Neuropathologyandpathophysiology Ofstroke
Cambridge University Press978-1-107-04749-5 - Textbook of Stroke Medicine: Second EditionEdited by Michael Brainin, Wolf-Dieter Heiss and Susanne TabernigExcerptMore informationSection 1Chapter1Etiology, pathophysiology, and imagingNeuropathology and pathophysiologyof strokeKonstantin-A. Hossmann and Wolf-Dieter HeissThe vascular origin of cerebrovasculardiseaseAll cerebrovascular diseases (CVDs) have their originin the vessels supplying or draining the brain. Therefore, the knowledge of pathological changes occurringin the vessels and in the blood are essential for understanding the pathophysiology of the various types ofCVD and for planning of efficient therapeutic strategies. Changes in the vessel wall lead to obstruction ofblood flow, by interacting with blood constituentsthey may cause thrombosis and blockade of bloodflow in this vessel. In addition to vascular stenosis orocclusion at the site of vascular changes, disruption ofblood supply and consecutive infarcts can also beproduced by emboli arising from vascular lesionssituated proximally to otherwise healthy brancheslocated more distal in the arterial tree or from asource located in the heart. At the site of occlusion,opportunity exists for thrombus to develop in anterograde fashion throughout the length of the vessel,but this event seems to occur only rarely.Changes in large arteries supplying the brain,including the aorta, are mainly caused by atherosclerosis. Middle-sized and intracerebral arteries can alsobe affected by acute or chronic vascular diseases ofinflammatory origin due to subacute to chronic infections, e.g. tuberculosis and lues, or due to collagendisorders, e.g. giant cell arteritis, granulomatousangiitis of the central nervous system, panarteritisnodosa, and even more rarely systemic lupus erythematosus, Takayasu’s arteritis, Wegener granulomatosis, rheumatoid arteritis, Sjögren’s syndrome, orSneddon and Behçet’s disease. In some diseasesaffecting the vessels of the brain the etiology andpathogenesis are still unclear, e.g. moyamoya diseaseand fibromuscular dysplasia, but these disorders arecharacterized by typical locations of the vascularchanges. Some arteriopathies are hereditary, such asCADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), in some such as cerebral amyloid angiopathy adegenerative cause has been suggested. All these vascular disorders can cause obstruction, and lead tothrombosis and embolizations. Small vessels of thebrain are affected by hyalinosis and fibrosis; this“small-vessel disease” can cause lacunes and, if widespread, is the substrate for vascular cognitive impairment and vascular dementia.Atherosclerosis is the most widespread disorderleading to death and serious morbidity includingstroke [1]. The basic pathological lesion is the atheromatous plaque, and the most commonly affectedsites are the aorta, the coronary arteries, the carotidartery at its bifurcation, and the basilar artery.Arteriosclerosis, a more generic term describinghardening and thickening of the arteries, includes asadditional types Mönkeberg’s sclerosis which is characterized by calcification in the tunica media andarteriolosclerosis with proliferative and hyalinechanges affecting the arterioles. Atherosclerosis startsat young age, lesions accumulate and grow throughout life and become symptomatic and clinically evident when end organs are affected [2].Atherosclerosis: atheromatous plaques, most commonlyin the aorta, the coronary arteries, the bifurcation of thecarotid artery and the basilar artery.The initial lesion of atherosclerosis has been attributed to “fatty streaks” and the “intimal cell mass.”Those changes already occur in childhood and adolescence and do not necessarily correspond to thefuture sites of atherosclerotic plaques. Fatty streaksTextbook of Stroke Medicine, Second Edition, ed. Michael Brainin and Wolf-Dieter Heiss. Published by Cambridge UniversityPress. Michael Brainin and Wolf-Dieter Heiss 2014. in this web service Cambridge University Presswww.cambridge.org1
Cambridge University Press978-1-107-04749-5 - Textbook of Stroke Medicine: Second EditionEdited by Michael Brainin, Wolf-Dieter Heiss and Susanne TabernigExcerptMore informationSection 1: Etiology, pathophysiology, and imagingFigure 1.1. The stages of development of an atherosclerotic plaque. (1) LDL moves into the subendothelium and (2) is oxidized bymacrophages and smooth muscle cells (SMC). (3) Release of growth factors and cytokines (4) attracts additional monocytes. (5) Macrophagesand (6) foam cell accumulation and additional (7) SMC proliferation result in (8) growth of the plaque. (9) Fibrous cap degradation and plaquerupture (collagenases, elastases). (10) Thrombus formation. IL-1 ¼ interlenkin-1; MCP-1 ¼ Monocyte chemotactic protein-1. (Modified withpermission from Faxon et al. [5].)2are focal areas of intra cellular lipid collection in bothmacrophages and smooth muscle cells. Various concepts have been proposed to explain the progressionof such precursor lesions to definite atherosclerosis[2, 3], most remarkable of which is the response-toinjury hypothesis postulating a cellular and molecularresponse to various atherogenic stimuli in the form ofan inflammatory repair process [4]. This inflammation develops concurrently with the accumulation ofminimally oxidized low-density lipoproteins (LDLs)[5, 6], and stimulates vascular smooth muscle cells(VSMCs), endothelial cells, and macrophages [7], andas a result foam cells aggregate with an accumulationof oxidized LDL. In the further stages of artherosclerotic plaque development VSMCs migrate, proliferate, and synthesize extracellular matrix componentson the luminal side of the vessel wall, forming thefibrous cap of the atherosclerotic lesion [8]. In thiscomplex process of growth, progression, and finallyrupture of an atherosclerotic plaque a large number ofmatrix modulators, inflammatory mediators, growthfactors, and vasoactive substances are involved. Thecomplex interactions of these many factors are discussed in the special literature [5–9].The fibrous cap of the atherosclerotic lesioncovers the deep lipid core with a massive accumulation of extracellular lipids (atheromatous plaque), orfibroblasts and extracellular calcifications may contribute to a fibrocalcific lesion. Mediators from inflammatory cells at the thinnest portion of the cap surfaceof a vulnerable plaque – which is characterized by a in this web service Cambridge University Presslarger lipid core and a thin fibrous cap – can lead toplaque disruption with formation of a thrombus orhematoma or even to total occlusion of the vessel.During the development of atherosclerosis the entirevessel can enlarge or constrict in size [10]. However,once the plaque covers 40% of the vessel wall, theartery no longer enlarges, and the lumen narrows asthe plaque grows. In vulnerable plaques thrombosisforming on the disrupted lesion further narrowsthe vessel lumen and can lead to occlusion or bethe origin of emboli. Less commonly, plaqueshave reduced collagen and elastin with a thin andweakened arterial wall, resulting in aneurysm formation which when ruptured may be the source ofintracerebral hemorrhage (Figure 1.1).Injury hypothesis of progression to atherosclerosis: fattystreaks (focal areas of intra cellular lipid collection) !inflammatory repair process with stimulation of vascularsmooth muscle cells ! atheromatous plaque.Thromboembolism: immediately after plaque ruptureor erosion, subendothelial collagen, the lipid core, andprocoagulants such as tissue factor and von Willebrand factor are exposed to circulating blood. Plateletsrapidly adhere to the vessel wall through the plateletglycoproteins (GP) Ia/IIa and GP Ib/IX [11] withsubsequent aggregation to this initial monolayerthrough linkage with fibrinogen and the exposed GPIIb/IIIa on activated platelets. As platelets are a sourceof nitric oxide (NO), the resulting deficiency of bioactive NO, which is an effective vasodilator, contributeswww.cambridge.org
Cambridge University Press978-1-107-04749-5 - Textbook of Stroke Medicine: Second EditionEdited by Michael Brainin, Wolf-Dieter Heiss and Susanne TabernigExcerptMore informationChapter 1: Neuropathology and pathophysiology of stroketo the progression of thrombosis by augmentingplatelet activation, enhancing VSMC proliferationand migration, and participating in neovascularization [12]. The activated platelets also release adenosine diphosphate (ADP) and thromboxane A2 withsubsequent activation of the clotting cascade. Thegrowing thrombus obstructs or even blocks theblood flow in the vessel. Atherosclerotic thrombiare also the source for embolisms, which are theprimary pathophysiological mechanism of ischemicstrokes, especially from carotid artery disease or ofcardiac origin.Rupture or erosion of atheromatous plaques ! adhesionof platelets ! thrombus ! obstruction of blood flowand source of emboli.Small-vessel disease usually affects the arterioles and isassociated with hypertension. It is caused by subendothelial accumulation of a pathological protein, thehyaline, formed from mucopolysaccharides andmatrix proteins, which leads to narrowing of thelumen or even occlusion of these small vessels. Oftenit is associated with fibrosis, which affects not onlyarterioles, but also other small vessels and capillariesand venules. Lipohyalinosis also weakens the vesselwall, predisposing for the formation of “miliaryaneurysms.” Small-vessel disease results in two pathological conditions: status lacunaris (lacunar state) andstatus cribrosus (état criblé). Status lacunaris is characterized by small irregularly shaped infarcts due toocclusion of small vessels; it is the pathological substrate of lacunar strokes and vascular cognitiveimpairment and dementia. In status cribrosus smallround cavities develop around affected arteries dueto disturbed supply of oxygen and metabolic substrate. These “criblures” together with miliary aneurysms are the sites of vessel rupture causing typicalhypertonic intracerebral hemorrhages [13–16].A second type of small-vessel disease is characterizedby the progressive accumulation of congophilic, βA4immunoreactive, amyloid protein in the walls ofsmall- to medium-sized arteries and arterioles. Cerebral amyloid angiopathy is a pathological hallmarkof Alzheimer’s disease and also occurs in rare genetically transmitted diseases, e.g. CADASIL and Fabry’sdisease [17]. For a more detailed discussion of theetiology and pathophysiology of the various specificvascular disorders see [18–20].Small-vessel disease: subendothelial accumulation ofhyaline in arterioles. in this web service Cambridge University PressTypes of acute cerebrovascular diseasesNumbers relating to the frequency of the differenttypes of acute CVD are highly variable dependingon the source of data. The most reliable numberscome from the in-hospital assessment of stroke inthe Framingham study determining the frequencyof completed stroke: 60% were caused by atherothrombotic brain infarction, 25.1% by cerebralembolism, 5.4% by subarachnoid hemorrhage,8.3% by intracerebral hemorrhage, and 1.2% byundefined diseases. In addition, transient ischemicattacks (TIAs) accounted for 14.8% of the totalcerebrovascular events [21].Ischemic strokes result from a critical reduction ofregional cerebral blood flow (rCBF) lasting beyond acritical duration, and are caused by atherothromboticchanges of the arteries supplying the brain or byemboli from sources in the heart, the aorta, or thelarge arteries. The pathological substrate of ischemicstroke is ischemic infarction of brain tissue, the location, extension, and shape of which depend on thesize of the occluded vessel, the mechanism of arterialobstruction, and the compensatory capacity of thevascular bed. Occlusion of arteries supplying definedbrain territories by atherothrombosis or embolizationlead to territorial infarcts of variable size: they may belarge – e.g. the whole territory supplied by the middlecerebral artery (MCA) – or small, if branches of largearteries are occluded or if compensatory collateralperfusion – e.g. via the circle of Willis or leptomeningeal anastomoses – is efficient in reducing the area ofcritically reduced flow (Figure 1.2) [14, 16]. In asmaller number of cases infarcts can also develop atthe borderzones between vascular territories, whenseveral large arteries are stenotic and the perfusionin these “last meadows” cannot be constantly maintained above the critical threshold of morphologicalintegrity [22]. Borderzone infarctions are a subtype ofthe low-flow or hemodynamically induced infarctionswhich are the result of critically reduced cerebralperfusion pressure in far-downstream brain arteries.The more common low-flow infarctions affect subcortical structures within a vascular bed with preserved but marginal irrigation [23]. Lacunar infarctsreflect disease of the vessels penetrating the brain tosupply the capsule, the basal ganglia, thalamus, andparamedian regions of the brainstem [24]. Most oftenthey are caused by lipohyalinosis of deep arteries(small-vessel disease); less frequent causes are stenosiswww.cambridge.org3
Cambridge University Press978-1-107-04749-5 - Textbook of Stroke Medicine: Second EditionEdited by Michael Brainin, Wolf-Dieter Heiss and Susanne TabernigExcerptMore informationSection 1: Etiology, pathophysiology, and imagingFigure 1.2. Various types and sizes of infarcts due to different hemodynamic patternsa. Total territorial infarct due to defective collateral supplyb. Core infarct, meningeal anastomosis supply peripheral zonesc. Territorial infarct in center of supply area, due to branch occlusiond. Borderzone infarction in watershed areas due to stenotic lesions in arteries supplying neighboring arease. Lacunar infarctions due to small-vessel disease. (Modified with permission from Zülch [14].)of the MCA stem and microembolization to penetrantarterial territories. Pathologically these lacunes aredefined as small cystic trabeculated scars about5 mm in diameter, but they are more often observedon magnetic resonance images, where they areaccepted as lacunes up to 1.5 cm diameter. The classiclacunar syndromes include pure motor, pure sensory,and sensorimotor syndromes, sometimes ataxic hemiparesis, clumsy hand, dysarthria, and hemichorea/hemiballism, but higher cerebral functions are notinvolved. A new classification of stroke subtypes ismainly oriented on the most likely cause of stroke:atherosclerosis, small-vessel disease, cardiac source,or other cause [25].Territorial infarcts are caused by an occlusion of arteriessupplying defined brain territories by atherothrombosisor embolizations.Borderzone infarcts develop at the borderzone betweenvascular territories and are the result of a criticallyreduced cerebral perfusion pressure (low-flowinfarctions).Lacunar infarcts are mainly caused by small-vesseldisease.4Hemorrhagic infarctions, i.e. “red infarcts” in contrastto the usual “pale infarcts,” are defined as ischemic in this web service Cambridge University Pressinfarcts in which varying numbers of blood cells arefound within the necrotic tissue. The size can rangefrom a few petechial bleeds in the gray matter ofcortex and basal ganglia to large hemorrhages involving the cortical and deep hemispheric regions. Hemorrhagic transformation frequently appears duringthe second and third phase of infarct evolution, whenmacrophages appear and new blood vessels areformed in tissue consisting of neuronal ghosts andproliferating astrocytes. However, the only significantdifference between “pale” and “red infarcts” is theintensity and extension of the hemorrhagic component, since in at least two-thirds of all infarcts petechialhemorrhages are microscopically detectable. Macroscopically, red infarcts contain multifocal bleedingswhich are more or less confluent and predominatein cerebral cortex and basal ganglia, which are richerin capillaries than the white matter[26]. If the hemorrhages become confluent intrainfarct hematomasmight develop, and extensive edema may contributeto mass effects and lead to malignant infarction. Thefrequency of hemorrhagic infarctions in anatomicalstudies ranged from 18% to 42% [27], with a highincidence (up to 85% of hemorrhagic infarcts) incardioembolic stroke [28].www.cambridge.org
Cambridge University Press978-1-107-04749-5 - Textbook of Stroke Medicine: Second EditionEdited by Michael Brainin, Wolf-Dieter Heiss and Susanne TabernigExcerptMore informationChapter 1: Neuropathology and pathophysiology of strokeMechanisms for hemorrhagic transformation aremanifold and vary with regard to the intensity ofbleeding. Petechial bleeding results from diapedesisrather than vascular rupture. In severe ischemic tissuevascular permeability is increased and endothelialtight junctions are ruptured. When blood circulationis spontaneously or therapeutically restored, bloodcan leak out of these damaged vessels. This can alsohappen with fragmentation and distal migration ofan embolus (usually of cardiac origin) in the damagedvascular bed, explaining delayed clinical worseningin some cases. For the hemorrhagic transformationthe collateral circulation might also have an impact:in some instances reperfusion via pial networksmay develop with the diminution of peri-ischemicedema at borderzones of cortical infarcts. Riskof hemorrhage is significantly increased in largeinfarcts, with mass effect supporting the importanceof edema for tissue damage and the deleteriouseffect of late reperfusion when edema resolves. Insome instances also the rupture of the vascular wallsecondary to ischemia-induced endothelial necrosismight cause an intra-infarct hematoma. Vascularrupture can explain very early hemorrhagic infarctsand early intrainfarct hematoma (between 6 and18 hours after stroke), whereas hemorrhagic transformation usually develops within 48 hours to 2weeks.Hemorrhagic infarctions are defined as ischemic infarctsin which varying amounts of blood cells are foundwithin the necrotic tissue. They are caused by leakagefrom damaged vessels, due to increased vascularpermeability in ischemic tissue or vascular rupturesecondary to ischemiaIntracerebral hemorrhage (ICH) occurs as a result ofbleeding from an arterial source directly into thebrain parenchyma and accounts for 5–15% of allstrokes [29, 30]. Hypertension is the leading riskfactor, but in addition advanced age, race and alsocigarette smoking, alcohol consumption, and highserum cholesterol levels have been identified. In anumber of instances ICH occurs in the absence ofhypertension, usually in atypical locations. The causesinclude small vascular malformations, vasculitis,brain tumors, and sympathomimetic drugs (e.g.cocaine). ICH may also be caused by cerebral amyloidangiopathy and rarely damage is elicited by acutechanges in blood pressure, e.g. due to exposure tocold. The occurrence of ICH is also influencedby the increasing use of antithrombotic and in this web service Cambridge University Pressthrombolytic treatment of ischemic diseases of thebrain, heart, and other organs [31, 32].Spontaneous ICH occurs predominantly in thedeep portions of the cerebral hemispheres (“typicalICH”) [33]. Its most common location is the putamen(35–50% of cases). The subcortical white matter isthe second most frequent location (approx. 30%).Hemorrhages in the thalamus are found in 10–15%,in the pons in 5–12%, and in the cerebellum in 7%[34]. Most ICHs originate from the rupture of small,deep arteries with diameters of 50 to 200 μm whichare affected by lipohyalinosis due to chronic hypertension. These small-vessel changes lead to weakeningof the vessel wall and miliary microaneurysm andconsecutive small local bleedings, which might befollowed by secondary ruptures of the enlarginghematoma in a cascade or avalanche fashion [35].After active bleeding has started it can continuefor a number of hours with enlargement o
Chapter 1: Neuropathology and pathophysiology of stroke 3 Cambridge U nive rsit y Pre ss 978-1-107-04749-5 - Textbook of Stroke Medicine: Second Edition Edited by Michael Brainin, Wolf-Dieter Heiss and Susanne Tabernig Excerpt More information. Excerpt.
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