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CHAPTER2
CEREBRALISCHEMIAANDSTROKE
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HIEGeneralPrinciples

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HIEPathology

Test

HIEClinicalFindings

InfarctsPathology

HemorrhagicInfarct

VascularDementia

CerebralHemorrhage

ArteriovenousMalformation

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LacunarInfarct

LearningObjectives

TheWhiteMatterinHIE

CausesofIschemicInfarction

HypertensiveHemorrhage

CerebralAmyloidAngiopathy

CerebralinfarctsClinicalFindings
SmallVesselDisease

HypertensiveEncephalopathy

OtherHemorrhagicStrokes

VenousInfarct

ArterialAneurysms

Strokeinchildren

PathologyofSeizures

CEREBRALINFARCTS
Cerebralinfarctionisfocalbrainnecrosisduetocompleteandprolongedischemiathataffectsalltissueelements,
neurons,glia,andvessels.

CLINICALFINDINGS
Ischemicinfarctscausefocalneurologicaldeficits.Inembolicinfarcts,theseappearabruptly.Inatherothromboticinfarcts,theyevolve
overaperiodoftime,usuallyhours.Atherothomboticinfarctsareoftenprecededbytransientischemicattacks(TIAs).ATIAisa
focalneurologicaldeficitthatlastslessthan24hoursandresolves.ThemechanismofTIAsisuncertain.Theymaybecausedbycritical
reductionofperfusionthatimpairsneurologicalfunctionbutfallsshortofcausingpermanenttissuedamage,orbyembolithatbreak
upsoonaftertheyoccludevessels.
Thereleaseofosmoticallyactivesubstances(arachidonicacid,electrolytes,lacticacid)fromthenecroticbraintissuecausescerebral
edema.Thisisaggravatedbyvascularinjuryandleakageofproteinsintheinterstitialspace.By34days,interstitialfluid
accumulatesintheinfarctandaroundit.Thisisthemostdangerousperiodforalargecerebralinfarct.Deathfromamassive
hemisphericinfarctiscausedbycerebraledemaandherniations,notbythelossofbraintissue.Recoveryoffunction,afteran
infarct,isdueinitiallytorestorationofperfusioninthepenumbra(seebelow)andthentosettlingdownofcerebraledema.
Additionalimprovementmayoccurlaterthroughmechanismsinvolvingneuronalplasticity.
ThebasicmechanismsofcellandtissueinjurythatwerediscussedunderHIEapplyalsotoinfarcts.Oneadditionalconcept,the
ischemicpenumbra,isworthstressing.Ineveryinfarct,thereisacentralcoreoftotalischemiaandnecrosiswhichisirreversible.
Thisareaissurroundedbyazoneofborderlineischemictissue,theischemicpenumbra.Ischemia,inthepenumbra,causesdysfunction
duetoionicandmetabolicdysfunctionbutisnotsevereenoughtoresultinstructuraldamage.Promptrestorationofperfusioninthe
penumbrabyinjectionofthrombolyticagentsmaypreventstructuraldamageinthisarea,thuslimitingtheneurologicaldeficit.
Ischemicstrokeisanemergency.Thewindowofopportunityforsalvagingthepenumbraisveryshort.Ifadequatebloodsupplyisnot
restoredwithin3hours,necrosisextendstothepenumbra.

PATHOLOGYOFISCHEMICINFARCTS
Inthefirstdayorso,theinfarctappearsasapoorlydemarcatedareaofsoftening.
CTImagingatthisstagemaybenegative,
especiallyinbrainsteminfarcts.MRIismuch
moresensitive.Atthepeakofedema,the
infarctappearshypodenseandbrightonT2
MRIimages.Theinfarctedtissuebecomes
sharplydemarcatedandsoftensprogressively.
AcuteRightMCA
infarct

AcuteRACAinfarct

OldrightMCAinfarct

OldrightPCA
infarct

Fromthesecondweekonward,itbeginsto
disintegrateandisgraduallyreplacedbya
cavity.Thesizeandlocationofinfarctsfollows

theanatomyofvascularterritories.

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Microscopical
examinationin
thefirst24to48
hoursreveals
anoxicneurons,
pallorofstaining

Axonalswellings

Neovascularization

Macrophages

Gemistocyticastrocytes

andvacuolization
ofthewhite
matterdueto

unravelingofmyelin,andaxonalswellings.Duringthefirstweek,thereisatransientinflammatoryreaction,especiallyaroundblood
vesselsandinthemeninges,duetoreleaseofarachidonicandotherfattyacids.Asthecoreoftheinfarctdisintegrates,endothelial
cellsfromtheperipheryproliferate,andcapillariesgrowintothedeadtissue.Neovascularization(whichaccountsforcontrast
enhancement)peaksat2weeks.Monocytesfromthebloodstreamentertheinfarctthroughdamagedvessels.Theyingestthe
productsofdegradationofneuronsandmyelinandaretransformedintolipidladenmacrophages.Macrophagereactionappears
earlyandpeaksat34weeks.Astrocytesfromthesurroundingundamagedbrainproliferateandformaglialscararoundtheinfarct.
Thisiscompletedinapproximately2months.Afterthat,theinfarctremainsunchanged.Withmaturationofnewcapillariesandglial
scarformation,thebloodbrainbarrierisonceagainsealed.Neuronsdonotregenerate.So,somebraintissueislostforever.
Ahemorrhagicinfarctisaninfarctstippledwithpetechiaeorshowingconfluentlargerhemorrhages,
especiallyinnecroticgraymatter.Bloodleaksfromcollateralvesselsorthroughnecroticcapillarieswhenthe
occludingthrombusorembolusbreaksupandtheinfarctedareaisreperfused.Hemorrhagicinfarctsare
mostcommoninembolism.Useofthrombolyticsoranticoagulantsmayconvertablandinfarctintoa
hemorrhagicone.
Hemorrhagicinfarct

Lacunarinfarctsaresmallinfarctsinthedeeperpartsofthebrain(basalganglia,thalamus,white
matter)andinthebrainstem.Theyareresponsibleforabout20percentofallstrokes.Theyarecausedby
occlusionofdeeppenetratingbranchesofmajorcerebralarteriesandareparticularlycommonin
hypertensionanddiabetes,whichareassociatedwithsevereatherosclerosisofsmallvesselsandsmall
vesseldisease(seebelow).Asmalllacunarinfarct(e.g.,oneinvolvingtheinternalcapsule)cancauseas
severeaneurologicaldeficitascanamuchlargerhemisphericinfarctbutwithoutthelifethreatening
Lacunarinfarcts

cerebraledemathatisseeninthelatter.

CAUSESOFISCHEMICINFARCTION
Thediversetypesofvasculardiseaseandotherconditionsthatcausecerebralinfarctionarepartiallylistedinthetablebelowand
brieflydiscussedfurtheron.Clinicalclassificationsystemsforischemicstroke,suchastheTOAST(TrialofOrg10170inAcuteStroke
Treatment)andtheASCO(Atherosclerosis,Smallvesseldisease,Cardiacsource,Othercause)systemshavebeenintroduced.These
systemsarebasedonclinicalandancillaryfindings,includingnoninvasiveangiographyandtransthoracicechocardiography.
Atherothrombosis,smallvesseldisease,andcardioembolismarethemostcommoncausesofischemicstrokeinelderlypatients.
Cardioembolismandtheotherentitieslistedcancausestrokeinyoungerindividuals,andsomeofthemeveninchildren.
Atherosclerosisatherothrombosis
Smallvesseldisease
Cardioembolism,includingparadoxicalembolismthroughapatentforamenovale
Vasculitis
Arterialdissection
Polycythemia,thrombocythemia,TTP
Systemiclupuserythematosus
Sicklecelldisease
Vascularspasm
Meningitisandfungalvasculitis
Hypercoagulability(FactorVLeiden,Prothrombin20210Amutation,antiphospholipidantibodysyndrome)
Inheritedmetabolicdisorders(Fabrydisease,homocystinuria,mitochondrialdisorders)
Fibromusculardysplasiaandotherangiopathies
Alargeproportionofinfarctsarecausedbyatherosclerosisof
largearteries,aloneorwithsuperimposedthrombosis.

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AtherosclerosisinvolvesthecircleofWillisandlarge
leptomeningealarteriesandextendsintotheirsmallerbranches.
Atheromatousplaquesbeginwithbyintimalthickeningand
accumulationofbloodderivedlipidsintheintima,followedby
disruptionoftheinternaelastica,accumulationoflipidladen

Severe
atherosclerosis

Atherosclerosisand
thrombosis

Smallvesseldisease

macrophages,formationofcholesterolcrystals,anddepositionof
calcium.Theprocessoflipidaccumulationisaccompaniedbyan
inflammatoryreactioninvolvinglymphocytesandmacrophages.
Atheromatousplaquesmaycausenarrowingorocclusionofthe

vascularlumenbythemselvesorafterruptureandthrombosis.Cholesterolcrystalsfromrupturedplaquesmayembolizedistalvessels.
Smallvesseldiseaseincludesatherosclerosisofsmallarteriesbutrefersmorespecificallytolipohyalinosisandhyaline
atreriolosclerosis,vascularlesionsthatareseenprimarilyinhypertensionanddiabetesbutoccuralsoinoldagewithoutthese
predisposingconditions.Thispathologyaffectssmallpenetratingarteriesandarteriolesthatoriginatefromthebaseofthebrain
andsupplythebasalganglia,thalamus,deepwhitematter,andthebrainstem.Affectedvesselsbecomethickened,andthenormal
componentsoftheirwallsarereplacedbyahomogeneous,glassy(hyaline)substance,composedofcollagenandotherproteins.
Foamymacrophagesarepresentinlipohyalinosis.Thepathogenesisofthischangevaries:inhypertension,itiscausedby
endothelialinjuryandleakageofplasmaproteinsinandaroundvesselsindiabetes,itprobablyhastodowithglycationofproteins
anddiffusebasementmembranethickening.Itseffectsarenarrowingofthelumenandtortuosity,whichlengthensthedistance
bloodhastotraveltoperfuseitstargets.Ischemia,resultingfromtheseprocesses,causessmallinfarcts(lacunarinfarcts)and
diffuselossofaxonsandmyelininthewhitematter(leukoaraiosisthinningoutofthewhitematter).Multipleinfarctsand
leukoencephalopathycausedementia.Inaddition,lossofelasticityfromdestructionofsmoothmuscleleadstodevelopmentofsmall
aneurysmsandmakesvesselsfragile,resultinginmicrobleedsandlargecatastrophichemorrhages,whichoccurspontaneouslyor
aftertrivialtrauma.Seealsogeneticangiopathiesfurtheron.
Accordingtosomeauthors,embolismisthemostfrequentcauseofischemicinfarction.Mostemboliarefragmentsofbloodclotsthat
originateintheheartormajorvessels.Conditionscausingcardiacemboliincludemyocardialinfarcts,atrialfibrillationandother
arrhythmias,rheumaticheartdisease,bacterialandnonbacterialendocarditis,prostheticvalves,mitralvalveprolapse,atrialmyxoma,
calcifiedmitralannulus,andcardiomyopathy.Anemboluscannotbedistinguishedgrosslyormicroscopicallyfromalocallyformed
thrombus.Aninfarctisassumedtobeembolicifitishemorrhagic,thereisasourceofemboli,therearemultipleinfarctsofthebrain
andotherorgans(kidney,spleen),andthereisnoatherosclerosisorothervasculardisease.Someemboliconsistofatheromatous
materialthatisdetachedfromulceratedatheromasoftheaortaorcarotidarteries.Vascularmanipulation(angiography,carotid
endarterectomy)maycauseatheromatousembolism.Rarercausesofembolismarefat,air,andtumoremboli.Unlikeatherothrombotic
infarcts,whichmayevolvewithinhoursordays,embolicinfarctshaveanabruptonset.
Vasculitis
CNSvasculitiscanbeclassifiedunderthefollowingcategories:
A.SystemicvasculitiswithCNSinvolvement:
giantcellarteritis,polyarteritisnodosa,Wegener
granulomatosis,Takayasuarteritis,Kawasakidisease.
Themostcommonoftheseentitiesisgiantcell
(temporal)arteritis(GCA)whichismorefrequentin
olderpeopleandwomenandisassociatedwith
Temporal(giantcell)arteritis

Aspergillusarteritis

Mucorarteritisofthe
basilararteryandpontine
infarct

polymyalgiarheumatica.GCAisalsocalledtemporal
arteritisbecauseitfrequentlyinvolvesthetemporal
artery.Biopsyofthetemporalarteryisdonefor
diagnosis.However,GCAaffectstheaortaandother

majorextracranialand,lessfrequently,intracranialbranches.Involvementoftheophthalmicarterycausesvisuallossinasignificant
numberofcases.GCAisaTcellmediatedautoimmuneconditionthataffectsmediumsizeandlargearteries.Lymphocytesand
multinucleatedgiantcellsinfiltratethevesselwall,disrupttheinternalelasticlamina,andcausenarrowingandthrombosis.
B.Secondaryvasculitis:Infectious(bacterial,fungal,spirochetal,viral)collagenvasculardisease(SLE,rheumatoidarthritis,Behset
disease)druginducedvasculitis.Fungalvasculitisismostfrequentlycausedbyaspergillusandmucor.
C.PrimaryangiitisoftheCNS(PACNS).ThecriteriaforPACNSare:Thepresenceofneurologicor
psychiatricdeficits,angiographicorpathologicaldocumentationofvasculitis,andabsenceofevidenceof
systemicorsecondaryvasculitis.Pathologically,PACNScanbesubdividedintogranulomatousand
nongranulomatousvarieties.GranulomatousPACNSaffectssmallandmediumsizeleptomeningealand
corticalvesselsandcausesheadaches,seizures,focaldeficits,andencephalopathy.Affectedvesselsmay
haveamyloiddeposits,inadditiontoepithelioidcellgranulomasandgiantcells.Thereisnovasculitis

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Cerebralvasculitis

outsidetheCNS.Thenongranulomatousformshowslymphocyticinflammation.PACNSthatinvolveslarge
vesselscanbedetectedbyangiographyandMRIimagingshowingvascularstenosesandischemicstrokes.
PACNSaffectingsmallvesselspresentswithfocalordiffuseneurologicabnormalitiesandenhancing

meningealandparenchymallesionsandisnotevidentonangiography.Theclinicalpictureoverlapsencephalitis.Thediagnosisofsuch
casescanbemadebybrainbiopsy,whichshowslymphocyticinflammationinvesselwallsandaroundvessels.Thisinflammationmay
bedifficulttodistinguishfromperivascularmononuclearinfiltratesthatareseeninMSandinfectiousdiseases.
Othercausesofarterialocclusionandinfarctioninclude:
HematologicdisordersPolycythemia,hemoglobinopathies(sicklecelldisease),deficienciesofanticoagulant
factors,thromboticthrombocytopenicpurpura.
MetabolicdisordersDyslipoproteinemias,Fabrydisease,homocystinuria,organicacidemias,mitochondrial
MCAinfarctin
sicklecell
disease

disorders.Someoftheseconditionscauseischemicinfarctseveninchildrenandinfants.Mitochondrialdisorderscan
causeTIAsandischemicstrokes.
HereditaryhypercoagulabilitydisordersFactorVLeiden,Prothrombin20210A.Thesepolymorphisms

derangethedelicatebalancebetweennaturalanticoagulantandprocoagulantpathways.Theyareveryprevalentinthepopulation
andcombinewithoneanotherandwithaquiredconditionsthatpromoteclotting,causingvenousandarterialinfarcts.
Traumatotheheadandneckcancausedissectinganeurysmsandotherlesionsofthecarotid
andvertebralarteries.Thepatternofbrainnecrosisinseveretraumaticbraininjuryoftensuggests
vascularocclusion.Insomecases,arterialdissectionoccursapparentlyspontaneously,withouta
traumaticevent.
Contraceptivesandestrogentherapycausemostcommonlyvenousthrombosisandrarelyintimal
Dissectinganeurysm

hyperplasiaandthrombosisofcerebralandextracerebralarteries.

VascularSpasm.Thisisacomplicationofsubarachnoidhemorrhage.
Geneticangiopathies:Cerebralautosomaldominantarteriopathywithsubcorticalinfarctsandischemicleukoencephalopathy
(CADASIL),causedbymutationsoftheNOTCH3gene,isasmallvesselarteriopathyinwhichdepositionofagranularosmiophilic
materialinthevesselwallcauseslossofsmoothmuscle,thickeningofthewall,andnarrowingofofthelumen.Thesymptomsare
duetoinvolvementofthebrainbutthepathologyaffectsotherorgansandtissuesandcanbediagnosedwithaskinbiopsy.An
autosomaldominantangiopathyduetomutationsofCOL4A1,whichencodesacollagenofthevascularadventitia,causes
porencephalyininfantsandaspectrumofdiseaseinadultswhichincludessmallvesseldisease,lacunarinfarcts,microhemorrhages,
deepintracerebralhemorrhages,intracranialaneurysms,andleukoencephalopathy.OtherCOL4A1relateddisordersarerenaland
livercysts,andeyeabnormalities.Cerebralamyloidangiopathy,causedbydepositionofvarioustypesofamyloid,causessimilar
vascularpathologybutaffectsprimarilyleptomeningealandcorticalvessels.
Miscellaneous:Spontaneousdissectinganeurysms,moyamoyadisease(narrowingofproximalcerebralarteries).
Thefatembolismsyndrome(FES)isacomplicationoflongbonefractures,orthopedicsurgery,andtraumaticlesionsoftheviscera
andsubcutaneoustissue,includingburns.ThemostcommonnontraumaticcauseoftheFESinchildrenandyoungindividualsissickle
celldisease.OthernontraumaticsettingsofFESinclude,osteomyelitis,pancreatitis,anddiabetes.Clinically,FESischaracterizedby
petechialrash,hypoxemia,deteriorationofmentalstatus,andthrombocytopenia.Pathologically,therearepetechialhemorrhagesand
microinfarctsinthebrain,heart,andotherorgans.
Fat,mobilizedduringtraumaorosteonecrosis,entersthevenouscirculation
andembolizespulmonaryarterybranchesandcapillaries.Ifthecapacityof
pulmonarycapillariesisexceededorthelungsarebypassedthrougha
patentforamenovale,fatglobulesenterthearterialcirculationandocclude
capillariesintheheart,brain,kidneys,andotherorgans,causing
hemorrhagicandischemiclesions.Thereissomedebateaboutthe
Fatembolismsyndrome

Fatembolismsyndrome

pathogenesisoftheFES.Someattributeittomechanicalobstructionbyfat
globules.Otherviewsmaintainthatitiscausedbyagglutinationof
chylomicronsandtoxicactionoffreefattyacidsandotherfatbreakdown

products.

VENOUSINFARCTANDSINOVENOUSTHROMBOSIS
Thrombosisofvenoussinusesandtheirtributariescausescongestion,hemorrhage,andnecrosisof

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braintissue(venousinfarction).Venousinfarctsfromthrombosisofthesuperiorsagittalsinusare
parasagittal.Thecausesofvenousthrombosisarediverseandincludeoralcontraceptives,inherited
thrombophilias,cancerand,ininfants,dehydration.Sinovenousthrombosisaccountsforsomecasesof
thesyndromeofpseudotumorcerebri,whichischaracterizedbyheadache,papilledema,increased
CSFpressureandnormalsizeventricles.Thesesymptomsandsignsarecausedbyintracranial

Sinovenousthrombosis

hypertensionwhichisduetoimpairedresorptionofCSFintothevenoussinusesandvenous
congestion.Thissyndromehasmanyothercauses,includingmeningealpathology,tumors,toxicand
metabolicdisorders,andconditionsthatcausemarkedelevationofCSFprotein,suchastheGuillain

Barrsyndrome.Inmanycases,nospecificetiologyisidentified(idiopathicintracranialhypertension)

VASCULARDEMENTIA
About10%ofcasesofdementiaarecausedbycerebrovasculardisease,mostcommonlymultipleischemiclesions.Examination,in
thesecasesrevealsacombinationofsmallorlargeinfarcts,hippocampalsclerosis,leukoencephalopathyduetocerebralamyloid
angiopathyorothersmallvesseldisease,andotherlesions.Theselesionsaffectcumulativelylargeareasofthecortex,especially
regionsinvolvedinmemoryandhigherfunctions.VascularpathologymaybecombinedwithAlzheimer'sdiseaseorother
neurodegeneration.

FURTHERREADING
RingelsteinEB,NabaviDG.Cerebralsmallvesseldiseases:cerebralmicroangiopathies.CurrOpinNeurol.200518:17988.
PubMed
AdamsHPJr,BendixenBH,KappelleLJ,etal.Classificationofsubtypeofacuteischemicstroke:definitionsforuseina
multicenterclinicaltrial:TOAST:TrialofOrg10172inAcuteStrokeTreatment.Stroke199324:3541.PubMed
AmarencoP,BogousslavskyJ,CaplanLR,etal.NewapproachtoStrokeSybtyping:TheASCO(Phenotypic)Classification
ofStroke.CerebrovascDis200927:5028.PubMed
ChabriatH,JoutelA,DichgansM,etal.CADASIL.LancetNeurol20098:64353.PubMed
GuidaA,TufanoA,PernaP,etal.Thethromboembolicriskingiantcellarteritis:acriticalreviewoftheliterature.IntJ
Rheumatol.20142014:806402.PubMed

Updated:December,2014
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