PATHOPHYSIOLOGY OF ACUTE ISCHEMIC STROKE OF ACUTE ISCHEMIC STROKE Tudor G. Jovin, Andrew M. Demchuk, Rishi Gupta ABSTRACT In acute ischemic stroke

  • View
    216

  • Download
    3

Embed Size (px)

Transcript

  • PATHOPHYSIOLOGYOF ACUTE ISCHEMICSTROKETudor G. Jovin, Andrew M. Demchuk, Rishi Gupta

    ABSTRACT

    In acute ischemic stroke, abrupt vessel occlusion results in a drop in regional CBF,leading to time-dependent compartmentalization of the ischemic brain into tissuethat is irreversibly damaged (ischemic core), tissue that is functionally impaired butstructurally intact and thus potentially salvageable (penumbra), and tissue that ishypoperfused but not threatened under normal circumstances (oligemic brain).At a cellular level, neuronal damage occurs through a complex interaction ofmechanisms (necrosis, apoptosis, excitotoxicity, inflammation, peri-infarct depo-larization, acidosis, and free radical formation) that are characteristic for eachcompartment. All these mechanisms are potential targets for neuroprotectivetherapy, which, combined with flow restoration strategies, is likely to improveoutcome significantly in human stroke.

    Continuum Lifelong Learning Neurol 2008;14(6):2845.

    INTRODUCTION

    Acute ischemic stroke is characterizedby abrupt neurologic dysfunction dueto focal brain ischemia resulting inpersistent neurologic deficit or accom-panied by characteristic abnormalitieson brain imaging (Albers et al, 2002).

    Until recently, stroke was definedusing clinical criteria alone, based onduration of symptoms lasting 24 hoursor longer (Ad Hoc Committee, 1975). Ifthe symptoms persisted for less than 24hours, the condition was termed tran-sient ischemic attack (TIA) However,modern neuroimaging techniques, es-pecially diffusion MRI, have shown thatdefining stroke or TIA based only onduration of symptoms may not be ac-

    curate, since permanent brain damagecan occur even when symptoms lastonly minutes (Ay et al, 1999; Engelteret al, 1999; Kidwell et al, 1999). There-fore, recently proposed definitions ofTIA take into account both the dura-tion of symptoms (typically less thanan hour) and lack of acute infarctionon brain imaging (Albers et al, 2002).Ovbiagele and colleagues (2003) esti-mated that adopting a definition ofTIA based on the above criteria wouldreduce estimates of the annual inci-dence of TIA by 33% (currently esti-mated to be 180,000 annually) andincrease annual number of strokesby 7% (currently estimated at 820,000per year).

    28

    Relationship Disclosure: Dr Jovin has received personal compensation for activities with CoAxia andConcentric Medical, Inc. Dr Jovin has received personal compensation as associate editor of Journal ofNeuroimaging. Dr Demchuk has received personal compensation for activities with AstraZeneca, BoehringerIngelheim Pharmaceuticals, Inc., and sanofi-aventis. Dr Demchuk has received grant support from NovoNordisk, Inc. Dr Gupta has received personal compensation for activities with Concentric Medical, Inc.Unlabeled Use of Products/Investigational Use Disclosure: Drs Jovin and Gupta have nothing to disclose.Dr Demchuk discusses the unlabeled use of emerging therapies with numerous references to potential therapies.

    Copyright # 2008, American Academy of Neurology. All rights reserved.

    Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

  • ETIOLOGIC ANDPATHOLOGIC ASPECTS

    It is important to recognize that ische-mic stroke results from a heteroge-neous group of disorders whose finalcommon pathway leading to clinicalmanifestations is interruption of bloodflow through vascular occlusion. Thisresults in an infarct of which the size isdependent on extent, duration, andseverity of ischemia. Brain infarctsresulting from arterial occlusion aredivided based on their macroscopicappearance into white (bland) and red(hemorrhagic) infarcts (Garcia et al,1998). By gross anatomy, the formerare composed of few or no petechiaewhile the latter are characterized bygrossly visible blood. This latter termis equivalent to hemorrhagic transfor-mation, which refers to leaking of redblood cells into a dying and ischemicbrain tissue, and should not be con-fused with parenchymal hematoma,which represents a homogenous col-lection of blood usually resulting froma ruptured blood vessel. Serial brainimaging studies in patients with acutestroke have demonstrated that hem-orrhagic transformation of an initiallybland infarct can occur in up to 80% ofpatients (Hart and Easton, 1986; Lydenand Zivin, 1993; Mayer et al, 2000). Therisk of early hemorrhagic transformationand parenchymal hematoma is greatlyincreased by administration of thrombo-lytics or anticoagulants in acute ische-mic stroke (Larrue et al, 1997).

    Gross anatomy studies reveal thatarterial infarcts evolve over severalstages (Garcia et al, 1998). In the first12 to 24 hours after the ictus, the le-sion is barely visible to the naked eye.Swelling reaches its zenith at days 3 to5; in large strokes this can become lifethreatening due to displacement andcompression of neighboring structures.Between days 5 and 10, the infarctedbrain becomes sharply demarcatedfrom the unaffected brain tissue. The

    chronic stage, occurring weeks ormonths after the ictus, features a fluid-filled cavity that results from reabsorp-tion of necrotic debris, hence the nameliquefaction necrosis.

    STROKE MECHANISMS

    Two major mechanisms are responsiblefor ischemia in acute stroke: thrombo-embolism and hemodynamic failure.The former usually occurs as a resultof embolism or in situ thrombosis andleads to an abrupt fall in regionalcerebral blood flow (CBF). The latterusually occurs with arterial occlusion orstenosis, when collateral blood supplymaintains CBF at levels that are suffi-cient for preservation of brain functionunder normal circumstances. In thesecases, cerebral ischemia may be trig-gered by conditions that decrease per-fusion proximally to the arterial lesion(systemic hypotension or low cardiacoutput) and increase metabolic de-mands (fever, acidosis) or conditionsthat lead to steal of blood from af-fected to unaffected areas in the brain(carbon dioxide retention) (Alexandrovet al, 2007). Strokes occurring throughthese mechanisms are located predom-inantly in the so-called borderzonesor watershed regions, which are areasin the brain bordering major vascularterritories such as the middle cerebralartery (MCA)/internal carotid artery orMCA/posterior cerebral artery interface(Klijn et al, 1997). Caplan and Hennerici(1998) postulated that embolism andhypoperfusion oftentimes coexist andpotentiate each other. They proposedimpaired clearance of emboli due tolow flow states as a link between thesetwo factors in the pathophysiology ofbrain infarction.

    Embolism

    Embolic material formed within theheart or vascular system travels throughthe arterial system, lodging in a vesseland partially or completely occluding it.

    29

    A Two major

    mechanisms are

    responsible for

    ischemia in

    acute stroke:

    thromboembolism

    and

    hemodynamic

    failure.

    A Embolism and

    hypoperfusion

    can coexist and

    potentiate each

    other.

    Continuum: Lifelong Learning Neurol 2008;14(6)

    KEY POINTS

    A Ischemic stroke

    results from a

    heterogeneous

    group of

    disorders whose

    final common

    pathway is

    interruption of

    blood flow

    through vascular

    occlusion.

    Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

  • The most common sources of emboliare the heart and large arteries. Otherrare sources of emboli are air, fat, cho-lesterol, bacteria, tumor cells, and par-ticulate matter from injected drugs(Caplan, 2000).

    Cardioembolism. Cardioembolismaccounts for 20% to 30% of all ischemicstroke (Grau et al, 2001; Kolominsky-Rabas et al, 2001; Petty et al, 2000;Sacco et al, 1995). Table 2-1 outlinesthe high risk versus low or uncertainrisk conditions for cardioembolic stroke(Ferro, 2003). Conditions considered athigh risk for embolization to the brainare atrial fibrillation, sustained atrialflutter, sick sinus syndrome, left atrialthrombus, left atrial appendage throm-bus, left atrial myxoma, mitral stenosis,prosthetic valve, infective endocarditis,noninfective endocarditis, left ventric-ular thrombus, left ventricular myxoma,recent anterior myocardial infarct, anddilated cardiomyopathy. Conditions con-sidered at low or uncertain risk for brainembolization include patent foramenovale, atrial septal aneurysm, sponta-neous atrial contrast, mitral annuluscalcification, mitral valve prolapse, cal-cified aortic stenosis, fibroelastoma,giant Lambl excrescences, akinetic ordyskinetic ventricular wall segment,subaortic hypertrophic cardiomyop-athy, and congestive heart failure(Marchal et al, 1999).

    Artery-to-artery embolism. Em-boli occluding brain arteries can alsooriginate from large vessels situatedmore proximally, such as the aorta,extracranial carotid, or vertebral ar-teries or intracranial arteries. In thesecircumstances, the embolic material iscomposed of clot, platelet aggregatesor plaque debris that usually breaks offfrom atherosclerotic plaques (Furlanet al, 1996). This is a major mechanismresponsible for stroke due to largevessel atherosclerosis, which accountsfor 15% to 20% of all ischemic strokes(Grau et al, 2001; Kolominsky-Rabas

    30

    Continuum: Lifelong Learning Neurol 2008;14(6)

    TABLE 2-1 High RiskVersus Low orUncertain RiskConditions forCardioembolicStroke

    " High Risk Conditions

    Atrial fibrillation

    Sustained atrial flutter

    Sick sinus syndrome

    Left atrial thrombus

    Left atrial appendagethrombus

    Left atrial myxoma

    Mitral stenosis

    Mechanical valve

    Infective endocarditis

    Noninfective endocarditis

    Left ventricular myxoma

    Recent anterior myocardialinfarct

    Dilated cardiomyopathy

    " Low or UncertainRisk Condition

    Patent foramen ovale

    Atrial septal