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ClinicalNeurology,9e>

13:Stroke
INTRODUCTION
StrokeisthefourthleadingcauseofdeathintheUnitedStates(afterheartdisease,cancer,andchroniclung
disease)andthemostcommondisablingneurologicdisorder.Approximately800,000newstrokesoccurand
approximately130,000peoplediefromstrokeintheUnitedStateseachyear.
Theincidenceofstrokeincreaseswithage,withapproximatelytwothirdsofallstrokesoccurringinthoseolder
than65years.Ageadjustedstrokeriskissomewhathigherinmenthaninwomenandinblacks>Hispanics>
whites.Modifiableriskfactorsforstrokeincludesystolicordiastolichypertension,atrialfibrillation,diabetes,
dyslipidemia,andphysicalinactivity(Table131).Theincidenceofstrokehasdecreasedinrecentdecades,
largelybecauseofimprovedtreatmentofhypertension,dyslipidemia,anddiabetes,andreductioninsmoking.
Table131.WellDocumentedRiskFactorsforStroke.
Nonmodifiableriskfactors
Increasedage
Malesex
Lowbirthweight
AfricanAmericanethnicity
Familyhistoryofstroke
Modifiableriskfactors
Vascular
Hypertension(BP>140mmHgsystolicor90mmHgdiastolic)
Cigarettesmoking
Asymptomaticcarotidstenosis(>60%diameter)
Peripheralarterydisease
Cardiac
Atrialfibrillation(withorwithoutvalvulardisease)
Congestiveheartfailure
Coronaryarterydisease
Endocrine
Diabetesmellitus
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Postmenopausalhormonetherapy(estrogenprogesterone)
Oralcontraceptiveuse
Metabolic
Dyslipidemia
Hightotalcholesterol(top20%)
LowHDLcholesterol(<40mg/dL)
Obesity(especiallyabdominal)
Hematologic
Sicklecelldisease
Lifestyle
Physicalinactivity
BP,bloodpressureHDL,highdensitylipoprotein.
DatafromGoldsteinLB,etal.Guidelinesfortheprimarypreventionofstroke.Aguidelineforhealthcare
professionalsfromtheAmericanHeartAssociation/AmericanStrokeAssociation.Stroke.201142:517584.
Geneticfactorsalsoappeartobeimportantinstrokepathogenesis,althoughthecauseofmoststrokesislikelyto
bemultifactorialandinvolvebothpolygenicandenvironmentalinfluences.Several,mostlyrareMendelian
disordershavestrokeasamajormanifestationsomeofthese,inwhichtheaffectedgenehasbeenidentified,are
listedinTable132.
Table132.SomeMonogenicDisordersAssociatedWithStroke.
Disorder
Gene
Protein
Inheritance StrokeType
AmyloidA4precursor
Amyloidangiopathy
APP
AD
ICH
protein
Integralmembraneprotein
Amyloidangiopathy
BRI
AD
Ischemic
2B
Amyloidangiopathy
CST3
Cystatin3
AD
ICH
Solutecarrierfamily2,
Arterialtortuositysyndrome
SLC2A10
AR
Ischemic
member10
Brainsmallvesseldiseasewith
CollagentypeIV,1
COL4A1
AD
ICH
hemorrhage
chain
CADASIL
NOTCH3 Notch3
AD
Ischemic
CARASIL
HTRA1 HTRAserinepeptidase1 AR
Ischemic
KREVinteractiontrapped
Cerebralcavernousmalformations1
KRIT1
AD
ICH
1
Cerebralcavernousmalformations2
CCM2 Malcavernin
AD
ICH
PDCD10 Programmedcelldeath10 AD
ICH
Cerebralcavernousmalformations3
Ischemic(arterial
CollagentypeIII,1
EhlersDanlossyndrome,typeIV
COL3A1
AD
dissection),
chain
aneurysmalSAH
Fabrydisease
GLA
GalactosidaseA
XLR
Ischemic
HERNS

TREX1

3Primerepair
exonuclease1

AD

Ischemic
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exonuclease1
Hereditaryhemorrhagictelangiectasia,
type1(OslerWeberRendudisease)
Hereditaryhemorrhagictelangiectasia,
type2
Hereditarythrombophilia
Hereditarythrombophilia
Homocystinuria
Homocystinuria
Isovalericacidemia
Methylmalonicaciduria
Marfansyndrome
MELAS
MERRF
Moyamoyadisease5
Neurofibromatosistype1
Polycystickidneydisease
Propionicacidemia
Pseudoxanthomaelasticum
Retinalvasculopathywithcerebral
leukodystrophy
Sicklecellanemia
Transthyretinrelatedhereditary
amyloidosis
VonHippelLindausyndrome

ENG

Endoglin

AD

ActivinAreceptor,type
AD
IIlike1
PROC
ProteinC
AD
PROS1 ProteinS
AD
CBS
Cystathioninesynthase AR
Methylenetetrahydrofolate
MTHFR
AR
reductase
IsovalerylCoA
IVD
AR
dehydrogenase
MethylmalonylCoA
MUT
AR
mutase
FBN1
Fibrillin1
AD
Severalmitochondrialgenes
M
Severalmitochondrialgenes
M
Vascularsmoothmuscle
ACTA2
AD
actin
NF1
Neurofibromin
AD
PKD1
Polycystin1
AD
PropionylCoA
PCCA,
carboxylase,or
AR
PCCB
subunit
ATPbindingcassette,
ABCC6
AR
subfamilyC,member6
3Primerepair
TREX1
AD
exonuclease1
HBB
Hemoglobin
AR
ACVRL1

Ischemic
(embolic)
ICH(AVM)
Ischemic
Ischemic
Ischemic
Ischemic
ICH
ICH,Ischemic
Ischemic
Ischemic
Ischemic
Ischemic
Ischemic
AneurysmalSAH
ICH,Ischemic
Ischemic
Ischemic
Ischemic

TTR

Transthyretin

AD

Ischemic

VHL

VonHippelLindau

AD

ICH(AVM)

AD,autosomaldominantAR,autosomalrecessiveAVM,arteriovenousmalformationCADASIL,cerebral
autosomaldominantarteriopathywithsubcorticalinfarctsandleukoencephalopathyCARASIL,cerebral
autosomalrecessivearteriopathywithsubcorticalinfarctsandleukoencephalopathyHERNS,hereditary
endotheliopathywithretinopathy,nephropathyandstrokeICH,intracerebralhemorrhageM,maternal
(mitochondrial)MELAS,mitochondrialmyopathy,encephalopathy,lacticacidosis,andstrokelikeepisodes
MERRF,mitochondrialencephalopathywithraggedredfibersSAH,subarachnoidhemorrhageXLR,Xlinked
recessive.
DatafromOnlineMendelianInheritanceinMan(http://www.ncbi.nlm.nih.gov/omim),TournierLasserveE.
Newplayersinthegeneticsofstroke.NEnglJMed.2002347:17111712,andLindgrenA.Strokegenetics:a
reviewandupdate.JStroke.201416:114123.

APPROACHTODIAGNOSIS
Strokeisasyndromecharacterizedbyfourkeyfeatures:
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1.SuddenonsetThesuddenonsetofsymptomsisdocumentedbythehistory.
2.FocalinvolvementofthecentralnervoussystemThesiteofinvolvementissuggestedbythe
symptomsandsigns,delineatedmorepreciselybyneurologicexamination,andconfirmedbyimaging
studies(computedtomography[CT]ormagneticresonanceimaging[MRI]).
3.LackofrapidresolutionThedurationofneurologicdeficitsisdocumentedbythehistory.Theclassic
definitionofstrokerequiredthatdeficitspersistforatleast24hourstodistinguishstrokefromtransient
ischemicattack(discussedlater).However,anysuchtimepointisarbitrary,andtransientischemicattacks
usuallyresolvewithin1hour.Inaddition,imagingstudiescansometimesdemonstratepriorstrokeinthe
absenceofdetectableclinicaldeficits.
4.VascularcauseAvascularcausemaybeinferredfromtheacuteonsetofsymptomsandoftenfromthe
patientsage,thepresenceofriskfactorsforstroke,andtheoccurrenceofsymptomsandsignsreferable
totheterritoryofaparticularcerebralbloodvessel.Whenthisisconfirmedbyimagingstudies,further
investigationscanbeundertakentoidentifyamorespecificetiology,suchasarterialthrombosis,
cardiogenicembolus,orclottingdisorder.
ACUTEONSET
Strokesbeginabruptly.Neurologicdeficitsmaybemaximalatonsetormayprogressoversecondstohours(or
occasionallydays).
Astrokethatisactivelyprogressingasadirectconsequenceoftheunderlyingvasculardisorder(butnotbecause
ofassociatedcerebraledema)orhasdonesoinrecentminutesistermedstrokeinevolutionorprogressing
stroke(Figure131).
Figure131.

Timecourseofcerebralischemicevents.Atransientischemicattack(TIA)producesneurologicdeficitsthat
resolvecompletelywithinashortperiod,usuallywithin1hour.Strokeinevolution,orprogressingstroke,
causesdeficitsthatcontinuetoworsenevenasthepatientisseen.Completedstrokeisdefinedbythepresence
ofpersistentdeficitsitdoesnotnecessarilyimplythattheentireterritoryoftheinvolvedvesselisaffectedor
thatnoimprovementhasoccurredsincetheonset.

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Focalcerebraldeficitsthatdevelopslowly(overweekstomonths)areunlikelytobeduetostrokeandsuggest
anotherprocess,suchastumororinflammatoryordegenerativedisease.
FOCALINVOLVEMENT
Strokeproducesfocalsymptomsandsignsthatcorrelatewiththeareaofthebrainsuppliedbytheaffected
bloodvessel.
Inischemicstroke,occlusionofabloodvesselinterruptstheflowofbloodtoaspecificregionofthebrain,
interferingwithneurologicfunctionsdependentonthatregionandproducingamoreorlessstereotypedpattern
ofdeficits.
Hemorrhageproducesalesspredictablepatternoffocalinvolvementbecausecomplicationssuchasincreased
intracranialpressure,cerebraledema,compressionofbraintissueandbloodvessels,ordispersionofblood
throughthesubarachnoidspaceorcerebralventriclescanimpairbrainfunctionatsitesremotefromthe
hemorrhage.
Globalcerebralischemia(usuallyfromcardiacarrest)andsubarachnoidhemorrhage(discussedinChapter
6,Headache&FacialPain)affectthebraininmorediffusefashionandproduceglobalcerebraldysfunctionthe
termstrokeisnotusuallyappliedinthesecases.

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Inmostcasesofstroke,thehistoryandneurologicexaminationprovideenoughinformationtolocalizethe
lesiontoonesideofthebrain(eg,tothesideoppositeahemiparesisorhemisensorydeficitortotheleftsideif
aphasiaispresent)andtotheanteriororposteriorcerebralcirculation.
ANTERIOR(CAROTID)CIRCULATION

Theanteriorcerebralcirculationsuppliesmostofthecerebralcortexandsubcorticalwhitematter,basal
ganglia,andinternalcapsule.Itconsistsoftheinternalcarotidarteryanditsbranches:theanteriorchoroidal,
anteriorcerebral,andmiddlecerebralarteries.Themiddlecerebralarteryinturngivesrisetodeep,
penetratinglenticulostriatebranches(Figure132).Thespecificterritoryofeachofthesevesselsislistedin
Table133.
Figure132.

Majorcerebralarteries.Theanteriorandposteriorcerebralcirculationsariseanteriorandposteriortothe
posteriorcommunicatingarteries,respectively.ThecircleofWillisisformedbytheanteriorcommunicating,
anteriorcerebral,internalcarotid,posteriorcommunicating,andposteriorcerebralarteries.(Usedwith
permissionfromWaxmanS.ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

Table133.TerritoriesofthePrincipalCerebralArteries.
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Artery
Territory
Anteriorcirculation
Internalcarotidarterybranches
Anteriorchoroidal
Hippocampus,globuspallidus,lowerinternalcapsule
Anteriorcerebral
Medialfrontalandparietalcortexandsubjacentwhitematter,anteriorcorpuscallosum
Middlecerebral
Lateralfrontal,parietal,occipital,andtemporalcortexandsubjacentwhitematter
Lenticulostriate
Caudatenucleus,putamen,upperinternalcapsule
branches
Posteriorcirculation
Vertebralarterybranches
Posteriorinferior
Medulla,lowercerebellum
cerebellar
Basilararterybranches
Anteriorinferior
Lowerandmiddlepons,anteriorcerebellum
cerebellar
Superiorcerebellar
Upperpons,lowermidbrain,uppercerebellum
Medialoccipitalandtemporalcortexandsubjacentwhitematter,posteriorcorpus
Posteriorcerebral
callosum,uppermidbrain
Thalamoperforate
Thalamus
branches
Thalamogeniculate
Thalamus
branches
Anteriorcirculationstrokesarecommonlyassociatedwithsymptomsandsignsthatindicatehemispheric
dysfunction(Table134),suchasaphasia,apraxia,oragnosia(describedinChapter1,NeurologicHistory&
Examination).Theyalsooftenproducehemiparesis,hemisensorydisturbances,andvisualfielddefects,but
thesecanoccurwithposteriorcirculationstrokesaswell.
Table134.SymptomsandSignsofAnteriorandPosteriorCirculationIschemia.
Incidence(%)1
SymptomorSign Anterior Posterior
Headache
25
3
Alteredconsciousness 5
16
20
0
Aphasia2
Visualfielddefect
14
22
Diplopia2

Vertigo2
Dysarthria

0
3

48
11

0
Dropattacks2
Hemiormonoparesis 38
Hemisensorydeficit 33

16
12
9

1Mostpatientshavemultiplesymptomsandsigns.
2Mostusefuldistinguishingfeatures.

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ModifiedfromHutchinsonEC,AchesonEJ.Strokes:NaturalHistory,PathologyandSurgicalTreatment.
Philadelphia,PA:Saunders1975.
POSTERIOR(VERTEBROBASILAR)CIRCULATION

Theposteriorcerebralcirculationsuppliesthebrainstem,cerebellum,thalamus,andportionsoftheoccipital
andtemporallobes.Itconsistsofthepairedvertebralarteries,thebasilarartery,andtheirbranches:the
posteriorinferiorcerebellar,anteriorinferiorcerebellar,superiorcerebellar,andposteriorcerebral
arteries(seeFigure132).Theposteriorcerebralarteryalsogivesoffthalamoperforateand
thalamogeniculatebranches.AreassuppliedbythesearteriesarelistedinTable133.
Posteriorcirculationstrokesproducesymptomsandsignsofbrainstemorcerebellardysfunctionorboth(see
Table134),includingcoma,dropattacks(suddencollapsewithoutlossofconsciousness),vertigo,nausea
andvomiting,cranialnervepalsies,ataxia,andcrossedsensorimotordeficitsthataffectthefaceononeside
ofthebodyandthelimbsontheother.Hemiparesis,hemisensorydisturbances,andvisualfielddeficitsalso
occur,butarenotspecifictoposteriorcirculationstrokes.
DURATIONOFDEFICITS
Strokeproducesneurologicdeficitsthatpersist.Whensymptomsandsignsresolvecompletelyafterbriefer
periods(usuallywithin1hour)withoutevidenceofcerebralinfarction,thetermtransientischemicattack
(TIA)isused(seeFigure131).RecurrentTIAswithidenticalclinicalfeatures(stereotypicTIAs)areusually
causedbythrombosisorembolismarisingfromthesamesitewithinthecerebralcirculation.TIAsthatdifferin
characterfromeventtoeventsuggestrecurrentembolifromdistant(eg,cardiac)ormultiplesites.Although
TIAsdonotthemselvesproducelastingneurologicdysfunction,theyareimportanttorecognizebecause
approximatelyonethirdofpatientswithTIAswillgoontohaveastrokewithin5yearsandbecausethisrisk
maybereducedwithtreatment.
VASCULARORIGIN
Althoughhypoglycemia,othermetabolicdisturbances,trauma,andseizurescanproducefocalcentral
neurologicdeficitsthatbeginabruptlyandlastforatleast24hours,thetermstrokeisusedonlywhensuch
eventsarecausedbyvasculardisease.
Theunderlyingpathologicprocessinstrokecanbeeitherischemiaorhemorrhage,usuallyarisingfroman
arteriallesion.Ischemiaandhemorrhageaccountforapproximately90%and10%ofstrokes,respectively.It
maynotbepossibletodistinguishthetwobyhistoryandneurologicexamination,butCTscanorMRIpermits
definitivediagnosis.Amongischemicstrokes,about50%areattributedtocardiacembolism,25%tolarge
arteryocclusion,and10%tosmallarteryocclusion,withtheremainderofunknownorigin(cryptogenic).
BogiatziC,HackamDG,McLeodAI,SpenceJD.Seculartrendsinischemicstrokesubtypesandstrokerisk
factors.Stroke.201445:32083213.

ISCHEMIA

Interruptionofbloodflowtothebraindeprivesneurons,glia,andvascularcellsofsubstrateglucoseand
oxygen.Unlessbloodflowispromptlyrestored,thisleadstoischemicdeathofbraintissue(infarction)within
theischemiccore,whereflowistypicallylessthan20%ofnormal.Thepatternofcelldeathdependsonthe
severityofischemia.Withmildischemia,asincardiacarrestwithrapidreperfusion,selectivevulnerabilityof
certainneuronalpopulationsmaybeobserved.Moresevereischemiaproducesselectiveneuronalnecrosis,in
whichmostorallneuronsdiebutgliaandvascularcellsarepreserved.Complete,permanentischemia,suchas
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occursinstrokewithoutreperfusion,causespannecrosis,affectingallcelltypes,resultinginchroniccavitary
lesions.
Whereischemiaisincomplete(20%40%ofnormalbloodflow)asintheischemicborderzoneorpenumbra
celldamageispotentiallyreversibleandcellsurvivalmaybeprolonged.However,unlessbloodflowis
restored,byrecanalizationoftheoccludedvesselorcollateralcirculationfromothervessels,reversibly
damagedcellsbegintodieaswell,andtheinfarctexpands.Deathofpenumbraltissueisassociatedwithaworse
clinicaloutcome.
Brainedemaisanotherdeterminantofstrokeoutcome.Ischemialeadstovasogenicedemaasfluidleaksfrom
theintravascularcompartmentintobrainparenchyma.Edemaisusuallymaximalapproximately2to3days
afterstrokeandmaybesufficientlyseverethatitproducesamasseffectthatcausesherniation(displacementof
braintissuebetweenintracranialcompartments)anddeath.
Twopathogeneticmechanismscanproduceischemicstrokethrombosisandembolism.However,the
distinctionisoftendifficultorimpossibletomakeonclinicalgrounds.
Thrombosis

Thrombosisproducesstrokebyoccludinglargecerebralarteries(especiallytheinternalcarotid,middlecerebral,
orbasilar),smallpenetratingarteries(asinlacunarstroke),cerebralveins,orvenoussinuses.Symptoms
typicallyevolveoverminutestohours.ThromboticstrokesareoftenprecededbyTIAs,whichtendtoproduce
similarsymptomsbecausetheyaffectthesameterritoryrecurrently.
Embolism

Embolismproducesstrokewhencerebralarteriesareoccludedbythedistalpassageofthrombusfromtheheart,
aorticarch,orlargecerebralarteries.Emboliintheanteriorcerebralcirculationmostoftenoccludethemiddle
cerebralarteryoritsbranches,becausemosthemisphericbloodflowisthroughthisvessel.Emboliinthe
posteriorcerebralcirculationusuallylodgeattheapexofthebasilararteryorintheposteriorcerebralarteries.
Embolicstrokesoftenproduceneurologicdeficitsthataremaximalatonset.WhenTIAsprecedeembolic
strokes,especiallythosearisingfromacardiacsource,symptomstypicallyvarybetweenattacksbecause
differentvascularterritoriesareaffected.
HEMORRHAGE

Hemorrhagemayinterferewithcerebralfunctionthroughavarietyofmechanisms,includingdestructionor
compressionofbraintissue,compressionofvascularstructures,andedema.Intracranialhemorrhageis
classifiedbyitslocationasintracerebral,subarachnoid,subdural,orepidural,allofwhichexceptsubdural
hemorrhageareusuallycausedbyarterialbleeding.
IntracerebralHemorrhage

Intracerebralhemorrhagecausessymptomsbydestroyingorcompressingbraintissue.Unlikeischemicstroke,
intracerebralhemorrhagetendstocausemoresevereheadacheanddepressionofconsciousnessaswellas
neurologicdeficitsthatdonotcorrespondtothedistributionofanysinglebloodvessel.
SubarachnoidHemorrhage

Subarachnoidhemorrhageleadstocerebraldysfunctionduetoincreasedintracranialpressure,resulting
hypoperfusion,directdestructionoftissue,andtoxicconstituentsofsubarachnoidblood.Subarachnoid
hemorrhagemaybecomplicatedbyvasospasm(leadingtoischemia),rebleeding,extensionofbloodintobrain
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tissue(producinganintracerebralhematoma),orhydrocephalus.Subarachnoidhemorrhagetypicallypresents
withheadacheratherthanfocalneurologicdeficitsitisdiscussedinChapter6,Headache&FacialPain.
SubduralorEpiduralHemorrhage

Subduralorepiduralhemorrhageproducesamasslesionthatcancompresstheunderlyingbrain.These
hemorrhagesareoftentraumaticinoriginandusuallypresentwithheadacheoralteredconsciousness.Because
oftheirimportanceascausesofcoma,subduralandepiduralhemorrhagesarediscussedinChapter3,Coma.

FOCALCEREBRALISCHEMIA
PATHOPHYSIOLOGY
Thepathophysiologyoffocalcerebralischemiaiscomplex,asitinvolvesaprocessthatevolvesovertime,
affectsthebrainnonuniformly,andtargetsmultiplecelltypes.Nevertheless,severalpotentiallyimportant
underlyingmechanismshavebeenidentified.Somemechanismsarelikelytohavetheirmajorimpactearlyand
otherslaterinthecourseofstroke.Moreover,somecontributetoischemicinjury,whereasotherspromotetissue
survivalorrepair.
INJURYMECHANISMS
EnergyFailure

Neuronsrelyonoxidativemetabolismtogenerateadenosinetriphosphate(ATP)fortheirhighenergydemands.
Reductionofbloodflowinterfereswiththedeliveryoftwokeysubstratesforthisprocessoxygenandglucose
causingATPlevelstofall.CellscancompensatetoalimitedextentbygeneratingATPviaglycolysisbut,
withoutpromptreperfusion,theyceasetofunctionandeventuallydie.Likeotherischemicinjurymechanisms,
energyfailureismostpronouncedintheischemiccoreandlesssointhesurroundingpenumbra.
IonGradients

Amajoruseofcellularenergyisthemaintenanceoftransmembraneiongradients.Withenergyfailure,theseare
dissipated.Na+ /K+ ATPase,whichaccountsforthemajorityofneuronalenergyexpenditureandisresponsible
formaintaininghighintracellularK+ concentrations,failstodoso.K+ leaksfromcellsanddepolarizesadjacent
cells,activatingvoltagegatedionchannelsandneurotransmitterrelease.ExtracellularK+ andneurotransmitter
glutamatetriggercorticalspreadingdepression,leadingtofurtherneuronandastrocytedepolarization.This
consumesadditionalenergyandmayextendtheinfarct.
CalciumDysregulation

Ca2+ ismaintainedatlowrestingcytoplasmiclevels,butischemicelevationofextracellularK+ causes


membranedepolarizationandtriggersCa2+ entry.Catabolicproteases,lipases,andnucleasesareactivated,
mitochondrialfunctioniscompromised,andcelldeathpathwaysaremobilized.
Excitotoxicity

Excitotoxicityreferstotheneurotoxiceffectsofexcitatoryneurotransmitters,especiallyglutamate.Ischemia
promotesexcitotoxicitybystimulatingneuronalglutamaterelease,reversingastrocyticglutamateuptake,and

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activatingglutamatereceptorcoupledionchannels.InfluxofCa2+ throughthesechannelscontributestoCa2+
dysregulationandactivatesneuronalnitricoxidesynthase,generatingpotentiallyneurotoxicnitricoxide.
OxidativeandNitrosativeInjury

Sometoxiceffectsofischemiaaremediatedbyhighlyreactiveoxidativeandnitrosativecompoundsincluding
superoxideandnitricoxide,whichactprimarilyduringthereperfusionphasethatfollowsischemia.Their
effectsincludeinhibitingmitochondrialenzymesandfunction,damagingDNA,activatingionchannels,causing
covalentmodificationofproteins,andtriggeringcelldeathpathways.
CellDeathCascades

Ischemiccelldeathoccursmostrapidlyintheinfarctcoreandmoreslowlyinthepenumbraandduring
reperfusion.Rapidcelldeathinvolvesnecrosis,inwhichcellsandorganellesswell,membranesrupture,and
cellularcontentsspillintotheextracellularspace,whereasmoredelayed(programmed)celldeath(eg,
apoptosis)predominatesinthepenumbraandduringreperfusion.
Inflammation

Cerebralischemiatriggersaninflammatoryresponsethatinvolvesbothresidentandbloodbornecellsofthe
innateimmunesystem.Theformerincludeastrocytesandmicroglia,andthelatterneutrophils,lymphocytes,
andmonocytes.Adaptiveimmuneresponsesemergelaterinthecourse.Molecularmediatorsofischemia
inducedinflammationincludeadhesionmolecules,cytokines,chemokines,andproteases.Althoughtheearly
inflammatoryresponsetoischemiaexacerbatesinjury,subsequentinflammatoryeventsmaybeneuroprotective
orcontributetorepair.
SURVIVAL&REPAIRMECHANISMS
CollateralCirculation

Thefirstlineofdefenseagainstischemiaiscollateralcirculation,which,ifadequate,canbypassanarterial
occlusion.Thecerebralcirculationcontainsnumerouscollateralpathways,accountingfortheobservationthat
patientswithtotalocclusionofamajorvesselaresometimesasymptomatic.However,thisisnotalwaysthe
case,especiallywhenocclusionisabrupt.Examplesofcollateralroutesforcerebralbloodflowincludethe
following:
1.Bilateralvertebralarteryocclusionanteriorspinalartery
2.Commoncarotidarteryocclusioncontralateralcommoncarotidarteryviaipsilateralexternalcarotid
arteryorvertebralarteryviaipsilateraloccipitalartery
3.Internalcarotidarteryocclusionipsilateralexternalcarotidarteryviaophthalmicarteryorcircleof
Willis
4.Middlecerebralarteryocclusionipsilateralanteriororposteriorcerebralarteryvialeptomeningeal
anastomoses
InhibitoryNeurotransmitters

EnhancedtonicinhibitionmediatedthroughextrasynapticGABAAreceptorsmaymitigateexcitotoxicinjury
earlyinthecourseofstroke.However,persistentinhibitionmayimpairrecovery.
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TranscriptionalHypoxiaResponse

Hypoxiaactivatestranscriptionofproteinsthatpromotecellsurvivalandtissuerecovery,includingglycolytic
enzymes,erythropoietin,andvascularendothelialgrowthfactor.Othercytoprotectiveproteinsinducedafter
ischemiaincludeantiapoptoticproteins,growthfactors,andheatshockproteins.
Neurogenesis

Cerebralischemiastimulatesneurogenesisandsomenewneuronsmigratetoischemicbrainregions.Herethey
maypromotesurvivalandrepairbyreleasinggrowthfactors,suppressinginflammation,orothereffects.
Angiogenesis

Ischemiaalsostimulatescapillarysproutingtoenhancelocalbloodsupply.Theimpactofthisprocess
(angiogenesis)intheacutephaseofstrokeisuncertain,butitmayhelptoprotectagainstsubsequentischemic
episodes.
IschemicTolerance

Ischemiamayprovideparadoxicalprotectionagainstsubsequentischemiathroughischemictolerance,inwhich
mildischemiapreconditionsbraintissueandconfersrelativeischemiaresistance.Ischemictoleranceinvolves
extensivechangesingeneexpressionandnumerousmolecularmediators.
RepairMechanisms

Mostpatientsrecovertosomeextentafterstroke,reflectingacapacityforspontaneouspostischemicrepairand
thebrainsinnateplasticity.Plasticchangesoccurintheperiinfarctregionandatremotesites,suchasthe
contralateralcerebralhemisphere,andincludechangesingeneexpression,increasedneuronalexcitability,
axonalsprouting,synaptogenesis,somatotopicreorganization,andformationofnewneuronalcircuits.
PATHOLOGY
LARGEARTERYOCCLUSION

Ongrossinspection,arecentinfarctfromlargearteryocclusionisaswollen,softenedareaofbrainthatusually
affectsbothgrayandwhitematter.Microscopyshowsacuteischemicchangesinneurons(shrinkage,
microvacuolization,darkstaining),destructionofglialcells,necrosisofsmallbloodvessels,disruptionofnerve
axonsandmyelin,andaccumulationofinterstitialfluid.Perivascularhemorrhagesmaybeobserved.Depending
ontheintervalbetweeninfarctionanddeath,cerebraledemamayalsobepresent.Itismaximalduringthefirst4
or5daysafterstrokeandcancauseherniationofthecingulategyrusacrossthemidlineorofthetemporallobe
belowthetentorium(seeFigure34inChapter3,Coma).
SMALLARTERYOCCLUSION

Infarctsfromsmallarteryocclusionrarelycausedeath,soonlychroniclesionsareusuallyfoundatautopsy.
Theseincludelacunes,orsmallcavitiesupto~15mmindiameterusuallylocatedinsubcorticalwhite(eg,
internalcapsule)ordeepgray(eg,basalgangliaorthalamus)matterwhitematter(includingperiventricular)
lesionsshowingpunctateorconfluentmyelinrarefaction,gliosis,andaxonallossandmicrobleeds.Small
vesselocclusionmaybeassociatedwithatherosclerosis,lipohyalinosis(collagenousthickeningand
inflammationofthevesselwall),orfibrinoidnecrosis(vesselwalldestructionwithperivascularinflammation).
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CLINICALANATOMICCORRELATION
Infarctioninthedistributionofdifferentcerebralarteriesoftenproducesdistinctiveclinicalsyndromes,which
canfacilitateanatomicandetiologicdiagnosisandhelpguidetreatment.
ANTERIORCEREBRALARTERY
Anatomy

Theanteriorcerebralarterysuppliestheparasagittalcerebralcortex(Figures133and134),whichincludes
portionsofmotorandsensorycortexrelatedtothecontralateralleg,thesocalledbladderinhibitoryor
micturitioncenter,andtheanteriorcorpuscallosum.
Figure133.

Arterialsupplyoftheprimarymotorandsensorycortex(lateralview).Themiddlecerebralarterysuppliesareas
oftheprimarymotorandsensorycortexrelatedtofaceandarmfunction,whereastheanteriorcerebralartery
suppliesareasrelatedtolegfunction.Thisexplainswhymiddlecerebralarterystrokesaffectthefaceandarm
mostseverely,whereasanteriorcerebralarterystrokesaffecttheleg.(UsedwithpermissionfromWaxmanS.
ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

Figure134.

Arterialsupplyoftheprimarymotorandsensorycortex(coronalview).(UsedwithpermissionfromWaxmanS.
ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

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ClinicalSyndrome

Anteriorcerebralarterystrokesproducecontralateralparalysisandsensorylossexclusivelyorprimarily
affectingtheleg.Theremayalsobeabulia(apathy),disconnectionsyndromessuchasthealienhand
(involuntaryperformanceofcomplexmotoractivity),transcorticalexpressiveaphasia(seeTable11inChapter
1,NeurologicHistory&Examination),andurinaryincontinence.
ToyodaK.AnteriorcerebralarteryandHeubnersarteryterritoryinfarction.FrontNeurolNeurosci.
201230:120122.

MIDDLECEREBRALARTERY
Anatomy

Themiddlecerebralarterysuppliesmostoftheremainderofthecerebralhemisphereanddeepsubcortical
structures(seeFigures133and134).Corticalbranchesincludethesuperiordivision,whichsuppliesmotor
andsensoryrepresentationoftheface,hand,andarm,andtheexpressivelanguage(Broca)areaofthe
dominanthemisphere(Figure135).Theinferiordivisionsuppliesthevisualradiations,visualcortexrelatedto
macularvision,andthereceptivelanguage(Wernicke)areaofthedominanthemisphere.Lenticulostriate
branchesofthemostproximalportion(stem)ofthemiddlecerebralarterysupplythebasalgangliaandmotor
fiberstotheface,hand,arm,andlegastheydescendinthegenuandtheposteriorlimboftheinternalcapsule.
Figure135.

Anatomicbasisofmiddlecerebralarterysyndromes.Strokeinthedistributionofthemiddlecerebralartery
causeshemiparesisaffectingprimarilyfaceandarm(duetoinvolvementoftheprimarymotorarea),
hemisensorydeficitaffectingprimarilyfaceandarm(duetoinvolvementoftheprimarysensoryarea),gaze
preferencetowardtheaffectedhemisphere(duetoinvolvementofthefrontaleyefield),aphasiaifthedominant
hemisphereisaffected(duetoinvolvementofBrocaarea,Wernickearea,orboth),andhemianopia(dueto
involvementoftheopticradiationsleadingtotheprimaryvisualarea.(UsedwithpermissionfromWaxmanS.
ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)
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ClinicalSyndrome

Dependingonthesiteofinvolvement,severalclinicalsyndromescanoccur.
1.Superiordivisionstrokeresultsincontralateralhemiparesisthataffectstheface,hand,andarmbut
sparestheleg,andcontralateralhemisensorydeficitinthesamedistribution,butnohomonymous
hemianopia.Ifthedominanthemisphereisinvolved,thereisBroca(expressive)aphasia,whichis
characterizedbyimpairedlanguageexpressionwithintactcomprehension.
2.Inferiordivisionstrokeresultsincontralateralhomonymoushemianopiathatmaybedenserinferiorly,
impairedcorticalsensoryfunctions(eg,graphesthesiaandstereognosis)onthecontralateralsideofthe
body,anddisordersofspatialthought(eg,anosognosia[unawarenessofdeficit],neglectofthe
contralaterallimbsandcontralateralsideofexternalspace,dressingapraxia,andconstructionalapraxia).
Ifthedominanthemisphereisinvolved,Wernicke(receptive)aphasiaoccursandismanifestedby
impairedcomprehensionandfluentbutoftennonsensicalspeech.Withinvolvementofthenondominant
hemisphere,anacuteconfusionalstatemayoccur.
3.Occlusionatthebifurcationortrifurcationofthemiddlecerebralarterycombinesthefeaturesof
superiorandinferiordivisionstroke,includingcontralateralhemiparesisandhemisensorydeficit
involvingthefaceandarmmorethanleg,homonymoushemianopia,andifthedominanthemisphereis
affectedglobal(combinedexpressiveandreceptive)aphasia.
4.Occlusionofthestemofthemiddlecerebralarteryoccursproximaltotheoriginofthelenticulostriate
branches,resultinginaclinicalsyndromesimilartothatseenafterocclusionatthetrifurcation.In
addition,however,involvementoftheinternalcapsulecausesparalysisofthecontralateralleg,so
hemiplegiaandsensorylossaffectface,hand,arm,andleg.
GiossiA,VolonghiI,DelZottoEetal.Largemiddlecerebralarteryandpanhemisphericinfarction.Front
NeurolNeurosci.201230:154157.

INTERNALCAROTIDARTERY
Anatomy

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Theinternalcarotidarteryarisesatthebifurcationofthecommoncarotidarteryintheneck.Inadditiontothe
anteriorandmiddlecerebralarteries,italsogivesrisetotheophthalmicartery,whichsuppliestheretina.
ClinicalSyndrome

Internalcarotidarteryocclusionmaybeasymptomatic,orcausestrokesofhighlyvariableseverity,depending
ontheadequacyofcollateralcirculation.Symptomaticocclusionresultsinasyndromesimilartothatofmiddle
cerebralarterystroke(contralateralhemiplegia,hemisensorydeficit,andhomonymoushemianopia,together
withaphasiaifthedominanthemisphereisinvolved).Monocularblindnessisalsocommon.
LanariA,SilvestrelliG.Acuteandchroniccarotidocclusionsyndromes.FrontNeurolNeurosci.201230:185
190.

POSTERIORCEREBRALARTERY
Anatomy

Thepairedposteriorcerebralarteriesarisefromthetipofthebasilararteryinmostcases(Figure136)and
supplytheoccipitalcerebralcortex,medialtemporallobes,posteriorcorpuscallosum,thalamus,androstral
midbrain.Emboliinthebasilararterytendtolodgeatitsapexandoccludeoneorbothposteriorcerebral
arteriessubsequentfragmentationcanproduceasymmetricorpatchyposteriorcerebralarteryinfarction.
Figure136.

Sitesofthromboticandembolicocclusionsinthevertebrobasilarcirculation.(A)Thromboticocclusionofthe
basilarartery.(B)Thromboticocclusionofbothvertebralarteries.(C)Embolicocclusionattheapexofthe
basilarartery.(D)Embolicocclusionofbothposteriorcerebralarteries.

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ClinicalSyndrome

Posteriorcerebralarteryocclusionproduceshomonymoushemianopiaaffectingthecontralateralvisualfield,
exceptthatmacularvisionmaybespared.Incontrasttovisualfielddefectsfrominfarctioninthemiddle
cerebralarteryterritory,thosecausedbyposteriorcerebralarteryocclusionmaybedensersuperiorly.With
occlusionneartheoriginoftheposteriorcerebralarteryatthelevelofthemidbrain,ocularabnormalitiesmay
occur,includingverticalgazepalsy,oculomotor(III)nervepalsy,internuclearophthalmoplegia,andvertical
skewdeviationoftheeyes.Involvementoftheoccipitallobeofthedominanthemispheremaycauseanomic
aphasia(difficultyinnamingobjects),alexiawithoutagraphia(inabilitytoread,withnoimpairmentofwriting),
orvisualagnosia.Thelastisfailuretoidentifyobjectspresentedintheleftsideofthevisualfield,causedbya
lesionofthecorpuscallosumthatdisconnectstherightvisualcortexfromlanguageareasofthelefthemisphere.
Bilateralposteriorcerebralarteryinfarctionmayresultincorticalblindness,memoryimpairment(from
temporallobeinvolvement),orinabilitytorecognizefamiliarfaces(prosopagnosia),aswellasavarietyof
exoticvisualandbehavioralsyndromes.
CeredaC,CarreraE.Posteriorcerebralarteryterritoryinfarctions.FrontNeurolNeurosci.201230:128131.

BASILARARTERY
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Anatomy

Thebasilararteryarisesfromthejunctionofthepairedvertebralarteries(seeFigure136)andcoursesoverthe
ventralsurfaceofthebrainstemtoterminateatthelevelofthemidbrain,whereitbifurcatestoformthe
posteriorcerebralarteries.Branchesofthebasilararterysupplytheoccipitalandmedialtemporallobes,medial
thalamus,posteriorlimboftheinternalcapsule,brainstem,andcerebellum.
ClinicalSyndromes

1.ThrombosisThromboticocclusionofthebasilararteryorbothvertebralarteries(seeFigure136)is
oftenincompatiblewithsurvival.Itcausesbilateralsymptomsandsignsofbrainstemandcerebellar
dysfunctionfrominvolvementofmultiplebrancharteries(Figure137).Temporaryocclusionofoneor
bothvertebralarteriescanalsoresultfromrotatingtheheadinpatientswithcervicalspondylosis,leading
totransientbrainstemdysfunction.
Stenosisorocclusionofthesubclavianarterybeforeithasgivenrisetothevertebralarterycanleadtothe
subclavianstealsyndrome,inwhichbloodpassesfromthevertebralarteryintothedistalsubclavian
arterywithphysicalactivityoftheipsilateralarm.Thesyndromeisnotpredictiveofstrokeinthe
vertebrobasilarsystem.
Basilarthrombosisusuallyaffectstheproximalbasilarartery(seeFigure136),whichsuppliesthepons.
Involvementofthedorsalpons(tegmentum)producesunilateralorbilateralabducens(VI)nervepalsy
horizontaleyemovementsareimpaired,butverticalnystagmusandocularbobbingmaybepresent.The
pupilsareconstrictedduetoinvolvementofdescendingsympatheticpupillodilatorfibers,butmaybe
reactive.Hemiplegiaorquadriplegiaisusuallypresent,andcomaiscommon.ACTorMRIbrainscan
willdifferentiatebetweenbasilarocclusionandpontinehemorrhage.
Insomepatients,theventralpons(basispontis)isinfarctedandthetegmentumisspared.Suchpatients
remainconsciousbutquadriplegic(lockedinsyndrome).Lockedinpatientsmaybeabletoopenor
movetheireyesverticallyoncommand.Anormalconventionalelectroencephalogram(EEG)further
distinguishesthelockedinstatefromcoma(seeChapter3,Coma).
2.EmbolismEmboliinthebasilararteryusuallylodgeatitsapex(seeFigure136).Interruptionofblood
flowtotheascendingreticularformationinthemidbrainandthalamusproducesimmediatelossor
impairmentofconsciousness.Unilateralorbilateraloculomotor(III)nervepalsiesarecharacteristic.
Hemiplegiaorquadriplegiawithdecerebrateordecorticateposturingresultsfrominvolvementofthe
cerebralpedunclesinthemidbrain.Thusthetopofthebasilarsyndromemaybeconfusedwithmidbrain
damagecausedbytranstentorialuncalherniation.Lesscommonly,anembolusmaylodgemore
proximally,producingasyndromeindistinguishablefrombasilarthrombosis.
Smallerembolimayoccludetherostralbasilararterytransientlybeforefragmentingandpassingintoone
orbothposteriorcerebralarteries(seeFigure136).Insuchcases,portionsofthemidbrain,thalamus,and
temporalandoccipitallobescanbeinfarcted.Patientsmaydisplayvisual(homonymoushemianopia,
corticalblindness),visuomotor(impairedconvergence,paralysisofupwardordownwardgaze,diplopia),
andbehavioral(especiallyconfusion)abnormalitieswithoutprominentmotordysfunction.Sluggish
pupillaryresponsesareahelpfulsignofmidbraininvolvement.
Figure137.

Arterialsupplyofthebrainstem.(A)Midbrain.Thebasilararterygivesoffparamedianbranchesthatsupplythe
oculomotor(III)nervenucleusandrednucleus(RN).Alargerbranch,theposteriorcerebralartery,courses
laterallyaroundthemidbrain,givingoffabasalbranchthatsuppliesthecerebralpeduncle(CP)anda
dorsolateralbranchsupplyingthespinothalamictract(ST)andmediallemniscus(ML).Theposteriorcerebral
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arterycontinues(upperarrows)tosupplythethalamus,occipitallobe,andmedialtemporallobe.(B)Pons.
Paramedianbranchesofthebasilararterysupplytheabducens(VI)nucleusandmediallemniscus(ML).The
anteriorinferiorcerebellararterygivesoffabasalbranchtodescendingmotorpathwaysinthebasispontis(BP)
andadorsolateralbranchtothetrigeminal(V)nucleus,vestibular(VIII)nucleus,andspinothalamictract(ST),
beforepassingtothecerebellum(upperarrows).(C)Medulla.Paramedianbranchesofthevertebralarteries
supplydescendingmotorpathwaysinthepyramid(P),themediallemniscus(ML),andthehypoglossal(XII)
nucleus.Anotherbranch,theposteriorinferiorcerebellarartery,givesoffabasalbranchtotheolivarynuclei
(ON)andadorsolateralbranchthatsuppliesthetrigeminal(V)nucleus,vestibular(VIII)nucleus,and
spinothalamictract(ST),onitswaytothecerebellum(upperarrows).(UsedwithpermissionfromWaxmanS.
ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

SantaluciaP.Extendedinfarctsinthevertebrobasilarterritory.FrontNeurolNeurosci.201230:176180.

LONGCIRCUMFERENTIALVERTEBROBASILARBRANCHES
Anatomy

Thelongcircumferentialbranchesofthevertebralandbasilararteriesaretheposteriorinferiorcerebellar,
anteriorinferiorcerebellar,andsuperiorcerebellararteries(seeFigure132).Theysupplythedorsolateral
brainstem,includingdorsolateralcranialnervenuclei(V,VII,andVIII)andpathwaysenteringandleavingthe
cerebelluminthecerebellarpeduncles.
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ClinicalSyndromes

Occlusionofacircumferentialbranchproducesinfarctioninthedorsolateralmedullaorpons.
1.Posteriorinferiorcerebellararteryocclusionresultsinthelateralmedullary(Wallenberg)syndrome
(seeChapter8,DisordersofEquilibrium).Thepresentationvaries,butcanincludeipsilateralcerebellar
ataxia,Hornersyndrome,andfacialsensorydeficitcontralateralimpairedpainandtemperature
sensationandnystagmus,vertigo,nausea,vomiting,dysphagia,dysarthria,andhiccup.Themotorsystem
ischaracteristicallysparedbecauseofitsventrallocationinthebrainstem.
2.Anteriorinferiorcerebellararteryocclusionleadstoinfarctionofthelateralportionofthecaudalpons
andproducesmanyofthesamefeatures.Hornersyndrome,dysphagia,dysarthria,andhiccupdonot
occur,butipsilateralfacialweakness,gazepalsy,deafness,andtinnitusarecommon.
3.Superiorcerebellararteryocclusioncauseslateralrostralpontineinfarctionandresemblesanterior
inferiorcerebellararterylesions,butimpairedoptokineticnystagmusorskewdeviationoftheeyesmay
occur,auditoryfunctionisunaffected,andthecontralateralsensorydisturbancemayinvolvetouch,
vibration,andpositionsenseaswellaspainandtemperaturesense.
LONGPENETRATINGPARAMEDIANVERTEBROBASILARBRANCHES
Anatomy

Longpenetratingparamedianarteriessupplythemedialbrainstem,includingthemedialportionofthecerebral
peduncle,sensorypathways,rednucleus,reticularformation,andmidlinecranialnervenuclei(III,IV,VI,XII).
ClinicalSyndrome

Occlusionofalongpenetratingarterycausesparamedianinfarctionofthebrainstemandresultsincontralateral
hemiparesisifthecerebralpeduncleisaffected.Associatedcranialnerveinvolvementdependsonthelevelof
thebrainstematwhichocclusionoccurs.Occlusioninthemidbrainresultsinipsilateraloculomotor(III)nerve
palsy,whichmaybeassociatedwithcontralateraltremororataxiafrominvolvementofpathwaysconnectingthe
rednucleusandcerebellum.Ipsilateralabducens(VI)andfacial(VII)nervepalsiesareseenwithlesionsinthe
pons,andhypoglossal(XII)nerveinvolvementinthemedulla.
SHORTBASALVERTEBROBASILARBRANCHES
Anatomy

Shortbranchesarisingfromthelongcircumferentialarteries(discussedpreviously)penetratetheventral
brainstemtosupplythebrainstemmotorpathways.
ClinicalSyndrome

Themoststrikingfindingiscontralateralhemiparesiscausedbycorticospinaltractinvolvementinthecerebral
peduncleorbasispontis.Cranialnerves(eg,III,VI,VII)thatemergefromtheventralsurfaceofthebrainstem
maybeaffectedaswell,givingrisetoipsilateralcranialnervepalsies.
BalucaniC,BarlinnK.Medullaryinfarctsandhemorrhages.FrontNeurolNeurosci.201230:166170.
MoncayoJ.Midbraininfarctsandhemorrhages.FrontNeurolNeurosci.201230:158161.
MoncayoJ.Pontineinfarctsandhemorrhages.FrontNeurolNeurosci.201230:162165.
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LACUNARINFARCTION
Anatomy

Smallvesselocclusionaffectingpenetratingarteriesdeepinthebrainmaycauseinfarctsintheputamenor,less
commonly,thethalamus,caudatenucleus,pons,posteriorlimboftheinternalcapsule,orothersites(Figure13
8).Thesearereferredtoaslacunarinfarctsorlacunes.
Figure138.

Arterialsupplyofdeepcerebralstructuresinvolvedinlacunarinfarction.Thebasalganglia(caudatenucleus,
putamen,andglobuspalliduslightblue)andinternalcapsulearesuppliedbytheanteriorcirculation
(lenticulostriatebranchesofthemiddleandtheanteriorchoroidalartery).Thethalamus(darkblue)issupplied
bytheposteriorcirculation(thalamoperforateandthalamogeniculatebranchesoftheposteriorcerebralartery).
Descendingmotorfiberstotheface(F),arm(A),andleg(L)andascendingsensoryfibersfromface(f),arm
(a),andleg(l)areshownintheposteriorlimboftheinternalcapsule.(UsedwithpermissionfromWaxmanS.
ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

ClinicalSyndromes

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Manylacunarinfarctsarenotrecognizedclinicallyandaredetectedonlyasincidentalfindingsonimaging
studiesoratautopsy.Inothercases,however,theyproducedistinctiveclinicalsyndromes.Lacunarstrokes
developoverhourstodays.Headacheisabsentorminor,andthelevelofconsciousnessisunchanged.
Hypertension,diabetes,andothercardiovascularriskfactorsmayormaynotbepresent.Theprognosisfor
recoveryfromalacunarstrokeisgood,butrecurrentstrokeiscommon.Althoughavarietyofdeficitscanbe
produced,therearefourclassicanddistinctivelacunarsyndromes.
1.PuremotorhemiparesisThisconsistsofhemiparesisaffectingtheface,arm,andlegtoaroughlyequal
extent,withoutassociateddisturbanceofsensation,vision,orlanguage.Lacunesthatproducethis
syndromeareusuallylocatedinthecontralateralinternalcapsuleorpons.Puremotorhemiparesisalso
maybecausedbyinternalcarotidormiddlecerebralarteryocclusion,subduralhematoma,or
intracerebralmasslesions.
2.PuresensorystrokeThisischaracterizedbyhemisensoryloss,whichmaybeassociatedwith
paresthesia,andresultsfromlacunarinfarctioninthecontralateralthalamus.Itmaybemimickedby
occlusionoftheposteriorcerebralarteryorbyasmallhemorrhageinthethalamusormidbrain.
3.AtaxichemiparesisInthissyndrome,sometimescalledipsilateralataxiaandcrural(leg)paresis,
puremotorhemiparesisiscombinedwithataxiaofthehemipareticsideandusuallyaffectstheleg
predominantly.Symptomsresultfromalesioninthecontralateralpons,internalcapsule,orsubcortical
whitematter.
4.DysarthriaclumsyhandsyndromeThisconsistsofdysarthria,facialweakness,dysphagia,andmild
weaknessandclumsinessofthehandonthesideoffacialinvolvement.Lacunescausingthissyndrome
arelocatedinthecontralateralponsorinternalcapsule.Infarctsorsmallintracerebralhemorrhagesata
varietyoflocationscanproduceasimilarsyndrome,however.Incontrasttothelacunarsyndromes
describedearlier,premonitoryTIAsareunusual.
MicheliS,CoreaF.Lacunarversusnonlacunarsyndromes.FrontNeurolNeurosci.201230:9498.
ETIOLOGY
Focalcerebralischemiacanresultfromunderlyingdisordersthatprimarilyaffecttheblood,bloodvessels,or
heart(Table135).
Table135.ConditionsAssociatedWithFocalCerebralIschemia.
Vasculardisorders
Atherosclerosis
Otherinflammatorydisorders
Giantcellarteritis
Systemiclupuserythematosus
Polyarteritisnodosa
Primaryangiitisofthecentralnervoussystem
Syphiliticarteritis
AIDS
Noninflammatorycerebrocervicalarteriopathies
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Fibromusculardysplasia
Carotidorvertebralarterydissection
Multipleprogressiveintracranialocclusions(moyamoya)
Lacunarinfarction
Drugabuse
Migraine
Venousorsinusthrombosis
Cardiacdisorders
Atrialfibrillation
Myocardialinfarction
Mechanicalprostheticheartvalves
Dilatedcardiomyopathy
Rheumaticmitralstenosis
Infectiveendocarditis
Maranticendocarditis
Atrialmyxoma
Paradoxicalembolus
Hematologicdisorders
Thrombocytosis
Polycythemia
Sicklecelldisease
Leukocytosis
Hypercoagulablestates
VASCULARDISORDERS
Atherosclerosis

Atherosclerosisofthelargeextracranialarteriesintheneckandatthebaseofthebrainandofsmaller
intracranialarteriesisacommoncauseoffocalcerebralischemia.Withinthecerebralcirculation,thesitesof
predilection(Figure139)aretheoriginofthecommoncarotidartery,theinternalcarotidarteryjustabovethe
commoncarotidbifurcationandwithinthecavernoussinus,theoriginofthemiddlecerebralartery,the
vertebralarteryatitsoriginandjustabovewhereitenterstheskull,andthebasilarartery.
Figure139.

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Sitesofpredilection(darkredareas)foratherosclerosisintheintracranialarterialcirculation,reflecting
preferentialinvolvementofarterialbranchpointsandcurvatures.

Thepathogenesisofatherosclerosisisincompletelyunderstood,butendothelialcelldysfunctionisthoughttobe
anearlystep(Figure1310).Thistendstooccuratsitesoflowordisturbedbloodflow,suchasarterial
curvaturesandbranchpoints.Endothelialdysfunctionpromotesadhesionandsubendothelialmigrationof
circulatingmonocytesandintramuralaccumulationoflipids.Inflammationensues,andengulfmentoflipidsby
monocytederivedmacrophagesproduceslipidladenfoamcells,whichcontributetoanearlyatheromatous
lesion,thefattystreak.
Figure1310.

Arteriallesioninatherosclerosis.Endothelialinjurypermitsentryoflowdensitylipoproteincholesteroland
circulatingmononuclearcellsintothevesselwall,wheretheyformafattystreak.Thesubsequentattachmentof
plateletsandproliferationofsmoothmusclecellswithinthislesionleadstoproductionofafibrousplaque,
whichmayencroachonthearteriallumenorrupturetooccludethevesselandprovideasourceofemboli.

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Atthisstage,growthandchemotacticfactorsfromendothelialcellsandmacrophagesstimulateproliferationof
intimalsmoothmusclecellsandmigrationofadditionalsmoothmusclecellstotheintimafromthetunica
media.Thesecellssecreteextracellularmatrixconstituents,leadingtotheformationofafibrouscapoverthe
atheroscleroticplaque,inwhichanecroticcoredevelops.Insomecases,fracturesinthecapleadtoplaque
rupture,aseriouscomplicationassociatedwiththereleaseofprocoagulantfactorsandsubsequentthrombosis.
Possibleoutcomesincludethromboticocclusionofthevessellumenorembolization.
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Majorriskfactorsforatherosclerosisleadingtostrokeincludesystolicordiastolichypertension,elevatedserum
LDLcholesterol,anddiabetesmellitus.Currentrecommendationsaretoreducebloodpressureto<140mmHg
systolicand<90mmHgdiastolic(<130systolicand<80diastolicifotherriskfactorsarepresent),holdLDL
cholesterolbelow160mg/dL(lowerwithotherriskfactors),andmaintainpreandpostprandialcapillaryblood
glucoseconcentrationsat90130and<180mg/dL,respectively.Thesegoalsmaybeachievedbylifestyle
change,dietarymodification,orpharmacotherapy(eg,antihypertensives,statins,oralhypoglycemicdrugs,or
insulin).
Specifictreatmentofatheroscleroticcerebrovasculardiseaseisdiscussedlater.
GimbroneMAJr,GarcaCardeaG.Vascularendothelium,hemodynamics,andthepathobiologyof
atherosclerosis.CardiovascPathol.201322:915.
LibbyP,RidkerPM,HanssonGK.Progressandchallengesintranslatingthebiologyofatherosclerosis.
Nature.2011473:317325.

OtherInflammatoryDisorders

1.Giantcell(temporal)arteritisproducesinflammatorychangesthataffectbranchesoftheexternal
carotid,cervicalinternalcarotid,posteriorciliary,extracranialvertebral,andintracranialarteries.
Inflammatorychangesinthearterialwallstimulateplateletadhesionandaggregation,leadingto
thrombosisordistalembolism.Physicalexaminationmayshowtender,nodular,orpulselesstemporal
arteries.Laboratoryfindingsincludeanincreasederythrocytesedimentationrateandevidenceofvascular
stenosisorocclusiononangiographyorcolorduplexultrasonography.Definitivediagnosisisbytemporal
arterybiopsy.Giantcellarteritisshouldbeconsideredinpatientswithtransientmonocularblindnessor
transientcerebralischemicattacksespeciallytheelderlybecausecorticosteroidtherapycanpreventits
complications,notablypermanentblindness.TreatmentisdiscussedinChapter6,Headache&Facial
Pain.
2.Systemiclupuserythematosusisassociatedwithavasculopathythatinvolvessmallcerebralvesselsand
leadstomultiplemicroinfarctions.Inflammatorychangescharacteristicoftruevasculitisareabsent.
LibmanSacksendocarditisaccompanyingsystemiclupusmaybeasourceofcardiogenicemboli.
3.Polyarteritisnodosaisasegmentalvasculitisofsmallandmediumsizedarteriesthataffectsmultiple
organs.Transientsymptomsofcerebralischemia,includingtypicalspellsoftransientmonocular
blindness,canoccur.
4.Primaryangiitisofthecentralnervoussystem(alsoreferredtoasgranulomatousangiitis)isan
idiopathicinflammatorydiseasethataffectssmallarteriesandveinsinthecentralnervoussystemandcan
causetransientorprogressivemultifocalischemiclesions.Clinicalfeaturesincludeheadache,hemiparesis
andotherfocalneurologicabnormalities,andcognitivedisturbances.Thecerebrospinalfluid(CSF)
usuallyshowspleocytosisandelevatedprotein,butbecausesystemicvasculatureisspared,the
erythrocytesedimentationrateistypicallynormal.Thediagnosisshouldbesuspectedinpatientswith
multifocalcentralnervoussystemdysfunctionandCSFpleocytosis.Angiographydemonstratesfocaland
segmentalnarrowingofsmallarteriesandveins,andameningealbiopsyisdiagnostic.Treatmentis
discussedinChapter4,ConfusionalStates.
5.Syphiliticarteritisoccurswithin5yearsafterprimarysyphiliticinfectionandmaycausestroke.
Mediumsizedpenetratingvesselsaretypicallyinvolved(Figure1311),producingpunctateinfarctsin
thedeepcerebralwhitematterthatcanbeseenonCTscanorMRI.Treatment(discussedinChapter4)is
importanttopreventtertiaryneurosyphilis(generalparesisortabesdorsalis).
6.AIDSisassociatedwithanincreasedincidenceofTIAsandischemicstroke.Insomecases,
cerebrovascularcomplicationsofAIDSarerelatedtoendocarditisoropportunisticinfections,suchas
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toxoplasmosisorcryptococcalmeningitis.
Figure1311.

Leftcarotidangiogram(APprojection)insyphiliticarteritisshowingmarkednarrowingoftheproximalmiddle
cerebralartery(tworightarrows)andanteriorcerebralartery(leftarrow).(Usedwithpermissionfrom
LowensteinDH,MillsC,SimonRP.Acutesyphilitictransversemyelitis:unusualpresentationof
meningovascularsyphilis.GenitourinMed.198763:333338.)

BroussalisE,TrinkaE,KrausJ,McCoyM,KillerM.Treatmentstrategiesforvasculitisthataffectsthe
nervoussystem.DrugDiscovToday.201318:818835.

NonInflammatoryCerebrocervicalArteriopathies

1.Fibromusculardysplasiaproducessegmentalmedialfibroplasiaoflarge(especiallyrenal,carotid,and
vertebral)arteriesandisassociatedwitharterialdissection(seebelow)andaneurysms.Familialcases
suggestautosomaldominantinheritancewithincompletepenetrance.Strokeismostcommoninchildren
andyoungandmiddleagedadults,especiallyfemales.Acharacteristicstringofbeadsappearanceon
angiographyisdiagnosticallyhelpful.Symptomaticcarotidarterydiseaseisusuallytreatedwith
antiplateletdrugsandintraluminaldilationoftheaffectedvessel.
2.Carotidorvertebralarterydissectionmayoccurspontaneouslyorinresponsetominortrauma,andis
mostcommoninmiddleage.Itresultsfrommedialdegenerationfollowedbyhemorrhageintothevessel
wall,andcausesstrokebyoccludingthevesselorpredisposingtothromboembolism.Carotiddissection
maybeaccompaniedbyprodromaltransienthemisphericischemiaormonocularblindness,jaworneck
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pain,visualabnormalitiesthatmimicthoseseeninmigraine,orHornersyndrome.Vertebraldissection
mayproduceheadache,neckpain,andsignsofbrainstemdysfunction.Treatmentiswithantiplatelet
drugs,sometimescombinedwithendovascularrepair.
3.Multipleprogressiveintracranialarterialocclusions(moyamoya)producebilateralnarrowingor
occlusionofthedistalinternalcarotidarteriesandadjacentanteriorandmiddlecerebralarterytrunks.
Reactivearteriogenesisleadstoafinenetworkofcollateralchannelsatthebaseofthebrain,whichcanbe
seenbyangiography(Figure1312).Moyamoyamaybeidiopathic(moyamoyadisease)ordueto
atherosclerosis,sicklecelldisease,orotherarteriopathies.Itismostcommoninchildrenandmiddleaged
adults,andmorecommoninfemalesthanmales,butoccursinallethnicgroups,andmaybesporadicor
inherited.Childrentendtopresentwithischemicstrokesandadultswithintracerebral,subdural,or
subarachnoidhemorrhage.Treatmentincludesantiplateletdrugsandsurgicalrevascularization
procedures.
Figure1312.

Rightcarotidangiograminmoyamoya.Themiddlecerebralarteryanditsbranchesarereplacedbyadiffuse
capillarypatternthathasbeenlikenedtoapuffofsmoke.(A)APview.(B)Lateralview.

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SoutherlandAM,MeschiaJF,WorrallBB.Sharedassociationsofnonatherosclerotic,largevessel,
cerebrovasculararteriopathies:consideringintracranialaneurysms,cervicalarterydissection,moyamoyadisease
andfibromusculardysplasia.CurrOpinNeurol.201326:1328.

LacunarInfarction

LacunarinfarctionwasdiscussedinmoredetailearlierunderClinicalAnatomicCorrelation.
DrugAbuse

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Useofcocainehydrochloride,alkaloidal(crack)cocaine,amphetamines,otherstimulants(eg,
phenylpropanolamine,ephedrine,orecstasy),orheroinisariskfactorforstroke.Intravenoususersmaydevelop
infectiveendocarditisleadingtoembolicstroke.Strokealsooccursindruguserswithoutendocarditis,however,
includingthosewhotakedrugsonlyorally,intranasally,orbyinhalation,oftenwithinhoursofdruguse.
Cocainehydrochlorideandamphetaminesaremostoftenassociatedwithintracerebralhemorrhage,whereas
strokefromalkaloidalcocaineuseisusuallyischemic.Proposedmechanismsincludedruginducedendothelial
dysfunctionleadingtoaprothromboticstate,vasospasm,vasculitis,andruptureofpreexistinganeurysmsor
vascularmalformations.
FonsecaAC,FerroJM.Drugabuseandstroke.CurrNeurolNeurosciRep.201313:325333.

Migraine

Migrainewith(butnotwithout)auraisararecauseofischemicstroke,whichismostcommoninwomen,
patientslessthan45yearsold,smokers,andoralcontraceptiveusers.Migraineursexhibitahigherincidenceof
subclinicalwhitematterlesionsintheposteriorcirculation,patentforamenovale,andcervicalarterydissection,
buttherelationshipofthesefactorstoclinicalstrokeisuncertain.Sporadicorfamilial(autosomaldominant)
hemiplegicmigraineisassociatedwithfocalcerebraledemaduringattacksandwithcerebellaratrophy,butnot
withstroke.
MawetJ,KurthT,AyataC.Migraineandstroke:insearchofsharedmechanisms.Cephalalgia.2014inpress.

VenousorSinusThrombosis

Thromboticocclusionofacerebralveinorvenoussinus(Figure1313)isanuncommoncauseofstroke.It
affectsyoungwomenmostoftenandmaybeassociatedwithapredisposingcondition,suchasotitisorsinusitis,
postpartumstate,dehydration,orcoagulopathy.Clinicalfeaturesincludeheadache,papilledema,impaired
consciousness,seizures,andfocalneurologicdeficits.LevelsofDdimer,afibrindegradationproduct,are
usuallyincreasedintheblood.CSFpressureistypicallyincreased,andincasesofsepticthrombosis,pleocytosis
mayoccur.ACTscanmayshowedema,infarct,hemorrhage,orfillingdefectinthesuperiorsagittalsinus
(deltasign).MRIwithMRangiographyisthemostdefinitivediagnostictest.Treatmentiswithanticoagulants
and,forsepticthrombosis,antibiotics.
Figure1313.

Majorcerebralveinsandvenoussinusessubjecttothromboticocclusion.(UsedwithpermissionfromWaxman
S.ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

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AgenoW,DentaliF.Venousischemicsyndromes.FrontNeurolNeurosci.201230:191194.

CARDIACDISORDERS
AtrialFibrillation

Atrialfibrillationiscommon,withaprevalencethatincreaseswithageandreaches~5%by65yearsofage.It
wasformerlyassociatedwithrheumaticheartdisease,butisnowusuallyrelatedtoischemicorhypertensive
heartdisease.Atrialfibrillationincreasesstrokerisk2to7foldand,whenvalvularheartdiseaseisalsopresent,
about17fold.Additionalriskfactorsincludeagegreaterthan75years,hypertensionordiabetes,andheart
failure.Atrialfibrillationpredisposestoembolicstrokefromthrombithatformintheleftatrialappendagedue
tostasisofblood.Treatmentiswithoralanticoagulants(seelater).Theantiarrhythmicdrugdronedarone(400
mgorallytwicedaily)mayprovideadditionalreductioninstrokerisk.Tachycardiabradycardia(sicksinus)
syndromeisalsoassociatedwithcardioembolicstroke,whereasotherarrhythmiasaremostlikelytocause
pancerebralhypoperfusionandsyncope(seeChapter12,Seizures&Syncope).
MyocardialInfarction

Myocardialinfarctionisfollowedbystroke,usuallycardioembolic,within1monthinabout2.5%ofpatients.
Factorsassociatedwithincreasedriskincludeleftventriculardysfunctionwithlowcardiacoutput,left
ventricularthrombusoraneurysm,andatrialfibrillation.Treatmentwithaspirin,otherantiplateletdrugs,
warfarin,orcombinationsofthesemayreducetheriskofstrokeaftermyocardialinfarction,butisalso
associatedwithariskforbleeding.
ProstheticHeartValves

Patientswithprostheticheartvalvesareatincreasedriskforembolicstroke,whichvarieswiththecomposition
andlocationofthevalve.Mechanicalvalvespresentthehighestriskandrequirechronicadministrationof
warfarin,withorwithoutaspirin.Transcathetervalvesareassociatedwithfewerthromboembolic
complications,andantiplatelettreatmentwithlowdoseaspirinandclopidogrelfor6monthsisthoughttobe
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adequate.Bioprosthetic(bovineorporcine)valvesaretheleastthrombogenicandareusuallymanagedwitha
3monthcourseofwarfarinorlowdoseaspirin.Mitralvalveprosthesesaregenerallyassociatedwithahigher
riskofthromboemboliccomplicationsthanareaorticvalveprostheses.
DilatedCardiomyopathy

Dilatedcardiomyopathycanbecausedbygeneticdisorders(eg,musculardystrophies),drugs(eg,alcoholor
cytotoxicagents),viralinfection,orautoimmunity.Strokeresultsfromembolizationofintraventricularthrombi,
butadditionalfactors(eg,atrialfibrillationorvalvularheartdisease)mayhelpaccountforthisassociation.
Neitherantiplatelettherapynoranticoagulationhasbeenshowntobeofclearbenefitforpatientswithdilated
cardiomyopathyinnormalsinusrhythm.
RheumaticMitralStenosis

Strokeincidenceisincreasedinpatientswithrheumaticheartdiseaseparticularlythosewithmitralstenosis
andatrialfibrillation.Definitivediagnosisisbytransthoracicortransesophagealechocardiography.Treatment
includesanticoagulationand,forseveresymptomaticstenosis,percutaneousmitralballoonvalvuloplastyor
surgicalvalverepairorreplacement.
InfectiveEndocarditis

Infective(bacterialorfungal)endocarditiscancausecardioembolicstrokeorleadtointracerebralor
subarachnoidhemorrhagefromruptureofamycoticaneurysm.Thesecomplicationsaremostcommonbefore
orsoonaftertheonsetoftreatment.Predisposingfactorsincludeintravenousdruguse,hemodialysis,
intravenouscatheterization,valvularheartdisease,andprostheticheartvalves.Staphylococcusaureusand
viridansstreptococciinfectionaremostcommonwithnativevalvesandcommunityacquiredendocarditis,
whereasS.aureuspredominatesinintravenousdrugusers,hospitalacquiredinfections,andrecentrecipientsof
prostheticheartvalves.Fungalendocarditisisrare,isusuallycausedbyCandidaorAspergillus,andhasaworse
prognosis.
Signsofinfectiveendocarditisincludeheartmurmur,petechiae,subungualsplinterhemorrhages,retinalRoth
spots(redspotswithwhitecenters),Oslernodes(painfulredorpurpledigitalnodules),Janewaylesions(red
maculesonthepalmsorsoles),andclubbingofthefingersortoes.Diagnosisisbyculturingtheresponsible
organismfromthebloodandimagingvegetationswithechocardiography.Treatmentiswithantibioticsand,for
recurrentemboliorlargeleftsidedvalvularvegetations,valverepairorreplacementsurgery.Anticoagulation,
antiplateletagentsandthrombolyticsshouldbeavoidedbecauseoftheriskofintracranialhemorrhage.
MaranticEndocarditis

Noninfectious(marantic)endocarditisismostfrequentinpatientswithcancerandcausesthemajorityof
ischemicstrokesinthispopulation.Thetumorsmostoftenassociatedwiththistypeofstrokeare
adenocarcinomasofthelung,gastrointestinaltract,orprostate.Vegetationsarepresentonthemitraloraortic
valves,butassociatedmurmursarerare.Vegetationsmaybedetectedbytransesophagealechocardiography,but
failuretodemonstratevegetationsdoesnotexcludethediagnosis.Treatmentvaries,partlybecausemany
patientshaveapoorprognosisrelatedtotheircancer.Anticoagulationwithheparinisofuncertainbenefitbutis
oftenused.Severevalvulardysfunctionorcongestiveheartfailureandrecurrentembolizationonanticoagulants
maybeindicationsforsurgicalexcisionofvalvevegetationsorvalvereplacement.
AtrialMyxoma

Atrialmyxoma,ararebenigntumoroftheheart,cancauseembolicstroke,especiallywhenlocatedintheleft
atrium.Itusuallypresentsinyoungpatientsandismorecommoninfemales.Multiple,bihemisphericstrokes
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maybeseen.Atrialmyxomacanalsoobstructleftventricularoutflow,causingsyncope.Diagnosisisby
echocardiography.Treatmentisbysurgicalresectionofthetumorinsomeinstances,anticoagulationor
antiplateletdrugsarealsoused.
ParadoxicalEmbolus

Congenitalanomaliesassociatedwithpathologiccommunicationbetweentherightandleftsidesoftheheart,
suchaspatentforamenovaleandatrialorventricularseptaldefect,maypermitparadoxicalpassageofemboli
fromthesystemicvenouscirculationtothebrain.However,patentforamenovaleispresentin~25%ofthe
populationand,althoughcommoninyoungpatientswithstroke,acausallinktostrokehasnotbeenestablished.
Antiplatelettherapyisaseffectiveaspercutaneousclosureinpreventingrecurrentstrokeinpatientswithpatent
foramenovale.
AndradeJ,KhairyP,DobrevD,NattelS.Theclinicalprofileandpathophysiologyofatrialfibrillation:
relationshipsamongclinicalfeatures,epidemiology,andmechanisms.CircRes.2014114:14531468.
ArboixA,AlioJ.Acutecardioemboliccerebralinfarction:answerstoclinicalquestions.CurrCardiolRev.
20128:5467.
MorrisNA,MatielloM,LyonsJL,SamuelsMA.Neurologiccomplicationsininfectiveendocarditis:
identification,management,andimpactoncardiacsurgery.Neurohospitalist.20144:213222.

HEMATOLOGICDISORDERS
Thrombocytosis

Thrombocytosisoccursinmyeloproliferativedisorders(essentialthrombocytosis),otherneoplasticorinfectious
diseases,andaftersplenectomyandmaypredisposetothromboticcomplicationsincludingstroke.Riskfactors
forarterialthrombosisinessentialthrombocytosisincludeageexceeding60years,historyofthromboticevents,
cardiovascularriskfactors(eg,hypertension,diabetesorsmoking),leukocytosis,andtheJAK2V617Fmutation.
Extremelyhighplateletcountsareparadoxicallyprotectiveagainstthrombosis,probablybecauseofan
associationwithacquiredstructuralorfunctionaldefectsinvonWillebrandfactor(vonWillebrandsyndrome).
Treatmentiswithaspirin,withorwithoutcytoreduction,togetherwithmorespecifictherapyoftheunderlying
disorderwhereapplicable.
Polycythemia

Polycythemiamayoccurasamyeloproliferativedisorder(polycythemiavera)orasacomplicationofchronic
obstructivelungdiseaseorerythropoietinproducingtumors.Polycythemiawithhematocritabove45%is
associatedwithreducedcerebralbloodflowandincreasedriskofstroke.Treatmentsincludephlebotomy,
antiplateletdrugs,cytoreductionwithhydroxyurea,andJAK2inhibitors.
SickleCellDisease

Sicklecell(hemoglobinS)diseaseresultsfromaHBBGLU6VALmutationinthehemoglobinbetachaingene
andmostcommonlyaffectsthoseofWestAfricandescent.Themutationcausessickleshapeddeformationof
erythrocyteswhenthepartialpressureofoxygeninbloodisreduced,resultinginvascularstasisandendothelial
injury.Clinicalfeaturesincludehemolyticanemiaandvascularocclusions,whichmaybeextremelypainful
(sicklecellcrises).Homozygotesaremoreseverelyaffectedthanheterozygotes.
Cerebrovascularcomplicationsofsicklecelldiseaseincludeischemicstroke,whichusuallyinvolveslarge
(intracranialinternalcarotidorproximalmiddleoranteriorcerebral)arteriesand,lesscommonly,aneurysmal
subarachnoidhemorrhage.Strokeoccursinmorethan10%ofpatientswithhomozygoussicklecelldiseaseby
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age20.IncreasedcerebralbloodflowvelocityontranscranialDopplerstudiescanidentifypatientsatincreased
riskforstroke.Patientswithsicklecelldiseasewhorequireangiographyshouldfirstreceiveexchange
transfusiontoreducehemoglobinSlevelstolessthan20%,becauseradiologiccontrastmediamayinduce
sickling.
TreatmentofacutestrokeinvolvesadministrationofintravenousfluidsandreductionofhemoglobinSlevelsto
lessthan30%byexchangetransfusionneitheranticoagulantsnorthrombolyticshavebeenshowntobe
beneficial.PrimarypreventionofstrokeinpatientswithabnormaltranscranialDopplerstudiesandsecondary
preventioninpatientswithpriorstrokebothinvolvebloodtransfusionevery3to4weekstoreducehemoglobin
Slevelstolessthan30%.Hydroxyureamaybeanalternativeapproach.
Leukocytosis

Ischemicstrokecanoccurinpatientswithleukemia,buttheroleofleukocytosisitselfisunclear,and
hemorrhageismorecommoninthissetting.Evenmildleukocytosisisassociatedwithanincreasedincidenceof
thrombosisinpatientswithpolycythemiavera,butmaynotbeanindependentriskfactor.
HypercoagulableStates

Causesofhypercoagulablestatesthatmaybeassociatedwithstrokeincludeparaproteinemia(especially
macroglobulinemia),estrogentherapy,oralcontraceptives,postpartumandpostoperativestates,cancer,
antiphospholipidantibodies,homocysteinemia,andhereditarycoagulopathies(eg,proteinSdeficiency,
factorVLeydenmutationandprothrombinmutation).
CasiniA,FontanaP,LecompteTP.Thromboticcomplicationsofmyeloproliferativeneoplasms:risk
assessmentandriskguidedmanagement.JThrombHaemost.201311:12151227.
GmezPuertaJA,CerveraR.Diagnosisandclassificationoftheantiphospholipidsyndrome.JAutoimmun.
20144849:2025.
WebbJ,KwiatkowskiJL.Strokeinpatientswithsicklecelldisease.ExpertRevHematol.20136:301316.
CLINICALFINDINGS
HISTORY
PredisposingFactors

Riskfactors(seeTable131)suchasTIAs,hypertension,diabetes,dyslipidemia,ischemicorvalvularheart
disease,cardiacarrhythmia,cigarettesmoking,andoralcontraceptiveuseshouldbesought.Hematologicand
othersystemicdisorders(seeTable135)canalsoincreasetheriskofstroke.Antihypertensivedrugscan
precipitatecerebrovascularsymptomsifthebloodpressureisloweredexcessivelyinpatientswithnearlytotal
cerebrovascularocclusionandpoorcollateralcirculation.
Onset&Course

Thehistoryshouldestablishthetimeofonsetofsymptomswhethersimilarsymptomshaveoccurredbefore
andwhethertheclinicalpictureisthatofTIA,strokeinevolution,orcompletedstroke(seeFigure131).The
historymayalsosuggestathromboticorembolicetiology.
1.FeaturessuggestingthromboticstrokeThromboticstrokeoftenpresentswithstepwiseprogressionof
neurologicdeficitsandmaybeprecededbyoneormoreTIAswithidenticalsymptoms.Lacunarinfarcts
arealsocharacteristicallythrombotic.
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2.FeaturessuggestingembolicstrokeCardioembolicstrokeissuggestedbymaximaldeficitwithin5
minutesofonset,impairedconsciousnessatonset,suddenregressionofdeficit,multifocalinfarction,
Wernickeorglobalaphasiawithoutassociatedhemiparesis,topofthebasilarsyndrome,hemorrhagic
transformationofinfarct,orassociatedvalvulardisease,cardiomegaly,arrhythmia,orendocarditis.
However,noneofthesefeaturesisdefinitive.
AssociatedSymptoms

1.Headacheispresentatonsetinabout25%ofpatientswithischemicstrokeandisespeciallycommonin
intracranialarterialdissectionandvenousorsinusthrombosis.
2.Seizurescanaccompanytheonsetofstrokeorfollowstrokebyweekstoyears,butdonotdefinitively
distinguishembolicfromthromboticstroke.
PHYSICALEXAMINATION
GeneralPhysicalExamination

Thegeneralphysicalexaminationshouldfocusonsearchingforanunderlyingsystemic(especiallytreatable)
causeofcerebrovasculardisease.
1.Thebloodpressureshouldbemeasuredtodetecthypertensionamajorriskfactorforstroke.
2.Comparisonofbloodpressureandpulseonthetwosidescanrevealdifferencesrelatedto
atheroscleroticdiseaseoftheaorticarchorcoarctationoftheaorta.
3.Ophthalmoscopicexaminationoftheretinacanprovideevidenceofembolizationintheanterior
circulation,intheformofvisibleembolicmaterialinretinalbloodvessels.
4.Neckexaminationmayrevealtheabsenceofcarotidpulsesorthepresenceofcarotidbruits.However,
reducedcarotidarterypulsationintheneckisapoorindicatorofinternalcarotidarterydisease,significant
carotidstenosiscanoccurwithoutanaudiblebruit,andaloudbruitcanoccurwithoutstenosis.
5.Cardiacexaminationcandetectarrhythmias,ormurmursrelatedtovalvulardisease,whichmay
predisposetocardioembolicstroke.
6.Temporalarterypalpationisusefulinthediagnosisofgiantcellarteritis,inwhichthesevesselsmaybe
tender,nodular,orpulseless.
7.Skinexaminationmayshowsignsofacoagulationdisorder,suchasecchymosesorpetechiae.
NeurologicExamination

Patientswithcerebrovasculardisordersmayormaynothaveabnormalneurologicfindings.Anormal
examinationisexpected,forexample,afteraTIAhasresolved.Wheredeficitsarefound,thegoalistodefine
theanatomicsiteofthelesion,whichmaysuggestthecauseoroptimalmanagementofstroke.Forexample,
evidenceofanteriorcirculationinvolvementmayleadtoangiographicevaluationforpossiblesurgical
correctionofaninternalcarotidlesion,whereassignsthatsuggestvertebrobasilarorlacunarinfarctionwill
dictateadifferentcourseofaction.
1.Cognitivedeficitssuchasaphasia,unilateralneglectorconstructionalapraxiasuggestacorticallesionin
theanteriorcirculationandexcludevertebrobasilarorlacunarstroke.Comaimpliesbrainstemor
bihemisphericinvolvement.
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2.Visualfieldabnormalitiesalsoexcludelacunarinfarction,buthemianopiacanoccurwithocclusionof
eitherthemiddleorposteriorcerebralartery,whichsupplytheopticradiationandvisualcortex,
respectively.Isolatedhemianopiasuggestsposteriorcerebralarterystroke,becausemiddlecerebralartery
strokeshouldproduceadditional(motorandsomatosensory)deficits.
3.Ocularpalsy,nystagmus,orinternuclearophthalmoplegiaassignstheunderlyinglesiontothe
brainstemandthustheposteriorcerebralcirculation.
4.Hemiparesiscanbeduetolesionsincerebralcorticalregionssuppliedbytheanteriorcirculation,
descendingmotorpathwaysinthebrainstemsuppliedbythevertebrobasilarsystem,orlacunesat
subcorticalorbrainstemsites.Hemiparesisaffectingtheface,hand,andarmmorethanthelegis
characteristicofmiddlecerebralarterylesions.Hemiparesisaffectingtheface,arm,andlegtoasimilar
extentisconsistentwithlargevesselstrokeintheinternalcarotid,middlecerebralstem,orvertebrobasilar
distribution,orwithlacunarinfarction.Crossedhemiparesis,whichinvolvesthefaceononesideandthe
restofthebodyontheother,assignsthelesiontothebrainstembetweenthefacial(VII)nervenucleusin
theponsandthedecussationofthepyramidsinthemedulla.
5.Corticalsensorydeficitssuchasastereognosisoragraphesthesia,withpreservedprimarysensory
modalities,implyacorticaldeficitwithinthemiddlecerebralarteryterritory.Hemisensorydeficits
withoutassociatedmotorinvolvementareusuallylacunar.Crossedsensorydeficitsresultfromlesionsin
themedulla,asseeninthelateralmedullarysyndrome(Wallenbergsyndrome,Chapter8,Disordersof
Equilibrium).
6.Hemiataxiausuallypointstoalesionintheipsilateralbrainstemorcerebellumbutcanalsobeproduced
bylacunarstrokeintheinternalcapsule.
INVESTIGATIVESTUDIES
BLOODTESTS
SerumGlucose

Hypoglycemiaandhyperglycemiacanbothpresentwithfocalneurologicsignsandmasqueradeasstroke.
Hypoglycemiarequiresimmediateadministrationofglucosetoavoidpermanentbraininjury.Hyperglycemia
(hyperosmolarnonketotichyperglycemiaordiabeticketoacidosis)alsorequirespromptspecifictreatment.
CompleteBloodCount

Thiscanidentifypossiblecausesofstroke(eg,thrombocytosis,polycythemia,sicklecelldisease)orsuggest
concomitantinfection,whichmaycomplicateitscourse.Aplateletcountlessthan100,000/Lcontraindicates
thrombolytictherapyforstroke(seelater).
CoagulationStudies

Coagulationdefectsduetoanticoagulantdrugsorliverdysfunctionmayaffecteligibilityforthrombolytic
therapyandotheraspectsofmanagement.Theprothrombintime(PT)andinternationalizednormalratio(INR)
areusefulfordetectingtheeffectsofwarfarinandliverdisease,butothertests(eg,thrombintimeorecarin
clottingtime)mayberequiredtodetectanticoagulationbydirectthrombin(dabigatran)orfactorXa
(rivaroxaban,apixaban)inhibitors.
InflammatoryMarkers

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Anincreasederythrocytesedimentationrate(ESR)isseeningiantcellarteritisandothersystemicvasculitides.
SerologicAssayforSyphilis

Apositiveserumtreponemalassay(FTAABSorMHATP)establishes,andanegativeassayexcludes,pastor
presentsyphilisinfection.PositiveCSFserology(VDRL)indicatesuntreatedorinadequatelytreated
neurosyphilisandsuggestssyphiliticarteritisasthecauseofstroke.
CirculatingTroponinLevel

Myocardialinfarction,whichrequiresspecificmanagement,shouldbeexcludedbymeasuringtroponinasa
markerofmyocardialischemia,aswellasbyelectrocardiogram.
ELECTROCARDIOGRAM(ECG)

AnECGshouldbeobtainedroutinelytodetectunrecognizedmyocardialinfarctionorcardiacarrhythmias,such
asatrialfibrillation,whichpredisposetostroke.
LUMBARPUNCTURE

Lumbarpuncture(seeChapter2,InvestigativeStudies)shouldbeperformedonlyinselectedcases,toexclude
subarachnoidhemorrhage(manifestedbyxanthochromiaandredbloodcells)ortodocumentmeningovascular
syphilis(reactiveCSFVDRL)asthecauseofstroke.
BRAINIMAGING

ACTscanorMRI(Figure1314)shouldbeobtainedroutinely(andalwayspriortothrombolytictherapy),to
distinguishbetweeninfarctionandhemorrhageasthecauseofstroke,toexcludeotherlesions(eg,tumor,
abscess)thatcanmimicstroke,andtolocalizethelesion.NoncontrastCTisusuallypreferredforinitial
diagnosisbecauseitiswidelyavailableandrapidandcanreadilymakethecriticaldistinctionbetweenischemia
andhemorrhage.However,itssensitivitywithinthefirst6hoursislimited.MRImaybesuperiortoCTscanfor
demonstratingearlyischemicinfarcts,showingischemicstrokesinthebrainstemorcerebellum,anddetecting
thromboticocclusionofvenoussinuses.
Figure1314.

Imagingstudiesinischemicstrokeintherightmiddlecerebralarteryterritory.(A)CTscanshowinglowdensity
andeffacementofcorticalsulci(betweenarrowheads)andcompressionoftheanteriorhornofthelateral
ventricle(arrow).(B)T1weightedMRIscanshowinglossofsulcalmarkings(betweenarrowheads)and
compressionoftheanteriorhornofthelateralventricle(arrow).(C)T2weightedMRIscanshowingincreased
signalintensity(betweenarrowheads)andventricularcompression(arrow).

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DiffusionweightedMRI(DWI)andperfusionweightedMRI(PWI)areadditionalimagingtechniquesthat
maybeusefulforearlydetectionandprognosticationinstroke.DWIissuperiortoCTfordetectingstroke
duringthefirst12hoursafteronsetandmayhelppredictfinalinfarctvolumeinanteriorcirculationstroke,
althoughdiffusiondefectsaresometimesseenwithTIAs,andsmallstrokesorbrainstemstrokesmayescape
detection.ThedifferencebetweenDWIandPWIabnormalities(diffusionperfusionmismatch)mayrepresent
tissuethatisatriskofinfarctionbutpotentiallysalvageablebythrombolysis,whichequatesroughlytothe
ischemicpenumbra.
VESSELIMAGING

Imagingtechniquescanidentifyunderlyingcausesofcerebrovasculardisease(eg,carotidstenosis,vasculitis,
fibromusculardysplasia,arterialdissection,aneurysm,arteriovenousmalformation),includingoperable
extracranialcarotidlesions.
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Dopplerultrasonographycandetectoperablestenosisoftheextracranialcarotidarteryandisnoninvasive.
However,itmaynotdistinguishstenosisfromocclusionanddoesnotvisualizethesurroundingvascular
anatomy,soitisusedprimarilyforscreening.
Digitalsubtractionangiographyismoresensitiveandspecific,butcarriesasmall(<1%)riskofserious
complications,includingstroke.
Magneticresonanceangiography(MRA)isanoninvasivesubstitutefordigitalsubtractionangiographyand
candetectextracranialcarotiddiseasewithhighsensitivityandspecificity.
CTangiographyisanalternative,butinvolvesradiationexposureandmaybeobscuredbyartifactfrom
calciuminatheroscleroticplaques.
ECHOCARDIOGRAPHY

Echocardiographymaybeusefulfordemonstratingcardiaclesionsresponsibleforembolicstroke(eg,mural
thrombus,valvulardisease,oratrialmyxoma).
DIFFERENTIALDIAGNOSIS
Inpatientspresentingwithfocalcentralnervoussystemdysfunctionofsuddenonset,ischemicstrokemustbe
distinguishedfromstructuralandmetabolicprocessesthatcanmimicit.Anunderlyingprocessotherthanfocal
cerebralischemiashouldbesuspectedwhentheresultingneurologicdeficitdoesnotconformtothedistribution
ofanysinglecerebralartery,orwhenconsciousnessisimpairedintheabsenceofseverefocaldeficits.
Disorderssometimesmistakenforischemicstrokeincludeintracerebralhemorrhage,subduralorepidural
hematoma,subarachnoidhemorrhage,braintumorandbrainabscess,whichcanbeexcludedbyCTscanor
MRI.Metabolicdisturbancessuchashypoglycemiaandhyperosmolarnonketotichyperglycemiamaypresentin
strokelikefashion,buttheserumglucoselevelisdiagnostic.
PREVENTION&TREATMENT
DrugsusedinthepreventionortreatmentofcerebrovasculardiseasearelistedinTable136.Treatmentrelated
tospecificunderlyingvascular,cardiac,andhematologiccausesofstroke(eg,antiinflammatory,antibioticor
antiarrhythmicdrugs)wasaddressedearlierinthesectiononEtiology.
Table136.DrugsforTreatmentofCerebrovascularDisease.
Drug
Route
Dosage
Anticoagulants
Heparin
IV
ToaPTT=1.52.0control
Warfarin
PO
ToINR=2.50.5
Rivaroxaban
PO
20mgqd
Dabigatran
PO
110150mgbid
Apixaban
PO
5mgbid
Antiplateletagents
Aspirin
PO
81325mg/d
1
PO
25/200mgbid
Aspirin/dipyridamole
Clopidogrel
PO
75mgqd
Thrombolytics
IV
0.9mg/kgonce
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Recombinanttissueplasminogenactivator(rtPA) IA

Notestablished

IA,intraarterialIV,intravenousPO,oral.
1Extendedreleaseformulation.
PRIMARYPREVENTION
Lifestyle

Moderatetovigorousaerobicactivityfor30to40minperday,3to4timesperweek,isrecommended.Adiet
lowinsodiumandsaturatedfatsandrichinfruits,vegetables,lowfatdairyproducts,andnutsmayalsoreduce
strokerisk,asmayweightreductioninoverweightorobesepatients,cessationofsmoking,andmoderationof
heavyalcoholuse.
Statins

Treatmentwithastatinisrecommendedforpatients,withorwithoutdyslipidemia,whoareatincreased(>10%)
10yearriskforcardiovascularevents,includingstroke.Riskisassessedbasedonsex,age,race,totalandHDL
cholesterol,systolicbloodpressure,antihypertensivetherapy,diabetes,andsmokinghistory(see
http://my.americanheart.org/cvriskcalculator).Thisapproachreflectsthefindingthatstatinshavevasoprotective
(eg,antiinflammatory)actionsbesidestheirlipidloweringeffects.
BloodPressureControl

Bloodpressureshouldbereducedbylifestylemodification,antihypertensivedrugs,orbothforpatientswith
hypertension(>140mmHgsystolicor>90mmHgdiastolicpressure).
GlycemicControl

Diabetesincreasestheriskofstrokeandshouldbetreated,althoughtherelationshipbetweenintensityof
glycemiccontrolandstrokeincidenceisunclear.Inadditiontowhatevereffectglycemiccontrolmayhave,
strokeriskindiabeticscanbereducedbystatinsandantihypertensivetreatment.
AntiplateletDrugs

Lowdoseaspirin(81100mg/d)mayreducetheriskofstrokeinpatientswithincreased(>10%)10yearrisk
forsuchevents(seehttp://my.americanheart.org/cvriskcalculator).
Anticoagulation

Anticoagulationisindicatedforpatientswithcertaincardiacdisordersthatpredisposetostroke,assumingan
acceptablylowlikelihoodofhemorrhagiccomplications.TheCHA2DS2VAScscorecanbeusedtoassess
strokeriskinatrialfibrillation:itassigns2pointseachforage75yearsandhistoryoftransientischemicattack
orstroke,and1pointeachforcongestiveheartfailure,treatedoruntreatedhypertension,diabetes,peripheral
arterialdiseaseoraorticplaqueorhistoryofmyocardialinfarction,age6574years,andfemalesex.Patients
withvalvularatrialfibrillationandCHA2DS2VAScscore2shouldreceivelongtermwarfarintreatment
targetedtoaninternationalnormalizedratio(INR)of2.50.5.Eitherwarfarin,aspirin,ornotreatmentmaybe
giveniftheCHA2DS2VAScscoreis1notreatmentisindicatedforaCHA2DS2VAScscoreof0.Inpatients
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withnonvalvularatrialfibrillationandCHA2DS2VAScscore2,dabigatran,rivaroxabanorapixabancanbe
substitutedforwarfarin.Mitralstenosiswitheitherahistoryofembolismorassociatedleftatrialthrombusis
alsoanindicationforwarfarin,andcertainpatientsshouldbetreatedwithbothwarfarinandaspirinfollowing
mechanicalaorticormitralvalvereplacement.Theroleofanticoagulationinreducingstrokeriskrelatedto
othercardiacdisorderssuchasbioprostheticvalvereplacement,heartfailure,severemitralstenosis,orST
elevationmyocardialinfarctionwithmuralthrombusorapicaldyskinesisislessclear.
AsymptomaticCarotidArteryStenosis

Asymptomatic70%to99%stenosisoftheextracranialinternalcarotidarteryorcarotidbulb(butnottotal
carotidocclusion)isalsoassociatedwithanincreasedriskofstroke,andpatientswithasymptomaticstenosis
shouldbetreatedwithlowdoseaspirinandstatins.Insomecaseswith>70%stenosis,carotidendarterectomy
orcarotidarterystenting(discussedlater)maybeemployed,assumingthatasurgicalcomplicationrateof3%
orlesscanbeanticipated.
MeschiaJF,BushnellC,BodenAlbalaBetal.Guidelinesfortheprimarypreventionofstroke:astatement
forhealthcareprofessionalsfromtheAmericanHeartAssociation/AmericanStrokeAssociation.Stroke.
201445:37543832.

TRANSIENTISCHEMICATTACK&ACUTEISCHEMICSTROKE

Transientischemicattack,orTIA,isanepisodeoffocalcerebralischemiathatresolvesfullyandrapidly,
usuallywithin1hour,withoutevidenceofcerebralinfarction.Thegoaloftreatmentistopreventsubsequent
stroke,whichoccursinupto10%ofpatientsin2daysandupto20%ofpatientsin90days.IncontrasttoTIA,
acuteischemicstrokeimpliesapersistentfocalneurologicdeficit,whichmaybeimproving,stable,or
worsening(strokeinevolutionorprogressingstroke)whenthepatientisseen.
Evaluationandtreatmentarelargelythesameinbothcasesthemajordifferenceisthatthrombolytictherapyis
notusuallyconsideredforTIA,inwhichthevascularocclusionthatcausedsymptomsisthoughttohave
resolvedwiththeresolutionofsymptoms.
Investigations

AdmissiontothehospitalisrecommendedforpatientswithTIApresentingwithin72hoursoftheeventwithan
ABCD2score3,andforpatientswithacuteischemicstroke.TheABCD2scaleassigns2pointseachforfocal
weaknessoraneventlasting60minutes,and1pointeachforage60years,bloodpressure140/90mmHg,
speechimpairmentwithoutweakness,aneventlasting10to60minutes,ordiabetes.Itisintendedtoidentify
patientswithTIAwhohaveahighshorttermriskofstroke.
Patientsshouldbeevaluatedurgentlywithbloodtests(completebloodcount,prothrombinandpartial
thromboplastintime,erythrocytesedimentationrate,treponemaltestforsyphilis,glucose)andECGtoidentify
underlyingcausesormimicsofcerebrovasculardisease,andCTscanorMRIwithdiffusionweighted
imagingtodocumentstrokeandexcludeotherdisorders.
Patientswithsymptomsorimagingfindingsconsistentwithanteriorcirculationischemiawhoaregoodsurgical
candidatesshouldundergoMRangiography,CTangiography,orDopplerultrasonographytodetect
operablelesionsintheextracranialcarotidartery.
Echocardiographyshouldbeperformedifthereisapredisposingcardiacdisorderorifsymptomssuggest
cardiogenicembolus(eg,recurrentTIAswithsymptomsrelatedtodifferentterritories).
MedicalTreatment
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1.Bloodpressureshouldusuallynotbeloweredacutely,exceptforpatientswithacuteischemicstrokein
whomitishighenough(>185mmHgsystolicor>110mmHgdiastolicpressure)tomakeanotherwise
suitablecandidateineligibleforthrombolytictherapy(seelater).Whenacuteantihypertensivetherapyis
indicated,recommendeddrugsincludeintravenouslabetalolornicardipine.
2.Hyperthermia,whichmayadverselyaffectoutcome,shouldbecorrected,andanyinfectiouscause
identified.
3.Hypoxia(oxygensaturation94%)shouldbetreatedwithsupplementaloxygen.
4.Hypoglycemia(bloodglucose<60mg/dL)shouldbecorrected.
5.Anticoagulationwithheparin,givenbycontinuousintravenousinfusiontoachieveanactivatedpartial
thromboplastintime(aPTT)1.5to2.5timescontrol,followedbywarfarin,givenorallydailytoachieve
anINRof2.50.5,oranotheroralanticoagulant(seeTable136),isindicatedifacardiacembolic
source(eg,atrialfibrillation,mitralstenosis,ormechanicalvalvereplacement)appearstoberesponsible
forTIAoracuteischemicstroke.
6.Antiplatelettherapywithaspirin(325mgorallyonce,followedby81325mgorallydaily)is
recommendedforpresumednoncardiogenicTIAoracuteischemicstroke,unlessthepatientistoundergo
thrombolysis.
7.Statinsshouldbecontinuedforpatientsreceivinglongtermstatintreatment.
InterventionalTreatment

Interventionaltreatmentisanoptionforselectedpatientswithacuteischemicstroke,butisnotusedforTIA.
1.IntravenousthrombolysisIntravenousadministrationofrecombinanttissueplasminogenactivator
(rtPAoralteplase)within4.5hoursoftheonsetofsymptomsreducesdisabilityandmortalityfromacute
ischemicstroke.Thedrugisadministeredatadoseof0.9mg/kg,uptoamaximumtotaldoseof90mg
10%ofthedoseisgivenasanintravenousbolusandtheremainderasacontinuousintravenousinfusion
over60minutes.Treatmentshouldbestartedwithin60minutesofthepatientsarrivalatthehospital,
whichprovidestimefordiagnosisandevaluationofpossiblecontraindications.
Contraindicationstothrombolysisaredesignedtoavoidunnecessarilytreatingpatientswhoare
improvingspontaneouslyorunlikelytobenefit,orexacerbatingbleedingcomplications(including
intracerebralhemorrhage).Contraindicationsdesignedtoavertunnecessaryorineffectualtreatment
includethepresenceofonlyminororresolvingneurologicdeficitsonsetofsymptomsmorethan6
hourspriortoinitiatingtreatmentandhypoglycemia(bloodglucose<50mg/dL),whichcanmimic
stroke.Contraindicationsrelatedtobleedingcomplicationsincluderecenttrauma,surgery,or
hemorrhagebloodpressuregreaterthan185mmHgsystolicorgreaterthan110mmHgdiastolic
pressureandimpairedcoagulation(INR>1.7,elevatedaPTT,orplateletcount<100,000/L).
Withinthefirst24hoursafteradministrationofrtPA,anticoagulantsandantiplateletagentsshould
notbegiven,bloodpressureshouldbecarefullymonitored,andarterialpunctureandplacementof
centralvenouslines,bladdercatheters,andnasogastrictubesshouldbeavoided.
IntraarterialthrombolysisIntraarterialadministrationofrtPAmaybebeneficialinpatientswith
acuteischemicstrokewhoarenotcandidatesforintravenousthrombolysis,suchasthosetreated4.5
to6hoursaftertheonsetofsymptomsorwitharecenthistoryofmajorsurgery,andinpatientsin
whomintravenoustherapyisunsuccessful.
ClotretrievalMechanicalthrombectomywithstentorcoilretrievers(eg,SolitaireFR,Trevoor
Merci),aloneorincombinationwithrtPA,mayalsobeusefulfortreatingacuteischemicstroke,
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especiallyinpatientswhoarenotcandidatesfororwhofailintravenousthrombolytictherapy.For
example,thecombinationofintravenousrtPAandintraarterialtreatmentwitharetrievablestent
within6hoursafteronsetofsymptomscanimprovefunctionaloutcomeat3monthsinpatients
withocclusionofthedistalintracranialinternalcarotidorproximalmiddleoranteriorcerebral
artery.
SurgicalTreatment

1.Carotidendarterectomy(surgicalremovalofthrombusfromastenoticcommonorinternalcarotidartery
intheneck)isindicatedforpatientswithanteriorcirculationTIAsandhighgrade(70%99%)
extracranialinternalcarotidarterystenosisandforselectedpatientswithmoderate(50%70%)stenosis
onthesideappropriatetoaccountforthesymptoms.Thenetbenefitofendarterectomyassumesa
combinedperioperativemorbidityandmortalityoflessthan6%.
2.Carotidarterystentingisaseffectiveasendarterectomyfortreatingextracranialcarotidstenosis,
assumingasimilarperioperativemorbidityandmortalityrate.Stentingisassociatedwithanincreasedrisk
ofperiproceduralstroke,butadecreasedriskofperiproceduralmyocardialinfarction.Consideringthe
generallygreateradverseeffectofstrokethanofmyocardialinfarctiononqualityoflife,carotid
endarterectomyprobablyremainssuperioroverall,althoughstentingmaybepreferableforsome(eg,
younger)patients.
3.Posteriorfossadecompressionwithevacuationofinfarctedcerebellartissuecanbelifesavingwhen
patientsdeteriorateasaconsequenceofbrainstemcompressionaftercerebellarinfarction.
4.Decompressivecraniectomyisalsosometimesusedtopreventtranstentorialherniationanddeathin
patientsyoungerthan60yearswhodeterioratewithin48hoursafterlargehemisphericstrokes.
BerkhemerOA,FransenPSS,BeumerDetal.Arandomizedtrialofintraarterialtreatmentforacuteischemic
stroke.NEnglJMed.2015372:1120.
JauchEC,SaverJL,AdamsHPJretal.Guidelinesfortheearlymanagementofpatientswithacuteischemic
stroke:aguidelineforhealthcareprofessionalsfromtheAmericanHeartAssociation/AmericanStroke
Association.Stroke.201344:870947.
SonniS,ThalerDE.Transientischemicattack:omenandopportunity.CleveClinJMed.201380:566576.

SECONDARYPREVENTION

Secondaryprevention(ie,preventionofasubsequentcerebrovasculareventinpatientswithpriorTIAor
ischemicstroke)involvesmeasuressimilartothoseemployedinprimaryprevention,withthefollowing
exceptions.
Statins

TreatmentwithastatinisrecommendedforallpatientswithpriorTIAorischemicstroke.
AntiplateletDrugs

AllpatientswithpriornoncardioembolicTIAorischemicstrokeshouldreceiveaspirin(81325mg/d)
aspirin/dipyridamole(25/200mgtwicedaily)orclopidogrel(75mg/d)alonearealternativeoptions.Forpatients
whoseTIAorstrokeoccurredwhiletakingaspirin,itisunclearifincreasingthedoseorsubstitutinganother
antiplateletdrugconfersadditionalbenefit.Thereisnoevidencethatanticoagulationorthecombinationof
antiplatelettherapyandanticoagulationiseffectiveinthissetting.
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Anticoagulation

PatientswithpriorTIAorischemicstrokeandvalvularatrialfibrillationormechanicalaorticormitral
valvereplacementshouldbegivenlongtermwarfarintreatmenttargetedtoanINRof2.50.5.Lowdose
aspirinisaddedforpatientswithmechanicalvalveswhoareatlowriskforbleedingcomplications.
Nonvalvularatrialfibrillationshouldbetreatedwithwarfarin(INR2.50.5),apixaban,dabigatranor
rivaroxaban.Shortterm(~3months)anticoagulationwithwarfarinisindicatedforpriorTIAorischemicstroke
withacutemyocardialinfarctionorcardiomyopathywheneitheriscomplicatedbymuralthrombus.Warfarin
for3to6monthsfollowedbylongtermlowdoseaspirinisrecommendedforrecipientsofbioprosthetic
valves.Eitherantiplateletdrugsoranticoagulationwithwarfarincanbeusedinrheumaticvalvulardisease
withoutatrialfibrillation.
SurgicalTreatment

SurgicaltreatmentforsecondarypreventionofTIAorstroke(carotidendarterectomyorstenting)isas
describedearlierfortreatmentofTIAoracuteischemicstroke.
DavisSM,DonnanGA.Secondarypreventionafterischemicstrokeortransientischemicattack.NEnglJ
Med.2012366:19141922.
KernanWN,OvbiageleB,BlackHRetal.Guidelinesforthepreventionofstrokeinpatientswithstrokeand
transientischemicattack:aguidelineforhealthcareprofessionalsfromtheAmericanHeart
Association/AmericanStrokeAssociation.Stroke.201445:21602236.

REHABILITATION

Mostpatientsshowspontaneousimprovementinneurologicfunctioninthe3to6monthsafterstroke,reflecting
theadaptiveplasticityofthebrain.Recoveryofmobilityandlimbfunctioncanbeenhancedbytrainingand
practice.Effectiverehabilitativemeasuresincludefitnessandstrengthtraining,overgroundgaittraining,
constraintinducedmovementtherapy,pharmacologicmodulationofspasticity,speechandlanguagetherapy,
andperhapsnoninvasivetranscorticalmagneticordirectcurrentstimulation.Earlycommencementof
rehabilitativetherapyandhighintensityregimensarerecommended,andpatientmotivationisanimportant
factor.
DobkinBH,DorschA.Newevidencefortherapiesinstrokerehabilitation.CurrAtherosclerRep.201315:331.

COMPLICATIONS
Medicalcomplicationsarecommonafterstrokeandstronglyaffectoutcome.Theyincludeinfections(especially
aspirationpneumoniaandurinarytractinfections),cardiacarrhythmias,dysphagia,gastrointestinalbleeding,
deepveinthrombosis,pulmonaryembolism,anddepression.Insomecases,suchasarrhythmiaanddepression,
complicationsmayresultdirectlyfrombraininjury.Thesedisordersaretreatedasunderothercircumstances.
CholletF,AcketB,RaposoNetal.Useofantidepressantmedicationstoimproveoutcomesafterstroke.Curr
NeurolNeurosciRep.201313:318324.
HannawiY,HannawiB,RaoCP,SuarezJI,BershadEM.Strokeassociatedpneumonia:majoradvancesand
obstacles.CerebrovascDis.201335:430443.
PROGNOSIS

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Outcomeafterstrokeisinfluencedbyanumberoffactors,themostimportantbeingthenatureandseverityof
theresultingneurologicdeficit.Thepatientsage,thecauseofstroke,andcoexistingmedicaldisordersalso
affectprognosis.Overall,somewhatfewerthan80%ofpatientswithstrokesurviveforatleast1month,andthe
10yearsurvivalrateis~50%.Ofpatientswhosurviveacutely,roughlyonehalftotwothirdsregain
independentfunction,whereas~25%requireinstitutionalcareat6months.
HollowayRG,ArnoldRM,CreutzfeldtCJetal.Palliativeandendoflifecareinstroke:astatementfor
healthcareprofessionalsfromtheAmericanHeartAssociation/AmericanStrokeAssociation.Stroke.
201445:18871916.
LakshminarayanK,BergerAK,FullerCCetal.Trendsin10yearsurvivalofpatientswithstrokehospitalized
between1980and2000:theMinnesotastrokesurvey.Stroke.201445:25752581.

INTRACEREBRALHEMORRHAGE
HYPERTENSIVEHEMORRHAGE
EPIDEMIOLOGY

Intracerebralhemorrhagecauses~10%ofstrokes,andhypertensionisthemostcommonunderlyingcauseof
nontraumaticintracerebralhemorrhage.Theincidenceislowerinwhitesthaninothergroups,whichrelatesto
ratesofhypertension.
PATHOPHYSIOLOGY
CerebralAutoregulation

Autoregulation(Figure1315)bychangesinthecaliberofsmallresistancecerebralarteriesmaintainsconstant
cerebralbloodflowassystemicbloodpressurerisesandfalls.Therangeofautoregulatedbloodpressuresis
variablebutnormallywide.
Figure1315.

Cerebrovascularautoregulation.(A)Cerebralbloodflowisnormallyheldconstantoverawiderangeofblood
pressures.Atverylowpressures,cerebralhypoperfusionoccurs,producingsyncope.Pressuresabovethe
autoregulatoryrangecancausehypertensiveencephalopathy.(B)Chronichypertensionshiftstheautoregulatory
rangetohigherbloodpressures.Hypoperfusionandsyncopecanoccuratnormalpressures,andpressures
associatedwithhypertensiveencephalopathyarehigher.

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Innormotensiveindividuals,autoregulationiseffectiveatmeanarterialbloodpressuresabove~60mmHg.
Belowthislevel,cerebralbloodflowdeclines,causinglightheadedness,confusion,anddimmingofvision.At
meanbloodpressureslessthan~35to40mmHg,somnolenceandlossofconsciousnessoccur.Conversely,
above~150to200mmHg,cerebralbloodflowincreases,whichcanleadtohypertensiveencephalopathy(see
Chapter4,ConfusionalStates).
Inchronicallyhypertensiveindividuals,thelowerlimitoftheautoregulatoryrangerises,socerebralbloodflow
declinesatmeanarterialbloodpressureslessthan~120mmHg.Thus,elevatedbloodpressureisrequiredto
maintainnormalcerebralperfusion.
ChronicHypertension

Chronichypertensionpromoteschangesinthewallsofpenetratingsmallcerebralarteriesandarterioles.These
consistoflipohyalinosis(collagenousthickeningandinflammationofthevesselwall)andfibrinoidnecrosis
(vesselwalldestructionwithperivascularinflammation),whichareassociatedwithischemicstrokeandmay
alsoleadtothedevelopmentofmiliary(CharcotBouchard)aneurysms(Figure1316),whichpredisposeto
hemorrhage.
Figure1316.

DistributionofCharcotBouchardaneurysms(stippling)underlyinghypertensiveintracerebralhemorrhage.
Areasinvolvedincludesubcorticalwhitematter,basalganglia,thalamus,pons,andcerebellum.

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AcuteHypertension

Theroleofacuteelevationofbloodpressureinintracerebralhemorrhageisuncertain.Mostpatientsare
hypertensiveafterintracerebralhemorrhage,butthismaybeduetoacombinationofbaselinechronic
hypertensionandthevasopressorresponsetoincreasedintracranialpressure(Cushingreflex).Thatsome
patientswithintracerebralhemorrhagehavenohistoryofhypertensionandlacksignsofhypertensiveendorgan
diseasesuggeststhatacutehypertensionmightbeatfault,asdoestheoccurrenceofintracerebralhemorrhagein
youngpatientsafteramphetamineorcocaineabuse.
HematomaEffects

Hypertensivehemorrhagecausesbothdestructionandcompressionofbraintissue.Inaddition,breakdown
productsofextravasatedbloodmaycauseinflammationandsecondaryinjury.Perihematomaedemacorrelates
withhematomasize,whichpredictsapooroutcome.Increasedintracranialpressureresultsintamponadeofthe
rupturedvessel,butcanalsoleadtobrainherniationanddeath.
PATHOLOGY

Mosthypertensivehemorrhagesoriginatefromlong,narrowpenetratingarterialbranchesalongwhich
lipohyalinosis,fibrinoidnecrosis,andCharcotBouchardaneurysmsarefoundatautopsy.Theseincludethe
caudateandputaminalbranchesofthemiddlecerebralarteries,branchesofthebasilararterysupplyingthe
pons,thalamicbranchesoftheposteriorcerebralarteries,branchesofthesuperiorcerebellararteriessupplying
thedentatenucleiandthedeepwhitematterofthecerebellum,andsomewhitematterbranchesofthecerebral
arteries,especiallyintheparietooccipitalandtemporallobes.Intheacutephaseafterintracerebralhemorrhage,
thereisedemasurroundingthehematomaandoftendisplacementofadjacentbrainstructuresandventricular
effacement.Aboutonehalfofhemorrhages,especiallythosearisingintheputamenorthalamus,extendintothe
ventricles.Inthechronicphasefollowingintracerebralhemorrhage,theonlyabnormalitymaybeaslitlike
defectcorrespondingtotheresorbedhematoma,withpigmentedmarginscontaininghemosiderinladen
macrophages.
ClinicalFindings

Hypertensivehemorrhageoccurswithoutwarning,mostcommonlywhilethepatientisawake.Headacheis
presentin~50%ofpatientsandmaybeseverevomitingiscommon.Bloodpressureiselevated,sonormalor
lowbloodpressureinapatientwithstrokemakesthediagnosisofhypertensivehemorrhageunlikely.
Afterhemorrhage,increasingedemaproducesclinicalworseningoverminutestodays.However,thedurationof
activebleedingisbrief,andrebleedingusuallydoesnotoccur.
Clinicalfeaturesvarywiththesiteofhemorrhage(Table137).
Table137.ClinicalFeaturesofHypertensiveIntracerebralHemorrhage.
Sensorimotor
Location
Coma
Pupils
EyeMovements
Disturbance
Putamen Common Normal Ipsilateraldeviation
Hemiparesis
Small,
Downwardandmedial
Thalamus Common
Hemisensorydeficit
sluggish deviationmayoccur
Normaloripsilateral
Hemiparesisor
Lobar
Uncommon Normal
deviation
hemisensorydeficit
Pons
Early
Pinpoint Absenthorizontal
Quadriparesis
Small,
Cerebellum Delayed
Impairedlate
Gaitataxia
reactive

Hemianopia

Seizures

Common
Mayoccur
transiently

Uncommon

Common

Common

None

None

None

None

Uncommon

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DeepCerebralHemorrhage

Themostcommonsitesofhypertensivehemorrhagearetheputamenandthalamus,whichareseparatedbythe
posteriorlimboftheinternalcapsule.Thissegmentoftheinternalcapsuleistraversedbydescendingmotorand
ascendingsensoryfibers,includingtheopticradiations(Figure1317).Pressurefromanexpandinglateral
(putaminal)ormedial(thalamic)hematoma,therefore,producesacontralateralsensorimotordeficit.
Figure1317.

Anatomicrelationshipsindeepcerebralhemorrhage.Top:Planeofsection.Bottom:Putaminal(1)andthalamic
(2)hemorrhagescancompressortransecttheadjacentposteriorlimboftheinternalcapsule.Thalamic
hemorrhagescanalsoextendintotheventriclesorcompressthehypothalamusormidbrainupgazecenter(3).

Putaminalhemorrhagetypicallyleadstomoreseveremotordeficitandthalamichemorrhagetomoremarked
sensorydisturbance.Homonymoushemianopiamayoccurtransientlyafterthalamichemorrhageandisoften
persistentinputaminalhemorrhage.Putaminalhemorrhageproducestoniceyedeviationtowardtheaffected
sideofthebrain,whereasthalamichemorrhagemaycausetonicdownwardandmedialdeviationfrompressure
onthemidbraincenterforupgaze.Aphasiamayoccurifputaminalorthalamichemorrhageexertspressureon
corticallanguageareas.
AmiciS.Thalamicinfarctsandhemorrhages.FrontNeurolNeurosci.201230:132136.
GhettiG.Putaminalhemorrhages.FrontNeurolNeurosci.201230:141144.

LobarHemorrhage

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Hypertensivehemorrhagesalsooccurinsubcorticalwhitematterunderlyingthefrontal,parietal,temporal,and
occipitallobes.Symptomsandsignsvaryaccordingtothelocation,butcanincludeheadache,vomiting,
hemiparesis,hemisensorydeficits,aphasia,andvisualfielddefects.Seizuresaremorefrequentthanwith
hemorrhagesinotherlocations,whereascomaislessso.
LunardiP.Lobarhemorrhages.FrontNeurolNeurosci.201230:145148.

PontineHemorrhage

Bleedingintotheponsproducescomawithinsecondstominutesandusuallydeathwithin48hours.Key
findingsarepinpointpupilsandabsentorimpairedhorizontaleyemovementsverticaleyemovementsmaybe
preserved.Theremaybeocularbobbingbilateraldownbeatingexcursionoftheeyesatabout5second
intervals.Patientsarecommonlyquadripareticwithdecerebrateposturing,andhyperthermiamaybepresent.
Pontinehemorrhageusuallyrupturesintothefourthventricle,andoftenextendsintothemidbrain,producing
midpositionfixedpupils.Smallpontinehemorrhagesthatsparethereticularactivatingsystemareassociated
withlessseveredeficitsandgoodrecovery.
MoncayoJ.Pontineinfarctsandhemorrhages.FrontNeurolNeurosci.201230:162165.

CerebellarHemorrhage

Cerebellarhemorrhageproducesheadache,dizziness,andvomitingofsuddenonset,andinabilitytostandor
walkwithinminutes.Patientsmayinitiallybealertoronlymildlyconfused,butlargehemorrhagesleadtocoma
within12to24hoursinmostcases.Whencomaispresentatonset,cerebellarhemorrhagemaybe
indistinguishablefrompontinehemorrhage.
Findingsincludeimpairedgazetowardorforceddeviationawayfromthelesion,causedbypressureonthe
pontinelateralgazecenter.Skewdeviation,inwhichtheeyeipsilateraltothelesionisdepressed,mayoccur.
Thepupilsaresmallandreactive.Impairedupgazeindicatesupwardtranstentorialherniationofthe
cerebellarvermisandmidbrain,andimpliesapoorprognosis.Ipsilateralfacialweaknessoflowermotorneuron
typeoccursin~50%ofcases,butlimbstrengthisnormal.Despiteprominentgaitataxia,limbataxiaisusually
minimal.Plantarresponsesareflexorearly,butbecomeextensorwithbrainstemcompression.
Cerebellarhemorrhageisespeciallyimportanttodiagnoseearlybecauseitistreatable(seelater).Themain
mistaketoavoidisfailingtoconsiderthediagnosiswhenlimbataxiaisabsentandgaitisnottested.
Accordingly,stanceandgaitshouldbeexaminedinanypatientwhopresentsacutelywithheadache,dizziness,
orvomiting.
WitschaJ,NeugebauerH,ZweckbergerK,JttlerE.Primarycerebellarhaemorrhage:complications,
treatmentandoutcome.ClinNeurolNeurosurg.2013115:863869.

DIFFERENTIALDIAGNOSIS

Putaminal,thalamic,andlobarhypertensivehemorrhagesmaybedifficulttodistinguishfrominfarctioninthe
samelocations.However,severeheadache,nauseaandvomiting,andimpairedconsciousnesssuggest
hemorrhage.CTorMRI(Figure1318)providesadefinitivediagnosis.
Figure1318.

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CTscaninhypertensiveintracerebralhemorrhage.Bloodproducesahighdensitysignalatthesiteof
hemorrhageinthethalamus(leftarrow)andextendsintothethirdventricle(toparrow)andtheoccipitalhorns
oftheipsilateral(bottomarrow)andcontralateral(rightarrow)lateralventricles.

Brainstemstrokeandcerebellarinfarctioncanmimiccerebellarhemorrhage,butarereadilydistinguishableby
CTscanorMRI.Acuteperipheralvestibulopathyalsoproducesnausea,vomiting,andgaitataxia,butnot
headacheorimpairedconsciousness.AlthoughbloodyCSFcanconfirmthediagnosisofhemorrhage,lumbar
puncturemayhastenherniation,andisthereforenotadvisedifcerebellarhemorrhageissuspected.
TREATMENT
Medical

Initialmanagementofintracerebralhemorrhageincludesairwaysupportwithventilatoryassistanceifrequired
andtreatmentofhypertension.Reducingsystolicbloodpressureto~140mmHgover1hourdoesnot
compromiseperfusionoftheperihematomaregionorarterialwatershedterritoriesoftheaffectedhemisphere,is
assafeasmoremodestreductionto~180mmHgover6hours,andmayleadtoabetteroutcome.
Antihypertensivedrugsthatmaybeusedinthissettingincludelabetalolandnicardipine.Neithercorticosteroids
norantiedemaagentsareeffective,andprophylacticadministrationofanticonvulsantsisnotrecommended.
Surgica

1.CerebellarhemorrhageNeurologicdeterioration,brainstemcompression,andhydrocephalusare
indicationsfordecompressiveposteriorfossasurgery,whichmayavertafataloutcome.Resultsarebestin
consciouspatients.
2.LobarhemorrhageSurgicalevacuationcanalsobeusefulforlobarhematomas,especiallythoselarger
than30mLinvolumeandlocatedwithinapproximately1cmofthebrainsurface.Patientswithgood
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neurologicfunctionwhobegintodeteriorateareoptimalcandidates.Prognosisisrelatedtothelevelof
consciousnessbeforesurgery.
3.DeephemorrhageSurgeryisnotbeneficialforpontineordeepcerebralhypertensivehemorrhage.
AndersonCS,QureshiAI.ImplicationsofINTERACT2andotherclinicaltrials:bloodpressuremanagement
inacuteintracerebralhemorrhage.Stroke.201546:291295.
GouldB,McCourtR,GioiaLCetal.ICHADAPTInvestigators.Acutebloodpressurereductioninpatients
withintracerebralhemorrhagedoesnotresultinborderzoneregionhypoperfusion.Stroke.201445:28942899.

PROGNOSIS

Considerablereturnofneurologicfunctioncanoccurafterintracerebralhemorrhage,dependingonitslocation
andsize.Mortalityis30%to40%,mostofwhichoccurswithinthefirstfewdays.Atdischargefromthe
hospital,about75%ofpatientshavesignificantdisability.
OTHERCAUSESOFINTRACEREBRALHEMORRHAGE
TRAUMA

Intracerebralhemorrhageisafrequentconsequenceofclosedheadtrauma.Traumatichemorrhagesmayoccur
at(coup)ordirectlyopposite(contrecoup)thesiteofimpact.Themostcommonlocationsarethefrontaland
temporallobes.TraumatichemorrhageisdiagnosedbyCTorMRI.
HEMORRHAGICTRANSFORMATIONOFCEREBRALINFARCTS

Hemorrhageintoacerebralinfarctiscommonandusuallyhasnoeffectonoutcome.Factorsthatpredisposeto
hemorrhagictransformationincludethrombolytictherapy,anticoagulation,cardioembolicstroke,massive
infarction,corticalgraymatterinfarction,andthrombocytopenia.Treatmentconsistsofdiscontinuing
thrombolyticoranticoagulantdrugswhereapplicable.
ANTICOAGULATION&THROMBOLYTICTHERAPY

Patientsreceivinganticoagulantsorthrombolyticagentsareatincreasedriskfordevelopingintracerebral
hemorrhage.
COAGULOPATHY

Intracerebralhemorrhagecancomplicatedisordersinvolvingeitherclottingfactors(eg,hepaticfailure,
hemophilia,disseminatedintravascularcoagulopathy)orplatelets(eg,idiopathicthrombocytopenicpurpura).
CEREBRALAMYLOIDANGIOPATHY

Cerebralamyloid(congophilic)angiopathyischaracterizedbyamyloiddepositsinthewallsof
leptomeningealandcorticalcapillaries,arterioles,andsmallarteries.Thedisorderismostcommoninelderly
patientsandtypicallyproduceslobarhemorrhageatmultiplesites.RiskfactorsincludeapolipoproteinE4and
2alleles,anticoagulationorantiplatelettherapy,headtrauma,andhypertension.Rarehereditarycases(eg,
amyloidA4precursorproteinmutations)areinheritedinautosomaldominantfashion.
AurielE,GreenbergSM.Thepathophysiologyandclinicalpresentationofcerebralamyloidangiopathy.Curr
AtherosclerRep.201214:343350.
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VASCULARMALFORMATIONS

Ruptureofarteriovenousmalformations(AVMs)orsaccular(berry)aneurysmscancauseintracerebral
hemorrhage.AVMsconsistoftortuousarteriesanddilatedveinsandarisedevelopmentallywhentheintervening
capillarybedsfailtoform.Saccularaneurysmsareacquiredlesionsofarterialwalls,locatedespeciallyatbranch
pointsaroundthecircleofWillis.AVMsmaybeasymptomaticorcausehemorrhage,seizures,headache,or
focalneurologicdeficits.ForunrupturedAVMs,theriskofruptureis1%to3%peryear.However,when
ruptureoccursitcarriesa10%to30%mortalityrateand,forsurvivors,a6%riskofreruptureoverthenext
year.AnticonvulsantsarethetreatmentofchoiceforAVMsthatpresentwithseizures.Inthecaseof
hemorrhage,however,surgicalresection,endovascularembolization,orradiosurgerycanpreventrebleeding.
Aneurysmsusuallypresentwithsubarachnoidhemorrhage,butatsomesites(eg,middlecerebralartery)they
maybleedintobrainparenchymatoproduceanintracerebralhematoma.Aneurysmsarediscussedindetailin
Chapter6,Headache&FacialPain.
AlShahiSalmanR,WhitePM,CounsellCEetal.ScottishAuditofIntracranialVascularMalformations
Collaborators.Outcomeafterconservativemanagementorinterventionforunrupturedbrainarteriovenous
malformations.JAMA.2014311:16611669.
[JAMAandJAMANetworkJournalsFullText]
ZachariaBE,VaughanKA,JacobyAetal.Managementofrupturedbrainarteriovenousmalformations.Curr
AtherosclerRep.201214:335342.

AMPHETAMINEORCOCAINEABUSE

Amphetamineorcocaineusecancauseintracerebralhemorrhage,typicallywithinminutestohoursafterthe
drugistaken.Mostsuchhemorrhagesarelocatedinsubcorticalwhitematterandmayberelatedtoacutely
elevatedbloodpressure,ruptureofapreexistingvascularanomaly,ordruginducedarteritis.
HEMORRHAGEINTOTUMORS

Bleedingintoprimaryormetastaticbraintumorsisanoccasionalcauseofintracerebralhemorrhage.Tumors
associatedwithhemorrhageincludemelanoma,lungcarcinoma,glioma,breastcarcinoma,renalcellcarcinoma,
andoligodendroglioma.Bleedingintoatumorshouldbeconsideredwhenapatientwithknowncancer
experiencesacuteneurologicdeteriorationitmayalsobethepresentingmanifestationofcancer.
ACUTEHEMORRHAGICLEUKOENCEPHALITIS

Thisraremonophasicdemyelinatingandhemorrhagicdisordertypicallyfollowsrespiratoryinfectionin
children.Multiplesmallperivascularhemorrhagesarefoundinthebrain.Clinicalfeaturesincludefever,
headache,confusionalstate,andcoma.CSFshowsapolymorphonuclearpleocytosisandCTorMRImay
demonstratehemorrhage.Theclassicclinicalpictureisofafulminantcourseleadingtodeathwithinseveral
days,butsomepatientsrespondtocorticosteroidsorplasmaexchange.
WangQT,TuhrimS.Etiologiesofintracerebralhematomas.CurrAtherosclerRep.201214:314321.

GLOBALCEREBRALISCHEMIA
ETIOLOGY
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Globalcerebralischemiaoccurswhenbloodflowisinadequatetomeetmetabolicrequirementsofthebrain,as
incardiacarrest.Globalischemiaproducesmoreseverebraininjurythanpureanoxiawithpreservedcirculation
(eg,primaryrespiratoryarrestorcarbonmonoxidepoisoning),presumablybecauseitalsoimpairsglucose
deliveryandremovaloftoxicmetabolites.
PATHOLOGY
Theseverityofcerebralpathologyfromglobalischemiaisdirectlyrelatedtoischemiaduration.Thedistribution
ofpathologyisgovernedbytheselectivevulnerabilityofcertainneuronalpopulationsandofarterialwatershed
(borderzone)regions.SelectivelyvulnerableneuronsincludeCA1pyramidalneuronsofthehippocampus
cerebellarPurkinjeneuronspyramidalneuronsofneocorticallayers3,5,and6thalamicreticularneuronsand
mediumsizedneuronsinthecaudatenucleusandputamen.Arterialwatershedsarelocatedattheborder
betweentheanterior,middle,andposteriorcerebralarteries(Figure1319).
Reducedcerebralenergyrequirements,suchasoccurwithdeepanesthesiaorhypothermia,canminimizeor
preventbraindamagefromischemicinsults,whereashyperglycemiaorhypermetabolicstates(eg,status
epilepticus)canincreasedamage.Superimposeddiseaseofthecraniocervicalarteriesmayleadtoasymmetries
inthedistributionofcerebraldamagefromglobalischemia.
Figure1319.

Distributionofcerebralwatershed(borderzone)infarcts(blueareas)associatedwithglobalcerebralischemia.

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CLINICALFINDINGS
BRIEFISCHEMIA

Reversibleencephalopathiesarecommonafterbriefcirculatoryarrest.Insuchcases,comapersistsforlessthan
12hours.Transientconfusionoramnesiamayoccuronawakening,butrecoveryistypicallyrapidandcomplete.
Somepatientsshowsevereanterogradeandvariableretrogradeamnesiaandabland,unconcernedaffectwithor
withoutconfabulation.Thissyndromemayreflectreversiblebilateraldamagetothethalamusorhippocampus.
PROLONGEDISCHEMIA
Coma

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Comalastingformorethan12hoursaftercardiacarrestmaybeassociatedwithlastingfocalormultifocal
motor,sensory,andcognitivedeficitsuponawakening.ItisdiscussedinChapter3,Coma.
FocalCerebralDysfunction

Focalneurologicsignsaftercardiacarrestincludepartialorcompletecorticalblindness,weaknessofbotharms
(bibrachialparesis),andquadriparesis.Corticalblindnessisusuallytransientandresultsfromischemiainthe
borderzonebetweenthemiddleandposteriorcerebralarteries.Bibrachialparesis(maninabarrel
syndrome)resultsfrombilateralinfarctionofthemotorcortexintheborderzonebetweentheanteriorand
middlecerebralarteries.
MyoclonusandSeizures

Posthypoxicactionmyoclonus(LanceAdamssyndrome)aftercardiacarrestproducesmultifocalmyoclonus
andissometimesassociatedwithsignsofcerebellardisease,includingdysarthria,dysmetria,ataxia,and
intentiontremor.Itoccursinconsciouspatientswithoutsevereischemicinjuryandtypicallyimprovesover
time.Treatmentwithclonazepam,valproicacid,orlevetiracetammaybeeffective.Myoclonicstatus,which
occursincomatosepatients,consistsofgeneralized,bilateral,synchronoustwitchingthatusuallyaffectstheface
andtrunk.Itsrelationshiptoepilepticseizuresisuncertain,asisthebenefitoftreatment,anditusuallyportends
afataloutcome.Partialorgeneralizedseizures,includingstatusepilepticus,arealsoseenaftercardiacarrest,
andshouldbetreatedwithanticonvulsants.
PersistentVegetativeorMinimallyResponsiveState

Somepatientswhoareinitiallycomatoseaftercardiacarrestsurviveandawaken,butremainfunctionally
decorticateandunawareoftheirsurroundings.Theytypicallyregainspontaneouseyeopening,sleepwake
cycles,rovingeyemovements,andbrainstemandspinalcordreflexes.Thispersistentvegetativeorminimally
responsivestate(seeChapter3,Coma)isthusdistinctfromcomaandappearstobeassociatedwithlaminar
necrosisoftheneocortex.Insomeapparentlyunawarepatients,however,functionalMRIorEEGcan
demonstrateresponsiveness.Mostsuchpatientshavetraumaticratherthanischemicbraininjury,butthe
possibilitythatapatientwithoutovertbehavioralresponsesremainssubclinicallyawareandresponsiveshould
alwaysbeexplored.Apersistentvegetativestateassociatedwithanisoelectric(flat)EEGistermedneocortical
death.Persistentvegetativestatesmustbedistinguishedfrombraindeath(seeChapter3,Coma),inwhich
bothcerebralandbrainstemfunctionsareabsent.
SpinalCordSyndromes

Spinalcordinjuryfromhypoperfusionisusuallyseenonlywithprofoundcerebralinvolvement.Althoughan
arterialwatershedoccursatthemidthoraciclevelofthecord,autopsystudiesshowthatischemicinjuryafter
cardiacarrestaffectslargeneuronsintheanteriorhornsofthelumbarspinalcordmostprominently.Thismay
beduetothelargesizeandhighmetabolicactivityoftheseneurons,andisconsistentwiththeclinicalfindingof
flaccidparaplegiaassociatedwithspinalcordinjuryaftercardiacarrest.
DAmoreC,PaciaroniM.Borderzoneandwatershedinfarctions.FrontNeurolNeurosci.201230:181184.
FernndezEspejoD,OwenAM.Detectingawarenessafterseverebraininjury.NatRevNeurosci.
201314:801809.
TREATMENT
Treatmentofglobalcerebralischemiainvolvesrestoringcerebralcirculation,eliminatingarrhythmias,
maintainingsystemicbloodpressure,andcorrectingacidbaseorelectrolyteabnormalities.Ventilatory
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assistanceandsupplementaloxygenmaybenecessary.
Inducedhypothermiato32to34Cfor12to24hoursbysurfaceorendovascularcoolingcanimprove6
monthsurvivalandneurologicoutcomeafteroutofhospitalcardiacarrestwithventricularfibrillation.
SchwartzBG,KlonerRA,ThomasJLetal.Therapeutichypothermiaforacutemyocardialinfarctionand
cardiacarrest.AmJCardiol.2012110:461466.
PROGNOSIS
Survivalratesforpatientswithoutofhospitalcardiacarrestrangefrom~5%withasystoleorpulseless
electricalactivity(electromechanicaldissociation)to~25%withventricularfibrillationorpulselessventricular
tachycardia.Thegoalofneurologicprognosticationaftercardiacarrestistodistinguishpatientswithand
withoutachanceformeaningfulrecovery.Inpatientswhohavenotundergonetherapeutichypothermia,
meaningfulrecoveryisexcludedbymyoclonusat24hours,orbypupillaryorcornealareflexiaorabsentor
decerebratemotorresponsestopainat72hoursafterarrest.Thesecriteriaassumenormothermiaandthe
absenceofdrug(eg,sedative)effectsthatcanconfoundtheirinterpretation.Inpatientswhohaveundergone
therapeutichypothermia,thesecriteriaarenotasreliablebecauseoftheeffectsofhypothermiaperse,drugs
administeredinhypothermiaprotocols(eg,sedativesandparalytics),andhypothermiainducedchangesindrug
metabolism.Absentpupillaryreflexesat72hoursremainsthebestclinicalindicatorofapoorprognosis,but
somatosensoryevokedpotentialsandneuroimagingfindingsmayhavesuperiorpredictiveability.
FribergH,RundgrenM,WesthallE,NielsenN,CronbergT.Continuousevaluationofneurologicalprognosis
aftercardiacarrest.ActaAnaesthesiolScand.201357:615.
GreerDM,RosenthalES,WuO.Neuroprognosticationofhypoxicischaemiccomainthetherapeutic
hypothermiaera.NatRevNeurol.201410:190203.

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