stroke ischemic

17/4/2015 IschemicStroke

http://emedicine.medscape.com/article/1916852overview#a0156 1/18

IschemicStrokeAuthor:EdwardCJauch,MD,MS,FAHA,FACEPChiefEditor:HelmiLLutsep,MDmore...

Updated:Jan20,2015

PracticeEssentialsIschemicstroke(seetheimagebelow)ischaracterizedbythesuddenlossofbloodcirculationtoanareaofthebrain,resultinginacorrespondinglossofneurologicfunction.Acuteischemicstrokeiscausedbythromboticorembolicocclusionofacerebralarteryandismorecommonthanhemorrhagicstroke.

Maximumintensityprojection(MIP)imagefromacomputedtomographyangiogram(CTA)demonstratesafillingdefectorhighgradestenosisatthebranchingpointoftherightmiddlecerebralartery(MCA)trunk(redcircle),suspiciousforthrombusorembolus.CTAishighlyaccurateindetectinglargevesselstenosisandocclusions,whichaccountforapproximatelyonethirdofischemicstrokes.

SeeAcuteStroke,aCriticalImagesslideshow,formoreinformationonincidence,presentation,intervention,andadditionalresources.

Essentialupdate:Studyindicatesintraarterialtreatmentimprovesfunctionalrecoveryinacuteischemicstroke

ArandomizedclinicaltrialfromtheNetherlandsindicatesthatendovascularinterventionbenefitsfunctionaloutcomesinpatientswithacuteischemicstrokeresultingfromaproximalintracranialarterialocclusion.Inthestudy,byBerkhemeretal,500patientswererandomizedtoreceiveintraarterialtreatment(within6hoursofsymptomonset)orusualtreatmentalone.Although89%ofthepatientsweretreatedwithtissuetypeplasminogenactivator(tPA)priortorandomization,onlythosewhowerefoundoncomputedtomography(CT)angiographytostillhaveaproximalarterialocclusionwereenteredintothestudy.Inmostofthepatientswhoreceivedintraarterialtreatment,theprocedurewasperformedwithlatestgenerationstentretrievers.[1,2]

Theinvestigatorsfoundthatat90days,therateoffunctionalindependence(modifiedRankinscalescoreof02)intheintraarterialtreatmentgroupwas32.6%,comparedwith19.1%intheusualtreatmentonlygroup,whileafter57days,theNationalInstitutesofHealthStrokeScale(NIHSS)scorewasanaverageof2.9pointslowerintheintraarterialtreatmentpatientsthanitwasintheothergroup.Thetwogroupsdidnotdiffersignificantlywithregardtotherateofmoralityorsymptomaticintracerebralhemorrhage.

Signsandsymptoms

Considerstrokeinanypatientpresentingwithacuteneurologicdeficitoranyalterationinlevelofconsciousness.Commonstrokesignsandsymptomsincludethefollowing:

Abruptonsetofhemiparesis,monoparesis,or(rarely)quadriparesisHemisensorydeficitsMonocularorbinocularvisuallossVisualfielddeficitsDiplopiaDysarthriaFacialdroopAtaxiaVertigo(rarelyinisolation)NystagmusAphasiaSuddendecreaseinlevelofconsciousness

Althoughsuchsymptomscanoccuralone,theyaremorelikelytooccurincombination.Nohistoricalfeaturedistinguishesischemicfromhemorrhagicstroke,althoughnausea,vomiting,headache,andsuddenchangeinlevelofconsciousnessaremorecommoninhemorrhagicstrokes.Inyoungerpatients,ahistoryofrecenttrauma,coagulopathies,illicitdruguse(especiallycocaine),migraines,oruseoforalcontraceptivesshouldbeelicited.

Withtheavailabilityoffibrinolytictherapyforacuteischemicstrokeinselectedpatients,thephysicianmustbeabletoperformabriefbutaccurateneurologicexaminationonpatientswithsuspectedstrokesyndromes.Thegoalsoftheneurologicexaminationincludethefollowing:

ConfirmingthepresenceofastrokesyndromeDistinguishingstrokefromstrokemimicsEstablishinganeurologicbaseline,shouldthepatient'sconditionimproveordeteriorate



Establishingstrokeseverity,usingastructuredneurologicexamandscore(NationalInstitutesofHealthStrokeScale[NIHSS])toassistinprognosisandtherapeuticselection

Essentialcomponentsoftheneurologicexaminationincludethefollowingevaluations:

CranialnervesMotorfunctionSensoryfunctionCerebellarfunctionGaitDeeptendonreflexesLanguage(expressiveandreceptivecapabilities)Mentalstatusandlevelofconsciousness

Theskullandspinealsoshouldbeexamined,andsignsofmeningismusshouldbesought.

SeeClinicalPresentationformoredetail.

Diagnosis

Emergentbrainimagingisessentialforconfirmingthediagnosisofischemicstroke.Noncontrastcomputedtomography(CT)scanningisthemostcommonlyusedformofneuroimagingintheacuteevaluationofpatientswithapparentacutestroke.Thefollowingneuroimagingtechniquesarealsoused:

CTangiographyandCTperfusionscanningMagneticresonanceimaging(MRI)CarotidduplexscanningDigitalsubtractionangiography

Lumbarpuncture

AlumbarpunctureisrequiredtoruleoutmeningitisorsubarachnoidhemorrhagewhentheCTscanisnegativebuttheclinicalsuspicionremainshigh

Laboratorystudies

Laboratorytestsperformedinthediagnosisandevaluationofischemicstrokeincludethefollowing:

Completebloodcount(CBC):Abaselinestudythatmayrevealacauseforthestroke(eg,polycythemia,thrombocytosis,thrombocytopenia,leukemia)orprovideevidenceofconcurrentillness(eg,anemia)Basicchemistrypanel:Abaselinestudythatmayrevealastrokemimic(eg,hypoglycemia,hyponatremia)orprovideevidenceofconcurrentillness(eg,diabetes,renalinsufficiency)Coagulationstudies:MayrevealacoagulopathyandareusefulwhenfibrinolyticsoranticoagulantsaretobeusedCardiacbiomarkers:ImportantbecauseoftheassociationofcerebralvasculardiseaseandcoronaryarterydiseaseToxicologyscreening:Mayassistinidentifyingintoxicatedpatientswithsymptoms/behaviormimickingstrokesyndromesPregnancytesting:Aurinepregnancytestshouldbeobtainedforallwomenofchildbearingagewithstrokesymptomsrecombinanttissuetypeplasminogenactivator(rtPA)isapregnancyclassCagentArterialbloodgasanalysis:Inselectedpatientswithsuspectedhypoxemia,arterialbloodgasdefinestheseverityofhypoxemiaandmaybeusedtodetectacidbasedisturbances

SeeWorkupformoredetail.

Management

Thegoalfortheemergentmanagementofstrokeistocompletethefollowingwithin60minutesofpatientarrival[3]:

Assessairway,breathing,andcirculation(ABCs)andstabilizethepatientasnecessaryCompletetheinitialevaluationandassessment,includingimagingandlaboratorystudiesInitiatereperfusiontherapy,ifappropriate

Criticaltreatmentdecisionsfocusonthefollowing:

TheneedforairwaymanagementOptimalbloodpressurecontrolIdentifyingpotentialreperfusiontherapies(eg,intravenousfibrinolysiswithrtPAorintraarterialapproaches)

Involvementofaphysicianwithaspecialinterestinstrokeisideal.Strokecareunitswithspeciallytrainedpersonnelexistandimproveoutcomes.

Ischemicstroketherapiesincludethefollowing:

FibrinolytictherapyAntiplateletagents[4,5]Mechanicalthrombectomy

Treatmentofcomorbidconditionsmayincludethefollowing:

ReducefeverCorrecthypotension/significanthypertensionCorrecthypoxiaCorrecthypoglycemiaManagecardiacarrhythmiasManagemyocardialischemia

Strokeprevention



Primarystrokepreventionreferstothetreatmentofindividualswithnoprevioushistoryofstroke.Measuresmayincludeuseofthefollowing:

PlateletantiaggregantsStatinsExerciseLifestyleinterventions(eg,smokingcessation,alcoholmoderation)

Secondarypreventionreferstothetreatmentofindividualswhohavealreadyhadastroke.Measuresmayincludeuseofthefollowing:

PlateletantiaggregantsAntihypertensivesStatinsLifestyleinterventions

SeeTreatmentandMedicationformoredetail.

BackgroundAcuteischemicstroke(AIS)ischaracterizedbythesuddenlossofbloodcirculationtoanareaofthebrain,typicallyinavascularterritory,resultinginacorrespondinglossofneurologicfunction.Alsopreviouslycalledcerebrovascularaccident(CVA)orstrokesyndrome,strokeisanonspecificstateofbraininjurywithneuronaldysfunctionthathasseveralpathophysiologiccauses.Strokescanbedividedinto2types:hemorrhagicorischemic.Acuteischemicstrokeiscausedbythromboticorembolicocclusionofacerebralartery.(Seetheimagebelow.)


Nearly800,000peoplesufferstrokeseachyearintheUnitedStates8292%ofthesestrokesareischemic.Strokeisthefourthleadingcauseofadultdeathanddisability,resultinginover$72billioninannualcost.[6]

Ischemicandhemorrhagicstrokecannotbereliablydifferentiatedonthebasisofclinicalexaminationfindingsalone.Furtherevaluation,especiallywithbrainimagingtests(ie,computedtomography[CT]scanningormagneticresonanceimaging[MRI]),isrequired.(SeeWorkup.)

Strokecategories

ThesystemofcategorizingstrokedevelopedinthemulticenterTrialofORG10172inAcuteStrokeTreatment(TOAST)dividesischemicstrokesintothefollowing3majorsubtypes[4]:

LargearterySmallvessel,orlacunarCardioembolicinfarction

Largearteryinfarctionsofteninvolvethromboticinsituocclusionsonatheroscleroticlesionsinthecarotid,vertebrobasilar,andcerebralarteries,typicallyproximaltomajorbrancheshowever,largearteryinfarctionsmayalsobecardioembolic.

Cardiogenicemboliareacommonsourceofrecurrentstroke.Theymayaccountforupto20%ofacutestrokesandhavebeenreportedtohavethehighest1monthmortality.[7](SeePathophysiology.)

Treatment

Recanalizationstrategies,includingintravenousrecombinanttissuetypeplasminogenactivator(rtPA)andintraarterialapproaches,attempttoestablishrevascularizationsothatcellsintheischemicpenumbra(ametabolicallyactiveregion,peripheraltotheischemicarea,wherebloodflowisreduced)canberescuedbeforeirreversibleinjuryoccurs.Restoringbloodflowcanmitigatetheeffectsofischemiaonlyifperformedquickly.

TheUSFoodandDrugAdministration(FDA)hasapprovedtheuseofrtPAinpatientswhomeetcriteriasetforthbytheNationalInstituteofNeurologicDisordersandStroke(NINDS).Inparticular,rtPAmustbegivenwithin3hoursofstrokeonsetandonlyafterCTscanninghasruledouthemorrhagicstroke.

OnthebasisofrecentEuropeandata,theAmericanHeartAssociationandAmericanStrokeAssociationrecommendedexpandingthewindowoftreatmentfrom3hoursto4.5hours,withmorestringentexclusioncriteriaforthelaterperiod(seeTreatment).TheFDAhasnotyetapprovedrtPAforthisexpandedindication,butthishasbecomethecommunitystandardinmanyinstitutions.

Otheraspectsoftreatmentforacuteischemicstrokeincludethefollowing:

Treatmentofneurologiccomplications

Supplementaloxygenasrequired



AntiplatelettherapyGlycemiccontrolOptimalbloodpressurecontrolPreventionofhyperthermia

SeealsoHemorrhagicStroke.

AnatomyThebrainisthemostmetabolicallyactiveorganinthebody.Whilerepresentingonly2%ofthebody'smass,itrequires1520%ofthetotalrestingcardiacoutputtoprovidethenecessaryglucoseandoxygenforitsmetabolism.

Knowledgeofcerebrovasculararterialanatomyandtheterritoriessuppliedbythecerebralarteriesisusefulindeterminingwhichvesselsareinvolvedinacutestroke.Atypicalpatternsofbrainischemiathatdonotconformtospecificvasculardistributionsmayindicateadiagnosisotherthanischemicstroke,suchasvenousinfarction.

Arterialdistributions

Inasimplifiedmodel,thecerebralhemispheresaresuppliedby3pairedmajorarteries,specifically,theanterior,middle,andposteriorcerebralarteries.

Theanteriorandmiddlecerebralarteriescarrytheanteriorcirculationandarisefromthesupraclinoidinternalcarotidarteries.Theanteriorcerebralartery(ACA)suppliesthemedialportionofthefrontalandparietallobesandanteriorportionsofbasalgangliaandanteriorinternalcapsule.(Seetheimagebelow.)

Lateralviewofacerebralangiogramillustratesthebranchesoftheanteriorcerebralartery(ACA)andSylviantriangle.ThepericallosalarteryhasbeendescribedtoarisedistaltotheanteriorcommunicatingarteryordistaltotheoriginofthecallosomarginalbranchoftheACA.ThesegmentalanatomyoftheACAhasbeendescribedasfollows:theA1segmentextendsfromtheinternalcarotidartery(ICA)bifurcationtotheanteriorcommunicatingarteryA2extendstothejunctionoftherostrumandgenuofthecorpuscallosumA3extendsintothebendofthegenuofthecorpuscallosumA4andA5extendposteriorlyabovethecallosalbodyandsuperiorportionofthesplenium.TheSylviantriangleoverliestheopercularbranchesofthemiddlecerebralartery(MCA),withtheapexrepresentingtheSylvianpoint.

Themiddlecerebralartery(MCA)suppliesthelateralportionsofthefrontalandparietallobes,aswellastheanteriorandlateralportionsofthetemporallobes,andgivesrisetoperforatingbranchestotheglobuspallidus,putamen,andinternalcapsule.TheMCAisthedominantsourceofvascularsupplytothehemispheres.(Seetheimagesbelow.)

Thesupratentorialvascularterritoriesofthemajorcerebralarteriesaredemonstratedsuperimposedonaxial(left)andcoronal(right)T2weightedimagesthroughthelevelofthebasalgangliaandthalami.Themiddlecerebralartery(MCAred)suppliesthelateralaspectsofthehemispheres,includingthelateralfrontal,parietal,andanteriortemporallobesinsulaandbasalganglia.Theanteriorcerebralartery(ACAblue)suppliesthemedialfrontalandparietallobes.Theposteriorcerebralartery(PCAgreen)suppliesthethalamiandoccipitalandinferiortemporallobes.Theanteriorchoroidalartery(yellow)suppliestheposteriorlimboftheinternalcapsuleandpartofthehippocampusextendingtotheanteriorandsuperiorsurfaceoftheoccipitalhornofthelateralventricle.

Frontalviewofacerebralangiogramwithselectiveinjectionoftheleftinternalcarotidartery(ICA)illustratestheanteriorcirculation.Theanteriorcerebralartery(ACA)consistsoftheA1segmentproximaltotheanteriorcommunicatingartery,withtheA2segmentdistaltoit.Themiddlecerebralartery(MCA)canbedividedinto4segments:theM1(horizontalsegment)extendstotheanteriorbasalportionoftheinsularcortex(thelimeninsulae)andgivesofflaterallenticulostriatebranches,theM2(insularsegment),M3(opercularbranches),andM4(distalcorticalbranchesonthelateralhemisphericconvexities).

Theposteriorcerebralarteriesarisefromthebasilararteryandcarrytheposteriorcirculation.Theposteriorcerebralartery(PCA)givesrisetoperforatingbranchesthatsupplythethalamiandbrainstemandthecorticalbranchestotheposteriorandmedialtemporallobesandoccipitallobes.(SeeTable1,below.)

Thecerebellarhemispheresaresuppliedasfollows:

Inferiorlybytheposteriorinferiorcerebellarartery(PICA),arisingfromthevertebralartery(seetheimagebelow)



Frontalprojectionfromarightvertebralarteryangiogramillustratestheposteriorcirculation.Thevertebralarteriesjointoformthebasilarartery.Theposteriorinferiorcerebellararteries(PICAs)arisefromthedistalvertebralarteries.Theanteriorinferiorcerebellararteries(AICAs)arisefromtheproximalbasilarartery.Thesuperiorcerebellararteries(SICAs)arisedistallyfromthebasilararterypriortoitsbifurcationintotheposteriorcerebralarteries(PCAs).

SuperiorlybythesuperiorcerebellararteryAnterolaterallybytheanteriorinferiorcerebellarartery(AICA),fromthebasilarartery

Table1.VascularSupplytotheBrain(OpenTableinanewwindow)

VASCULARTERRITORY StructuresSuppliedAnteriorCirculation(Carotid)AnteriorCerebralArtery Corticalbranches:medialfrontalandparietallobe

Mediallenticulostriatebranches:caudatehead,globuspallidus,anteriorlimbofinternalcapsule

MiddleCerebralArtery Corticalbranches:lateralfrontalandparietallobeslateralandanteriortemporallobe

Laterallenticulostriatebranches:globuspallidusandputamen,internalcapsule

AnteriorChoroidalArtery Optictracts,medialtemporallobe,ventrolateralthalamus,coronaradiata,posteriorlimboftheinternalcapsule

PosteriorCirculation(Vertebrobasilar)PosteriorCerebralArtery Corticalbranches:occipitallobes,medialandposteriortemporalandparietallobes

Perforatingbranches:brainstem,posteriorthalamusandmidbrain

PosteriorInferiorCerebellarArtery

Inferiorvermisposteriorandinferiorcerebellarhemispheres

AnteriorInferiorCerebellarArtery

Anterolateralcerebellum

SuperiorCerebellarArtery Superiorvermissuperiorcerebellum

PathophysiologyAcuteischemicstrokesresultfromvascularocclusionsecondarytothromboembolicdisease(seeEtiology).Ischemiacausescellhypoxiaanddepletionofcellularadenosinetriphosphate(ATP).WithoutATP,thereisnolongertheenergytomaintainionicgradientsacrossthecellmembraneandcelldepolarization.Influxofsodiumandcalciumionsandpassiveinflowofwaterintothecellleadtocytotoxicedema.[8,9,10]

Ischemiccoreandpenumbra

Anacutevascularocclusionproducesheterogeneousregionsofischemiaintheaffectedvascularterritory.Localbloodflowislimitedtoanyresidualflowinthemajorarterialsourceplusthecollateralsupply,ifany.

Affectedregionswithcerebralbloodflowoflowerthan10mL/100goftissue/minarereferredtocollectivelyasthecore.Thesecellsarepresumedtodiewithinminutesofstrokeonset.[11]

Zonesofdecreasedormarginalperfusion(cerebralbloodflow



systemsfail.Disruptionofcellularmetabolismalsoimpairsnormalsodiumpotassiumplasmamembranepumps,producinganintracellularincreaseinsodium,whichinturnsincreasesintracellularwatercontent.Thiscellularswellingisreferredtoascytotoxicedemaandoccursveryearlyincerebralischemia.

Cerebralischemiaimpairsthenormalsodiumcalciumexchangeproteinalsofoundoncellplasmamembranes.Theresultinginfluxofcalciumleadstothereleaseofanumberofneurotransmitters,includinglargequantitiesofglutamate,whichinturnactivatesNmethylDaspartate(NMDA)andotherexcitatoryreceptorsonotherneurons.

Theseneuronsthenbecomedepolarized,causingfurthercalciuminflux,furtherglutamaterelease,andlocalamplificationoftheinitialischemicinsult.Thismassivecalciuminfluxalsoactivatesvariousdegradativeenzymes,leadingtothedestructionofthecellmembraneandotheressentialneuronalstructures.[12]Freeradicals,arachidonicacid,andnitricoxidearegeneratedbythisprocess,whichleadstofurtherneuronaldamage.

Ischemiaalsodirectlyresultsindysfunctionofthecerebralvasculature,withbreakdownofthebloodbrainbarrieroccurringwithin46hoursafterinfarction.Followingthebarriersbreakdown,proteinsandwaterfloodintotheextracellularspace,leadingtovasogenicedema.Thisproducesgreaterlevelsofbrainswellingandmasseffectthatpeakat35daysandresolveoverthenextseveralweekswithresorptionofwaterandproteins.[13,14]

Withinhourstodaysafterastroke,specificgenesareactivated,leadingtotheformationofcytokinesandotherfactorsthat,inturn,causefurtherinflammationandmicrocirculatorycompromise.[12]Ultimately,theischemicpenumbraisconsumedbytheseprogressiveinsults,coalescingwiththeinfarctedcore,oftenwithinhoursoftheonsetofthestroke.

Infarctionresultsinthedeathofastrocytes,aswellasthesupportingoligodendroglialandmicroglialcells.Theinfarctedtissueeventuallyundergoesliquefactionnecrosisandisremovedbymacrophages,withthedevelopmentofparenchymalvolumeloss.Awellcircumscribedregionofcerebrospinalfluidlikelowdensity,resultingfromencephalomalaciaandcysticchange,iseventuallyseen.Theevolutionofthesechronicchangesmaybeseenintheweekstomonthsfollowingtheinfarction.(Seetheimagesbelow.)

Vasculardistributions:Middlecerebralartery(MCA)infarction.Noncontrastcomputedtomography(CT)scanningdemonstratesalargeacuteinfarctionintheMCAterritoryinvolvingthelateralsurfacesoftheleftfrontal,parietal,andtemporallobes,aswellastheleftinsularandsubinsularregions,withmasseffectandrightwardmidlineshift.Thereissparingofthecaudateheadandatleastpartofthelentiformnucleusandinternalcapsule,whichreceivebloodsupplyfromthelaterallenticulostriatebranchesoftheM1segmentoftheMCA.Notethelackofinvolvementofthemedialfrontallobe(anteriorcerebralartery[ACA]territory),thalami,andparamedianoccipitallobe(posteriorcerebralartery[PCA]territory).

Vasculardistributions:Anteriorcerebralartery(ACA)infarction.Diffusionweightedimageontheleftdemonstrateshighsignalintheparamedianfrontalandhighparietalregions.TheoppositediffusionweightedimageinadifferentpatientdemonstratesrestricteddiffusioninalargerACAinfarctioninvolvingtheleftparamedianfrontalandposteriorparietalregions.Thereisalsoinfarctionofthelateraltemporoparietalregionsbilaterally(bothmiddlecerebralartery[MCA]distributions),greaterontheleftindicatingmultivesselinvolvementandsuggestingemboli.

Vasculardistributions:Posteriorcerebralartery(PCA)infarction.Thenoncontrastcomputedtomography(CT)imagesdemonstratePCAdistributioninfarctioninvolvingtherightoccipitalandinferomedialtemporallobes.Theimageontherightdemonstratesadditionalinvolvementofthethalamus,alsopartofthePCAterritory.

Vasculardistributions:Anteriorchoroidalarteryinfarction.Thediffusionweightedimage(left)demonstrateshighsignalwithassociatedsignaldropoutontheapparentdiffusioncoefficient(ADC)mapinvolvingtheposteriorlimboftheinternalcapsule.Thisisthetypicaldistributionoftheanteriorchoroidalartery,thelastbranchoftheinternalcarotidartery(ICA)beforebifurcatingintotheanteriorandmiddlecerebralarteries.Theanteriorchoroidalarterymayalsoarisefromthemiddlecerebralartery(MCA).

Hemorrhagictransformationofischemicstroke

Hemorrhagictransformationrepresentstheconversionofanischemicinfarctionintoanareaofhemorrhage.Thisisestimatedtooccurin5%ofuncomplicatedischemicstrokes,intheabsenceoffibrinolytictreatment.Hemorrhagictransformationisnotalwaysassociatedwithneurologicdecline,withtheconversionrangingfromthedevelopmentofsmallpetechialhemorrhagestotheformationofhematomasthatproduceneurologicdeclineandmay



necessitatesurgicalevacuationordecompressivehemicraniectomy.

Proposedmechanismsforhemorrhagictransformationincludereperfusionofischemicallyinjuredtissue,eitherfromrecanalizationofanoccludedvesselorfromcollateralbloodsupplytotheischemicterritoryordisruptionofthebloodbrainbarrier.Withdisruptionofthebloodbrainbarrier,redbloodcellsextravasatefromtheweakenedcapillarybed,producingpetechialhemorrhageormorefrankintraparenchymalhematoma.[8,15,16]

Hemorrhagictransformationofanischemicinfarctoccurswithin214dayspostictus,usuallywithinthefirstweek.Itismorecommonlyseenfollowingcardioembolicstrokesandismorelikelytooccurwithlargerinfarctvolumes.[5,8,17]HemorrhagictransformationisalsomorelikelyfollowingadministrationofrtPAinpatientswhosenoncontrastCT(NCCT)scansdemonstrateareasofhypodensity.[18,19,20]

Poststrokecerebraledemaandseizures

Althoughclinicallysignificantcerebraledemacanoccurafteranteriorcirculationischemicstroke,itisthoughttobesomewhatrare(1020%).[3]Edemaandherniationarethemostcommoncausesofearlydeathinpatientswithhemisphericstroke.

Seizuresoccurin223%ofpatientswithinthefirstdaysafterischemicstroke.[3]Afractionofpatientswhohaveexperiencedstrokedevelopchronicseizuredisorders.

EtiologyIschemicstrokesresultfromeventsthatlimitorstopbloodflow,suchasextracranialorintracranialthromboticembolism,thrombosisinsitu,orrelativehypoperfusion.Asbloodflowdecreases,neuronsceasefunctioning.Althougharangeofthresholdshasbeendescribed,irreversibleneuronalischemiaandinjuryisgenerallythoughttobeginatbloodflowratesoflessthan18mL/100goftissue/min,withcelldeathoccurringrapidlyatratesbelow10mL/100goftissue/min

Riskfactors

Riskfactorsforischemicstrokeincludemodifiableandnonmodifiableconditions.Identificationofriskfactorsineachpatientcanuncovercluestothecauseofthestrokeandthemostappropriatetreatmentandsecondarypreventionplan.

Nonmodifiableriskfactorsincludethefollowing(althoughtherearelikelymanyothers):

AgeRaceSexEthnicityHistoryofmigraineheadaches[21]FibromusculardysplasiaHeredity:Familyhistoryofstrokeortransientischemicattacks(TIAs)

Inaprospectivestudyof27,860womenaged45yearsorolderwhowereparticipatingintheWomen'sHealthStudy,Kurthetalfoundthatmigrainewithaurawasastrongriskfactorforanytypeofstroke.Theadjustedincidenceofthisriskfactorper1000womenperyearwassimilartothoseofotherknownriskfactors,includingsystolicbloodpressure180mmHgorhigher,bodymassindex35kg/m2orgreater,historyofdiabetes,familyhistoryofmyocardialinfarction,andsmoking.[22]

Formigrainewithaura,thetotalincidenceofstrokeinthestudywas4.3per1000womenperyear,theincidenceofischemicstrokewas3.4per1000peryear,andtheincidenceofhemorrhagicstrokewas0.8per1000peryear.

Modifiableriskfactorsincludethefollowing[23]:

Hypertension(themostimportant)DiabetesmellitusCardiacdisease:Atrialfibrillation,valvulardisease,heartfailure,mitralstenosis,structuralanomaliesallowingrighttoleftshunting(eg,patentforamenovale),andatrialandventricularenlargementHypercholesterolemiaTIAsCarotidstenosisHyperhomocystinemiaLifestyleissues:Excessivealcoholintake,tobaccouse,illicitdruguse,physicalinactivity[24]ObesityOralcontraceptiveuse/postmenopausalhormoneuseSicklecelldisease

In2014,theAmericanHeartAssociationandtheAmericanStrokeAssociationissuedguidelinesforthereductionofstrokeriskspecificallyinwomen.Thesegenderspecificrecommendationsincludethefollowing[25,26]:

AstrokeriskscoreshouldbedevelopedspecificallyforwomenWomenwithahistoryofhighbloodpressurebeforepregnancyshouldbeconsideredforlowdoseaspirinand/orcalciumsupplementtreatmenttoreducetheriskofpreeclampsiaBloodpressuremedicationmaybeconsideredforpregnantwomenwithmoderatelyhighbloodpressure(150159mmHg/100109mmHg),andpregnantwomenwithseverehighbloodpressure(160/110mmHgorabove)shouldbetreatedWomenshouldbescreenedforhighbloodpressurebeforetheystartusingbirthcontrolpillsbecauseofanincreasedriskofstrokeWomenwithmigraineheadacheswithaurashouldbeencouragedtoquitsmokingtoreducetheriskofstrokeWomenoverage75shouldbescreenedforatrialfibrillation

Geneticandinflammatorymechanisms



Evidencecontinuestoaccumulatethatinflammationandgeneticfactorshaveimportantrolesinthedevelopmentofatherosclerosisand,specifically,instroke.Accordingtothecurrentparadigm,atherosclerosisisnotablandcholesterolstoragedisease,aspreviouslythought,butadynamic,chronic,inflammatoryconditioncausedbyaresponsetoendothelialinjury.

Traditionalriskfactors,suchasoxidizedlowdensitylipoprotein(LDL)cholesterolandsmoking,contributetothisinjury.Ithasbeensuggested,however,thatinfectionsmayalsocontributetoendothelialinjuryandatherosclerosis.

Hostgeneticfactors,moreover,maymodifytheresponsetotheseenvironmentalchallenges,althoughinheritedriskforstrokeislikelymultigenic.Evenso,specificsinglegenedisorderswithstrokeasacomponentofthephenotypedemonstratethepotencyofgeneticsindeterminingstrokerisk.

Anumberofgenesareknowntoincreasesusceptibilitytoischemicstroke.MutationstotheF2andF5genesarerelativelycommoninthegeneralpopulationandincreasetheriskofthrombosis.Mutationsinthefollowinggenesalsoareknowntoincreasetheriskofstroke:

NOS3:Anitricoxidesynthetasegeneinvolvedinvascularrelaxation[27]ALOX5AP:Involvedinthemetabolismofarachidonicacid[28]PRKCH:Involvedinmajorsignaltransductionsystems[29]

Hyperhomocysteinemiaandhomocystinuria

Hyperhomocysteinemiaisimplicatedinthepathogenesisofischemicstroke.Themostcommonconcernismutationsinthe5,10methylenetetrahydrofolatereductase(MTHFR)gene.Inmanypopulations,themutantallelefrequencyreachespolymorphicproportions,andtheriskfactorforcerebrovasculardiseaseisrelatedtotheserumlevelofhomocysteine.Furthermore,inpersonswhoarecompoundheterozygotesforMTHFRmutation,ifelevatedhomocysteineisfounditcanbeloweredwithoralfolicacidtherapy.

Inaddition,hyperhomocysteinemiacanbeseenincystathionebetasynthetase(CBS)deficiency,whichisgenerallyreferredtoashomocystinuria.Thisdisorderisinheritedinanautosomalrecessivemanner.Symptomsusuallymanifestearlyinlife.Patientshaveamarfanoidhabitus,ectopialentis,andmyopiaandgenerallyhaveintellectualdisability.[30]

Thromboemboliceventsarethemostcommoncauseofdeathforpatientswithhomocystinuriaandmaybeofanytype,includingmyocardialinfarction.Theriskofhavingavasculareventinhomocystinuriais50%byage30.[31]ItwaspreviouslysuggestedthatpersonswhoareheterozygousformutationsintheCBSgenemayhaveanincreasedriskofcerebrovasculardiseaseaswell,butseveralmorerecentstudiesonthissubjectfailedtoreplicatethisfinding.

Amyloidangiopathies

Amyloidangiopathiesarealsoknowntoincreaseriskforstrokeanddementia.MutationsintheCST3genearecausativeandareinheritedinanautosomaldominantmanner.Suffererswillhavediffusedepositionofamyloid,includinginthebrain.Theonsetofsymptomsistypicallyinthethirdorfourthdecadeoflife,withdeathoccurringbeforeage60years.TheseangiopathiesappeartobemostcommonintheIcelandicpopulation.[32]

CADASIL

Cerebralarteriopathy,autosomaldominant,withsubcorticalinfarctsandleukoencephalopathy(CADASIL),iscausedbymutationsintheNOTCH3gene.Itaffectsthesmallarteriesofthebrain.Strokelikeepisodestypicallyoccuratameanageof46years,withanagerangeof1967years.Whitematterchangesinthebrainaretypicallyevidentbyyoungadulthoodandprogressovertime.[33]

Migraineheadachesoccurin3040%ofpeoplewithCADASIL.Approximately60%ofsymptomaticindividualshavecognitivedeficits,whichcanstartasearlyasage35years,andmanydevelopmultiinfarctdementia.[34]

Othermutations

Genomewideassociationstudieshaverevealedadditionallocithatarecommonlyassociatedwithischemicstroke.Earlyonsetischemicstrokehasbeenfoundtobeassociatedwith2singlenucleotidepolymorphismson2q23.3.[35]

LargevesselstrokehasbeenassociatedwithvariationsinHDAC9,PITX2,andZFHX3.[36]HDAC9islocatedon7p21.1,whilePITX2andZFHX3arelocatedon9p21.Itisofnotethatthe9p21locushasalsobeenassociatedwithcardiovasculardisease.

Apolymorphismat2q36.3wasfoundinwhichadenosinesubstitutionconferredalowerriskofischemicstrokeinanadditivefashion.[37]Anadditionalstudysuggestedanassociationbetweenischemicstrokeandalocuson12p13.[38]

Formoreinformation,seeGeneticandInflammatoryMechanismsinStroke.Inaddition,completeinformationonthefollowingmetabolicdiseasesandstrokecanbefoundinthefollowingmainarticles:

MethylmalonicAcidemiaHomocystinuria/HomocysteinemiaFabryDiseaseMELASSyndromeHyperglycemiaandHypoglycemiainStroke

Largearteryocclusion

Largearteryocclusiontypicallyresultsfromembolizationofatheroscleroticdebrisoriginatingfromthecommonorinternalcarotidarteriesorfromacardiacsource.Asmallernumberoflargearteryocclusionsmayarisefromplaqueulcerationandinsituthrombosis.LargevesselischemicstrokesmorecommonlyaffecttheMCAterritory,withtheACAterritoryaffectedtoalesserdegree.(Seetheimagesbelow.)



Noncontrastcomputedtomography(CT)scanina52yearoldmanwithahistoryofworseningrightsidedweaknessandaphasiademonstratesdiffusehypodensityandsulcaleffacementwithmasseffectinvolvingtheleftanteriorandmiddlecerebralarteryterritoriesconsistentwithacuteinfarction.Therearescatteredcurvilinearareasofhyperdensitynotedsuggestiveofdevelopingpetechialhemorrhageinthislargeareaofinfarction.

Magneticresonanceangiogram(MRA)ina52yearoldmandemonstratesocclusionoftheleftprecavernoussupraclinoidinternalcarotidartery(ICA,redcircle),occlusionorhighgradestenosisofthedistalmiddlecerebralartery(MCA)trunkandattenuationofmultipleM2branches.Thediffusionweightedimage(right)demonstrateshighsignalconfirmedtobetruerestricteddiffusionontheapparentdiffusioncoefficient(ADC)mapconsistentwithacuteinfarction.


Lacunarstrokes

Lacunarstrokesrepresent1320%ofallischemicstrokes.TheyresultfromocclusionofthepenetratingbranchesoftheMCA,thelenticulostriatearteries,orthepenetratingbranchesofthecircleofWillis,vertebralartery,orbasilarartery.Thegreatmajorityoflacunarstrokesarerelatedtohypertension.(Seetheimagebelow.)

Axialnoncontrastcomputedtomography(CT)scandemonstratesafocalareaofhypodensityintheleftposteriorlimboftheinternalcapsuleina60yearoldmanwithacuteonsetofrightsidedweakness.Thelesiondemonstrateshighsignalonthefluidattenuatedinversionrecovery(FLAIR)sequence(middleimage)anddiffusionweightedmagneticresonanceimaging(MRI)scan(rightimage),withlowsignalontheapparentdiffusioncoefficient(ADC)mapsindicatinganacutelacunarinfarction.Lacunarinfarctsaretypicallynomorethan1.5cminsizeandcanoccurinthedeepgraymatterstructures,coronaradiata,brainstem,andcerebellum.

Causesoflacunarinfarctsincludethefollowing:

MicroatheromaLipohyalinosisFibrinoidnecrosissecondarytohypertensionorvasculitisHyalinearteriosclerosisAmyloidangiopathyMicroemboli

Embolicstrokes

Cardiogenicembolimayaccountforupto20%ofacutestrokes.Embolimayarisefromtheheart,theextracranialarteries,includingtheaorticarchor,rarely,therightsidedcirculation(paradoxicalemboli)withsubsequentpassagethroughapatentforamenovale.[39]Sourcesofcardiogenicemboliincludethefollowing:

Valvularthrombi(eg,inmitralstenosisorendocarditisorfromuseofaprostheticvalve)Muralthrombi(eg,inmyocardialinfarction,atrialfibrillation,dilatedcardiomyopathy,orseverecongestiveheartfailure)Atrialmyxoma

Acutemyocardialinfarctionisassociatedwitha23%incidenceofembolicstrokes,ofwhich85%occurinthefirstmonthaftertheinfarction.[40]Embolicstrokestendtohaveasuddenonset,andneuroimagingmaydemonstratepreviousinfarctsinseveralvascularterritoriesormayshowcalcificemboli.



Cardioembolicstrokesmaybeisolated,multipleandinasinglehemisphere,orscatteredandbilateralthelatter2typesindicatemultiplevasculardistributionsandaremorespecificforcardioembolism.Multipleandbilateralinfarctscanbetheresultofembolicshowersorrecurrentemboli.Otherpossibilitiesforsingleandbilateralhemisphericinfarctionsincludeembolioriginatingfromtheaorticarchanddiffusethromboticorinflammatoryprocessesthatcanleadtomultiplesmallvesselocclusions.(Seetheimagebelow.)[41,42]

Cardioembolicstroke:Axialdiffusionweightedimagesdemonstratescatteredfociofhighsignalinthesubcorticalanddeepwhitematterbilaterallyinapatientwithaknowncardiacsourceforembolization.Anareaoflowsignalintheleftgangliocapsularregionmaybesecondarytopriorhemorrhageorsubacutetochroniclacunarinfarct.Recurrentstrokesaremostcommonlysecondarytocardioembolicphenomenon.

Formoreinformation,seeCardioembolicStroke.

Thromboticstrokes

Thrombogenicfactorsmayincludeinjurytoandlossofendothelialcellsthislossexposesthesubendotheliumandresultsinplateletactivationbythesubendothelium,activationoftheclottingcascade,inhibitionoffibrinolysis,andbloodstasis.Thromboticstrokesaregenerallythoughttooriginateonrupturedatheroscleroticplaques.Arterialstenosiscancauseturbulentbloodflow,whichcanpromotethrombusformationatherosclerosis(ie,ulceratedplaques)andplateletadherence.Allcausetheformationofbloodclotsthateitherembolizeoroccludetheartery.

Intracranialatherosclerosismaybethecauseofthromboticstrokeinpatientswithwidespreadatherosclerosis.Inotherpatients,especiallyyoungerpatients,othercausesshouldbeconsidered,includingthefollowing[8,43]:

Hypercoagulablestates(eg,antiphospholipidantibodies,proteinCdeficiency,proteinSdeficiency,pregnancy)SicklecelldiseaseFibromusculardysplasiaArterialdissectionsVasoconstrictionassociatedwithsubstanceabuse(eg,cocaine,amphetamines)

Watershedinfarcts

Vascularwatershed,orborderzone,infarctionsoccuratthemostdistalareasbetweenarterialterritories.Theyarebelievedtobesecondarytoembolicphenomenonortoseverehypoperfusion,asoccurs,forexample,incarotidocclusionorprolongedhypotension.(Seetheimagebelow.)[44,45,46]

Magneticresonanceimaging(MRI)scanwasobtainedina62yearoldmanwithhypertensionanddiabetesandahistoryoftransientepisodesofrightsidedweaknessandaphasia.Thefluidattenuatedinversionrecovery(FLAIR)image(left)demonstratespatchyareasofhighsignalarrangedinalinearfashioninthedeepwhitematter,bilaterally.Thisconfigurationistypicalfordeepborderzone,orwatershed,infarction,inthiscasetheanteriorandposteriormiddlecerebralartery(MCA)watershedareas.Theleftsidedinfarctshavecorrespondinglowsignalontheapparentdiffusioncoefficient(ADC)map(right),signifyingacuity.Anoldleftposteriorparietalinfarctisnotedaswell.

Flowdisturbances

Strokesymptomscanresultfrominadequatecerebralbloodflowbecauseofdecreasedbloodpressure(andspecifically,decreasedcerebralperfusionpressure)orasaresultofhematologichyperviscosityfromsicklecelldiseaseorotherhematologicillnesses,suchasmultiplemyelomaandpolycythemiavera.Intheseinstances,cerebralinjurymayoccurinthepresenceofdamagetootherorgansystems.Formoreinformation,seeBloodDyscrasiasandStroke.

Epidemiology

StrokeistheleadingcauseofdisabilityandthefourthleadingcauseofdeathintheUnitedStates.[47,48]Eachyear,approximately795,000peopleintheUnitedStatesexperiencenew(610,000people)orrecurrent(185,000people)stroke.[6]Epidemiologicstudiesindicatethat8292%ofstrokesintheUnitedStatesareischemic.

AccordingtotheWorldHealthOrganization(WHO),15millionpeoplesufferstrokeworldwideeachyear.Ofthese,5milliondie,andanother5millionareleftpermanentlydisabled.[49]

Race,sex,andagerelateddemographics

IntheUnitedStates,blackshaveanageadjustedriskofdeathfromstrokethatis1.49timesthatofwhites.[50]Hispanicshavealoweroverallincidenceofstrokethanwhitesandblacksbutmorefrequentlacunarstrokesandstrokeatanearlierage.

Menareathigherriskforstrokethanwomenwhitemenhaveastrokeincidenceof62.8per100,000,withdeathbeingthefinaloutcomein26.3%ofcases,whilewomenhaveastrokeincidenceof59per100,000andadeathrateof39.2%.

Althoughstrokeoftenisconsideredadiseaseofelderlypersons,onethirdofstrokesoccurinpersonsyoungerthan



65years.[48]Riskofstrokeincreaseswithage,especiallyinpatientsolderthan64years,inwhom75%ofallstrokesoccur.

PrognosisIntheFraminghamandRochesterstrokestudies,theoverallmortalityrateat30daysafterstrokewas28%,themortalityrateat30daysafterischemicstrokewas19%,andthe1yearsurvivalrateforpatientswithischemicstrokewas77%.However,theprognosisafteracuteischemicstrokevariesgreatlyinindividualpatients,dependingonthestrokeseverityandonthepatientspremorbidcondition,age,andpoststrokecomplications.[4]

AstudyutilizingthelargenationalGetWithTheGuidelinesStrokeregistryfoundthatthebaselineNationalInstitutesofHealthStrokeScale(NIHSS)scorewasthestrongestpredictorofearlymortalityrisk,evenmoresothancurrentlyusedmortalitypredictionmodelsincorporatingmultipleclinicaldata.[51]Cardiogenicemboliareassociatedwiththehighest1monthmortalityinpatientswithacutestroke.

Thepresenceofcomputedtomography(CT)scanevidenceofinfarctionearlyinpresentationhasbeenassociatedwithpooroutcomeandwithanincreasedpropensityforhemorrhagictransformationafterfibrinolytictherapy(seePathophysiology).[5,52,53]Hemorrhagictransformationisestimatedtooccurin5%ofuncomplicatedischemicstrokesintheabsenceoffibrinolytictherapy,althoughitisnotalwaysassociatedwithneurologicdecline.Indeed,hemorrhagictransformationrangesfromthedevelopmentofsmallpetechialhemorrhagestotheformationofhematomasrequiringevacuation.

Acuteischemicstrokehasbeenassociatedwithacutecardiacdysfunctionandarrhythmia,whichthencorrelatewithworsefunctionaloutcomeandmorbidityat3months.Datasuggestthatseverehyperglycemiaisindependentlyassociatedwithpooroutcomeandreducedreperfusioninfibrinolysis,aswellasextensionoftheinfarctedterritory.[54,55,56]

InstrokesurvivorsfromtheFraminghamHeartStudy,31%neededhelpcaringforthemselves,20%neededhelpwhenwalking,and71%hadimpairedvocationalcapacityinlongtermfollowup.Formoreinformation,seetheMedscapeReferencearticleMotorRecoveryinStroke.

PatientEducationPubliceducationmustinvolveallagegroups.Incorporatingstrokeintobasiclifesupport(BLS)andcardiopulmonaryresuscitation(CPR)curriculaisjustonewaytoreachayoungeraudience.Avenuestoreachanaudiencewithahigherstrokeriskcouldincludelocalchurches,employers,andseniororganizationstopromotestrokeawareness.

TheAmericanStrokeAssociation(ASA)advisesthepublictobeawareofthesymptomsofstrokethatareeasilyrecognized,includingthesuddenonsetofanyofthefollowing,andtocall911immediately:

Numbnessorweaknessofface,arm,orleg,especiallyon1sideofthebody

ConfusionDifficultyinspeakingorunderstandingDeteriorationofvisionin1orbotheyesDifficultyinwalking,dizziness,andlossofbalanceorcoordinationSevereheadachewithnoknowncause

Inthespringof2013,theASAlaunchedastrokepubliceducationcampaignthatusestheacronymFASTtoteachthewarningsignsofstrokeandtheimportanceofcalling911,asfollows:

F:FacedroopingA:ArmweaknessS:SpeechdifficultyT:Timetocall911

Forpatienteducationinformation,seetheStrokeHealthCenterandtheBrainandNervousSystemHealthCenter,aswellasStroke,TransientIschemicAttack(TIA,Ministroke),andStrokeRelatedDementia.

ContributorInformationandDisclosuresAuthorEdwardCJauch,MD,MS,FAHA,FACEPProfessor,Director,DivisionofEmergencyMedicine,Professor,DepartmentofNeurosciences,AssociateViceChairofResearch,DepartmentofMedicine,MedicalUniversityofSouthCarolinaCollegeofMedicine

EdwardCJauch,MD,MS,FAHA,FACEPisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergencyPhysicians,AmericanHeartAssociation,AmericanMedicalAssociation,NationalStrokeAssociation,SocietyforAcademicEmergencyMedicine,andSouthCarolinaMedicalAssociation

Disclosure:GenentechGrant/researchfundsSitePI

Coauthor(s)BrianStettler,MDAssistantProfessor,ProgramDirector,EmergencyMedicineResidencyProgram,DepartmentofEmergencyMedicine,andFacultyGreaterCincinnati/NorthernKentuckyStrokeTeam,UniversityofCincinnati

Disclosure:Nothingtodisclose.

ChiefEditorHelmiLLutsep,MDProfessorandViceChair,DepartmentofNeurology,OregonHealthandScienceUniversitySchoolofMedicineAssociateDirector,OregonStrokeCenter

HelmiLLutsep,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofNeurologyandAmericanStrokeAssociation

Disclosure:StrykerNeurovascularConsultingfeeReviewpanelmembership



AdditionalContributorsJeffreyLArnold,MD,FACEPChairman,DepartmentofEmergencyMedicine,SantaClaraValleyMedicalCenter

JeffreyLArnold,MD,FACEPisamemberofthefollowingmedicalsocieties:AmericanAcademyofEmergencyMedicineandAmericanCollegeofPhysicians


JosephUBecker,MDFellow,GlobalHealthandInternationalEmergencyMedicine,StanfordUniversitySchoolofMedicine

JosephUBecker,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergencyPhysicians,EmergencyMedicineResidentsAssociation,PhiBetaKappa,andSocietyforAcademicEmergencyMedicine


SalvadorCruzFlores,MD,MPH,FAHA,FCCMProfessorofNeurologyandEpidemiology,SidneyWSouersEndowedChair,DirectorofSouersStrokeInstitute,CerebrovascularandNeurointensiveCareSection,Director,VascularNeurologyFellowshipTrainingProgram,InterimChairman,DepartmentofNeurologyandPsychiatry,StLouisUniversitySchoolofMedicineDirector,NeuroscienceIntensiveCareUnit(5ICU),StLouisUniversityHospital

SalvadorCruzFlores,MD,MPH,FAHA,FCCMisamemberofthefollowingmedicalsocieties:AmericanAcademyofHospiceandPalliativeMedicine,AmericanAcademyofNeurology,AmericanCollegeofPhysicians,AmericanHeartAssociation,AmericanSocietyofNeuroimaging,AmericanStrokeAssociation,NationalStrokeAssociation,NeurocriticalCareSociety,andSocietyofCriticalCareMedicine

Disclosure:AxioincHonorariaReviewpanelmembershipRocheHonorariaReviewpanelmembershipLillyHonorariaReviewpanelmembershipBiotronikHonorariaReviewpanelmembership

JStephenHuff,MDAssociateProfessorofEmergencyMedicineandNeurology,DepartmentofEmergencyMedicine,UniversityofVirginiaSchoolofMedicine

JStephenHuff,MDisamemberofthefollowingmedicalsocieties:AmericanAcademyofEmergencyMedicine,AmericanAcademyofNeurology,AmericanCollegeofEmergencyPhysicians,andSocietyforAcademicEmergencyMedicine


RichardSKrause,MDSeniorClinicalFaculty/ClinicalAssistantProfessor,DepartmentofEmergencyMedicine,UniversityofBuffaloStateUniversityofNewYorkSchoolofMedicineandBiomedicalSciences

RichardSKrause,MDisamemberofthefollowingmedicalsocieties:AlphaOmegaAlpha,AmericanAcademyofEmergencyMedicine,AmericanCollegeofEmergencyPhysicians,andSocietyforAcademicEmergencyMedicine


FranciscoTalavera,PharmD,PhDAdjunctAssistantProfessor,UniversityofNebraskaMedicalCenterCollegeofPharmacyEditorinChief,MedscapeDrugReference

Disclosure:MedscapeSalaryEmployment

CharlesRWiraIII,MDAssistantProfessor,SectionofEmergencyMedicine,YaleUniversitySchoolofMedicineDEMLiaisonandAttendingPhysician,YaleAcuteStrokeService,DepartmentofNeurology,YaleNewHavenHospital

CharlesRWiraIII,MDisamemberofthefollowingmedicalsocieties:AmericanCollegeofEmergencyPhysicians,AmericanHeartAssociation,AmericanStrokeAssociation,NeurocriticalCareSociety,SocietyforAcademicEmergencyMedicine,andSocietyofCriticalCareMedicine


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