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
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,althoughthecauseofmoststrokesislikely
tobemultifactorialandinvolvebothpolygenicandenvironmentalinfluences.Several,mostlyrareMendelian

disordershavestrokeasamajormanifestationsomeofthese,inwhichtheaffectedgenehasbeenidentified,
arelistedinTable132.
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
Cerebralcavernousmalformations3
PDCD10 Programmedcelldeath10 AD
ICH
Ischemic(arterial
CollagentypeIII,1
EhlersDanlossyndrome,typeIV
COL3A1
AD
dissection),
chain
aneurysmalSAH
Fabrydisease
GLA
GalactosidaseA
XLR
Ischemic
3Primerepair
HERNS
TREX1
AD
Ischemic
exonuclease1
Hereditaryhemorrhagictelangiectasia,
Ischemic
ENG
Endoglin
AD
type1(OslerWeberRendudisease)
(embolic)
Hereditaryhemorrhagictelangiectasia,
ActivinAreceptor,type
ACVRL1
AD
ICH(AVM)
type2
IIlike1
Hereditarythrombophilia
PROC
ProteinC
AD
Ischemic
Hereditarythrombophilia
PROS1 ProteinS
AD
Ischemic
Homocystinuria
CBS
Cystathioninesynthase AR
Ischemic
Methylenetetrahydrofolate
Homocystinuria
MTHFR
AR
Ischemic
reductase
IsovalerylCoA
Isovalericacidemia
IVD
AR
ICH
dehydrogenase
MethylmalonylCoA
Methylmalonicaciduria
MUT
AR
ICH,Ischemic
mutase
Marfansyndrome
FBN1
Fibrillin1
AD
Ischemic
MELAS
Severalmitochondrialgenes
M
Ischemic
MERRF
Severalmitochondrialgenes
M
Ischemic
Vascularsmoothmuscle
Moyamoyadisease5
ACTA2
AD
Ischemic
actin
Neurofibromatosistype1
NF1
Neurofibromin
AD
Ischemic
Polycystickidneydisease
PKD1
Polycystin1
AD
AneurysmalSAH
PropionylCoA
PCCA,
Propionicacidemia
carboxylase,or
AR
ICH,Ischemic
PCCB
subunit
ATPbindingcassette,
Pseudoxanthomaelasticum
ABCC6
AR
Ischemic
subfamilyC,member6
Retinalvasculopathywithcerebral
TREX1 3Primerepair
AD
Ischemic
exonuclease1
leukodystrophy
Sicklecellanemia
Transthyretinrelatedhereditary
amyloidosis
VonHippelLindausyndrome

HBB

Hemoglobin

AR

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,X
linkedrecessive.
DatafromOnlineMendelianInheritanceinMan(http://www.ncbi.nlm.nih.gov/omim),TournierLasserveE.
Newplayersinthegeneticsofstroke.NEnglJMed.2002347:17111712,andLindgrenA.Strokegenetics:a
reviewandupdate.JStroke.201416:114123.

APPROACHTODIAGNOSIS

Strokeisasyndromecharacterizedbyfourkeyfeatures:
1. SuddenonsetThesuddenonsetofsymptomsisdocumentedbythehistory.
2. FocalinvolvementofthecentralnervoussystemThesiteofinvolvementissuggestedbythe
symptomsandsigns,delineatedmorepreciselybyneurologicexamination,andconfirmedbyimaging
studies(computedtomography[CT]ormagneticresonanceimaging[MRI]).
3. LackofrapidresolutionThedurationofneurologicdeficitsisdocumentedbythehistory.Theclassic
definitionofstrokerequiredthatdeficitspersistforatleast24hourstodistinguishstrokefromtransient
ischemicattack(discussedlater).However,anysuchtimepointisarbitrary,andtransientischemic
attacksusuallyresolvewithin1hour.Inaddition,imagingstudiescansometimesdemonstrateprior
strokeintheabsenceofdetectableclinicaldeficits.
4. VascularcauseAvascularcausemaybeinferredfromtheacuteonsetofsymptomsandoftenfromthe
patientsage,thepresenceofriskfactorsforstroke,andtheoccurrenceofsymptomsandsignsreferable
totheterritoryofaparticularcerebralbloodvessel.Whenthisisconfirmedbyimagingstudies,further
investigationscanbeundertakentoidentifyamorespecificetiology,suchasarterialthrombosis,
cardiogenicembolus,orclottingdisorder.
ACUTEONSET
Strokesbeginabruptly.Neurologicdeficitsmaybemaximalatonsetormayprogressoversecondstohours(or
occasionallydays).
Astrokethatisactivelyprogressingasadirectconsequenceoftheunderlyingvasculardisorder(butnot
becauseofassociatedcerebraledema)orhasdonesoinrecentminutesistermedstrokeinevolutionor
progressingstroke(Figure131).
Figure131.

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

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.
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.
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
callosum,uppermidbrain

Posteriorcerebral
Thalamoperforate
branches
Thalamogeniculate
branches

Thalamus
Thalamus

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
2
20
0
Aphasia
Visualfielddefect
14
22
0
7
Diplopia2
Vertigo2
Dysarthria

0
3

0
Dropattacks2
Hemiormonoparesis 38
Hemisensorydeficit 33

48
11
16
12
9

1Mostpatientshavemultiplesymptomsandsigns.
2Mostusefuldistinguishingfeatures.

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
occursinstrokewithoutreperfusion,causespannecrosis,affectingallcelltypes,resultinginchroniccavitary
lesions.
Whereischemiaisincomplete(20%40%ofnormalbloodflow)asintheischemicborderzoneor
penumbracelldamageispotentiallyreversibleandcellsurvivalmaybeprolonged.However,unlessblood
flowisrestored,byrecanalizationoftheoccludedvesselorcollateralcirculationfromothervessels,reversibly
damagedcellsbegintodieaswell,andtheinfarctexpands.Deathofpenumbraltissueisassociatedwitha
worseclinicaloutcome.
Brainedemaisanotherdeterminantofstrokeoutcome.Ischemialeadstovasogenicedemaasfluidleaksfrom
theintravascularcompartmentintobrainparenchyma.Edemaisusuallymaximalapproximately2to3days
afterstrokeandmaybesufficientlyseverethatitproducesamasseffectthatcausesherniation(displacementof
braintissuebetweenintracranialcompartments)anddeath.
Twopathogeneticmechanismscanproduceischemicstrokethrombosisandembolism.However,the
distinctionisoftendifficultorimpossibletomakeonclinicalgrounds.
Thrombosis

Thrombosisproducesstrokebyoccludinglargecerebralarteries(especiallytheinternalcarotid,middle
cerebral,orbasilar),smallpenetratingarteries(asinlacunarstroke),cerebralveins,orvenoussinuses.
Symptomstypicallyevolveoverminutestohours.ThromboticstrokesareoftenprecededbyTIAs,whichtend
toproducesimilarsymptomsbecausetheyaffectthesameterritoryrecurrently.
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
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,whereasotherspromote
tissuesurvivalorrepair.
INJURYMECHANISMS
EnergyFailure

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

Amajoruseofcellularenergyisthemaintenanceoftransmembraneiongradients.Withenergyfailure,these
aredissipated.Na+ /K+ ATPase,whichaccountsforthemajorityofneuronalenergyexpenditureandis
responsibleformaintaininghighintracellularK+ concentrations,failstodoso.K+ leaksfromcellsand
depolarizesadjacentcells,activatingvoltagegatedionchannelsandneurotransmitterrelease.ExtracellularK+
andneurotransmitterglutamatetriggercorticalspreadingdepression,leadingtofurtherneuronandastrocyte
depolarization.Thisconsumesadditionalenergyandmayextendtheinfarct.
CalciumDysregulation

Ca2+ ismaintainedatlowrestingcytoplasmiclevels,butischemicelevationofextracellularK+ causes

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

Excitotoxicityreferstotheneurotoxiceffectsofexcitatoryneurotransmitters,especiallyglutamate.Ischemia
promotesexcitotoxicitybystimulatingneuronalglutamaterelease,reversingastrocyticglutamateuptake,and
activatingglutamatereceptorcoupledionchannels.InfluxofCa2+ throughthesechannelscontributestoCa2+
dysregulationandactivatesneuronalnitricoxidesynthase,generatingpotentiallyneurotoxicnitricoxide.
OxidativeandNitrosativeInjury

Sometoxiceffectsofischemiaaremediatedbyhighlyreactiveoxidativeandnitrosativecompoundsincluding
superoxideandnitricoxide,whichactprimarilyduringthereperfusionphasethatfollowsischemia.Their
effectsincludeinhibitingmitochondrialenzymesandfunction,damagingDNA,activatingionchannels,
causingcovalentmodificationofproteins,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.
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.Itismaximalduringthefirst
4or5daysafterstrokeandcancauseherniationofthecingulategyrusacrossthemidlineorofthetemporal
lobebelowthetentorium(seeFigure34inChapter3,Coma).
SMALLARTERYOCCLUSION

Infarctsfromsmallarteryocclusionrarelycausedeath,soonlychroniclesionsareusuallyfoundatautopsy.
Theseincludelacunes,orsmallcavitiesupto~15mmindiameterusuallylocatedinsubcorticalwhite(eg,
internalcapsule)ordeepgray(eg,basalgangliaorthalamus)matterwhitematter(includingperiventricular)
lesionsshowingpunctateorconfluentmyelinrarefaction,gliosis,andaxonallossandmicrobleeds.Small
vesselocclusionmaybeassociatedwithatherosclerosis,lipohyalinosis(collagenousthickeningand
inflammationofthevesselwall),orfibrinoidnecrosis(vesselwalldestructionwithperivascular
inflammation).
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).(UsedwithpermissionfromWaxman
S.ClinicalNeuroanatomy.26thed.NewYork,NY:McGrawHill2010.)

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,visualcortexrelated
tomacularvision,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.)

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

Theinternalcarotidarteryarisesatthebifurcationofthecommoncarotidarteryintheneck.Inadditiontothe
anteriorandmiddlecerebralarteries,italsogivesrisetotheophthalmicartery,whichsuppliestheretina.
ClinicalSyndrome

Internalcarotidarteryocclusionmaybeasymptomatic,orcausestrokesofhighlyvariableseverity,depending
ontheadequacyofcollateralcirculation.Symptomaticocclusionresultsinasyndromesimilartothatofmiddle
cerebralarterystroke(contralateralhemiplegia,hemisensorydeficit,andhomonymoushemianopia,together
withaphasiaifthedominanthemisphereisinvolved).Monocularblindnessisalsocommon.
LanariA,SilvestrelliG.Acuteandchroniccarotidocclusionsyndromes.FrontNeurolNeurosci.
201230:185190.

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.

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
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.Thusthetopofthebasilarsyndromemaybeconfusedwith
midbraindamagecausedbytranstentorialuncalherniation.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
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.
ClinicalSyndromes

Occlusionofacircumferentialbranchproducesinfarctioninthedorsolateralmedullaorpons.
1. Posteriorinferiorcerebellararteryocclusionresultsinthelateralmedullary(Wallenberg)
syndrome(seeChapter8,DisordersofEquilibrium).Thepresentationvaries,butcanincludeipsilateral
cerebellarataxia,Hornersyndrome,andfacialsensorydeficitcontralateralimpairedpainand
temperaturesensationandnystagmus,vertigo,nausea,vomiting,dysphagia,dysarthria,andhiccup.The
motorsystemischaracteristicallysparedbecauseofitsventrallocationinthebrainstem.
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,whichmaybeassociatedwithcontralateraltremororataxiafrominvolvementofpathwaysconnecting
therednucleusandcerebellum.Ipsilateralabducens(VI)andfacial(VII)nervepalsiesareseenwithlesionsin
thepons,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.

LACUNARINFARCTION
Anatomy

Smallvesselocclusionaffectingpenetratingarteriesdeepinthebrainmaycauseinfarctsintheputamenor,less
commonly,thethalamus,caudatenucleus,pons,posteriorlimboftheinternalcapsule,orothersites(Figure
138).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

Manylacunarinfarctsarenotrecognizedclinicallyandaredetectedonlyasincidentalfindingsonimaging
studiesoratautopsy.Inothercases,however,theyproducedistinctiveclinicalsyndromes.Lacunarstrokes
developoverhourstodays.Headacheisabsentorminor,andthelevelofconsciousnessisunchanged.
Hypertension,diabetes,andothercardiovascularriskfactorsmayormaynotbepresent.Theprognosisfor
recoveryfromalacunarstrokeisgood,butrecurrentstrokeiscommon.Althoughavarietyofdeficitscanbe
produced,therearefourclassicanddistinctivelacunarsyndromes.
1. PuremotorhemiparesisThisconsistsofhemiparesisaffectingtheface,arm,andlegtoaroughly
equalextent,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
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.

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.

Atthisstage,growthandchemotacticfactorsfromendothelialcellsandmacrophagesstimulateproliferationof
intimalsmoothmusclecellsandmigrationofadditionalsmoothmusclecellstotheintimafromthetunica
media.Thesecellssecreteextracellularmatrixconstituents,leadingtotheformationofafibrouscapoverthe
atheroscleroticplaque,inwhichanecroticcoredevelops.Insomecases,fracturesinthecapleadtoplaque
rupture,aseriouscomplicationassociatedwiththereleaseofprocoagulantfactorsandsubsequentthrombosis.
Possibleoutcomesincludethromboticocclusionofthevessellumenorembolization.
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,
hemiparesisandotherfocalneurologicabnormalities,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
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
pain,visualabnormalitiesthatmimicthoseseeninmigraine,orHornersyndrome.Vertebraldissection
mayproduceheadache,neckpain,andsignsofbrainstemdysfunction.Treatmentiswithantiplatelet
drugs,sometimescombinedwithendovascularrepair.
3. Multipleprogressiveintracranialarterialocclusions(moyamoya)producebilateralnarrowingor
occlusionofthedistalinternalcarotidarteriesandadjacentanteriorandmiddlecerebralarterytrunks.
Reactivearteriogenesisleadstoafinenetworkofcollateralchannelsatthebaseofthebrain,whichcan
beseenbyangiography(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.

SoutherlandAM,MeschiaJF,WorrallBB.Sharedassociationsofnonatherosclerotic,largevessel,
cerebrovasculararteriopathies:consideringintracranialaneurysms,cervicalarterydissection,moyamoya
diseaseandfibromusculardysplasia.CurrOpinNeurol.201326:1328.

LacunarInfarction

LacunarinfarctionwasdiscussedinmoredetailearlierunderClinicalAnatomicCorrelation.
DrugAbuse

Useofcocainehydrochloride,alkaloidal(crack)cocaine,amphetamines,otherstimulants(eg,
phenylpropanolamine,ephedrine,orecstasy),orheroinisariskfactorforstroke.Intravenoususersmay
developinfectiveendocarditisleadingtoembolicstroke.Strokealsooccursindruguserswithoutendocarditis,
however,includingthosewhotakedrugsonlyorally,intranasally,orbyinhalation,oftenwithinhoursofdrug

use.Cocainehydrochlorideandamphetaminesaremostoftenassociatedwithintracerebralhemorrhage,
whereasstrokefromalkaloidalcocaineuseisusuallyischemic.Proposedmechanismsincludedruginduced
endothelialdysfunctionleadingtoaprothromboticstate,vasospasm,vasculitis,andruptureofpreexisting
aneurysmsorvascularmalformations.
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.2014in
press.

VenousorSinusThrombosis

Thromboticocclusionofacerebralveinorvenoussinus(Figure1313)isanuncommoncauseofstroke.It
affectsyoungwomenmostoftenandmaybeassociatedwithapredisposingcondition,suchasotitisorsinusitis,
postpartumstate,dehydration,orcoagulopathy.Clinicalfeaturesincludeheadache,papilledema,impaired
consciousness,seizures,andfocalneurologicdeficits.LevelsofDdimer,afibrindegradationproduct,are
usuallyincreasedintheblood.CSFpressureistypicallyincreased,andincasesofsepticthrombosis,
pleocytosismayoccur.ACTscanmayshowedema,infarct,hemorrhage,orfillingdefectinthesuperior
sagittalsinus(deltasign).MRIwithMRangiographyisthemostdefinitivediagnostictest.Treatmentiswith
anticoagulantsand,forsepticthrombosis,antibiotics.
Figure1313.

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

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

CARDIACDISORDERS
AtrialFibrillation

Atrialfibrillationiscommon,withaprevalencethatincreaseswithageandreaches~5%by65yearsofage.It
wasformerlyassociatedwithrheumaticheartdisease,butisnowusuallyrelatedtoischemicorhypertensive
heartdisease.Atrialfibrillationincreasesstrokerisk2to7foldand,whenvalvularheartdiseaseisalso
present,about17fold.Additionalriskfactorsincludeagegreaterthan75years,hypertensionordiabetes,and
heartfailure.Atrialfibrillationpredisposestoembolicstrokefromthrombithatformintheleftatrialappendage
duetostasisofblood.Treatmentiswithoralanticoagulants(seelater).Theantiarrhythmicdrugdronedarone
(400mgorallytwicedaily)mayprovideadditionalreductioninstrokerisk.Tachycardiabradycardia(sick
sinus)syndromeisalsoassociatedwithcardioembolicstroke,whereasotherarrhythmiasaremostlikelyto
causepancerebralhypoperfusionandsyncope(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
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,andhasa
worseprognosis.
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
maybeseen.Atrialmyxomacanalsoobstructleftventricularoutflow,causingsyncope.Diagnosisisby
echocardiography.Treatmentisbysurgicalresectionofthetumorinsomeinstances,anticoagulationor
antiplateletdrugsarealsoused.
ParadoxicalEmbolus

Congenitalanomaliesassociatedwithpathologiccommunicationbetweentherightandleftsidesoftheheart,
suchaspatentforamenovaleandatrialorventricularseptaldefect,maypermitparadoxicalpassageofemboli
fromthesystemicvenouscirculationtothebrain.However,patentforamenovaleispresentin~25%ofthe
populationand,althoughcommoninyoungpatientswithstroke,acausallinktostrokehasnotbeenestablished.
Antiplatelettherapyisaseffectiveaspercutaneousclosureinpreventingrecurrentstrokeinpatientswith
patentforamenovale.

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
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.
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,
significantcarotidstenosiscanoccurwithoutanaudiblebruit,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.
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,or
vertebrobasilardistribution,orwithlacunarinfarction.Crossedhemiparesis,whichinvolvesthefaceon
onesideandtherestofthebodyontheother,assignsthelesiontothebrainstembetweenthefacial(VII)
nervenucleusintheponsandthedecussationofthepyramidsinthemedulla.
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

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)CTscanshowinglow
densityandeffacementofcorticalsulci(betweenarrowheads)andcompressionoftheanteriorhornofthe
lateralventricle(arrow).(B)T1weightedMRIscanshowinglossofsulcalmarkings(betweenarrowheads)
andcompressionoftheanteriorhornofthelateralventricle(arrow).(C)T2weightedMRIscanshowing
increasedsignalintensity(betweenarrowheads)andventricularcompression(arrow).

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.
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.Metabolicdisturbancessuchashypoglycemiaandhyperosmolarnonketotichyperglycemiamaypresent
instrokelikefashion,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
Aspirin/dipyridamole1
Clopidogrel
Thrombolytics
Recombinanttissueplasminogenactivator(rtPA)

PO
PO

25/200mgbid
75mgqd

IV

0.9mg/kgonce

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
withnonvalvularatrialfibrillationandCHA2DS2VAScscore2,dabigatran,rivaroxabanorapixabancan
besubstitutedforwarfarin.Mitralstenosiswitheitherahistoryofembolismorassociatedleftatrialthrombus
isalsoanindicationforwarfarin,andcertainpatientsshouldbetreatedwithbothwarfarinandaspirinfollowing
mechanicalaorticormitralvalvereplacement.Theroleofanticoagulationinreducingstrokeriskrelatedto
othercardiacdisorderssuchasbioprostheticvalvereplacement,heartfailure,severemitralstenosis,orST
elevationmyocardialinfarctionwithmuralthrombusorapicaldyskinesisislessclear.
AsymptomaticCarotidArteryStenosis

Asymptomatic70%to99%stenosisoftheextracranialinternalcarotidarteryorcarotidbulb(butnottotal
carotidocclusion)isalsoassociatedwithanincreasedriskofstroke,andpatientswithasymptomaticstenosis
shouldbetreatedwithlowdoseaspirinandstatins.Insomecaseswith>70%stenosis,carotid
endarterectomyorcarotidarterystenting(discussedlater)maybeemployed,assumingthatasurgical
complicationrateof3%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

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,suchasthosetreated
4.5to6hoursaftertheonsetofsymptomsorwitharecenthistoryofmajorsurgery,andinpatients
inwhomintravenoustherapyisunsuccessful.
ClotretrievalMechanicalthrombectomywithstentorcoilretrievers(eg,SolitaireFR,Trevoor
Merci),aloneorincombinationwithrtPA,mayalsobeusefulfortreatingacuteischemicstroke,
especiallyinpatientswhoarenotcandidatesfororwhofailintravenousthrombolytictherapy.For
example,thecombinationofintravenousrtPAandintraarterialtreatmentwitharetrievablestent
within6hoursafteronsetofsymptomscanimprovefunctionaloutcomeat3monthsinpatients
withocclusionofthedistalintracranialinternalcarotidorproximalmiddleoranteriorcerebral
artery.
SurgicalTreatment

1. Carotidendarterectomy(surgicalremovalofthrombusfromastenoticcommonorinternalcarotid
arteryintheneck)isindicatedforpatientswithanteriorcirculationTIAsandhighgrade(70%99%)
extracranialinternalcarotidarterystenosisandforselectedpatientswithmoderate(50%70%)stenosis
onthesideappropriatetoaccountforthesymptoms.Thenetbenefitofendarterectomyassumesa
combinedperioperativemorbidityandmortalityoflessthan6%.
2. Carotidarterystentingisaseffectiveasendarterectomyfortreatingextracranialcarotidstenosis,
assumingasimilarperioperativemorbidityandmortalityrate.Stentingisassociatedwithanincreased
riskofperiproceduralstroke,butadecreasedriskofperiproceduralmyocardialinfarction.Considering
thegenerallygreateradverseeffectofstrokethanofmyocardialinfarctiononqualityoflife,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.For
patientswhoseTIAorstrokeoccurredwhiletakingaspirin,itisunclearifincreasingthedoseorsubstituting
anotherantiplateletdrugconfersadditionalbenefit.Thereisnoevidencethatanticoagulationorthe
combinationofantiplatelettherapyandanticoagulationiseffectiveinthissetting.
Anticoagulation

PatientswithpriorTIAorischemicstrokeandvalvularatrialfibrillationormechanicalaorticormitral
valvereplacementshouldbegivenlongtermwarfarintreatmenttargetedtoanINRof2.50.5.Lowdose
aspirinisaddedforpatientswithmechanicalvalveswhoareatlowriskforbleedingcomplications.
Nonvalvularatrialfibrillationshouldbetreatedwithwarfarin(INR2.50.5),apixaban,dabigatranor
rivaroxaban.Shortterm(~3months)anticoagulationwithwarfarinisindicatedforpriorTIAorischemicstroke
withacutemyocardialinfarctionorcardiomyopathywheneitheriscomplicatedbymuralthrombus.
Warfarinfor3to6monthsfollowedbylongtermlowdoseaspirinisrecommendedforrecipientsof
bioprostheticvalves.Eitherantiplateletdrugsoranticoagulationwithwarfarincanbeusedinrheumatic
valvulardiseasewithoutatrialfibrillation.
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,
reflectingtheadaptiveplasticityofthebrain.Recoveryofmobilityandlimbfunctioncanbeenhancedby
trainingandpractice.Effectiverehabilitativemeasuresincludefitnessandstrengthtraining,overgroundgait
training,constraintinducedmovementtherapy,pharmacologicmodulationofspasticity,speechandlanguage
therapy,andperhapsnoninvasivetranscorticalmagneticordirectcurrentstimulation.Earlycommencementof
rehabilitativetherapyandhighintensityregimensarerecommended,andpatientmotivationisanimportant
factor.
DobkinBH,DorschA.Newevidencefortherapiesinstrokerehabilitation.CurrAtherosclerRep.
201315:331.

COMPLICATIONS
Medicalcomplicationsarecommonafterstrokeandstronglyaffectoutcome.Theyincludeinfections
(especiallyaspirationpneumoniaandurinarytractinfections),cardiacarrhythmias,dysphagia,gastrointestinal
bleeding,deepveinthrombosis,pulmonaryembolism,anddepression.Insomecases,suchasarrhythmiaand
depression,complicationsmayresultdirectlyfrombraininjury.Thesedisordersaretreatedasunderother
circumstances.
CholletF,AcketB,RaposoNetal.Useofantidepressantmedicationstoimproveoutcomesafterstroke.
CurrNeurolNeurosciRep.201313:318324.
HannawiY,HannawiB,RaoCP,SuarezJI,BershadEM.Strokeassociatedpneumonia:majoradvancesand
obstacles.CerebrovascDis.201335:430443.

PROGNOSIS
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.Trendsin10yearsurvivalofpatientswithstroke
hospitalizedbetween1980and2000: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.

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.

AcuteHypertension

Theroleofacuteelevationofbloodpressureinintracerebralhemorrhageisuncertain.Mostpatientsare
hypertensiveafterintracerebralhemorrhage,butthismaybeduetoacombinationofbaselinechronic
hypertensionandthevasopressorresponsetoincreasedintracranialpressure(Cushingreflex).Thatsome
patientswithintracerebralhemorrhagehavenohistoryofhypertensionandlacksignsofhypertensiveend
organdiseasesuggeststhatacutehypertensionmightbeatfault,asdoestheoccurrenceofintracerebral
hemorrhageinyoungpatientsafteramphetamineorcocaineabuse.
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,theduration
ofactivebleedingisbrief,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

DeepCerebralHemorrhage

Themostcommonsitesofhypertensivehemorrhagearetheputamenandthalamus,whichareseparatedby
theposteriorlimboftheinternalcapsule.Thissegmentoftheinternalcapsuleistraversedbydescendingmotor
andascendingsensoryfibers,includingtheopticradiations(Figure1317).Pressurefromanexpandinglateral
(putaminal)ormedial(thalamic)hematoma,therefore,producesacontralateralsensorimotordeficit.
Figure1317.

Anatomicrelationshipsindeepcerebralhemorrhage.Top:Planeofsection.Bottom:Putaminal(1)and
thalamic(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

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,butlargehemorrhagesleadto
comawithin12to24hoursinmostcases.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.

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.Resultsarebest
inconsciouspatients.
2. LobarhemorrhageSurgicalevacuationcanalsobeusefulforlobarhematomas,especiallythoselarger
than30mLinvolumeandlocatedwithinapproximately1cmofthebrainsurface.Patientswithgood
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.

VASCULARMALFORMATIONS

Ruptureofarteriovenousmalformations(AVMs)orsaccular(berry)aneurysmscancauseintracerebral
hemorrhage.AVMsconsistoftortuousarteriesanddilatedveinsandarisedevelopmentallywhenthe
interveningcapillarybedsfailtoform.Saccularaneurysmsareacquiredlesionsofarterialwalls,located
especiallyatbranchpointsaroundthecircleofWillis.AVMsmaybeasymptomaticorcausehemorrhage,
seizures,headache,orfocalneurologicdeficits.ForunrupturedAVMs,theriskofruptureis1%to3%peryear.
However,whenruptureoccursitcarriesa10%to30%mortalityrateand,forsurvivors,a6%riskofrerupture
overthenextyear.AnticonvulsantsarethetreatmentofchoiceforAVMsthatpresentwithseizures.Inthecase
ofhemorrhage,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
Globalcerebralischemiaoccurswhenbloodflowisinadequatetomeetmetabolicrequirementsofthebrain,as

incardiacarrest.Globalischemiaproducesmoreseverebraininjurythanpureanoxiawithpreservedcirculation
(eg,primaryrespiratoryarrestorcarbonmonoxidepoisoning),presumablybecauseitalsoimpairsglucose
deliveryandremovaloftoxicmetabolites.
PATHOLOGY
Theseverityofcerebralpathologyfromglobalischemiaisdirectlyrelatedtoischemiaduration.The
distributionofpathologyisgovernedbytheselectivevulnerabilityofcertainneuronalpopulationsandof
arterialwatershed(borderzone)regions.SelectivelyvulnerableneuronsincludeCA1pyramidalneuronsofthe
hippocampuscerebellarPurkinjeneuronspyramidalneuronsofneocorticallayers3,5,and6thalamic
reticularneuronsandmediumsizedneuronsinthecaudatenucleusandputamen.Arterialwatershedsare
locatedattheborderbetweentheanterior,middle,andposteriorcerebralarteries(Figure1319).
Reducedcerebralenergyrequirements,suchasoccurwithdeepanesthesiaorhypothermia,canminimizeor
preventbraindamagefromischemicinsults,whereashyperglycemiaorhypermetabolicstates(eg,status
epilepticus)canincreasedamage.Superimposeddiseaseofthecraniocervicalarteriesmayleadtoasymmetries
inthedistributionofcerebraldamagefromglobalischemia.
Figure1319.

Distributionofcerebralwatershed(borderzone)infarcts(blueareas)associatedwithglobalcerebralischemia.

CLINICALFINDINGS
BRIEFISCHEMIA

Reversibleencephalopathiesarecommonafterbriefcirculatoryarrest.Insuchcases,comapersistsforlessthan
12hours.Transientconfusionoramnesiamayoccuronawakening,butrecoveryistypicallyrapidand
complete.Somepatientsshowsevereanterogradeandvariableretrogradeamnesiaandabland,unconcerned
affectwithorwithoutconfabulation.Thissyndromemayreflectreversiblebilateraldamagetothethalamusor
hippocampus.
PROLONGEDISCHEMIA
Coma

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,synchronoustwitchingthatusuallyaffectsthe
faceandtrunk.Itsrelationshiptoepilepticseizuresisuncertain,asisthebenefitoftreatment,anditusually
portendsafataloutcome.Partialorgeneralizedseizures,includingstatusepilepticus,arealsoseenaftercardiac
arrest,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,andisconsistentwiththeclinicalfinding
offlaccidparaplegiaassociatedwithspinalcordinjuryaftercardiacarrest.
DAmoreC,PaciaroniM.Borderzoneandwatershedinfarctions.FrontNeurolNeurosci.201230:181184.
FernndezEspejoD,OwenAM.Detectingawarenessafterseverebraininjury.NatRevNeurosci.
201314:801809.
TREATMENT
Treatmentofglobalcerebralischemiainvolvesrestoringcerebralcirculation,eliminatingarrhythmias,
maintainingsystemicbloodpressure,andcorrectingacidbaseorelectrolyteabnormalities.Ventilatory
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.Continuousevaluationofneurological
prognosisaftercardiacarrest.ActaAnaesthesiolScand.201357:615.
GreerDM,RosenthalES,WuO.Neuroprognosticationofhypoxicischaemiccomainthetherapeutic
hypothermiaera.NatRevNeurol.201410:190203.

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