infection. cardiac defects. This 2 g tid or ceftriaxone 2 g bid i. sepsis or meningitis. underlying disease. There is a high incidence of intracranial hemorrhages (40–60% hemorrhagic infarctions.g. third-generation cephalosporins (e. Leading than that of arterial stroke. Other causes of acute death include CVT in neonates status epilepticus. headache or focal deficits. deep venous system thrombosis.g. although controlled studies on the efficacy of botic events is observed in about 5% of CVT patients these measures in septic CVT are lacking. clinical presen- mental status.or puerperium-related CVT are no CVT. etiology and therapy of monary embolism. mostly symptomatic and comprises rehydration. with about two-thirds of clinical symptoms are epileptic seizures in two-thirds CVT patients recovering without sequelae [14]. the teratogenic effects of these drugs [14]. associated with the underlying disorder. 175 tinued not only to facilitate the recanalization of the biotics in the case of sepsis. women on vitamin K antagonists nancy. A significant number of children are left with a considerable impairment thrombosis (motor or cognitive deficits. anticoagulation should be initiated those cases where recurrent CVT is suspected. symptoms such as seizures. [pre-] ate. CVT and The vital and functional prognosis of patients with acute even pregnancy. cefaloxim lization cannot be expected after this point. with an overall death or dependency tic prophylaxis during pregnancy is probably unneces- rate of about 15% [2].or extracerebral thrombosis. multiple brain lesions or diffuse Special aspects brain edema. intracranial should be advised not to become pregnant because of hemorrhage. Treatment is After the acute phase of CVT. anticoagulation is con. Long-term predictors of poor sary. and management are very different. Antithrombo- ingly favorable. but the overall illness at the time of diagnosis. if follow- treatment and – often – surgical treatment of the up MRI or MRV examinations are not available. However. the case fatality is around 4–8% [2.v. with worsening of most respects. underlying disease (e. medical complications and pul- While the symptomatology. On the basis of available evidence. and antiepileptic therapy. concern has been Prognosis raised about the risk of future pregnancies in women with CVT. as further recana- able. [2]. is astonish- contraindication for future pregnancies. in neonates the causes. epilepsy). or with new tation. anti. who may need reassuring of the very low treatment and often surgical treatment of the risk of further thrombotic events. sinusitis. and respiratory distress or apnea in one-third of the The overall death or dependency rate is about 15%. coma upon admission. immediately and symptomatic therapy of septic CVT However. As follow-up venography may serve as a reference in in aseptic CVT. . Chapter 11: Cerebral venous thrombosis Infectious thrombosis occluded cerebral veins. The individ- The vast majority of neonates present with an acute ual prognosis is difficult to predict. The main causes of acute death are transtentorial herniation secondary to a large hemorrhagic lesion. mastoiditis). Section 3: Diagnostics and syndromes Heparin is rarely used in neonates, although a pilot headache in CVT is subacute over hours and is study did not show any detrimental effect [25]. due to the increased intracranial pressure. Taken together, the nonspecific presentation of Epileptic seizures, focal neurological signs, impair- neonatal CVT and its common association with an ment of the level of consciousness and psych- acute illness make the diagnosis even more difficult otic symptoms can occur. than in adults or older children. There is no consen- Septic CVT is accompanied by symptoms of sus on heparin therapy in neonates, and the prognosis systemic infection. of CVT in neonates is more severe than in adults [14, 26]. Diagnostic workup The main indication of CCT is to rule out other conditions. CVT in elderly patients MRI and MRV are highly sensitive in detecting CVT. Only recently, older patients were identified as a dis- They allow direct imaging of the thrombus; the tinct subgroup of CVT patients. In ISCVT, about 8% signal intensity depends on clot age. of all patients were older than 65 years [27]. In gen- The diagnostic value of lumbar puncture in CVT eral, these patients presented with clinical symptoms patients is the exclusion or confirmation of and signs different from those in younger patients: infectious meningo-encephalitis in septic CVT. isolated intracranial hypertension was uncommon, whereas disturbances of mental status, alertness and Therapy the level of consciousness were common. Carcinoma Stabilization of the patient. Prevention of herniation. was found more often in older patients with CVT. Immediate initiation of anticoagulant treatment The prognosis was worse, with half of the patients (LMWH with a body-weight-adjusted dose of 90 being dead or dependent at the end of follow-up. anti-Xa units twice daily or intravenous heparin with the therapeutic goal of doubling of aPTT). Future developments Treatment of bacterial infections with broad antibiotics and surgery. Many issues in the etiology, diagnosis and manage- Switch to oral anticoagulation with vitamin K ment of CVT are still unresolved and controversially antagonists (therapeutic goal: INR 2.0–3.0) for discussed. Epidemiological data on CVT are lacking long-term treatment. from many parts of the planet. Open questions con- Treatment of epileptic seizures with parenterally cern many of our current management decisions, administered antiepileptic drugs (phenytoin, such as the role of local or systemic thrombolysis, valproic acid, levetiracetam). decompressive hemicraniectomy, initiation and dur- ation of antiepileptic prophylaxis, and the duration of anticoagulation treatment. It is mandatory to increase the level of evidence supporting our diagnostic or Acknowledgement therapeutic decisions through prospective registries, The author expresses his gratitude to Dr Ioannis case–control studies, and, whenever possible, random- Tsitouridis, Director of the Department of Diagnostic ized controlled trials. As CVT is a rare disease with Radiology at the General Hospital “Papageorgiou” few cases diagnosed annually even at large tertiary (Thessaloniki, Greece), in whose department the health-care facilities, close cooperation between these neuroimaging procedures shown in this article were centers is necessary to achieve progress in the diagno- performed. sis and treatment of CVT. References Chapter Summary 1. Einhaupl K, Bousser MG, De Bruijn SFTM, et al. Guidelines on the treatment of cerebral venous and sinus thrombosis. Eur J Neurol 2006; 13:553–9. Clinical features 2. Ferro JM, Canhao P, Stam J, et al. Prognosis of The most common and frequently the first cerebral vein and dural sinus thrombosis. Results 176 symptom of CVT is headache. The onset of of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke 2004; 35:664–70. Chapter 11: Cerebral venous thrombosis 3. Amery A, Bousser MG. Cerebral venous thrombosis. 16. Sacco RL, Adams R, Albers G, et al. Guidelines for Clin Neurol 1992; 19:87–111. the prevention of stroke in patients with ischemic 4. Stam J. Thrombosis of the cerebral veins and sinuses. stroke or transient ischemic attack. Stroke 2006; N Engl J Med 2005; 352:1791–8. 37:577–617. 5. Schmiedek P, Einhaupl KM, Moser E. Cerebral blood 17. Stam J, de Bruijn SFTM, de Veber G. Anticoagulation flow in patients with sinus venous thrombosis. In: for cerebral sinus thrombosis. Cochrane Database Syst Einhaupl KM, Kempski O, Baethmann A, eds. Cerebral Rev 2002; 4:CD002005. Sinus Thrombosis: Experimental and Clinical Aspects. 18. Van Donden CJJ, van den Belt AGM, Prins HM, et al. New York: Plenum Press; 1990: 75–83. Fixed dose subcutaneous low molecular weight 6. De Bruijn SFTM, Stam J, for the Cerebral Venous heparins versus adjusted dose unfractionated heparin Sinus Thrombosis Study Group. Randomized, for venous thromboembolism. Cochrane Database Syst placebo-controlled trial of anticoagulant treatment Rev 2004; 4:CD001100. with low-molecular-weight heparin for cerebral sinus 19. Buller HR, Agnelli G, Hull RH, et al. Antithrombotic thrombosis. Stroke 1999; 30:484–8. therapy for venous thromboembolic disease. The 7. Cantu C, Barinagarrementiera F. Cerebral venous seventh ACCP conference on antithrombotic and thrombosis associated with pregnancy and thrombolytic therapy. Chest 2004; 126:401–28. puerperium: a review of 67 cases. Stroke 1993; 20. Canhao P, Falcao F, Ferro JM. Thrombolytics for 24:1880–4. cerebral sinus thrombosis: a systematic review. 8. Einhaupl K, Villringer A, Meister W, et al. Heparin Cerebrovasc Dis 2003; 15:159–66. treatment in sinus venous thrombosis. Lancet 1991; 21. Ciccone A, Canhao P, Falcao F, Ferro JM, Sterzi R. 338:597–600. Thrombolysis for cerebral vein and dural sinus 9. Van den Bergh WM, van der Schaaf I, van Gijn J. The thrombosis. Stroke 2004; 35:2428. spectrum of presentations of deep venous infarction 22. Ferro JM, Correia M, Rosas MJ, et al. Seizures in caused by deep cerebral vein thrombosis. Neurology cerebral vein and dural sinus thrombosis. Cerebrovasc 2005; 65:192–6. Dis 2003; 15:78–83. 10. Renowden S. Cerebral venous sinus thrombosis. 23. Canhao P, Cortesao A, Cabral M, et al. Are steroids Eur Radiol 2004; 14:215–26. useful for the treatment of cerebral venous 11. Tsitouridis I, Papapostolou P, Rudolf J, et al. thrombosis? ISCVT results. Cerebrovasc Dis 2004; Non-neoplastic dural sinus thrombosis: An MRI and 17(Suppl. 5):16. MRV evaluation. Riv Neuroradiologia 2005; 18:581–8. 24. Rudolf J, Hilker R., Terstegge K, et al. Extended 12. Baumgartner RW, Studer A, Arnold M, et al. haemorrhagic infarction following isolated cortical Recanalization of cerebral venous thrombosis. J Neurol venous thrombosis. Eur Neurol 1999; 41:115–16. Neurosurgery Psychiatry 2003; 74:459–61. 25. deVeber G, Chan A, Monagle P, et al. Anticoagulation 13. Bono F, Lupo MR, Lavano A, et al. Cerebral MR therapy in pediatric patients with sinovenous venography of transverse sinuses in subjects with thrombosis: a cohort study. Arch Neurol 1998; normal CSF pressure. Neurology 2003; 61:1267–70. 55:1533–7. 14. Bousser MG, Ferro J. Cerebral venous thrombosis: an 26. Golomb MR. Sinovenous thrombosis in neonates. update. Lancet Neurology 2007; 6:162–70. Semin Cerebrovasc Dis Stroke 2001; 1:216–24. 15. Lalive PH, de Moerloose P, Lovblad K, et al. Is 27. Ferro JM, Canhao P, Bousser M-G, measurement of D-dimer useful in the diagnosis of Barinagarrementeria F. Cerebral vein and dural cerebral venous thrombosis? Neurology 2003; sinus thrombosis in elderly patients. Stroke 2005; 61:1057–60. 36:1927–32. 177 Chapter 12 Behavioral neurology of stroke José M. Ferro, Isabel P. Martins and Lara Caeiro Cognitive functions are related to our ability to build lesions are circumscribed, the conceptual representa- an internal representation of the world, the concep- tion system is not affected and these patients are not tual representation system, based on a large-scale demented. This is an important distinction that neuronal network. This system is connected with should be explained to the family and caregivers. more circumscribed and lateralized operational Language disorders occur following middle cere- systems that allow us to translate thoughts into words bral artery territory lesions of the left hemisphere. (spoken, written or gestures), images, numbers or other symbols, to store and retrieve information when A brief bedside evaluation of language comprises necessary and to make decisions or act upon them. four cardinal tests that are useful in the taxonomic Most of these operational abilities are subserved by classification of aphasia and to localize lesions, since distributed networks with areas of regional specializa- they have neuroanatomical correlates [1]. Although tion, organized according to their specific processing these tests are also included in brief exams of cogni- capacities. tive assessment, such as the Mini Mental State The pattern of cognitive/behavioral impairment Examination (MMSE), they should be evaluated observed after ischemic stroke is relatively stereo- beforehand. In fact, language impairment will affect typed, since it follows the distribution of the vascular the majority of cognitive functions and needs to be territories. However, in the hyperacute stage symp- ruled out before proceeding to the assessment of toms are likely to be amplified by additional regions orientation, memory or executive functions. of ischemic penumbra, mass effects and diaschisis The most sensitive task for the diagnosis of apha- (impairment of intact regions that are functionally sia is confrontation naming, for it depends upon a connected with the damaged area), and, in the large network around the Sylvian fissure and can be chronic stage, functional reorganization and brain disrupted even by small lesions. It is also a rough plasticity mechanisms make neuroanatomical corre- measure of aphasia severity. The ability to retrieve a lations loose and less predictable. name is related to word frequency and the familiarity/ In hemorrhagic lesions, vasculitis, and cerebral imageability of stimuli. Presented objects should be venous thrombosis the pattern of cognitive defects is common and easily recognized (spoon, comb, spec- less stereotyped due to the variability of lesion local- tacles, pencil, wristwatch), to make the task specific ization, size and number, or particular pathogenic for aphasia and not sensitive to cultural factors or mechanisms that may cause diffuse impairment. aging. Patients’ responses vary from pauses (word- In this chapter we will present the most common finding difficulties), tip-of-the tongue phenomenon, cognitive and neurobehavioral deficits secondary to paraphasias, the use of supraordinal responses (fruit stroke, according to symptom presentation. for apple) and descriptions of use (circumlocutions). There are rare patients who suffer from a selective naming difficulty affecting a single category of names Language disorders (“category-specific impairments”), such as living Language disorders, or aphasia, occur following peri- entities, actions but not objects, or proper names sylvian lesions (middle cerebral artery territory) of the but not common names. These unusual cases demon- left hemisphere and have a marked impact on the strate that the mental lexicon/semantic system is 178 individual quality of life, autonomy and the ability organized by the functional or physical properties of to return to work or previous activities. Since these objects or living entities (see Martin [2] for review). Chapter 12: Behavioral neurology of stroke The analysis of speech is performed during spon- with posterior temporal lesions, while inferior frontal/ taneous or induced conversation (asking patients to opercular lesions tend to impair the understanding of tell you an episode or to describe a picture). Speech is syntax and verbs but not the nouns. classified, dichotomically, as fluent (associated with Finally, one should ask the patient to repeat temporo-parietal lesions) or nonfluent (pre-rolandic words, pseudowords (pronounceable strings of speech or subcortical lesions) [1] (Table 12.1). To make this sounds that do not belong to the lexicon) and sen- classification easy the listener should try to ignore the tences, to evaluate the ability to decode, retain briefly content of speech (as if listening to a foreign lan- in memory and reproduce phonemes (speech guage) and concentrate on the effort, speech rate sounds). Transcortical aphasias are characterized by and the number and duration of pauses. Fluent a disproportionate capacity to repeat, compared to speech “sounds” normal as opposed to nonfluent other language abilities. Sometimes these patients speech. repeat compulsively, a phenomenon called echolalia. Verbal auditory comprehension is tested through In conduction aphasia, in contrast, patients have out- simple verbal commands (“close your eyes”, “raise standing difficulty in repeating pseudowords or even your arm”, etc.). Poor comprehension of words/ words they can otherwise produce. nouns (lexical comprehension) is usually associated Difficulty in any of these four tasks may vary from mild (occasional difficulty) to severe, and the taxo- nomic classification of aphasia varies accordingly Table 12.1. Classification of speech fluency. (Table 12.2). Effective language recovery, in adults, depends Speech fluency mostly upon the reorganization of the intact areas of Fluent Non-fluent the left hemisphere in the neighborhood of the lesion [3]. Normal output Slow output Four cardinal tests are useful for a bedside evalu- ation of aphasia and to localize lesions, since they (words/minute) Single words have neuroanatomical correlates: (1) confrontation Normal phrase Telegraphic sentences naming; (2) analysis of speech (fluent and nonflu- length ent); (3) verbal auditory comprehension; (4) repeti- tion of words, pseudowords and sentences. Effortless Effortful Language should be evaluated before cognitive No pauses Hesitations, pauses, interruptions assessment. Normal prosody Loss of prosody Certain brain lesions may impair the ability to Sounds “normal” Sounds “atypical” read (alexia or acquired dyslexia) or to write (agra- phia/dysgraphia). Both conditions are commonly Table 12.2. Classification of aphasic syndromes. Taxonomic classification of aphasia Speech fluency Lexical comprehension Word-pseudoword repetition Aphasia type Non-fluent Normal Normal Transcortical motor Non-fluent Normal Poor Broca’s Non-fluent Poor Normal Isolation of speech areas Non-fluent Poor Poor Global Fluent Normal Normal Anomic Fluent Normal Poor Conduction Fluent Poor Normal Transcortical sensory Fluent Poor Poor Wernicke’s 179 Section 3: Diagnostics and syndromes found in aphasia but may occur in isolation following but are unable to read function words or nonwords lesions of the left hemisphere. that are deprived of meaning. In contrast, in “surface The study of patients with reading or writing dyslexia” patients can read aloud regular words and disorders has contributed to the understanding of pseudowords (because they can convert letters, writ- the cognitive processes subserving those abilities and ten graphemes, to their corresponding sound), but to the building of theoretical models of them. They have difficulty reading irregular words or accessing have shown that there are separate pathways to pro- their meaning. These opposite types of impairment cess particular categories of words (regular vs. irregu- have shown the existence of two pathways for reading, lar; meaningful words vs. functional words, such as a fast whole-word recognition with access to meaning “to”, “if ”, “so”) or specific tasks (copying vs. writing (used when one reads frequent meaningful words) spontaneously). This information has been incorpor- and a step-by-step conversion that is useful for read- ated into the assessment and classification of these ing new or infrequent words. disorders (Figure 12.1) [4]. Likewise, in central agraphias, the writing impair- Alexia and agraphia can be classified as central or ment is similar across different output modalities peripheral, depending on whether the impairment (handwriting, spelling or typing) and can be of a affects the central processing or the afferent or effer- “deep type” (phonological dysgraphia) with preserved ent pathways. access to meaning, or a “surface type” (lexical agra- The best known peripheral alexia is “pure alexia” phia, with preserved sound-to-grapheme conversion (alexia without agraphia or letter-by-letter reading). and particular difficulty writing irregular words). In this syndrome, patients can read through the tactile There are also cases whose defect involves the “graph- and auditory modalities (read a word that is spelled emic buffer” (a short-term memory “device” that aloud to them), showing that the central processing is enables the writer to keep the word “on line” as it is intact. They can also write to dictation or sponta- being written in real time), which is characterized by a neously. However, they cannot associate visually pre- particular difficulty writing long words. In contrast, sented written words with their sound or meanings peripheral agraphia is a selective damage in the selec- (cannot read). This syndrome results from a discon- tion or the act of drawing letters (during handwriting) nection between the visual areas and the “word form that can be overcome by typing or the use of ana- area”, due to left temporo-occipital infarcts involving grams and is associated with normal spelling. the posterior splenium. Deep forms of dyslexia and dysgraphia are associ- In central dyslexias, the impairment is indepen- ated with large left hemisphere strokes [5], while dent of the presentation modality (visual, auditory or surface types result from more limited lesions. It is tactile) and therefore also involves writing and spell- possible that reading and writing/spelling rely on ing. “Deep dyslexic” patients may reach the meaning the same cognitive processes, but in reverse order of some written words, including irregular words (the “shared components hypothesis”) and share the (producing semantic paraphasias, orange for lemon), same neural network that includes the angular, Figure 12.1. Cognitive models of Written word from reading. (After Plaut et al. [4].) orthographic lexicon Irregular words Nonwords Regular Familiar words regular words Semantics Phonology 180 (meaning) (sound of words) Chapter 12: Behavioral neurology of stroke supramarginal and fusiform gyrus (BA 37) and BA 22 Table 12.3. Memory systems. and 44/45, as suggested in a study performed in acute Primary (short term) stroke patients [6]. Declarative Alexia and agraphia are commonly found in apha- Semantic sia, but may occur in isolation following lesions of the left hemisphere. Alexia can be classified as Episodic central and peripheral, and as ‘deep’ and ‘surface’ Implicit types. Procedural Priming – facilitation from a previous exposure Neglect Neglect is an inability to attend to, orient or explore Classic conditioning the hemispace contralateral to a brain lesion. Since Sensory recording systems the right hemisphere is dominant for selective atten- tion, this syndrome is usually observed following right hemisphere stroke (affecting some 36–80% of acute stroke patients) [7] and affecting awareness of Neglect is an inability to attend to, orient or explore the left-hand side. Neglect has a negative impact on the hemispace contralateral to a brain lesion, usu- daily living activities and on functional recovery, ally of the right hemisphere. because patients cannot be expected to focus on a symptom that consists exactly of lack of awareness. Selective attention relies on a large network Memory disturbances involving the anterior cingulate gyrus (responsible Memory is not a unitary function. It consists of five for its motivational aspects), frontal-parietal and independent systems and involves three processes superior temporal regions (afferent and intentional/ (encoding, storing/consolidation and retrieval). Both exploratory aspects) as well as subcortical structures, depend on specific neural networks that may dissoci- such as the thalamus and the striatum. Lesions at any ate following a brain lesion. of these areas may produce neglect. Classification of memory systems (Table 12.3) [9] Neglect can produce different symptoms that depends upon three main vectors: duration of must be looked for to be detected. It may be evident memory traces (fractions of seconds, seconds or “for in different types of space: in the personal space life”), content (explicit knowledge or motor routines) (forgetting to dress, groom the left side of the body), and access to consciousness (explicit or implicit). the “hand reach” or peri-personal space (failing to According to the processes affected amnesia is further detect or orient to surrounding objects or persons), subdivided in reference to a specific time event into the distant space (“at eye reach”) leading to spatial anterograde (patients cannot encode/consolidate new disorientation, or in representational space (mental information) and retrograde (the difficulty lies in imagery). It may be present spontaneously or during retrieving information that was already stored). competing sensory stimulation (extinction phenom- Amnesic strokes, i.e. infarcts presenting amnesia ena) and in any sensory modality (visual, tactile, for recent events as the main clinical feature, can auditory). In its most severe form it comprises ano- result from posterior cerebral artery, posterior com- sognosia or denial of illness/impairment and a loss of municating artery, anterior and posterior choroidal identification of body parts as belonging to the self. artery, anterior cerebral and anterior communicating The most common tests used to diagnose neglect are artery thrombosis or embolism. Infarcts in the terri- performed in the peri-personal space and require the tories of the two last arteries can also be secondary to patient to draw, copy or cross out lines or other stimuli subarachnoid hemorrhage and its complications and (cancellation tasks) or to read or write. A qualitative to the surgical and less often to the endovascular analysis of the defect allow us to further classify the treatment of aneurysms located in these arteries. defect as person-centered “egocentric neglect” (involv- Single case reports or small case series of amnestic ing the angular gyrus) or object-centered or “alocentric stroke have been reported following infarcts of the 181 neglect” (right superior temporal gyrus) [8]. inferior genu of the internal capsule inferior, the subarachnoid hemorrhage due to ruptured anterior The memory defect is more frequent and severe after communicating artery aneurysms and may also left-sided and especially after bilateral infarcts. grade and a moderate retrograde amnesia (Table 12. Anterolateral and medial thalamic hemor. but for spontaneous confabu- 182 than after right thalamic infarcts. These ibility. and thalamic). alternating good and poor performance and amnestic strokes usually have mesial temporal better performance on first attempts are also involvement and the damage extends beyond the characteristic. Amnesia following rupture of anterior communi- In thalamic infarcts [12].4).4) are also a distinct feature of anterior. including deficits noid Haemorrhage Group (2000) [13] found prob- in the memory for familiar faces or locations and lems with memory in 50% of survivors. Amnesia is related to damage to the anterior cingu- Left thalamic infarcts can produce “pure amnesia” in lum. In thalamic amnesia confabulations. Combined polar and paramedian recognitions. hippocampus to the entorhinal cortex. deficit [15]. Temporal the form of a verbal or global amnesia. Memory error contexts are associated with ventromedial pre- disturbances are more frequent and severe after left frontal cortex damage. the fornix and the retrosple. topographical amnesia.4. infarcts also cause a severe and persistent amnesia. while right lesions pro. perirhinal Memory defects are a frequent clinical feature of cortex. Following unilateral infarcts (left or right) a complete nium [10]. collateral isthmus or parahippocampal gyrus. Summary of main features of major amnestic stroke syndromes. A quarter of posterior cerebral artery infarcts intrusions and perseveration are frequent. The brain has a mechanism to distinguish . confabulations and anosognosia. Characteristic Hippocampal Thalamic Basal forebrain stroke type PCA infarct anterior or mesial thalamic infarct rupture of ACoA aneurysm Anterograde amnesia severe severe severe Retrograde amnesia none or mild none or mild moderate Encoding defect severe severe severe Consolidation defect severe severe severe Retrieval defect none or mild severe severe Recognition defect none or mild none or mild false recognitions Working memory normal none or mild defect normal Procedural memory normal normal normal Meta-memory normal or mild defect normal or mild defect impaired Confabulations occasional frequent very frequent mammillothalamic tract. subcalosal area and basal forebrain.4). Distract- result in memory defects [11] (Table 12. anteromedian There is a high susceptibility to interference. Confabulations appear to be hippocampal atrophy was found on neuroimaging more likely if there is a dual lesion (temporo-occipital studies in subarachnoid hemorrhage survivors [14]. with slow and limited system also produce memory defects. Right thalamic lations to occur there must be additional orbitofrontal infarcts cause visual and/or visuospatial amnesia. the Australian Cooperative Research on Subarach- duce visuospatial memory defects. false and central infarcts. in the variant types. dorsomedial and. posterior cerebral artery infarcts cause either a verbal They are a frequent and disabling long-term sequela: amnesia or a global amnesia. improvement. Left follow posterior communicating aneurysm rupture. Bilateral infarcts produce global and severe venous infarcts due to thrombosis of the deep venous amnesia and a persistent deficit. Recently. Section 3: Diagnostics and syndromes Table 12. or partial recovery of memory disturbances can be rhages. caudate and intraventricular hemorrhages and expected. memory defects cating aneurysms is characterized by a severe antero- (Table 12. These functions are display executive deficits in formal testing [17. shifting and inhibition [16]. and access to consciousness. Confabulations can be traced to fragments of previous actual experi. consisting of gambling task inhibition of impulses and of non-relevant sensorial information and motor activity. Problem solving – mazes. thalamus or basal forebrain. intracerebral hemorrhages. subarachnoid hemorrhage lation or utilization behavior. lateral prefrontal lobe There are few systematic studies of executive func. being dis. 18].  uninhibited behavior – corresponding to the tioning and other “frontal” syndromes in stroke lateral orbital prefrontal lobe patients. Neuropsychological evaluation of “frontal lobe” functions.or bilateral anterior cerebral artery and being stubborn or rigid. Speed and motor control – tapping test. Pordue Pegboard grade and retrograde. behavior include inappropriate familiarity. Stroke in function produces three distinct clinical syndromes some specific locations can cause executive deficits. Recent models propose due to rupture of anterior communicating artery four main executive functions: dual task coordination. Trail Making A campus. uninhib. disinhibition or apathy. content. thalamic. Concept formation and set shifting – Wisconsin Card ming/planning. Three types of prefrontal lobe functions tasks are usually considered: (1) dorsolateral (executive/ cognitive). whose dys. served by three prefrontal-subcortical loops: dorsolat. so-called working memory. reality from memories and ideas. Confabulators confuse ongoing reality with the Frontal Behavioral Inventory past because they fail to suppress evoked memories that do not pertain to the current reality. Chapter 12: Behavioral neurology of stroke mental activity representing ongoing perception of Table 12. Towers (Hanoi. selective attention and holding and the deep venous system. striatocapsular. Executive difficulties mani. including motivation.5. leaving decisions to proxy involvement. It represents Bedside evaluation “now” in human thinking. London). Examples are middle cerebral ited behavior and apathy. Examples of uninhibited infarcts. The role of EXIT-25 – Executive Interview the anterior limbic system is the suppression of cur. including working memory. monitoring of Sorting Test. Sustained attention – letter or other cancellation test. Amnesia can result from lesions in hippo. aneurysms and thrombosis of the saggital sinus or of switch retrieval. Trail Making B Executive deficits Inhibition – Stroop Test B Executive functions are classically assigned to the pre- Initiative – phonological and semantic verbal fluency frontal lobes. half to two-thirds have executive deficits [19]. mazes actions and external cues and metacognition. and (3) mesial (action regulation). times.5 lists instruments that can be used to evalu. Frontal Assessment Battery at bedside Classification of memory systems depends upon Specific tests duration of memory traces. (2) orbital (emotional/self-regulatory). manipulation of information stored in long-term memory. and three execu. Interview ences. lateral orbital and anterior cingulate. composed respectively of executive deficits. Among patients with subarachnoid hemorrhage one- eral. Speed and shifting – Digit-Symbol or Symbol-Digit. intraventricular or frontal tractible and shouting when constrained and manipu. Executive deficits due to lesions in the prefrontal lobe occur in about one-third of stroke patients and tive processes: updating.  executive deficits – corresponding to the dorso- ate executive functions. concept formation. About one-third of acute stroke patients  apathy – corresponding to the anterior cingu. Neuropsychiatric Inventory (NPI) rently irrelevant mental associations. artery infarcts with frontal lobe or striatocapsular fest as difficulty deciding. uni. reaction Amnesia can be further subdivided into antero. 183 show either disinhibition or indifference and 30–40% late prefrontal lobe. can be divided into three distinct clinical syndromes: Table 12. program. . anterior or paramedian thalamic infarcts. color or luster. shape. auditory) but also a correct use of objects.2). It refers to a perceive single contours but cannot integrate them syndrome closely linked to visual agnosia and to in a coherent structure of the object. In contrast. Naming errors are match identical colors. tionate difficulty in naming stimuli presented visually. In the literature objects. Disconnection or loss of semantic access Apperceptive visual object agnosia is characterized by the presence of perceptual defects in visuopercep. They objects. To evaluate whether there is color 184 access agnosia (visuo-verbal or visuo-semantic anomia and to ensure that language is intact we ask . Classification of visual agnosias. A careful check for achromatopsia in the whole or the perception of elementary perceptual features part of the visual field should precede other tasks. although and have a superior naming of actions than of they can perceive brightness. To test the visual–verbal con- semantic-related.6). and is often found predominantly visual similarity errors. Their (tactile. temporal lesions. but otherwise do not display other features of visual In associative visual object agnosia the distinctive agnosia (Figure 12. (color. Visual agnosias can be classi. feature is the intact perception. shape. Visual agnosia The human brain has two parallel visual systems: a According to the type of visual stimuli ventral occipito-temporal stream. whose main func. They may also be able to describe visual agnosia: form and integrative agnosia. They perform better with real objects than object in multiple-choice tasks and can sort objects by with drawings. based on visual They may be able to select the correct name of an similarity. The paradigm of Colors human dysfunction of the ventral system is visual Objects agnosia while that of the dorsal system is Balint’s syndrome. Associative visual agnosia results from left have a better recognition of moving than of static or bilateral occipito-temporal lesions. contour. Section 3: Diagnostics and syndromes Table 12. Agnosias can be seen in patients improving According to the functional processes involved from cortical blindness. Loss of semantic knowledge tive tasks and a defective perception of elementary perceptual features (color.6. nection we ask the patient to name colors and to point A variety of associative visual agnosia is semantic to named colors. perseverations or confabulatory. patients with integrative agnosia the term optic aphasia is also found. The most distinctive feature of patients with disconnection). Patients with this type of agnosia apperceptive visual agnosia is visual matching errors show not only intact naming in other modalities when trying to match identical visual stimuli. Specific classes of objects Visual agnosias are disorders of visual recognition Faces and are one of the clinical manifestations of posterior Locations cerebral artery infarcts and occipito-temporal hemor- rhages. Visual agnosia for tion is the recognition of visual stimuli (the “what” Letters and words system) and a dorsal occipito-parietal stream. naming errors are morphological. Apperceptive during recovery from this. bright- ness). whose main function is the spatial localization of visual Other symbols stimuli (the “where” system) [20]. as is Color perception is checked by asking the patient to the matching of visual stimuli. There are two varieties of apperceptive semantic categories. errors can be detected in complex perceptual tasks. Apperceptive visual agnosia fied following the type of stimuli that is defectively Form agnosia recognized or following the impaired functional step in the processing of information from the visual Integrative agnosia system to the semantic and the language systems Associative visual agnosia (Table 12. and produce transcortical sensory aphasia. contour. Patients have a dispropor- visual agnosia is due to bilateral occipital or occipito. Patients or pantomime the use of visually presented objects with form agnosia cannot perceive contours. brightness) is correct. Although minor Testing for color agnosia deserves a note. rior temporal involvement. we can test visual–semantic connections by showing the patient drawings of stimuli which are painted in the correct and the wrong colors (e. delusions or hallucinations and knowledge and to emotion related to or triggered by disturbed sleep cycle.2. nor with the common com. V4a areas and the lingual gyrus are the disturbance. scar. moustache.7). human brain areas activated by personally familiar Strokes in strategic locations (e. posterior cerebral faces (family. defect. Figure 12. dorsomedial thalamic. fluc- human brain “color areas” [21]. politicians. Prosopagnosia can be “Optic” found in 4–7% of posterior cerebral artery infarcts. They may be able to identify gender. hyperactive motor behavior.) and even of hemorrhages. e. Recent tation. Delirium must be differentiated clinically nize visually familiar faces. sports people. famous familiar faces artery. “Tell me ceptive and associative visual object agnosia. with a Functional and lesion localization studies found that change in cognition or development of a perceptual the V4v. agnosia and prosopagnosia. color the names of the colors of the national flag”). friends. ethnicity. Visual agnosias are disorders of visual recognition and are one of the clinical manifestations of pos- terior cerebral artery infarcts and occipito-temporal hemorrhages. delirium often (15–48%) complicates acute stroke Prosopagnosia is defined as an inability to recog. the perception of a face [22].). explained by pre-existing dementia (Table 12. They Auditory Visual Apperceptive visual may also be able to recognize faces by facial features. faces known by the from disorientation in time. Semantic Agnosia due to loss of semantic knowledge the fusiform face area and the superior temporal system sulcus as the areas crucial in processing information relative to human faces [23]. with a core system necessary for the recognition of visual variable combination of declarative episodic memory appearance (the system which is disturbed in proso. psychosis and even severe depression. . fluent studies using functional imaging indicate that the aphasia. i. perception rings. Delirium is a disturbance of consciousness. blue banana) Delirium and asking the patient whether the colors are correct. familiar unrelated children are in tricular hemorrhage. Semantic access age and emotional expression. Language Aphasia Hyperfamiliarity for unknown faces has also been reported.e.g. aphasia either bilateral inferomedial or less commonly right inferomedial [24].g. Color agnosia is more Stroke is a rare cause of delirium. topographical disorien- patient. Strokes causing color tuates during the course of the day and cannot be agnosia are left posterior cerebral infarcts with infe. size and clothes. delusions and hallucinations. gait. subarachnoid hemorrhage) [29] part distinct. etc. On the other hand. Finally. Current cognitive models consider a can cause acute agitated confusional states.g. despite preserved visual perception. spectacles. Patients with prosopagno. intraven- one’s own child vs. Functional and anatomical studies identified the occipital face area. mania. caudate infarcts and (media.g. Chapter 12: Behavioral neurology of stroke other cues. Prosopagnosia should Delirium can be detected by the routine testing of not be confused with visuo-perceptive deficits in tests mental status or with a specific simple instrument using unknown faces. which develops over a short period. apathy and other pagnosia). and an extended system relative to person personality changes. frequent than object agnosia. etc. Special testing can identify apper- for color names in responsive naming (e. [25–28].g. V8. They have a normal agnosia semantic knowledge about people. or accessories. Processing of visual stimuli and visual agnosias. Tactile perception agnosia e. amnesia. such as the Delirium Rating Scale or the CIWA-Ar 185 sia retain their ability to recognize people through scale (if delirium is related to alcohol withdrawal). right middle cerebral artery. such as voice. The plaint of prosopanomia (difficulty in recalling the severity of the delirium can be graded using scales names of known persons). such as the Confusion Assessment Method. hyper-vigilant gic activity. intracerebral hemor. There is reduced oxidative metabolism and cerebral blood flow. such as SSRIs. previous delirium or vision impair. precipitants of delirium is given in Table 12.8.8. increased ACTH levels in the first hours of delirium ment are more prone to become delirious. recently proposed. night-time insomnia. TNF-a) has been patients. irritability.7. total anterior circulation infarct (TACI) delirious patients. Main clinical features of delirium. anxiety.6. infection Difficulty maintaining conversation or following  Pain: shoulder. A role of inflammation stroke patients can be grouped as (a) vulnerable and of cytokines (interleukin-1.3). fragmented sleep. lethargy ipratropium bromide) before or during hospitaliza- tion. dopamine and glutamate Predictors of the development of delirium in are probably also involved. high blood urea nitrogen/creatinine. GABA. Acute onset  Previous dementia. hallucinations be complicated by delirium. baclofen or Hypoactive type: decreased motor activity. immobility commands  Fall with bone fracture Disorganized thinking  Subdural hematoma Disorganized or incoherent speech  Full bladder Rambling or irrelevant conversation or an unclear or  Respiratory distress illogical flow of ideas  Metabolic disturbance Altered level of consciousness  Sleep apnea Clouding of consciousness. Precipitating factors of delirium in stroke patients include intake of drugs Psychomotor disturbances with anticholinergic activity (even subtle anticholiner- Hyperactive type: agitated. Table 12. with reduced clarity of awareness of environment  Nonconvulsive epileptic status Cognitive deficits  Sensory deprivation Global or multiple: orientation.2. (b) stroke type and (c) precipitating factors. A check-list for the Daytime drowsiness. mainly in the Intermittent or labile fear. paranoia. memory. cardioembolic strokes. anger or euphoria cholinergic deficit and of increased serum anticholi- nergic activity. over a period of hours or days  Previous delirium Fluctuating course  Medication side-effect Symptoms came and go and fluctuate in severity over a 24-hour period  Medication with anticholinergic activity Lucid intervals  Medication intoxication or withdrawal Inattention  Alcohol or illicit drug intoxication or withdrawal Difficulty focusing. MCI or cognitive decline Occurs abruptly. other neurotransmitters such as serotonin. There is evidence of a depression. sustaining and shifting attention  Fever. apathy. infections Altered sleep–wake cycle and metabolic complications. 186 type. and of higher post-dexamethasone cortisol levels in torial strokes. visceral. Delirium is an ominous prognostic sign: acute rhage as well as strokes causing severe paresis or stroke patients with delirium have a higher risk of . language Perceptual disturbances neglect or a decrease in alertness are more likely to Illusions. Supraten. However. Check-list for precipitants of delirium in stroke patients. The stress-hypercortisolemia Older patients and those with previous dementia or hypothesis of delirium is based on the finding of cognitive decline. anti-emetics. bed sores. reversed sleep cycle The pathogenesis of delirium is incompletely Emotional disturbances understood (Figure 12. Section 3: Diagnostics and syndromes Table 12. frontal lobes and parietal lobes. In acute stroke. aggressive behavior appears to be mainly due to a failure of regulatory inhibitory con- Anger and aggressiveness trol. The and behaviors depending on several anatomical struc. dysarthria. [32] described Delusions are of two main types: delusional misiden- an association with motor dysfunction. in-hospital death. tification syndromes and delusional ideation. and Psychotic disorders due to stroke are rare. Anger is a primary In acute stroke. lenticulocapsu- dependency at 6–12 months. lesion to the frontal pole. Proposed schematic STROKE pathophysiological model of post-stroke delirium. aggressive behavior appears to emotion with three components: the emotional be mainly due to a failure of regulatory inhibitory (anger).3. Kim et al. Glutamate Inflammation Cortisol release release Hippocampal cholinergic deficits Damage to Drugs brain areas related to vigilance Increased attention Infections SA activity memory emotions DELIRIUM longer hospital stay. found no association with a specific stroke rent delirium and dementia. depression. This 187 emotional incontinence and higher frequency of can be observed in patients with Wernicke’s aphasia . localization. (aggression). the amygdala. death and anger in strokes involving the frontal. were found in other studies. cognitive and behavioral components of anger and Delirium is related to  vulnerable patients between the subjective experience of anger and what  stroke type and could be observed [33]. the cognitive (hostility) and the behavioral control. lower MMSE. Chapter 12: Behavioral neurology of stroke Figure 12. but three other studies nursing home or other long-term care facility. while no such associations with prominent hallucinations or with delusions. the investigated. hallucinations found a frequency ranging from 17% to 34%. role of premorbid personality traits has not yet been tures. Patients may behave aggres-  precipitating factors. being admitted to a lar and basal pontine areas. A few studies [30–34] have evaluated anger and its components systematically in stroke patients and Psychotic disorders. In some studies. On the other hand the hospital environment may Anger and aggression are complex human emotions be or may be perceived as hostile or humiliating. sively without feeling angry or experience only hostility. including the frontal lobes. They are with hemorrhagic strokes with the proximity of the classified according to the predominant symptom. hypothalamus and the brainstem. An interesting aspect is the dissociations that were Delirium often complicates acute stroke and is a found in acute stroke patients between the emotional. bad prognostic sign. recur. anxiety. anger in stroke patients was associated with and delusions younger age. stereotyped. The phenomen- and infarct site. hallucinations are was transient. and last for tive correlates include irritability and ideas of refer- minutes. In right temporal and left dorsomedial thalamic strokes. (3) rostral brainstem priate stimuli but also by appropriate stimuli in an and thalamic lesions (peduncular hallucinosis) (sub. hallu. Visual hallucinations can be asso- replaced by a similar one. Other behavioral and cogni- 188 They appear during the day or night. This disorder consists of uncontrollable nantly visual and can be due to: (1) sensory depri. cinations are complex. There is no mood change during with visual hallucinations there was activation of the the episode and no sense of relief when it ends. In cutory. In rostral brainstem and thalamic strokes. where spontaneously. they can be dissociated. Most frequent are visual hallucinations related to rostral have three grades of severity or stages of evolution: brainstem. even in the face of compelling counter-evidence. Peduncular hallucinosis stroke. Disturbances of emotional (3) chimeric assimilation: “I am not in the real hospital X but in my house which was transformed expression control into a hospital”. drugs). where ciated with seizures and the EEG may show epilepti- the patient believes it is the same person but with form activity. The outbursts are (“release” hallucinations) (cortical hallucinations). naturalist and sometimes associated with depression but more often scenic. been estimated at between 12% and 27%. Section 3: Diagnostics and syndromes and severe comprehension defect. ology of hallucinations does not always reflect the The delusional misidentification syndromes localization of the lesion. but dis- spatial disturbances and is seen predominantly after orders of emotional expression control are more fre- right-hemispheric lesions. decreased sexual activity and lower MMSE . (1) confabulatory mislocation: “I am not in hospital X but in hospital Y”. Patients cannot control the cortical hallucinations). inappropriate context. featuring tion (1–5%) in stroke survivors is also low. transient duration of seconds or minutes. colored. but sometimes there is a strong emotional [35] found that delusions started 0–3 days after reaction of anxiety and fear. memory or visuo. . Fregoli syndrome. Hallu- The prevalence of psychosis and of delusional idea. Somatoparaphrenia is associated with visual hallucinations and have been reported following hemiassomatognosia and denial of hemiplegia. quent (11–40%) and often appear delayed after stroke Hallucinations in stroke patients are predomi. crying or both. jealousy and suspicion. There ventral extrastriate visual cortex and that the type of are many crying situations and many content areas of hallucinations reflected the functional specialization crying situations. The crying frequency is very high. Delusional ideation posterior cerebral artery infarcts. neglect. complex. and intermetamorphosis. precipitated by nonspecific or inappro- withdrawal (alcohol. Patients have variable insight and reactive ence. with paroxys- vation: poor vision (Charles Bonnet syndrome). and the predominant types were mixed. visual. mal onset. different place than the actual one. with a mean duration of 13 days. more common after partial occipital lesions. spatial delirium the patient believes he/she is in a These auditory hallucinations are transient [36]. There is no association between delusion type delay of days after the vascular event. . the familiar person has been transformed into Auditory hallucinations are much rarer than another one. darkness. Disorders of emotional expression control are cinations are vivid. but are resistant to treatment. (4) partial occipital lesions extent or duration of the episode.. incongruent or exaggerated in comparison with the Functional imagery studies showed that in subjects emotional feelings. Visual hallucinations usually resolve different features. is more frequent in men and in the presence of others. (2) delirium and substance stereotyped. Spatial delirium is in some cases The prevalence of crying in acute stroke patients has associated with delirium. Kumral and Oztürk behavior. deafness . thalamic and partial occipital lesions. It of the activated region. onset [37]. Less frequently they are auditory or combined. where the patient believes may serve as the focus of an abnormally activated a familiar person is not the real person but has been neuronal network. can recur in a stereotyped manner over weeks. perse. outbursts of laughing. (2) reduplication: “I am not in the real hospital X but in an identical building”. They are apparent in the predominantly associated with right hemispheric abnormal visual field. It is animal or human figures. Spatial delirium can Psychotic disorders due to stroke are rare. They appear in general with a strokes. because the damaged area include Capgras syndrome. recovery but is associated with worse social function- bursts of laughing. Post-stroke anxiety without depression does not influence functional or cognitive Disorders of emotional expression control (out. strokes. Chapter 12: Behavioral neurology of stroke scores. They can disrupt communication. than in community studies (11. The prevalence of post-stroke anxiety. while during follow-up restlessness and also basal pontine strokes. event and it may be re-experienced as an unpleasant . ent clinical and psychiatric correlates are previous cuitry. Diagnostic and Statistical embarrassment and therefore curtail social activities. Uncontrolled laughing and crying and alcohol abuse. There is recent evi. ranging from one-quarter to called after Féré fou rire prodromique. Post-stroke anxiety disorders are often associated with depression. Anxiety in acute stroke can also be secondary to Post-traumatic stress disorder substance use or withdrawal (alcohol. 6–17 and 3–11%. which initiates voluntary laughter and ively). circulation strokes. younger age. Besides depression. one-half. association of post-stroke anxiety was with anterior dence of disruption of ascending serotoninergic path. and usually lasts longer. history of insom- trol center from the motor cortex or from disruption nia and cognitive impairment. decreased energy. but also bilateral pontine and unilateral poor concentration. cortico-subcortical insomnia are more common in “anxious or worried” lesions. nervous tension and strokes. Disorders of emotional expression control The core symptoms of generalized anxiety dis- have an adverse impact on the quality of life of stroke order are being anxious or worried and having diffi- survivors. poor concentration. ways in disorders of emotional expression control. Wilson [38] proposed a patho-anatomical model con. More recent systematic studies have shown sion and insomnia. lenticulocapsular or thalamocapsular lesions. do not recover: post-stroke anxiety with ally anticipate by seconds to days the onset of the focal associated depression has an unfavorable prognosis deficit in acute stroke [40]. nervous ten- strokes. The most consistent anatomical cognitive and situational context. which initiates and also terminates involuntary psychiatric disorders. Less consistent correlates include could result from release of the fasciorespiratory con. that they can follow not only bilateral subcortical In the acute stage restlessness. aphasia. irritation. 8 and 1–2%. can exception. with a dual route of control from the motor cortex: stroke survivors: 24. benzodiaze. respectively. Post-stroke anxiety disorders have received compara- tively less attention than post-stroke depression. cause culty in controlling worries. including large anterior. other consist- frontal/temporal–basal ganglia–ventral brainstem cir. previous psychiatric disorders and Anxiety disorders alcohol abuse. is higher in hospital settings (acute for emotional expression located in the brainstem stroke patients: 28. while decreased energy is a nonspecific bursts of laughing and crying is poorly understood. being in which the cerebellar structures play a role in single. a sizeable proportion. decreased been classically associated with bilateral subcortical energy. with anxiety. respectively) a voluntary pathway through the pyramidal and gen. Manual (DSM) IV criteria require in addition three Disorders of emotional expression control have or more symptoms such as restlessness. irritation. and are often associated with bilateral subcortical strokes. and an involuntary pathway consisting of a or minor depression. pre-stroke depression or anxiety laughter or crying. with or with- sisting of a putative fasciorespiratory control center out depression. stroke patients. The prevalence of agoraphobia is estimated to be crying and inhibits involuntary initiated laughter or 17%. Parvizi and the Damasios correlates of anxiety include impairment in activities of [39] proposed a modified version of Wilson’s model. living alone or having no social contacts outside adjusting the execution of laughter and crying to the the family [41–43]. daily living. Concerning the outcome of post-stroke anxiety. crying or both) are frequent ing and quality of life. Functional and social of the involuntary pathway. Anxiety disorders are often associated with major crying. female gender. An uncontrollable prolonged burst of laughing. Stroke and TIA can be experienced as a traumatic 189 pines and illicit drugs). impairment in social functioning. and nervous tension are more consistently associated The pathophysiology of the uncontrolled out. 15–17 and 3–13%. respect- iculate tracts. complaint. indifference. Patients with post-stroke mania can experience recurrent episodes. Loss of energy. interest and concern. their lifestyle. mania and a reactivation of previous undiagnosed The relationship between depression and disabil- primary mania. defined as a Post-stroke depression change from the previous characteristic personality. mania can also be detected in stroke patients Post-stroke depression has a prevalence of about without personal or familial predisposing factors. common. However. disinhi- major depressive episode. In the Figures related to the epidemiological features of apathetic type the predominant feature is marked post-stroke depression are highly variable. the time since motivation. Guilt and suicidal ideation are less disturbance in mood characterized by elevated. Severe depression has a frequency stroke survivors and is associated with depression ranging from 9 to 26%. (fronto-basal ganglia-thalamic-cortical) pathways. the case mix and the criteria/method used to emotion. their subjectivity (i. as Post-stroke mania is an infrequent complication of well as the somatic symptoms of decreased appetite stroke (1–2%) [45]. there is lack of feeling. subcortical minism. Apathy is a disorder of they depend on the setting of the study. the subjective experi- symptoms. In severe cases distractibil- after stroke. bited. closely followed by Post-stroke mania anhedonia. It is a prominent and persistent and insomnia. flat affect. A systematic review of 51 studies reported neuroticism or with a negative affect or appraisal of a mean prevalence of 33% (29–36%) [47]. Acute of post-stroke mania to predisposing genetic (family/ depressive symptoms mainly have a biological deter- personal history of mood disorder) factors. Post-stroke depression is a prominent and persistent are one of the most annoying behavioral disturbances mood disturbance characterized by depressed mood found after stroke. To distinguish between true post-stroke ated with a higher risk of post-stroke depression. 18–55% of stroke survivors are low educational level. There are several types of person- two subtypes: with depressive features and similar to a ality changes in stroke patients: aggressive. 190 stroke. expansive or irritable mood. lesions in both hemispheres and also after subarach- noid hemorrhage. [45] emphasized the relationship neurological impairment and social isolation. although in some studies the racing thoughts. it is crucial to obtain a careful history ity depends on several factors: the personality of the of previous manic or hypomanic episodes or patients. the stroke experience. Post-traumatic stress disorder after depression is present in 16–52% of the patients [46]. while in the acute phase and anxiety. cerebral atrophy. and in those with premorbid depressed.e. ity. Personality changes Persistent personality disturbances. Clinical features of Concerning the features of stroke which increase post-stroke mania also include increased rate or the risk of post-stroke depression. in particular during the first months decreased need for sleep. labile and apathetic types. Higher lesion volumes. talkativeness. stroke is more common in women. while post-stroke depression at 1–2 years has brain atrophy and damage to the right corticolimbic an additional psycho-social determinism. grandiose ideation and lack of frequency and severity of depression were higher after insight. hyperactivity and social disinhibition and left-sided lesions. ence of the stroke). delusions and hallucinations may be silent infarcts and white matter lesions are all associ- also present. The prevalence of post-stroke no initiative or decisions and little spontaneous . confusion. the severity of Starkstein et al. decreased concentration and psychomotor retardation are also frequent. For the caregiver these changes are or lack of interest or lack of pleasure (anhedonia) in hard to cope with and they are difficult to control all or almost all activities. The hemispheric side is and content disturbance. Section 3: Diagnostics and syndromes and uncontrollable intrusion. also not relevant [48]. such as flights of ideas. in patients with At two years. Post-traumatic stress depression ranges from 5 to 67% among all types of disorder is estimated to affect 10% to 31% [44] of stroke patients. In severe forms. because apathy and indifference. diagnose depression. all stroke types are amount of speech. Post-stroke depression has pharmacologically. The symptomatology of post-stroke depression is dominated by depressed mood. paranoid. after 30%. language thought similarly prone to depression. cerebral atrophy. but may occur in isolation following Leclercq M. corresponding to the tional level. aphasia. All stroke types are similarly prone to depression. Godefroy O. which is associated with older age. Chapter Summary silent infarcts and white matter lesions are asso- ciated with a higher risk. (2) analysis of speech (fluent and nonfluent). working memory and reasoning) with deficits hemorrhages. 191 brain. orient or delayed or slow. Amnesia can result from thrombosis or response to other people. 17–71% of the patients present ity. but higher lesion volumes. basal ganglia and thalamus. labile and apathetic) are frequent sensory deprivation or delirium or substance and for the caregiver one of the most annoying withdrawal. revisited. was independent of depression [49. Apathy factors (e. preference for passive activities traces. uni. pseudo- words and sentences. further subdivided into anterograde and retro- paucity in starting a conversation. anterior and posterior “low” mood.6) and are 1–6 months after stroke. caudate.  Amnesia can be classified according to the affec- sonality change include lack of interest in previous tion of the memory system (duration of memory activities and hobbies. Relatives are more worried than the choroidal artery and anterior cerebral and anter- patient. et al. drugs or infections). and lack of complaining. concen. Predictors are a vulnerable which comprised the ipsilateral frontal white matter. They can be clas. Annu Rev Psychol 2007.g. Subtle symptoms of apathic per. Debachy B. bad prognostic sign. (3) verbal auditory comprehension. utilization behavior). Neurology 2000. corresponding to the anterior cingu- Systematic studies investigating apathy in stroke lated prefrontal lobe. Cardinal tests: (1) confrontation naming. and access to consciousness) and (sitting. A key feature is the dissociation explore the hemispace contralateral to a brain between impaired self-activation and preserved lesion. Lesion: rostral brainstem and thal- Persistent personality changes (aggressive. but they deny ior communicating artery. ing.  Neglect is an inability to attend to.  uninhibited behavior (inappropriate familiar- In acute stroke. (4) repetition of words. cerebral artery infarcts and occipito-temporal tration. low educa. and as ‘deep’ and 2. watching TV).  Visual agnosias are disorders of visual recogni- survivors detected apathy in 20–40% of the patients tion (for classification see Table 12. behavioral disturbances found after stroke. 4:1117–23.  Persistent personality changes are most  Aphasia occurs following middle cerebral artery annoying for caregivers of patients after stroke. in activities of daily living.  apathy. paranoid. Apathy was associated with  Delirium often complicates acute stroke and is a right-sided lesions involving subcortical circuits. References  Alexia and agraphia are commonly found in 1. These include anterior thalamic. content. speaking mainly in grade. territory lesions of the left hemisphere. Delmaire C. amic and partial occipital. usually of the right hemisphere. Responses are either absent.50]. The representation of object concepts in the ‘surface’ types. disin. the type of stroke and precipitating anterior capsule. . Other reasons: hibited.  Depression has a prevalence of about 30%. Pruvo JP. stubborn or rigid). poster- Apathetic patients look depressed. The anatomy of aphasia lesions of the left hemisphere. hetero-activation.  Prefrontal lobe deficits: the cingulate-subcortical thalamo-striate loop can  executive deficits (showing difficulty decid- produce apathy. patient. corresponding to the bilateral palidal.  Hallucinations in stroke patients are predomin- antly visual. Chapter 12: Behavioral neurology of stroke speech or actions. Kreisler A. inferior capsular genu. being distractible and manipulation or apathy. cognitive impairment (mostly executive lateral orbital prefrontal lobe functions) and denial. 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Dis 2003. slight VaD cannot be used for all patients who have had cognitive or behavioral changes may have conse. ment without dementia. vascular. espe- Post-stroke dementia (PSD) includes any dementia cially after the age of 75 years. dementia that occurs – or was already present – in the burden of stroke-related dementia is also likely to patients who have had clinical symptoms of stroke. Dementia is also frequent in Western countries. and tively influences the time-course of Alzheimer’s dis.e. vascular. arterial hypertension and bleeds and leukoaraiosis). and among institutionalized resi- dents two-thirds are demented [6]. 2400 when isolated). The term Even in stroke survivors who are independent. and neurodegenerative lesions. irrespective of its cause. and a factor that nega.9% 194 degenerative dementia (especially AD) and mixed to 32%. increase in the future [5]. exclusion or not of patients with aphasia . our review will focus only on and the aging of Western populations [9]. before an extensive diagnostic workup makes to stroke and new-onset dementia occurring after possible a classification into vascular dementia (VaD). stroke [5]. (ii) dementia associated with apparently purely “silent” ease (AD). countries. irrespective of its cause.e. i. had a stroke than in stroke-free controls [11]. The prevalence of PSD ranges from 5. micro- AD. people have a stroke every year. such as increasing age. i. rhages and white matter changes [10]. but we should bear in mind Stroke and dementia are both frequent and their that the cognitive burden of stroke is severely under- relationship is more complex than being just a coex. stroke also shares many risk factors with vascular lesions of the brain (silent infarcts. Stroke is the leading cause of physical not necessarily severe enough to induce dementia disability in adults: of one million inhabitants. because many of them quences for familial and professional activities [5]. The prevalence of stroke and of ably of vascular origin that occur in the absence of dementia is likely to increase in the coming years. estimated. the This chapter will not cover: (i) cognitive impair- economic burden of dementia is important. Therefore. About 40% of demented people live i. in an institution. Therefore. cognitive impairment without dementia istence of two frequent disorders. a stroke and are demented. of whom more than VaD is a dementia syndrome that is the direct 50% will die or become dependent 1 year later [3]. Descriptive epidemiology Definitions of dementia occurring after stroke Post-stroke dementia (PSD) includes any dementia Prevalence of dementia that occurs after a stroke. degenerative or mixed [5]. The concept in stroke survivors of PSD is useful for patients who are followed-up after Prevalence studies include both dementia pre-existing a stroke. brain lesions presum- ApoE4 genotype [7]. at least one will develop dementia. Besides being a being three times more frequent in patients who have potential cause of dementia. depending on the mean age of the study dementia (dementia due to the coexistence of vascular population. clinical symptoms of stroke or transient ischemic because of the decline in mortality after stroke [8] attacks. have AD. degenerative or mixed. Therefore. close to 18% [6]. stroke usually of Alzheimer type.e. consequence of cerebral infarcts. cerebral hemor- Dependency after stroke is often due to dementia [4]. where its prevalence is that occurs after a stroke. both types of lesions being or both [1. Chapter 13 Stroke and dementia Didier Leys and Marta Altieri For every three people currently living in Western lesions of the brain. 2]. delay stroke [29]. i. the incidence of dementia after stroke ranged from 9% [23] to 16.5 after 10 years. Many so-called PSDs are not actually “new. a risk factor for vascular dementia 8. cardiac arrhythmias Framingham study. but pre-existing dementia revealed after stroke. atrial fibrillation and myocar- In the Rochester study. in sufficiently powered studies. 24% to 28. the relative risk of dementia dial infarction were also independent risk factors for (i. the results of hospital. 15% after 5 years. found in at least two independent studies. or have 10% after 3 years. the statistical relationship found . pre-existing dementia being present in Factors influencing the occurrence 7–16% of stroke patients. Pre-stroke after 10 years.8% [24] after 1 year. and then declines. Arterial by the risk of dementia in stroke-free controls) was hypertension. and 2. the best who have had a stroke than in stroke-free controls. are listed in Table 13. The incidence of dementia after stroke depends on whether the study excluded Stroke doubles the risk of dementia. ated with an increased risk of dementia after stroke 195 tion level and exposure to individual risk factors for [5]. In a community-based study of dementia after stroke conducted over a 25-year period. Details of studies dementia. only 6% of survivors developed are increasing age and low education level.8-fold more frequent in patients ever strokes.0 after 25 years [22]. mortality rates. 5–6-fold higher than in stroke-free controls [27.3% [27] after 4 years. The Incidence of dementia after stroke is 7% after risk of dementia after stroke is higher in patients who 1 year. and the relative risk of dementia remains stable around 2.8 one year after stroke.5–5. the cumulative inci. gender. and often undiagnosed before stroke [15–21]. Relative risk of dementia after stroke Diabetes mellitus. 28] after 5 years. 12]. Determinants of post-stroke dementia that have been dence of dementia after stroke was 7% after 1 year. and only 1 year of follow-up. In the Epileptic seizures [33].1. cognitive decline without dementia.e. demented at month 6. 23% after 10 years been identified recently. Chapter 13: Stroke and dementia or severe physical disability. conducted in non-aphasic patients. (ii) the attributable risk is the highest within the first year after stroke. and with an increased risk of dementia [30] was actually criteria used for the diagnosis of dementia [5. able risk is the highest within the first year after tia or not. educa. is also associated with a higher risk of dementia after stroke [5. after adjustment for age.and community- Dementia is 3. logical issues [5].5% [25] Demographic and medical after 3 years. with mild first- Dementia is 3. 15% after 5 years. onset” dementia. 21. has not been clearly identified as a to 2. The risk factor for dementia after stroke.8-fold more frequent in patients based studies can be summarized as follows: (i) stroke who have had a stroke than in stroke-free controls. assessed by standardized questionnaires. 31].5% [26] to 33. In hospital-based studies. risk of AD was also doubled after 25 years [22]. 10% after 3 years.e. 23% were already dependent before stroke [5]. However. gender when the analysis is adjusted for age [5]. and 48% after 25 years. and (iii) the risk of delayed dementia in stroke survivors (including AD) also remains doubled 10 years and Incidence studies are limited by similar methodo. the attribut- patients with pre-existing cognitive decline or demen. the results were similar 10 years and congestive heart failure are independently associ- after stroke. and 48% after 25 years [22]. In the Lille Stroke/ The most important demographic predictors of Dementia cohort after exclusion of patients who were dementia after stroke. In hospital-based studies the risk of new- evaluating the prevalence of PSD are provided in onset dementia within 4 years after ischemic stroke is Table 13. 14]. but not really “new-onset” dementia after 3 years [25].2. sepsis. A study where stroke was not associated between stroke onset and cognitive assessment. stroke. 32]. then Incidence of new-onset dementia declines. characteristics of the patient and was 32% [27. more after stroke. doubles the risk of dementia. conditions to minimize the incidence of new-onset after adjustment for age [13. Finally. then declined progressively (VaD) and AD.5–5. the risk of dementia in stroke survivors divided dementia after stroke in several studies [5]. 8 55–85 years Desmond. [5]. 2003 3 283 Ischemic stroke.3 years Censori. 2000 3 251 Stroke. 1998 3 337 Ischemic stroke.0 60–80 years Rating Scale Hénon. 2001 6 202 Stroke.4 Rasquin. 2004 18 149 Stroke. age  60 Clinician’s 16.6 Hénon. 1990 7–10 days 726 Ischemic stroke.9 previous functional deficit Lin. 2004 3 434 Ischemic stroke. 2001 3 237 Stroke patients with no NINDS-AIREN 5.3 with small vessel disease dementia rating scale  1 Zhou. age  18 years DSM IV 22.2 patient with previous TIA Tang. DSM IV 10. age  40 years ICD-10 22.5 Mok.8 Inzitari. The same study may appear several times if several assessments were performed at different time intervals after stroke. 2001 36 202 Stroke. age  60 DSM III R 26.1 Madureira. 1992 3 251 Ischemic stroke.0 age  40 years MMS  15 (acute stage) Linden. Prevalence of post-stroke dementia. year Follow-up Number of Population Criteria for Prevalence (%) (months) patients characteristics dementia Tatemichi. 2000 3 453 Ischemic stroke. age  70 years DSM III R 28. age  60 DSM III R 26. age  40 years ICD-10 21. age  60 years DSM IV 15. 2001 12 202 Stroke. Studies are classified by increasing duration of follow-up. 1996 1 220 First-ever stroke.8 interview based on ICD-10 Hénon. no ICD-10 9.0 60–80 years Rating Scale Tatemichi.5 age  40 years MMS  15 (acute stage) Andersen. 2004 12 196 First-ever ischemic stroke. 1996 3 110 First-ever ischemic stroke NINDS-AIREN 13.1.2 years Rasquin.2 196 . Section 3: Diagnostics and syndromes Table 13. References of the studies cited in this table can be found in Leys et al. 2001 24 202 Stroke. 2004 6 146 First-ever ischemic stroke. age: DSM III 31. 2004 3 75 Ischemic stroke associated Clinical 13. age  55 DSM IV 27. 1st author. 2004 3 280 Stroke.3 years Barba. 1998 12 339 Stroke Proxy-informant 16.3 years opinion Andersen. age  40 years ICD-10 21. DSM IV 8.6 Pohjasvaara. 1996 6 220 First-ever stroke. age  40 years ICD-10 19. age: Mattis Dementia 26.0 Hénon. age: Mattis Dementia 32. 7. 50] congestive heart failure. This table between these disorders and dementia does not mean includes only determinants of dementia after stroke that have been found in at least two independent studies or identified a causal relationship: it is also possible that dementia recently. myocardial infarction. are associated with an Epileptic seizures [33] increased risk of dementia after stroke [5]. atrial fibrillation. Location of the cerebral lesions even after exclusion of patients who had pre-stroke Supra-tentorial lesions cognitive impairment [5]. Global cerebral atrophy is associated with a higher Stroke characteristics risk of dementia after stroke [5]. because smoking influences mor- Increasing age tality and stroke recurrence. Their Sepsis influence is more important when the follow-up is longer: in the Lille study. A few determinants may not have been confirmed increases the risk of such events [5].e. 197 but there are many potential confounders. often because of lack of statistical power. cerebral infarcts seen on CT or MRI scans that have never been associated with a Hypoxic-ischemic disorders relevant neurological deficit. such as . Stroke patients with associated silent infarcts seem to have Global cerebral atrophy a steeper decline in cognitive function than those Medial temporal lobe atrophy [36] without. The influence of hyperlipidemia. but this decline might be confined to those Leukoaraiosis with additional silent infarcts after base-line. 36]. teinemia. Vascular risk factors Diabetes mellitus Atrial fibrillation Pre-existing silent brain lesions Myocardial infarction in stroke patients ApoE4 genotype [34] Silent infarcts. but not after 1 or 6 months [35]. Medial temporal Stroke severity lobe atrophy (MTLA) is more frequent in stroke More severe clinical deficit at onset patients who have pre-existing dementia but it may Stroke recurrence also be present in non-demented stroke patients. sepsis. Stroke patients with MTLA may have pre-clinical AD that is clinically revealed by Left hemispheric lesions stroke [5. Pre-stroke dependency Risk factors for dementia after stroke include Dependency increasing age. low education level. silent infarcts were associ- Cardiac arrhythmias ated with dementia after stroke at year 3 [25] but not Congestive heart failure at year 2 and in the Maastricht study silent infarcts Silent brain lesions were independently related to dementia after 12 Silent infarcts months. The Demographic and medical characteristics of the patient results concerning cigarette smoking should be inter- Demographic variables preted with caution. hyperhomocys- References to the studies cited in this table and published before 30 April 2005 can be found in Leys et al. diabetes Pre-stroke cognitive decline mellitus. Determinants of dementia after stroke. ApoE4 genotype is associated with an increased risk of dementia after Low education level stroke [34]. However. in other studies. i. [5]. Chapter 13: Stroke and dementia Table 13. MTLA clearly differentiates demented from non- Stroke volume [50] demented patients after a first-ever ischemic stroke. alcohol consumption and cigarette smoking on dementia after stroke remains unproven [5]. epileptic seizures. MTLA is not specific for Anterior and posterior cerebral artery territory infarcts AD. Strategic infarcts The presence and severity of leukoaraiosis are Multiple lesions independent predictors of dementia after stroke [5]. cardiac arrhythmias and Pre-stroke cognitive decline without dementia [32.2. as it has also been observed in VaD [5]. e. at onset is associated with a higher risk of dementia but in one [40] the study population was at least after stroke [5]. “Strategic infarcts” may lead tematically addressed. (ii) lacunar infarcts.3). lesions. However. However.g. differences in survival were more cognitively impaired at the acute stage. i. impaired immediately ated with more severe deficits. thalami. AD and mixed AD-VaD [5]. Previous stroke and stroke recurrence In many other circumstances dementia is the con- are also associated with a higher risk of dementia after sequence of the coexistence of Alzheimer and vascular stroke [5]. (iii) when a specific vascular stroke when they survive [5]. and rates between stroke subtypes make the results diffi. required to induce dementia [7]: when a stroke occurs tia on their own in the absence of any other lesion. The most frequent causes of dementia after stroke are VaD. inferomesial temporal and mesiofron. These results are influenced ted just after stroke. cases [5]. AD and mixed AD-VaD account for 19% to 61% of patients with Stroke characteristics dementia after stroke (Table 13. which is more frequent in lesions and coexisting AD cannot be excluded in most stroke patients with leukoaraiosis [5]. which are the less specific [41]. and patients are not influenced by the type of stroke (ischemic or who were lost to follow-up at the 3-month evaluation hemorrhagic) [5]. left hemispheric lesions. which share a single case reports. [37] and in patients with VaD. caudate These concepts of mixed dementia emphasize the fact . Two Asian studies Most studies found that a more severe clinical deficit did not confirm this high proportion of AD patients. tal locations. more frequent in patients with nuclei) were described more than 20 years ago. such as silent infarcts. the question of their influence on Stroke characteristics. to dementia on their own in the absence of any Pre-existing silent brain lesions in stroke patients. strategic locations (left [7]. artery infarcts. the risk tia after stroke: (i) in stroke patients who are too of dementia after stroke was lower in patients with young to have Alzheimer lesions. In other studies. dementia [39]. that appears several months or years after stroke. or (iv) between a higher stroke volume and the risk of when the lesion is located in a strategic area. and became demen- small-vessel disease [5]. multiple infarcts and so-called “strategic association may reach the threshold of brain lesions infarcts”. other lesion. the clinical onset of AD may therefore be anticipated ent studies [5]. (ii) when cognitive functions by the higher mortality rate in stroke subtypes associ. and did not worsen over time. medial temporal lobe atrophy and leukoaraiosis. in the other [21] the diagnosis of VaD was based on the cult to interpret. such as severity of the clinical deficit or stroke localization. in leukoaraiosis. influence the risk of the risk of post-stroke dementia has never been sys- dementia after stroke. or in small series. in stroke patients after. global cerebral atrophy. In the Framingham study large. this concept should be revisited Microbleeds are frequent in stroke patients and in large prospective studies. The risk of dementia and its severity 10 years younger than in all other studies. usually without common pathogenesis with leukoaraiosis. or even slightly who are the most likely to develop dementia after improved over time. with MRI and a follow-up especially those with intracerebral arteriolopathies long enough to exclude associated AD [5].e. are associated with a higher risk of dementia after Causes of post-stroke dementia stroke. A study where stroke condition known to cause stroke and dementia (e. left capsular genu. i. Therefore. were normal before stroke. and without follow-up [5]. have been found to be associated with an increased the period of pre-clinical AD may be shortened and risk of dementia after stroke in at least two independ. Other vascular brain (iii) stroke recurrence. Patients usually have a clinical presentation of AD 198 angular gyrus. and to a lower degree AD [38]. Supratentorial lesions. their infarcts. cerebral infarcts that may lead to demen. lacunar infarcts and infarcts of In the following circumstances vascular lesions are unknown origin were associated with a higher risk the most prominent or only determinants of demen- of dementia after stroke [29]. DSM IV criteria. Section 3: Diagnostics and syndromes (i) cerebral atrophy. Even when vascular lesions or Alzheimer path- anterior and posterior cerebral artery territory ology do not lead to dementia by themselves. volumes were evaluated showed a relationship CADASIL) is proven by a specific marker. in a patient with asymptomatic Alzheimer pathology. and MRI. However. independently of age and co-morbidities tion. as it is associated with an increased 199 shown that stroke patients with dementia after stroke risk of stroke recurrence [25]. AD. The hypothesis of adjustment for demographic factors. Studies are classified by increasing duration of follow-up. 2004 120 – Community 51 – 37 Notes: *In months unless specified. 43]. in substudy showing that nitrendipine decreases the the presence of dementia. that those patients have two disorders and should be have higher mortality rates than non-demented stroke treated for AD and receive appropriate stroke preven. Chapter 13: Stroke and dementia Table 13. 46–48]. Even when vascular lesions or Alzheimer pathology do Stroke recurrence not lead to dementia on their own. associated car- a possible summation of lesions is supported by the diac diseases. those with brain infarcts had poorer overall mortality rate in patients with dementia. vascular dementia. 2004 3 280 Hospital 98 – 2 Kokmen. [5]. 1992 3 251 Hospital 56 36 – Pohjasvaara. patients receive less incidence rate of AD [44]. VaD. Stroke patients prevention reduces the risk of new-onset AD. The long-term mortality rate after stroke is may lead to an underestimation of the need for sec. 1996 12 – Community – 41 – Hénon. their summa. Considering those patients as having pure AD [45]. Leukoaraiosis could also be a con- Both population. Frequently dementia is the consequence of the coexistence of Alzheimer and vascular lesions. patients. The same study may appear several times in this table if several assessments were performed at different time intervals. References to the studies cited in this table can be found in Leys et al. stroke severity and stroke recurrence results of the Optima and the Nun studies. ated with a 3-fold increased risk of stroke recurrence [49]. a cognitive functions before death and a higher preva. Dementia may be a marker for a more severe Influence of dementia vascular disease leading to an increased risk of recur- on stroke outcome rence [5]. 3 337 Hospital 81 19 – 1998 Desmond. Alzheimer’s disease. . 2–6-fold higher in patients with dementia. year Follow-up after Number of Study VaD (%) AD (%) AD + VaD (%) stroke* patients** population Tatemichi.3. with dementia may also be less compliant for stroke prevention.and hospital-based studies have founding factor. This hypothesis was also risk of any nonspecific complication in patients supported by the results of the Syst-Eur dementia with dementia [5]. showing [27. after ondary stroke prevention measures. 1990 7–10 days 726 Hospital 39 36 25 Tatemichi. Dementia diagnosed 3 months after stroke is associ- tion might induce dementia. more severe underlying vascular disease or a higher lence of dementia [42. 2001 36 202 Hospital 67 33 – Zhu. It is also possible that. 2000 3 453 Hospital 57 39 – Barba. Causes of new-onset dementia after stroke. This increase in mortality rate in stroke that amongst patients who met neuropathological patients with dementia may be due to the increased criteria for AD. **available only for hospital-based studies. 2000 3 251 Hospital 75 25 – Tang. Author. suggesting that stroke appropriate stroke prevention [5]. 2000 36 – Community 100 – – Ivan. Less intensive stroke prevention and lack of compliance may contribute to the increased risk of Mortality recurrence [49]. 200 peutic approaches. 1. epileptic seizures. location and recurrence. silent cerebral tia after stroke [5]. on functional outcome after stroke suggest that stroke patients with dementia are more impaired and more dependent in daily living activities than stroke Chapter Summary patients without dementia [5]. In the absence of studies specifically Dementia in stroke patients may be due to vascular designed for stroke patients with dementia. PSD does not require specific treatment. Henon H. low education level. mately 30% and the incidence of new-onset demen- tia after stroke increases from 7% after 1 year. Section 3: Diagnostics and syndromes Functional outcome the burden of dementia after stroke at the community level. Pasquier F. J Neurol ary stage of dementia after stroke. Wolf PA. Leys D. and are more often functionally is not addressed in any guidelines. Leys D. Seshadri S. tional impairment. The proportion of but we should bear in mind that the specific issue of patients with presumed Alzheimer’s disease amongst those with dementia after stroke varies between 19% secondary prevention of stroke in patients with and 61%. symptomatic approach to the dementia syndrome is necessary. Lancet 1999. The risk of dementia is Treatments of stroke doubled after stroke. Other epidemiological studies are Pasquier F. delineation of the concept of post-stroke cognitive Influence of cognitive impairment on the decline without dementia. 5. atrial fibrillation. patients. 6:1106–14. Poststroke dementia. white matter changes guidelines for stroke prevention should be applied. The 2005 Thomas Willis Lecture: stroke and vascular cognitive impairment: a transdisciplinary. matic management of prevailing symptoms. Mackowiak-Cordoliani MA. 354:1457–63. pre-stroke cognitive decline without may help in determining how acute stroke therapy dementia. . 2. Stroke-related variables treatment. Hankey GJ. infarcts. Research should now focus on a 4. but prag- translational and transactional approach. Henon H. the increase in stroke recurrence and with higher prevalence of dementia in stroke survivors is approxi- mortality. global and medial temporal lobe atrophy PSD is not a specific entity that requires a specific and white matter changes. congestive heart failure. Alzheimer pathology. more recurrences and more func. 38:1396. Hachinski V. Lancet Neurol 2007. cardiac patients who are demented before or develop demen. Lifetime risk of stroke and Conclusions dementia: current concepts. also necessary to evaluate the evolution over time of 4:752–9. institutionalisation rate 3 years after a stroke. Patient-related variables associ- in patients with dementia ated with an increased risk of dementia after stroke are increasing age. Patients with dementia after stroke are associated with an increased risk of dementia after patients with dementia and they are also stroke stroke are severity. Accordingly. and both conditions show References improvement under cholinesterase inhibitors [5]. Recognition of dementia in stroke patients is impor- 3. or a summation of these lesions. and effects on mortality rates. sepsis. Dementia is one of the major causes of dependency Dementia after stroke is associated with a 3-fold in stroke patients. Treatment and secondary tant because it indicates a worse outcome with higher prevention of stroke: evidence. myo- and stroke prevention should be conducted in cardial infarction. Both AD and VaD share a cholinergic deficit. In community-based studies. dependency There are no data in randomized clinical trials that before stroke. Lancet Neurol 2005. Stroke 2007. VaD or mixed AD-VaD). Rousseaux M. and estimates from the Framingham Study. Warlow CP. and be a better target for thera. individuals and populations. which may be a prelimin. be much more Neurosurg Psychiatry 2007. costs. in order to have better knowledge of the need in The few available data on the influence of dementia terms of resources and its evolution over time. Pasquini M. arrhythmias. diabetes mellitus. volume. depending on the presumed cause (AD. frequent in practice. Stroke patients with dementia have higher dementia (either pre-existing or new-onset dementia) mortality rates. a impaired. up to almost 50% after 25 years. 78:56–9. current lesions. stroke. et al. Kalaria R. Factors associated with pre-stroke Leys D. Rothwell PM. et al. 67:742–8. Association of stroke with after first ischemic stroke? Stroke 1996. case-fatality. Change in older stroke survivors without dementia. Derambure P. et al. Peres K. del Mar Morin M. J Neurol Neurosurg 32. Why are stroke patients prone to Beard CM. Kenny R. Fratiglioni L. stroke. Dementia in 21. Jin YP. Tatemichi TK. Pera J. informant interview method in a hospital-based stroke Vascular dementia: diagnostic criteria for research registry. et al. Stephens S. Pasquier F. Tatemichi TK. Frequency and subjects aged 75 years or over within the PAQUID determinants of poststroke dementia in Chinese. Beiser A. Zonderman AB. Clinical Incidence of dementia after ischemic stroke: results of and radiological determinants of prestroke cognitive a longitudinal study. Szczudlik A. et al. Skoog I. O’Brien R. Hachinski V. Baseline frequency. O’Brien J. Di Legge S. of dementia. Demographic and CT scan 201 cohort. determinants of prestroke dementia in a Chinese Lousberg R. Barba R. et al. J Neurol 2004. Di Piero V. Incidence and (Oxford Vascular Study). 67:1363–9. associated factors. Gamaldo A. Whisnant JP. Stroke 1997. Slowik A. severity. Dement Stroke 2004. Dziedzic T. brain infarctions predict the development of dementia Winblad B. J Neurol 2004. Fagerberg B. Paik M. Stroke 2002. 251:599–603. Delayed 12. Pasquier F. Henon H. Kokmen E. features related to cognitive impairment in the first . Polczyk R. Lebert F. Ukraintseva S. 78:514–6. Stern Y. Neurology Cognitive impairment and dementia 20 months after 2001. Helmer C. Stroke. et al. Seshadri S. 11:216–24. Pasquier F. 33:2254–60. 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Leukoaraiosis more than dementia is a predictor of 61:343–8. 34:2935–40. 33:1993–8. Gold G. J Neurol Neurosurg Psychiatry 2004. This remain unknown. About 50% of strokes. However. as does the incidence rate of ischemic Stroke is a major public health issue because of its stroke in other age categories. and on the other hand a disorder that is not Cerebral ischemia occurring during pregnancy too rare. ever. The clinical Diagnostic work-up deficits and acute management have no specificity in The diagnostic work-up should not differ from that of young people. The main specificities of ischemic strokes in young patients are their causes. million inhabitants. continuous ECG used upper age limit is 45 years. based estimates of the incidence of stroke in Most strokes occurring in young patients are ischemic children. such as ather. Chapter 14 Ischemic stroke in the young and in children Didier Leys and Valeria Caso Introduction incidence remains stable over time and does not decline. their outcome and the pos. atrial fibrillation and lipohyalinosis. The incidence is high frequency.3 to 13. are very be detailed in this chapter. same rules as in older patients. including hemorrhagic strokes.0 per 100 000 children [12]. The incidence of ischemic strokes increases requires the same diagnostic work-up as in non- with age even in young people: most young people pregnant women. Therapeutic options should therefore take into account the presumed cause. similar to that observed in non- of 75 years in Western countries [4–6]. with a from community. Cervical and transcranial upper thresholds can be found in the literature. higher incidence in boys [12]. i. the incidence of of recurrent vascular events that may be cerebral or ischemic strokes during pregnancy is about 43 per cardiac [1–3]. and the risk populations [4]. older patients except for the search for a cause. the natural history of the disease and the long life expectancy. MRI is the investigation with stroke are between 40 and 45 years of age [7]. They account for from 2 to 12% of all 2. of choice over CT and percutaneous angiography. transthoracic and transesophageal echo- good compromise between an age category where cardiography should be performed according to the common causes of cerebral ischemia. In young women. Population- occur in younger patients. Three for this age category [13]. The incidence of ischemic stroke in young people although its safety profile for the fetus has never varies between 60 and 200 new cases per year per been evaluated. Although strokes occur at a mean age million deliveries. 9].or hospital-based data [8. depending on whether figures are provided incident strokes in children are ischemic. . rare. the risk of death and residual physical higher in non-industrialized countries and in black cognitive or behavioral impairments. The incidence of ischemic stroke in young people sibility of occurring during pregnancy. although they are not specific Figures depend on the definition of “young”.e. magnetic resonance angiography of 30. Gadolinium enhancement is. varies between 60 and 200 new cases per year per ficities may influence the management of patients. and even in children [4–7]. These speci. range from in origin. 45 and 55 years of age. and will therefore not be addressed. and will therefore not oma. depending on the charac. not recommended as its effects on the fetus 203 teristics of the population and the age limit. The most frequently cervical and intracranial arteries. at ultrasounds. It constitutes a monitoring. The same principles as those detailed in the recommenda- tions of the European Stroke Organisation are also Epidemiology valid in young people. how- million inhabitants [10]. they may also pregnant women of similar age [11]. oral or genital cholesterol and triglyceride levels. as CADASIL) should lead to a search for lupus family history of migraine with aura. unexplained fever. fibrinogen. protein C. so-called Degos disease) Diagnostic work-up must include a large variety livedo racemosa (in favor of Sneddon disease) of symptoms and careful examination of other 204 neurofibromas and “taches café-au-lait” (in favor of systems (skin. varicose veins. the same biological work-up as in photosensitivity. papulosis (in favour of malignant atrophic papulosis. older patients: blood cell count. anemia. proteinuria (in favor of cerebral protein vasculitis) in selected patients in the absence of a clearly family history of ischemic stroke occurring in identified cause of cerebral ischemia: young patients (in favor of genetic causes. erythrocyte aphthosis. . sary. It should focus on the following features: Fundoscopic examination presence of cervical pain or headache that may Fundoscopic examination is necessary. a specific etiology of cerebral ischemia. with the patient and close relatives. It should be repeated. The biological work-up should include: or suggestive clinical features such as in all patients. pericarditis. but these causes features of abnormal skin elasticity. abnormal scars (in favor ischemia except in the case of cerebral venous of Ehlers-Danlos disease) thrombosis. It should be performed with the patient naked. antithrombin III. mutation of factor V Leiden. repetitive spontaneous miscarriage. false positivity of syphilitic serology. or systemic disorder  search for congenital thrombophilia in the Skin examination presence of personal or family history of Skin examination is an important step in the search for a multiple venous thrombosis (proteins C and S. such  activated cephalin time (when increased. toxic angiopathies) history of migraine with aura (in favor of migrainous infarct) The biological work-up history of definite systemic inflammatory disorder. deep venous thrombosis. severe anticoagulant) depression or dementia occurring in young patients  serology for syphilis and human (in favor of CADASIL) immunodeficiency virus personal history of irradiation (in favor of  electrophoresis of proteins post-irradiation arteriopathy)  dosage of antiphospholipid antibodies in the any medical history that may orient towards case of multiple spontaneous miscarriages. the potential cause of cerebral ischemia. resistance to activated and requires the advice of a dermatologist when neces. cause. of thrombophilia are rarely causes of cerebral spontaneous ecchymosis. sedimentation rate. Section 3: Diagnostics and syndromes The patient interview angiokeratomas (in favor of Fabry disease) facial lentiginosis (possibly associated with cardiac The patient interview can provide information on myxoma). arthritis. pleuritis. retina) as well as a search for systemic von Recklinghausen disease) diseases. The examination should focus on the search for: mutation of thrombin gene). glucose level. as it may have occurred before stroke (in favor of a identify signs of: dissection) hypertensive retinopathy presence of pulsatile tinnitus (in favor of a dissection) cholesterol emboli recent intake of illicit substances (in favor of toxic perivascular retinitis (in favor of Eales’ syndrome) angiopathies) multiple retinal ischemia (in favor of Susac’s recent intake of vasoconstrictive drugs (in favor of syndrome). and C-reactive thrombopenia. Cardioembolism or an underlying cardiopathy. the search for paroxysmal detail. and an overall favorable outcome.1. Most studies were con- Atrial fibrillation is associated with a very low risk of ducted in too small cohorts. 20. or logies depending on the centers and countries where vascular risk factors or previous systemic emboli the data are collected [7. cardioembolism and small-vessel occlusion) are rare in young patients. suggesting a genetic predisposition [27]. Chapter 14: Ischemic stroke in the young and in children Table 14. paradoxical emboli through a PFO or interatrial communication The main differences between ischemic strokes congenital cardiopathies with cyanosis occurring in young adults and children and those occurring later in life are the breakdown of causes. The most frequent cause in Western countries acute myocardial infarction is cervical artery dissection. atrial fibrillation by endovascular stimulation pro- vided results that are difficult to interpret in the Atrial fibrillation absence of reliable controls. aortic stenosis and is found mainly in men between 40 and 45 years of age. isolated PFO risk factors for stroke. and a family history is frequent. the cause of cerebral mitral stenosis ischemia remains undetermined in up to 45% of mechanical prosthetic valve patients [7. it may be at risk. 14. In this chapter we present ventricular akinesia the etiologies according to the TOAST classification dilated cardiomyopathy [26] although the first three categories (large-vessel intracardiac tumor (myxoma. infectious endocarditis even in specialized centers it may happen that the diagnostic work-up is negative because it is not exten. Main cardiac sources of cerebral ischemia in Causes of ischemic strokes young adults. 23–25]. such as patients with interatrioseptal 205 confers a high risk of cerebral emboli when there are abnormalities [28]. papillary fibroelastoma) atherosclerosis. Despite an extensive diagnostic work-up. Depending on how exhaustive the diagnostic Low-risk cardiopathies work-up is. in the young High-risk cardiopathies There are huge differences in the breakdown of etio- atrial fibrillation associated with cardiopathy. Atherosclerosis has no specificity concerning bicuspid aortic valve the clinical presentation. and in non-industrialized countries valvulopathies. marastic endocarditis sive enough or is performed too late after the onset intracardiac thrombus [24]. and lack statistical power. 8. 15. However. diagnosis or predisposing Lambl excrescence factors. In the absence of evidence of are listed in Table 14. especially high blood pressure. A few of them deserve more atrial fibrillation on ECG. even in subgroups that fibrillation) and of vascular risk factors. such as mitral stenosis The main causes of cardioembolism in young patients or cardiomyopathy. cerebral emboli in young people when occurring in The question of whether endovascular stimulation is the absence of underlying cardiopathy (lone atrial useful remains unresolved. Smoking is a major risk factor in this age isolated IASA category. mitral valve prolapse Large-vessel atherosclerosis mitral calcification Large-vessel atherosclerosis accounts for less than bioprosthesis 10% of cerebral ischemia before the age of 45 years. 10. complication of catheterism and cardiac surgery mined” causes. IASA plus PFO with a prominence of “unknown" and “other deter. up to 50% of patients have no clearly lone atrial fibrillation identified cause. 19. However. 10. 8. 14–23].1. . Ischemic stroke Interatrioseptal aneurysm is a protrusion of the patients with coexistence of PFO and IASA have a interatrial septum in either atrium. It is rare in the higher risk of recurrence and are eligible for clinical absence of PFO [32]. isolated IASA. Valsalva maneuver).2% (95% CI 1. IASA is coagulant or antiplatelet therapy. . sometimes the cause of risk of recurrence under aspirin [32]. of recurrent strokes was 15. It may be familial. PFO Figure 14. which is a rare dis. transthoracic echocardio- graphy (TTE) and transesophageal echocardiography (TEE) may reveal vegetations. after 4 years of follow-up.3–4. Diagnostic criteria are. The association of PFO and IASA (Figure 14. in most cases. a marker of the pres. the rate arteriovenous malformation. A causal rela- tionship will be proven only if ongoing trials aiming at the closure of PFO show a clear reduction in the Associated PFO and IASA risk of recurrence after closure. When there is a causal relationship. almost never proven) or paroxysmal atrial fibrillation Paroxysmal atrial fibrillation and local thrombosis [28]. mic stroke of unknown cause is a marker of increased ence of a PFO. pulmonary embolism and cere. pulmonary embolism. 30].2-fold increased risk Interatrioseptal aneurysm (IASA) of recurrence (95% CI 1. and 0. However.1) in left shunt by transcranial Doppler with contrast patients aged 55 years or less who have had an ische- enhancement is.2% (95% confidence inter- order that occurs mainly in patients with Rendu. these investigations should be repeated. 4.1.6%) in patients with PFO and IASA.3% (95% CI 0. or foramen ovale and an interatrioseptal aneurysm. local absence of associated PFO. However. Evidence of a shunt without whereas it was only 2. the presence of an IASA is thrombosis in the PFO (most likely hypothesis but not a marker of increased risk of recurrence [32]. of similar age who have no PFO [32].g.8). PFO consists of a communication between right and left atrium which becomes functional when the pressure in the right atrium becomes higher than in the left one (e. At an early stage. val [CI] 1.0% in those with Chapter 9). ischemic stroke of unknown cause [30].8–6. possible mechanisms of cerebral ischemia are paradoxical emboli (requiring deep more frequent in young patients who have had an venous thrombosis. Therefore the coexistence of PFO and IASA is associated with a 4. Section 3: Diagnostics and syndromes Infectious endocarditis Infectious endocarditis is not always associated with fever.6%) in for pulmonary arteriovenous malformation (see those without PFO and IASA. and efficacy of closure of PFO compared with anti- traction. In the FOP- the right-to-left shunt is not a PFO but a pulmonary ASIA study [32]. but. Patent foramen ovale (PFO) Patent foramen ovale is present in 10 to 20% of young patients with cerebral ischemia [29. on TEE. Evidence of a right-to. The risk of recurrence after a first ischemic stroke in the presence of an isolated PFO The association of a patent foramen ovale and an interatrioseptal aneurysm is a marker of an does not differ from that in ischemic stroke patients increased risk of recurrence.8–28. the presence of a PFO is frequent in the IASA are the most likely mechanisms of cere- in practice and the causal relationship is unlikely in bral ischemia when a causal relationship exists. randomized trials aiming at evaluating the safety 206 an excursion of 10 mm or more during cardiac con. transcranial Doppler with contrast. in the bral ischemia without other potential cause).5–11. Transesophageal echography showing a patent may be diagnosed by TTE or TEE with contrast. and a base of at least 15 mm [32]. When negative.3%) in those evidence of a PFO should therefore lead to a search with isolated PFO. Osler-Weber disease. especially in women [31]. many patients. 37]. CADASIL quent intracardiac tumour. The clin- ical presentation is that of a cardiac failure [35]. Papillary fibroelastoma Papillary fibroelastoma is a benign tumor which Other definite causes of cerebral ischemia is usually located on a cardiac valve and is difficult These are actually the most frequent causes of cere.3) and genetic criteria [36. They are the consequence of the occlusion of a single deep perforating intracerebral artery of less than 400 µm in diameter. Chapter 14: Ischemic stroke in the young and in children Peripartum cardiomyopathies Peripartum cardiomyopathies are very rare in Western countries but are reported quite frequently in sub-Saharan countries during the last month of pregnancy and the post-partum period [34]. However. Mitral valve prolapse Lipohyalinosis of the deep perforators Mitral valve prolapse is a protrusion of one or two Arterial hypertension is the most important risk mitral valves in the left atrium.2) is the most fre- (Figure 14. remain asymptomatic and are revealed by an ischemic White matter changes are always already severe on stroke. Its prevalence is 10 per is due to a mutation of the Notch3 gene on chromo- million inhabitants and it is usually located in the left some 19 [36]. found in 2–6% of factor for lipohyalinosis of the deep perforators. 20 years after the first symptoms (see Chapter 9) [37]. The risk of cerebral emboli in patients with mitral valve pro- lapse is very low except in the case of associated atrial CADASIL fibrillation or endocarditis. MRI Intracardiac myxoma (Figure 14. and sion. The presence of facial lentiginosis (a rare auto- MRI when the first symptoms occur. sometimes cardiac signs such as dyspnea. CADASIL is associated with migraine with aura.2. but people in the community [33]. The short-term outcome is usually good. 207 to distinguish from vegetations. CADASIL (Cerebral Autosomal Dominant Arterio- pathy with Subcortical Infarcts and Leukoencephalo- Intracardiac myxoma pathy) is a genetic disorder of small deep perforating arteries identified on the basis of clinical. diagnostic such hypertensive arteriolopathies are very rare criteria often lacked precision in studies and its role in before the age of 45 years. bral ischemia when a cause can be identified. Transesophageal echography showing a left atrial myxoma (arrow). but the risk is cognitive decline and dementia in the event of recurrences. murmur depression. basal ganglia and brainstem. . weight loss. Small-vessel occlusion Lacunar infarcts are small infarcts of less than 15 mm located in the deep white matter. In less than 50% of cases it leads to systemic of small perforators leading to a progressive occlu- emboli associated with fatigue. often associated with cerebral emboli [35]. fever. This dis- order is multifactorial and is associated with a high case-fatality rate. 37]. leading to an accumulation in the wall atrium. multiple subcortical infarcts and. leading to death within myxoma. Most myxomas end-stage. cerebral ischemia remains very controversial. usually during somal dominant disorder) may be associated with a the third decade of life [37]. dementia with pseudobulbar palsy [36. These perforators have no collaterals and their occlusion always leads to an Figure 14. infarct. at the or variations in blood pressure. 39]. 41] or to irradiation. especially when diagnosis should be possible using exclusively located in the vertebrobasilar territory. The outcome is usually more a trivial trauma of daily life [7] occurring on an dependent on the underlying disorder that led artery prone to dissect for genetic [40. Patients always have radiodermitis relationship between a trivial trauma and in the area of irradiation. Section 3: Diagnostics and syndromes Figure 14. It may be found in patients with von they occur. being able to show the mural hematoma [38. and less frequently to identified. both techniques exist. Recurrences of stroke and of dissections are rare  Intracranial dissections are very rare and difficult [38. The arterial lesion is dissection is even disputable [38. but may also lead severe at the acute stage [38. Figure 14. irradiation being a local factor in likely hypothesis to explain most cases is that of atheroma. Nowadays the to subarachnoid hemorrhage. or the trauma is mild and a causal throat cancers. if they ultrasonography and MRI. Angiography 208 countries and is usually associated with a good shows a tight stenosis or occlusion of the outcome in patients who survive the acute stage. It can be isolated associations with intracranial aneurysms and cases or associated with other locations such as renal occurring in the same family are rare but. especially in asymptomatic cases [43]. Diseases of large arteries  Cervical artery dissections are the leading cause of cerebral ischemia in the young in Western  Post-irradiation cervical arteriopathies in young countries when a cause can be clearly identified persons are often due to irradiation for [7. disorders. They may occur in children. Inherited elastic tissue per se. The most atheroma. especially Doppler prognosis is usually poor but benign cases. MRI of an internal carotid artery dissection. Recklinghausen disease or elastic tissue disorder. are in favor of elastic tissue disorder. 39]. intracranial carotid arteries associated with . hemorrhage. are often considered excellent except when stroke was revealed by cerebral ischemia. or both.3.4. The except in the case of dissection. In most cases no trauma can be hematological disorders. Brain MRI of a CADASIL patient showing severe white matter abnormalities and lacunas. Figure 14. when arteries. especially Ehler-Danlos type IV. 39]  Moyamoya disease is a progressive intracranial (see Chapter 9.4). vasculopathy that usually becomes symptomatic Cervical artery dissection is the leading cause in children or young adults and may lead to of cerebral ischemia in young adults in Western ischemia. may remain undiagnosed. 39]. showing the mural hematoma (arrow). and the overall outcome can be to diagnose. Their non-invasive investigations. 38]. than on irradiation arteriopathy infectious reasons [42].  Cervical fibromuscular dysplasia of cervical arteries predispose to dissections but they are rare and is associated with a low risk of ischemic stroke probably underdiagnosed in practice.  Acute multifocal placoid pigment epitheliopathy is a bilateral primary disorder that may rarely be associated with cerebral vasculitis and lead to permanent visual deficits Figure 14. cryptococcosis. Any corticosteroids and immunosuppressant disorder that can lead to progressive stenosis or therapy are recommended [44]. Behcet syndrome. depending non-infectious vasculitis with giant cells.).  Secondary vasculitis occurring in a context of or be the first manifestation. sarcoidosis) or The incidence is approximately 2. Conventional angiography of moyamoya (arrow) [44]. etc. HIV.  Buerger disease. occlusion of intracranial carotid arteries in  Köhlmeier-Degos disease (or malignant children or in young adults may be a cause of atrophic papulosis) is a systemic vasculitis that moyamoya. parasites systemic lupus erythematosus. is a segmental inflammatory vasculitis involving arteries of intermediate and small calibers and also superficial veins. predominantly involves the skin. The causal relationship with cerebral ischemia is uncertain. infectious disorder. cysticercosis.g. Churg-Strauss syndrome. which may exceptionally involve cerebral arteries. Cerebral ischemia may be due to associated with hemorrhages. etc. The first  Takayasu disease is a chronic inflammatory symptom is usually headache. etc. usually not the most prominent feature tuberculosis. viral infections (panarteritis nodosa. Such vasculitis may occur in a vasculitis involving the brain or the bowel. (ophthalmic herpes zoster. either a to the leptomeningeal and cerebral arteries [45].) or mycotic infections syndrome. restricted on the type of systemic disorder. and seizures [45]. The diagnosis is based on evidence of specific lesions at fundoscopy and inflammatory CSF.4 new cases per association of diagnostic criteria (e. Crohn disease. sarcoidosis. Chapter 14: Ischemic stroke in the young and in children cervical arteries when they arise from the aortic arch. candidosis. Sjögren (malaria. This is usually a disorder involving peripheral arteries. sometimes and the brachiocephalic arteries. Fever is possible. Lyme disease. It occurs transient. They occur in lupus erythematosus). neuropathological proof (e. ulcerative rectocolitis) are  Primary vasculitis of the central nervous system is usually diagnosed on the basis of other granulomatous inflammatory non-sarcoidosic manifestations of the disease and. followed by disease that progressively involves the aorta subacute focal neurological deficits.5.).  Eales disease is an inflammatory vasculitis that involves predominantly retinal arteries and very rarely cerebral arteries.g. patient whose systemic disorder is already known. systemic year per million inhabitants [45]. both genders around 40 years of age. The clinical picture is that of decreased with distal occlusion of the internal carotid artery.). so-called thromboangiitis obliterans. visual acuity and fever. Intravenous intracerebral neo-vessels (Figure 14. etc. Cerebral infarcts are predominantly in women before 45 years of usually multiple. progressive stenosis or occlusion of the There is no systemic biological sign of 209 . The severity  Secondary vasculitis occurring in the context of of the disease is due to the consequences of the systemic disorder. (aspergillosis. cortical and sometimes age. Such vasculitis may occur in  Systemic disorders where cerebral vasculitis is patients with bacterial infections (syphilis.5). more prominent in posterior clinical presentation consists of a combination of areas. carcinoid racemosa.6). Each episode is usually of mild presentation and outcome as the post-partum severity but their repetition may lead to dementia. Elevated Liver  Post-partum cerebral angiopathy is a rare entity enzymes. epileptic seizures and between the cortex and the subcortical white focal neurological deficits [46. does not disappear with cutaneous warming. 47]. possible that primary vasculitis of the central nervous system is a heterogeneous entity that actually consists of several subsets of diseases [45]. but in most in large intracranial arteries that disappear patients who survive the acute stage the long-term spontaneously within a few weeks [46. associated. 49]. MRI shows in FLAIR or T2 sequences delivery. Despite a severe clinical presentation. Angiography matter [51. reversible hypertensive ischemia of mild severity preceded by livedo encephalopathies. Antiphospholipid antibodies are usually The clinical presentation consists of headache. multiple hyperintense signals.  Other acute reversible cerebral angiopathies have  Sneddon syndrome is a potential cause of recurrent been reported.6. It might be a variety of toxic  Unruptured aneurysms of intracranial arteries may angiopathy favored by estrogen withdrawal. in the event of failure of treatment. This finding is not specific and the proof of diagnosis is provided by a biopsy of leptomeningeal arteries. be a cause of cerebral ischemia secondary to a the use of vasoconstrictive drugs and possibly local intra-saccular thrombosis and subsequent 210 bromocriptine [46. Low Platelets) is a subtype of eclampsia that occurs usually in the first 2 weeks after [50]. 52]. type. pheochromocytoma. These abnormalities completely (either conventional or preferably magnetic disappear after a few days or weeks. isolated or more the outcome is usually excellent [46. vomiting. dementia and a high mortality rate [45]. 47] outcome is favorable [11]. They have the same clinical cerebral ischemia. It is Figure 14. 47]. . The CSF may be normal. Brain imaging is suggestive when it shows (i) on CT or MRI scans multiple infarcts of small size in cortical areas. In the absence of treatment (corticosteroids sometimes associated with cyclophosphamide for at least 1 year) or. 47].  Eclampsia is the main cause of maternal mortality opposite to the more trivial livedo reticularis. but is usually characterized by an increased number of lymphocytes with or without oligoclonal bands. Post-partum angiopathy: beading (arrows) of cerebral arteries. confusion or coma. Section 3: Diagnostics and syndromes inflammation. distal emboli. the outcome is poor. and (ii) on conventional angiography or MRA multiple beadings in intracranial arteries in various territories [45]. The HELLP syndrome (Hemolysis. illicit substances such as cocaine or young patient has recurrent episodes of cerebral amphetamines). which is a purple livedo. oral anticoagulation is recommended seizures and focal neurological deficits [48. with occurrence of cognitive decline. The frequently confluent. involving the tumors or vasospasm after subarachnoid trunk and the most proximal part of the limbs that hemorrhage. located at the junction severe headache. Although there is not a high level of visual impairment. (Figure 14. with or without associated hemorrhages. frequently bilateral. Cerebral resonance angiography) shows multiple beadings infarcts may lead to residual deficits. by experts. Possible etiologies are toxic (vasoconstrictive This diagnosis should be discussed each time a drugs. and preterm birth in Western countries [48]. epileptic evidence. disseminated intravascular mutation in the mitochondrial DNA. reductase (MTHFR) can be found. unexplained fever. whether it also reduces the rate of vascular  Other hematological causes of cerebral ischemia in events remains to be proven. thrombocytopenia. iron-deficiency  MELAS syndrome (Mitochondrial Encephalopathy anemia. Cerebral infarcts are crisis of painful acroparesthesia of feet and hands. young people are polycythemia. important to recognize such cases C and S.2% in young cerebral ischemia. but Libman-Sachs endocarditis or early atheroma. and later in the manifestations may be the first manifestations of time-course of the disease cardiac and renal the disease [53]. plasma alpha-galactosidase activity or mutation but their role in arterial ischemia remains in the alpha-GAL gene in men. and biological changes such as venous or arterial event during their life. The neurological corneal opacities. and hyperviscosity syndromes. cognitive impairment and storage disease resulting from deficient recurrent episodes of headache and vomiting. The and mutation of the thrombin gene are clearly diagnosis is performed on the basis of a low proven causes of cerebral venous thrombosis. identification of the mutation in women  Acquired thrombophilia: antiphospholipid (see Chapter 9) [55]. The major coagulation. It is more It may be primary or associated with a clearly frequent to find a slight increase in plasma defined systemic disorder such as systemic lupus homocysteine (>15 mmol/l). progressive deafness. cardiopathies pregnancies [12] and prothrombotic state. antibody syndrome. hypohydrosis. but this (Marchiafava-Micheli disease). One-third of patients have a miscarriages. recurrent spontaneous million inhabitants. ischemic stroke patients with a negative diagnostic  Nocturnal paroxysmal hemoglobinuria work-up in a large German study [55]. The frequency of the  Beta thalassemia is also a possible cause of disorder has been found to be 1. mutation of factor V Leiden. Metabolic disorders usually transient and located in posterior  Fabry disease is an X-linked recessive lysosomal territories. which is more a erythematosus. cutaneous angiokeratomas thrombocytopenia and hemolytic anemia with a located in the trunk and proximal part of limbs.  Thrombotic thrombocytopenic purpura Various types of mutation have been identified. false positivity of syphilis A mutation in the gene for methyltetrahydrofolate serology and activated cephalin time increase. search for schizocytes. leukemia. reduces the serum level of homocysteine. Cerebral ischemia may be due factor than a cause. or antithrombin III. in a patient around 30 years of age. Folic acid supplementation to various mechanisms: prothrombotic state. . renal failure.  Congenital thrombophilia: deficits in proteins however. This is a cause of arterial  Homocystinuria has a prevalence of three per and venous occlusions. Strokes are more prominent in the vertebrobasilar  Hemoglobinopathies: territory. negative Coombs test [53]. rate has never been confirmed thereafter. with Lactic Acidosis and Stroke-like episodes) is a hypereosinophilic syndrome. seizures.  Sickle-cell disease is a cause of ischemic stroke occlusions of the deep perforating arteries due to in children and young adults and during the accumulation of sphingolipids. resistance to because of possible therapeutic consequences activated protein C. The possible mechanisms of ischemic stroke are dolichomega intracranial arteries. Ischemic strokes occur during the fourth the determination of platelet count and the decade and are often associated with headache. Chapter 14: Ischemic stroke in the young and in children Hematological diseases A few female cases have been reported [55]. with infusion of alpha-galactosidase [55]. stroke-like episodes. It causes an endothelial Progressive external ophthalmoplegia with ptosis. 211 vasculopathy followed by cerebral ischemia [55]. The diagnosis is made easy by failure. endovascular mitochondriopathy due to several types of lymphoma. (Moschcowitz syndrome) is a systemic disorder The clinical picture associates episodes of characterized by fever. present in most cases [53]. clinical features are. alpha-galactosidase. and only by disputable [54]. thrombocythemia. It is. This relative risk increases in purple skin lesions where a neutrophilic smokers. ischemia may occur but a causal relationship is not proven. Section 3: Diagnostics and syndromes muscular pain at exercise. the presence of a vaginal lesion.3–6. and arthritis [60]. cataract. . seizures and coma.5. hearing loss by other manifestations of the disease. subclavian catheter accidents. diabetes mellitus. Migraine  Kawasaki syndrome is a panarteritis of arteries of Migraine is associated with a relative risk of ischemic 212 intermediate and small caliber that may lead to stroke of 3.9 (95% characterized by multiple pustulae and painful CI 1. the absolute risk is low. Therefore types of ocular inflammation. They are frequent in patients that occurs in one pregnancy in 40 000. Cerebral had a stroke or have other risk factors. or even more in the presence of vascular risk factors.  HERNS syndrome (Hereditary Endotheliopathy with Retinopathy and Stroke) is an autosomal Non-cruoric emboli dominant hereditary syndrome consisting of  Gas emboli occur during cesarean sections. leading to blindness. reaching 6 for migraine with aura [65] coronary or cerebral artery occlusions [61]. nephropathy and ischemic stroke. has been extensive enough and repeated over time. especially those who have already may be associated with cancer [60]. More specific risk factors in the young Rare causes of cerebral ischemia in young people Oral contraceptive therapy of undetermined mechanism Oral contraceptive therapy increases the risk of ische-  Sweet syndrome (acute febrile neutrophilic mic stroke even with compounds with low-dose estro- dermatosis) is a dermatological disorder gens: the relative risk of cerebral ischemia is 2. hypogonadism.  Amniotic emboli occur after difficult deliveries in Sometimes the etiology is found during the follow-up. retinopathy. traumatic deliveries. leading Before classifying a patient in this category it is to death [56]. preceded by severe anxiety and Cerebral ischemia of undetermined dyspnea [56]. The clinical picture consists of acute respiratory failure and acute diffuse encephalopathy. Fundoscopic examination gynecological and cardiac surgery or diving reveals a typical vasculopathy [63]. but the attributable risk is lower Choriocarcinoma is a malignant trophoblastic tumor than in older patients. smoking and hypercholesterolemia) are also risk Choriocarcinoma factors in the young. The patient develops acute pulmonary edema and seizures [11. unknown pathogenesis consisting of a triad hypothyroidism and cardiomyopathy are the with retinal arterial occlusion. As soon as the diagnosis is suspected important to be sure that the diagnostic work-up the patient should be turned onto the left side. conjunctivitis or other cular risk factors treated during 1 year [64]. This dermatological case of cerebral ischemia can be attributed to oral disorder has accompanying features of systemic contraceptive therapy for 5880 women without vas- inflammation such as fever. arterial wall may occur and lead to cerebral ischemia in the absence of metastasis [59]. accidents [56]. mutation (see Chapter 9). 57]. Classic risk factors for stroke (arterial hypertension. presence of ragged red fibers on muscle rare disease occurring in young women of biopsy. oral contraceptive therapy is contraindicated only in It occurs mainly around the age of 40 years and high-risk women.7) [64]. lactic acidosis after  Susac syndrome (or Sicret syndrome) is a exercise. In a few minutes the patient and unknown causes develops tachycardia. Risk factors for stroke in the young  Fat emboli occur in long bone fractures or Classic risk factors liposuction surgery [58]. The diagnosis cochlear ischemia and diffuse vascular needs evidence of the mitochondrial DNA encephalopathy [62]. Lesions of the with a negative diagnostic work-up [7]. However. and one infiltration can be found [60]. many Studies that evaluated the long-term outcome of of them lost their job or divorced during the 3 years young stroke patients are heterogeneous and can after the ischemic stroke [7]. 23. A study per year during the next 2 years. Chapter 14: Ischemic stroke in the young and in children Case–control studies conducted in several countries subarachnoid hemorrhages [10. in the presence of vascular risk factors.5% after 1 year. However. The concept of migrainous infarct is not proven: it requires exclu- Mortality sion of other causes and a typical temporal relation. but depression.4% during the first year then 1. 22.0% supporting this classic statement are scarce. the neurological deficit being a prolongation of a ate term [7. reaching 6 for migraine with aura or even more first year after stroke [7. 71] and even suggest that the association between migraine with sometimes TIA. behavioral changes or alteration in social cognition . Stroke occurring during pregnancy is one of the leading causes of maternal death [68–70]. with a risk at smoking. In the Lille cohort typical aura. Quality of life Outcome Even if most patients remained independent. the mortality rate was 4. reason. In the Lille cohort the risk of recur- risk of ischemic stroke [6. 23. most proof of association. 73. 10. 75] or Similarly. mild cognitive or 213 ing intracerebral ischemia [10. 74]. Moreover. leading to a selection bias towards less severe cases tives compared with those who use low-estrogen oral and better outcomes. 39. There is no convincing evidence on the mechanism that would be implicated. and that of myocar- conducted in high-risk women. had a partial follow-up [15. includ.5. 77]. 38. 10. 0. ence during pregnancy is the breakdown of etiologies. 76. but they depend on the presumed cause of Pregnancy is classically associated with an increased cerebral ischemia. with an important Recurrent vascular events (stroke role of vasculitis and hypercoagulability state [66]. of 287 patients aged between 15 and 45 years. 19. 73]. also associated with a low risk of new events [7. fatigue. A negative diagnostic work-up is periods of subsequent pregnancy. 23. In cervical artery already had an ischemic stroke. of the association among nonusers of oral contracep. 73]. 67]. 78].8% per year HIV infection during the next 2 years [7]. 71. women who have dial infarction 0. Those studies used different age aura and stroke is not an artifact. The mortality rate is low in the short and intermedi- ship. 8. there are few data examining the magnitude included only those who survived the acute stage. The mechanisms of stroke are multiple in HIV-infected patients. 19. young patient than stroke recurrence. 78]. It is less clear whether migraine studies were conducted in small samples. In the absence of a hardly be compared. Most patients had Migraine: the relative risk of ischemic stroke is post-stroke epilepsy and the first seizure during the 3. 32]. and may have suffered recruitment bias in these studies can be considered as providing a definite specialized centers [7. hypercholesterolemia. 15–23. with a mean follow-up of 3 years and none lost to follow-up. contraceptives. were retro- without aura is associated with stroke or whether spective. 72]. excluded recurrent cases [10. i. 25. although none of limits. HIV infection is also associated with an increased risk of ischemic stroke. Epilepsy Epilepsy is more frequent after an ischemic stroke in a Classic risk factors for stroke: arterial hypertension. 19. the association is restricted to migraine with aura. 71. Their findings are influenced systematic evaluation it is difficult to identify the by the inclusion or not of all types of stroke.e. data rent stroke was 1. 25. The main differ. or coronary syndromes) The risk of recurrent vascular events is low in this age Pregnancy category. showed no significant dissections the risk of recurrent stroke is very low increase in incidence of recurrent stroke during [2. 19. 71. 11.2% per year [7]. are rare in non-pregnant women. In children the recurrence rate is higher than in with specific causes described that do not exist or young adults. 3 years between 5 and 7% [7. e. of pregnancy (continue aspirin except during the last 6 weeks. the overall good work-up is negative. As for elderly subjects. the reasons for women (contraception.8% (95% CI 0. an appropriate antithrombotic ther. 7. as well as an extensive evaluation of risk ate antithrombotic therapy and removal of the factors. have no clear cardiac indica- more prone to have seizures. altered mental status tion for clopidogrel and do not develop headache. i. or PFO an ischemic stroke have an overall low risk of recur. cervical artery dissections may consecutive women who had an ischemic stroke be treated either by antiplatelet therapy or by anti- between 15 and 40 years of age and followed-up over coagulation [80]. specific cases (severe internal artery stenosis. years are rather weak. Due to the low risk of recurrence outcome and interference with hormonal life in in patients without any risk factor. patients The mortality rate (4. cardiac New causes should now be identified. The overall management of secondary pre. their causes.and long-term mortality decline in quality of life that is not explained by rates are low. vention is based on principles similar to those in elderly subjects. Therefore young women who have had foramen ovale (PFO) at risk (large PFO. and also dystonia and dyskinesia than adults [12]. Therefore ischemic strokes myxoma.5% at year 5 (95% CI 0. apy will not be recommended when the menopause especially in patients with a negative diagnostic occurs. (iii) patients pregnancies and puerperium. Section 3: Diagnostics and syndromes are likely explanations. 17]. . events is also low. there is no reason to give stroke of 0. (iv) aspirin plus Specificities for children dipyridamole is the standard therapy for patients Besides a higher recurrence rate.95) in periods oral anticoagulation for more than a few weeks or in without pregnancy and 1. For this Secondary prevention measures mainly depend on the presumed cause and consist of an optimal reason. associated with an interatrioseptal aneurism) have a rence during a subsequent pregnancy and do not 4-fold increased risk of recurrence under aspirin. an extensive and early diagnostic work-up is management of vascular risk factors. because of the low rate of recur- a 5-year period found an overall risk of recurrent rence after the 4th week. Conclusion apy (oral anticoagulation and antithrombotic agents The etiologies of ischemic stroke in the young are 214 depending on the cause) and removal of the source in multiple and the outcome is good in most patients. Risk of epilepsy after an ischemic stroke attitude is inappropriate at that time. an optimal management of vas- cular risk factors. An important question that remains unanswered stroke in young adults is how long young patients should receive antiplatelet The main characteristics of ischemic stroke occurring therapy after an ischemic stroke when the diagnostic in young patients.). if there are no new data showing that this work-up.3–0. Stroke prevention measures should in young people are frequently associated with a take into account that short.5% after 1 year) and the risk of should be informed that hormonal replacement ther- recurrent stroke (1. continuing antiplatelet therapy for more than a few pause). i.4% during the first year) are low. children are also who can tolerate aspirin. etc. The specificities of stroke prevention in young adults are the following: (i) oral contraceptive therapy Pregnancy after an ischemic stroke should be avoided in most cases.5–7. Behavioral changes and dystonia women should be informed what to do in the event in children are frequent sequelae. replace oral anticoagulation by subcutaneous Secondary prevention after ischemic heparin if pregnant). and that the overall risk of new vascular handicap [5. (v) as randomized controlled trials suggest that estro- gens increase the severity of ischemic strokes. source in specific cases. but. and significantly increase this risk during pregnancy [79]. an appropri- required.5) during patients at increased risk of bleeding. should preferably be randomized in trials comparing oral anticoagulation and closure. influence secondary prevention after stroke. secondary prevention meas- ures mainly depend on the presumed cause. pregnancy and future meno. (ii) in the absence of A multicenter French study [79] conducted with 373 evidence-based data. (vi) young is 5–7% at 3 years.e. without significant who have a negative diagnostic work-up but a patent difference. disability. et al.  Cardioembolism (see Table 14. Thomassen L. Leys D. Incidence and short-term outcome of cerebral infarction in young adults in western Norway. cortical infarcts. of strokes associated with pregnancy and puerperium. patients. Neurol Clin 1992. Pierre P. Carolei A. careful fundoscopic risk factor.1) Warlow C. depending on the cause).  Intracranial dissections and the contribution of risk factors: Global Burden  Moyamoya of Disease Study. amniotic emboli or fat emboli 7. Milan C. 33:2105–8. Burn J. 30:2320–5. Secondary prevention 10. Lancet 1992. Lamy C. drug abuse. Chapter 14: Ischemic stroke in the young and in children Chapter Summary Specificities of stroke prevention in young adults: oral contraceptive therapy should be avoided in Diagnostic work-up (additionally to the standard most cases. the reasons for continuing antiplatelet examination. Ischemic stroke in patients cervical artery dissection.  Gas emboli. The most frequent cause in Western countries is 8. Nyland G.  Cervical artery dissections 2. . Incidence and  Post-partum cerebral angiopathy and eclampsia survival rates during a two-year period of intracerebral  Unruptured aneurysms of intracranial arteries and subarachnoid haemorrhages. Henon H. Sharshar T. system  Sneddon syndrome 6. Long-term prognosis Secondary prevention measures mainly depend on of cerebral ischemia in young adults. Totaro R. Incidence and causes antithrombotic agents. 26:930–6. Bogousslavsky J. 10:113–24. Beuriat P. an appropriate anti. Marini C. et al. First year’s results. Lopez AD. Giroud M. Stroke 215 internal artery stenosis. tinnitus. 28:2500–6. 337:1521–6. arteries in patients with von Recklinghausen 354:1457–63. Stroke 2002. Stroke 1999. Myhr KM. cystinuria and MELAS syndrome 20:892–9. Global mortality. Classification and natural history of  Small-vessel occlusion such as CADASIL clinically identifiable subtypes of cerebral infarction. and removal of the source in specific cases (severe A study in public hospitals of Ile de France. Takayasu disease or Buerger disease or the context of infectious 5. thrombotic therapy (oral anticoagulation and 11. Di Napoli M. in Pregnancy Study Group. et al. cardiac myxoma. Mas JL.  Secondary vasculitis in the context of a systemic 4. electrophoresis of proteins.  Diseases of large arteries: Lancet 1991. Sandercock P. but the cause of cerebral ischemia remains undetermined in up to 45% of 9. Warlow CP. Young.). lupus erythematodes. High stroke disorder incidence in the prospective community-based  Primary vasculitis of the central venous L’Aquila registry (1994–1998). Bandu L. Carolei A. etc. antiphospholipid antibodies and testing for thrombophilia. Aarseth J. Lancet 1999. Epidemiology of stroke. the low risk of recurrence in patients without any careful skin examination. Treatment and secondary  Post-irradiation cervical arteriopathies prevention of stroke: evidence. for syphilis and HIV. cervical artery dissections may be treated work-up as in older patients): either by antiplatelet therapy or by anticoagulation Intensive patient interview about the presence of (oral anticoagulation only for a few weeks). countries valvulopathies. homo. Hankey GJ. 59:26–33. Bamford J. Neurology 2002. Naess H. Lancet 1997. Marini C. systemic 339:342–4. Causes: References  Large-vessel atherosclerosis 1. Stroke 1997. The Stroke  Metabolic disorders such as Fabry disease. and in non-industrialized under age 45. Int J Epidemiol 1991. Nyland HI. 349:1436–42. Clinical outcome  Choriocarcinoma in 287 consecutive young adults (15 to 45 years) with ischemic stroke. Dennis M. and effects on  Cervical fibromuscular dysplasia of cervical individuals and populations. Murray CJ. 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Roine and Markku Kaste Introduction symptoms of acute stroke and calling the emergency There is strong evidence that treatment of stroke number immediately before doing anything else. secondary prevention of stroke ation [3. true for EMS professionals. in light of current guidelines. and significantly gement and proactive prevention of complications reduce the time from symptom onset to CT evalu- (Chapters 17 and 18). respect to the possibility of timely recanalization The purpose of this chapter is to characterize the therapy [5. the Cincinnati Prehospital prehospital critical pathway. . or Face-Arm-Speech-Test [FAST]) The general emergency phone number 112 (in and the Melbourne Ambulance Stroke Screen (MASS). An acute There is class II level B evidence that educational stroke unit is one of the key elements in the critical programs to increase awareness of stroke at the pathway and the chain of recovery of acute stroke population level are beneficial. 9. physician referral and self-transport. The electronic validated stroke patients. 6]. both paramedics and Only stroke unit care. and early the most common and most devastating error. mainly covered presenting within the 3-hour time window allowing in other chapters of this book. Section 4 Therapeutic strategies and neurorehabilitation Chapter 15 Stroke units and clinical assessment Risto O. thrombolysis to be considered. 219 always emphasize the importance of recognizing the gency phone call. including cli. prehospital pro- The essential building blocks for prehospital stroke fessionals should use a prehospital stroke screening care are the emergency medical service (EMS) orga. Prehospital care and referral To optimize stroke identification. The acute therapies and arrives: EMS transport to and arrival at the emergency interventions in stroke are described in Chapter 16. the EMS providers and the admitting stroke Such instruments include the Los Angeles Prehospital center. reproducibility and validity. since the stroke dependency and need for institutional care compared patient is not able to make the call himself/herself. all of which should be involved in planning the Stroke Screen (LAPSS). to treatment in general medical wards [1]. are etiological diagno. with rehabilitation (Chapter 20). general mana. 4]. Failure to use the emergency number is and other vascular endpoints (Chapter 19). Delays during acute stroke manage- chain of recovery of acute stroke patients from emer. specificity. This patients in stroke units significantly reduces death. National stroke-awareness campaigns algorithm of questions should be used during the emer. (ERC). department (ED) increase the likelihood of a patient The basic functions of the stroke unit. Stroke Scale (CPSS. 11]. Finland) (911 in the United States) is the first link which all have been reported to have a sensitivity in the chain of survival and recovery for acute exceeding 90% [7. at stroke management that can be optimally delivered in the level of the emergency services and emergency stroke units. thrombolytic therapy and physicians [2]. physicians (due to a failure to implement stroke code) and at the hospital level (due to delays in in-hospital logistics and neuroimaging) [6]. 8. ment have been identified at three levels: at the popu- gency phone call to acute stroke unit. hemicraniectomy have been shown to improve the It does matter who is called and how the patient outcome of stroke patients. 10. instrument that has been prospectively evaluated nization consisting of an emergency response center for sensitivity. and the same holds patients. lation level (due to failure to recognize the symptoms nical evaluation of the patient and aspects of general of stroke and calling the emergency number). compared to private stic work-up (Chapters 2–4 and 7–13). is usually done by a family member.  emergency department reorganization with priority EMS dispatch and priority transport with easy-access CT. laboratory and team of specialists who are knowledgeable about imaging evaluation. which is based on over 200 patients treated. 18]. Stroke alarm also means that the patient has  emergency medical service transport to the a priority for CT and emergency laboratory evalua. Reasons for in-hospital delays are a failure to givers.  digital patient records.e. availability transport. ciated with stroke unit care in routine practice are valid and reliable means of facilitating thrombolysis comparable to those of RCTs [1]. an identify stroke as emergency. prenotification of the receiving hospital. The most distinctive features are a multi- decision and administration of appropriate treat. several pre-admission conditions have notification to mobilize necessary resources for to be guaranteed: the patient. which will be notified in advance. patients (i. written care protocols and. emergency department tion. Prehospital and short. the patient will be transported to the stroke level B).and long-term outcomes are similar for notification of an inbound stroke patient has been acute stroke patients treated with rtPA via a tele- demonstrated to shorten the delay from ED arrival medicine consultation at local hospitals and those to initial neurological assessment and initial brain treated in academic centers [17. i. In Helsinki. The quality of treatment. complication rates center. educa- total time lost between stroke onset and recanalization tional programs for the staff. clinical. disciplinary team specialized in the care of stroke ments at the receiving hospital [2]. more recently. including digital imaging There have been concerns that the benefits revealed in randomized clinical trials (RCT) including system (PACS) [16]. nurses. Acute stroke patients are stroke care has been shown to result in reduced delays more likely to survive. where timely stroke is suspected [12. and to increase the proportion of patients treated with rtPA.  ED prenotification by the EMS geriatric and neurology wards by non-specialized staff  ED rebuild with easy-access CT and only about 14% receive stroke unit care [24]. Elderly patients and those with The main components of the reorganization were: severe stroke benefit the most [23]. In spite of such  Triage strong scientific evidence. nursing staff and therapists In-hospital delay may account for at least 16% of with expertise in stroke and rehabilitation). inefficient in-hospital integrated emergency response system. Using a predefined proto. and a class III level B recommendation that suspected stroke victims should be transported without delay to the Stroke unit care nearest medical center with a stroke unit that can A stroke unit is defined as an organized inpatient area provide ultra-early treatment [2]. The present mean door-to-needle time is unit care is effective for all age groups and for any 25 minutes. delayed medical assessment and imaging of computed tomography scans 24 hours every day. . Stroke times. 19–22]. Section 4: Therapeutic strategies and neurorehabilitation The stroke code is activated immediately when for patients in distant or rural hospitals. imaging. CT/MR tech. In current guide. involvement of care- therapy. return home and regain inde- in acute stroke treatment. To ensure that a stroke patient presents within the time window allowing thrombolysis to be nologists and pharmacists are able to utilize early considered. Telemedicine is also a feasible. stroke type or severity. The ESO Guidelines include a class II level B  prehospital notification of the stroke patient recommendation for immediate EMS contact. 13]. Cochrane systematic reviews may not be possible to In remote and rural areas helicopter transfer achieve in routine practice. Physicians. accurate diagnosis. and uncertainty in administering thrombolysis rapid laboratory testing and experience in stroke [14–16]. the majority of stroke  neuro-ED with written protocols patients in Europe are treated in general medicine. there is also a class III level B recommendation stroke patients and is managed by a multidisciplinary for immediate ED triage. air or ground transportation is not feasible (class II col. the ED reorganization of acute thrombolysis [2. therapeutic stroke care. A recent systematic review should be considered to improve access to treatment of observational studies verified that the benefits asso- 220 (class III level C) [2]. shorter door-to-rtPA pendence if they receive stroke unit care [1]. that exclusively or nearly exclusively takes care of lines.e. medical staff. This is called the Stroke Alarm at the  awareness of stroke at the population level ED. Chapter 15: Stroke units and clinical assessment There are many types of stroke units. Infrastructure components considered as absolutely necessary (in bold) or as important in AHW treating acute stroke acute stroke units. Monitoring The European Stroke Initiative (EUSI) recently Automated ECG monitoring at bedside performed a survey among 83 European stroke spe.3.1. physiotherapists. including diagnostics and secondary prevention Extracranial duplex sonography  automated monitoring of vital functions within Transthoracic echocardiography the first 72 hours Transesophageal echocardiography  thrombolysis for selected patients. procedures and protocols patients were able to provide appropriate care as evalu- Stroke pathways ated by these criteria.e. Personnel while mobile stroke teams have no major impact on death. Stroke-trained physician on call Five principles are relevant for the beneficial effect of stroke units [23–32]: Diagnostic radiologist on call  a dedicated stroke unit confined only to acute Internist on staff stroke patients Cardiologist on staff  a multidisciplinary team approach including Social worker physicians. 221 Community stroke-awareness program mately one-third of all stroke patients supposed to . all of which have category to qualify as suboptimal minimal standard) [28].2 and those for CSC in Table 15. The results needed for Emergency department (in-house) AHW are shown in Table 15. those needed for PSC Collaboration with outside rehabilitation center in Table 15. 25– Emergency department staff 27]. speech therapists. These 886 hospitals Intravenous rt-PA protocols 24/7 treated over 330 000 acute stroke patients. combined acute and rehabilitation patients on a regular basis by more than 50% of the experts stroke units. all specialized in the care of stroke patients Diagnostic procedures  a comprehensive stroke unit concept delivering Brain CT scan 24/7 both hyper-acute treatment and early CT priority for stroke patients mobilization and rehabilitation by the same Extracranial Doppler sonography multidisciplinary team. The criteria were Multidisciplinary ICU clearly too demanding for many hospitals. The first generation of stroke intensive care units Multidisciplinary team failed to improve the outcome of stroke patients and Stroke-trained nurses there are no RCTs comparing modern stroke intensive Neurologists on call care unit care with ordinary acute stroke unit care. A questionnaire was sent to 4261 randomly selected hospitals. including Table 15. been shown to improve the outcome of stroke patients. nurses. Defini- Stroke outpatient clinic tions are in line with the American recommendations of Primary Stroke Centers [33]. approxi. and rehabilitation stroke units admitting (centers had to meet only 50% of these requirements within each patients after a delay of 1–2 weeks. as was Respiratory support detected in the second random survey. 1688 of which admitted Stroke care map for patient admission acute stroke patients. dependency or need for institutional care [1. i. neuropsychologists Physiotherapy start within 2 days and social workers. Of these 886 agreed to participate Prevention program and returned the questionnaire. Automated monitoring of pulsoximetry cialists to learn which in their opinion are the essential Automated monitoring of blood pressure components and facilities for good stroke care at three Monitoring of temperature levels: any hospital treating stroke patients (AHW). Outpatient rehabilitation available gated whether European hospitals treating acute stroke Treatment. primary stroke centers (PSC) and comprehensive Infrastructures stroke centers (CSC) [28]. occupational Speech therapy start within 2 days therapists. which investi.1. 6%) for PSC and 356 (40. Sweden.3% were treated in Social worker hospitals meeting none of the accepted levels [24].3% were treated in CSC.2. of whom 8489 received thrombolysis. 5. According to the Transthoracic echocardiography survey.4) Automated ECG monitoring at bedside and accepted that these criteria may not be met in Automated monitoring of pulsoximetry all stroke units in all EU member states owing to economic constraints [30]. 30]. the Netherlands Transesophageal echocardiography and Luxemburg were the criteria for decent care met [1. Of all Emergency department staff stroke patients 8. Infrastructural components considered as absolutely necessary or as important in the PSC by more than Stroke care map for patient admission 75% of the experts (in bold) or by more than 50% of the experts Community stroke-awareness program (normal print) [28].9%) met the criteria for CSC.2%) for AHW. return home and regain independence if they Monitoring of temperature receive stroke unit care. procedures and protocols  acute assessment of neurological and vital functions parallels treatment of acutely life- Intravenous rt-PA protocols 24/7 222 threatening conditions . while 42. There were Extracranial duplex sonography huge disparities between countries.1% in AHW.4%) did not meet even the lowest level of care as defined by the European stroke specialists. only in Finland. Section 4: Therapeutic strategies and neurorehabilitation Table 15. Neurologists on staff Of 886 hospitals 43 (4. Automated monitoring of blood pressure Automated monitoring of breathing Acute stroke patients are more likely to survive. The points which must be kept in mind include: Inpatient rehabilitation (in-house)  acute emergency management of stroke requires Outpatient rehabilitation available parallel processes at different levels of patient Collaboration with outside rehabilitation center management Treatment. The Diagnostic procedures recent guidelines by the European Stroke Organisa- tion (ESO) recommends the same thing although the Brain CT scan 24/7 EUSI survey revealed that only one out of seven acute CT priority for stroke patients stroke patients are treated in an acute stroke unit and Extracranial Doppler sonography only a minority of European hospitals can provide an optimal level of care for stroke patients. Prevention program Personnel Stroke pathways Multidisciplinary team Stroke-trained nurses Neurologists on call have suffered stroke in 2005. while Diagnostic radiologist on call 455 (51. Both the First and Second Helsingborg Declar- Speech therapy start within 2 days ations recommend that all stroke patients should have Physiotherapy start within 2 days access to care in specialized stroke units [29.3% of ischemic strokes. constituting 3. The Second Helsingborg Declaration listed Monitoring the minimum criteria for stroke units (Table 15. 24]. Stroke-trained physician (24/7) 32 (3. Infrastructures Emergency department (in-house) Early activities at a stroke unit The time window for treatment of patients with acute Stroke outpatient clinic stroke is narrow and requires well-organized services Multidisciplinary ICU at the ED and acute stroke unit.5% in PSC Physician expert in carotid ultrasonography and 44. FLAIR) 24/7 preferable but not an absolute requirement for a Diffusion-weighted MRI stroke unit Extracranial Doppler sonography 24/7  Immediate start of mobilization and access to early Extracranial duplex sonography 24/7 rehabilitation Transcranial Doppler 24/7  Continuing staff education CT angiography 24/7 Magnetic resonance angiography 24/7  the selection of special treatment strategies may Transfemoral cerebral angio 24/7 already be ongoing before the final decision on the Transesophageal echo subtype of acute stroke has been made. It is realized Brain CT scan 24/7 that this criterion may not be met in all stroke units in all EU member states due to economic constraints CT priority for stroke patients  Written protocols and pathways for diagnostic Extracranial Doppler sonography procedures. occupational therapy) Diagnostic procedures  Immediate imaging 24 hours (CT or MRI). acute treatment. During those hours the following tasks need to be Automated monitoring of pulsoximetry performed: Automated monitoring of blood pressure  differentiate between different types of stroke Automated monitoring of breathing  assess the underlying cause of brain ischemia  provide a basis for physiological monitoring of Monitoring of temperature 223 the stroke patient . speech Physiotherapy start within 2 days therapy. especially Automated ECG monitoring at bedside the first minutes and hours after stroke onset. Physician expert in echocardiography  Dedicated beds for stroke patients Speech therapy start within 2 days  Dedicated team: stroke physician. vascular surgery. T2*. Helsingborg Declaration 2006: minimum criteria Physician expert in carotid ultrasonography for a stroke unit [30].3. Chapter 15: Stroke units and clinical assessment Table 15. cardiology is MRI (T1. T2. trained nurses and rehabilitation staff (e. Components considered as absolutely necessary for a CSC by 75% (in bold) or 50% of the experts (normal Invasive treatments provided print) [28].4. physical therapy. monitoring to prevent Extracranial duplex sonography complications and secondary prevention Transthoracic echocardiography  Availability of neurosurgery. Monitoring Time is the most important factor. interventional neuroradiology. Intravenous rtPA protocols 24/7 Personnel Carotid surgery Multidisciplinary team Angioplasty and stenting Stroke-trained nurses Intra-arterial thrombolysis 24/7 Physiotherapy start within 2 days Respiratory support Neurologists (24/7) Surgery for aneurysms Stroke-trained physician (24/7) Hemicraniectomy Interventional neuroradiologist on call Ventricular drainage Neurosurgeon on call CEA vascular surgeon Emergency department staff Table 15.g. 6 and 15. a 24-hour Holter ECG monitoring stones of this approach. PTT. blood glucose. CRP or sedimentation rate ment of complications.7 and will be monitoring systems may have the same functionality discussed in more detail in Chapter 17 [2]. Diagnostic tests at the acute stroke unit recommended by ESO [2]. . routine blood tests and 12-channel dations are based on consensus statements of experts electrocardiography (ECG) followed by continuous such as Guidelines for Management of Ischaemic Stroke ECG recording should be performed according to and Transient Ischaemic Attack by the ESO and Rec- the ESO class I level A recommendation. Diagnostic cardiac ultrasound is recom- intensive care may be necessary until the clinical mended in selected patients (class III level B). atic use of these methods may result in an increased proportion of cardioembolic stroke [2. the initial examination should include: 6 Diffusion and perfusion MR or perfusion CT  observation of breathing and pulmonary function 7 Echocardiography (transthoracic and/or  early signs of dysphagia. 24].5. Diagnostic work-up Table 15. careful monitoring and nor- and is already applied in the majority of stroke centers malization of physiological parameters. built in. organized stroke unit care appears to reduce the risk prothrombin time or INR. and complications lar diagnosis based on predominantly non-invasive The success of stroke unit care is believed to depend angiographic tests is soon likely to be the standard. Although not yet clearly stated in the guidelines. associated with stroke  rule out other brain diseases In all patients  assess prognosis. are summarized in Tables 15. preferably using a transesophageal) validated scale 8 Chest X-ray  evaluation of concomitant heart disease 9 Pulse oximetry and arterial blood gas analysis  assessment of blood pressure (BP) and heart rate  determination of arterial oxygen saturation using 10 Lumbar puncture infrared pulse oximetry. 1 Brain imaging: CT or MRI Stroke unit care reduces the risk of death after 2 ECG stroke but it is not entirely clear how that is achieved. monitoring ures as advocated by the ESO. therefore level I In addition to imaging. as well as pro- [2. In addition. Hepatic and renal chemical analysis When indicated Clinical assessment 4 Extracranial and transcranial duplex/Doppler There is general agreement that stroke severity should ultrasound be assessed by trained staff using the National Insti- 5 MRA or CTA tutes of Health Stroke Scale (NIHSS). breathing and cardiovascular function). early evaluation of physio. System- situation is stable. General management. in particular infections [2]. the exact neurovascu. In-depth discussion of diagnostic work-up can active prevention and treatment of medical be found in Chapters 2–4. If they are compromised. 11 EEG 12 Toxicology screen Close monitoring is essential (see Chapter 17) to ascertain stable vital functions (airway. 3 Laboratory tests Further analysis of systemic reviews revealed that Complete blood count and platelet count.5 lists the recommended diagnostic proced. although modern patient. complications. class A recommendations do not exist. of death after stroke through prevention and treat. The corner- stroke is found. No RCTs address this. Section 4: Therapeutic strategies and neurorehabilitation  identify concurrent diseases or complications Table 15. The recommen- logical parameters. 224 should also be performed. When ommendations for the Establishment of Primary Stroke arrhythmias are suspected and no other cause of Centers by the Brain Attack Coalition [33]. as recommended by the ESO. on general management. 34]. serum electrolytes. Decompressive craniect- for non-dysphagic stroke patients who are omy has now a class I level A recommendation in malnourished 225 malignant ischemic MCA stroke patients younger than . DVT or with severe cardiac failure.8 mmol/l]) should be treated lytic therapy is most often administered in the ED with intravenous dextrose or infusion of 10–20% instead of the stroke unit. rtPA requires immediate trans- fanning is recommended fer of the patient. temperature and oxygen saturation is recommended for 72 hours in patients with  It is recommended that percutaneous enteral significant persisting neurological deficits gastrostomy (PEG) feeding should not be considered in stroke patients in the first 2 weeks  It is recommended that oxygen should be administered if the oxygen saturation falls below 95% Table 15.  Early commencement of nasogastric (NG) feeding (within 48 hours) is recommended in stroke patients  Intermittent monitoring of neurological status. pulse. and levofloxacin can be detrimental after stroke in acute stroke patients  Routine blood pressure lowering is not  Early rehydration and graded compression stockings recommended following acute stroke are recommended to reduce the incidence of venous  Cautious blood pressure lowering is recommended thromboembolism in patients with extremely high blood pressures  Early mobilization is recommended to prevent (>220/120 mmHg) on repeated measurements.7.5 C) should prompt a search for is still open and depending on the indications and concurrent infection. GCP) be treated with appropriate antibiotics  Normal saline (0.v. The specific  Antibiotic prophylaxis is not recommended in treatments at a stroke unit are shown in Table 15. recommended in patients with severe stroke or  It is recommended that infections after stroke should swallowing problems (class IV.9%) is recommended for  Prophylactic administration of antibiotics is not fluid replacement during the first 24 hours recommended. aortic dissection or and pressure ulcers hypertensive encephalopathy  It is recommended that low-dose subcutaneous  It is recommended that abrupt blood pressure heparin or low molecular weight heparins should lowering be avoided. where rescue therapies glucose after unsuccessful intravenous thrombolysis may  It is recommended that the presence of pyrexia still be considered.8 [2].5 C) with paracetamol and administration of i. complications such as aspiration pneumonia. provided that the time window (temperature > 37. Chapter 15: Stroke units and clinical assessment Table 15. From the  It is recommended that severe hypoglycemia organizational point of view. immunocompetent patients  Swallowing assessment is recommended but there Elevated intracranial pressure are insufficient data to recommend a specific The most common cause of death in the acute stage of a approach for treatment major stroke is increased intracranial pressure and her-  Oral dietary supplements are only recommended niation due to brain edema. intravenous thrombo- (<50 mg/dl [<2. ESO Guidelines for management of  Regular monitoring of fluid balance and electrolytes is complications [2]. Treatment of pyrexia possible contraindications for the therapy. bypassing the ED. with impaired swallowing blood pressure. ESO Guidelines for general monitoring and treatment [2]. It is recommended that be considered for patients at high risk of DVT or low blood pressure secondary to hypovolemia pulmonary embolism or associated with neurological deterioration in acute stroke should be treated with volume expanders Acute treatment  Monitoring serum glucose levels is recommended Acute treatments and interventions for stroke inclu-  Treatment of serum glucose levels >180 mg/dl ding thrombolytic therapy and endovascular pro- (>10 mmol/l) with insulin titration is recommended cedures are discussed in Chapter 16.6. Stroke unit (temperature > 37. Intravenous Early rehabilitation thrombolysis for basilar occlusion is an acceptable Rehabilitation of stroke patients will be discussed in alternative even after 3 hours Chapter 19. Many patients need the rehabili- should start as early as possible. ESO Guidelines for elevated intracranial pressure [2].9) [2.8. if the neurological deficit is related to acute cerebral ischemia of treatment is based on the most likely etiology of the  It is recommended that intravenous rtPA may also be stroke and all the patient’s risk factors. tion will endure. ESO Guidelines for specific treatments [2]. at the ED or in the tation services of the community from time to time stroke unit at the latest. knowing 226 hours after ischemic stroke if thrombolysis is not that such late rehabilitation is not supported by administered. maximum 90 mg). Except for craniectomy for selected and design of the rehabilitation plan of every acute patients. although this is outside the stroke unit and continued in community health care by current European labeling a general practitioner or family doctor as soon as the  Intra-arterial treatment of acute MCA occlusion within patient has been discharged from the hospital [2]. i. recommendations are based on a lower level of stroke patient.9 mg/kg body weight. Table 15. which is started at the stroke unit advice on how to treat stroke patients with increased and continued and modified based on the progress intracranial pressure (Table 15.  Intravenous rtPA (0. outpatient clinic and at home. and it is currently the only treatment ical regions and hospitals.e. The rehabilitation plan is much like a evidence. Selection RCTs [2]. . All patients need to be assessed at the  It is recommended that aspirin (160–325 mg loading stroke unit by a physiotherapist. For all stroke patients follow-up by community health care is crucial to ensure that Secondary prevention the functional outcome reached during rehabilita- Secondary prevention. Section 4: Therapeutic strategies and neurorehabilitation Table 15. It is recommended that aspirin to be able to keep their independence in daily life (160–325 mg loading dose) should be given within 48 and to be able to live in their own homes. speech therapist and neurophysiologist of the multidisciplinary stroke team within the first week after the onset of stroke. with 10% of the dose given as a bolus  Surgical decompressive therapy within 48 hours after followed by a 60-minute infusion. of the patient at a rehabilitation hospital. There is great variability in rehabilitation resources and staff between geograph- 60–65 years of age. Secondary pre- administered in selected patients under 18 years and vention strategies should be planned and initiated at the over 80 years of age. The recent ESO Guidelines give practical tailor-made suit. but in general all available shown in RCTs to be able to reduce mortality in this therapists should be involved in the early assessment patient group [32]. a 6-hour time window is recommended as an option  Intra-arterial thrombolysis is recommended for acute basilar occlusion in selected patients.9. is recommended symptom onset is recommended in patients up to within 3 hours of onset of ischemic stroke 60 years of age with evolving malignant MCA infarcts  Intravenous rtPA may be of benefit also for acute  It is recommended that osmotherapy can be used to ischemic stroke beyond 3 hours after onset but is not treat elevated intracranial pressure prior to surgery if recommended for routine clinical practice this is considered  The use of multimodal imaging criteria may be useful  No recommendation can be given regarding for patient selection for thrombolysis but is not hypothermic therapy in patients with recommended for routine clinical practice space-occupying infarctions  It is recommended that blood pressures of  It is recommended that ventriculostomy or surgical 185/110 mmHg or higher are lowered before decompression be considered for treatment of large thrombolysis cerebellar infarctions that compress the brainstem  It is recommended that intravenous rtPA may be used in patients with seizures at stroke onset. occupational thera- dose) be given within 48 hours after ischemic stroke pist. 20–22]. discussed in detail in Chapter 19. or 24 hours after thrombolysis. including type of stroke. national ERC administration providing emergency response services for the entire country. To reduce delays. and pulmonary function. likely to survive. dysphagia.  early assessment. Chapter 15: Stroke units and clinical assessment Advantages of centralized stroke awareness. including thrombolytic of stroke patients and is managed by a multidisci- therapy and endovascular procedures plinary team of specialists who are knowledgeable  implementation of secondary prevention and about stroke care. breathing acute stroke care will be centralized acute care. awareness of first admitting hospitals for most stroke patients. sex. including stroke type. so that all involved in the chain of evaluated for sensitivity. management organization EMS and ED involvement in prehospital manage- In Finland. rehabilitation by the same multidisciplinary team. Prehospital The Nordic type of centralized care also means easier professionals should use a prehospital stroke screening instrument that has been prospectively administration. of brain ischemia and other brain diseases A stroke unit is defined as an organized inpatient  management of complications area that exclusively or nearly exclusively takes care  acute treatment. well-organized systematic routines for fast implemen- tralized manner if compared to most EU countries tation of evidence-based medicine. concomitant 227 shortening delays at every step. opment of clinical networks. The devel. it is now recommended (class I level A) that all  a multidisciplinary team approach stroke patients irrespective of age. i. increasing stroke . specificity.e.  diagnostic work-up. Five principles are relevant for the beneficial effect of stroke units: Conclusions  a dedicated stroke unit confined only to acute According to the frequently cited ESO 2008 Guide. stroke ment. only one hospital is in charge for acute stroke stroke patient to the emergency department (ED) care of the municipality. Emergency medical service (EMS) transport of a more. cause i. as in most Scandinavian countries. including tele- and the USA.e. stroke patients lines.  emergency management Reorganization of acute stroke care has been shown  clinical assessment of vital functions to result in reduced delays in acute stroke treatment. shorter door-to-rtPA times. including telemedicine. in-hospital pathways and protocols as well as care is organized in a more straightforward and cen. stroke at the population level is pivotal.  thrombolysis for selected patients. There are no overlapping EMS services. can be instantly instructed in new stroke patients has been demonstrated to shorten paradigms. The health. is recommended to expand the access to high-technology Activities at a stroke unit: specialist stroke care (class II level B) [2]. the Is this the recipe for the future? It is easy to predict underlying cause of brain ischemia and other brain diseases that among the key elements for future success in  clinical assessment of stroke severity. including diagnostics and secondary prevention care system should ensure that acute stroke patients  automated monitoring of vital functions within can access high-technology medical and surgical the first 72 hours stroke care when required (class III level B). Further. identification of barriers that may prevent direct and immediate access to a stroke center. return home and regain independ- ence if they receive stroke unit care. supervised by an EMS physician at the university hospital or regional hospital. Prehospital notification of inbound health care. Tertiary referral is rare increases the likelihood of a patient presenting because even comprehensive stroke centers take within the 3-hour time-window allowing thromboly- primary responsibility for stroke care. Acute stroke patients are more rehabilitation.  a stroke unit concept delivering both hyper- ity of stroke should be treated in a stroke unit in a acute treatment and early mobilization and primary (or comprehensive) stroke center. are the sis to be considered. reproducibility recovery. gender or sever. the delay from ED arrival to initial neurological assessment and initial brain imaging. from EMS to rehabilitation and community and validity. The EMS organization consists of a stroke in selected hospitals. and to increase Astroke unit oversees: the proportion of patients treated with rtPA. and in many areas only Chapter Summary one EMS provider. ERC. Door for management of ischaemic stroke and transient to thrombolysis: ER reorganization and reduced ischaemic attack 2008. A systematic review of 20. Paramedic  acute treatments and interventions of stroke. et al. Louw S. Latchaw RE. Determinants of use of emergency medical services in a population with stroke symptoms: the second delay in 18. et al. et al. Rosamond W. Agreement Guidelines for the early management of adults with 228 between ambulance paramedic – and physician – ischemic stroke: a guideline from the American Heart recorded neurological signs using the Face Arm Speech Association/American Stroke Association Stroke . 4. 31 stroke centers. Heuschmann P. et al. Jauch E. (11):2585–90. Stroke 1994. Sandercock P. Belvis R. Brain Attack Coalition. Kallela M. Schenkel J. 3. Age Heart Association. Starkman S. Cochrane 15. Pancioli A. Morgenstern LB.8) 2005. Cooper G. Adams HP Jr. Expert Panel on Emergency Medical Services Systems. Häppölä O. identification of stroke: community validation of the including thrombolytic therapy and endovascular Melbourne ambulance stroke screen. et al. European Stroke Organisation (ESO) Executive Project. stroke therapy: The TLL Temple Foundation Stroke 2. Identifying  general management. et al. Guidelines 16. Nor AM. et al. Bray JE. 25(5):457–507. Lindsberg PJ. 5:742–8. Cerebrovasc Dis 2005. 26(6):937–41. 67(2):334–6. blood pressure. Hess DC. 5(3):275–8. Effects stroke: delays to presentation and emergency of the implementation of a telemedical stroke network: department evaluation. 6. heart disease.g. Telestroke: extending accessing stroke healthcare (dash ii) study. Acker JE 3rd. arterial oxygen saturation  diagnostic work-up 10. Frequency and emergency medical services within stroke systems of accuracy of prehospital diagnosis of acute stroke. Wang S. 19(2):96–101. 14. Prehospital 19. Pancioli AM. et al. The Recognition of Stroke in the Emergency Room (ROSIER) scale: References development and validation of a stroke recognition 1. Lancet Neurol 2005. Alberts MJ. 5. Alberts MJ. Audebert H. 33:116–21. Stroke Unit Trialists’ Collaboration: Organised instrument. Benefits of a (e. careful monitoring and stroke in the field. e. Ann Emerg Med 1999. Stroke care: a policy statement from the American Heart 1995. American barriers to delivery of thrombolysis for acute stroke. et al. delays to acute stroke treatment. 33(1):160–6. Committee. del Zoppo G. et al. 31(1):71–6. and emergency department delays after acute stroke: the Recommendations for the establishment of primary Genentech Stroke Presentation Survey. the Telemedic Pilot Project for Integrative Stroke Care 33(1):3–8. Sauer CM. Implementation strategies for 7. Nor A. 9. Kothari R. 25(10):1920–3. 20(1):28–33. Stroke normalization of physiological parameters. Malkoff MD. Neurology 2006. et al. Council. stroke expertise into underserved areas. Gomez CR. et al. Brott T. et al. et al. 21. 283(23):3102–9. aspirin 13. heart rate and 35:1355–9. et al. Cerebrovasc Dis procedures (see Table 15. Stroke 2000. Kothari RU. 33(4):373–8. Ann Emerg Med 1999. Improving delivery of acute Database Syst Rev 2007. Schroeder EB. Mc Allister C. Broderick J. decompressive craniectomy) prehospital stroke code system. Sen B. Stroke 2000. Kothari R. Hand P. Cincinnati on Emergency Medical Services Systems and the Stroke prehospital stroke scale: reproducibility and validity. Association/American Stroke Association Expert Panel 8.  start of secondary prevention measures. Morris DL. Davis J. Barsan W. Lancet Neurol 2006. Cocho D. Liu T. Martin J. et al. Stroke 2007. Morris DL. Code stroke. 38(11):3097–115. et al. Martí-Fàbregas J. CD000197. Lancet Neurol 31:2591–6.  management of elevated intracranial pressure 12. Kidwell CS. Kwan J. (TEMPiS) in Bavaria. Gross H. Cerebrovasc Dis 2008. Madden K. Eckstein M. 4(11):727–34. et al. JAMA 2000. Hademenos G. Rosamond WD. ESO Writing Committee. Section 4: Therapeutic strategies and neurorehabilitation Test (FAST) in acute stroke patients. well as proactive prevention and treatment of medical complications 11. Crocco TJ. Germany.  design of the rehabilitation plan.g. Stroke Council. An attempt to shorten inhospital therapeutic delays. Acute 17. Prospective validation of the Los Angeles prehospital stroke screen (LAPSS). American Stroke Association Ageing 2004. 2006. inpatient (stroke unit) care for stroke. Stroke 2002. Stroke 2004. as 2000. Initiative. 38(6):1886–92. Kaste M. Vahedi K. Langhorne P. Stroke 2007. 23(2–3):231–41. Langhorne P. Aboderin I. Indredavik B. Stroke 2007. Does the prevention of complications explain the survival benefit of 23. 29. Langedijk M. Sulter G. Kjellström T. Management stroke care monitoring unit versus a conventional of Acute Ischemic Stroke. et al. Kaste M. et al. Leys D. et al. 38(5):1655–711. 38 24. for the Pan European 22. Ringelstein E. and the (9):2536–40. Helsingborg the American Heart Association/American Stroke Declaration 2006 on European stroke strategies. Clinical Cardiology Council. 229 . et al. Facilities Available in European DESTINY. Stroke 2005. Woodman M. Early Hospitals Treating Stroke Patients. for the management of spontaneous intracerebral J Intern Med 1996. 38 decompressive surgery in malignant infarction of the (11):2985–91. Atherosclerotic Peripheral Vascular Disease and The main components of stroke unit care: results Quality of Care Outcomes in Research of a European Expert survey. Juettler E. Stroke 2003. eds. 1999. London: BMJ Books. Lancet Neurol 2007. and the European Stroke Initiative executive committee. Cardiovascular 28. analysis of a systematic review. Unit Trialists’ Collaboration. Ringelstein EB. Langhorne P. 38(6):2001–23. Dennis M. Hofmeijer J. a consensus statement of the Brain Attack Coalition. Connolly S. Broderick J. Age Aging 2005. Association Stroke Council. Feldmann E. Asplund K. for the Stroke Group. 27. Stroke 2007. High Blood Pressure Cerebrovasc Dis 2007. 1997: 3–15. Chapter 15: Stroke units and clinical assessment Council. hemorrhage in adults: 2007 update: a guideline from 30. Research Council. Executive Committee of the European Stroke 32. 34:101–4. Barcelona: Springer Verlag stroke unit: a randomized pilot study. Interdisciplinary Working Groups. Stroke 2007. Davalos A. Alberts MJ. Latchaw RE. and HAMLET investigators. Stroke Units: an evidence organized inpatient (Stroke Unit) care? Further based approach. Leys D. Guidelines Consensus Meeting. Govan L. 36(7):1597–616. Stroke 2007. Systematic review of observational 6(3):215–22. Dey P. Admitting acute ischemic stroke patients to a In: Castillo J. Stroke units in their randomised controlled trials. for DECIMAL. Stroke management in Europe. Iberica. Hacke W. middle cerebral artery: a pooled analysis of three 25. Toni D. Selman WR. natural habitat. Stroke units and stroke 34. 240(4):173–80. Venables G. Norrving B. et al. Long M. Seenan P. Is stroke unit Recommendations for comprehensive stroke centers: care portable? A systematic review of the clinical trials. for the Radiology and Intervention Council. 26. 23(5–6):344–52. studies. 34(4):324–30. Elting JW. et al. and the Quality of Care and Outcomes in Research Interdisciplinary Working 31. Weir CJ. Cerebrovasc Dis 2007. Langhorne P. teams: evidence-based management of stroke. Shatchkute A. 33. Chapter 16 Acute therapies and interventions Richard O’Brien. Favorable outcome at essential. the interventions intravenous thrombolysis [7]. This analysis included discussed will generally be limited to the initial 2775 patients in whom thrombolysis was initiated 48 hours following ictus. European Stroke Organisation Guidelines 2008 and However.7 (95% confidence interval 1.6) With advances in pharmacotherapeutics. The odds of therapies may not be universal and may be dictated a favorable outcome were inversely associated with by local availability at individual stroke units. These Alteplase Thrombolysis for Acute Noninterventional benefits have been demonstrated without a signifi- Therapy in Ischaemic Stroke (ATLANTIS) trials cantly increased risk of death. patients treated earliest following their stroke having ation and inter-disciplinary communication are the most favorable outcome. one of the most 0 or 1.40 treatment of ischemic stroke is recombinant-tissue (1.47) when thrombolytic plasminogen activator (rtPA). 3 months was defined as a modified Rankin Score of 0 or 1. based upon the tration occurred within 6 hours of ictus [3.85) and 1.15 (0. alteplase. and the two-part National defined as blood clot exceeding 30% infarct volume 230 Institute of Neurological Disorders and Stroke with significant space-occupying effect. but the proportion of A and B.55 (1. which may account for Over recent decades the early management of acute some of the differences in outcomes reported in each stroke has changed dramatically and the early post. achieve a favorable outcome of 7 [4].15) when treatment was commenced only thrombolytic agent licensed in Europe for the 91–180 minutes following onset. analysis of the pooled data from the the European Stroke Initiative recommendations for ATLANTIS. Lees Introduction (NINDS) rtPA study [1. The NINDS rtPA study demonstrated an stroke period has been the focus of much research. odds ratio of 1. firmed the beneficial effect of timely intervention with For the purposes of this chapter. of the trials.81 (95% confidence interval 1.50) for a standard therapy for a well-selected population of patients treated within the first 90 minutes of stroke. Thorsten Steiner and Kennedy R. More specifically. was larger . with the number needed to treat to 24–48 hours following acute stroke are numerous. falling to 1. ECASS and NINDS rtPA trials has con- the management of intracranial hemorrhage [1. This chapter will present the evidence and best the ECASS studies (I and II) did not confirm signifi- practice guidance for interventions during the first cant benefit of rtPA although this was when adminis- 24–48 hours following stroke. and on the for a favorable outcome at 3 months with rtPA treat- basis of many randomized controlled trials.05–1. These studies varied in timing and dose of rtPA. The evidence treatment was commenced within 181–270 and 271–360 for its use comes from six landmark clinical trials: the minutes from stroke onset respectively [7]. 2]. close cooper.12–2. and Thrombolysis National Institutes of Health Stroke Scale score of In respect of acute interventions. patients with acute ischemic stroke. Access to some of these within 6 hours of ischemic stroke onset.2 to 2. with those other aspects of stroke care. a Barthel Index between 95 and 100. 5]. (ECASS) and ECASS II. In contrast. however. 3–6]. the European Cooperative Stroke Study patients with significant parenchymal hemorrhage. the 1. the ment when administered within 3 hours of ischemic potential interventions now available within the first stroke onset. As with delay from stroke onset to treatment. the analysis identified an significant advances during the last two decades has adjusted odds ratio for favorable outcome at 3 months been the introduction of intravenous thrombolysis as of 2.90–1. At present.75–4. Within the 3-hour window the number needed to treat to achieve one favorable port the routine use of intravenous rtPA in patients outcome is 7. The benefits extend ‘physiological age’ rather than their ‘chronological beyond 3 hours. Of clinical importance.5-hour istered as an intravenous bolus with the remaining limit. Ten percent of the total dose is admin- window for alteplase treatment in favor of a 4. a well-selected population of patients with acute At present European regulatory agencies do not sup- ischemic stroke. The SITS register has age’ [9]. which found an odds ratio for achieving for the first 24 hours after.1.02–1. The benefits tion. Chapter 16: Acute therapies and interventions in rtPA-treated patients (5. window [55]. increasing age and increasing stroke but not with time from onset to treatment or baseline severity are among the poor prognostic factors which NIHSS score.0–4. regulatory authorities patients and therefore most clinicians will base their have placed an upper limit of 3 hours for routine decision to offer thrombolysis upon the patient’s use of alteplase after stroke. but these are but are present after 3 months following stroke [7]. as should arterial disability following their stroke. Patients with severe hypertension cannot start within 3 hours should not be deprived at the time of admission were excluded from the trials of therapy for the sake of a few minutes delay. or in those with severe stroke (NIHSS > 24). favorable outcome of 1. This suggests that whilst early treatment confusion with Todd’s paresis. Patients who receive timely treatment with platelets or anticoagulants should be avoided for intravenous rtPA have better odds of minimizing 24 hours following thrombolysis. provided that all unnecessary delays are 90% delivered over 1 hour. The dose of alteplase is thus good reason for clinicians and regulatory author. have been identified [8]. of the patients being independent several months but such procedures are not currently in routine use 231 after their stroke. risks of parenchymal hemorrhage are slightly greater Various techniques have been employed to help in patients who receive thrombolysis. the odds of facilitate effective thrombolysis and vessel recanaliza- death are not significantly increased. of thrombolysis and therefore blood pressure is rec- More compelling are the results of the third ECASS ommended to be below 185/110 mmHg before. effectively confirming the estimate of Indications and contraindications for thrombolysis 1. beyond 3 hours. The European license for alteplase does. Until now. have helped to inform clinical practice. however. There is are listed in Table 16. Thrombolysis is contraindicated in patients remains as safe as earlier treatment in routine clinical with seizure at stroke onset due to the possibility of practice [54].4 that derives from meta-analysis [7]. Elevated mal hemorrhage was associated with increasing age.6% versus 1. extended early ischemic changes on The benefits of intravenous thrombolysis are CT or in those over the age of 80 years [1].9 mg/kg up to a maximum ities to consider relaxation of the strict 3-hour dose of 90 mg. 10]. and although the puncture at a non-compressible site. patients in whom treatment as a stroke mimic. Multi- is good practice to discuss the risks and benefits of modal imaging technologies. exclude its use in those over the age of minutes and out until 4. Appropriate patient selection is therefore important when considering whether a Intravenous thrombolysis is a standard therapy for patient may be suitable for thrombolysis treatment. and are beyond the scope of this chapter. shown that treatment at an average of 3 hours 15 however. There is therefore greatest when treatment is initiated early some evidence that thrombolysis is safe in elderly following stroke. and diffusion-weighted MRI. which may be present remains desirable. weight-dependent at 0. thrombolytic therapy. Aspirin and other anti- avoided. . It not currently in routine clinical use [1. such as perfusion CT treatment with patients or their family before treat. the following intravenous thrombolysis.5 hours after stroke onset 80 years.0% in those Post hoc analyses of thrombolysis data have who received treatment between 91 and 180 minutes identified factors associated with a poor outcome following stroke onset).34 (95% confidence interval Severe hypertension increases the risks of hemor- 1. and trial. including transcranial Doppler “sonothrombo- of thrombolysis are not necessarily seen immediately lysis” and microbubble administration.76) with treatment in the 3.5-hour rhagic transformation following thrombolysis [8]. are being studied in ment is commenced and to emphasize that the aim of the hope of improving patient selection for thrombo- thrombolytic treatment is to improve the chances lysis and extending the time window for intervention. and these results proportion of patients suffering secondary parenchy. serum glucose. with rates for nosed by physicians experienced in stroke care [1. Indications and contraindications for intravenous In practice. This confirms the safety and efficacy of using rtPA for acute ischemic stroke in well-selected patients with acute ischemic stroke. Whilst strategies are being 232 with the appropriate experience and training.7 and Seizure at stroke mic stroke thrombolysis. it is not currently established as a routine with a delay > 3 hours. with recovery lower rates of symptomatic intracerebral hemorrhage and mortality observed in the SITS-MOST data. alteplase. intravenous thrombolysis varying. therapy within 3 hours of stroke onset. Patients onset. in a dose of of intra-arterial thrombolysis for proximal occlusions 0. No of a stroke service will vary depending on local significant difference between intravenous and intra- factors. although developed to improve the rapid recognition and assess- this does not necessarily need to be a radiologist. 90% over 1 hour). The exact structure thrombolysis alone is currently under way [1]. Section 4: Therapeutic strategies and neurorehabilitation Table 16. thrombolysis remain in the minority. have been employed in some rural areas.4 pendence (modified Rankin Score. The approved agent is recombinant tissue plasmi. and intra-arterial rtPA compared to intravenous ment and imaging once admitted. such a service will differ depending on local needs and no single model can be claimed to be superior to Intra-arterial thrombolysis is used in selected cases up to 6 hours after MCA occlusion. severe stroke (NIHSS > 24) studies investigating intra-arterial thrombolysis have or seizure at stroke onset should be excluded. used pro-urokinase. treatment option in the majority of centers [1]. which is currently not available Having identified patients who are potential can. blood pres. mRS < 3) at Platelets < 150  109/l 3 months were similar in the SITS-MOST group com- Rapid neurological pared to the pooled randomized controlled trials. systems must intra-arterial agent are lacking. age > 80 years. hemorrhage A request associated with the European license for CT/MRI exclusion of Ischemic stroke alteplase was that outcome data should be collected hemorrhage and extensive within 3 months prospectively for the first 3 years or 1000 patients on infarct (>1/3 of MCA territory) patients in whom alteplase was used for acute ische- Serum glucose >2. Although some evidence exists to support the use nogen activator (rtPA). The proportions of patients achieving inde- Age 18–80 years INR > 1. 11]. The import- ant common factors which ensure a safe and effective Patients who meet the criteria for intravenous service are that patients should be assessed and diag. Structuring thrombolysis services in places arterial thrombolysis has been demonstrated for patients where patient populations are spread over large rural with basilar artery occlusion in non-randomized areas can be particularly challenging. it provided evidence that the use of intravenous thrombolysis in routine clinical practice results in NIHSS >3 and <25 Unexplained hemorrhage outcomes comparable to those observed in clinical trials.9 mg/kg up to a maximum dose of 90 mg (10% of the middle cerebral artery (MCA) within 6 hours of administered as a bolus. and large-scale studies using rtPA as an didates for intravenous thrombolysis. consideration Indication Contraindication needs to be given to the geographical location of the acute stroke unit in comparison to radiology and Stroke onset within 3 hours Previous intracranial other acute services.1. The Safe Implementation of <22. Novel technologies such as telemedicine lished as a routine treatment option. due to the time constraint of initiating thrombolysis in acute ischemic stroke. in Europe. but is not estab- another. The sure > 185/110 mmHg. throughout Europe. but relatively Brain imaging should also be reviewed by a physician low. Reassur- or 110 mmHg diastolic ingly. The structure of comparisons [1]. ment of patients who may be suitable for intravenous .2 mmol/l onset Thrombolysis in Stroke – Monitoring Study (SITS- BP <185 mmHg systolic and/ Recent major surgery MOST) collected data on 6483 patients [11]. A clinical trial investi- be in place to ensure their timely transfer to an gating the efficacy of the combination of intravenous appropriate medical facility and rapid access to assess. In both studies. the majority of patients remain ineli.6% vs. Aspirin was com. ischemic stroke or myocardial infarc. this intervention not realized until the publication of two large random. the Chinese Acute Stroke Trial suffered ischemic strokes. ferred with 75 mg daily whilst avoiding the potential tion have been established for more than 10 years [13]. For those who are ineligible for intravenous results were observed in the IST with a significant thrombolysis as part of routine clinical care. between the CAST and IST (160 mg daily and 300 mg tion in a high proportion. with the rent serious vascular events in patients with transient evidence suggesting that the same benefit can be con- ischemic attack. To date there are no randomized con- has been excluded. CT readily distinguishes between trolled trial data available for embolectomy devices ischemic and hemorrhagic stroke within the first 5–7 and consequently their use is not currently part of days and is most cost-effective when performed immedi- routine clinical practice. Therefore. these two landmark studies pro. between groups [14]. offered and other alternative interventions should be although the number of early deaths was similar considered. Evidence exists . The benefits of low-dose aspirin in preventing recur. The dose of aspirin prescribed varied Mechanical embolus removal achieves recanaliza. Similar gible. 15]. Early aspirin use (within 48 hours of stroke onset) was associated with a significant Mechanical embolus removal reduction in death or non-fatal recurrent stroke. 4 weeks in CAST. In absolute terms.1% vs. is available to the majority of patients who have ized controlled trials.3% vs.9%) without inappropriate or impossible.9%). other studies. aspirin observed in those patients who achieved successful re- can justifiably be withheld until intracerebral bleeding canalization. 16]. offset by a significant 14% reduction in Other antiplatelets mortality (3. published in 2005. Sub- ies. is proportion expected from a historical control popula- now generally universally available within the first tion (18%) and favorable neurological outcomes were 24 hours of admission to an acute stroke unit. a computed tomography vessel re-canalization in 68 of the 141 (48%) patients (CT) scan to exclude intracerebral hemorrhage was ineligible for conventional intravenous thrombolysis mandatory only in comatose patients. by several thousand worldwide. but controlled trial data daily respectively) and other doses have been used in are not yet available. Once intracranial hemorrhage has been excluded aspirin should be administered at the earliest opportunity at a dose of 300 mg either orally or rectally Aspirin depending on the patient’s ability to swallow safely. with or stroke (1. Given within 8 hours of stroke onset [12]. In the CAST aspirin treatment was associated with a slight increase in hemorrhagic stroke (1. reported their stroke. With a combined study population of more tial to reduce the number of recurrent vascular events than 40 000 patients. although it was and in whom the embolectomy device was deployed considered preferable prior to randomization. 3. ately [1. A dose of 300 mg aspirin should be administered within 48 hours of stroke onset after exclusion of menced within 48 hours of stroke onset in both stud- intracerebral hemorrhage through a CT scan.8% vs.1%). 2.9%) and early recurrent ischemic Whether or not other antiplatelet agents. Chapter 16: Acute therapies and interventions thrombolysis. 13 fewer patients per 1000 treated with The Mechanical Embolectomy Removal in Cerebral aspirin were dead or dependent at 6 months following Ischemia (MERCI) trial. 233 patients per 1000 treated with aspirin who were dead tion has been extensively investigated. side-effects which are more commonly observed at The potential benefits of commencing aspirin therapy higher doses [17]. Although the absolute benefits pro- in patients early after the onset of ischemic stroke were vided by early aspirin use are small. or dependent at the time of discharge [15]. confer additional vascular risk reduc. 3. vide strong evidence supporting the early introduction of aspirin following ischemic stroke. best supportive care is an associated excess of intracerebral hemorrhage. and in reduction in early recurrent ischemic stroke observed whom participating in a clinical research trial is either in the aspirin-treated group (2. either by CT or MRI. on a population (CAST) and the International Stroke Trial (IST) level. 0. This exceeds the that access to brain imaging. initiating early aspirin treatment has the poten- [14. Subsequent doses can be lower (75–300 mg). and continued for up to 14 days in IST and up to sequent doses can be lower (75–300 mg). This corresponded to 11 fewer without aspirin. 24) [23]. two-by-two factorial design. The free-radical-trapping to those who were not. and also observed was almost identical to the risk excess for that the antiplatelet agent clopidogrel is at least symptomatic intracranial hemorrhage [22]. . although the same combination has also embolic etiology. risk of re-embolization [1]. or a combination of antiplate- disease and uncontrolled arterial hypertension are let agents in the context of acute stroke. onset of cerebral ischemia and therefore a substance After 6 months.68. 0.89. anticoagulation was associated with a non- However. There is equivalent to aspirin and dipyridamole combined therefore currently no evidence to support the routine [19]. however. following ischemic stroke.2% neuroprotective agent when introduced within 6 hours vs. heparin use agent NXY-059 showed initial promise as a potential was associated with more hemorrhagic strokes (1. The combination of aspirin and clopidogrel use of anticoagulants in all patients in the early after- has been shown to be of some value in patients with math of ischemic stroke.06) without any significant change in death therefore there is no evidence to support their routine or disability at final follow-up (odds ratio 1. good practice confidence interval 0. Furthermore there was also no effect to show significant benefit when commenced early in patients with primary intracerebral hemorrhage.g. 95% confidence platelet therapy at the earliest opportunity in appro. the efficacy of either dipyridamole.8%) [14]. Unfortunately. Neuronal injury progresses rapidly following the 3. >50% of the middle There is no evidence of the efficacy of either dipyri.9% vs. The agent was also ineffective in those dose of subcutaneous heparin. Heparin for cardioembolic stroke The International Stroke Trial investigated the use of There is currently no evidence to support the rou- tine use of anticoagulants in all patients in the early aspirin and subcutaneous unfractionated heparin in a aftermath of ischemic stroke. in a meta-analysis of seven trials been shown to be associated with increased hemor. 0. the mortality rate was iden.82–1.44–1. there is currently no evidence to support benefit [1]. but a larger randomized transfused or fatal extracranial hemorrhages per 1000 controlled trial involving more than 3000 patients patients treated. stroke patients but showed an increased risk of symp.4%) and resulted in a significant excess of nine of ischemic stroke onset. the reduction in recurrent ischemic stroke dipyridamole in secondary prevention [18]. The risk of hemorrhagic complica. contraindications to full anticoagulation in the early post-stroke period.01. clopidogrel. clopido. with the increased risk of Whilst other studies of novel neuroprotective agents 234 hemorrhagic complications outweighing any potential are ongoing. significant internal carotid artery stenosis with distal For patients in whom stroke is due to a cardio- emboli [20]. The beneficial effects of aspirin have already been discussed but the study also identified three fewer deaths within 14 days per 1000 patients treated with heparin (non-significant) and Neuroprotection significantly fewer early recurrent strokes (2. onset. Studies of other patients who had been treated with intravenous unfractionated heparin preparations have also failed thrombolysis. The glycoprotein.5% vs. A significant and to commence appropriate secondary prevention anti. which attenuates this process may potentially reduce tical in those patients treated with heparin compared the extent of cerebral damage. interval 1.8%) and pulmonary emboli (0. however. almost 3-fold risk (odds ratio 2. or a combination of antiplatelet agents has not stroke (odds ratio 0. Evidence of a large infarc- tion on brain imaging (e.19–7. involving 4624 patients within 48 hours of stroke rhagic risk in patients with completed stroke [21]. It is. Section 4: Therapeutic strategies and neurorehabilitation to support the use of the combination of aspirin and therapy. did not demonstrate any benefit of NXY-059 over tions was greater in the group which received a higher placebo [24]. cerebral artery territory) or extensive microvascular damole. Despite the lack of supporting evidence.01) of symptomatic intracranial hem- priate patients with a safe swallow. significant reduction in early recurrent ischemic grel. 95% confidence interval been investigated in the context of acute stroke and 0. some authorities would advocate early anticoagula- tomatic or fatal intracranial hemorrhage without an tion with full-dose heparin in selected patients at high associated benefit and therefore its use is not advised [1]. In a meta-analysis of early anticoagulant their routine clinical use at present. orrhage was identified with number needed to harm IIa-IIIb inhibitor abciximab has been studied in acute being 55. 95% use in the acute setting. published studies examining various interventions Analysis of the IST revealed a 3. with one. is therefore yet to be identified. following thrombolytic treatment. Cardiovascular complications quarter of patients having systolic BP  180 mmHg as well as early stroke recurrence in patients with within 48 hours of admission [15]. blood pressure antihypertensive medication should be continued or tends to spontaneously fall within the first hours and withdrawn following stroke and this is the focus of days following the acute event. Within the first 24 hours post-stroke BP is associated with a poor outcome. High had systolic blood pressures measured in excess of pre-thrombolysis BP has also been shown to be asso- 140 mmHg during the first 48 hours following admis. of randomization. the early management of blood pres. 19% had admission systolic BP > 185 mmHg and There is therefore evidence that high (and low) diastolic BP > 110 mmHg. with BP Hypertension is a well-recognized risk factor for first having been shown to fall spontaneously in response ever and recurrent stroke [25. 29]. 33]. Hypertension may sustain cerebral Blood pressure – see Chapter 17 perfusion to the ischemic penumbra [34]. following stroke and also upon stroke sub-type and sure following ischemic stroke remains controversial co-morbidities. ment of cerebral autoregulation. Precipitous falls in blood pressure have. with the pattern of current research [37]. how this common clinical situation is best managed.2% increased risk of early recurrent 2 weeks of acute stroke concluded that there was insuffi- stroke within 14 days with each 10 mmHg rise in cient evidence to evaluate the effects of altering BP systolic BP above 150 mmHg. between admission BP and stroke outcome has been identified. Indeed. with very high and very low blood pressure A Cochrane systematic review of published and un- being associated with poor post-stroke outcome. with 28% having a systolic BP  180 mmHg [27]. 60% had blood pressure in excess although the relationship is not a straightforward of 180 mmHg systolic or 105 mmHg diastolic [28]. Chapter 16: Acute therapies and interventions Up to now all neuroprotective therapies have been systemic arterial BP following stroke due to impair- without clinical efficacy. one.9%. 82% of patients the restoration of cerebral autoregulation [35]. 26] and is commonly to successful re-canalization of cerebral vessels observed in the immediate post-stroke period. Until evidence is available to the contrary. hypertension may contribute to worsening cerebral Similarly. perhaps suggesting In the International Stroke Trial. it is also unclear as to whether pre-existing stroke period is frequently observed. edema and hemorrhagic transformation following quarters had systolic BP  140 mmHg. A ‘U-shaped’ association onstrated in clinical trials. Cerebral perfusion becomes dependent upon stroke period unless there is a concurrent indication . and and is the subject of ongoing research.6% at 6 months [27]. For every 10 mmHg on outcome during the acute phase of stroke [38]. in the Chinese Acute Stroke Trial three. and therefore changes in systemic BP can directly influence cerebral perfusion [26. Of the 624 patients elevated post-stroke blood pressures have been pro- who were included in the NINDS rtPA Stroke Trial. posed as possible mechanisms for poor outcome [32]. blood pressure and both early and late death or however. how to achieve it. Further analyses have confirmed the association This lack of certainty is reflected in clinical between elevated systolic. admission systolic BP was below 150 mmHg. acute ischemic stroke. with clinicians avoiding the active reduc- BP in the acute stroke period and poor outcome tion of blood pressure in the early post-stroke period following ischemic stroke. and the risk of death or hopes to provide valuable knowledge and insight into dependency was increased by 3. Early recurrent stroke has [39].8% increased risk aimed at deliberately altering blood pressure within of death and 4. diastolic and mean arterial guidance. the risk Numerous clinical trials are currently ongoing and each of early death rose by 17. 31]. cur- been suggested as one possible mechanism by which rent clinical guidelines do not advocate the active elevated BP may be associated with poor outcome reduction of hypertension in the immediate post. ciated with poor re-canalization [36] and sustained sion. The true relationship may depend on a combi- Despite high blood pressure being very common nation of absolute BP level and the variability in BP following stroke. Although hypertension in the immediate post. The optimum post-stroke BP. 235 [32]. blood pressure change varying with stroke subtype A U-shaped relationship between baseline systolic [26. been associated with poor outcome and dependency after ischemic stroke has been dem- should be avoided [30. to glucose-potassium-insulin (GKI) infusion versus tolic BP exceeds the threshold required for thrombo. 45]. be recommended.6 mmol/l in of 15–25% in the first 24 hours) [40]. diabetes mellitus [41]. Based upon clinical opinion. and by means the active treatment and control groups respectively. Hypoglycemia (serum required in order to determine the optimum method glucose < 2. which probably reflects period. The routine use of insulin regimes to control restricted to those patients with previously diagnosed post-stroke hyperglycemia cannot be recommended. A short-acting intravenous The 90-day mortality did not differ significantly beta-blocker such as labetolol or intravenous nitrates between the groups although this study was limited may be useful in this situation as the effects are readily by slow recruitment and therefore underpowered.8 mmol/l and 7. reversed on withdrawal of the agent. some centers have developed rhagic) recruited 933 patients and randomized them local protocols for cautiously lowering BP when sys. If difference between the active treatment and control elevated BP is to be lowered in the acute post-stroke groups being 0. If elevated BP is to available. Section 4: Therapeutic strategies and neurorehabilitation to do so [1]. shown to be associated with poor outcome. There is Body temperature – see Chapter 17 evidence of a positive association between elevated Increased body temperature following stroke has been admission plasma glucose and poor post-stroke out. The prevalence of previously unrecognized diabetes mellitus or impaired glucose tolerance may be between 20% and 30% [42]. Its occurrence should alert the clin- context of acute stroke [44. 43]. 0. units appears to confer a beneficial outcome. A rise in body tem- ically ill patients being managed in intensive care perature can be centrally mediated following stroke. and is not sion. Hypoglycemia trose [1]. Measurement of blood glucose is mandatory for all patients with suspected stroke. Current clinical guidelines do reductions in post-stroke hyperglycemia may not be not advocate the active reduction of hypertension in the immediate post-stroke period unless there is well tolerated. Tight control of hyper. the reduction should be cautious (North the median glucose at admission. Until additional evidence becomes a concurrent indication to do so. which raises the possibility that large is yet to be identified. Currently. the routine use of insulin infusion regimes be lowered in the acute post-stroke period. Similarly. with the mean clinical experience rather than specific evidence [1]. although these are based on tions in plasma glucose were achieved.57 mmol/l. of achieving and maintaining post-stroke euglycemia. of a short-acting agent. Hyperglycemia has a reported prevalence of should be corrected by an intravenous dextrose infu- up to 68% of acute stroke admission. the to control moderate post-stroke hyperglycemia cannot reduction should be cautious. myocardial infarction. however. tion and pre-eclampsia. using GKI. if clinically appropriate. and so but more commonly it suggests the presence of inter- 236 it has been suggested that the same may be true in the current infection.8 mmol/l) with consequent neuroglyco. there is no conclu. it is good practice to monitor and treat pyrexia in the glycemia following myocardial infarction and in crit. Until strong evi. some acute stroke units may intervene to control post- stroke hyperglycemia in patients with blood glucose Blood glucose – see Chapter 17 >10 mmol/l. Further research is patients with suspected stroke.9% saline (control group) [46]. ician to this possibility and. although this decision must be made Measurement of blood glucose is mandatory for all on an individual patient basis [1]. euglycemia following stroke (ischemic and hemor- dence becomes available. Such indications include hypertensive there is no evidence to support the routine active encephalopathy. Sub-lingual A post hoc analysis identified an increase in the calcium-channel blockers should be avoided. Only small reduc- lysis (185/110 mmHg). Studies of come. The largest randomized controlled trial of an active sive evidence that low BP should be actively elevated intervention aimed at achieving and maintaining following acute ischemic stroke [1]. immediate post-stroke period. . which was only American guidelines suggest a maximum reduction modestly elevated at 7. and how to achieve it. higher mortal. lowering of hyperglycemia following acute stroke. anti-pyretic medication and thermal cooling devices ity and reduced functional recovery observed in those have not provided conclusive evidence of efficacy but with hyperglycemia [41. aortic dissec. proportion of patients with a poor outcome where a reduction in glucose of 2 mmol/l was achieved The optimum post-stroke BP. penia is an important stroke mimic and is readily corrected by the intravenous infusion of 10–20% dex. with increasing stroke severity. glycerol (4  250 ml 10% glycerol over 30–60 minutes) or Brain edema and surgical intervention hypertonic saline. 70 mmHg and can be lowered by using intraven- ous mannitol (25–50 g every 3–6 hours). expert opinion advises that decom- should be maintained at 70 mmHg and can be pressive surgery and ventriculostomy can be con- lowered by using intravenous mannitol (25–50 g sidered in cases of cerebellar infarction as prognosis every 3–6 hours). pain control and tions. Medical therapy includes patients with space-occupying posterior fossa infarc- airway management. Importantly. Mild hypothermia in combination infarct in >50% of the MCA territory on CT [1]. arteriovenous malformation treatment of malignant infarction of the middle cere. Cerebellar infarction but usually becomes evident between days 2 and 5 Neurosurgical opinion should also be sought in following stroke onset [1]. Whilst a detailed descrip- niectomy after middle cerebral artery infarction with tion of the management of all ICH is beyond the scope life-threatening edema trial) [47]. with antipyretic medication [1]. ICH is commonly associated with hypertension or pressive craniotomy: the DECIMAL (decompressive cerebral amyloid angiopathy. The effects of sur. there was no increase in the 4 g/24 h in adult patients. 4 and 2 respect- be administered every 4–6 hours. high as 80% [47]. mRS  3 at temperature following stroke is commonly treated 1 year and survivors at 1 year irrespective of function. (AVM). Paracetamol 1 g can The numbers needed to treat were 2. including recurrent intracranial on item 1a of the NIHSS) and who have evidence of pressure crisis [1]. but study. which can occur within 24 hours of stroke. the DESTINY (decompressive surgery for the not limited to. over 30–60 minutes) or hypertonic saline. while secondary ICH surgery in malignant middle cerebral artery infarcts) results from a number of pathologies including. although the evidence for such interventions comes from mainly observational data [1]. and the HAMLET trial (hemicra. neoplastic disease. Chapter 16: Acute therapies and interventions such infections should be treated. induced mild hypo. aneurysms. glycerol (4  250 ml 10% glycerol can be favorable [1]. with decompressive surgery may be of benefit in Neurosurgical opinion should be sought at an early patients with severe MCA infarction. via the oral. Intracranial pressure is not available. but increases the risks of severe side-effects whom consciousness is impaired (score of 1 or greater during re-warming. but a term used to describe the consequences Surgical decompression of evolving malignant of a variety of pathologies. cerebral vasculitis and bral artery) study. an outline of the principles of the initial gery in the three trials were consistent and. Although randomized controlled trial evidence control of body temperature [1]. upon the 93 patients included in the pooled analysis. For patients who have suffered severe 5). Evidence for this comes from the and subarachnoid hemorrhage (SAH) [2]. Intracranial pressure should be maintained at monly treated with antipyretic medication. with the aim of performing surgery evidence for temperature reduction is limited [1]. 237 showed a significant improvement in the proportion some aspects of the patients’ immediate management . oxygenation. Raised body of patients with mRS  4 at one year. numbers of survivors left with severe disability (mRS venous routes. Once ICH has been confirmed on brain imaging. although the opportunity. It accounts for around 20% MCA infarction should be considered in certain of strokes and includes primary ICH. Patients who should be considered for decompres- middle cerebral artery infarction. sive hemicraniectomy are those up to 60 years old thermia (brain temperature 32–33 C) reduces mor. Early deterioration and death are often due to cerebral edema and rising intracranial pressure. ical entity. to a total dose of ively [47]. Primary pooled analysis of three European studies of decom. rectal or intra. Raised body temperature following stroke is com. secondary ICH selected patients. venous sinus thrombosis [2]. within 48 hours of stroke onset. of this chapter. Dexamethasone and Intracerebral hemorrhage corticosteroids are not indicated and hypotonic and Intracerebral hemorrhage (ICH) is not an isolated clin- dextrose-containing solutions should be avoided [1]. based management of ICH will be discussed here. Surgical decompression of evolv- For patients suffering from large middle cerebral ing malignant MCA infarction should be considered artery (MCA) territory infarctions mortality is as in certain selected patients. with evolving MCA infarction and NIHSS > 15 in tality. Furthermore. However. Raised intracranial pressure can be lowered if tension. although evidence of the efficacy of is used for such patients. and perhaps require. A target BP of 160/100 mmHg logically stable. although been studied and no single agent has been shown to be ICH associated with oral anticoagulation will be superior.3% propor. Conversely. No difference in death. Where this is unsuccessful. there was no difference and continued for 7 days (13. although vention. 36. ventricular drainage for subsequent . outcomes is under way. results from Although not confirmed by randomized controlled the Antihypertensive Treatment of Acute Cerebral trials. data to support the association between active blood In particular. surgical intervention for cerebellar hematoma 238 Haemorrhage (ATACH) study provide additional should be considered. neurological deterioration surface) and no IVH compared to patients with deep or disability was identified between the groups at hematomas who do not benefit from surgical inter- 90-day follow-up in this study of 404 patients. upper limits of 160/95 mmHg are accepted necessary by using medical methods previously dis- before BP lowering is advocated. cerebral perfusion pressure. In support ventilation can be utilized in order that adequate of active blood pressure reduction following ICH. which will require anticon- following ICH without intraventricular hemorrhage vulsant therapy [2]. hypertension may be following ICH. higher cerebral stroke patients. although their use is widespread [2]. Clearly. which is currently ongoing. Although the difference surgical intervention (<24 hours) and those who in proportional mean hematoma growth within 6 hours were managed conservatively [51]. Section 4: Therapeutic strategies and neurorehabilitation differ from that following ischemic stroke. and the those patients who received standard-guideline-based presence of intraventricular expansion of the hemor- blood pressure control (target systolic blood pressure rhage (IVH). in whom the ICH was superficial (1 cm from the sion. pressure lowering and reduced hematoma expansion thrombolysis is contraindicated! Coagulopathy should [49]. Titration and revision of these thresholds discussed separately. versial in patients with ICH. location. Graduated compression stockings perfusion pressures in order to maintain adequate have not yet been confirmed to be effective in patients cerebral perfusion. BP Antithrombotic and Thrombolytic Therapy recom- should be gradually lowered to below a mean arterial mends that low doses of unfractionated or low pressure (MAP) of 120 mmHg. Seizure the Intensive Blood Pressure Reduction in Acute is more commonly encountered in patients with ICH Cerebral Haemorrhage Trial (INTERACT) reported compared to ischemic stroke and non-convulsive reductions in mean hematoma growth in patients status has been described. ant in patients following ICH as it is in post-ischemic fore tolerate. but may cause hematoma expansion and are therefore the current European Stroke Initiative recommend.04) [48]. Limited Anticoagulants in the form of subcutaneous heparins data are available to guide clinical practice. In patients without a history doing so is not available [50]. A number of oral and intravenous agents have be identified and treated as quickly as possible. best avoided within the initial days following ICH ations advise that in patients following ICH in [2]. associated with hematoma expansion [2]. the data would suggest that intensive lowering a Glasgow Coma Score of between 9 and 12. or clinical evidence of previously sustained hyper. in outcome between those patients who received early tional increase. therapeutic hyper- of 150/90 mmHg (MAP 110 mmHg) [2]. who had intensive blood pressure lowering (target Surgical intervention for ICH depends on a systolic blood pressure of 140 mmHg) compared to number of factors. including size. This particular subset of patients warrants a larger study to determine the effects on clinical further investigation. with a target BP cussed. a trend was no longer significant (p ¼ 0. and of blood pressure appears to reduce hematoma expan. from CT. The advice of the Seventh ACCP Conference on whom there is a history of chronic hypertension. cerebral perfusion pressures are achieved [2].7% vs. and MAP should not be lowered second day following ICH in patients who are neuro- below 84 mmHg. may be required in order to maintain an adequate Early blood pressure manipulation is also contro. p ¼ 0. as outcomes are favorable [2]. whilst avoiding molecular weight heparin can be started on the reductions of >20%. In the Surgical Trial in Intracerebral of 180 mmHg) commenced within 6 hours of onset Haemorrhage (STICH) study.06) after adjustment towards a significant benefit was observed in patients for initial hematoma volume and time from onset to who suffered a deterioration in conscious level. Patients with ICH are Avoiding venous thromboembolism is as import- frequently chronically hypertensive and may there. good practice and an appreciation that patients with suspected stroke 239 to commence appropriate secondary prevention should be transported to an appropriate medical . Aspirin and other antiplatelets or anti- coagulants should be avoided for 24 hours following With intracerebral hemorrhage. cose. Recombinant factor VIIa initiates coagulation and therefore may be associated with increased throm- Chapter Summary botic tendency. percent of the total dose is administered as an intra- venous vitamin K and prothrombin complex concen. but after exclusion of intra- cerebral hemorrhage through a CT scan. investigated in the context of acute stroke and there- fore there is no evidence to support their routine Patient education and early recognition of symptoms use in the acute setting. Until more data are changes on CT or in those over the age of 80 years. trials of its use have been limited to patients without a history of previous Intravenous thrombolysis is a standard therapy for ischemic events.9 mg/kg up to a maximum dose of 90 mg. the individual patient. however. micro- lowered. For patients with intraventri. patients beyond 3 hours. diagnosis and treatment agents administered via the catheter to prevent cath. larger re-bleeds and a worse out. Chapter 16: Acute therapies and interventions hydrocephalus should be considered depending on facility in a time-efficient manner have been essential. been studied in patients with spontaneous ICH [2].5 hours can be discussed. Strong evidence supports the early introduction of location. thrombolysis is thrombolysis. though trials on this continue [2]. Consequently. For routine use of alteplase after thromboembolic events were significantly increased stroke there is an upper limit of 3 hours after the in the highest-dose group (160 µg/kg). 53]. Blood pressure is recom- come. acute stroke therapies. A dose of 300 mg expansion of the hemorrhage. but an extension of this time limit to involving more than 800 patients also found reduced 4. including size. ICH whilst anticoagulated is associated with more Thrombolysis is contraindicated in patients with severe hemorrhage. although arterial (rtPA). Additionally. hematoma expansion and significantly improved At present European regulatory agencies do not NIHSS scores compared to placebo when rFVIIa support the routine use of intravenous rtPA in was used within 4 hours of ICH at a dose of 80 µg/kg. Raised intracranial pressure can be bubble and intra-arterial thrombolysis administration lowered if necessary. significant changes in the way or a combination of antiplatelet agents has not been stroke services are configured have been required. (orally or rectally) should be administered within 48 hours of stroke onset. Surgical intervention for ICH are currently not in routine clinical use. extended early ischemic outcome was identified [52. decreased mortal- stroke is recombinant tissue plasminogen activator ity and improved 3-month outcome. In the first clinical trial with rFVIIa. a well-selected population of patients with acute the use of recombinant factor VIIa within 4 hours of ischemic stroke. alteplase. It is. and the presence of intraventricular aspirin following ischemic stroke. seizure at stroke onset. A further trial onset of stroke. with an increased risk of death [2]. use of rFVIIa cannot be regarded as part Factors associated with a poor outcome following intravenous thrombolysis are elevated serum glu- of standard clinical care. Ten effectively achieved by using a combination of intra. there is some evidence to support staff of stroke as a medical emergency necessitating the use of intraventricular drainage with thrombolytic rapid clinical assessment. available. from the array of established and evolving acute The use of recombinant factor VIIa (rFVIIa) has stroke interventions. depends on a number of factors. For patients mended to be below 185/110 mmHg. the recognition by medical and nursing cular hemorrhage. Subsequent Summary doses can be lower (75–300 mg). Hypertension should be gradually Transcranial Doppler ‘sonothrombolysis’. or in those with severe but no sustained advantage in terms of functional stroke (NIHSS > 24). clopidogrel. contraindicated. has been essential in maximizing the potential benefit eter obstruction. This can usually be 0. or fresh frozen plasma. venous bolus with the remaining 90% delivered trate. the priority The dose of alteplase is weight-dependent at is to reverse the anticoagulation. over 1 hour. The only thrombolytic agent licensed in Europe for the treatment of ischemic ICH limited hematoma expansion. who suffer ICH whilst anticoagulated. increasing age and increasing stroke severity. In order that patients obtain the full potential benefit of The efficacy of either dipyridamole. Raised controversial. JAMA 1995. the early management of heparin may be started on the second day following blood pressure following ischemic stroke remains ICH in patients who are neurologically stable.g. Clark WM. Surgical intervention for ICH depends on a number fied. hemispheric stroke. 1017–25. activator (alteplase) for ischemic stroke 3 to 5 hours after symptom onset: the ATLANTIS Study: . with very high and very low blood pressure of factors. as well as leading to cardio- vascular complications. Randomised double-blind placebo Raised body temperature following stroke is controlled trial of thrombolytic therapy with commonly treated with antipyretic medication. with increasing stroke severity. Current clinical guidelines do not advocate the 1. Surgical decompression of evolv- Despite the lack of supporting evidence. admission BP and stroke outcome has been identi. cautious (North American guidelines suggest a max- 2. Cerebrovasc Dis 2006. A ‘U-shaped’ association between intracranial pressure can be lowered if necessary. The optimum post-stroke BP. Guidelines for the management of ischaemic stroke and cation to do so. extreme hyperglycemia can be corrected. is therefore yet to be identi. Committee. sive agent has been shown to be superior. and how to achieve it. 352:1245–51. Currently. There is evidence of a positive association 3. how. The European Stroke Initiative Writing Committee and imum reduction of 15–25% in the first 24 hours). Low Despite high blood pressure being very doses of unfractionated or low molecular weight common following stroke. No single antihyperten- to full anticoagulation in the early post-stroke period. with full-dose heparin in selected patients at high With intracerebral hemorrhage. >50% of the middle cerebral lowered (target blood pressure 160/100 mmHg in artery territory) or extensive microvascular disease and patients with. contribute to worsening cerebral edema and hemor- rhagic transformation. but sustained hypertension may recommended. If elevated BP is to be lowered in the transient ischaemic attack 2008. ommended. acute post-stroke period. location. Recombinant tissue-type plasminogen 240 side-effects. 5. there is no evidence to support the routine active lowering of hyperglycemia following acute stroke. References fied. of intraventricular expansion of the hemorrhage. ever. hypertonic saline. et al. The National Institute of Neurological Disorders and Stroke rt-PA stroke study group. Lancet 1998. Hacke W. some ing malignant MCA infarction should be considered authorities would advocate early anticoagulation in certain selected patients. but increases the risk of severe 6. the reduction should be 25:457–507. Recommendations for the Management of Measurement of blood glucose is mandatory for Intracranial Haemorrhage – Part 1: Spontaneous all patients with suspected stroke. et al. Cerebrovasc Dis 2008. infusion. and the presence being associated with poor post-stroke outcome. The Hypertension may sustain cerebral perfusion to the use of recombinant factor VIIa (rFVIIa) cannot be ischemic penumbra. Intravenous thrombolysis with between elevated admission plasma glucose and poor recombinant tissue plasminogen activator for acute post-stroke outcome. et al. including size. N Engl J Med 1995. moderate post-stroke hyperglycemia cannot be rec- 333:1581–8. and the Writing Committee for the EUSI Executive by means of a short-acting agent. Hypoglycemia Intracerebral Haemorrhage. Section 4: Therapeutic strategies and neurorehabilitation antiplatelet therapy at the earliest opportunity in Intracranial pressure should be maintained at appropriate patients. Tissue plasminogen routine use of insulin infusion regimens to control activator for acute ischaemic stroke. Induced intravenous Alteplase in acute ischaemic stroke mild hypothermia (brain temperature 32–33oC) (ECASS II). Hypertension should be gradually on brain imaging (e. thrombolysis is risk of re-embolization. The European Stroke Organisation (ESO) Executive active reduction of hypertension in the immediate Committee and the ESO Writing Committee. Evidence of a large infarction contraindicated. reduces mortality. The 4. Hacke W. post-stroke period unless there is a concurrent indi. 70 mmHg and can be lowered by using intra- There is currently no evidence to support the venous mannitol (25–50 g every 3–6 hours). The European Cooperative higher mortality and reduced functional recovery Acute Stroke Study (ECASS). and 150/100 mmHg in patients with- uncontrolled arterial hypertension are contraindications out chronic hypertension). should be corrected by an intravenous dextrose 22:294–316. On an individual patient basis. glycerol routine use of anticoagulants in all patients in the (4  250 ml 10% glycerol over 30–60 minutes) or early aftermath of cardio-embolic ischemic stroke. 274(13): observed in those with hyperglycemia. Collaborative overview of randomised trials of (11):2652–7. CD000024. 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Risk factors of symptomatic detection: the Clopidogrel and Aspirin for Reduction intracerebral hemorrhage after tPA therapy for acute of Emboli in Symptomatic Carotid Stenosis (CARESS) stroke. subcutaneous heparin. 282 19. 77(7):826–9. et al.435 patients with acute ischaemic stroke. 10. Thrombolysis with Alteplase treatment in acute cardioembolic stroke: a meta- for acute ischaemic stroke in the Safe Implementation analysis of randomized controlled trials. et al. BMJ 1994. stenosis evaluated using Doppler embolic signal 8. A systemic review. J Neurol Neurosurg Psychiatry 2006. 72:467–72. et al. Potter JF. and stroke by prolonged antiplatelet stroke. et al. Circulation 2005. 349:1641–9. strategy for acute stroke? Health Technol Assess 2004. et al. Wardlaw JM. 61:1047–51. et al. International Society of Hypertension 15. 111(17):2233–40. Thrombolysis in patients older than 80 21. Sylaja PN. 8:1–180. Safety and efficacy of mechanical 357:562–71. 12. 32. Detrimental effect of blood 17. 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Seventh ACCP Conference on Antithrombotic and 8(6):408–15. et al. the value of this guideline as an educational tool for neurologists. et al. Continue or Stop Antihypertensives Collaboration Lancet Neurol 2007. in acute cerebral haemorrhage trial (INTERACT): a 38. 26:57–65. N Engl J Med 2001.1002/ Stroke Conference. J Am Coll Cardiol 1995. Hacke W. Weir CJ. Gray CS. Stress hyperglycaemia and prognosis hemorrhage. Cardiovascular Radiology and Haemorrhage (STICH): a randomised trial. Efficacy and safety of recombinant activated Factor VII for acute intracerebral 41. Peripheral Vascular Disease and Quality of Care 52. pooled analysis of three randomised controlled trials. et al. for the European Cooperative Acute 44. Gray C. pressure with tissue plasminogen activator-induced 47. Section 4: Therapeutic strategies and neurorehabilitation 34. Mayer SA.5 hours for diabetic patients with acute myocardial infarction. Powers W. N Engl J Med 2005. et al. 40. 43:461–7. Lancet Neurol 2008. Glucose and insulin therapy in acute acute ischaemic stroke in the Safe Implementation stroke. et al. of a long term follow up study. Mayer SA. et al. the management of post-stroke hyperglycaemia: the Stroke 2005. 38:961–6. 36:264–9. Antithrombotic and 39. A practical guide. Clinical International Surgical Trial in Intracerebral Cardiology Council. http://www. Chapter 17 Management of acute ischemic stroke and its complications Natan M. Bornstein and Eitan Auriel General management of elevated Blood pressure and outcome blood pressure, blood glucose and Analysis of 17 398 patients in the International Stroke Trial [4] demonstrated a U-shaped relationship body temperature between baseline systolic blood pressure and both Monitoring the blood pressure (BP), glucose levels early death and late death or dependency. Both high and temperature in acute stroke patients is an often blood pressure and low blood pressure were inde- neglected matter although it may have an important pendent prognostic factors for poor outcome. Early impact upon the patients’ outcome. In the Tel Aviv death increased by 17.9% for every 10 mmHg below stroke register, recorded between the years 2001 and 150 mmHg (P < 0.0001) and by 3.8% for every 2003, 32% of acute stroke patients in the emergency 10 mmHg above 150 mmHg (P ¼ 0.016). A prospect- room had glucose levels higher than 150 mg/dl, higher ive study among 1121 patients admitted within systolic BP than 140 mmHg was found in 77% of the 24 hours from stroke onset and followed up for patients and 17% of patients had temperatures above 12 months demonstrated similar findings of the 37 C on admission. These numbers are representative “U shape” phenomenon [5]. It should be taken into of other centers as well. This chapter will summarize consideration that prolongation of the elevated blood the current knowledge regarding the management of pressure may be caused by more severe stroke as the above. compensation for the persistent vessel occlusion. On the other hand, the GAIN study [6], done among 1455 patients with ischemic stroke, demon- Hypertensive blood pressure values strated that baseline mean arterial pressure was not in acute ischemic stroke associated with poor outcome. However, variables Several observations have demonstrated spontaneous describing the course of BP over the first days have elevation of blood pressure in the first 24–48 hrs after a marked and independent relationship with 1- and stroke onset with a significant spontaneous decline 3-month outcomes. after a few days [1–3]. Several mechanisms may be In a Cochrane systematic review of 32 studies responsible for the increased blood pressure, includ- involving 10 892 patients [7] after ischemic and hem- ing stress, pain, urinary retention, Cushing effect due orrhagic stroke, death was found to be significantly to increased intracranial pressure and the activation associated with elevated mean arterial BP (OR, 1.61; of the sympathetic, renin–angiotensin and ACTH– 95% CI 1.12–2.31) and high diastolic BP (OR, 1.71; cortisol pathways. Despite the increased prevalence 95% CI 1.33–2.48). of hypertension following stroke, optimal manage- A U-shaped relationship between baseline systolic ment has not been yet established. Several arguments blood pressure and both early and late death speak for lowering the elevated BP: risks of hemor- or dependency after ischemic stroke has been rhagic transformation, cerebral edema, recurrence of demonstrated in clinical trials. stroke and hypertensive encephalopathy. On the other hand, it may be important to maintain the hyperten- sive state due to the damaged autoregulation in the BP and outcome in thrombolysed patients ischemic brain and the risk of cerebral hypoperfusion Several observations, including the NINDS-tPA trial 243 exacerbated by the lowered systemic blood pressure. [8, 9], found an association between high blood Section 4: Therapeutic strategies and neurorehabilitation pressure on admission, and its prolongation, with that phase [3]. Despite the controversy over the man- poor outcome and mortality. Although in one study agement of BP in the acute phase, the benefit of blood no such association was found in alert patients, stroke pressure reduction as a secondary prevention of patients with impaired consciousness showed higher stroke is well established and has been demonstrated mortality rates with increasing blood pressure [10]. in many studies. However, in most of these studies The association between elevated blood pressure and antihypertensive agents were administrated several recanalization was evaluated in 149 patients after weeks after stroke onset. Only a few trials were per- intra-arterial thrombolysis using angiography [11]. formed in the acute stage. The ACCESS trial [18] was The study demonstrated that the course of elevated a prospective, double-blind, placebo-controlled, ran- systolic blood pressure, but not diastolic blood pres- domized study evaluating the angiotensin receptor sure, after acute ischemic stroke was inversely associ- blocker candesartan vs. placebo for 342 hypertensive ated with the degree of vessel recanalization. When patients in the first week following stroke. Treatment recanalization failed, systolic BP remained elevated was started with 4 mg candesartan or placebo on day longer than when it succeeded. 1 and dosage was increased to 8 or 16 mg candesartan or placebo on day 2, depending the blood pressure values. Treatment was aimed at a 10–15% blood pres- Controlling BP in the acute stroke phase sure reduction within 24 hours. Although no differ- The theory that elevated systemic BP may compensate ence was found in stroke outcome at 3 months, a for the decreased cerebral blood flow in the ischemic significantly lower recurrent cardiovascular event rate region led to attempts to elevate blood pressure as a and lower mortality after 1 year were documented in treatment for acute ischemic stroke. The hemody- the treatment group. The authors concluded that namic and metabolic impact of pharmacologically when there is need for or no contraindication against increased systemic blood pressure on the ischemic early antihypertensive therapy, candesartan is a safe core and penumbra was evaluated in rats. The mild therapeutic option. induced hypertension was found to increase collateral In the UK’s Control of Hypertension and Hypo- flow and oxygenation and to improve cerebral meta- tension Immediately Post-Stroke (CHHIPS) pilot trial bolic rate of oxygen in the core and penumbra [12]. [19], researchers randomized 179 patients who had Several small studies in humans have addressed this suffered ischemic or hemorrhagic strokes within the question and administered vasopressors, including previous 36 hours and who also had hypertension phenylephrine and norepinephrine, to patients with defined as systolic blood pressure greater than acute stroke [13–15]. Despite a documented improve- 160 mmHg. Patients received doses of either the anti- ment in CBF [16], the concept was abandoned hypertensive drugs lisinopril at a dosage of 5 mg or because of the increased risk of hemorrhage and brain labetalol at a dosage of 50 mg or a placebo at increas- edema. In a systemic review of 12 relevant publica- ing doses for 14 days. Three months after treatment tions including 319 subjects, the small size of the trials began, the active treatment group had a significantly and the inconclusive results limit conclusion as to the lower mortality compared to the placebo group. effects on outcomes, both benefits and harms. Despite the somewhat confusing and unclear data A randomized controlled trial is needed to determine the current European Stroke Organisation (ESO) the role of pressors in acute ischemic stroke [17]. 2008 Guidelines [20] recommend that blood pressure up to 220 mmHg systolic or 120 diastolic may be Elevated systemic BP may compensate for the tolerated in the acute phase without intervention decrease of cerebral blood flow in the ischemic unless there are cardiac complications. According to region, but raises the risks of hemorrhagic trans- formation, cerebral edema, recurrence of stroke the American guidelines [21] it is generally agreed and hypertensive encephalopathy. that patients with markedly elevated blood pressure may have their blood pressure lowered by not more According to a systematic review of the literature than 15% during the first 24 hours after the onset of [3] no conclusive evidence to support the lowering of stroke. There is an indication to treat blood pressure blood pressure in the acute phase of ischemic stroke only if it is above 220 mmHg systolic or if the mean 244 was found and more research is needed to identify the blood pressure is higher than 120 mmHg. No data are effective strategies for blood pressure management in available to guide selection of medication for the Chapter 17: Management of acute ischemic stroke and its complications lowering of blood pressure in the setting of acute hyperglycemia) or could not be fully classified due ischemic stroke. The recommended medication and to missing data in the oral glucose tolerance test. doses are based on general consensus. More studies Increased mortality [25] was found in both dia- are needed to identify the optimal strategy for BP betic and stress-induced hyperglycemia groups, inde- management. Several ongoing clinical trials such as pendent of age, stroke type and stroke size. Stress the Efficacy of Nitric Oxide in Stroke (ENOS) trial hyperglycemia was associated with a 3-fold risk of may help answer the remaining questions. fatal 30-day outcome and 1.4-fold risk of poor func- tional outcome in non-diabetic patients with acute Guidelines recommend blood pressure lowering ischemic stroke. Similar findings were also demon- therapy above 220 mmHg (European Stroke Orga- strated in the NINDS tPA stroke trial. Hyperglycemia nisation (ESO) 2008 Guidelines and American Guidelines) systolic blood pressure. on admission [26] was correlated with decreased neurological improvement and the risk of hemor- rhagic transformation in reperfused thrombolysed patients but not in non-reperfused tPA-treated Hyperglycemia patients. On the other hand, in the NINDS study, It has been well established that elevated glucose levels glucose level on admission was not associated with play a major role in microvascular and macrovascular altered effectiveness of thrombolysis. All of these morbidity and in hematological abnormalities as well. findings suggest that glucose level is an important risk Several processes were found to be associated with factor for morbidity and mortality after stroke. How- these conditions, including impaired vascular tone ever, it is not clear whether hyperglycemia itself and flow, disruption to endothelial function, changes affects stroke outcome or reflects, as a marker, the at the cellular level, intracellular acidosis and severity of the event due to the activation of stress increased aggregation and coagulability. Some animal hormones such as cortisol or norepinephrine. studies [22, 23] have demonstrated the relations Diffusion–perfusion MRI analysis supports the first between acute ischemic stroke and hyperglycemia. hypothesis. Hyperglycemia greater than 12.1 mmol/l In these models the administration of glucose to in patients with perfusion–diffusion mismatch, shown animals resulted in worsened brain ischemia. Those on diffusion-weighted imaging–perfusion-weighted findings were attributed to the accumulation of imaging (DWI–PWI) MRI, was associated with lactate, decreased intracellular pH, increase in free higher lactate production and with reduced salvage radicals and excitatory amino acids, damage to the of mismatch tissue and increased conversion of tissue blood–brain barrier (BBB), formation of edema “at risk” of infarcted tissue compared with patients and elevated risk of hemorrhagic transformation. who arrived with the value of 5.2 mmol/l [27]. Pretreatment with insulin was found to limit the Among the factors found to contribute to the ischemia. post-acute-stroke hyperglycemia [28] are the involve- As mentioned, 30–40% of acute stroke patients are ment of the insular cortex, which is known to play a found to have elevated glucose levels on admission, role in sympathetic activation, involvement of the about half of them have known diabetes, while the internal capsule, pre-existing diabetes, elevated sys- others are newly diagnosed or suffer from stress- tolic BP and NIHSS higher than 14 points. induced hyperglycemia [24]. In one systematic study [24b] it was shown that Glucose level is an important risk factor for morbid- ity and mortality after stroke, but it is unclear glucose pathology is seen in up to 80% of acute whether hyperglycemia itself affects stroke out- patients, many of them showing a high probability comes or reflects the severity of the event as a of previously unrecognized diabetes. Out of 238 con- marker. secutive acute stroke patients, 20.2% had previously known diabetes; 16.4% were classified as having newly The previous data raise the question how, and diagnosed diabetes, 23.1% as having impaired glucose especially to what extent, should post-acute-stroke tolerance (IGT), and 0.8% as having impaired fasting hyperglycemia be treated. Intensive insulin therapy glucose; and only 19.7% showed normal glucose administered i.v. and aimed at maintaining blood levels. Another 47 patients (19.7%) had hypergly- glucose levels at 4.5–6.1 mmol/l in the surgical inten- 245 cemic values only in the first week (transient sive care set-up was found to reduce mortality by Section 4: Therapeutic strategies and neurorehabilitation more than 40% [29]. Similar results were documented infusion last? What level of monitoring is required? among patients after myocardial infarction [30]. The All these questions are still to be answered. question remains regarding the application in acute stroke patients. The GIST-UK trial [31] addressed this Guidelines recommend i.v. insulin therapy for blood glucose levels of 180 mg/dl (10 mmol/l). In question. The study was conducted among 933 hyper- pre-thrombolysis patients, an even more aggres- glycemic acute stroke patients who received glucose- sive approach may be advisable. potassium-insulin infusion versus placebo. In the treatment group significantly lowered glucose and blood pressure values were documented; however, Hyperthermia no clinical benefit was found among the treated Several animal studies [35, 36] demonstrated the cor- patients. The time window for treating post-stroke relation of elevated temperature and poor outcome in hyperglycemia still remains uncertain. There are a ischemic stroke models. Similar results were found in variety of methods of insulin administration, includ- human observations. In the Copenhagen stroke study ing continuous intravenous (i.v.) infusion, repeated [37] stroke severity was correlated with hyperthermia subcutaneous dosing and i.v. infusion containing higher than 37.5 C, while a temperature lower than insulin and dextrose with potassium supplementation 36.5 C was associated with a favorable outcome. [32]. Ongoing trials address the role of i.v. insulin for Other studies limited the correlation between hyperglycemic stroke patients. The Glucose Regula- stroke severity and hyperthermia to only the first 24 tion in Acute Stroke Patients Trial (GRASP) is con- hours following stroke onset. In a prospective study tinuing recruitment. Patients with hyperglycemia temperature was recorded every 2 hours for 72 hours (glucose > 6.1 mmol/l) within 24 hours of symptom in 260 patients with a hemispheric ischemic stroke. onset are randomized to tight glucose control (3.9 to Hyperthermia initiated only within the first 24 hours 6.1 mmol/l), loose glucose control (6.1 to 11.1 mmol/l), from stroke onset, but not afterward, was associated or normal care. The insulin is delivered as a GKI with larger infarct volume and worse outcome [38]. infusion. The primary outcome of the GRASP trial is These animal studies and human observations the rate of hypoglycemic events, and definitive infor- raised the question regarding the role of hypothermia mation on clinical endpoints is not expected [33]. as a treatment for acute stroke. Hypothermia was A randomized, multicenter, blinded pilot trial, introduced more than 50 years ago as a protective Treatment of Hyperglycemia in Ischemic Stroke measure for the brain [39]. Mild induced hypother- (THIS) [34], compared the use of aggressive treat- mia was found to improve neurological outcomes and ment with continuous intravenous insulin, with no reduce mortality following cardiac arrest due to ven- glucose or potassium in the insulin solution, with tricular fibrillation [40]; on the other hand, treatment insulin administered subcutaneously in acute stroke with hypothermia aiming at 33 C within the first 8 patients. The aggressive-treatment group was associ- hours after brain injury was not found to be effective ated with somewhat better clinical outcomes, which [41]. Other applications for which therapeutic hypo- were not statistically significant. According to the thermia was suggested include acute encephalitis, ESO 2008 recommendations [20], a blood glucose of neonatal hypoxia and near drowning [39]. 180 mg/dl (10 mmol/l) or higher is an indication for The use of antipyretics, such as acetaminophen, in treatment with i.v. insulin. According to the American high doses ranging between 3900 and 6000 mg daily guidelines [21], even lower serum glucose levels, pos- [42,43], caused only very mild reduction in body sibly between 140 and 185 mg/dl, should trigger temperature, ranging from 0.2 to 0.4 C respectively. administration of insulin. Despite the current recom- The clinical benefit of this reduction is not well estab- mendation, a more aggressive approach is advised, lished. The use of external cooling aids [44], such as especially in pre-thrombolysis patients. Many ques- cooling blankets, cold infusions and cold washing, tions surrounding the role of glucose lowering ther- aiming at a body temperature of 33 C for 48 to 72 apy remain unanswered [32]. What level of blood hours in patients with severe middle cerebral artery glucose is best for intervention? What is the thera- (MCA) infarction, was not associated with severe peutic time window? Will identification of the pen- side-effects and was found to help control elevated 246 umbra with CT and MR imaging help in selecting ICP values in cases of severe space-occupying edema. appropriate patients? How long should the insulin Similar results, of decreasing acute post-ischemic Chapter 17: Management of acute ischemic stroke and its complications cerebral edema, were found in a small pilot study Summary of endovascular induced hypothermia [45]. The use Optimal management of hypertension following of an endovascular cooling device which was inserted stroke has not been yet established. A U-shaped rela- into the inferior vena cave was evaluated among tionship between baseline systolic blood pressure and patients with moderate to severe anterior circulation both early death and late death or dependency has territory ischemic stroke in a randomized trial. been demonstrated in clinical trials: early death Although no difference was found in the clinical increased by 17.9% for every 10 mmHg below 150 outcome between the treatment group and the group mmHg and by 3.8% for every 10 mmHg above 150 randomized to standard medical management, the mmHg. Stroke patients with impaired consciousness results suggest that this approach is feasible and that showed higher mortality rates with increasing blood moderate hypothermia can be induced in patients pressure. On the other hand, elevated systemic BP with ischemic stroke quickly and effectively and is may compensate for the decrease in cerebral blood generally safe and well tolerated in most patients flow in the ischemic region. The benefit of blood [46]. However, the current data do not support the pressure reduction as a secondary prevention of use of induced hypothermia for treatment of patients stroke is well established, but only a few trials have with acute stroke. In conclusion, despite its thera- been performed in the acute stage. However, these few peutic potential, hypothermia as a treatment for trials demonstrate a beneficial effect of lowering acute stroke has been investigated in only a few very blood pressure. The current European Stroke Organ- small studies. Therapeutic hypothermia is feasible isation (ESO) 2008 guidelines recommend that blood in acute stroke but owing to side-effects such as pressure up to 200 mmHg systolic or 120 diastolic hypotension, cardiac arrhythmia, and pneumonia it may be tolerated in the acute phase. According to the is still thought of as experimental, and evidence of American guidelines, indication to treat blood pres- efficacy from clinical trials is needed [47]. According sure starts with a systolic blood pressure of 220 to the 2008 ESO recommendations [20], at a temp- mmHg, and lowering of blood pressure should not erature of 37.5 C or above reducing the body exceed 15% during the first 24 hours after the onset of temperature should be advised. The American Heart stroke (Table 17.1). and Stroke Association [21] recommend that antipyr- Increased mortality was found in both diabetic etic agents should be administered in post-stroke and stress-induced hyperglycemia groups, independ- febrile patients but the effectiveness of treating either ent of age, stroke type and stroke size. Glucose level is febrile or non-febrile patients with antipyretics is an important risk factor for morbidity and mortality not proven. after stroke, but it is unclear whether hyperglycemia Hyperthermia within the first 24 hours from stroke itself affects stroke outcomes or reflects the severity of onset was associated with larger infarct volume the event as a marker. According to the ESO 2008 and worse outcome, but the current data do not recommendations (Table 17.2) a blood glucose of support the use of induced hypothermia aiming at 180 mg/dl (10 mmol/l) or higher is an indication for a body temperature of 33 C for treatment of treatment with i.v. insulin. According to the Ameri- patients with acute stroke. The 2008 ESO guidelines can guidelines even lower serum glucose levels, pos- recommend reducing body temperature only if sibly between 140 and 185 mg/dl, should trigger above 37 C. administration of insulin. In pre-thrombolysis In summary, hypertension, hyperglycemia and patients, an even more aggressive approach may be hyperthermia are common conditions following acute advisable. stroke. All three have a major and independent Hyperthermia within the first 24 hours from impact on the severity of outcome. Occasionally, the stroke onset was associated with larger infarct volume benefit of this impact is no less than that of more and worse outcome. Mild induced hypothermia “heroic” strategies such as intravenous and intra- was found to improve neurological outcome and arterial thrombolysis. Despite the lack of consensus reduce mortality following cardiac arrest due to on the data and optimal management, one should ventricular fibrillation, but the current data (few very carefully monitor these three “hyper links” and treat small studies) do not support the use of induced them appropriately. hypothermia for treatment of patients with acute 247 Section 4: Therapeutic strategies and neurorehabilitation Table 17.1. ESO 2008 and American Heart and Stroke Table 17.2. General stroke treatment recommendations Association recommendations in the acute stroke phase. according to current European Guidelines of the European Stroke Organisation [20]. European American Stroke Heart Recommendations Organisation Association/  Intermittent monitoring of neurological status, pulse, (ESO) 2008 American blood pressure, temperature and oxygen saturation is Stroke recommended for 72 hours in patients with significant Association persisting neurological deficits (Class IV, GCP) 2008  It is recommended that oxygen should be Blood pressure Treat only if Treat only if administered if the oxygen saturation falls below 95% higher than higher than (Class IV, GCP) 220/120 unless 220/120. Not to there are cardiac lower BP by  Regular monitoring of fluid balance and electrolytes is complications more than 15% recommended in patients with severe stroke or in the first swallowing problems (Class IV, GCP) 24 hrs  Normal saline (0.9%) is recommended for fluid Hyperglycemia Treat with i.v. Insulin should replacement during the first 24 hours after stroke insulin if glucose be administered (Class IV, GCP) levels are higher even at glucose  Routine blood pressure lowering is not recommended than 180 mg/dl levels between following acute stroke (Class IV, GCP) 140 and 185 mg/dl  Cautious blood pressure lowering is recommended in patients with extremely high blood pressures (>220/ Hyperthermia Antipyretics Antipyretics 120 mmHg) on repeated measurements, with severe should be should be cardiac failure, aortic dissection, or hypertensive administered if administered encephalopathy (Class IV, GCP) body in febrile temperature post-stroke  It is recommended that abrupt blood pressure higher than patients lowering be avoided (Class II, Level C) 37.5 C  It is recommended that low blood pressure secondary to hypovolemia or associated with neurological deterioration in acute stroke should be treated with stroke. Because of side-effects such as hypotension, volume expanders (Class IV, GCP) cardiac arrhythmia and pneumonia, therapeutic  Monitoring serum glucose levels is recommended hypothermia aiming at a body temperature of 33 C (Class IV, GCP) is feasible in acute stroke, but is still thought of as  Treatment of serum glucose levels >180 mg/dl experimental. The 2008 ESO recommendations are to (>10 mmol/l) with insulin titration is recommended reduce body temperature at temperatures of 37.5 C (Class IV, GCP) or above.  It is recommended that severe hypoglycemia (<50 mg/dl [<2.8 mmol/l]) should be treated with Management of post-stroke intravenous dextrose or infusion of 10–20% glucose complications (Class IV, GCP points) Stroke is a major cause of long-term physical, cogni-  It is recommended that the presence of pyrexia tive, emotional and social disability. In addition to the (temperature >37.5 C) should prompt a search for neurological impairment appearing in the acute concurrent infection (Class IV, GCP) phase, there are infrequently late complications which  Treatment of pyrexia (temperature >37.5 C) with are often neglected. These complications have a great paracetamol and fanning is recommended (Class III, impact on the quality of life, outcome and chances of Level C) rehabilitation and may include post-stroke epilepsy,  Antibiotic prophylaxis is not recommended in 248 dementia, depression and fatigue. Other complica- immunocompetent patients (Class II, Level B) tions, such as infections, are dealt with in the 6%) developed epi. Post-stroke epilepsy was found to be more previous fractures (Class II. A post-stroke seizure is defined as early if it  Administration of anticonvulsants is recommended occurs in the first 2 weeks after the stroke.3 gives an overview of the Table 17. A seizure to prevent recurrent post-stroke seizures (Class I. The every stroke patient (Class IV. complications such as aspiration pneumonia. management of complications [20]. DVT The common definition of epilepsy includes at and pressure ulcers (Class IV. a non-dysphagic stroke patients who are malnourished second episode. terminologies and  An assessment of risk of falls is recommended for sizes of the populations in the different studies. Level B) found in 2.  Early mobilization is recommended to prevent treatment and outcome of post-stroke seizures. Level B) 249 . assessment and management are recommended sphere and MCA territory. and levofloxacin can be detrimental most commonly identified etiology of secondary epi. seizures in the gastrostomy (PEG) feeding should not be considered elderly are sometimes difficult to diagnose and may in stroke patients in the first 2 weeks (Class II. GCP) to the different methodologies. In that study 14% of the patients treatment (Class III. The with impaired swallowing (Class II. thromboembolism (Class IV.  In stroke patients with urinary incontinence. The wide range is due (Class IV. Level B) lepsy and accounts for 30% of newly diagnosed  Early rehydration and graded compression stockings seizures in patients older than 60 years [48]. Prophylactic administration of The estimated rate of early post-ischemic stroke anticonvulsants to patients with recent stroke seizures ranges from 2 to 33% and that of late seizures who have not had seizures is not recommended varies from 3 to 67% [50–58]. GCP) overall rate of post-stroke epilepsy. GCP) Epilepsy is one of the most common serious neuro- logical disorders and is associated with numerous  Prophylactic administration of antibiotics is not social and psychological consequences.  Oral dietary supplements are only recommended for orrhagic stroke had seizures during the first year. Table 17. insufficient data to recommend a specific approach for orrhagic stroke [49]. GCP) least two seizures with a time interval of at least 24  It is recommended that low-dose subcutaneous hours between the episodes. GCP) with ischemic stroke and 20% of patients with hem.14 to 13%. Prevention and management of complications according to current European Guidelines of the European recommendations of the ESO for the prevention and Stroke Organisation [20]. Level C) Stroke Study) was a prospective multicenter study  Swallowing assessment is recommended but there are held among 1897 patients after an ischemic or hem. Most of the patients  Early commencement of nasogastric (NG) feeding with post-stroke epilepsy have simple partial seizures. GCP) many questions still arise regarding the epidemiology. in acute stroke patients (Class II. etidronate and after stroke [58]. as previously defined as at least two episodes. risedronate) are recommended in women with lepsy.5% of the patients. Level B) common among patients with hemorrhagic strokes. Level B) in patients who have had a late seizure [58]. Recommendations Post-stroke seizures  It is recommended that infections after stroke should be treated with appropriate antibiotics (Class IV. Level B) risk of status epilepticus varies from 0. required to establish epilepsy. (within 48 hours) is recommended in stroke patients while complex partial seizures are relatively rare. 51 patients (3.3. specialist venous infarctions and localization in the right hemi. Chapter 17: Management of acute ischemic stroke and its complications following chapter. The SASS (Seizures After (Class III. In an observational study among 1428 patients  Bisphosphonates (alendronate. Level A). It should be emphasized that it is not always clear  It is recommended that percutaneous enteral whether the patient has had a seizure. heparin or low molecular weight heparins should be sification of post-stroke seizures is made according to considered for patients at high risk of DVT or the period between the stroke and the first epileptic pulmonary embolism (Class I. The current clinical clas. Stroke is the recommended. Although are recommended to reduce the incidence of venous recognized as a major cause of epilepsy in the elderly. was (Class II. is 3–4% and is higher  Calcium/vitamin D supplements are recommended in stroke patients at risk of falls (Class II. Level A) episode. occurring later is defined as late [49]. Patients in this population most frequent and important neuropsychiatric conse- should be advised to avoid factors increasing the risk quence of stroke and has a major impact on func- of seizures. 53]. treatment should mia. Section 4: Therapeutic strategies and neurorehabilitation present as acute confusion. According most of whom had minor depression with dysthy- to the common clinical approach. [66]. because of aminergic pathways and depletion of cortical biogenic their pharmacokinetic profile and interactions with amines.06) [67]. 29–36) and that the depression A cortical cerebral infarction disability was found to resolves spontaneously within several months of be greater in patients with seizures. including the point in time at which patients were The pathophysiology of early seizures is thought assessed relative to the stroke onset and the different to be due to the increased excitatory activity mediated instruments and criteria for diagnosing depression by the release of glutamate from the hypoxic tissue that were used in the different studies. Although no correlation between PSD and tional studies suggest that isolated early seizures after mortality was found in the DESTRO study. tolerated and with a trend to be also more efficacious (p ¼ 0. Other predictors for post-stroke seizures found in various studies are cortical location. disorder. The overall rate is 3–4% of stroke patients. on the other hand. ive study the presence of chronic obstructive pulmon. more likely to have died by 15-month follow-up than continuing the medication [64].21). to the tendency of the latter to involve the cortex [54– 57]. psychological mechanisms such as the difficulty in ment. lamotrigine was found to be significantly sodes of seizures. intracerebral drug over the others. An interesting question is whether post-stroke 2002 found that the frequency of post-stroke depres- seizures worsen the outcome of patients after stroke. onset in most of the patients. Post-stroke seizures are also more common among patients with pre-existing dementia evaluated Post-stroke depression using the validated IQCODE questionnaire (risk ratio Post-stroke depression (PSD) is considered to be the of 4. Once again. PSD was detected in 36% of the patients. rather than major depression. an Aus- stroke do not require treatment [52. the first being whether to event. this recommendation should be taken adjusting to the new limitations and requirements of . such as certain drugs [60]. CI 1. however. and adaptation be initiated only after the second episode. Late seizures are due to the development of A systematic review [68] of collected data from 51 tissue gliosis and neuronal damage in the infarct area observational studies conducted between 1977 and [63]. tional recovery. in rehabilitation the depressed ones were eight times ciated with reduction of recurrent seizures after dis. large infarct. A single study frontal and left basal ganglia territories [72]. the large variation risk factor for the development of seizures in stroke in frequencies is due to methodological differences. Patients with depression were followed for start treatment after the first episode and the second 2 years. sion is 33% (95% CI. and 250 has found neurontine to be a safe and effective treat. [62]. especially phenytoin. The incidence of PSD ranges in various studies ary disease (COPD) was found to be an independent between 18 and 61%. especially in the case of lesions in the left anticoagulants and salicylates [65]. behavioral changes or with caution since the study had no control group syncope of unknown origin [59].34–16. being which anti-epileptic drug to prefer. There is no evidence to prefer one antiepileptic evaluated clinically or radiologically. the non-depressed. In a retrospect. but it is advised to avoid phenytoin because of interactions with anticoagu- hemorrhage and cardiac emboli. Beginning tralian study [70] found that among stroke patients treatment after early-onset seizures has not been asso. In a prospective study comparing lamotrigine versus carbamazepine in 64 patients with post-stroke Post-stroke epilepsy is defined as at least two epi- epilepsy. cognition and even survival. It is best to roanatomic mechanisms such as disruption of mono- avoid the old drugs. most probably due lants and salicylates. patients [61]. TRO) [69] assessed 1064 patients with ischemic or The attending physician is required to deal with hemorrhagic stroke in the first 9 months after the two important questions. The Italian multicenter in patients with cortical hemorrhage disability was observational study of post-stroke depression (DES- found to be less [49]. At this stage there are no evidence-based studies The potential etiology for PSD [71] includes neu- to recommend one drug over the others.66. Observa. while others have not cognitive decline. the use of different tools escitalopram in a population of non-depressed and diagnostic difficulties in distinguishing between patients following stroke [76]. apraxia. dence indicative of cerebrovascular disease that is lactic use of antidepressants in post-stroke patients judged to be etiologically related to the disturbance. fatigue and disprosody [74]. better tolerated than heterocyclics.42 respect- development of standardized measure of depression. According to the NINDAS-AIREN obtained similar results [74]. depression than ones who received escitalopram after Since several studies used different tools for the diag- 12 months follow-up. neurological signs and symptoms or laboratory evi- Despite some encouraging data regarding the prophy. agnosia. There is no good compared to 76% using the DSM-4 as a diagnostic evidence to recommend psychotherapy for treatment tool. done among a population of elderly demented reuptake inhibitors (SSRIs) and heterocyclics can patients. although in the incidence rates between countries. and the risk of PSD no significant correlation was found. course of an episode of delirium. In a systematic review [73] of 26 studies the creation of predictors for PSD and identifying regarding the correlation of left hemispheric stroke the appropriate management. One [20] antidepressant drugs such as selective serotonin study. fold difference in the age-standardized incidence In spite of growing information. Despite the lack of accurate data due to poor controlled study evaluated the administration of definition of the disorder. Differences in the measurement of depression. Antidepressant drugs can improve mood after stroke. prevention. in order to make the diagnosis of post-stroke found to be an important predictor for the develop. previous depression and history of psychiatric and emotional liability during Post-stroke dementia the first days after stroke. to the Diagnostic and Statistical Manual of Mental Disorders. includ. apraxia and memory disturb. either historical. Problem-solving therapy did nosis of PSD and there were also differences in the not achieve significant results over placebo. an almost 3- such therapy can elevate mood. Patients who received PSD and other types of dementia. the incidence According to the ESO 2008 recommendations varies in the different studies from 8 to 30%. demonstrated that the frequency of dementia improve mood after stroke. fourth edition (DSM-4) [78]. many questions ratios (SIR) of PSD rates between Germany and the still surround various aspects of PSD. SSRIs are only 14% of the patients were diagnosed with PSD. indicating that geographical variation is 251 the optimal time after stroke onset to screen for PSD. PSD is considered placebo were significantly more likely to develop to be the second most common type of dementia. clinical or radiological evidence of cerebrovascular disease and the two disorders must be The frequency of post-stroke depression is 33% reasonably related [77]. including the Netherlands was demonstrated (1. agnosia and disturbance in ances. On the other hand. Other risk factors for PSD include female gender. and at least one of the following cognitive disturb- ing aphasia.23 and 0. severe physical disability. vascular The treating physician should be aware of the dementia is diagnosed by the development of multiple diagnosis of depression in stroke survivors since it cognitive deficits manifested by memory impairment may be hindered by a number of conditions. according and it resolves spontaneously within several months of onset in most patients. there is still insufficient randomized evidence to The deficits should not occur exclusively during the support this approach in routine post-stroke manage. For instance. methodologies and study populations. Chapter 17: Management of acute ischemic stroke and its complications the disease. and presentations of results may also can be effective in a major depressive episode or have contributed to the heterogeneity of the findings. with ment of PSD [75]. apathy. still present after taking into account the countries’ . dementia (PSD) the patient has to be demented. but there is less evidence was found to depend upon the diagnostic criteria used that these agents can effect full remission of a major [79]. ances: aphasia. ment [68]. Interestingly there are also noticeable differences or prevention of post-stroke depression. A single recent double-blind placebo. The differential diagnosis of PSD includes executive functioning with the presence of focal anosognosia. ively) [80]. Dementia was also criteria. but there is less evidence that these agents study design. Some studies have found Stroke is an important risk factor for dementia and aphasia as a risk factor. using the NINDAS-AIREN criteria depressive episode or prevent depression. in the management of stroke and should always be 252 erate vascular dementia. as in the previous trials mentioned. There are insufficient data to taken into consideration when dealing with stroke recommend the use of these agents in PSD [89]. exer- cates cortical involvement [87]. It is estimated that about 70% of post-stroke It is suggested that cerebrovascular disease may play an patients experience fatigue and 40% of patients rate it among their worst symptoms. hypoxic-ischemic disorders conditions. beside stroke. while in another higher grades symptom or among their worst symptoms. It is unclear whether The frequency of dementia (PSD) in post-stroke these differences are due to genetic or environmental patients is about 28%. patients. Silent is estimated that about 70% of post-stroke patients brain infarcts demonstrated on CT. eral sclerosis. there treatment for PSD. There is no evidence-based factors since. 91]. Other mechanisms rest. Abnormal EEG per. or small-vessel disease such related to previous exertion and not ameliorated by as lacunes or leukoaraiosis. impairment. collagen diseases and others [92–95]. visible and both types of dementia include many similar risk factors and clinical and pathological characteristics. Many other central and peripheral neurological include hypoperfusion. would lower the risk of PSD. amyotrophic lat- dementia. however. including general tiredness that is a result of overexertion and multi-infarcts or single infarcts in a strategic area can be ameliorated by rest. basal forebrain fatigue. especially Alzheimer type. Fatigue was of white matter findings on MRI were associated with found to be an independent predictor of functional impaired cognitive function [86]. In amantadine and modafinil. probably because it indi. pain and depression. The mechanisms of guish between “normal” fatigue. are a crucial component tain clinical significance in patients with mild to mod. The pharmacological therapy includes the erative type and vascular dementia are nowadays less stimulant agents amantadine and modafinil. It predictors for the development of PSD [82–84]. living alone or in an institution. Some are correlated with the risk of PSD. Section 4: Therapeutic strategies and neurorehabilitation differential age distributions. Diabetes. Since it has also disability and mortality [97]. which are administered for the Appropriate diagnosis and treatment of the treatment of degenerative-type dementia. bilateral infarcts. hippocampus. poor even in normotensive patients. it would be studies suggest the involvement of the brainstem and reasonable to assume that lowering blood pressure thalamus [91]. not always a part of post-stroke depression and can lipidemia and atrial fibrillation were also found as occur in the absence of depressive features [90. 96]. including multiple sclerosis. were methodological differences between the studies. anxiety. ior therapy. infarcts. which are often under- to produce only small benefits in cognition of uncer. large It is important to emphasize that post-stroke fatigue is MCA infarcts and previous strokes. Parkinson’s disease. Despite the conflicting data the overall estimated Post-stroke fatigue frequency of dementia in post-stroke patients is about Another common and disabling late sequel of stroke 28% and the fact that stroke is a major risk factor for is general fatigue [90. logical treatment includes the stimulating agents There is no evidence-based treatment for PSD. cise. stress reduction and cognitive behav- The borders between dementia of the neurodegen. Pharmaco- important role in the presence and severity of AD [88]. which is a more chronic condition. and since these lesions general health. Fatigue was also not found to predict the development of PSD in one rated by 40% of stroke patients as either their worst prospective study [85]. optimizing the management of potential factors. diagnosed and undertreated. were found late complications of stroke. 83] consist of large-vessel disease. were experience “pathological” fatigue. hyper. The caring physician should be alert to identify formed close to the ischemic stroke appears to be an possible predisposing factors and to diagnose “patho- indicator of subsequent PSD in a prospective study logical” fatigue. The initial treatment should focus on done among 199 patients. ADL matter lesions is related to the blood pressure level. . frontal lobe infarcts. a meta-analysis of randomized controlled trials cho- linesterase inhibitors. post-polio syn- Risk factors for PSD include large and left-sided drome. It is important to distin- dementia is well established [81]. Risk factors for post- been shown in that study that the extent of white stroke fatigue include older age and female sex. sleep hygiene. which is a state of PSD [82. are known to be a cause of and shared pathogenic pathways with degenerative fatigue. HIV. and “pathological” such as the thalamus. not or the angular gyrus. et al. Crit Care Clin 2006. 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Stegmayr B. ent risk factor for cerebral infarction (odds ratio 3. cination lowers the risk of cerebral infarction (for Then. will not be by the classic risk factors (age. hypertension. etc. viral and parasitic infections are associated spasms in vascular smooth muscle.4– pneumoniae is an obligate intracellular bacterium 14. tions. and impairment of endothelial are preceded by a bacterial infection in the month prior function by endotoxin and bacterial toxins have been to stroke. pneumoniae in per se. cytomegalovirus. moniae (for review see Watson and Alp [5]).). Furthermore. occurring later Atherosclerosis is a common disease and a major risk than a week after stroke. and usually causes mild upper respiratory tract infec- ary tract infections can trigger ischemic stroke [4]. diet. alteration of the lipid metabolism. and chronic meningitis. diseases such as seasonal flu may trigger stroke. low physical activity. and occasionally pneumonia. Furthermore.5) [1–3]. aspiration pneu- monia is discussed. Infections preceding stroke herpes simplex virus and Chlamydia pneumoniae have been proposed to be associated with atherosclerosis. Bacterial. a detailed molecular understanding the initiation. common viral sion and impaired swallow and cough reflexes. C. . probably more important than microbial invasion Animal models support a role of C. such as endocarditis. diabetes. conclusive direct cause of stroke. Especially bacterial respiratory and urin. pathogens such as Helicobacter pylori. Third. Additionally. Aside from bacterial infections. genetic predis- covered since they are common infections in the hos. tious complications due to post-stroke immunodepres. inflammation has shortcoming might be explained by the difficulty in 258 been implicated in atheroma instability and subse. such as ventilator-associated factor for stroke. Recent infection and stroke Most studies on the infectious etiology of athero- Several studies have supplied evidence that acute sclerosis have been focused on Chlamydia pneu- infection in the week preceding stroke is an independ. attributing causality to a common pathogen and a quent plaque rupture. Late infectious complications. For example. the systemic inflammatory response is individuals are seropositive. vasculitis evidence for a protective effect is still lacking. Sev- In this chapter. Apart from these factors. specific infectious diseases are reviewed that are a review see Lichy and Grau [4]). hypercholesterolemia. pital with no specific link to stroke. This have been discussed. platelet aggregation. a role. position. First. bed nervous system are able to directly cause stroke. many pathogens that affect the central reported. gender. as an example of an early infectious complication that arises within the first week after Chronic infections and stroke stroke. However. Chapter 18 Infections in stroke Achim Kaasch and Harald Seifert Introduction system. alteration of the coagulation multifactorial disease. Numerous mechanisms studies have not come to conclusive results. we will briefly summarize available eral observational studies suggest that influenza vac- evidence on how bacterial infections can trigger stroke. maintenance and rupture of athero- of events that lead to a higher susceptibility to cere. rest and mechanical factors such as sneezing may play patients who suffer a stroke are prone to develop infec. adhesion and lysis. Its etiology can largely be explained pneumonia or catheter-related infections. Exposure to this Since a heterogeneous group of microbial pathogens agent is common and by the age of 20 years 50% of is involved. but clinical and epidemiological bral infarction is lacking. at least 20% of strokes antibody formation. However. sclerotic lesions. Second. dehydration. anti-phospholipid with stroke in several ways. smoking. . determines stroke risk rather than the occurrence of a Haemophilus influenzae. (i) emboli from infected heart valves may obstruct cerebral arteries in Mycotic aneurysm bacterial or fungal endocarditis.. Infectious causes of stroke and associated mechanisms. Treponema pallidum Acute and chronic infections can raise the risk of cerebral infarction. whether and when antimicrobial tuberculosis. . The main risk factors for endocarditis are injection drug use.1). and others ized interventional trials. However. In the following section we will review some of these diseases is about 5–10 cases per 100 000 person-years and it is and associated pathogenic principles. be included in a stroke-risk panel and how the micro. the “infectious burden concept” was developed. The incidence of IE first year following surgery [11]. variety of bacteria). information has been published [6. chronic bacterial infections to the etiology of stroke is unclear. a serious disease with about 20% mortality.. an underlying structural heart disease (such as congenital Embolic stroke heart defects or degenerative valvular lesions). Fungi Chronic meningitis Cryptococcus neoformans. viral and parasitic diseases. Candida spp. Carriers of a prosthetic heart valve are especially at cardium.1. and to wall destruction and obliteration of the lumen. a thin tissue layer that lines heart valves and risk. Chagas disease Trypanosoma cruzi Since an association between a single pathogen and Meningitis an increased risk of stroke has so far not been proven. pneumoniae infection. HIV is presented in Table 18. Vasculitis view of organisms implicated in infectious diseases that Virus may lead to stroke and their associated pathophysiology Vasculopathy Varicella zoster virus. Aspergillus spp. 9]. (iv) mycotic aneurysms can rupture and cause hemorrhagic stroke. the contribution of Table 18. It Bacteria states that the aggregate burden of microbial antigens Acute meningitis Neisseria meningitidis. An over. (iii) Fungi Aspergillus. pneumonia by macrolide therapy. 7] and random. and periodontal disease (caused by a great Infective endocarditis Staphylococcus aureus. (ii) direct microbial Bacteria Staphylococcus aureus. with a 1–4% chance of developing IE within the 259 mural myocardium (Figure 18. For example. Borrelia intervention may be appropriate. Infective endocarditis (IE) is an infection of the endo. chronic inflammation of the meninges leads to stroke through several mechanisms. even more so. H. Infective endocarditis hemodialysis and invasive intravascular procedures. invasion and inflammation of the vessel wall can lead Salmonella enteritidis. Some studies found an increased risk of Embolism stroke in patients with elevated antibody titers sug- Bacteria and fungi gesting previous C. Coccidioides immitis Infectious diseases that Helminths cause stroke Chronic meningitis Taenia solium Multiple pathophysiological mechanisms can lead to stroke in bacterial. single pathogen [10]. aiming at the eradication of C. burgdorferi. pylori gastritis. Chapter 18: Infections in stroke As with atherosclerosis. For these pathogens conflicting Streptococcus spp. Enterococcus spp. as Chronic meningitis Mycobacterium does. and others bial burden is measured remains an open question. as in others obliterative vasculitis or necrotizing panarteritis. for example.1. which bacteria should Streptococcus pneumoniae. Protozoa failed to reduce the incidence of vascular events [8. 1. Infective endocarditis: a 53-year-old male presented with a 1-week history of malaise. University Hospital of Cologne). On clinical examination mild meningeal signs. left-sided ataxia. Department of Cardiac Surgery. behavioral changes and headache. Department of Radiology. Staphylococcus aureus was cultured from blood and cerebrospinal fluid. bar ¼ 1 cm). A CT scan 3 weeks after initial symptoms showed abscess formation with contrast enhancement and marked edema 260 (e). Wippermann. and splinter hemorrhages (a) were noted. (a) (b) (c) (d) (e) Figure 18. Lackner. F. fever (up to 41 C). and J. Dodos. . Computed tomography (CT) of the brain showed several ischemic lesions in both hemispheres and right cerebellum (b). Department of Cardiology. (Courtesy of K. Transesophageal echocardiography revealed a large mitral valve lesion (c) which was subsequently removed surgically (d. Fever. heart diseases that are associated with a turbulent negative staphylococci (about 30% of all cases). Aspergillus 1% 0–1 have been developed. Microorganisms that have gained access to compromised patients. Candida spp. Other streptococci 17% 5–33 Enterococci 8% 6–10 Clinical presentation and diagnostic criteria in IE Clinical signs and symptoms for IE are highly variable Staphylococci 30% 29–38 and often misleading. may occur in immuno. Most neurological complications may go valve and grow into vegetations measuring up to several unnoticed. seizures. meningitis.g. on traumatized endothelium. e. more than 2 months after surgery) pathogenesis. fibrin and platelets are deposited Although fungal pathogens are rarely a cause of IE. It is caused by congenital or acquired is less often caused by S. encephalopathy. and mycotic aneurysm (frequencies in and damage the endocardium or the prosthetic Table 18. some of which the site of endocardial cell damage. Chapter 18: Infections in stroke Table 18.g. Therefore IE is often recognized late. which results in Candida or Aspergillus spp.e. Distribution of etiological agents in patients with aureus and Enterobacteriaceae such as Escherichia coli endocarditis (adapted from Wisplinghoff and Seifert [50]). e. Patients with IE due to enterococci or viridans group streptococci usually Streptococci 50% 35–53 report several weeks of symptoms before a clinical Viridans group streptococci 33% 17–48 diagnosis is made. aureus (>80%). Eikenella corrodens. Staphylococcus and lead to IE. and Kingella kingae. malaise. e.) examination. Pathogenesis of IE IE is the result of a complex interaction between Microbiology of IE microorganism. destruction of the were detected by MRI in 65% of patients with left-sided heart valve ultimately leads to heart failure and death. They include stroke. blood flow.2. TEE) Polymicrobial infections 3% 3–4 a clinical score is derived that describes the likelihood of IE in a specific patient (e. HACEK group*) when complications have occurred. The pathophysio- are listed with their overall frequency of isolation in logical process can be divided into several stages: Table 18. Duke criteria. heart murmur.g. NBTE. or Klebsiella pneumoniae are associated with an acute Pathogen Mean Range course and high mortality.g. Notes: *Haemophilus aphrophilus. Gram-negative aerobic bacilli 3% 1–3 (e. Then.g. blood cultures and ultrasound imaging Other bacteria 2% 1–4 (preferably transesophageal echocardiography. (about 20–40%) and are associated with a worse out- come. bacterial colonization of the lesion and drug abusers is commonly caused by Staphylococcus growth into vegetations [13]. Aggregatibacter Neurological complications of IE are common actinomycetemcomitans. Different clinical conditions favor certain formation of nonbacterial thrombotic endocarditis microbes.4). can arise when emboli break patients [12]. right-sided endocarditis in injection (NBTE). matrix molecules and platelets at Many bacteria and fungi can cause IE. The clinical course can be acute or subacute. In a recent study cerebrovascular events centimeters in size. stroke. IE is caused by bacteria or fungi that attach to brain abscess. IE. diagnostic criteria Fungi (e. If left untreated. aureus than by coagulase.g. From the results of the clinical spp. the bloodstream (bacteremia) and possess the neces- Depending on the causative organisms different sary virulence factors may now colonize the lesion 261 clinical courses can be observed. off from the vegetation and occlude blood vessels. night sweats and myalgia may Coagulase-negative staphylococci 7% 6–8 or may not occur.2. late IE (i. weight loss. see Culture negative 8% 6–12 Table 18. Staphylococcus aureus 23% 22–31 anorexia.3).. but clinical symptoms were observed in only 35% of Complications. In patients with prosthetic heart Endocardial damage is the starting point of IE valves. intracranial or subarachnoi- dal hemorrhage. . To facilitate diagnosis of IE. leading to infarction of the supplied tissues. Cardiobacterium hominis. which hides bacteria from hemorrhage. rated at least ‘possible IE’ by clinical  4 days of antimicrobial treatment. Emboli 20–57% HACEK group. such as artificial heart valves. 262 siveness to antimicrobial treatment is decreased. The microorganisms Janeway’s lesions proliferate and produce a mucilaginous polysac- Immunological phenomena charide matrix which is called biofilm. and enterococci. Osler’s nodes. is facilitated by virulence factors. Minor criteria IE-causing pathogens adhere to the NBTE.3. or (ii) three minor organism consistent with IE criteria are met. or on implanted material in the populated by a dense endogenous flora with many absence of an alternative anatomic explanation. [53]). streptococci. mycotic aneurysm. septic pulmonary ition of further fibrin and platelets and a secluded infarcts. All mucosal surfaces. in the absence of a primary focus) Mycotic aneurysm 3–16% or Microorganism consistent with IE from Meningitis 6–39% persistently positive blood cultures (defined as Abscess 2–16% at least two positive cultures of blood samples drawn >12 h apart. or (iii) no pathological criteria. Roth’s spots. conjunctival hemorrhage. with first and last sample drawn at least 1 h apart) Headache 9–25% Evidence of endocardial involvement Echocardiogram positive for IE* as follows: A frequent cause of bacteremia is damage of a oscillating intracardiac mass on valve or mucosal surface. Vascular phenomena Following adhesion. Staphylococcus aureus. or criteria for possible or (iv) definite IE are not met. or new partial dehiscence of prosthetic valve as tooth brushing or tooth extraction may lead to a temporary occurrence of bacteria in the bloodstream or New valvular regurgitation (worsening or (transient bacteremia). Streptococcus bovis. many of which have been identified Fever (temperature >38 C) in staphylococci. such as oral supporting structures. or (iii) one major and three minor. TTE as first test in evidence of IE at surgery or autopsy with  4 days of other patients. 52]. diverse bacterial species. and the host immunological defense.4. or Intra. Section 4: Therapeutic strategies and neurorehabilitation Table 18. Modified Duke Criteria for the diagnosis of infective endocarditis [51. bacteria stimulate the depos- major arterial emboli. or all of three or a Encephalopathy 17–33% majority of four or more separate cultures Seizure 2–29% of blood. or complicated IE (paravalvular abscess). Typical microorganism consistent with IE isolated from two separate blood cultures Complication Frequency (viridans group streptococci. or (ii) two major criteria. It is rejected when (i) a firm alternative diagnosis Notes: *Transesophageal echocardiography (TEE) recommended in explaining evidence of IE or (ii) resolution of IE syndrome with patients with prosthetic valves. Frequencies of neurological complications in Blood culture positive for IE infective endocarditis based on 1365 cases from seven studies (adapted from Cavassini et al.or subarachnoidal hemorrhage 7–25% community-acquired enterococci. GI tract. intracranial compartment is formed. urethra or vagina. Even a minor trauma such or abscess. or (iv) five minor criteria are met. Adhesion Predisposition (predisposing heart condition or injection to fibrin and platelets or to the surface of medical drug use) devices. antimicrobial treatment. are regurgitant jets. IE is or serological evidence of active infection with possible when (i) one major and one minor. changing of pre-existing murmur not sufficient) After having gained access to the bloodstream. In a biofilm less than 10% of bacteria divide actively and respon- glomerulonephritis. The diagnosis of IE is definite Suggestive microbiological findings when (i) pathological/microbiological examination of vegetation positive blood culture not meeting major criterion shows active endocarditis. Major criteria Table 18. in the path of cavity. and rheumatoid factor Additionally. nasopharynx. antimicrobials need to penetrate the . Depending on the localiza- With the use of current technology. Emboli from the right heart according to the results of antimicrobial susceptibility are filtered by intrapulmonary arteries and cause pul- testing. from vegetations on Antimicrobial therapy should be carefully selected the mitral or aortic valve. e. 15]. A brain In addition to antimicrobial drug treatment. pathogenicity. Furthermore. In many performed at earlier time points. system is usually the left heart. It is a rare complication of relapse or treatment failure. tricuspid valve endo- lines that recommend specific drug treatment carditis. . and meningitis. Successful surgery has been margin with bacteria and immune cells. apy for at least 4–6 weeks. focal clinical 40–60 ml of blood is considered sufficient. which is common among intravenous drug schemes for certain organisms [14. but available data cases antimicrobial therapy of a brain abscess alone are scarce and thus careful judgement is required in is unsuccessful and has to be backed by surgical each individual case. The standard users. lique- rhagic transformation of a non-hemorrhagic infarct. can also lead to stroke. (TIA) or manifest stroke. weeks. by immune-complex deposition. treated with a carefully selected antimicrobial ther- orrhagic stroke through rupture of a mycotic aneur. opti. ary bypass will greatly augment the risk of hemor- During abscess development tissue necrosis. Over the weeks a clearly fungal or highly resistant organisms. faction. local Initial imaging studies show a poorly demarcated extension of infection (e. Ischemic stroke (IE). heart failure. persistently positive blood cultures. A typical histological finding is a central necrotic replacement surgery should be performed later than area containing bacteria and debris and a hyperemic two weeks after stroke. and before antimicrobial drugs are The source of emboli to the central nervous administered. Hematogenous seeding of microorganisms to the Occlusion of cerebral arteries by septic or sterile meninges causes bacterial meningitis. defined lesion develops. rarely leads to stroke. paravalvular abscess). multifocal clinical signs may blood cultures are drawn at the beginning of a fever become apparent. therapy needs to be considered in the case of severe A brain abscess typically develops over 2–3 weeks. When multiple emboli occlude several chances of a successful isolation are higher when independent vessels. slope. Many scientific societies have issued guide- monary embolism. such as brain abscesses microbials with different modes of action is advised. especially when a pros- IE. The significance of immune-mediated injury in therapy needs to be considered. The signs occur. a combination therapy of two anti- Other complications of IE. Therapy of IE Pathogenic mechanisms leading to stroke in IE Before the advent of antimicrobials.g. drainage. The resulting emboli that originate from the vegetations is a inflammation can damage arterial vessel walls and common cause for stroke in infective endocarditis cause mycotic aneurysms (see below). therapy of IE. and a fibrotic capsule become more promi- Therefore. Therefore enough blood needs to be cultured. Additionally. Chapter 18: Infections in stroke biofilm to reach the bacterial targets. If possible. it has been suggested that heart valve nent. surgical 263 ysm. However. Therefore. The early stage is called cerebritis considered to be at a high risk during cardiac surgery. and lesion with localized edema. Impairment of the causative organism and its antimicrobial susceptibil- cerebral blood flow can lead to transient ischemia ity. in rare cases duration of antimicrobial therapy is at least 4–6 paradoxical embolism has been reported. often accompanied by an Patients who have suffered a recent stroke are extensive edema. Selection of the appropriate anti- emboli that originate from the vegetations is a microbial depends strongly on the isolation of the common cause of stroke in IE. culturing about tion and duration of reduced blood flow. surgical the source of bacteria. is mal antimicrobial treatment is crucial for a successful unknown. but in 2–4% of patients with brain abscesses IE is thetic heart valve is involved. IE has inadvert- Occlusion of cerebral arteries by septic or sterile ently led to death. and is histologically defined by acute inflammation The anticoagulation necessary for the cardiopulmon- without tissue necrosis.g. hem. IE is often diagnosed late and should be occurs through obstruction of inflamed vessels. Therefore. sur- abscess occurs after hematogenous seeding of bacteria gical therapy needs to be considered in the case of to the brain parenchyma. the damage to the heart is irreversible and thus effort Common complications of acute bacterial menin- needs to be directed towards prevention of Trypano. Patients present with fever. as PCR. such and nuchal rigidity. Streptococcus insect vector (Triatoma and other assassin bug (1 month) agalactiae (group B species) and can lead to a persistent chronic infection. There are many infec- by bacteria or fungi leads to an inflammatory response tious and non-infectious causes of chronic meningitis which causes the typical clinical symptoms. seizures. . which contains has a subacute onset. Other less Tuberculous meningitis frequent symptoms are photophobia. which is attributed to a more susceptible brain tissue. and soma infection by vector control and improvement of hyponatremia. and leads to thrombosis and subsequent ischemia or ninges. survive within granulomata. the Meningitis as a cause of stroke spreading inflammation involves intracranial vessels Meningitis denotes the inflammation of the leptome. but the causative organisms vary only natural reservoir is the human.5. Stroke is most prevalent in infants (less basic housing conditions. the inhalation. Depending on the time course. following sections we will discuss several organisms Acute bacterial meningitis is prevalent worldwide that cause chronic meningitis with a high incidence of and accounts for an estimated 1. where an exudative Diagnosis is based on clinical symptoms. These layers ensheath the spinal cord and brain Chronic meningitis lasts for more than 4 weeks. Chagas disease is an infection with the protozoan parasite Trypanosoma cruzi which is most prevalent Age group Main pathogens in South and Central America. pneumoniae Embolic stroke may be the first sign of cardiac Adults (>15 years) Streptococcus pneumoniae. Conditions that predispose to cardiac Neisseria meningitides emboli in Chagas disease are cardiac arrhythmias. 185 000 deaths per year. gitis include raised intracranial pressure. congestive heart failure. and lethargy or confusion. and arthritis. negative staphylococci myopathy. The choice of host immune system finally mounts a T-cell response. probably through chronic inflammation. During the first couple of analysis and microbiological testing. In the meningitis can be classified as acute or chronic. The disease occurs tuberculosis. lymph nodes. apical aneurysms and mural thrombus formation. a hardy slow-growing bacterium whose in all age groups. By the time stroke occurs. coagulase- Parasitic invasion of the heart muscle leads to cardio. headache. (in preterm infants) Cardiomyopathy develops in about 10–30% of Children (1 month Haemophilus influenzae. and transported to the lung tissue. streptococcus). Most likely. mater. Infection of the meninges fever. and vomiting. It is taken up by depending on age (Table 18. headache and despite advances in diagnostic techniques. mycobacteria are undetected by the cellular crobial treatment needs to be initiated as early as immune system and spread to the draining hilar possible with antimicrobials that reach adequate bac. and confine the subarachnoidal space. which consist of the pia mater and arachnoid hemorrhage [17]. Empiric antimi. Research into the molecular pathogenesis of stroke in meningitis has been scarce. antimicrobial therapy needs to be reconsidered when Depending on the capacity of the host immune 264 the causative organism is identified and susceptibility system the infection can be cleared or mycobacteria testing results become available. If left untreated. Streptococcus itself years or even decades after initial infection [16].5). and is often accompanied by cerebrospinal fluid (CSF). seizures. phagocytosed by alveolar macrophages disease is fatal. nuchal rigidity.2 million cases with stroke. It is transmitted by an Neonates Enterobacteriaceae. about 30% of cases are idiopathic. Tuberculous meningitis is caused by Mycobacterium petechial bleeding. Neisseria patients with long-lasting parasitemia and manifests to 15 years) meningitidis. Section 4: Therapeutic strategies and neurorehabilitation Embolic stroke due to Chagas disease Table 18. weeks. There they slowly proliferate and the tericidal concentrations in the CSF. Chagas disease. CSF inflammation is initiated. Acute bacterial meningitis: age groups and most common causative organisms. and treatment. as well as early diagnosis than 1 year of age) with an incidence of up to 10%. especially in pathogen with a high potential to invade the central developing countries. and stretch. In the human. Coccidioides immitis is a fungal pathogen restricted to The granuloma at the site of initial infection the deserts of south-western USA and Central and and the swollen hilar lymph nodes together are South America. From there lymphogenous and hemato- monary symptoms. A diagnosis is based or M2 segment of the middle cerebral artery by the on serological testing of cerebrospinal fluid. whereas mul. Borrelia burgdorferi. itionally. Most cerebral infarcts occur in the earlier stage. i. caused Ischemic stroke is a relatively frequent complica. Bacteria are released into the a 40% risk of developing cerebral infarcts and they surrounding tissue. are pathogenic mechanisms. by T. rarely causes stroke [24]. e. unknown. until the conditions for growth become more favorable. the meningeal inflam- there is a significant risk of relapse [21].g. disease.g. nervous system. patient. despite Taenia solium lives as a tapeworm in the small intes. matory infiltration of medium to large arteries. in the case of a often develop communicating hydrocephalus. mation produces a basilar. syphilis can cause stroke by other mechan- tiple infarcts are most likely due to secondary isms. direct microscopic tion with B. or PCR-based techniques. 20]. a disseminated disease within weeks to months after e. gelatinous inflammatory exudate in the subarachnoid space. Meningovascular syphilis. a typical feature of early mally leads to asymptomatic infection or mild pul- tuberculosis. compression of the left carotid artery by a thrombosis. culture. 265 antimycotic therapy. Compression of the M1 the onset of stroke is subacute. Strangulation and spasm of Stroke in syphilis develops as a result of inflam- blood vessels by an intense inflammatory exudate. The walls of small and medium-sized arteries that traverse the exudate Neurosyphilis and neuroborreliosis are invaded by inflammatory cells. they allow the pathogen to persist come [19.g. A long meningeal granuloma. course of antifungal drug treatment is required and In tuberculous meningitis. of a granuloma liquefies. where further granulomata are exposure. periarteriitis or necrotizing panarteritis.e. e. to tuberculous meningitis. The cystic larval . However. the center meninges and the skeleton. Chapter 18: Infections in stroke Granulomata are caseous foci with a fibrotic cap. It causes an often fatal disease. Other bacterial infections that have been implicated turbance of CSF circulation leads to an increased in stroke are the spirochetes Treponema pallidum and intracranial pressure. Especially immunocompromised tine and sheds eggs with the feces. when the host Coccidioidomycosis immune system is impaired. pallidum. The frequency of ischemic complications is teria contained and prevent further spread of infec. Add- exudate causes large artery infarctions.g. Fewer than 2% of patients develop genous spread may occur to various distant organs. anterior circulation. is now a rare complication. which leads. Neurocysticercosis Neurocysticercosis is the most common parasitic cen- Cryptococcal meningitis tral nervous system infection. They are AIDS patients) are at risk of developing cryptococcal formed by the host immune system to keep the bac. the diagnosis needs to be confirmed by Chronic meningitis in neuroborreliosis. large aneurysm of the thoracic aorta has been When tuberculous meningitis is suspected in a reported [23]. since tion of tuberculous meningitis and occurs in about syphilis is most often recognized and treated at an 30% of cases [18]. within its host for decades. the When reactivation of the disease occurs. Inhalation of contaminated soil nor- called the primary complex. Typically. Furthermore. but stroke is associated with a worse out- tion. dis. Most often the middle cerebral artery and to a lesser ing of blood vessels by increased intracranial pressure extent basilar arteries are involved [22]. an infec- microbiological techniques. sule that enwraps viable mycobacteria. Most common extrapulmonary sites of formed. burgdorferi. individuals with a defect in cellular immunity (e. The pork tapeworm The fungus Cryptococcus neoformans is a soil Taenia solium is prevalent worldwide. coccidioidal meningitis have the granuloma ruptures. the definite host. the meninges. infection are skin and subcutaneous soft tissue. examination. before a long-lasting drug therapy is initiated. mycobacteria proliferate and Patients with basilar. tuber- young patients with stroke in South Africa suggests culosis. disease. and thrombosis and can lead to ischemic or hemorrhagic VZV particles. Cysticerci Several cohort studies around the world have shown normally die within 5–7 years after arrival in the that stroke in patients with acquired immunodefi- brain. e. headache. opportunistic infection is still under debate [29]. varicella zoster vasculopathy. show a diffuse asymptomatic microinfarcts and may predispose to inflammation of cerebral blood vessels of all sizes. can lead that the mechanisms leading to stroke in HIV- to stroke when the spreading inflammation positive patients are largely similar to those in HIV- involves intracranial vessels and leads to negative controls [27]. radiographic. It results in fusiform aneurysms. a granulomatous can be found. Erosion of large vessels can occasionally lead has significantly diminished VZV-related morbidity to a large artery stroke. The rash invasive larvae may develop in the intestines. About 50% of ment includes intravenous acyclovir in combination patients develop arteriitis with associated lacunar with steroids. current treat- lems. see Nagel et al. pene. imaging studies. and occasional perivascular inflammatory of the patient. unifocal or multifocal vascular lesions with Cysticerci have a predilection for neural tissue and corresponding lesions in CT or MRI imaging studies can settle in the brain. However. . and analysis of the cerebrospinal fluid (CSF). [25]). cryptococcal meningitis). visual prob.g. Section 4: Therapeutic strategies and neurorehabilitation form (termed cysticercus) is usually found in the pig. stroke. Symptoms depend on localization and size of Randomized clinical trials for standard treatment the larvae and include seizures. HIV-associated vasculitis was Varicella zoster virus vasculopathy suspected as a cause of stroke. HIV-associated vasculitis ter associated cerebral angiitis. a process which can be accelerated by antipar. pigment can be differentiated depending on the immune status deposition. When cerebral angiography is per- the tissues and mature into cysticerci. stenosis or cleated giant cells. Immunocompromised individuals. Immunocompetent patients may develop herpes zos- In later stages of AIDS. In both involves large or medium sized intra. Based on expert opinion. In this study. Two different types of infection perivascular space dilatation. In many cases of symptomatic an age-adjusted HIV-negative population. and cardioembolism. subarachnoid space.or extracranial cases. coagulopathy. and hydrocephalus. neurosyphilis or neuroborreliosis. ischemic stroke. A recent cohort study on Chronic meningitis. It 266 should be suspected in patients with ischemic lesions Vasculitis from infectious diseases. a poorly characterized entity that angiitis that usually affects larger arteries. enter the bloodstream. when humans ingest shed tapeworm eggs often reveals a typical herpetiform rash. stroke has yet to be proven. A vaccination for VZV is available and infarcts. e. serological detection of VZV IgG. HIV-associated vasculopathy and vasculitis ical. Cowdry A inclusion bodies. combined with a positive VZV PCR or ter virus and HIV. neurosy- philis. can be found. and ven. formed. confusion. In the early stages of HIV infection an intracranial Varicella zoster virus (VZV) can lead to stroke due to vasculopathy of small arteries can be found [28]. were opportunistic infections (tuberculosis. tricle. Whether HIV-associated vasculitis is directly Diagnosis of VZV vasculopathy can be difficult. for example. frequent causes thrombosis. Prevention of herpes zoster of the middle cerebral artery. cell infiltrates. are lacking. Patient history However. viral infection of the cerebral artery walls (for review Histological features are thickening of the vessel wall. caused by HIV infection or is due to an undetected and is based on patient history. and serological criteria. can precede the manifestation of stroke by up to trate the mucosa. ciency syndrome (AIDS) is more frequent than in asitic drug treatment. by this vaccine has so far not been demonstrated [26]. In Infectious diseases causing vasculitis 10–20% of the cases. varicella zos- in MRI or CT. a firm causal relationship between HIV infection and surgical procedures are required. The diagnosis in non-endemic areas can be diffi- cult and is generally made by a combination of clin. drug treatment is not sufficient and neuro. preferentially in the territory and mortality in children. rarefaction. caused by. histopathological features include multinu- arteries. migrate to several months.g. can result in ischemic stroke. This condition is associated with organ transplant or AIDS patients. S. especially in AIDS rupture of a mycotic aneurysm without adequate patients. and localized at multiple is often subacute. with mycotic aneurysms who survived have not been Additionally. in contrast to acute ischemic stroke. which degrades elastic fibers of ted by mosquitoes (Anopheles spp. especially in the brain and muscle Different mechanisms have been implicated in tissue.. dormant tissue cysts. requires histological demonstration of the organism mainly viridans group streptococci. and other Streptococcus spp. To prevent the occurrence of cocci. (2) hematogenous seeding of bac. falciparum invades red blood fests as a triad: mycotic aneurysm. the membrane of infected erythrocytes reported. Enterobacteriaceae. saccular. stroke. (1) septic microemboli to the an impaired immune response leads to lesions with vasa vasorum. manifestations of cerebral malaria are seizures. During infection P. occurs in immunocompromised patients and mani. Bacterial aneurysms lesions and. a necrotic central area. risk after a full course of antimicrobial treatment is During often asymptomatic initial infection. but the Clinical signs depend on the localization of the intima often remains intact. and impaired consciousness. often localized in the basal ganglia. an infection with the proto- (3–16%). and show multiple ring enhancing lesions that can occur fusiform. In these patients. reduc- In patients with infective endocarditis and in tion of the blood–brain barrier. As in stroke. [33]). are a well similarity with stroke (for review see Idro et al. cause intracranial aneurysms. described cause of true fungal mycotic aneurysms. and (4) direct contam. Common clinical the vessel wall [31]. MR and CT imaging studies often sites. the reduced blood flow impairs the delivery of substrates. Central nervous system aspergillosis usually respiratory distress. The pathogenesis of cerebral malaria shares some Among the fungi. entero. The mortality associated with erythrocytes stick to the endothelium of the cerebral intracranial aspergillosis is at least 85% and patients blood vessels and reduce the microvascular flow. or PCR-based methods. Thus cerebral toxoplasmo- hemorrhage. Definite diagnosis ysms are the same as for infective endocarditis. cells and alters their surface properties. hyperemic border and some- teria to atherosclerotic vessels. although it is a potentially devastating parasite disseminates into various tissues and forms event [30]. can lead to stroke by thrombotic occlusion due to narrow capillaries is more difficult. At autopsy petechial hemorrhages are 267 aneurysms can be the cause of stroke. Aspergillus spp. They develop in a significant encephalitis fraction of patients with infective endocarditis Cerebral toxoplasmosis. aureus. and gran. play an mary antimicrobial prophylaxis is initiated depending important role in extracranial aneurysms but rarely on CD4þ T-cell counts. uloma formation.). due to microemboli that congest the vasa zoan parasite Toxoplasma gondii. onset are usually small. rupture of mycotic swelling. arteriitis with or without thrombotic arterial occlusion Infection of the vessel wall leads to necrosis. anywhere in the brain or spinal cord. Reactivation of the dormant parasites during aneurysm formation. The causative organism of malaria tropica is the An important virulence factor of Aspergillus spp. and ultimately brain immunocompromised patients. is protozoan Plasmodium falciparum. whereas fungal aneurysms are long. pri- in particular non-typhi Salmonella spp. local that causes discrete infarcts. which causes hypoxia. As a result. A feature that distinguishes a contiguous infected focus. vascular extension of hyphae. The muscu. but are most The causative organisms of intracerebral aneur. . Chapter 18: Infections in stroke Mycotic aneurysms as cause of stroke Infectious diseases with similarities Mycotic aneurysms are caused by bacteria or to stroke – toxoplasmosis and malaria fungi and account for a minority (about 3%) of all intracranial aneurysms. The parasite is transmitted by undercooked antimicrobial therapy is frequent (57%) but the meat or cat feces and taken up by the oral route. immunocompromised individuals. which is transmit- the enzyme elastase. toxoplasmosis in immunocompromised patients. and abscess formation. sis results in a slowly expanding ischemic lesion [32]. the very low. these lesions from an abscess is a hypertrophic ination through trauma of the arterial wall. Aside from aneurysm rupture. Aspergillus becomes less deformable and thus travelling through spp. laris and elastica layers are destroyed. (3) extension from times a thin fibrotic capsule. large. mainly occurs in vasorum of the cerebral arteries. 7. If pneumonia is suspected. Dampening of the sym- pathetic activation by propranolol prevented pneu- Early-onset infectious complications monia and bacteremia in 80% of the mice and Infectious complications after acute stroke are improved 7-day survival by 50% [41. aspirate should be sampled. and a few small clinical trials have Diagnostic work-up of infections been carried out to assess its usefulness.01–0. 36]. In up to 70% bronchoalveolar lavage and blood cultures. was not sufficiently by the clinical signs and symptoms and should powered to show significant differences between the include blood cultures. leukocytosis. 5-day regimen of moxifloxacin vs. In a murine model. necrosis.g. [34. The PANTHERIS trial. bacteria can initiate an infectious process. 42]. urine culture. ische. A diagnostic work-up is guided within 36 hours of stroke onset. However. Preventive antimicrobial therapy is effective in a mouse model [45]. and a chest groups [47].2 ml [40]. and large The high frequency of aspiration pneumonia in hemorrhages are rare. onia and 6. 24% and 22% respectively [35]. Empiric regimens therapy is initiated. proper Pneumonia in stroke patients is most often caused specimens for microbiological analysis. When clinical signs or laboratory testing results placebo started within 24 hours of stroke onset did (e. infection. but infarction. controlled clinical trials in stroke patients are lacking. To assess the usefulness of preventive X-ray. a 3-day regimen of levofloxacin vs. Section 4: Therapeutic strategies and neurorehabilitation regularly observed. Major risk Urinary tract infections factors for aspiration pneumonia are older age. Haemophilus influenzae. S. In a prospective study of 3866 patients lation of the immune system during a life-threatening with ischemic stroke hospitalized in neurological condition seems paradoxical but it may serve to pre- stroke units in Germany. tube feeding) have been proposed for higher fatality and worse long-term clinical outcome the prevention of aspiration pneumonia. post-stroke after cerebral infarction [34]. Urinary tract infections (UTI) are common infections stroke. sputum or tracheal antibiotic therapy further trials are needed. fever or hypothermia. since many patients have indwelling cath- 268 gastroesophageal reflux disease (for review see Shige. stroke patients has led to the search for other mech- anisms that may facilitate pneumonia [39].4% developed pneum. which convey a significant risk of mitsu and Afshar [38]). aspiration pneumonia [46]. since aspiration of nasopharyngeal secretions regu- mic lesions mimicking stroke can occur. should of stroke patients the cough and swallow reflexes be obtained. pneumoniae. especially In the course of malaria and toxoplasmosis. Downregu- common. In the post-stroke ESPIAS trial. oral hygiene. aureus. preferably by dysphagia and secondary aspiration. Gram-negative enteric bacilli and anaer- obic bacteria and should follow current treatment Aspiration pneumonia guidelines [48]. at an estimated volume of 0. adapted accordingly [44]. Asymptomatic occurrence of bacteria in . larly occurs in healthy individuals during sleep. Other studies report an patients need to be screened for potential aspiration even higher incidence of urinary tract infections of fluids or semi-solids and the diet should be and pneumonia. Therapy of aspiration pneumonia is largely mens should be obtained before antimicrobial dependent on antibiotic treatment. eters in place. elevated not improve outcome or reduce the frequency of CRP serum levels) point towards an infection. altered mental state. stroke induces a severe Infectious diseases as immunodepression through over-activation of the complication of stroke sympathetic nervous system. and post-stroke. placebo started biological testing. To guide further treatment. Microbiological speci. vent damage to the brain by immune cells [43]. In the lungs. should cover S. are impaired and oropharyngeal or gastric content may gain access to the lungs [37]. Other measures (position- Stroke-associated pneumonia is associated with a ing. poor oral hygiene. a diagnostic specimens should be obtained for micro.3% urinary tract infections within 7 days To prevent aspiration pneumonia. N Engl J Med 2004. 26:373–9. post-stroke patients independent risk factor for cerebral infarction. Lozano E. Embolic stroke can be caused by infective endo- carditis (IE). expanding ischemic lesion because it leads to a hypertrophic arteritis with or without thrombotic Infectious complications after acute stroke are arterial occlusion that causes discrete infarcts. e. 5:535–40. influenza vaccination and reduced stroke risk. Expert Meningitis can lead to stroke. Urine cultures should be obtained Cerebral toxoplasmosis results in a slowly prior to the start of antimicrobial therapy. Marquardt L. lines (e. Heindl S. Grau AJ. surgical therapy 351:2611–8. In addition. bacteremia and sepsis. Lichy C. cocci- a true infection. dysuria. et al. 114:509–31. identifies the causative organ- ism. frequent. mostly pneumonia and urinary tract infec- tions. Occlusion of cerebral arteries by septic or sterile emboli that originate from vegetations. Expert Rev Neurother 269 2006. Lichy C. hemorrhage. and provides susceptibility testing results. Thomas SL. Patients with basilar. Rupture of a mycotic aneur- Initial treatment is strongly dependent on local ysm without adequate antimicrobial therapy is resistance patterns and should follow current guide. needs to be considered. [49]). Antimicrobial therapy 3. varicella zoster virus and HIV.  Neurosyphilis and neuroborreliosis. enough blood needs to be cultured (40–60 ml). Stroke 2003. Pneumonia in stroke patients is most often caused by dysphagia and secondary aspiration. Organisms that cause chronic meningi- 6. Elkind MS. such as frequency and urgency. Chapter 18: Infections in stroke the urine (bacteriuria) needs to be distinguished from  Coccidioidomycosis. and vaccinations on stroke risk. . spreading inflammation involves intracranial vessels 5. Microbiological examination of a urine specimen  Neurocysticercosis. Ischemic stroke is a relatively frequent complication of tuberculous meningitis 7. 6:175–83. Clinical signs References 1. Paganini-Hill A. Grau AJ.g. Clin Sci (Lond) 2008. The main risk factors for endocarditis are injection drug use.g. Grau AJ. mostly pneumonia and urinary tract cerebral malaria the infected erythrocytes stick to infections. intracranial aneurysms. Stroke 1995. misleading. 34:452–7. Most likely the Rev Vaccines 2006. Infectious complications after acute stroke are Chapter Summary common. risk rather than the occurrence of a single pathogen. is a common cause of stroke in IE. an underlying structural heart disease (especially prosthetic valves). therefore IE is often diagnosed late. Buggle F. Risk of should be carefully selected according to the results myocardial infarction and stroke after acute of antimicrobial susceptibility testing and be given infection or vaccination. antimicrobial treatment is initiated only in symptom- Mycotic aneurysms account for about 3% of all atic infections. Do common infections cause tis with a high incidence of stroke are: stroke? Semin Neurol 2006. and severe systemic manifestations. et al. et al. Watson C. the need to be screened for potential aspiration of fluids “infectious burden concept” states that the aggre- or semi-solids and the diet should be adapted gate burden of microbial antigens determines stroke accordingly. Investigating the association between the first sign of cardiac Chagas disease. Infection left heart. Alp NJ. for at least 4–6 weeks. Hall AJ. 26:88–99. Signs of UTI include mild irritative dioidal meningitis have a 40% risk of developing symptoms. isolate the causative organism. The effect of infections and occurs in about 30% of cases. To Acute infection in the week preceding stroke is an prevent aspiration pneumonia. such as nicating hydrocephalus. Cole JW. can result in ischemic stroke. Smeeth L. usually in the 2. the endothelium of the cerebral blood vessels and reduce the microvascular flow. Since Vasculitis from infectious diseases. routine culture is not recommended. hemodialysis and invasive intravascular procedures. Recent infection as a and symptoms of IE are highly variable and often risk factor for cerebrovascular ischemia. Role of Chlamydia pneumoniae in and leads to thrombosis and subsequent ischemia or atherosclerosis. To and risk of ischemic stroke: differences among stroke subtypes. In common. confirms the diagnosis. Fischberg G. Embolic stroke may also be 4.  Tuberculosis. cerebral infarcts and they often develop commu- fever. Vidal JE. Jackson LA. Rosengren L. diagnosis and treatment of infective 29. 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Chagas cardiomyopathy and ischemic subarachnoid hemorrhage. disorders of the circulatory system and stroke in 31. Circulation infarction in adult AIDS patients: observations from 2005. 146:851–6. et al. von Cramon DY. 47:911–7. Ngeh J. infection. Horstkotte D. 2008. 17:313–20. HIV-infected patient: case report and literature review. Okada Y. Goodbourn C. Leite AG. 197 Suppl 2:S224–7. and Legionella Vasculitic and encephalitic complications associated pneumophila in elderly patients with stroke (C-PEPS. Stroke 2005. Clin Infect Dis neuroborreliosis? Eur J Neurol 2003. 26. the Edinburgh HIV Autopsy Cohort. caused by syphilitic aortic aneurysm. Nakane H. Stroke in Disease. Infectious and inflammatory 18:1057–60. Stroke 1987. with Coccidioides immitis infection of the central M-PEPS. et al. 78:1320–4. Clin Infect Dis 2006. Connor MD. antimicrobial therapy. 8:175–9. and the Councils on Clinical Cardiology. 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Complications of immunodepression: experimental evidence and clinical infective endocarditis. Preventive neurological intensive care medicine. et al. Bhogal S. Trapl M. eds. Jenkins NE. Stroke 2005. Seifert H. 37. and Healthcare-associated Pneumonia. Eur Neurol 2002. New criteria for 42. Dysphagia after stroke: incidence. Aspiration pneumonias: Care Med 2005. Preventive 34. Meisel C. 31:1223–9. features. et al. 171:388–416. Nowotny M. under-diagnosed and under-treated. Love CP. Duke bacterial infections and is mediated by Endocarditis Service. followed by the scientific justification.S. of patients with TIA or stroke as the qualifying event. first ischemic stroke [1. In the subgroup therapy is not more effective than placebo. Chapter 19 Secondary prevention Hans-Christoph Diener and Greg W. In after a first stroke. risk of myocardial infarction (MI) by 21%  Antihypertensive therapy reduces the risk of and the risk of all vascular events by 21% [11]. In the may try to achieve a maximum of blood pressure following sections. Treatment with antihypertensives reduced the risk of stroke by 24%. congestive 15% suffer a recurrent stroke in the first year. About 80–85% of patients survive a many cases this requires combination therapy. pleiotropic and protective vascular effects beyond  Early initiation of antihypertensive therapy with lowering high blood pressure. eprosartan) therapy with an ACE inhibitor (7% N. Albers Introduction important than the choice of a class of antihypertensives is to achieve the systolic and Secondary prevention aims at preventing a stroke after diastolic blood pressure targets (<140/90 mmHg a transient ischemic attack (TIA) or a recurrent stroke in non-diabetics and <130/80 in diabetics). A meta-analysis com- prised seven studies of 15 527 patients with TIA. More absolute risk reduction of 6. Vascu- risk factors. Placebo-controlled trials based treatment is of major importance [9]. ischemic or hemorrhagic stroke who were followed Treatment of risk factors for 2–5 years. treatment.or intracranial with vascular risk factors even with normal blood arteries. The combination of an ACE inhibitor endpoint stroke the combination of an ACE inhibitor (perindopril) with a diuretic (indapamide) was with a diuretic was more effective (45% risk reduc- significantly more effective than placebo. . 7]. Of those between 8% and Concomitant diseases (kidney failure. non-fatal stroke Hypertension by 21%. mono- angiotensin-receptor blocker (ARB.) or a beta- was more effective than a calcium-channel blocker blocker (7%). Risk of heart failure) have to be considered. (nitrendipin). we will deal with the treatment of lowering in patients with high blood pressure. Therefore the HOPE telmisartan on top of the usual antihypertensive study compared ramipril with placebo. MI or vascular death by 24% and an (atenolol) show the lowest efficacy. antithrombotic therapy and surgery or lar protectives such as HOPE [10] include patients stenting of significant stenosis of extra. as the brain will be protected. 2]. Stroke risk after a TIA is highest There are very few studies investigating the effi- in the first 3 days [8]. Ramipril reduces vascular events in ACE inhibitors and ARBs were thought to have patients with vascular risk factors. identification of the stroke prevention.3% in 5 years [12].  Most likely all antihypertensive drugs are effective ramipril resulted in a relative reduction of the combined 272 in secondary stroke prevention. One has to remember that two pathophysiology and initiation of pathophysiology concepts exist in this field. stroke recurrence is highest in the first few weeks and  Lifestyle modification will lower blood pressure declines over time [3–5]. Each paragraph will be introduced by recom. PAD) and vascular risk factors and can be estimated by risk models [6. Beta-blockers endpoint of stroke. For the stroke. pressure under the assumption that end organs such mendations. The risk of recurrence and should be recommended in addition to drug depends on concomitant vascular diseases (CHD. Therefore immediate evaluation cacy of classes of antihypertensive drugs in secondary of patients with stroke or TIA. and an tion) than a diuretic as monotherapy (32%). 2% in 190 mg/dl. eprosartan was superior to CHD. ing event [20]. without CHD and LDL cholesterol levels between Across the 4-year observation time blood pressure 100 and 190 mg/dl will benefit from a treatment was lowered on average by 9/4 mmHg. 3. gated in a subgroup of the Heart Protection Study Patients were treated either with eprosartan (600 mg) (HPS) and the SPARCL trial. reduction for combination therapy was 43% [13]. Monotherapy with  Lowering high LDL is more important than the the ACE inhibitor was not superior to placebo. relative risk reduction was 28%. lower the risk of Patients were randomized to receive either candesar. ACCESS was a small phase II safety study in The association of cholesterol levels and the risk of stroke patients with high blood pressure (>200/110 recurrent stroke is lower than the association with the mmHg) in the early phase after an acute stroke. Recurrent strokes occurred CHD and LDL cholesterol levels between 100 and in 8. risk patients [18]. The RRR for the combined endpoint of Most likely all antihypertensive drugs are effective stroke. Therefore lowering LDL also did not achieve the same level of blood pressure cholesterol <100 mg/dl or 50% of the initial lowering as the combination therapy. continued with candesartan [14]. which was not significant. In the overall pressure in the MOSES trial was 120–140 mmHg. The LDL cholesterol significantly lower in the candesartan group (9. The discrepancy with the HPS trial nificantly lower the rate of recurrent strokes. Optimal systolic blood the absolute risk reduction 5. In the 12-month NCEP ATP III guidelines recommend treating stroke observation period the rate of vascular events was patients with CHD with a statin. had TIA or stroke. 274) whereas hemorrhagic strokes were more High cholesterol frequent with atorvastatin (55 vs.5%. The relative risk tan or placebo in the first 7 days after stroke and reduction calculated from a meta-analysis is 21% [17]. population the RRR for stroke was 25%. 33). The absolute with 80 mg atorvastatin.8/2. The rate of ischemic stroke was reduced (218 vs. did not sig. and endpoint (stroke) was reduced by 16% relative and continuation for a median of 2.9 years the primary fore initiation of telmisartan early after a stroke. The sudden . population of 20 536 high-risk patients. risk of MI. but use of a particular statin.4 years. SPARCL. Patients (n ¼ level. The relative risk LDL cholesterol level is recommended. however. 2. 6105) were treated with perindopril as monotherapy Patients with atherosclerotic ischemic stroke or TIA or in combination with indapamide or placebo. MI and vascular death was 20% and the ARR in secondary stroke prevention. The relative risk reduction achieved by simvas- nitrendipin in preventing recurrent vascular events tatin given for 5 years for vascular events was 20% and (21% relative risk reduction). whereas there PRoFESS randomized 20 332 patients with a was no significant reduction in the stroke rate in the recent ischemic stroke to receive telmisartan at subgroup of patients with TIA or stroke as the qualify- 80 mg/day or placebo in addition to other therapies. 1820 of them without concomitant cal drop in blood pressure. Mean blood pres.3 years after the initial vascular event whereas this time interval was only 6 months in Antihypertensive therapy reduces the risk of stroke. Patients received either 80 mg atorvastatin the placebo group.1% [19]. statin irrespective of the initial LDL cholesterol ally performed in patients after stroke. There. Statins will. Statin therapy reduces the risk reduction for recurrent stroke was 4% and the rate of recurrent stroke and vascular events. or placebo. The Stroke Prevention by Aggressive for a median duration of 2. 18.4 years. Chapter 19: Secondary prevention PROGRESS was the first large-scale trial specific. 3280 patients hypertensive therapy when appropriate. patients on average 4. The target range of LDL is 70–100 mg/dl.8% level should be <100 mg/dl and <70 mg/dl in high- vs.7% in the telmisartan group compared to 9. other might be explained by the fact that HPS recruited major vascular events or new diabetes [15]. relative risk reduction RRR ¼ 52%).0 mmHg. Within the HPS patient or with nitrendipin (10 mg) on top of additional anti. After an average of 4. MOSES included 1352 patients with hypertension Patients with stroke without CHD were investi- who had suffered a stroke in the previous 24 months. For an identi.2% absolute [21].7%. Reduction in Cholesterol Levels (SPARCL) study was sure over the trial period was lower in the telmisartan performed in 4731 patients with TIA or stroke without group by 3. stroke in patients with CHD [16].  Patients with TIA or ischemic stroke and coronary Therapy with a statin should be initiated early 273 heart disease (CHD) should be treated with a after an ischemic stroke or TIA. The choices are patients on a statin should continue treatment acetylsalicylic acid (ASA 50–150 mg). The HOPE-2 evaluated and the antiplatelet therapy adapted to study also failed to demonstrate benefit [28]. 26]. the following an acute ischemic event. This has may even increase the risk of fatal strokes. protection. When there is an indication for the treatment of high homocysteine in stroke patients antiplatelet therapy the recurrence risk should be with B-vitamins and folic acid [27]. The RRR for non-fatal A randomized. combination of ASA (2  25 mg) and extended Patients with TIA or ischemic stroke and coronary release dipyridamole (ER-DP 2  200 mg) or heart disease (CHD) should be treated with a statin clopidogrel (75 mg). 23]. weight loss and regular exercise.8% to replacement therapy after menopause found an 8. the combination of clopidogrel and ASA for at least 3 months. ASA þ patients with diabetes mellitus [24]. hor. and carries a higher bleeding risk. Therefore.4% to 17% in 29 months). the study the new risk. (from 21. MI and vascular death is reduced by 17% in non-fatal strokes [29]. lowering of blood glucose does not reduce the risk  Doses of ASA >150 mg/day result in an increased of stroke and might even increase mortality [25.  The efficacy of antiplatelet therapy beyond 4 years after the initial event has not been studied in Supplementation of vitamins randomized trials. placebo-controlled study in stroke achieved by antiplatelet therapy in patients women who suffered a stroke receiving hormone with TIA or stroke is 23% (reduced from 10. Aggressive ER-DP has more side-effects. Section 4: Therapeutic strategies and neurorehabilitation discontinuation of a statin in patients with a stroke or Antiplatelet therapy acute coronary syndrome might be associated with  Patients with TIA or ischemic stroke should higher morbidity and mortality [22.  ASA is recommended in patients with a low risk of recurrence (<4%/year). in general. min B6 and 1 mg vitamin B12. The same is true for patients with a coronary stent. Therefore. been shown in many placebo-controlled trials and in several meta-analyses [30–32]. risk of bleeding complications. Theoretically.5 mg folic acid. receive antiplatelet drugs. B12 and folic acid  In the case of a recurrent ischemic event the is not effective in secondary stroke prevention. 274 mone replacement should be avoided following A meta-analysis of eleven randomized and placebo- a stroke. controlled trials investigating ASA monotherapy in .3% in 3 years) [31]. This resulted in a  Patients with a history of TIA or ischemic stroke significant reduction in homocysteine levels but not and an acute coronary syndrome should receive in a reduction of vascular events. ASA þ ER-DP and an effect of glitazones on vascular events in stroke clopidogrel appear to be equally effective. This therapy is also typically Hormone replacement therapy extrapolated to patients with carotid stents. after menopause  Hormone replacement after menopause is not Antiplatelet drugs are effective in secondary stroke effective in the secondary prevention of stroke and prevention after TIA or ischemic stroke. Therefore. There is no evidence that changing included 5522 patients aged >55 years and a vascular antiplatelet therapy from ASA plus ER-DP to event or diabetes mellitus and treated them for 5 years clopidogrel or vice versa provides greater with either placebo or 2. 50 mg vita. irrespective of the initial LDL cholesterol level. monotherapy. treatment of diabetes mellitus should not  The combination of clopidogrel plus ASA is not be restricted to drug treatment but should also more effective than either ASA or clopidogrel include diet. The combined endpoint of increase in stroke mortality and a poorer prognosis stroke. treatment should  Treatment of increased plasma levels of continue beyond that period. homocysteine with vitamin B6. pathophysiology of the ischemic event should be The VISP study was unable to show a benefit of evaluated. Patients with a higher Diabetes mellitus risk of recurrent stroke should be treated with Randomized controlled studies were unable to show ASA þ ER-DP or clopidogrel. 9% vs. carry a higher bleeding risk as shown in the BRAVO The combination of low-dose ASA and extended. the recommended Cardiac events occurred at similar frequency in the dose of ASA is 75–150 mg/day.9%).8%). stroke. domized 2739 patients with presumed atherothrombo- cantly beyond a daily ASA dose of 150 mg [35. The ARR was 0. vascular death and hospital. in 5. A meta- 17. [44]. The risk of GI bleeds (1.7% in endpoint was 16% with ASA monotherapy and 13% favor of clopidogrel. [42]. The study randomized 20 332 patients with ization due to a vascular event. prevention [31. MI. Gastrointestinal adverse groups treated with dipyridamole compared to ASA events (AEs) and bleeding complications are. release dipyridamole (ER-DP) was investigated in the second European Stroke Prevention Study (ESPS2) Patients with TIA or ischemic stroke should receive antiplatelet drugs.99% versus trial prematurely. showed a trend towards a benefit for com. effective in the acute coronary syndrome [47]. MI or peripheral arterial disease (PAD). combination therapy and displayed a higher bleeding Glycoprotein-IIb/IIIa-receptor antagonists are rate with the combination. Therefore. The combination ischemic stroke and followed them for a mean period resulted in a significant increase in bleeding compli.9%) and dipyridamole monotherapy with oral anticoagulation (INR 2. should be treated 275 by 18% (AAR 2. Major CI 6–19) for the combined endpoint of stroke. 34]. whereas DP the dose of ASA and its efficacy in secondary stroke monotherapy had a similar bleeding rate to placebo. MI and vascular bleeding complications. combination of vascular death. MI and major The combined endpoint of stroke. The calculation of the to MATCH. Chapter 19: Secondary prevention secondary stroke prevention found a RRR of 13% (95% by 16% (AAR 2. resulting in a RRR of 20% (ARR 1%). Symptomatic patients.6%) was smaller with clopidogrel than with ASA. ASA þ The CHARISMA trial (Clopidogrel for High ER-DP resulted in more intracranial bleeds and a Atherothrombotic Risk and Ischemic Stabilization. There was no difference in efficacy across cations.0 to 3. AAR  Patients with a cardiac source of embolism.0). tic TIA or minor stroke to ASA (30 to 325 mg) or the Clopidogrel monotherapy (75 mg/day) was com.6%) compared to placebo. For the primary endpoint stroke. and Avoidance) was a combined pri. There is no relationship between ASA and the ASA þ ER-DP combination. ER-DP (200 mg bid). highest benefit of clopidogrel was seen in patients In the combination arm 34% of patients terminated the with PAD. with 6602 patients with TIA or stroke [41]. higher drop-out rate due to headache compared with Management.5 years. 36]. 46]. mary and secondary prevention study in 15 603 Table 19. Oral however.2 [7. of 2. Patients were randomized to ASA (25 mg bid). The primary endpoint was the with stroke. 33. The with ASA þ DP. mic stroke [38] and failed to show the superiority of A head-to-head comparison of clopidogrel and combination antiplatelet therapy for the combined ASA þ ER-DP was performed in the PRoFESS study endpoint of stroke. the study failed to show a benefit of Essen risk score is shown in Table 19. combination of ASA with DP and followed them for a pared to ASA (325 mg/day) in almost 20 000 patients mean period of 3. tive risk reductions for different approaches in sec- grel and ASA with ASA monotherapy [39]. MI and bleeding complications were seen more frequently with vascular death [33].1 gives an overview of absolute and rela- patients and compared the combination of clopido. vascular endpoint of 18% (95% CI 9–26) [43]. and therefore is not recommended. . The industry-independent ESPRIT study [43] ran- dose-dependent and bleeding rates increase signifi. trial [35]. the combination of ASA and ER-DP Anticoagulation in cerebral ischemia or placebo.4 years. clopidogrel (5. all endpoints and no subgroup of patients.66%) and gastrointestinal side-effects (15% versus headache (13% in the ASA arm of the study). Similarly ondary stroke prevention. ASA monotherapy lowered the risk of stroke particular atrial fibrillation (AF). ARR 3%) and placebo (RRR 37%. the combination was superior to ASA monotherapy due to cardiac embolism (RRR 23%. analysis of all stroke prevention trials testing ASA The MATCH study compared the combination of monotherapy versus ASA þ DP showed a relative risk clopidogrel 75 mg and ASA 75 mg with clopidogrel reduction in favor of the combination for the combined monotherapy in high-risk patients with TIA or ische. 0. The event rate for the primary death showed a relative risk reduction of 8. mostly because of AEs such as 2.51% [37]. 45. GP-IIb-IIIa-antagonists are not superior to ASA and bination antiplatelet therapy [40]. however. Essen risk score for the calculation of the risk of a recurrent stroke after an initial ischemic stroke of  Patients with mechanical heart valves should atherothrombotic origin.5% 200 Based on a subgroup analysis from CAPRIE Surgery of a high-degree carotid 65% 3. oral Age 65–75 years 1 anticoagulation can be initiated immediately after Age >75 years 2 the exclusion of cerebral hemorrhage.5% 40 In patients with contraindications for warfarin Notes: *Outcome stroke and death.5% 33–100 Combination also superior to versus ASA placebo Clopidogrel versus ASA 8% 0. Strategies for prevention of recurrent stroke after an initial TIA or ischemic stroke.0 available (EAFT) ASA in AF 19% 2. Risk factor Points  Patients with biological heart valves are Age <65 years 0 anticoagulated for 3 months.  In patients with TIA or minor stroke.4% 250 Proven for atorvastatin and simvastatin ASA 50–150 mg after TIA or ischemic 18–22% 1.5. is by far the most effective treatment for secondary . oral anticoagulation in patients with AF 100–300 mg/day. RR ¼ risk reduction. Intervention Relative Absolute NNT/ Comments RR RR/year year Antihypertensive therapy 24% 0. This randomized placebo-controlled trial showed a 68% relative risk reduction for a recurrent Additional TIA or ischemic stroke 1 stroke for patients treated with warfarin compared to only 19% for patients receiving 300 mg ASA. Table 19.0–1. and 3. Section 4: Therapeutic strategies and neurorehabilitation Table 19.2.0 recurrence risk of 4%/year. AF ¼ atrial fibrillation.3% 77 ASA doses >150 mg ¼ higher stroke bleeding risk ASA 50 mg þ dipyridamole 400 mg 23% 1.1.1% 32 Efficacy declines with time interval stenosis* from event ASA in high-degree intracranial stenosis ? ? ? In comparison to warfarin there was no significant benefit Oral anticoagulation in cardiac source 68% 8% 12 Only one placebo-controlled study of embolism (AF) INR 3. 276 use oral anticoagulation should receive ASA Therefore. NNT ¼ number needed to treat/year. Myocardial infarction 1 The evidence that oral anticoagulation prevents Other cardiovascular events 1 recurrent strokes in patients with atrial fibrillation Peripheral arterial disease 1 results from the European Atrial Fibrillation Trial Smoking 1 [48]. A score of 3 points indicates a be anticoagulated with an INR between 2.  Patients with contraindications or unwilling to Numbers needed to treat (NNT) are 12/year [48].46% 217 Proven for perindopril þ indapamide and eprosartan Statins 16% 0. Hypertension 1  The combination of ASA plus clopidogrel is inferior to oral anticoagulation with warfarin and Diabetes mellitus 1 carries a similar bleeding risk. The relative risk of major bleeding nation of ASA and clopidogrel versus oral anticoagu. The risk of bleeding was increased Carotid endarterectomy and stenting by a factor of 1. 95% CI found a lower rate of ischemic events with anticoagu- 0.5 resulted in a of warfarin.4%. This result for the prevention of vascular events (OR 0. lation counterbalanced by an increased risk of intra- cations is significantly increased but not the risk of cranial bleeds. 95% was replicated in the ESPRIT study [57]. intracranial bleeds. should be treated with vascular death in patients with antiphospholipid anti- oral anticoagulation (INR 2. with 4076 have a similar stroke risk to patients with permanent patients.59–2. There was in addition Anticoagulation in cerebral ischemia no difference in event rates between patients positive of non-cardiac origin or negative for aPL. Study (APASS) found no difference in stroke.49–2.0 to 4.5 versus ASA 30 mg in antiplatelet drugs for the endpoints death and severe patients with TIA or minor stroke without a cardiac disability [61].0 lead to an increased risk of major bleeding anticoagulation relative risk (RR) 0. 95% CI 3.79–2.0. protein C or S deficiency or factor in 116 patients with angiographically proven dissec- V (Leiden) mutation.9–21) [58]. 51]. 95% CI complications in particular in the elderly [53]. Patients with intermittent AF A Cochrane analysis of five trials.27 (95% CI 0. The ACTIVE study [54] compared the combi.0). and in patients receiving ASA 12. The evidence for anticoagulation  Oral anticoagulation is not superior to ASA and is in patients with protein C.91) or recurrent stroke (OR 0. been studied in a randomized trial compared to anti-  Patients with cryptogenic stroke and coagulation platelet drugs.96–2. The Antiphospholipid Antibodies and Stroke Patients with a cardiac source of embolism.4–2. e. The and specific coagulation disorders that warrant event rate in patients with anticoagulation was 8.13). The risk of major bleeding compli. ESPRIT CI 0. high-intensity anticoagulation RR 1.02. A Cochrane analysis concluded warfarin (INR 1. the difference was not statistically significant [60]. was unable to show that anticoagulants are AF [50.0 [52]. 0.3% anticoagulation are not clear. High-intensity reduction of stroke and systemic embolism in favor oral anticoagulants with INR 3. MI or ticular atrial fibrillation (AF). Chapter 19: Secondary prevention stroke prevention. The study was terminated conclusion [62].41).5. in par. A Cochrane The Stroke Prevention in Reversible Ischemia review of 26 observational studies in 327 patients Trial (SPIRIT) studied oral anticoagulation with an found no difference between anticoagulation and INR between 3.43 (95% CI 0.8) and ASA in stroke patients that oral anticoagulation is more effective than ASA without a cardiac source of embolism [56].50–0. An observational study from Canada disorders. stroke or death in the first year of 15%.13) for an increase of the INR by 0. was not different between the two regimens. The optimal INR range for oral anti. The optimal treatment duration TIA.03) and for medium-intensity was terminated prematurely due to a significant anticoagulation 1.19 (95% CI 0.0 and 4. arterial dissection of the vertebral or carotid The possible benefit of oral anticoagulation for arteries versus antiplatelet drugs has not been the long-term treatment of dissections has never studied in head-to-head trials. may benefit from oral tion of the vertebral or carotid arteries found a rate of anticoagulation.72) [49].42.0 to 3. A more recent review came to a similar source of embolism [55]. more or less efficacious in the prevention of vascular coagulation is between 2.96. 95% CI 0. bodies (aPL) treated with warfarin (INR 1.38–2.0 and 3. complications for low-intensity anticoagulation was lation with warfarin in patients with AF: the study 1.33–0. INR values events than antiplatelet therapy (medium-intensity >3.67. The Warfarin Aspirin Recurrent with balloon angioplasty Stroke Study (WARSS) had a similar rate of ischemic  Symptomatic patients with significant stenosis of 277 events and bleeding complications comparing the internal carotid artery (ICA) should undergo .g. The rate of major bleeding complications higher risk of major bleeding complications (RR 9.4–2.8) compared to 325 mg ASA [59]. deficiency is derived from patients with deep vein  The benefit of anticoagulation for patients with thrombosis and not from patients with stroke. protein S or antithrombin not recommended.49. due to a significantly increased bleeding risk with anticoagulation. during and tection system did not influence the complication after endarterectomy. SPACE randomized 1200 symptomatic and 95%. This benefit is mainly seen in males. was 6. during and after carotid were the degree of stenosis. after 527 patients were randomized due to a signi-  At present carotid stenting has a slightly ficant difference in the 30-day complication rate higher short-term complication rate and similar favoring carotid surgery (9.93) [73]. medium-term outcomes. The EVA3S study was terminated prematurely replaced by ASA 5 days before surgery.34% in patients who were operated. based on extrapolation from studies of coronary stents. The study was terminated prematurely due to a absolute RR for the endpoint ipsilateral stroke higher rate of bleeding complications with warfarin is 4. recurrent ischemic events stenting might be con- 278 cant ICA stenosis to carotid endarterectomy or sidered [77. Section 4: Therapeutic strategies and neurorehabilitation carotid endarterectomy. Lower doses are better tolerated and plication rates (stroke and death) were 6. Predictors for a recurrent ischemic event should be given prior to. Therefore ASA is recommended in these Patients with <50% ICA stenosis do not benefit patients. The intracranial stenosis and randomized them to either risk reduction is even higher in stenosis >90%. pared to medical treatment in patients with high.5. In oral anticoagulation (INR 2.25–4. The benefit of surgery interventional neuroradiologists had to pass a quality increases with the degree of stenosis between 70% control.2% for appear to have equal efficacy in other ischemic stroke stenosis >70% and 8.5% over 5 years for the combined endpoint of stroke and The WASID-II study recruited 569 patients with death in favor of carotid endarterectomy [69]. Intracranial stenosis  Symptomatic patients with intracranial stenosis or Two large randomized trials (NASCET and occlusions should be treated with antiplatelet ESC) found a clear benefit of carotid surgery com. therapy.6% vs.0–3.6%. At present carotid stenting ASA (75–100 mg) is recommended in has a slightly higher short-term complication rate patients after carotid stenting for 1–3 months and similar medium-term outcomes.4% for 50–69% stenosis. stenting can be degree stenosis of the ICA [63–69]. not known. the internal carotid artery (ICA) should undergo  The combination of clopidogrel (75 mg) plus carotid endarterectomy.0) or ASA (1300 mg/ patients with 50–69% ICA stenosis the 5-year day).  In patients with recurrent events. as a factor in a lower complication rate in patients  The benefit of surgery is no longer present when treated with stenting. The use of a pro-  Patients should receive ASA prior to. of the two studies show a lower complication rate The restenosis rate is higher after stenting. cases when surgery is performed 12 weeks or later A post hoc subgroup analysis identified age <68 years after the initial event. rate of carotid stenting is age dependent and Symptomatic patients with significant stenosis of increases beyond the age of 65–68 years. The short-term com. The complication rate of sur- the complication rate exceeds 6%. ASA etiologies. in high-degree within 30 days. The benefit of surgery is highest in the patients with a >50% stenosis (NASCET criteria) or first 2 to 4 weeks after the initial TIA or minor >70% (ESC criteria) within 6 months after TIA or stroke. ipsilateral stroke or death stenosis between 50 and 70%. In patients with Several studies randomized patients with signifi. 3. The complication was higher after carotid stenting. although not based on the results of balloon angioplasty with stenting. OR 2. Whether the high dose of ASA is needed is from carotid endarterectomy. stenosis in the vertebro- surgery [70]. The use of protection 95% CI 1. The primary endpoint. The reported medium-term Whether this translates into higher long-term outcomes were comparable and the restenosis rate event rates is not yet known.9%. .84% in patients undergoing stenosis (pseudo-occlusion). gery was not age-dependent [72]. Taken together the results systems does not decrease the complication rate. for endarterectomy [74]. Clopidogrel should be rate. the trials found an absolute risk reduction of 13. minor stroke to carotid endarterectomy or stenting  The benefit of surgery is lower in patients with a [71]. basilar system and female sex [76]. 78]. Surgeons and randomized trials. [75]. Taken together considered. in women and in stenting and 6. Kober L. Neurology 2004. 32:2559–66. Lancet 2007. Stroke 2001. Grau AJ. (EXPRESS study): a prospective population-based  Symptomatic patients with significant stenosis sequential comparison. Heinrich A. 62:2015–20. Jeerakathil T.0 to 3. LDL is 70–100 mg/dl. N Engl J Med after endarterectomy or the combination of clo. Pogue J. Cobb JL. 62:569–73. Stein BM. 5. Weimar C. Eur Neurol 2002. The target range of population-based study. In Barnett HJM. Int J Stroke strokes. Busse O. 3(1):3–10. A systematic review. 7. 6. reduction and secondary prevention of stroke and  Symptomatic patients with intracranial stenosis other vascular events. et al. Lancet Neurol 2007. Glahn J. Goertler M. Diagnosis and targets (<140/90 mmHg in non-diabetics and Management. requires combination therapy and lifestyle 3. et al. or both in Patients should receive ASA prior to. Schopflocher DP. Long-term ACE-inhibitor therapy in 279 . Wimmer  Treatment of increased plasma levels of ML. Leonardi-Bee J.0). 254(11):1562–8. Svenson LW. Yusuf S. Telmisartan.  Hormone replacement after menopause is Subramaniam S. Stroke 2003. Risk of stroke early after particular atrial fibrillation (AF). Rothwell PM. 358(15):1547–59. Buchan AM. Chapter 19: Secondary prevention Chapter Summary References 1. Goertler M. the combination Darius H. should be transient ischaemic attack: a systematic review and treated with oral anticoagulation (INR 2. Complications following acute homocysteine with vitamin B6. stent. acid is not effective in secondary stroke prevention. Yusuf S. 370(9596): (degree of stenosis between 70% and 95%) of 1432–42. Scott JN. therapy. and treatment of stroke. in 8. the systolic and diastolic blood pressure eds. J Neurol 2007. Systemic Risk Score of ASA (2  25 mg) and extended-release dipyri. ramipril. Mohr JP. Rashid P. D’Agostino RB. Evaluation in Ischemic Stroke Patients (SCALA): a damole (ER-DP 2  200 mg) or clopidogrel prospective cross sectional study in 85 German stroke units. et al. Flather MD. 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Neurology 2005. Fraedrich G. Neurology. Klucznik R. Brey RL. Chapter 20 Neurorehabilitation Sylvan J. It has been a high-intensity training in the first hours to few days long way. and active therapies and the coordinated work and The overall benefit of stroke units results not only from multimodality of a specialized team [3]. first by might be problematic). in severe disorders recovery can others) with structured organization and processes and vary and these patients may even show onset of func- the stroke patient taking part in a multimodal. neurological patients to improve physiological func. that therapeutic exercises influence the course of spon- datory for outcome optimization (whereas ultra-early taneous recovery of a brain affection [5]. minimization of complications. thrombolysis. inducing several means of recovery includ. high intensity. after a lesion and afterwards the recovery curve flat- disciplinary team (physicians. which can be selectively promoted [6]. thrombolysis – only a small proportion of all stroke patients (less than 10%) are treated with this regimen – but more generally from the multidisciplinary stroke Neuroplasticity unit management.g. especially in elderly people. (e. treatment program which is well adapted in detail to the Such recovery of the central nervous system over 283 individual goals of rehabilitation and deficits. on a stroke unit) to a specialized die. Recovery and reconditioning [1]. While for many decades of the last century it was After the acute treatment. tens. As an exception. A key point in successfully (e. In the adult brain the unit. measurement of the effects of rehabilitation. a paradigm shift neurorehabilitation ward or clinic is still under dis. making its way term disability in adults. has taken place. A few years later in 1936 it was reported cussion. The best timing for transferring a patient after nerve paths are fixed and immutable: everything can initial treatment (e. nursing staff. intense tional recovery after a longer period [7].g. It adds a social perspective with Although progress in the acute treatment of stroke emphasis on participation. therapists. Disability and Health. neurorehabilitation (mainly come of neurorehabilitation in stroke with early initi- organized inpatient multidisciplinary rehabilitation) ation of treatment. stroke patients with believed that. and elements of early Mechanisms of neuroplasticity neurorehabilitation [1.g. measured by motor scores) takes place more diminishing negative long-term effects after stroke and quickly and more effectively up to the first 8–12 weeks achieving recovery is the work of a specialized multi. into clinical practice. to what we now know. tioning. The the course of time after the onset of stroke is possible . 2]. including treatment optimization. the relevant neurological deficits should in general be sources of growth and regeneration of axons and treated by a specialized neurorehabilitation clinic or dendrites are irretrievably lost. that the Neurorehabilitation nowadays is considered as a central nervous system of the adult human being has an multidisciplinary and multimodal concept to help astounding potential for recovery and adaptability. nothing can be regenerated” [4]. “once development is complete. compensation bral lesion being the predominant factor. the concept of stroke units) has There is growing evidence indicating a better out- occurred over recent years. Albert and Jürg Kesselring Introduction and overview WHO’s ICF (The International Classification of Functioning. accepted as a useful tool in goal-setting. activity and participation by creating learning The extent of recovery in stroke is dependent on situations. 2001) is now widely Stroke is one of the most common causes of long. however. but early initiation of rehabilitation is man. specifically aimed remains one of the cornerstones of stroke treatment. many factors. functional remodeling. the initial size and location of the cere- ing restitution. and Basic underlying mechanisms of these findings contralateral activation patterns were noted. In this respect interaction models) affecting the motor control of the between lesional and contralesional hemispheres may contralateral hand were assessed over several also play an important role [19]. however. motor homunculus recent studies also demonstrate These findings suggest a very variable cortical the representation of movements within the primary representation [14]. and in cortical representation areas. A persistent activation.and/or can be taken over by different regions of the brain. activation was again ipsilesional networks and synapses. pathophysiological mechanisms in the 284 compared to controls. it is described neuroplasticity with regard to the function suggested that of synapses [8]. For this early which include: compensation detailed longitudinal fMRI  Vicariation (vice ¼ instead of) describes the studies show initial upregulation in primary hypothesis that the functions of damaged areas and secondary motor regions (ipsi. on the other hand. of summary refer to Ward [11]). In the first follow-up. supplementary motor areas [16]. second- emission tomography (PET) and functional ary motor areas have direct projections to spinal cord magnetic resonance tomography (fMRI) different motor neurons. By using transcranial the goal of achieving the best results by recruitment magnetic stimulation (TMS) mapping in stroke and adaptation of surviving secondary motor areas in patients. Section 4: Therapeutic strategies and neurorehabilitation due to a mechanism described as neuroplasticity. Another clinical which are reminiscent of normal activation example is the change in lateralization of speech in patterns. variable size of cortical representation “loco typico” of motor fields [12. however. which include . reflecting functional perilesional region are initiated. the area of cortical representation of the both hemispheres [16]: in addition to a static point-by- abductor minimi muscle (ADM) transiently point view of the somatotopic organization of the increased even after a single training session. contralateral) but also activity of other non- In clinical practice this ability may vary widely primary structures of the sensorimotor and may be insufficient for a large group of network [9]. recruitment of secondary motor areas such as Several (overlapping and interacting) mechanisms the dorsolateral premotor cortex and of neuronal plasticity can be identified [7. After include both different functional use of existing several months.g. and. Later such For better understanding of these mechanisms a enlargement of cortical representations was also main strategy for recovery in such patients seems to be demonstrated in humans. it focused and efficient brain activity in a later could be demonstrated that vicariation takes place phase reflecting reorganization [17]. although they are less numerous than patterns of activation have been described (for a those from M1. reorganization in the motor cortex adjacent to the which can be observed and investigated by different lesion. months. To summarize fMRI and PET studies after approaches. Enhanced activity of the ipsilesional some younger patients. and later this principle was also linked  interruption of projections from the primary to the functioning of neurons in the wider context of motor cortex (M1) leads to increased neuronal networks. 9–11]. followed by patients with remaining difficulties after brain  more precise activation patterns with more damage. the better the recovery. With functional imaging. 13]. e. but also to a certain extent and closer to the former representation and more structural changes. primary motor cortex induced by motor  Plasticity of areas of cortical representation was training is paralleled by improved motor described in animal models in connection with the function [18]. ipsi. a small group of stroke or failed reorganization in chronic stroke patients: the patients with comparable circumscribed M1 higher the involvement of the ipsilesional motor net- lesions (similar to experimental lesions in animal work. In the early course of ischemic dorsal for the function of finger-extension as stroke. Hebb first deficits with damage to corticospinal tract. Using functional positron sensorimotor cortex. from a clinical to a neurobiological focal ischemic brain lesions resulting in motor and neuropathological point of view. In an illustrative many different areas may also indicate a less successful longitudinal study [15]. Therefore its practical use in stroke infarction. Such learning conditions also take place in the of growth factor GAP-43 in the adult central ner. especially on days 3–18 techniques. Chapter 20: Neurorehabilitation upregulation of plasticity-related proteins. The main techniques are repetitive “spines” between two neurons. synapsin I and certain brain to reorganize itself during ontogeny. bar. however. A valuable principle in animal models sprouting of neurons after lesions to force the individual to learn is the use of constraint- and also after interventions to reduce production induced therapies (CIT). several trials have been undertaken and are plastic changes. including the lack of of behavior by repetitive interactions with the social Schwann cells (functioning as a leading structure environment. this mechanism is reduced (but not development of human individuals leading to changes excluded) for several reasons. In clinical neurorehabilita- to morphological changes. transcranial magnetic stimulation (rTMS) and tran- Diaschisis is a term used by von Monakow (1914) scranial direct current stimulation (TDCS). However. effect of the multidisciplinary teamwork and applied riers of gliosis produced by glia cells. Sprouting of neurons after damage of the neuron Inducing neuroplasticity itself is well known in the peripheral nervous system. which is available in the peripheral the neurorehabilitation ward in interactions with nerve system over the entire lifespan [7]. neurotransmitters. physicians and the nursing team. Neuroplasticity is the dynamic potential of the derived neurotrophic factor. In addition other stimulation much more common than the limited sprouting techniques and enhancement by use of medications of axons. wire currently ongoing to evaluate non-invasive cortical together” by Hebb [8]. leading to routine. patients is limited. Furthermore an enriched environment must also The main theory behind influencing cortical activ- be mentioned in terms of neuroplasticity [7. learning. as ity is the hypothesis of contralesional hemisphere has been demonstrated in animal models: rats with an overexcitability. where axons may re-grow after Wallerian There are many parallels between postlesional neuro- degeneration. In the central nervous system of the plasticity (re-learning) and normal learning in the adult. Collateral sprouting can lead to a change of function in a damaged neuron by receiving new synaptic input Supporting neuroplasticity by peripheral from dendrites of non-lesioned sprouting neurons.g. which can to describe the phenomenon that a focal lesion may be used for both cortical enhancement and inhibition. are under evaluation. 16]. which however. and brain stimulation techniques Synaptic plasticity refers to the altered synaptic Although not yet to be recommended for clinical function when cells are communicating. also lead to changes in brain functioning of areas depending on the set-up parameters. brain. incomplete therapies is to create a stimulating learning atmosphere remyelinization by oligodendrocytes. An example demonstrated by epidural electrical stimulation (EES) is an invasive several recent neuroimaging studies is an enhanced approach using a grid of electrodes implanted neuro- contralesional cerebellar activity after cortical surgically. disturbed function on other areas described as vicar- sion showed much better recovery when held in an iation and changes of cortical representation (see enriched environment with free access to physical above). but also involved are effects of locally ischemic lesion due to middle cerebral artery occlu. These modifications probably lead or following damage. stated as “cells that fire together. e. cannot be of inhibitory factors has already been shown to used in the treatment of the majority of stroke lead to a better outcome. synaptic plasticity and tion this potential is utilized by creating a stimula- ting learning atmosphere and using stimulation sprouting as discussed below. The main approaches to brain stimulation 285 activity and social interactions [24]. Furthermore located far away. are to increase the excitability of the cortex in the . production of that matches the patient’s individual needs and def- inhibitory factors by these cells and low production icits. In clinical neurorehabilitation the main for sprouting in the peripheral nerve system). Changes in synaptic activity stimulation techniques with the purpose of enhancing can be measured by alterations in the number of neuroplasticity and recovery. after stroke [19–23]. using clinical outcome NMDA receptors and are morphologically seen as measures or fMRI. Sprouting of dendrites is patients (see below). therapeutic sessions (see below) and in everyday life on vous system. Levodopa. however. This can be achieved noninvasively in conscious humans using repetitive transcranial magnetic stimulation (rTMS) and tran- scranial direct current stimulation (TDCS). the use of levodopa or a Increasing input from the paretic hand using central stimulating agent may be an alternative treat- somatosensory stimulation may also improve ment option (see Table 20. No single medication evaluated for its beneficial effect With the application of these newer treatment by modulating plasticity in the human motor cortex methods in stroke patients. repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (TDCS) can be used for both cortical ence) are placed on the skin. As far as is known now.1). Higher frequencies of more than 5 Hz increase cortical excitability and can be applied to stimulate the cortex on the ipsilesional hemisphere. recent findings suggest a in stroke patients has reached class I evidence so far. found to have no effect. In rTMS an electric current is induced in the underlying cortex by a magnetic field which then activates the axons of cortical neurons.1). This effect to take part in therapies due to diminished alertness might – at least partially – also play a role in and drive should be carefully evaluated for depression constraint-induced therapies (CIT). Low- frequency rTMS around 1 Hz results in decreased cortical excitability (which persists after the applica- tion of rTMS) and is therefore used on the contrale- sional hemisphere for downregulation. If treatment with stimulating antidepressants is not successful or not possible. d-amphetamine. cortex. Usually Supporting neuroplasticity by 10–20 minutes of TDCS at 1–2 mA are regarded as pharmacological interventions safe and painless. enhancement and inhibition. depending on the set-up parameters ing electrical current leading to different effects in the used. more trials to be beneficial in trials evaluating motor recovery are needed to assess the long-term benefit and to after stroke.1. depending on the polarity: anodal TDCS has an excitatory effect. Motor training of the paretic hand Non-invasive cortical stimulation techniques (repeti- 286 itself increases somatosensory input as well as tive transcranial magnetic stimulation and direct constraint-induced therapies (CIT) (Figure 20. sine and clonidine [31]. but only limited data are available now. larger controlled trials are needed hand was shown to lead to improved performance before such treatments can be generally recom- of the paretic hand in stroke patients using mended. Reduction of sensori-motor input from the intact However. motor function [29. current stimulation) are used in rehabilitation to . 10–20% functional improvement in single sessions as Only a few preliminary studies using this approach well as in a small but increasing number of longer- have been conducted. Section 4: Therapeutic strategies and neurorehabilitation ipsilesional hemisphere and/or suppression of the contralesional hemisphere. Stroke patients presenting a reduced ability cutaneous anesthesia [28]. cor- studies are contradictory. prazo- influencing cortical activity are under evaluation. 30]. donepezil and fluoxetine are found intervention for stroke patients. haloperidol. delivering weak polariz. Special pat- terns of rTMS (theta bursts) have been used in humans. and the results of some term therapeutic trials. first. but in one study d-amphetamine was optimize protocols [16. tical stimulation appears to be a safe and promising methylphenidate. 26. 27]. Non-invasive brain stimulation in stroke refers partly modulatory capacity [25]. Negative effects on outcome On the other hand peripheral techniques indirectly were noted for benzodiazepines. and are reported to have longer-lasting Figure 20. to the “contralesional hemisphere over-excitability hypothesis” – In TDCS two electrodes (one active and one refer. cathodal TDCS induces inhibition via presumed hyperpolarization. 1. also useful in pathological crying mirtazapine with sleep disorders. phenytoin. 50–200 mg/day (main dosage at bedtime).v. lorazepam and i.v. restricted substance. 2000(þ) mg/day in monotherapy antiepileptic drugs (i. 10 mg/day (50–75 mg/day) only 2nd line in depression pregabaline slow elevation diminishes side-effects.g.5–25 mg psychosis Agitation. sleep disorder. e. application possible: several benzodiazepines. other indications include other benzodiazepines anxiety. sometimes also used in central pain epilepsy syndrome carbamazepine 600–1200(þ) mg/day. sometimes also used in central pain syndrome and paroxysmal symptoms phenytoin 250–300(þ) mg/day levetiracetame and other 1000–3000 mg/day. Chapter 20: Neurorehabilitation Table 20. depression (temporarily) negative effect on cognition and learning. levetiracetame) clonazepam. application in status epilepticus. inpatient evaluation Agitation. in elderly patients start with 12. Selected medications used in the course of neurorehabilitation. Indication Substance Remarks Post-stroke venlafaxine 75–300(þ) mg/day depression citalopram 20–40 mg/day. pipamperone 20–80(þ) mg/day (at bedtime) for sleep disorder of the elderly sleep disorder Post-stroke valproate 800–1800(þ) mg/day. quetiapine 25–300(þ) mg/day. consider very slow syndrome initiation. valproate. ibuprofen and other NSAIDs combine with positioning and physical therapies arm pain Shoulder-hand prednisone start trial with 50–70 mg/day syndrome Central pain amitryptiline especially useful in constant burning pain. 5–50(þ) mg/day 287 . can also be used in the elderly Diminished drive l-dopa/benserazide evaluate 100/25–200/50 mg/day (studies for motor recovery undertaken with pulsed use in combination with physical therapies) methylphenidate start with 10 mg/day. adverse drug reaction with agitation in the elderly Pain/shoulder. 75–300(600) mg/day gabapentine slow elevation diminishes side-effects. combination with venlafaxine and other possible trazodone with agitation. 900–3600 mg/day tramadole combination with pregabaline or gabapentine. 50–150(þ) mg/day oxycodone in severe central pain syndrome. add-on. 15–45 mg/day (at bedtime). ) Indication Substance Remarks Bladder oxybutynin detrusor spasticity. (see below). cardiovascular diseases and infections are not included. intrathecal application in severe (spinal) spasticity tizanidine 4–24 mg/day (orally baclofen and tizanidine have very limited effects in cerebral spasticity) Notes: Please note that (1) substances mentioned are examples of their group. and has been shown to improve outcome significantly only 13% engaged in activities with the potential by reducing death rates and dependency (NNT 7 to prevent complications and improve recovery for thrombolysis versus NNT 9 for stroke unit treat. 20 μg/day given intranasally at bedtime Reflux. neurorehabilitation ward or clinic is still under ents of neurorehabilitation. dementia. (4) medications for secondary prophylaxis.1. In prelimin. odds of death. as a multicenter study examining physical activity within the first teamwork for stroke recovery 14 days of acute stroke unit care has shown: in In addition to thrombolysis the multidisciplinary the daytime patients spent more than 50% of the management in a stroke unit or by a stroke team time resting in bed. (cont. pantoprazole and consider administration twice daily in critically ill patients ulcers other proton pump inhibitors (prevention) Spasticity botulinum toxin A period of >3 months between intramuscular injections to diminish risk of antibodies baclofen 30–75(þ) mg/day orally. of mobility. linary neurorehabilitation as compared to general treatment. 7. Section 4: Therapeutic strategies and neurorehabilitation Table 20. (3) there are not enough data for all of the mentioned substances to provide evidence-based recommendations (expert opinion or observational studies). please verify with your national regulation standards. an extra five returned home in an inde- pendent state [32]. The best timing for transfer- achieved by structural organization and interdiscip. tient multidisciplinary rehabilitation (as compared to After acute stroke treatment medically stable 288 treatment on a general ward and other nonspecific patients with relevant neurological deficits should rehabilitation clinics) is associated with reduced be treated in a specialized neurorehabilitation clinic . and concerns regarding optimal timing According to a large meta-analysis (n ¼ 1437) and intensity might also contribute to the problem the benefit of postacute treatment in organized inpa. gastritis. enhance neuroplasticity and recovery. some medications such as levodopa Of 100 patients treated by organized multidiscip- were found to be beneficial for motor recovery. omeprazole. Furthermore patients were alone for ment) [2]. ary studies. but also by the early use of elem. neurorehabilitation The amount of rehabilitation treatment in the Importance of multidisciplinary acute phase may vary widely. ring a patient after initial treatment to a specialized linary management. 28% sitting out of bed.5–15(20) mg/day dysfunction alfuzosine and other α-inhibitors increased urethral sphincter activity or detrusor sphincter dyssynergia desmopressin in severe nycturia. The positive effect of stroke units is 60% of their time [33]. institutionalization and dependency. discussion. (2) several of the indications are “off-label”. Therefore the beneficial elements Structured multidisciplinary of acute and postacute stroke treatment should be combined. if neces. Finally. The required equipment in superior outcome (functional measures and more a neurorehabilitation department must be defined dendritic sprouting) as compared to a later beginning in detail to ensure structural quality. physical and occupational ther. The positive effect of stroke units is organization and processes: the patient takes part gained by structural organization and interdiscip- in a multimodal. including clinical neurological examin. however. The occurrence of these negative consequences is explained by cytotoxic This approach should be centered on the indi. a better functional result centers. social and personal account: immobilization increases the rate of compli- background and coping strategies. cations after acute stroke. 24 hours) and intense forced activity could lead to an  program of staff training. Furthermore in primates of medical and organizational processes using a reorganization of cortical representation areas was quality-management system and “learning from found to be more effective after early activation mistakes”. including thrombosis.g. is also important for rehabilitation above-mentioned studies. physicians. without signs of enlargement of lesion areas was At the onset of the rehabilitation process a multi. On the basis of pathophysiological  input from a multidisciplinary team of data. interacting bra region. humans. home with a lower degree of disabilities [44] as com- In the course of rehabilitation the patients’ progress pared to later activation on a medical ward. intensive treatment program linary management. whereas inactivity results in additional meetings. nursing and therapy staff with an a particularly promising period: in animal models expertise in stroke and rehabilitation whose active training leads to better functional recovery work is coordinated through regular weekly and sprouting. (n ¼ 1760) with reduction of disability and better 289 sary [34–36]. other factors should be taken into ities of daily living (ADL). 23]. term outcome. days and structured training at an early stage on a ment. Other recent animal studies. In ation. enlargement of lesion areas. A description (at days 14 and 30) [20]. kinesiotherapists. focal hyperthermia and other factors [37–41]. but also by the early use of elements of neurorehabilitation. Better and abilities are critically discussed and re-evaluated long-term outcome is reported in stroke patients with in the multidisciplinary team in at least weekly ses. using a critical incidence reporting (within 7 days) [12. Chapter 20: Neurorehabilitation or stroke unit in an in. quality-of-life measures [45]. loss of ability [12. in contrast to the system (CIRS). effects of glutamate. In another large study . speech and language path. early start of an organized inpatient multidisciplinary sions with an adaptation and reconsideration of rehabilitation within 7 days in a multicenter study treatment strategies and goals (see below). some experimen-  involvement of patients and family in the tal studies in rats show that very early (starting within rehabilitation process. Early mobilization in the first reintegrate the patient into his/her social environ. however. psychologists.or outpatient setting to Treatment in an organized inpatient multidisciplin- take advantage of the impact of the work of a ary setting improves the outcome after stroke sig- specialized multidisciplinary team with structured nificantly. the first 3 weeks after stroke are considered as medical. 42]. recreational therapists activation after focal ischemia starting at day 5 had a and social workers [3]. support the apists. activ. 20. mandatory. metabolic collapse of the penum- vidual patient and family/caregivers. inhibition of upregulation of signal pro- closely with a multidisciplinary team consisting of teins. Clinical data are consistent with these findings. achieved by early motor training in rats beginning disciplinary assessment of deficits and resources is 24 hours after maturation of ischemic lesions [43]. early initiation of appropriate activation. ery of physical and psychological functions and to infections. Timing and intensity A short and useful definition for an organized Clinical studies indicate that an early start and high inpatient multidisciplinary rehabilitation includes: [33] intensity of therapies are decisive for a favorable long-  interdisciplinary goal-setting. Early motor ologists (SLP). To achieve recov. However. which must be adapted to the individual goals of rehabilitation with regular interdisciplinary re- evaluation. assessment of functional performance. therapies and other interventions must be stroke unit enhances the rate of discharges to the adapted to the individual abilities and disabilities. and ulcers. nurses. e. A modified version tion” as an important objective. The RMI contains in stroke rehabilitation a series of 14 questions and one direct Assessment outcome in stroke is directly linked to the observation. body functions. The ICF (The International Classification of performed with increased intensity. e. social communication. In determining mobility using gait speed and endurance.2. .  including in the course of treatment a high Activity scales evaluate abilities and have their proportion of multimodal therapies. 2001. “International Classification of Functioning. Therapy intensity Functioning. participation.2). (Figure adapted from achieved by the additional use of rehabilitation robot. with the aim of better sensitivity. including two context factors: A higher intensity of therapies can also be environmental and personal factors. and structures Not only early initiation of treatment but also the intensity of rehabilitative therapies is of significant importance. Its validity as a Most widely accepted is the “The International Clas. and covers a range of activities from model of illness and definition of treatment goals. in the case of instable brain treatment schedule. exam. Even if some somatic functions cannot be demonstrating treatment effects in patients regained directly. ics in the multidisciplinary approach. Activity can be assessed by activ- days after stroke ity scales and scales of activities of daily living. Interdiscip- (and should be reserved for specific rare linary goal-setting is crucial for determining the exact situations. Disability and Health”. WHO 2001) transforms the former was also related to shorter lengths of stay and to WHO concept of “disability” into activity and stresses the improvements in patients’ functional independence. The early stage improves the outcome after stroke. individually adapted neurorehabilitation of the It adds evaluation of quality of life to activity as an medically stable patient. To summarize:  immobilization after stroke is counterproductive by establishing compensatory strategies. be used in hospital or at home.) for arm functioning and walking. as shown in a meta-analysis [47] with higher mobility. a highly significant correlation of early treatment start and functional outcome was Body functions Activities Participation detected [46]. value in detailed measurement of aspects of specific Early mobilization and structured training at an therapies or in motor function research [48]. for estimating the duration of perfusion due to arterial stenosis) and neurorehabilitation and for evaluating rehabilitative  an appropriate amount of activity should take potential (Figure 20. as established World Health Organization. and improved executive Environmental factors Personal factors functions when different therapeutic modalities are Figure 20. Treatment goals has been developed [50] in which the number of measure the physical and psychological status.g. higher social goals can be reached following stroke. ideally within the first outcome parameter. measure of mobility after head injury and stroke sification of Functioning. Section 4: Therapeutic strategies and neurorehabilitation (n ¼ 969) specifically examining the impact of the Health condition timing of the initiation of neurorehabilitation and functional recovery. and by treatment goals the medical model is extended by standing balance. body structures. Disability and Health” was tested by concurrent measurement of (ICF) proposed by the WHO in 2001. turning over in bed to running. Assessment in stroke is crucial to demonstrate the place very early after the onset of stroke course of recovery and benefit of neurorehabilitation  with the initiation of specific and intense and also to deliver instruments for research purposes. The RMI forms a scale and can adding a social perspective and defining “participa. interrelation of the several components: activity. Disability and Health. or ability to physical therapists consider essential for 290 work. test items was reduced from 15 to eight items in ining the impact of deficits on social aspects such as order to measure mobility-related items that everyday life. most commonly used activity scales are:  The Rivermead Mobility Index (RMI) [49]: a Goal-setting and assessment clinically relevant measure of disability which concentrates on body mobility. autonomy. and sit down again. (1996) and the Early Rehabilitation to provide an estimate of muscle tone on the Barthel Index (ERI) proposed by Schönle (1995). one by also considered. which is a self-report (patient It assesses the ability to handle objects differing in and caregiver) health status measure to assess multi- size. groceries or clothes. of a square board with nine pegs and the patient is memory and thinking. are instructed to take pegs from a container. affected side. e. It is aimed at the back). functional capacities of stroke patients. walk a short distance. The ARAT consists of 19 items grouped into four Stroke-specific instruments include the Stroke subscales: grasp. balanced sitting. are most commonly used. bowel control. turn For assessing the ability of a person to live independ- around. such as performing light housework. ment is obligatory using validated scales. toilet use. walking. shopping for measure of balance in elderly people. upper-arm function. general tonus. feed- assessment of eight areas of motor function and ing. The NHPT is easy to perform Interdisciplinary goal-setting is crucial for determin- and estimates parts of the upper limb function. transfers (bed to chair and scored on a scale from 0 to 6. The SIS can show persisting difficul- one. which attracts criticism as being The Functional Independence Measure (FIM) [57] difficult to rate. often resulting in reduced independence and . the modified 10-item version Modified Motor Assessment Scale (MMAS): also by Collin et al. hand tional disability but there are numerous extensions movements and advanced hand activities. dressing. grooming. Assess- living (ADL) the Barthel Index (BI) and the Func. The get-up which of the items. Balance ently within a community an instrumental activities of function is scored on a five-point scale. using the telephone and managing  The Action Research Arm Test (ARAT) [54] is an money. activity limitation. grip. i. and go test is regarded as a satisfactory clinical preparing a meal. weight and shape and therefore can be dimensional stroke outcomes: in addition to func- considered to be an arm-specific measure of tional status such as strength and hand function. tional Independence Measure (FIM). manual dexterity. good correlation with laboratory tests.e. the extended BI (EBI) by included is a single item. It determines the item was deleted. activities of daily living and other dimensions of  The Nine Hole Peg Test (NHPT) [55] is composed health-related quality of life. supine to sitting also indicating the need for assistance in care. pinch. sitting to Barthel Index (BI) is a widely used measure of func- standing. It is debatable. mobility (on level surfaces) and stair climbing. for estimating duration as well as intensity of neurorehabilitation Of the numerous scales to assess activities of daily and for evaluating rehabilitative potential. blad- one item related to muscle tone. ity of life refer to Graham [48]. In a special version [52] item was developed based on the Barthel Index and meas- descriptions were modified and the general tonus ures overall performance on ADL. bathing. The over the edge of a bed. It is aimed at measuring fine been considered independent using ADL measures. however. evaluative measure to assess specific changes in For an overview on the scales used for instrumen- limb function among individuals who have tal activities of daily living and measurements of qual- sustained cortical damage resulting in hemiplegia. Each item is der control. Chapter 20: Neurorehabilitation  The Motor Assessment Scale (MAS) [51] is a brief mobility in activities of daily living (ADL). such as communication. showing the items of basic self-care. and gross movement. and many others. and the resulting in a cumulative score between 0 and 100 and items are: supine to side lying. return. intended Prosiegel et al. Impact Scale (SIS) [58]. need for assistance by another person (burden of  The Get-up and Go Test [53] requires patients to care) and includes a cognitive domain score. which includes additional items assessing the function of cognition. ing the exact treatment schedule. should be included. and place them into the holes on the board.g. (1988). as ties in the physical domain of stroke patients who had quickly as possible. Motor rehabilitation The Barthel Index (BI) [56] measures the extent to Motor impairment is the most common deficit in 291 which somebody can function independently and has stroke. and modifications. In the daily living (IADL) is necessary. taking medications. and social role function. which includes several development the same patients undergo important and more complex functions that go beyond laboratory tests for gait and balance. stand up from a chair. however. consisting of constraining the the studies can be criticized for low treatment contrast unaffected limb. a repeti- for patients with neglect or pusher syndrome. in addition to body-weight and walking speed [70. resulting in better gait speed and floor being routine practice. their relevance to practical neuro- doubt about the benefit in terms of easing the burden rehabilitation and experimental neuroscience came on the therapists and overall being regarded as useful later: at that time Taub argued that. Using this method motor rehabili- tional training. With the aim of enhan. Constraint-induced therapy (CIT) The principles of CIT and constraint-induced move- In rehabilitation practice these methods are used ment therapy (CIMT) were described by Taub in 1993 in addition to conventional modalities. occupa. In addition. forcing use of the affected limb. after stroke. such as the Lokomat or Gait embedded in music. (their benefit having already been shown by Beer still detectable at 2-year follow-up (Figure 20. if a selective parameters and intensities make a comparison of the function for the paretic wrist and fingers is present results harder. and in addition different outcome tation of the upper limb is possible.g. burden on the therapists. [67]. et al. compared to conventional gait training [66]. at least tional and other therapies (see below) the following for crucial parameters such as functional walking methods are aimed especially at motor recovery. complementary tool in gait rehabilitation including tation. Later three principles for this kind of ther- different outcome parameters of gait [59–63]. The limited. A placebo-controlled study applying CIMT authors recommend that currently BWSTT should be over a 2-week period in patients with stroke onset at reserved for patients whose physical condition is too 3–9 months before therapies showed highly signifi- weak to tolerate intense training. leaving no [72]. benefits are seen when integrating treadmill Treadmill training training with structured speed dependence as a Walking is an important objective in stroke rehabili. indicators such as velocity and distance can be easily Discouragement due to initial failure leads to “learned monitored. Beside the concepts of physical. measurement of gait patients try unsuccessfully to use the affected side. ability and walking speed by Laufer et al. conventional gait training programs on the physiotherapy. resulting in gait symmetry used to gain better stepping kinematics in stroke improved with acoustic pacing. training with rhythmic cueing by a metronome or  gait machines. aerobic exercises stroke patients (with similar patient selection criteria) and specific muscle strength training but the results are not available yet. cantly greater improvements than in the control Gait-training devices in stroke rehabilitation group in motor and functional improvement [73]. cadence after a 2-week training program for hemi- cing the efficacy of gait training and also of easing the paretic outpatients [68]. 71]. supported treadmill training. Several studies investigated the efficacy on non-use”. It has been According to learning theories and knowledge assumed that there might be an additional benefit derived from studies of neuronal plasticity. Non-blinded studies patients unable to walk. e. multiple sclerosis) are currently being investigated as to the potential benefit for certain subgroups of Repetitive training. three groups of treadmill training concepts have been developed and evaluated: Gait training with rhythmical acoustical pacing  body-weight supported treadmill training Auditory stimulation is useful combined with tread- (BWSTT): partial body weight support can be mill training [69]. resulting in better stride length Trainer GTI. can provide a “gait pattern” even for seriously paretic limbs. However a meta-analysis [64] con- before initiation of treatment with CIMT. As for tion of tasks in rehabilitation in order to achieve 292 treadmill training without body-weight support better functional outcome is mandatory. Section 4: Therapeutic strategies and neurorehabilitation mobility.3) [74]. A review of no evidence was found for better effectiveness repetitive task training after stroke revealed modest . and since control groups also received intense conven- intensive practice. for certain patients. Most of apy were formulated. How- ever. [65] in neurorehabilitation of other diseases. illustrate the positive effect of conventional gait  treadmill training without body-weight support. Therefore cludes that there is weak evidence for the overall its use as a general treatment method in stroke is effectiveness in improvement of gait endurance. enforced use of the affected limb. The illustration shows a patient training the affected left arm in everyday life situations and therapeutic exercises. is instructed to watch the non-affected limb in the morbidity [64]. showing that strength is related [83]. and hand-related functioning than a similar treatment ures such as walking speed and endurance.3. maximal workload.g. muscle without mirroring.g. In an observational rehabilitation is not clear yet. functioning started post-treatment and continued One concern in specific muscle strength training is during the 6-month follow-up evaluation rated by increasing abnormal tone. by water-based with severe motor affection without aphasia or exercise for cardiovascular fitness in stroke patients apraxia [82]: approximately 1 hour of mirror therapy [78] or task-related circuit training [79. Hereby benefit of general strengthening and aerobic exercises. e. thereby helping to activate the premotor muscle weakness of central origin without any nega. he or she is getting the visual impression that the limb In a retrospective analysis whole-body intensive in the mirror – attributed as the affected limb – is now rehabilitation was found to be feasible and effective fully functioning. The beneficial effect on hand strength.g. In mirror therapy a mirror is placed at 90 close to the Stroke patients suffer not only from neurological midline of the patient. Several studies address the possible mirror with both eyes and perform excercises. improvement in lower limb function only. e. The principles of constraint-induced therapy (CIT) and constraint-induced movement therapy (CIMT) described by Taub are: constraining the unaffected limb. and repetitive practice. Several functional recovery. a promising random- found to be decreased in hemiplegic stroke patients ized controlled trial (n ¼ 40) has been published for but were directly correlated with each other [77]. leading to better outcome not only gram was more beneficial in terms of motor recovery in physical fitness but also in various secondary meas. Contralateral activation of visual fields was also 293 statistically to functional and walking performance. an observational stitution of mirror illusions of a normal movement of study [81] showed that targeted strength training the affected hand for decreased proprioceptive infor- significantly increased muscle power in patients with mation. sub- on acquired data have changed. leading to worsening of Functional Independence Measure subscales. upper limb rehabilitation of subacute stroke patients Adding physical fitness programs. Using this arrangement the patient deconditioning and sometimes also from cardiac co. 80]. e. Chapter 20: Neurorehabilitation Figure 20. . current opinions based underlying mechanisms have been discussed. was daily in addition to a conventional rehabilitation pro- found to be useful. after meth- study aerobic capacity and walking capacity were odologically weak publications. cortex and promoting rehabilitation by enhancing tive effects on spasticity. positioning the affected limb deficits but also to varying extents from physical behind the mirror. The role of mirror therapy in motor in chronic stroke survivors [76]. However. but recently. and others [79. not in Mirror therapy upper limb function [75]. Instead it was beneficial for connections between visual input and premotor areas functional outcome. 80]. Section 4: Therapeutic strategies and neurorehabilitation shown using fMRI [84]. tactile control. a significant treatment effect of speech therapy on Basically the Bobath concept involves “24 h manage. proprioceptive neuro. Brunnstrom. The treatment itself uses several stimuli. no advantage The predominant common concepts of physiother. The concept of neuronal 23 weeks. average provided 8. who also supplied the analysis [86] shows that studies which demonstrated neurophysiological background to their concept. single movement elements Concepts of physiotherapy and others. The Bobath concept includes assessments of tonus.8 hours of therapy per week for ment” in which first of all the patient’s basal and about 11 weeks. in spastic hemipar- esis synergetic patterns are regarded as early adapta- Treadmill training. avoidance of “learned non-use” and tive days) intervention using communication lan- forced-use therapy. is a common consequence of stroke. only a minimal neurophysiology has changed. single While spontaneous recovery can also be expected to movement elements and others. in which facilitation and inhibition play a basic role. reciprocal inhibition and move. In comparative studies. As knowledge of some extent within the first year. including pos- itioning. In contrast. Mirror therapy could be an additional developed by the Swedish physical therapist Signe option for the rehabilitation of severely paretic limbs. the negative studies only everyday needs are targets of the therapeutic and provided an average of 2 hours per week for about nursing management. investigated training principles and can be used especially for enhancing motor recovery. These . e. as measured by the Token Test. repetitive training. uli. it is no surprise that effect size is reported after 1 year post-onset [85]. (see above) but there have not been sufficient data including speech. of “normal central postural control mechanism” regu. regarding the effectiveness of aphasia therapy. have techniques. goal after intensive (3 hours/day) short-term (10 consecu- 294 orientation. for treatment concepts [85]. But several modern sia and an appeal for episodic concentration of ther- principles of plasticity and learning can be identified apies has been made. some of the former explanations may sound outdated Therefore there is a need for therapy in chronic apha- from a modern point of view. Because of its enormous in many central European countries. tactile control. It also uses facilitation techniques but. the importance of a high on by the physical therapist Berta Bobath and the treatment intensity has been demonstrated: a meta- physician Dr Karel Bobath. mirror ther. reciprocal inhibition and movement patterns. In addition the concept has guage games in a group-therapy setting [87]. including positioning. but more data need to be collected. in common that they claim to have a neurophysio- logical basis. In the ment patterns. mirroring. The treatment itself uses several stim. with the result that healthy developed. The evaluation according to Bobath includes newer studies correct the former uncertainty assessments of tonus. mainly superior. tions which are eventually transitioned by therapy apy and constraint-induced therapy are newly into voluntary activation of movements. activating the visual cortex opposite to the The Brunnstrom approach is based on a concept seen hand. acute stage intense daily therapies are recommended. whereas in impact on patients’ lives rehabilitative therapy is northern America and Scandinavia the Brunnstrom mandatory and uses principles such as forced-use method is more common. From an evidence-based point of view Rehabilitation of speech disorders there is no doubt about the benefits of physiotherapy Aphasia with its affection of different modalities. the Bobath. Brunnstrom. repetition. comprehension. apy. The Bobath method is the leading approach of the left hemisphere. Brunnstrom and other muscular facilitation (PNF) and Vojta methods. Furthermore the total number of hours of reorganization aims at preventing the development aphasia therapy applied were directly linked to out- of pathological movements by recognizing variations come. as positive effects were found in the concept. has been found for one technique over the other. task specificity. Rehabilitation of aphasia needs to be intense and lations. including the Bobath. in contrast to the Bobath concept. Even more than in other The Bobath concept was developed from the 1940s therapeutic modalities. and available to identify one of these special concepts as writing. reading. for example.g. and changes in several aspects of its prac- subjects view their hand as their opposite hand by tical implementation have occurred. nuclei of caudal cranial nerves Dysphagia is a potentially life-threatening compli. depends more on the integration of available Dysphagia occurs in the acute state of stroke in language-related brain regions than on recruiting more than 50% of patients. including cortical (mainly sensory and motor cortex. which in about half of cases is due to lacunar neurological complications. Dis- cessful regeneration from post-stroke aphasia ability and Health. dysphagia was found to be highly associated with 23 patients had mild residual dysarthria. In a restoration (for the right-handed patient) of the left meta-analysis of more than 15 studies using tech- hemisphere network seems to be more effective. . (The International Classification of Functioning. Neurogenic swallowing disorders are common in the course of stroke due to widespread involvement Special topics of different brain areas. when appropriate treatment seven suffered from ongoing severe speech disturb. by the clinician can be initiated. using. Chapter 20: Neurorehabilitation intensive therapies of several hours daily demand is the most common cause of neurogenic swallowing high cognitive functioning of treatable stroke patients disorder. protocols [96]. Afterwards mortality syndrome [94]. 96] was identified.  pneumonia due to aspiration. and only preventing pneumonia. were identified with a rate of pneumonia in patients However. aspiration in more than about 20% of them. underlining the rather good prognosis under variations in food consistency and fluid viscosity or standard rehabilitation. varies depending on Rehabilitation of aphasia needs to be intense and the examination method and is highest for instru- newer studies support the efficacy of speech mental testing. For transfer of results from the therapeutic The main dangers are: situation into the patients’ environments there is also  incidence of bolus. implementation of swallowing techniques [99. and “central pattern generators” within the medulla 295 cation of many neurological disorders. At follow-up evaluation of It is therefore encouraging that the detection of 38 patients. The rate of detection. duration. of more than 440 patients in the first month after Dysarthria is an impairment of speech intelligibil. it is premature to deduce a recommenda. as for aphasic patients there with the highest number reflecting patients with is currently no evidence that these task-specific proven aspiration [97]. 91]. probably leading to new brain regions. which surpasses clinical testing therapy. tion for clinical routine. Extracerebellar infarcts causing dys. with these patients and will for many patients be considered an methods. of the pyramidal tract. premotor cortex) and Dysphagia brainstem areas. ances. In a study focusing on improvements are persistent or have any impact on cause-specific mortality after first cerebral infarction real-life communication abilities [93]. and stroke oblongata. niques such as fiberoptic endoscopic examination of although in some cases right hemisphere areas are swallowing (FEES) a wide variety of dysphagia rates integrated successfully. for example. WHO 2001). mortality resulted predominantly from ity. 40% were judged to have normal speech. showing that suc.  dysphagia can also lead to malnutrition. identified as dysphagic ranging from 7% to 68%. e. leading to acute blockage of an indication for lower-frequency therapies of long airways. stroke. The Several studies examined the additional benefit rate of pneumonia in stroke is at least twice as high from brain stimulation techniques [92] and medica. between 30% and 78% [95. but mainly because of pneumonia [98]. Using PET and rTMS interference. strated using functional imaging such as PET [89]. however.g. [88]. From functional imaging it is known that clinical On the other hand swallowing and food intake are aphasia syndromes in practice are not strictly linked important for the quality of life and autonomy of to anatomical regions and furthermore. remained high because of respiratory and cardiovas- arthria were located in all patients along the course cular factors. the courses of recovery and less successful important goal of rehabilitation. 100]. in dysphagic patients: in a meta-analysis nine trials tion on recovery from aphasia with positive results. The effect of aphasia therapy was also demon. according to the ICF progress can be revealed [90. postural checking of. (adapted from Prosiegel et al. viscosity. dry/clearing swallows.  exercises (to increase strength of muscle groups). However.  change rate of food/liquid delivery. drinking. The rate of detection of dysphagia is higher with  modify sequence of delivery.g. FEES (c) history of recurrent respiratory infections. e. consistency. (FEES) [102]: the value of laryngoscopy has effortful swallow). laryngis prematurely. percutaneous endoscopic gastrostomy. First anatomical structures and ingestion of 5 ml clear and clean water portions in landmarks are identified at rest without contrast. 296 its ability to identify salient findings. consisting of: swallow the pharyngeal air space is obliterated by  clinical neurological examination with emphasis tissue contacting other tissue and the bolus passing on bulbar symptoms. has only limited ability to assess the upper (d) coughing. which furthermore allows deter. which in interventions. At the onset of the ical evaluation. promptly initiated. Section 4: Therapeutic strategies and neurorehabilitation Evaluation of swallowing functions includes clin. After defining the individual problems of swallow-  quality of life. become appreciated for its direct view of the larynx. when the swallow  noting the most important warning signs: is over. nonfluid and fluid nutrition. targets should be considered:  aspiration. technical evaluation. above the vocal cords.  penetration: fluids/food are reaching the aditus and assesses the severity of aspiration risk and recom. disturbed through. the appropriateness of com. become a standard procedure. an adequate treatment schedule can diagnosis and description of the swallowing be set up. It is especially dangerous if food/fluid intake until a detailed treatment plan is coughing or other cleaning procedures are not set up. elaborated and easy-to-use bedside examinations include: test. with liquid and food of varying consistencies is administered [104]. (b) bubbling respiration. [101]). and its value  sensory stimulation techniques (thermal-tactile in guiding treatment.4) [105]. without direct vision.  retention: fluids/food remain in the hypopharynx If a stroke patient presents with warning signs after swallowing. pensatory maneuvers and adaptation of food/fluid consistency. offering food should begin with simple consistencies. including silent aspiration: fluids/food  avoiding aspiration: mandatorily discontinue oral pass the vocal cords. its success or failure can be judged by the (a) gurgling voice. resulting in a so-called “swallow whiteout” sensation and reflexes of the oropharynx. especially while/after eating or esophageal sphincter (UES) and its dysfunctioning. including several therapeutic compensatory problems previous to individual therapy. in the sinus piriformis and/or has failed a bedside test at least three main (carrying the risk of later aspiration). mends a special diet accordingly. examinations the Rosenbek penetration– nasogastric tube (up to 4 weeks) or in many cases aspiration scale is established (Figure 20.  Videofluoroscopic swallowing study (VFSS): the  performing clinical bedside tests: various tests stroke patient must be able to sit in front of a exist.g. ascending volume (which can be combined with Then radiopaque material (usually barium) mixed oximetry) with monitoring of warning.  change method of food/liquid delivery. dysarthria. for example: most cases will include technical evaluation  modify bolus volume. such as the 50 ml water test with successive fluoroscope. Particularly if technical evaluation is not performed. e.  leaking/pooling: fluids/food reach the pharynx in allows a graded rating with separate evaluations for an uncontrolled way. changes).g. for example. The main pathological findings of the technical A more structured. mination of the degree of swallowing disorder and  alter behavior (e. To rate the findings of such  nutrition: choose an alternative pathway. and therefore FEES has stimulation and others) [103]. . The methods predominantly used are: and rehabilitative techniques which include:  Fiberoptic endoscopic examination of swallowing  swallow maneuvers (supraglottic swallow. residue of colored test food and fluids [103]. regaining autonomy: continuing ing dysfunction. starting with nonfluids. the Gugging Swallowing Screen (GUSS) [100]. taneous tracheotomy should be avoided because of ment and technical evaluation (fiberoptic endos. it can fenestration is used. nursing care. treatment [107]. disappointing effect vs. the high rate of long-term complications. level of consciousness and/or pul. if a model with have a certain beneficial compensatory aspect. residuals. or the fenes. and “silent” aspiration (patient shows no coughing at any time). Basically when limit. occupational therapy and in ation of the cannula should be performed. If physical treatment reaches a ically for the individual patient). granulomas. This successful treatment option in many cases. in generalized symptoms of spasticity one might withdrawal from the cannula is formulated as a goal want to consider the option of oral agents and because a patient with tracheostomy improves as intrathecal baclofen. Respir. and also carries the risk of second- tration of the cannula might not be suitable anatom. Tracheostomy Treatment of spasticity Patients admitted with tracheostomy often also need The treatment of spasticity requires mainly physio- intense dysphagia management. pain and other prob- modification of the ingested substances and lems such as the often difficult exchange by care- rehabilitative techniques. pain. ation of episodes with aeration of the larynx and In focal or sometimes multifocal spasticity. checking the fenestration (which also lead to increased disability. requiring can be achieved by using a cannula with fenestration patient assessment and definition of the goals of and/or deblockage of the cannula and a valve. Chapter 20: Neurorehabilitation Figure 20. Whereas spasticity for the correct distal position (to avoid lesions of the as a consequence of a stroke might in many cases also trachea by chronic pressure) and. Findings from an 18-year-old female (cerebral venous sinus thrombosis) with tracheostomy showing severe dysphagia with penetration. If long-term tracheostomy is needed. one should try to increase the dur. looking many cases orthotic management. side-effect ratio in most cases. and hindered care.4. therapy. loss of function. Endoscopic evalu. Fiberoptic endoscopic examination of swallowing (FEES). It must be treated by rates of bleeding. 106]. as baclofen in cortical or subcortical stroke has a monary function. givers [101. with high copy or videofluoroscopy). ary complications. proteins A–G) acts on . Botulinum toxin (which exists in 297 ation and swallowing function must be controlled seven different serotypes. is often closed by material or granuloma. percu- after stroke and can be detected by clinical assess. but orally given medication such regards dysphagia. botulinum pharynx in order to diminish sensory loss of the toxin as a part of a longer-term strategy is an often mucosa and to increase swallowing function. Later withdrawal of the cannula after laryngopharyngeal sensory training (aeration with fenestrated cannula and a valve) was successful. Dysphagia is a common and dangerous problem carefully. workgroups. symptoms are clinically less consistent than in right cation helps to improve the cost-effectiveness and the hemispheric neglect [110]. Type A was the first botulinum toxin important and increasingly recognized field in for medical use. Only a few pilot studies have been pub- course of treatment. fractures. [109]. In general. It imum dosage per session and time interval between is a complex deficit in attention and awareness which injections because of case reports about exacerbation can affect extrapersonal space and/or personal per- of preexisting swallowing disorders and neurological deterioration in higher-dosage applications. [113] used inhibitory bosis and many others should be considered. several aspects of the rehabilitation progress and the positioning of the bed. which might be useful in further research. bladder dysfunctioning. use of lower dosages. Restoration or preservation of cognition is an mitter release. most frequently of the right hemisphere. have already reported success- fully provoking a “model neglect” in healthy subjects [114]. e. and safety in traffic. Individual assessment includes evaluation of several aspects of attention. there have been stroke. intrathecal spatial neglect for at least 6 weeks. and other domains has to be considered days and 1 week. Elements of spatial neglect may also be seen Practically. stroke rehabilitation. lasting for 3–6 months. pre- safety warnings regarding the adherence to the max- dominantly but not exclusively of the parietal lobe. a more practical treatment options such as visual field training are evaluation including out-of-hospital observations controversial. proprio- If multimodal treatment of spasticity (maybe also considering serial casting) fails. resulting in decreased unilateral ment comes to a limit. small pilot study. Impairment of attention. as the impairment usually has an impact on includes stimulation from the hemianopic side (e.g. oral agents. In num toxin A and B with different rates of effective- multidisciplinary neurorehabilitation. however. additional alertness training as well as visual. surgical therapy in ceptive and vestibular stimulation techniques are used some cases may finally be a therapeutic option. Applied into the muscles by injection. two treatment sessions with botulinum toxin are help- ful to regain therapeutic benefit from intense physical Spatial neglect therapies. the use of electromyography for appli. however. Depending on treatment goals. memory. may persist in the postacute and also the chronic phase. talking). which appears in problems in reading. documentation of the the affected side is enforced as much as possible. Using compensatory visual field 298 can also be useful. cog. perception via ness per unit are available. botulinum toxin is considered a Spatial neglect is a common syndrome following safe therapeutic agent [108]. ception. parietal cortex for six sessions over 2 weeks in a ing care and occupational therapy. Basic rehabilitative management ciplinary. Shindo et al. Several rTMS- baclofen and botulinum toxin are treatment options. intelligence. Often one or when setting up treatment goals. which can be neu. While spontaneous ability to cope with the activities of daily living. symptomatic factors such as lished to evaluate the benefit of cortical stimulation infections. with infarctions of the left hemisphere. As several products of botuli- The therapeutic process is often prolonged. and product used is indispensable. hemispheric stroke and needs active and pro- nitive impairment after a stroke is very common and longed attention in the rehabilitation process.g. throm- techniques. orientation ropsychologically specific but should also be interdis. 112]. [111. Section 4: Therapeutic strategies and neurorehabilitation cholinergic neuromuscular junctions to block trans. Cognitive recovery after stroke Spatial neglect is a frequent syndrome of right Besides defined neuropsychological syndromes. If physical treat. For detailed guidelines on cognitive training compared to a control group no formal rehabilitation refer to Cappa et al. change of visual defect was reported by Nelles et al. recovery might occur at least up to several months. . low-frequency rTMS over the unaffected posterior Spasticity can be treated with physiotherapy. Other neuropsychological syndromes executive functions and personality prior to devising Hemianopia has a large impact on daily activities an individual treatment schedule. a positive effect can be expected after between several memory. in this condition a hemispheric imbalance may be of clinical In the event of an increase in spasticity in the relevance. however. In addition to focal disturbances. nurs. using reaction perimetry patient–computer interfaces such as infrared eye- treatment [116]. using cation (see Table 20. Disorders of storage can be treated by bladder retraining and pelvic floor exercises. from a ventro-pontine lesion. Other groups recently LiS [119]. associated with spasticity (see The locked-in syndrome (LiS) typically originates above) or related to a central post-stroke syndrome. coping may be necessary. thalamic structures quadriplegia and anarthria without coma (in stroke or spinal stroke contribute to this problem. anti- spared vertical eye movements or blinking. mittent catheterization. They deserve active with or without urethral sphincter dysfunction. as a small orientation (affecting a person’s topographical orien. Other common problems initely be part of the overall neurorehabilitation pro. and infection should be ruled pational therapy refer to Steultjens et al. The syndrome is a distinctive clinical Like in other brainstem syndromes. apraxia has been shown to be 20% of survivors suffer from it. [118]. In storage prob- Hemianopia.1). resulting in a complete Mostly affections of the brainstem. In most cases communication remains pos. syndrome”. pathological disorder after unilateral left or right brain lesions in crying can also occur in locked-in syndrome (SSRI the posterior thalamus or in the insula and postcen. see Table 20. proportion of patients to some extent develop tation). tion in cases of pure brainstem lesions are normal in Hemiplegic shoulder (arm) pain has multiple 299 many cases. cific pain can be episodic but more often is constant. They experience their body as oriented upright when it is in fact tilted to one side. In the first treatment Space perception disorders can lead to spatial dis. The patient should be improved by occupational therapy. and apraxia lems provoked by detrusor spasticity. For a review of investigated for residual urine by ultrasound or inter- apraxia treatment and also on other aspects of occu. in A misperception of the body’s orientation in the spite of severe disability most of these patients do not coronal plane is seen in stroke patients with a “pusher want to die. well known in right-hemisphere infarction. This spe- caused by basilar artery occlusion or brainstem hem. try to resist any attempt to passively correct their body posture. It often severely hinders ADL independence (apart from contributing to speech disorders as speech apraxia) and treatment of apraxia should def. tral gyrus [117]. with evaluation of the use of stroke after a hemorrhage. The levels of cognitive func. orrhage). severe brainstem syndromes with vegetative state or Apraxia is a syndrome of left-hemisphere infarc. out. movement detectors and others. Because of the clinician it is important to know this syndrome and to chronic course. ment with anticholinergic drugs such as oxybutynin should be evaluated (see Table 20. motor recovery [120]. Patients should receive early and intensive reported an improvement of the visual field of up to multidisciplinary rehabilitation with the goal of estab- 5 for ischemic lesions and up to 10 benefit for lishing communication. episode the prognosis is undetermined. minimally conscious state. visual perception deficits. medication should be evaluated.1) such as antidepressants. is often prolonged. According to the authors. while additional brain injuries are most causes. The shoulder joint in hemiplegia is sensitive . For the convulsants and opioid analgetics. treat- screening and should be considered in goal-setting. Pain in the post-stroke episode may be due to Rehabilitation of brainstem syndromes different causes. Bladder dysfunction: urine incontinence occurs fre- gram [109]. tion. Individual assessment is necessary in contralateral side. Although the literature on recovery and quently in the acute state of stroke and after 1 year treatment is limited.1). and The locked-in syndrome – quadriplegia and anar- thria without coma – is usually caused by basilar therefore use the unaffected arm or leg to actively artery occlusion and represents a challenge to push away from the unparalyzed side and typically rehabilitation teams. e. Treatment options include physiotherapy. The recovery under physical therapy. which can occur are frequent and disabling. Brainstem lesions should be carefully evaluated by trying to enhance sensorimotor input from the for dysphagia. psychological support to improve make an early diagnosis.g. and medi- sible (by simple or elaborate speech coding). Chapter 20: Neurorehabilitation [115]. although the training improved detection of likely responsible for associated cognitive deficits in and reaction to visual stimuli. behavioral therapy. In underdiagnosed because of overlapping symptoms addition to the direct consequences of stroke. with exclusion of certain Social problems after stroke can severely affect neurological deficits such as aphasia. As a first step there are certain Acknowledgement 300 medical and neurological conditions where clinical The authors would like to thank Serafin Beer for judgement will confirm stroke patients as being helpful discussion and comments on the manuscript. It manifests itself in subtle social issues and depression are likely to contribute to signs. physical therapy in many cases affected by the post-stroke condition. which includes. many authors consider been shown that simulator-based driving training it a form of reflex sympathetic dystrophy/complex improved driving ability. neglect and relevant cognitive impairment. such as refusal to participate in treatments. Erectile dysfunctioning can be treated with supportive therapy to be beneficial [3]. . It is often stroke. health insurance. specific neuropsychological assess- capsulitis (50%). persistent complete hemi- subluxation can lead to injuries. vements of PDS by medication. The etiology of shoulder-hand syndrome with reassessment in the further course of rehabilitation pain of the shoulder or arm and edema of the hand with appropriate therapies can be a goal. sal prostaglandin E-1 injections. Management includes Partnership and sexual functioning: partnership is positioning. There is no doubt that rehabilitation. the problem. In a Cochrane phosphodiesterase type 5 inhibitors or intracaverno- review. owing to altered physical and psychological condi- In more severe cases intermediate dosage treatment tions with their implications for everyday life and with oral prednisone is effective [122]. tional studies suggest that the frequency and range teria and the timing of assessments [123]. As the problems are often choice. and is treatable with indicate that the heterogeneity of the studies and prob. populations. a [121]. tion about social security systems. SSRI and antiandrogens. Pre-existing vascular disorders may also Antidepressive treatment with SSRI and related cause erectile difficulties as well as antihypertensive substances (see Table 20. orthotic management. prevent subluxation by orthotic management.g. It is impor. difficulties with housing. The authors [123] Hypersexuality rarely occurs. shoulder subluxation (44%). observa- due to varying definitions. psycho- with the stroke itself. family tive crash risk associated with medical conditions issues. anopia. PDS often of sexual disorders after stroke are high and a notice- hinders the course of rehabilitation and influences able decline in sexuality occurs in both genders after recovery and outcome following stroke. especially for well-educated regional pain syndrome. however. financial problems.1) is the first treatment agents and other drugs. and shoulder-hand syndrome (16%) stroke patient is evaluated as not capable of driving. furthermore partner dissatisfaction is high. Hemi. e. Summarized in a review [127]. in addition studies suggest adaptations of complex. social services. treatment suggestions have to be compre- cognitive-behavioral therapy techniques and brief hensive. Couple psychotherapy can be initi- Depression: post-stroke depression (PDS) occurs ated and also improvements to assistance in the vari- in at least one-third of patients in the first year after ous fields can indirectly help relieve the often serious onset. including tendons. might have led various aspects of patients’ lives. danger of making inappropriate decisions about their driving capabilities without professional advice and/or evaluation. communication. mechanisms mentioned above. for example. including steps for reduction of edema. exclusion cri. Social coun- (n ¼ 4448) the diagnosis “previous stroke” was only seling is therefore mandatory in the course of stroke a nearly significant risk [124]. such as unemploy- to the result. social contacts and other factors. Section 4: Therapeutic strategies and neurorehabilitation to traumatization of various structures and inferior incapable of driving. problems with Driving after stroke: in a study investigating rela. there was no evidence for impro. informa- driving ability in the post-stroke period needs assess. capsule or peripheral nerves and plexus. If a post- cuff tears (22%). ment. whereas pure motor deficits can often be solved by tant to keep the shoulder correctly positioned to car adaptation. lematic patient selection. The extent of further evaluation ranges from plegic shoulder pain in stroke may be due to adhesive screening tests. It has also and arm is controversial. rotator ments and simulator tests to full road tests. probably initiated by and less disabled stroke patients [126]. invalidity. self- ment. and a study [125] shows that patients are in help and stroke groups. and analgetics. although estimates differ widely between studies problems. repetitive transcranial magnetic stimulation 2. Neurorehabilitation nach Hirnschlag. be used for downregulation of the contralesional Graham GD. Sandercock P. oral agents. Management of Adult Stroke or stimulation of the ipsilesional hemisphere. Clarke S. Wardlaw J. adequate therapeutic compensatory inter- system.  Vicariation describes the hypothesis that func. within 7 days) the benefit of cortical stimulation techniques (e. depending on the frequency. 1936. nursing and therapy staff. intense dysphagia management. Warlow C. constraint-induced therapy (CIT: the unaffected limb is constrained to enforce the use of the References affected limb under intensive practice). or Speech disorders need intense training because following damage. The central nervous system of the of their enormous impact on the patient’s life. After of reorganization. but and viscosity. (rTMS) leads to decreased or increased cortical Stroke. a weak polarizing electrical current is 4. 1928. 8. In the central nervous system of the ventions.g. (TDCS). which can be select. benzodiazepines. e. repetitive 1. If physical Neuroplasticity can be supported by: treatment reaches a limit. Duncan PW. et al. baclofen and botulinum toxin are treatment options. probably leading to different regions of the brain. Berlin: Julius Springer. treatment goals following physical and psycho- logical status evaluation. Only team of medical. Rehabilitation Care: a clinical practice guideline. opti- a few pilot studies have been published to evaluate mal timing and early initiation (i. Dennis M.  Special training. for example modification of bolus volume adult. and rehabilitative techniques. et al. aspiration in more than about 20% of them. Sudlow C.e. 362(9391):1211–24. Newer adult human being has an astounding potential for studies with therapies taking place daily for several regeneration and adaptability. training or mirror therapy. this mechanism is reduced. and the definition of inhibitory low-frequency rTMS). London: Oxford University Press.  Diaschisis describes the phenomenon that a focal Patients admitted with tracheostomy often also need lesion may also lead to changes in brain func.g. Chapter 20: Neurorehabilitation Chapter Summary and others were found to be beneficial for motor recovery. can be set up. Übungstherapie In Handbuch der 301 Neurologie. Degeneration and Regeneration of The Nervous delivered to the cortex. Foerster O. Vol. Stroke With transcranial direct current stimulation 2005. nursing care and occupational therapy. had a negative effect on outcome. while others. clinical evaluation can be com- damage to the brain leads to an increased bined with technical tests such as fiberoptic endo- recruitment of secondary areas of representation scopic examination of swallowing (FEES) and as early compensation. of intensive rehabilitation. Schnider A. .  Peripheral and brain stimulation techniques: Schweiz Med Forum 2007. Beer S. Brain stimulation Several mechanisms of neuronal plasticity can be techniques and medication might add additional identified: benefit. Spasticity can be treated with physiotherapy. followed by a later phase videofluoroscopic swallowing studies (VFSS). Zorowitz R. 36(9):e100–43. In this setting input from a proprioceptive stimulation techniques are used. 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Dekker J. visual exploration behaviour after theta burst 121. Nyffeler T. Maas CP. Karnath HO. 2001. The shoulder-hand Diener HC. AIDS (acquired immunodeficiency angiopathy (CAA) energy in. 184 patient criteria for thrombolysis. 71. 187–8 141 (AIDS). 290–1 (ACA) Alteplase Thrombolysis for Acute activity type. 98 anginal chest pain. 142–3 anaerobic glycolysis. see Alzheimer’s disease (AD) treatment. 135. 71 acute infarction. secondary prevention. 233. 121 relative risk. 16 (ARAT). 291 alcohol consumption anastomotic steal phenomena. 70–1. 182 Disease Preterax and Diamicron Modified agraphia. 91 anger. 247 acidotoxicity. 91 stroke prevention. 121. 166. 187–8 activation studies. see recombinant tissue ACA. 267 amyloidosis. 230–1 accuracy. see anterior choroidal artery ischemic stroke risk. 210 healthy lifestyle. 212 Release Controlled Evaluation AICA (anterior inferior cerebellar amyloid proteins. 109 53–4 light-moderate. 278 (ADLs) amaurosis fugax. differential Ischemic Stroke (ATLANTIS) ACCESS trial. 97. of results. 95 artery). 92 Noninterventional Therapy in accelerated thrombolysis. 58 acute strokes Alzheimer’s disease (AD) acetaminophen. 98. 48–9. 105 American Heart Association Stroke young adults. 124 post-thrombolysis.Index abciximab. 114. 92 290. 126 see also cerebral amyloid action potential propagation. 16 stroke risk. with stroke. 113 Action Research Arm Test akinesia. risk factors and. 195 on hyperthermia. 82 amnesia. 246 post-stroke dementia and. 233 ADLs. 95–6 heavy. 278 amantadine. 200 carotid stenosis. 11 Action to Control Cardiovascular abuse. 225. 244 achromatopsia. 198–9 imaging. 266. 5. 191 alteplase. 191 abdominal adiposity. 191 amniotic emboli. 12 syndrome). 98 AF and. 130 Action in Diabetes and Vascular agnosia. 130. 273 diagnosis. 49–50. 173–4 thalamic ischemia. unruptured. ICH risk factor. see activities of daily living intracranial stenosis. on stroke risk. 32 (AChA) Association. 234 activities of daily living (ADLs). 230 stroke and. acquired immunodeficiency syndrome aggression. 140–1. 179–81. 61–5 275–7 age warfarin compared. on TCD diagnosis. during ischemia. rCMP and. 95 American Heart Association/Stroke AChA. 157–8 Council. 191 PCA territory bilateral ischemia. 189 Risk in Diabetes (ACCORD) aneurysms. alexia. 123 anxiety and. 189 ablation of atrial fibrillation. 16 post-TIA stroke risk score. see anterior cerebral artery plasminogen activator (rt-PA) activity scales. 65–9 post-stroke dementia and. 141. 157–8 (ADVANCE) study. 226. 79 hypertension and. 97. 184 amnestic stroke syndromes. 252 early treatment. 266. 274–5. 58–9. 82 study. 148 trial. see atrial fibrillation (AF) American Academy of Neurology. 156 angina pectoris. 174 treatment. 83 acid-sensitive ion channels (ASICs). 94. 246 emboli monitoring. 231 on hyperglycemia. 36 BP targets. 114 307 . 194 acetylsalicylic acid (ASA) AD. 82. 231 AF. 248 lacunar infarcts. 291 alien-hand syndrome. 195 acetazolamide. 214 CAA and. 107–8 apathy and. 179–81. 89. 65. 267 agitation. 36. 127 perfusion CT images. 189 assessment outcome. 130 aortic atheromas. 278 artery-to-artery embolism. anterior cingulate prefrontal aortic arch neurorehabilitation. 123. Index angiography. 3 143–5. 91 movement rehabilitation. 175 transcortical motor. 69 aspirin. astrocytes. PRoFESS trial. 30 agnosia. 58 anterior communicating artery repair. 272–3 atherosclerosis Antihypertensive Treatment of Acute angiotensin-receptor blockers (ARBs). 98 intracranial stenosis. 183–4 atherosclerosis. 181 BA stroke. 131 anterior inferior cerebellar artery aphasia. arterial atherosclerosis. 97–8 142 aspiration pneumonia. 237. 279 see also large artery HOPE study. 29. 123. 190–1 prevention. 258–9 endocarditis. 30 associative visual object agnosia. 184 anterior circulation strokes. 268. 35 sensory. 277 aquaporin water conductance. 251 acute ischemic distal arm paresis. 150 135–6. 33. 231 34. thalamic. 273 arterial occlusion. 69 anosognosia. 52. 30–1 antibiotic therapy passive smoking. 233–4 arteriovenous malformations. 123 antithrombotic therapy Aspergillus spp. 275–7 apoptosis. 29 . 123 animal models focal ischemia. 85 AF and. 97–8 apical ballooning. digital subtraction antidepressants angiography (DSA). see acetylsalicylic acid (ASA) infarcts. 19 (CTA). 127 rehabilitation. 122. shortcomings. 28–9. 7–8. 239 apraxia. 174 pain. small-vessel disease. 179. magnetic arms post-stroke depression. 124–5. 52–3. 277 95. 13 AF and. 246 aseptic CVT. 6 HOPE study. 184 large-vessel emboli on. 191 microbleed risk. 267 contralateral akinesia/hypokinesia. 94–5. 239 flavonoids in prevention. 183–4. 191 atheromatous plaques. 2 (AICA). anterior boundary-zone infarcts. 268 syndrome classification. 149–50. 211 angular gyrus lesions. 21–2 post-thrombolysis. 214 113. 89 anterior cyngulate gyrus lesions. 111 asymptomatic people. 171–3 apperceptive visual object hemorrhage. 2 ICH risk in. 28. 12 aortic valve 121–4. 272 (ATACH) study. 115 anterior cerebral artery (ACA) lesions. 204 arteriosclerosis. 1. 175 post-stroke apathy. 132 MOSES trial. 114 cardiac embolism. 205 infectious CVT. 273 arterioles. 95. 28–9 inhibitors. 41 anterolateral lesion. antipyretics. 122. 19–20 atherosclerotic plaques. 9–10 antiplatelet therapy. dissection. 290–1 lobe.. 126 evaluation. stroke (ACoA). 123 apathy. balloon. 296. 238. 158 aspiration. 130 pre-stroke infections and. 179 thalamic lesions. hereditary. 297 anterior choroidal artery (AChA) patient selection. 91 308 in CVT. 132 endocarditis. 110 young adults/children. see computed post-ICH. 272 272–3. 187 atherosclerotic ischemic strokes. 123–4 anxiety. 263 arterial stenosis. 166 64. 299–300 angiotensin-converting enzyme (ACE) antihypertensive therapy. in dysphagia. 167. AF and. 299 tomography angiography secondary prevention. 277 arteriopathies. 1 in pregnancy. risk anticoagulant therapy factors. 294–5 lacunar infarcts. 1–2 anterograde amnesia. 51 angioplasty. 272–3 antimicrobial therapy. 135 large artery. 154. Cerebral Haemorrhage arterial dissection. 273 antiphospholipid syndrome. 90 aspiration pneumonia. 274–9 ASA (atrial septal aneurysm). 130 ataxic hemiparesis. 34 resonance angiography (MRA) smoking cessation therapy. 181 secondary prevention. 135 young adults post-stroke. 30 anterior circulation syndromes. 278 antiepileptic drugs. 124. 122 atherosclerosis. 157 functional threshold. 111 asymptomatic carotid plaques. in IE. 181 thalamic ischemia. 238 ACCESS trial. 156. 261. 295 in pregnancy. 123 Wernicke’s. 8. 180 anticoagulant study. 178–9 MCA infarction. 30. 189 astasia. 244–5 brainstem syndromes lesions. 237 bleeding volume. 140–2 baclofen. 272 see also paroxysmal atrial border-zone infarcts. 191 Bobath concept. 122. 143. 122. stroke risk. 204–5 bradycardia. 115 biofilm. 297–8 brain functions blood flow. 294 atorvastatin. 113. 165 stroke risk. post-stroke dementia and. 205 beta-blockers. 89. 278 and outcome. 151 33. 22 body-weight supported treadmill stroke risk. 123. rehabilitation. 261–2 in secondary prevention. 125 Barthel Index (BI). 267 (CBF) energy requirements. 274 meningeal. 299 lesions. 243–5 with eponyms. 108. 258 smoking and. 91 atrial septal aneurysm (ASA). 36 focal ischemia models. 91 gaze disturbance. 178 body temperature. 92 brainstem lesions balloon angioplasty. 125 weight loss and. 264–5 post-stroke. 97–8. 150–1. 65. 10. 126 basal ganglia post-ICH management. 161–2 in CVT. see ischemia pre-stroke. 277 B vitamin supplementation. 36. balance test. 290 105–8. 141 body mass index (BMI) atrial enlargement. 138 brain stimulation techniques. 11 bleeding complications. 141 see also hypertension Broca’s aphasia. 123 smoking and. 235–6. CVD origins in. 109–10 stenosis. 235–6. 147. 109 birth weight. 91–2. 297 binge drinking. venous system. 1–2 atherosclerotic stenosis territories. 30. 113–14 exercise and. 50–2 fibrillation Borrelia burgdorferi. 50 subclavian arteries. 244. 162 blind-sight. 95. 275. 273 basolateral limbic circuit. 94 breath-holding index. 97. 124 vertebrobasilar circulation. 142 difference between arms. 19 carotid arteries. 52. 239. 89 alcohol and. migrainous. 129. 239 benzodiazepine receptor (BZR) prevalence. 107 botulinum toxin. 291 285–6. boundary-zone infarcts. 32–3 personality changes. 130 body mobility test. see cerebral blood flow bacterial aneurysms. 125 atrial natriuretic peptide (ANP). 299 brain abscess. 139–40 malignant MCA stroke. 90 brain perfusion imaging. 49–50 bacterial infections blood glucose hemoglobin changes in. 43. 9 post-stroke management. 111 236–7. 108 autonomic ganglia. post-valve repair. 65. Index atherosclerotic risk factors. 236. 265 bilateral signs. 195 overview. 83 smoking and. hyperviscosity. 34. 138 differential diagnosis. 165 venous system. 275–7 behavioral neurology. 61 syndrome baso-frontal strokes. 115 aura. 135–6. 128 sensorimotor functions. see basilar artery (BA) blindness. 146. 263 autoregulation of cerebral blood flow. 92 309 occlusion. 71 basilar artery (BA). 165 blood plasma. 91 cerebral artery infarcts. 126 post-ICH. 90 cardioembolic stroke and. 179 . 274 brain edema. 124 see also top of the basilar blood-oxygen-level-dependent extracranial vertebral and (BOLD) signal. 292 young adults/children. 127–9. 108. increase. 291 heavy alcohol intake. 92 atrial fibrillation (AF). 98 training (BWSTT). 19. 187–8 healthy lifestyle. 182 management guidelines. 141 in acute stroke. 248 dorsolateral medullary stroke. 190–1 stroke risk. 124 basal forebrain. 295 blood pressure (BP) Balint’s syndrome. 239 brain ischemia. 236. thalamic ischemia. 82. young adults/ children. 132 additive effects of exercise. 123 Babinski-Nageotte syndrome. 243–4 cranial nerve palsy. 188 biological work-up. 212–13 QT prolongation and. 98 see also obesity management in stroke prevention. 115 behavioral changes. 50 in IE. 69–70 septic CVT. 138 blood vessels. post-stroke. antiplatelet brain cysts. 262 brachiofacial involvement. 238 lacunar infarcts. 107 bladder dysfunction. 3. 106 ligands. 132 bihemispheric reorganization. 31. sudden bilateral. 174–5 BA. 82 stroke risk. 267 therapy. 127 blood–brain barrier breakdown. 191 238. 11–12. 90 brainstem. 51 post-TIA stroke risk score. 122–3 auditory hallucinations. 210 see also anterior calcium toxicity. 11. 109 cerebral angiopathies. 234 central nervous system buccolingual apraxia. 167 thresholds for damage. 278 carotid stenosis. 138 see also regional cerebral blood endocarditis and. posterior cerebral antagonist. 236 in QT prolongation. 22. 6–9 . 12 CBV. 124 see also common cerebral artery territory infarcts. 122 neuroimaging. 159 95. young adults. ischemic cerebral blood volume (rCBV) delirium. see also troponin CBF. 30. 16. 114 cavernous sinus thrombosis. 147. 61 lacunar infarcts. 36 10. 300 carotid stenosis. 151 blood flow characteristics. 279 (CADASIL). 110 flow (rCBF) post-stroke. IMT measurement. 30. 58–9 cerebral blood flow (CBF) post-stroke dementia and. 28–9 Capgras syndrome. sensorimotor functions. 59 caspase C. 277 arteries (PCAs) emboli. 36. 31–2. 59 brain MRI. delayed. 32. 273 statin therapy. 22. see cerebral blood flow (CBF) 14. 29. 106 values. 291 beading. Index Brunnstorm approach. cerebellum leukencephalopathy peripartum cardiomyopathy. 261 post-stroke dementia and. 34 primary vasculitis. 208 carbamezabine. 37 centrum ovale. 71 lacunar infarcts and. hyperviscosity. 198 cancer. 154. 156. 59 tachycardia case fatality from stroke. see cerebral amyloid angiopathy cardiogenic embolism (CAA) cerebellar hematoma. 135 ultrasonography. 60 microbleeds. 37 young adults/children. anticoagulation. 20 cardiac embolism. 11 in Takotsubo syndrome. 17 cerebral artery (ACA). 30 see also bradycardia. carotid stenting. 294 heparin therapy. dietary intake. 105 Doppler color imaging. 114 low flow syndromes. 12–13. internal carotid cerebral atrophy artery (ICA) depression and. young adults. 105–9 low blood flow. 78–9 cytotoxic edema. 69 cerebellar hemorrhages. 34–5 imaging. 209 sources. 10. 165 calcium (rCMP) cerebral amyloid angiopathy (CAA). 283 Buerger disease. 207 cardiac arrhythmias. 195 atherosclerosis. 50 see also regional 310 AF and. 205–7 cereal foods. 110 CADASIL. 238 MI as cause.. 139 carotid plaques. 123 bupoprion. in degree of stenosis. fMRI recording. 91 dissection. 186 stroke. 210 MOSES trial. 19. 17 and ICH. carotid arteries callosal disconnection syndrome. see dilatative cerebellar infarction. 49 cardiac enzymes regulation. 205 157–8 mitochondrial overload. 273 secondary prevention. 19 cerebral blood volume (CBV) cardioembolic strokes. 58 infarcts and leukencephalopathy car driving. 188 cerebral autosomal dominant carotid endarterectomy. middle cerebral arteries cannabinoid type 1 receptor 121–4 (MCAs). 277–8 arteriopathy with subcortical capsular warning syndrome. 51 (CADASIL) restrictive cardiomyopathy venous system. 190 Candida spp. 71–2 cardiac surgery cell count increase. 131. 18 cell swelling. 91 young adults/children. 123 anterior circulation syndromes. 143 carotid artery (CCA). 157 cardiovascular conditions calcium-channel blockers (CCBs). 272–3 carotid artery. 250 extracranial. 31. 93 CAA. 156 carbon dioxide (CO2) reactivity. 272 cerebral arteries care needs assessment. 30 ICH risk factor. see cerebral autosomal TCD monitoring. 105 cellular pathology. NBTE and. external candesartan. 22–3 cardiac event monitoring belt. see cerebral blood volume (CBV) vasomotor reactivity. 135–9 275–7 caudate hemmorhages. 50 catecholamine toxicity. 263 cell death. lesions. 59–61. 5 dominant arteriopathy with cardiomyopathy (CMP). 93 cardiopathies. 237 subcortical infarcts and cardiomyopathy (dCMP). 5 PET imaging. 197 carotid bifurcation. 209 cardioembolism recovery in. 19 cardiac diseases. 168–9 vascular origin. 71 (CTA). post-stroke complications. 123 large artery atherosclerosis. 165 ESO guidelines. 184 BP in acute stroke. 77 DSA image. 168–71. 43 see also non-contrast CT cervical arteries. 5. 175. 183–4 MRI images. 41 in QT prolongation. 277 IE and. 238 thrombophilia screening. 43 glucose). 176 in neonates. 272 classification of strokes. 165 common carotid artery (CCA). 96. 233. 171. stroke epidemiology. 10 computed tomography angiography cervical artery dissections (CADs). Index cerebral computed tomography (CCT). 264–6 brain tissue activation. 212 color agnosia. post-stroke sequelae. 176 clinical findings of stroke. 175 Clopidogrel and Aspirin for Reduction therapy. of MCA. 49 sudden pressure drop. 136 in PET studies. 10. 151 aphasia and hemiparesis. 124 cerebral ischemia CAA and. 285 (CMRO2). 165 therapy. 166 cardioembolic ischemic. 121. 176 in stroke unit. 122 anatomy. causes and risk factors. 143 see also intracerebral ischemic strokes. anatomy. 258–9 color-coded maps PWI maps. 12. 127 cerebral perfusion choriocarcinoma. 44 chronic meningitis. cord sign on CT. 170–1 dementia. 22 . 121. 109 Ischemia Stabilization CVT diagnosis. 233 (CHARISMA) trial. 171–5. 1–2 Management and Avoidance ICH detection. 296 communicating arteries. 5. 149 silent lacunar infarcts. 156 combination antihypertensive 6. 157–8 cardiac embolism. 165–6 clinical syndromes. 277 chiropractic manipulation. 37 young adults. 49. 40–3 acute. 145 for oxygen (CMRO2) cerebral embolism. 165. 159–61 compensatory processes. 289 laboratory findings. 203 (SAH) cognitive disturbances. spontaneous ICH. 154. 191 non-cardiac origin. 1. 121 pathophysiology. 71 cerebral hemorrhage children coagulation disorders. 77. 77 China. 168 181–2 diagnosis. 130 strokes Chlamydia pneumoniae. 150. 89–91. 59–61 clinical features. 176 syndrome. 156–7 collagen disorders. 166–7 pre-surgery for carotid stenosis. 167–8. 208 clot embolism. 158–9 cholinesterase inhibitors. 45 149. 3–6 Atherothrombotic Risk and aphasia and hemiparesis. 171 Carotid Stenosis (CARESS). see embolism childbirth-associated emboli. 79 AChA infarcts. 235 MCA infarcts. fibromuscular (NCCT) dysplasia. 274–5 neuroimaging in. 219. 275–7 Chinese Acute Stroke Trial (CAST). 235 post-stroke hypertension. 205–12 Coccidioides immitis (coccidioidal hemorrhage (ICH). pre-stroke. 200 management mortality overview. 12. 250 coma as leading symptom. 243 chronic infections. 223 recurrence. 98 cognitive recovery. 208. 182. 22 ICH and. 69 computed tomography (CT) cerebrovascular diseases (CVDs) Clopidogrel for High acute hemorrhagic stroke. 203–5. 41 CMRG1 (cerebral metabolic rate for 311 young adults/children. 264 CMRO2. 205 see also ischemic thalamic ischemia. 141 cerebral venous thrombosis (CVT). 156 secondary prevention. 233–4. 11. 30–1 post-stroke apathy and. 200 Collier sign. 284 future developments. CLOTBUST trial. 265 subarachnoid hemorrhage stroke epidemiology. 275 issues. 12. 90–1. 166 clinical assessment 59. 22–3. 176 of Emboli in Symptomatic compression stockings. locked-in elderly patients. 42. 222–4 of dysphagia. 273–4 cerebral metabolic rate for oxygen see also low density collateral vessels. 214 meningitis). 34–5 communication. prognosis. 50 lipoprotein (LDL) Collet Sicard syndrome. 149 cerebral microbleeds (CMBs). cigarette smoking. 169 clopidogrel. 50 chronic obstructive pulmonary disease cerebral venous system. 299 etiology. 122. 50–2. 175–6 clinical variables. 176 221–2. 165 (COPD). 298 cerebral metabolic rate for glucose (CMRG1). 249–52. 275–7 comprehensive stroke centers (CSCs). see cerebral metabolic rate see computed tomography (CT) chicken pox/zoster rash. 212 CO2 reactivity. 258–9 cholesterol levels. Chagas disease. 214 ICH detection. 278 secondary prevention. 161–2. 45. 286 middle cerebral artery infarcts post-traumatic stress disorder. 194–5 (CTA) incidence. 196–7 Control of Hypertension and CVDs. see dilatative cardiomyopathy corpus callosum. 127 cortical signs. 253 contralesional hemisphere plasticity. d-amphetamine. plasticity deep cerebral veins. 144 incidence. 249–50 contralateral akinesia/hypokinesia. 181 coronary artery disease. 123 diabetes mellitus (DM) cortical stimulation techniques. 251 contrast imaging definitions. toxoplasmosis. 40 see also ultrasound contrast agents (UCAs) Cushing’s triad. 167 partial contralateral. 157–8 constraint-induced therapies (CIT). with stroke. 53 differential diagnosis. 123. 159 crossed signs. 286. 198–9 283–4 CT. 300 delirium. 195. 77–8 emotional expression disorders. 77 hypertension control. 292. differential degenerative dementia. 199 Post-Stroke (CHHIPS) CVT. at infarct core. 123 devastating strokes. 197–9 CT angiography. 250 focal paresis. 178–9 diagnosis. 237 rehabilitation and. 34 (DECIMAL) trial. 168 cysts. 176 criblures. 186 connective tissue disease. 237 etiology. 111. 15–16 cortical blindness. 168 consciousness changes CVT. 36 pathophysiological model. 265 seizures. hyperglycemia and stroke. 18 differentiation. 112 causes. 285–301 deep perforating arteries. 167. 125 anxiety and. see cerebrovascular diseases risk factors. 37 251–2. 188 cortical lesions decompressive surgery. 19 deoxyhemoglobin. 252 Hypotension Immediately (CVDs) secondary prevention. 250–1. 195 cranial nerve palsies. 33. delayed cell death. 8 treatment lack. uncontrolled. cortical CVT. see computed determinants. 15 structures. 191 congenital thrombophilia. 95 . 125 delusional syndromes. 200. 126 confusional states. 141. 121. 250 PCA infarcts. 37 aortic arch atherosclerosis. 115. 200 cord sign. sudden. 3 delusional ideation. 252 prevalence. 115 dependence. of MCA. 189 cortical excitability. 165 treatment. 286 109–10. 188–9 CAA and. 6. 123 (dCMP) depolarizations. 188 ICH. 123 deep perforator territories. 251 deaths from stroke. 53–4 dementia (post-stroke). 195–8. 251 in. 126 mechanisms. 246–7 cystic infarct. 129 Déjerine syndrome. 189 cortical MCA syndrome. 28 silent lacunar infarcts. 130 dementia see also delirium crying. worldwide. 127 253 cortical energy expenditure. 188 thalamic ischemia. 190. 130 cooling device. 42 tomography angiography issues. Index confabulations. absent. 143–5 craniotomy. 185 congestive heart failure. 225. 293 meningitis). 112 couple relationships. 244 (CVT) thalamic dementia. ischemic stroke. 225 precipitants. PFO and. 139–40 deafness ipsilateral with tinnitus. Cryptococcus neoformans (cryptococcal risk factor for post-stroke 285. 126 depression (post-stroke). brainstem lesions. 179 craniectomy. 30 undiagnosed pre-stroke. 194–5. 194 confrontation naming test. ASA and. 300 cortical representation. endovascular. 194 CT angiography (CTA). 170 coronary heart disease. imaging. 200 dCMP. 185 cortical watershed (CWS). post-stroke dementia. 211 COX-2 inhibitors. 182 cortical strokes. 129 decompressive surgery in malignant motor recovery and. 18 infarcts. 113 52–3. rTMS in. see computed tomography (CT) criteria. see cerebral venous thrombosis stroke outcome. 195 contralateral hemisphere deactivation. 12 sudden unilateral. 132 congenital remains of embryonic delayed phase of ischemic injury. 194. statins and. 43 epidemiology. 191. 251–2 perfusion CT. 97 cytotoxic brain edema. 267 denial of illness. 252 treatments. 122. 142 cryptogenic strokes. 237 Delta sign. 245–6 312 285–6 definition of stroke. 199–200 trial. 232 disinhibited behavior. 286 eastern Europe. 112 healthy. 275 clinical. 105 14–15 dysarthria clumsy hand syndrome. 43–4 36. 124 centralized management. 156. 132 disability. 298 color Doppler. 37 dyslipidemia. 296 EMBRACE study. 183–4 stroke risk. infective causes. 98. (IE). 105 DSA (digital subtraction QT prolongation. rtPA therapy. 60 lipid-lowering. ICH and. 93 electromyography. 78. 79 endomyocardial fibrosis. 286 in proximal vertebral artery. 296 risk of. 180 intravenous thrombolysis (rTPA). 40 monitoring. see diffusion weighted MRI cardiogenic. depression and. 283 see also infective endocarditis dizziness. 128 268–9 endocarditis (NBTE). 62 poor diet and. 21 intracranial stenosis. 62 LAA occluder device. 143. Index management. 123. 224 drug abuse. 148–9 distal basilar artery occlusion. stroke epidemiology. 123 emotional changes. 83 77–8 infrastructure needed. 195 ESO recommendations. 61. 274. 126 echolalia. 227 videofluoroscopic study. 18. neurorehabilitation. brain activity. 221 dysphonia. 95–6 eclampsia. 111. 19 embolism dyslexias. 215 paroxysmal AF. 224 drugs (medications) neuroimaging in. 187–8. 106 77–8. 10 extended release (ER-DP). basilar artery. 113 stress response. non-infective endocarditis donepezil. 115 door-to-needle times. 131 risk in RFA. 157 dementia. 92. 296–7 emergency stroke care. 259–64 acute stroke. 107 energy requirements. 18 carotid stenosis. 59 aortic valve endocarditis. 110–11. 190 see also paradoxical embolism neurorehabilitation. 233 aspiration pneumonia. 300 diagnosis in acute strokes edema. 77. 296 watershed infarcts. 32 technical evaluation. 108 brain edema. 114 313 11–12. 210 driving. 227 disconjugate gaze. 289–90 endocarditis. 170 dysphagia. 121 electrocardiogram (ECG) ICH and. 263 Dietary Approaches to Stop dynamic perfusion CT. 188–9 disorientation. 135 Eales disease. 92 medullary stroke. 108 young adults/children. 301 mechanical removal. 52–3. QT prolonging. 126–7 early neurorehabilitation. 127. 268 recipient sites. 113 in cerebral arteries. 127 assessment 33. 96–7 cardiogenic. 98 (dw-MRI) endocarditis and. 138 accuracy. 143 diuretics. 61 calcium release from. 129. 29 digital subtraction angiography (DSA). 170 electroencephalogram (EEG). 126 embolic strokes. 129 bedside tests. post-stroke early evaluation. 171 diet duplex ultrasonography. 269 diffusion-weighted MRI (dw-MRI). 34. 89. worldwide impact. 85. 35 dilative cardiomyopathy (dCMP). 272. 126 timely patient transfer. 108. 92–4 dw-MRI. 111 ASA diagnosis. 58. 296 disease burden. 219–20. 273 recovery and. 49–50 . 233–4 by FEES. 138 early-onset infectious complications. 296 dipyridamole. 64 LVHT. 97 emboli poor. 95. 137. 220 echocardiography endoplasmic reticulum (ER) Doppler ultrasonography. 283. 110 see also cholesterol levels large-vessel atherosclerosis. 285 angiography). 295 cardiac diseases in. 44–5 education level. 82. 274 dorsolateral lesions echo-contrast enhancing agents obesity and. 109 diaschisis. 195 prefrontal lobe. 16. 109 summary. post-stroke. 127 (ECE). 126 high-risk patient identification. see brain edema drop attacks. 130 dyspraxia. 93 dysarthria. 129. 209 encephalopathy. 105 lacunar infarcts. 92 BA infarct. Wallenberg syndrome. 295–7 disability-adjusted life years (DALYs). 92 therapeutic interventions. 36. MCA occlusion. 157 bradycardia. pathological findings. 296–7 tracheostomy and. 42 AF and. 179 post-stroke dementia and. 65–9 Hypertension (DASH). non-bacterial thrombotic dolichoectasia. 17. 32 stroke prevention. 2 functional imaging. 21–2 flumazenil (FMZ) binding. in stroke. 90. 251 functions. atherosclerotic lesion. 78 imaging (fMRI). 17 plasticity in cortical representation. 167. 221–2. 48–9 depression (post-stroke). radioactive tracer. 142–3. 9–10 functional magnetic resonance European Stroke Prevention Study Finland. 261. decompressive fluctuating patients. 138 Framingham Stroke Profile escitalopramin. 267 exercise. 248 52–3. 189 free radicals. 41 extracranial vertebral artery. 275. craniotomy. 126 forebrain lesions. 252 lesions. 51. 183 European Cooperative Stroke Study differential diagnosis. 297 functional disability. 23 neuroplasticity. 314 fluid regulation. 66 stroke epidemiology. 277 family history. 296. 225. 83–5 ESPRIT study. 45 environmental richness. 212 European Atrial Fibrillation Trial. fatty streaks. 252 frontal operculum. 227. 144 oculomotor nerve palsy. 98 radioactive tracer. 258 brain activity in hand grip. 274 in malaria. 220. differential diagnosis. 159 focal neurological signs. 85 experimental concepts. 92. 50 (ESPS2). functional imaging. 224 Functional Independence Measure fibrous cap. 278 falls. drop attacks. 2 (FIM). Index. 253 post-stroke dementia and. 203 Fregoli’s syndrome. 18 ethnicity fast-track neurovascular examination. 58–9 resonance imaging (fMRI) in neonatal CVT. 195 eye disorders focal lesions. 126 deformability. 167 48–9 213 deviation. 211 erythrocytes fogging effect. 94. 183–4 and. cavernous sinus thrombosis. 30–1. 44. acute multifocal. 267 facial palsy. 151. stroke epidemiology. 1 93–4 European Stroke Initiative (EUSI). 209 ophthalmoplegia. 143. 248 swallowing (FEES). 252 Societies. 230. 52. clinical (FLAIR) imaging. 168 focal seizures. 147–8. 274 fasciorespiratory control center. 122. 225. 9–10 post-stroke. 51 compensatory mechanisms. 247 filament occlusion of the MCA. 29–30 65. 149–50 animal models. see functional magnetic in CVT. 77. epidural electrical stimulation (EES). 251 false-negative/positive results. 58 (FSP). 182 ESC. young adults/children post-stroke. 174 extracranial ultrasonography. 234–5 atherosclerosis sites. 49 epileptic seizures extracranial large artery atherosclerosis. 135. 293 fluid-attenuated inversion recovery environmental factors. free-radical-trapping agent. eprosartan. 82. 131 disturbed functional networks. 59 2-[18F] fluoro-2-deoxyglucose (FDG). 275 flu infection. 181 (ECASS). Barthel complication management. 230–1 incidence. 179 48–9 excitotoxicity. 207 diagnostic tests. 168. 252 risk factors. 107 . 61 fMRI. 251 fibro-elastoma. 230. 49–50 European Stroke Organization (ESO) FDG (2-[18F]fluoro-2-deoxyglucose) guidelines. 17. carotid surgery trial. pre-stroke. 62 fruit and vegetable intake (dietary). on CT. 144 European Federation of Neurological treatment. LAA elimination 284 executive deficits. Index Enterobacteriaceae. 137. 138 folic acid supplementation. 78–9. 167 episodic memory. 188 fat emboli. fluoxetine. 276 frontal cortex fatigue (post-stroke). 167. 82. 49 functional deactivation (diaschisis). in application. 142 PCT in brain perfusion data. 273 136 Fabry disease. 272. 50–2 European studies. 286 differential diagnosis. 226. 97 estrogen replacement therapy. 226 hyperthermia management. 142 epitheliopathy. papillary. 246. 230 functional and activation PET studies. 237 fluent/nonfluent speech. lesions. 175 focal ischemia. 141 fundoscopic examination. 204. 61. 204 Framingham Study. 238 favorable outcome. 204 focal paresis. 291 elevated intracranial pressure. 108 29–30. 40 facial hypesthesia. defined. 285 external carotid artery. 285 extracerebral hemorrhage. 291 249 fibrocalcific lesion. 253. 285 fiberoptic endoscopic examination of acute stroke. 154. Gugging Swallowing Screen (GUSS). 155 glucose tolerance. 154. and heart valves cardiac embolism. 246 see also migraine hemorrhagic infarctions. 167 hemoglobin. 287 296 threatening edema (HAMLET) gaze disturbance. 147–9 glutamate. 237 midbrain ischemia. 292 157. 143 fungal endocarditis. 275 expansion. 34 thrombolysis. 156 deviation. 122. 93 alcohol consumption. 92 heavy alcohol consumption. 17 hemaglobinopathies. 246 heart valve surgery. in neurorehabilitation. 261 glycolipid disorder. 274 Health Professionals’ Follow-up Study. 122 age and. 36. 4–5 glitazones. 122. 237 hyperviscosity. 114 imaging. 89. 93 healthy lifestyle. 110. 291 compensatory cortical processes. 204 glutamate-induced glycolysis. 127 hemihypesthesia. 17 Helsingborg Declarations. 130 acute complete MCA infarction. brain activity fMRI. 258–9 hereditary causes of stroke. 51 pontine strokes. 238. 126 gradient-echo (GRE) MRI. rotation. 130. 124 hemorrhage giant cell arteritis. 264 hemicraniectomy after middle cerebral gastrointestinal drug side-effects. 82 dysarthria clumsy hand aphasia and. 91 see also cerebral metabolic rate heart failure. and exercise. 265 glycoprotein-IIa-IIIb inhibitors. 127 genetic susceptibility. 212 . 92 glucose control. 245–6. 136–7 TIAs and. hemorrhagic strokes global signs of stroke. 91 heparins. 125 hand grip. TB meningitis. 49–50. 131 ataxic. 219. in ICH risk. Index fundoscopic examination. 85 headache. 95–6 Heart Protection Study (HPS). 33 see also endocarditis CT classification. 204 volume in ICH. 143. 79 post-stroke re-training. 171–3. 123 paresis. 231 prosthetic. 139 genetic disorders. 41 alcohol consumption. 145 posterior circulation stroke. 173–4 in ICH. 40–3. 43–4 for glucose (CMRG1) see also congestive heart oral contraceptive use. hematoma fusiform gyrus lesions. 124–5. 77 82. 158 hemicraniectomy. 267 glycerol therapy. 89. to stroke. 1 infusion. 131 50–2 stroke mortality rates. 83 82. magnetic properties. 129 gait ataxia. 234 Glucose Regulation in Acute Stroke statins. 51. 7–8 night-time. 187–8. 50 ghost cells. 107. 89 11–12. formation. 97 Patients Trial (GRASP). 154. 273 post-stroke heparin therapy. 180 234. 160 hemiplegic shoulder pain. 89 function test. 129. 239 goal-setting. 212 granuloma. 43 290–1 hemianopia. 22. 91 syndrome. 91 glucose consumption (in the brain). 123 head pure motor. hemichorea-hemiballism. 145 sudden. healthy diet. 83 area. pre-stroke hereditary arteriopathies. 291 intense and diffuse. 237 gas emboli. 90 failure physical activity. 238 glucose-potassium-insulin (GKI) Helicobacter pylori. 211 fungal meningeal infections. 191 trial. 141 hands hemiparesis gender abnormal position. 286 lenticulostriated arteries ischemic stroke risk factors. 111 hemorrhagic transformations glucose serum levels. smoking and. 211 retinopathy and stroke 315 (HERNS) syndrome. 143 gait training. 122. 90 jerky dystonic unsteady. 148 spread in ICH. 82 in CVT. artery infarction with life 275. 83. 126 thalamic ischemia. 125 hallucinations. 15. 82. 82. 127 hand–eye coordination disorder. 129 hemimedullary stroke. 122 severe. 52–3 high BMI. 223 hereditary endotheliopathy with glutamate antagonists. 155 GIST-UK trial. 138 malignancies. 234. and stroke risk. 222. 124 healthy lifestyle. 291 German EPIC Potsdam Study. 159. 167. 299–300 Get-up and Go Test. 77 hemiplegia. 168. 147 young adults/children. and stroke. 12 hematological diseases fungal aneurysms. 5–6 gadolinium contrast MRI. 161–2 young adults/children. 236 infection. 157. 78. 259 human immunodeficiency virus immunocompromised individuals therapy. 5. 274 ICH. of temporal lobes. stroke imitators. 69 insulin therapy. see internal carotid artery (ICA) incidence. 272–3 molecular mechanisms. 182 hypophoria. 21 diagnosis. 15 CT scans. 77–8 hypesthesia. 96 hyperviscous state. 142–3 267–8 hippocampal lesions. in acute stroke. 231 infarcts intensity in neurorehabilitation. 248 infections in stroke. 143 microbiology. 173 Hypertension in the Very Elderly Trial peri-infarct. 14. 15–16 failure of. 123 hyperthermia. 125. 267 Horton’s arteritis. 148 patient criteria for real-time visualization. Holter monitoring. 175 (HITS). on CT. 268–9 high-income countries. 72 hypoglycemia. 156. 18 290. 126 causative. 96–7 in tuberculous meningitis. 151 induced hypothermia. worldwide. 266 cerebral toxoplasmosis. 151 infective endocarditis (IE). 157 lacunar. 53 3-hydroxy-3-methylglutaryl coenzyme (AIDS). 237 causative agents. Index hereditary thrombophilias. 40 infectious CVT. 247 recorder. 265 inferior cerebellar lesions. 78–9 inflammatory response. 126 VZV infection. 248. see intracerebral hemorrhage (ICH) ischemic stroke patterns. 35. 141 incidence of stroke. 77–8. 145–7 HMG-CoA reductase inhibitors. 258 diabetes type. 35–7 Intensive Blood Pressure Reduction in secondary prevention. 124 infections. 245–6 implantable event-triggered inflammatory diseases. 274 hypoxia-inducible factor 1 (HIF-1). 123 mycotic aneurysms. 238 . 145 IE. 96–7 in acute stroke. 264–5 hyperglycemia impact of stroke. post-stroke. 261–3 hospital care (non-specialised). 238 immunodeficiency syndrome inferior frontal gyrus. 261 HOPE studies. 93 PCT identification. 8 inhibitors. denial of. 236 infectious diseases. 127 ideomotor apraxia. 6. regulatory lacunar infarcts. 294–5 post-stroke. 124. 269 homocystinuria. 181 risk factors. 18–19 in acute stroke. 15 hypertensive encephalopathy. 157. 237 pre-stroke. 263 (HIV) infection. 94–5. 235 sudden. 238 induced hypertension. ICA. 52. 114. 261. 221–2 illness. 122 (HYVET). 259–68 high-density lipoprotein (HDL) hypertonic saline therapy. 162. stroke imitator. 259 high-intensity transient signals hypoattenuation. 4 Heuber. induced. 259 homonymous hemianopsia. 41 Trial (INTERACT). 83 hypokinesia. 77–8 injury response. post-stroke. 92 inflammatory response to. 261 Horner’s syndrome. 8 vasculitis. see infective endocarditis (IE) neurological complications. 15 herniation. 262 hormone replacement therapy. 36 infarct core. 266–7 hypotension vasculopathies. pre-stroke hypertension incomplete MCA strokes. 98. human inferior/posterior M2 MCA infarct. 258 hiccup. 261 hypoxia. 3 cryptococcal meningitis. 187–8 management. 235–6 143–5. 244 inflammatory vasculopathies. 14. 245–6 thrombolysis. 135–6. 209–11. 95 progression of. 247. 206 hyaline. 236. 272. 210 inhibitory control. 237 induced. 151 infections. 238 infarction obesity and. 138. 91 indapamide. in small-vessel disease. 161 types and sizes. 126. 213 primary ICH. 167 acute (differential diagnosis). 95 inflammatory vasculitis. 2. 262 pathogenesis. 16–18 Acute Cerebral Haemorrhage 316 sodium intake. 92 inner cerebral vein CVT. 123 development. 211. 1 hypersomnolence. 95. 129 infectious burden concept. 110. 108 259–64. 110. 258–9 cholesterol. 123 A (HMG-CoA) reductase immunodeficiency virus (HIV). 105. high-risk patient identification. 106 atherosclerosis in. infection inflammation. 273 ICH and. 274 hypothermia. 266 see also acquired hydrocephalus. 213. 272–3. 123 infective disorders hippocampus. 154. 267 young adults/children. 110–11. 209 heavy alcohol intake. recurrent artery of. poor diet and. 259 94. 131–2 alcohol consumption. 21 silent. 155 ischemic cell death. 145–7 post-stroke complications. 3. 154. 30–1 endomyocardial fibrosis. 276 Health (ICF) WHO. 162 ionotropic glutamate receptors. 40–3. 276 International Stroke Trial (IST). 239 205–12 see also cardioembolic BA ischemia. 22. 3–4. 37 43. 44–5. 283. 19–20 lactate production. 154. 41 delirium. 203–5. 243–5 thrombosis (CVT) centrum ovale involvement. 127 strokes intimal cell mass. 220. 150 post-stroke management. 36–7 intracranial dissections. 209 meningeal infections. jerky dystonic unsteady hand 154–5. 82. 232 isolated cranial nerve palsy. 230–3. 243–4 acute intervention. 226 high BMI and. 237 heparin therapy. 278 ultrasound. 246–7 internal carotid artery (ICA) post-ICH. 91 iodinated contrast in CT. 155 ischemic injury lacunar infarcts. risk factors. 37 atherosclerosis. 208 brain edema interventions. occlusion. 40. 157–61. 174–5 hyperthermia. 37 classic. 135–6. 98 irreversible damage Kawasaki syndrome. 238 intravenous thrombolysis bilateral hypoplasia. 77. 135–6 in acute stroke. 132 intracranial stenosis flow velocities. 91 see also cerebral venous AChA infarcts. 36. 5. 225 hyperglycemia management. 42 IWS (internal watershed) infarcts. 265 stenosis. 20–1 young adults/children. 233 ischemia disturbances of flow regulation. 274–5. 85. 7–8. 41 capsular warning syndrome. 155–6. 89. unruptured aneurysms. 128 regeneration. 85 risk factors. 131 delayed phase. imaging. 92 intracranial vasculopathies. 232 dissection. 65 intracranial pressure healthy lifestyle. 41 intracranial arteries. 154 progression. 124 blood pressure management. 277–8 secondary prevention. 40 risk factors. 225 young adults/children. 207 intraventricular hemorrhage. 136 post-stroke dementia. 90. 37 small-vessel disease. 89. 28 differential diagnosis. 132 intra-arterial thrombolysis. 207 intracranial hypertension ischemic strokes. 234 lamotrigine. 22. 42. 22–3 Köhlmeier-Degos disease. 6–9 diagnosis/detection. 16–18 dolichoectasic arteries. 232–3 post-treatment scans. 15 brainstem. 78. 167 Japan. 11–21. 209 etiology. 132 physical activity and. 168 lacunar syndromes. 162 LAA (left atrial appendage). 36 intracranial large artery cellular pathology. 155. 186 prediction. 156–7. 142 intimal–medial thickness (IMT). 245–6 management in CVT. 61. 6 ischemic heart disease. 235. 239 contraindications. secondary prevention. 146. 61. 125 statins and. 18 involuntary movements. 245 labetalol. 245 recurrence. 115 dysarthria. 234. 149. 62 136–8 occlusion. 249–52 International Classification of rCMP and. 142–3 intracerebral hematoma. 42 JAK (janus kinase)/STAT (signal intracardiac myxoma. 295 estrogen replacement therapy. intrathecal baclofen. 45 small-vessel disease. 94 intracranial occlusion. 90 internal watershed (IWS) infarcts. 93 lacunes. 123 causes. 148–9 sites of. 82. imaging. 131 anticoagulant therapy and. 206 ESO guidelines. 162 management. 237–9 hyperglycemia and. 36 intracranial hemorrhage. 43–4. ischemic post-conditioning. 122. 155–6. infarcts. 162 lactic acidosis. 250 317 . 61–5 in CADASIL. 208 low flow syndromes. 34. Index interatrioseptal aneurysm (IASA). 297–8 risk factors. 198 rare clinical syndromes. 40. 1 contraindications. 29. 295 intravenous thrombolysis (iv-RTP). 131. 90. 139 warning signs. 113 Functioning Disability and intracranial vertebral artery. 11 106–7 incidence. 29–30. 61–5 oral contraceptive use. 21 imaging. 35–6 ischemic pre-conditioning. 212 complications. 15–16. 96–7 identification. 90 CT in patient selection. 90 290. 43 intracerebral hemorrhage (ICH). 147 fast-track imaging. 36. 40 PCT in outcome prediction. 59–61. 162 transducer and activator of intracerebral aneurysms. 244 prognosis. 233. 210 ischemic ophthalmopathy. 17 syndrome. 208 ischemic penumbra. 267 transcription pathway). 161–2 identification. 149 recurrent risk scoring. 82. 91 internal boundary-zone infarcts. 124. 112. 169–70 lipid mobilization. 2 Mechanical Embolectomy Removal left hemispheric lesions reduction. 135 weighted MRI (dw-MRI) large artery atherosclerosis. 98 CVT. Index language disorders. on stroke risk. 59–61 laughter. 263 318 stroke prevention. 264 secondary prevention. 299 maximal systolic flow. 30. 210 mannitol. 150 medullary perforating arteries. 61. 264. 69 livedo racemosa. 126 52–3 see also diffusion- residual performance. 178–9 stroke risk. 82–3 ICH. 122. left atrial wall. 174 memory disturbances. 183–4 locked-in syndrome. 97 syndrome. 43 in IE. stroke risk. 123 malignant atrophic papulosis. 237 lateral genticulate body. TCD monitoring. NBTE and. 34 large artery infarcts lipohyalinosis malaria. 143 post-stroke dementia and. 123 low-risk lifestyle. 89 memory content. activation patterns. 299 in Cerebral Ischaemia secondary prevention. 28–9. 151 114–15 medial temporal lobe atrophy hyperviscosity. 171. cerebral. 197 left ventricular thrombi. 264 levodopa. 123 low molecular weight heparin 148–9. 122 young adults/children. 37 lipid-lowering therapies. 65. leptomeningeal artery system. 92 low flow infarctions. 207 malignant MCA stroke. occlusion. 171–3 membrane function. 123. 211–12 leptomeningeal branch (LMWH). 146 . 50 meningeal arteries. 138 (MTLA). 123 large-vessel atherosclerosis. 35 malignancies. post-stroke. 30–1 limb-shaking TIA. 273 medial lenticulostriate arteries. 106–7 low birth weight. luxury perfusion. pathological. 269 in MCA. 275 lateral orbital prefrontal lobe. 125 lobar hemorrhages. 43–4 chronic. 158 see also aphasia Action Research Arm Test penumbra. 269 Levovist. 264 memory traces. 43 diagnosis. 189–90 literature reviews. 123 left ventricular hypertrabeculation/ low flow medial medullary stroke. 96–7 post-stroke dementia. 79 man-in-the-barrel. 198 MCA territory infarcts. 29–30 major cerebral hemispheric stroke in ischemic stroke. 121. 34 in ICH. 272 criticisms. PCT data. 124.and intracranial. 159 MATCH study. 123 low flow syndromes. 198 target levels. 77–8 (MCAs) left atrial appendage (LAA). 178–80 stroke risk. 264–6 lifestyle factors brain perfusion. 158. 126 non-compaction (LVHT). 107 extra. 181 lesions amenable to intervention (LAIT). 96 apraxia. brain ischemia. 291 sensorimotor cortex overaction. 205 mania. 244 adults/children. young lisinopril. 209 large infarcts. see middle cerebral arteries countries. 13 involvement. interaction with lumbar puncture. 169–70 tuberculous. 291 lateral medullary lesions. 181 lymph nodes. 52 limb function changes. 67 magnetic properties of hemoglobin. duration of. 264 (MRA). 123 leukoaraiosis. 132 large-vessel embolism. 286 magnetic resonance imaging (MRI) cause of stroke. 273–4 (MERCI) trial. 122. RFA for AF. 151. 127. 30 (MRV). 11 283–4 memory systems. 161 manual dexterity test. 181–3 contralesional hemisphere. 122. 107 low-density lipoprotein (LDL) 40–1 oxidized. 233 language disorders. 123 microbleed. 123 leisure-based physical activity. flow thresholds. 157 regions of impairment. 89. 5. 110 in moyamoya. 137 magnetic resonance venography aortic arch. 178. 197 magnetic resonance angiography meningitis. 157 lacunar infarcts. 3 MELAS (mitochondrial encephalopathy lenticulostriated arteries. 181 lesional hemisphere. 136. 14–15 language function (ARAT). in MCA. 154. 127. 135–6 lactic acidosis and stroke). 62 acute stroke. 53–4 weakness. 82 mean transit time (MTT). 188–9 low and middle income MCAs. 53 ataxia. 43–4 acute bacterial. 267–8. 124 lobar hematoma. 284 transcranial. (MRI) 151. imaging. 221 mental status. 44 MRA (magnetic resonance negative predictive value (NPV). 146. 211–12 mitral valve repair. 130 necrosis. 65–9 rheumatic. 158–9 molecular injury pathways. acidosis and stroke (MELAS). 143. 194 multiparametric MRI. 189–90 mycotic endocarditis. 107–8 deep perforator territories. 110 segments. 123 intracranial pressure. 212–13 pulvinar lesions. 269 midbrain lesions. 291 myxoma. 58 319 mitochondria. 225 induced hypothermia. 31. 123 (post-stroke) MES detection. 111 multimodal hemineglect. 107 complete. of neurons. 9–10 MOSES trial. 173–4 stroke imitation. 33 stenosis. 65–9 225 mycotic aneurysms. microemboli. 10 mitral valve prolapse. 71 transorbital. 4 mismatch concept. 273 myogenic theory of autoregulation. 246 lacunar infarcts. 98 in neurorehabilitation. 89 Evaluation (MORE) trial. 175 myocardial ischemia. 265 148–9. tuberculous meningitis. worldwide. 43–4 . 211–12 multidisciplinary team. 122 mortality. 143 middle cerebral arteries (MCAs) see also anxiety. 178–80 morphological integrity. 278 middle cerebral artery strokes. Index meningo-encephalitis. 171 mitochondrial encephalopathy lactic MRI. 12–13 embolism caused by. 195 ultrasound in outcome cigarettes as cause. 94 109–10 brain edema. 123 NASCET trial. 150–1 SCA infarcts. 122 methyl mercury in fish. 34 hypertension levels. 109–10 prediction. 93 proximal. 237. 147. 33–4. 107 trends in. 288–95 metabolic blood flow regulation. 9 motor hemineglect. 71 79. 78–9 ischemic stroke risk. 70 CVT and. 293 moyamoya disease. 213 fibrosis capsular warning syndrome. 41 motor rehabilitation. 70. 16–18 multivariate prediction models. 68 myocardial infarction (MI) perisylvian lesions. 71 n-3 fatty acids. 283. 129 Disorders and Stroke motor neglect. 124 movement abnormalities stroke risk. see magnetic resonance imaging meningovascular syphilis. 147 modifiable risk factors. 142–3 endocarditis). 151. 226–7 endocarditis. 8 mirror therapy. ultrasound contrast. 124 National Institute of Neurological 122–3. 79 in LVHT. 252 Multiple Outcomes of Raloxifene microangiopathy. 267 monitoring patients. 36. 151. reorganization. 94 microbleeds. 45 thalamic ischemia. 122. 33 NBTE (non-bacterial thrombotic frontal lobe ischemia. 150. 199 in LAA. 114–15 middle cerebral artery occlusions. 143 (NINDS). 208 69. 93 mixed dementia. RFA targets. 237 ICH and. 286 modafinil. 232–3 motor cortex. 131 NCCT (non-contrast CT). 212–13 lacunar strokes. 7 Motor Assessment Scale (MAS). 89 with stroke. 132 young adults/children. 82–3 Mycobacterium tuberculosis. 41. 150–1. 131 myocardium visualization. migrainous stroke. impairment. AF and. 80. 166. 162 myocardial sleeves. 79–81. motor hemiparesis. 131 young adults. 235 migraine brain perfusion data. 208–9 necrotic tissue. 127 mood disturbance post-stroke mania. 69 post-stroke dementia. 168. 19 angiography). 77–8 see also endomyocardial 10. 10 neuronal changes. 9 motor deficits. ESO guidelines. 291–4 nausea and vomiting. 288–9 metabolic disturbances. 52–3. 50–2. 176 mitral valve disease early rehabilitation. mural hematoma. 18. 220. 165. with stroke. 267. 230–1. 127 post-stroke dementia and. 125. 207 prognosis. MONICA Stroke Study (WHO). 143 with aura. depression myocardial fibrosis. 40. 64. 44 methylphenidate. 142 nanobubbles. 136. 44–5 microbubbles. 51. 45. 207 organization and management. middle cerebral artery infarctions. 77. 155–6. 64 BA infarct. 221 MES (microembolic signs). 110 emergency stroke care. 127 43. 139 filament-induced. 129. 264–5 microembolic signs (MES). Index neglect, 191 nitric oxide (NO) toxicity, 17 in CVT, 172–3 neonatal CVT, 175–6 non-bacterial thrombotic endocarditis in dCMP, 113 neurocysticercosis, 265–6 (NBTE), 143, 261 oral contraceptive use, 90, 212, 214 neurogenesis, ischemia-induced, 21 non-cardiac origin cerebral osmotic diuretics, 174 ischemia, 277 osmotically induced cell swelling, 19 neuroimaging cardioembolic strokes, 34 non-contrast CT (NCCT), 40, 41, 43, 45 outcomes lesion localization, 121 non-cruoric emboli, 212 after timely thrombolysis, 230–1 stroke classification, 77 non-infective endocarditis, 143 PCT in prediction, 42 see also computed tomography post-stroke fatigue and, 252 (CT); magnetic resonance non-modifiable risk factors, 81, 82, 89 Oxfordshire stroke classification, 121 imaging (MRI) non-smokers, tobacco smoke exposure, 90 oxygen extraction fractions (OEFs), neurological deficits, functional 22, 49 threshold, 13 non-valvular atrial fibrillation, 31, 32–3 oxygen levels, in hemoglobin, 50 neuromuscular disorders, 115 North America, 78 oxygen utilization in brain, 11, 22–3 neuromyocardial failure, 114 nortriptyline, 91 see also cerebral metabolic rate neurons nuclear palsy, 127 for oxygen (CMRO2) activity mapping, 49–50 pain, 130, 173–4, 299 cell damage, 13 Nurses’ Health Study, 82 cell death, 7, 20 low-risk lifestyle, 89 palipsychism, 130 delayed death, 8–9 on diet, 93 smoking cessation, 90 Papez circle, 141 energy requirements, 11–12 flow thresholds, 12–13 NXY-059, free-radical-trapping papillary fibro-elastoma, 207 integrity markers, 22–3 agent, 234–5 paracetamol, 173–4 sprouting, 285, 289 nystagmus, 125 paradoxical embolism, 33, 112 neurontine, 250 AICA infarcts, 126 paramedian arteries, 130 neuroplasticity, 283–8 PICA stroke, 126 SCA infarcts, 126 paramedian thalamic infarction, 141 induction, 285–8 mechanisms, 283–5 obesity, 89, 91–2, 107 parasitic cardiomyopathy, 264 pharmacology, 286–8 parenchymal hemorrhages occipito-temporal hemorrhages, 184 neuroprotection after thrombolysis, 230–1 occlusion in ICH, 5, 6, 154 post-stroke therapy, 234–5 flow signal changes, 70 signaling cascades, 20–1 parietal cortex, 51, 181 investigation, 61 neurorehabilitation, 283 ultrasound diagnosis, 61–5 paroxysmal atrial fibrillation, 33, 98, assessment, 289, 290–1 105–6 occupational-based physical dysphagia, 295–7 activity, 92 partial occipital lesions, 188 goal-setting, 290–1 in acute unit, 288 ocular apraxia, 129 partnership relationships, 300 intensity, 290 ocular manifestations motor rehabilitation, 291–4 passive smoking, 90 cavernous sinus thrombosis, 167 multidisciplinary team, 288–95 midbrain ischemia, 127 patent foramen ovale (PFO), 111–13, 115 pharmacology, 287–8 PCA infarcts, 129 ASA and, 113 speech disorders, 294–5 cryptogenic stroke, 37 timing, 289–90 see also early ocular tilt reaction, 125 imaging, 206 neurorehabilitation oily fish consumption, 93 recurrent strokes, 112–13 neurotransmitters, 17 15 right-to-left shunt detection, 72 O-labeled tracers, 49 stroke risk, 33, 112–13 neurovascular examination, fast-track, ophthalmic artery, 61, 121 surgical closure, 113 65, 66 young adults/children, 206–7, 214 ophthalmoplegia, 167, 168 neutrophilic dermatosis, 212 pathological laughter, 127, 188–9 optic tract involvement, 124 nicotine receptor partial agonist, 91 patient care oral anticoagulation therapy nicotine replacement therapy, 90 (OAC), 279 clinical application of experimental AF and, 97–8 concepts, 21–2 320 Nine Hole Peg Test (NHPT), 291 stroke units, 220–7 cardiac embolism, 275–7 nitrendipin, 272, 273 Index patient characteristics, post-stroke Physicians’ Health Study, 90 post-irradiation cervical dementia, 195–7, 200 physiotherapy, concepts, 294 arteriopathies, 208 patient criteria piracetam, 53 post-menopausal HRT, 94, 274 for hemicraniectomy, 237 post-partum cerebral angiopathy, 210 for IV thrombolysis, 231 PLAATO occluder device, 107 see also lesions amenable to plaques post-stroke complications, 289, 289 intervention (LAIT) sonographic characteristics, 58 see also individual see also atheromatous; plaques, complication/condition patient interview, young adults/ children, 204 atherosclerotic plaques post-stroke dementia. see dementia Plasmodium falciparum, cerebral (post-stroke) PCAs. see posterior cerebral arteries (PCAs) malaria, 267–8 post-synaptic ion fluxes, 12 peak systolic velocities (PSVs), 59–61 plasticity, 301–285 post-traumatic stress disorder, 189 penumbra platelets, in thromboembolism, postural tone, sudden loss of, 137 and infarct core, 15 2–3, 29 potassium, dietary intake, 93 imaging, 13–15, 22, 41 pneumonia, aspiration-induced, ischemic, 11–21 prefrontal lobe deficits, 191, 183–4 268, 295 PWI>DWI mismatch concept, pregnancy-related disorders, 213 44 polycythemia vera, 138 childbirth-associated emboli, 212 perfusion CT (PCT), 45 pontine hemorrhages, 6 choriocarcinoma, 212 aphasia and hemiparesis, 41 pontine strokes, 125, 127, 189 CVT, 6, 167, 175 in acute stroke, 40–2 post-stroke, 214 population-level stroke awareness, 219 stroke in, 203, see also eclampsia; sensitivity, 40, 42 positive predictive value (PPV), 58 peripartum cardiomyopathy; perfusion harmonic imaging, 69 post-partum cerebral positron emission tomography (PET), angiopathy perfusion pressures, regulation, 10 22, 23, 48–9, 49–50 perfusion-weighted images (PWI), advantages over fMRI, 50 prehospital care, 219–20 MRI and CT compared, 43 compensatory mechanisms, 50–2 pre-posterior circulation stroke, 124 perfusion-weighted MRI (pw-MRI), penumbra imaging, 14 with rTMS, 53–4 primary intracerebral hemorrhage, 43–4 154, 157, 237 mismatch concept, 44 positrons, radioisotope decay scheme, 50 primary ischemic cell death, 7–8 peri-infarct spreading depressions, 15–16 posterior cerebral arteries (PCAs), 121 primary stroke centres infarcts, 129 (PSCs), 221–2 perindopril, 272, 273 blind-sight, 137 primary vasculitis of the CNS, 209 peripartum cardiomyopathy, 207 memory defects, 246–7 prodromal symptoms, 124, 127 peripheral nerve system, neuronal visual agnosias, 184, 185 sprouting, 285 ischemia, cortical blindness, PRoFESS trial, 273, 275 139–41 prognosis peripheral techniques, plasticity segments, 129 induction, 286 delirium and, 186 stenosis and occlusion, 64 in ICH, 122, 154, 155 perisylvian lesions, 178–80 posterior choroidal artery (PChA) microbleeds and, 159 personality changes, 130, 190–1 infarcts, 130–1 post-stroke anxiety and, 189 reperfusion and, 70 PET. see positron emission posterior circulation syndromes, ultrasound in, 70–1 tomography (PET) 124–5, 132 PROGRESS trial, 273 PFO. see patent foramen ovale (PFO) posterior circulation, low cerebral flow, 136–8 progressive strokes, 36, 70 phenytoin, 250 posterior inferior cerebral artery proprioceptive systems, 51 phospholipid nanobubbles, 71 (PICA) infarcts, 125–6 prosopagnosia, 184–5 photons, radioisotope decay scheme, 50 posterior reversible encephalopathy prosthetic heart valves, 111 syndrome (PRES), 129 AF and, 98 physical activity embolism risk, 33 healthy lifestyle, 82, 89 posterior splenium lesions, 180 IE and, 110, 259, 262, 263 neurorehabilitation, 285 posterior WS stroke, 132 321 stroke prevention, 92, 98 protein kinases, 21 Index protein synthesis inhibition, 18 real time visualization, 69 restrictive cardiomyopathy (rCMP), prothrombotic conditions/states, recanalization speed, 70–1 113–14 166, 171 recombinant factor VIIa (rFVIIa), 239 result statistics, 58 protozoan parasite, stroke imitator, 267 recombinant tissue plasminogen retinal ischemia, 124, 136 pro-urokinase, 232 activator (rt-PA), 10, 70, retrograde amnesia, 181 proximal vertebral artery disease, 230–3 Reveal XT, 106 137–8 door-to-needle times, 220 dosage, 231 RFA (radiofrequency-catheter- pseudoradicular sensory deficit, 130 ablation), 107–8 recurrent artery of Heuber (raH), 123 pseudoseizures, 127 rheumatic heart disease, 105 recurrent cerebral ischemia, 210 psychiatric disorders, post-stroke rhythm disturbances, 105–9, 115 anxiety and, 189 recurrent coronary syndromes, 213 rhythmical acoustical pacing, 292 psychological interventions, for weight recurrent CVT, 175 right corticolimbic pathway lesions, 190 loss, 92 recurrent post-stroke mania, 190, 191 right hemisphere lesions, 191 psychosocial interventions, for delusions, 188 smoking, 91 recurrent strokes neglect symptoms, 181, 298–9 psychotic disorders, 187–8 post-stroke dementia and, 198, 199 space perception, 299 prevention, 233, 272, 276 pulse, difference between arms, 138 risk scoring, 276 right-to-left shunt, 72, 206 pulvinar lesions, 130–1, 148 young adults/children, 206–7, 213 risk assessment, for antithrombotic pure motor hemiparesis red-ragged fibres myopathy, 148–9 therapy, 97 capsular warning syndrome, 139 reduced vigilance, as symptom, 141 risk factors for stroke, 79–82 lacunar syndrome, 36, 131 additive effects in, 90 referral to stroke unit, 219–20 causal significance, 85 pure sensory stroke, lacunar syndrome, 36, 131 reflux, medications, 287 in secondary prevention, 272–9 regeneration of ischemic injury, 21 modifiable, 79–81 pusher syndrome, 299 non-modifiable, 81 putaminal hemorrhages, 5, 159, 160 regional cerebral blood flow (rCBF), novel, 85 40–1, 166 young adults/children, 212–13 putaminothalamic hemorrhages, 159, 160 regional cerebral blood volume risk score, post-TIAs, 83 (rCBV), 40–1 PWI. see perfusion-weighted images risk-assessment tools, 83–5 (PWI) regional cerebral metabolic rate for glucose (rCMRG1c), 49–50 Rivermead Mobility Index (RMI), 290 pyrexia, post-stroke, 236–7 rostral brainstem strokes, 188 regulatory inhibitory control, QT-prolongation, 108, 109, 115 failure of, 187–8 rotational vertebral artery occlusion quality of life, 188, 213, 248, 290 rehabilitation, 283 (RVAO), 136–7 radioactive tracers, 49–50 early, 226–7 rTMS. see repetitive transcranial motor reorganization, 51 magnetic stimulation (rTMS) radiofrequency-catheter-ablation see also neurorehabilitation (RFA), 107–8 Russia, stroke epidemiology, 78, 79 reorganization, motor cortex, 284 saline, hypertonic, 237 radioisotope venography, 112 reperfusion, 4–5, 10, 70 Salmonella spp. infection, 267 radioisotopes, decay scheme, 50 reperfusion therapy, 44 SCA (superior cerebellar artery) raloxifene, 94 repetitive training, 292 infarcts, 126–7 Raloxifene Use for the Heart (RUTH) trial, 94 repetitive transcranial magnetic secondary intracerebral hemorrhage stimulation (rTMS), 53–4, (ICH), 154, 157, 237 ramipril, 272 285–6 secondary prevention, 121, 226, 272–9 rash, herpetiform, 266 respiratory distress, neonatal CVT, 175 young adults/children, 215 rCMP (restrictive cardiomyopathy), respiratory infection, pre-stroke, 258 secondary vasculitis, 209 113–14 response to injury hypothesis, 1–2 seizures reading disorders, 191, 180–1 in ICH, 238 322 reading, cognitive models, 180 restlessness, anxiety and, 189 in MELAS, 148 Index post-stroke, 249–50 secondary ICH, 157 steroids, 174 classification, 249–50 young adults/children, 207 stimulating agents, 252 incidence rate, 249–50 smoking, 89–91, 156 pathophysiology, 250 stimulating learning atmosphere, 285 risk factors, 249–50 smoking prevention/cessation, 90–1, 98 strategic infarcts, 198 treatment, 250 healthy lifestyle, 82, 89 thrombolysis and, 231 strength training, 293 Sneddon syndrome, 143–5, 210 selective estrogen receptor modulators Streptococcus spp. infection, 261 social functioning (SERMs), 94 anxiety and, 189 stress, physical or emotional, 114 selective serotonin reuptake inhibitors depression and, 190 stress-induced hyperglycemia, 245 (SSRIs), 251 treatment goals, 290 striatum lesions, 181 sensitivity of results defined, 58 social interaction, in neuroplasticity, 285 stroke awareness, population-level, 219 sensorimotor cortex, 51, 52–3 social issues, stroke rehabilitation, 300–1 stroke classification, 77, 121, 122 sensorimotor hemiparesis, 124, 159 sodium intake, 93 stroke imitators, 42, 121, 124, 231, 236 sensorimotor stroke, lacunar somatoparaphrenia, 188 Stroke Impact Scale (SIS), 291 syndrome, 36, 131 somatosensory deficits, 50–2 stroke prediction sensory deficits, 77 general population, 83–5 AChA infarcts, 124 SonoVue, 69 post-TIAs, 83 isolated cranial nerve palsy, 142 lacunar stroke syndrome, 131 space perception disorders, 299 Stroke Prevention by Aggressive PCA infarcts, 129 spasticity, 301, 297–8 Reduction in Cholesterol thalamic ischemia, 130 Levels (SPARCL) study, 273 spatial delirium, 188 sensory hemisyndromes, 123 stroke recurrence. see recurrent strokes spatial disorientation, 129 sepsis, post-stroke dementia and, 195 stroke risk spatial neglect, 301, 298–9 carotid surgery and, 278 septic CVT, 6, 165, 168 specificity, of results, 58 IMT increase, 61 serum cholesterol levels. PFO in, 112–13 spectacular shrinking deficit, 34 see cholesterol vasomotor reactivity, 71 spectral analysis, 59 young adults/children, 212–13 serum lipids, exercise and, 92 speech analysis test, 179 stroke screening, emergency protocols, sexual functioning, 300 speech fluency, classification, 179 219–20 shoulder pain, 299–300 speech impairment, 77, 130, 301 stroke severity, 34, 224 shoulder-hand syndrome, 300 hyperthermia and, 246 neurorehabilitation, 294–5 sickle-cell anemia, 138, 211 post-TIA, 83 patient criteria for thrombolysis, 231 signal intensities of perfusion, 14–15 speech-relevant brain regions, 52 stroke syndromes, 129, 121 signaling cascades, neuroprotective speed of clot dissolution, 70–1 stroke treatment effect, 20–1 acute phase, 225 spontaneous ICH, 5 centralised care organization, 227 signaling, energy requirements, 12 emergency management, 224–7 spousal cigarette smoking, 90 silent CVTs, 167 ESO guidelines, 248 sprouting, neuronal, 285, 289 silent infarcts, 197–8 stroke units, 219, 227 SS-TOAST stroke classification, 121 silent intracerebral hemorrhages, 155 benefits, 220–2 Staphylococcus aureus, 261, 267 early activities, 222–4 simvastatin, 273 essential components, 222 statins, 96–7, 156–7, 273–4 sinus aplasia/hypoplasia, 169 guidelines, 224–5 steal phenomena, 11 importance, 219 skin abnormalities, 147, 204 patient care, 220–7 steal syndrome, subclavian, 137–8 small artery disease, 37 referral to, 219–20 stenosis small penetrating artery occlusion. cerebral arteries, 61, 64 strokes, acute. see acute strokes see small-vessel disease degree of, 59–61 subarachnoid hemorrhage (SAH) small-vessel disease, 3, 131 ultrasound diagnosis, 61–5 diagnostic imaging, 45 in CADASIL, 147 stenting, 278 incidence, 77 323 lacunes in, 35–7, 131 intracranial ICA dissections, 149 Index subarachnoid hemorrhage (SAH) syncope, 114 thromboembolism, 2–3, 111 (cont.) syphilis, 204 thrombolysis, 219 memory defects, 181 meningovascular, 146, 151, 265 accelerated, 71 post-stroke mania, 190 acute intervention, 219, 230–1 risk factors, 82, 89–90 systemic disorders lupus erythematosus, 145 BP and outcome, 243–4 subclavian artery, 61 secondary vasculitis, 209 experimental, 10 subclavian steal syndrome, 137–8 stroke manifestations, 143–5 flow signal changes, 70 prognosis, 70, 71 subcortical boundary-zone infarcts, systolic dysfunction, 114 research studies, 230–1 135–6 systolic velocity ratios ICA/CCA, 59–61 see also intravenous subcortical brain atrophy, 190 thrombolysis (iv-RTP) tachycardia, 108, 115 subcortical infarcts, 52 Thrombolysis in Brain Ischemia Taenia solium, 265 (TIBI), 70 subcortical lesions, 181, 191 Takayasu disease, 209 thrombophilias, 171, 204, 211 subcortical lunar infarctions, 161 Takotsubo syndrome (TTS), 114 thrombosis, 1, 30 subcortical strokes, 129, 189 tamoxifen, 94 thrombotic strokes, incidence, 77 subdural hematomas (SDHs), 45 tapeworm infestation, 265–6 thrombotic thrombocytopenic substance use, 189, 204 TCD. see transcranial color Doppler purpura, 211 sudden cardiac death, 109 (TCD) sonography thrombus superficial cerebral veins, 165 telemedicine, 220, 227, 232 formation, 107, 113 MRI imaging, 44, 169–70 superior cerebellar artery (SCA) telmisartan, 272, 273 infarcts, 126–7 tinnitus, 137 temporal arteritis, 145 superior temporal gyrus lesions, 52 tissue acidosis, 11 temporal herniation, 122 superior temporal region lesions, 181 tissue damage, 22–3 temporal lobe infarcts, 141 superior/anterior M2 MCA infarction, tissue plasminogen activator (t-PA) temporo-parietal cortex, 52 122–3 therapy, 71 territorial infarcts, 3, 41 supplementary motor area (SMA) TOAST stroke classification, 28, 37, functions, 51 thalamic dementia, 130 121, 122 lesions, 142 thalamic hand, 130 top of the basilar syndrome, 129, 139–40 supramarginal gyrus lesions, 52, 180 thalamic hemorrhages, 5 torsades de pointes, 109 supratentorial infarcts, 125, 198 GRE-MRI, 160 toxoplasmosis, 267, 269 in ICH, 159 supratentorial strokes, 186 tracer imaging, 49–50 thalamic lesions, 188 surgical abscess drainage, 263 amnestic stroke syndromes, 182 tracheostomy, 296–7 surgical decompression, 237 memory defects, 181, 182 transcallosal inhibition, 50–2, 53, 54 surgical intervention, for ICH, 238–9 post-stroke apathy, 191 transcortical motor aphasia, 123 Surgical Trials in Intracerebral thalamic pain syndrome, 130 transcranial color Doppler (TCD) Haemorrhage (STICH) thalamocortical pathway sonography study, 238 involvement, 124 accelerated thrombolysis, 71 Susac (Sicret) syndrome, 212 thalamogeniculate (inferolateral) fast-track assessment, 65 arteries, 130 intracranial stenosis and occlusion, susceptibility-weighted imaging, 44–5 61–5 swallowing disorders. see dysphagia thalamus, 129–31, 181 microembolic signs, 65–9 bilateral infarcts, 141 sweet syndrome, 212 PFO detection, 72 PCA infarcts, 129 result correlation with Sylvian artery. see middle cerebral vascularization, 129–30 angiography, 70 arteries (MCAs) therapeutic interventions, acute vasomotor reactivity, 71–2 symptomatic carotid plaques, 58 stroke, 230 transcranial color-coded duplex symptoms of stroke, 77 thermoalgesic deficits, 126 (TCCD) sonography, 61–4, 65 duration, 83 thiazide diuretics, 95 transcranial direct current stimulation 324 synaptic plasticity, 285 (TDCS), 285–6 thromboangiitis obliterans, 209 Index transcranial magnetic stimulation ultrasonography venous thromboembolism (TMS), 50, 51, 54 accelerated thrombolysis, 71 paradoxical, 112 transcranial middle cerebral artery fast-track, 65, 66 risk post-ICH, 238 occlusion, 9 prognostic value of, 70–1 ventral paramedian lesion, 127 screening for intervention, 67 transient filament occlusion, 10 sensitivity and specificity, 58 ventricular aneurysms, 110 transient global amnesia (TGA), 141 stenosis grading, 61, 64 ventricular conditions, cardioembolic see also Doppler sources, 32 transient ischemic attacks (TIAs) ultrasonography; duplex atherosclerosis and, 29, 30 ultrasonography; extracranial ventricular enlargement, 113 capsular warning syndrome, 139 ultrasonography ventricular repolarization, cardioembolism and, 34 prolongation, 109 hemi-paresis and, 36 ultrasound contrast agents (UCAs), limb-shaking TIA, 124, 136, 137 69–70 ventricular segments, akinesia or low flow, 135–6, 136–8 unfractionated heparin (UFH), hypokinesia, 114 MES detection, 66, 69 171–3 verb generation, 53–4 PCT in brain perfusion data, 41 pre-lacunar syndrome, 36 unilateral weakness. see hemiparesis verbal auditory comprehension pre-stroke, 124 uninhibited behavior, 183–4 test, 179 secondary prevention, 272, 274–5, unruptured aneurysms of intracranial vertebral arteries (VAs) 276 arteries, 210 compression in RVAO, 136–7 stroke prediction, 83 dissections, 149–50, 277 syphylitic meningovasculitis, 146 upper spinal cord, watershed infarcts, 125–6 area, 132 low blood flow, 135 transorbital middle cerebral artery occlusion, 9 urinary incontinence, 299–300 stenosis, 59, 61, 64 subclavian steal syndrome, 137–8 transport, emergency, 219, 220 urinary tract infections (UTI), 258, 268 vertebrobasilar circulation, 124–31 treadmill training, 292 valve repair, 111 vertebrobasilar insufficiency, 64 Treatment of Hyperglycemia in Ischemic Stroke (THIS) valve surgery, pre-stroke, 111 vertebrobasilar ischemia, 137 trial, 246 valvular conditions, and vertigo, 126, 137 treatment time window, 219–20, cardioembolism, 32 vessel occlusion, MRA in location 222–4, 230–1 valvular heart disease, 110–11, 115 of, 44 treatment work-up, 121 varenicline, 91 vicariation, 301 treatment, ESO guidelines, 225, 226 varicella zoster virus (VZV) videofluoroscopic swallowing study treatments, 233 vasculopathy, 145–6, 151, 266 (VFSS), 296 Treponema pallidum infection, vascular dementia (VaD), 194, 198, viral diseases, pre-stroke, 258 146, 265 200, 251–2 viral intracranial vasculopathies, post-stroke dementia and, 252 145–6 Trial of Organon in Acute Stroke (TOAST). see TOAST stroke vascular lesions, 157 visual disorientation, 135 classification vascular permeability/rupture, 4–5 visual hallucinations, 188 troponin biomarkers, 109–10 vasculitis, 209, 269 visual impairment true-negative/positive results, 58 infectious diseases in, 266–7 acuity loss, 136 young adults/children, 209 agnosias, 184, 185, 191 truncular ataxia, 125 vasculopathies, 143–5, 145–6, 266–7 blurred vision, 77 Trypanosoma cruzi infection, see also varicella zoster virus focal signs, 77 264 (VZV) vasculopathy giant cell arteritis, 145 TTS (Takotsubo syndrome), 114 in stroke type, 124 vasogenic brain edema, 19 PCA infarcts, 129 tuberculous meningitis, 146, 151, vasomotor reactivity, 71–2 subclavian steal syndrome, 138 264–5 visual field deficits, 122, 130, 298–9 vasorelaxation, 11 tuberothalamic (polar) artery visual-spatial disturbance, 130 infarcts, 130 vegetations, 261, 263 venography, 112 vitamin K antagonists, 172–3 tumors. see intra-cardiac myxoma, papillary fibro-elastoma venous infarcts, 6 vitamin supplementation, 274 325 148. IE. 206 waveform analysis. 148 Fabry disease. 78 worldwide impact of stroke. 186 (WMHs). 206–7 Wernicke’s aphasia. see also pregnancy-related interatrioseptal aneurysm. 197. 205–7 wine. 92 metabolic disorders. 275–7 whole grain intake. 93 cardioembolism. 132 women hematological diseases. 191. 211–12 weight reduction. 92 Disability and Health (ICF) secondary prevention. 206 203. 190 stroke risk factors. 205–12 vulnerable plaque. 213 Wallenberg syndrome. delirium. 215 white matter abnormalities writing disorders. 126. 147. 159. 82. 179. 187 word repetition. carotid stenosis. 211 watershed stroke. 154 small-vessel occlusion. 90 MELAS. 212–13 post-stroke dementia. 207 depression. 126 AF. 2 MELAS. 278 CADASIL. 123. 207 secondary prevention. 206–7. 125. 147–8 WHO ICF. 124 ischemic stroke in young adults. 17 white matter hemorrhages. 5 326 . 215 arterial stenosis. unilateral. 252 young adults cerebral ischemia. Index vomiting. see MONICA Stroke young adults/children. 208 watershed infarcts. 213 secondary prevention. 205 Study (WHO) warfarin. 205 weakness. 179 PFO. 160 white matter hyperintensities cervical artery dissection. risk/benefits. see International ischemic stroke. 3. 77–8. 132 diagnostic workup. 211–12 word repetition test. 149–50 vulnerable patients. 214 WHO stroke risk. 213–14 western Europe. 52 post-stroke sequelae. 98. 59 disorders large-vessel atherosclerosis. 91 cervical artery dissections. see hemiparesis Women’s Health Study. 292 WHO study. post-stroke aphasia. 205 zinc toxicity. 208 Wühlblutung. 33 walking rehabilitation. 79 recurrent strokes. 209 CADASIL. hemorrhage spread. 203. 180 secondary vasculitis. 148–9 Classification of Functioning waist-to-hip ratio.