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StrokeinChildrenandYoungAdultsExpertConsult
OnlineandPrint2ndEditionJoseBillerMdFaanFacp
Author(s):JoseBillerMDFAANFACPFAHA
ISBN(s):9780750674188,0750674180
Edition:2
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Year:2009
Language:english
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STROKEINCHILDRENANDYOUNGADULTSISBN:978-0-7506-7418-8
Copyright # 2009bySaunders,animprintofElsevierInc.
Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorby anymeans,electronicormechanical,includingphotocopying,recording,oranyinformation storageandretrievalsystem,withoutpermissioninwritingfromthepublisher.Permissionsmaybe soughtdirectlyfromElsevier’sHealthSciencesRightsDepartmentinPhiladelphia,PA,USA:phone: (þ1)2152393804,fax:(þ1)2152393805,e-mail: healthpermissions@elsevier.com.Youmayalso completeyourrequeston-lineviatheElsevierhomepage(http://www.elsevier.com),byselecting “CustomerSupport”andthen“ObtainingPermissions”.
Notice
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperience broadenourknowledge,changesinpractice,treatment,anddrugtherapymaybecomenecessaryor appropriate.Readersareadvisedtocheckthemostcurrentinformationprovided(i)onprocedures featuredor(ii)bythemanufacturerofeachproducttobeadministered,toverifytherecommended doseorformula,themethodanddurationofadministration,andcontraindications.Itisthe responsibilityofthepractitioner,relyingonhisorherexperienceandknowledgeofthepatient,to makediagnoses,todeterminedosagesandthebesttreatmentforeachindividualpatient,andtotake allappropriatesafetyprecautions.Tothefullestextentofthelaw,neitherthePublishernortheAuthor assumesanyliabilityforanyinjuryand/ordamagetopersonsorpropertyarisingoutoforrelatedto anyuseofthematerialcontainedinthisbook.
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Biller,Jose ´ Strokeinchildrenandyoungadults/Jose ´ Biller.--2nded. p.;cm.
Includesbibliographicalreferencesandindex.
ISBN-13:978-0-7506-7418-8
ISBN-10:0-7506-7418-0
1.Cerebrovasculardiseaseinchildren.2.Cerebrovasculardisease.I.Title. [DNLM:1.Stroke.2.Adolescent.3.Child.4.Infant.5.YoungAdult.WL355B597s2009] RJ496.C45S772009
618.920 81--dc22
AcquisitionsEditor: AdrianneBrigido
DevelopmentalEditor: JoanRyan
PublishingServicesManager: HemamaliniRajendrababu
ProjectManager: JagannathanVaradarajan
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Lastdigitistheprintnumber:987654321
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ThisbookisdedicatedtothememoryofDr.WilliamDeMyer.Knownandlovedbymanyas preeminentneuroanatomist,eruditeteacher,tirelessadvisor,compassionatecaregiver, gregarioussportsman,andconsummatefamilyman.Hewillbemissed bythosewhomhetouchedwithanyfacetofhismultidimensionallife.
CONTRIBUTORS
ThomasJ.Altstadt,MD
NeurologicalSurgery,MedfordNeurologicalandSpineCenter,Medford, Oregon
Jose ´ Biller,MD,FACP,FAAN,FAHA
ProfessorandChairman,DepartmentofNeurology,LoyolaUniversityChicago, StritchSchoolofMedicine,Maywood,Illinois
RimaM.Dafer,MD,MPH
AssociateProfessor,DepartmentofNeurology,LoyolaUniversityChicago, StritchSchoolofMedicine,Maywood,Illinois
WilliamE.DeMyer,MD
ProfessorEmeritusofChildNeurology,IndianaUniversity; RileyHospitalforChildren,Indianapolis,Indiana
MeredithR.Golomb,MD,MSc
AssistantProfessor,DepartmentofNeurology,DivisionofPediatricNeurology, IndianaUniversitySchoolofMedicine;RileyHospitalforChildren, Indianapolis,Indiana
LotfiHacein-Bey,MD
Professor,DepartmentsofRadiologyandNeurosurgeryand Director,NeuroradiologyandInterventionalNeuroradiology, LoyolaUniversityMedicalCenter,Chicago,Illinois
BetsyB.Love,MD
AdjunctClinicalAssociateProfessor,DepartmentofNeurology,Loyola UniversityChicago,StritchSchoolofMedicine,Maywood,Illinois
JamesF.Meschia,MD
ProfessorandDirector,CerebrovascularDivision,DepartmentofNeurology, MayoClinic,Jacksonville,Florida
ThomasC.Origitano,MD,PhD,FACS
ProfessorandChair,DepartmentofNeurologicalSurgery,Co-Director,The CenterforCranialBaseSurgery,Director,LoyolaNeuroscienceServiceLine, LoyolaUniversityMedicalCenter,Maywood,Illinois
HemaPatel,MD
AssociateProfessor,DepartmentofNeurology,SectionofPediatricNeurology, IndianaUniversitySchoolofMedicine;AssociateProfessor,Departmentof
Neurology,SectionofPediatricNeurology,ClarianHealthPartners–JamesWhitcombRiley HospitalforChildren,Indianapolis,Indiana
MichaelB.Pritz,MD,PhD
Professor,DepartmentofNeurologicalSurgeryandDirector,CerebrovascularandSkullBase Surgery,IndianaUniversitySchoolofMedicine;AttendingNeurosurgeon,University Hospitals,Indianapolis,Indiana
RichardB.Rodgers,MD
AssistantProfessor,DepartmentofNeurologicalSurgery,IndianaUniversitySchoolof Medicine,Indianapolis,Indiana
MichaelJ.Schneck,MD
AssociateProfessorofNeurologyandNeurosurgery,DepartmentofNeurology, LoyolaUniversityChicago,StritchSchoolofMedicine,Maywood,Illinois
EugeneR.Schnitzler,MD
AssociateProfessorofNeurologyandPediatricsandChief,DivisionofPediatricNeurology, LoyolaUniversityChicago,StritchSchoolofMedicine;DepartmentofNeurologyand Pediatrics,LoyolaUniversityMedicalCenter,Maywood,Illinois
MiteshV.Shah,MD,FACS
AssociateProfessorandCo-Director,SkullBaseSurgery,DepartmentofNeurosurgery, IndianaUniversity,Indianapolis,Indiana
DeborahK.Sokol,MD,PhD
AssociateProfessorofClinicalNeurology,SectionofPediatrics,IndianaUniversitySchoolof Medicine;PediatricNeurologist,RileyHospitalforChildren,Indianapolis,Indiana
MarcG.Weiss,MD
AssociateProfessor,DepartmentofPediatricsandDirector,DivisionofNeonatology, LoyolaUniversityChicago,StritchSchoolofMedicine;MedicalDirector,NeonatalIntensive CareUnit,RonaldMcDonaldChildren’sHospitalofLoyolaUniversityMedicalCenter, Maywood,Illinois
StrokeinChildrenand YoungAdults:Overview, RiskFactors,and Prognosis
BetsyB.Love Jose ´ Biller
KEYTERMS
CADASIL cerebralautosomaldominant arteriopathywithsubcorticalinfarcts andleukoencephalopathy
CNS centralnervoussystem
CSVT cerebralsinovenousthrombosis
FMD fibromusculardysplasia
HDL high-densitylipoprotein
HIV humanimmunodeficiencyvirus
MELAS mitochondrialencephalomyopathy, lacticacidosis,andstrokelike symptoms
SAH subarachnoidhemorrhage
TIA transientischemicattack
Cerebrovasculardiseaseisthecauseof deathinmorethan3000individualsyounger than45yearsannuallyandisoneofthetop 10causesofchildhooddeath.1 Childrenand adultsyoungerthan45yearsaccountfor5% to10%ofallstrokecases.2-4 Indeveloping countries,theproportionisevenhigher, with19%to30%ofstrokesoccurringinindividualsyoungerthan45years.5,6 Theimpact ofstrokesinthisagegroupisdevastatingto childrenandyoungadults,theirfamilies, andsociety.7
Therearenotabledifferencesinincidence,presentation,riskfactors,andprognosisinstrokeoccurringinindividuals youngerthan45yearscomparedwithindividualsolderthan45years.Also,thereare significantdifferencesintheseparameters withinthebroadagegroupsfromneonates tochildhoodtoyoungadults.Whereappropriateandwheredataexist,thesedifferencesareaddressedinthischapter.Althoughneonatal/perinatalstrokeisan importantareaofclinicalstudy,thisagegroupisaddressedonlybriefly.
StrokeIncidence
Thereareworldwidefluctuationsintheincidenceratesofstrokeinyoungindividuals.Thepeakrateofstrokeinthispopulationoccursintheperinatal
period,with26.4strokesper100,000live birthsininfantslessthan30daysold(6.7 forhemorrhagicstrokeand17.8forischemic stroke).8 Theincidenceofstrokeinchildren intheUnitedStateswasstableoverthe 10-yearperiodfrom1988to1999.7 Theincidenceofallstrokesinchildrenyoungerthan 15yearswas6.4per100,000in1999;thisfigurewasnotsignificantlyincreasedcompared withstatisticsfrom1988.7 Conservativeestimatesin2004indicatedthatapproximately 3000childrenandadultsyoungerthan20 yearswouldexperienceastrokeperyearin theUnitedStates.9 After30to35yearsof age,theratesofischemicstrokeatleastdoubledinsomeseriestoanincidenceof2.7to9 per100,000.5,10
Racialdifferencesintheincidenceof ischemicstrokeexist.Theincidenceinyoung blackmenandwomenwastwicetherateof non-HispanicwhitesindatafromBaltimore.6 Morerecently,datafromnorthernManhattan showedahigherratenotonlyinblacks,but alsoinHispanicswithanincidenceof8per 100,000.11
Theage-specificrateofintracerebral hemorrhageinindividualsyoungerthan45 yearsmaybe7per100,000population,and 14per100,000inyoungblackmales.6,10 Generally,theratesarehigherformalesthan females.BlacksandHispanicshaveahigher ratethannon-Hispanicwhites.11
Theincidenceratesofsubarachnoidhemorrhage(SAH)areelevatedsignificantly amongSwedishandFinnmenandwomen 25to44yearsoldcomparedwithother regionsat20per100,000.12 IncentralItaly, theratesper100,000areseentoincreaseprogressivelyfrom0.41at0to14years,to0.96at 15to24years,2.74at25to34years,and5.94 at35to44years.13 InastudycomparingdifferentethnicgroupsinnorthernManhattan, therateper100,000was3fornon-Hispanic whites,6forblacksand6forHispanics.11
StrokePresentationinYoung Individuals
Thepresentationofstrokediffersinneonatesandchildrencomparedwitholder agegroups.Perinatalischemicstrokeis definedas“acerebrovasculareventoccurringduringfetalorneonatallife,before28
days,withpathologicalorradiologicalevidenceoffocalarterialinfarctionofbrain.”14 Signsinthisagegroupmaybenonspecific, includinghypotonia,apnea,orneonatalseizures.14 Theremaybenodetectablefocal neurologicsignsevidentattheonset,but focalneurologicsignsmayappearduring thefirstyearafterthestrokeasmotorskills develop.15 Strokesmaymanifestduringthe firstyearaspathologicearlyhandpreference,new-onsetseizures,orfailuretoreach developmentalmilestones.14,15
Inchildrenwithstroke,thereisoftenaconsiderabledelaybetweentheonsetofsymptomsandpresentationtoahealthcarefacility. Thisdelaymaybeattributabletoaninsidious orstutteringtypeofonset.16 Afteronsetof symptomsofstroke,diagnosismaybesignificantlydelayed.17 Cerebralvenousocclusions tendtobediagnosedmorepromptly,probably becauseofthepresenceofseizures.
Olderchildrenwithstrokestypicallypresentwithsuddenhemiparesis,oftenassociatedwithseizures.18 Seizuresattheonset orshortlyafterstrokearemorecommonin youngchildren,particularlychildrenyounger than3or4years.19 Newbornswithneonatal seizuresasamanifestationofischemicstroke maybeclinicallynormalbetweenseizures,or theymayhaveothersignsofencephalopathy, suchasabnormalitiesoftoneorfeeding, ordepressedlevelofalertness.20 Children withstrokeresultinginaphasiamaypresent withlossofspeech,paraphasia,and dysgraphia.9,21,22
Feverorinfectionatthetimeofanacute strokeismuchmorecommoninchildren comparedwitholderpopulationswith stroke.23 Approximately50%to55%ofchildrenpresentingwithcerebralinfarctionhave feverorevidenceofinfection,oftenupper respiratoryinnature.24,25 Possiblemechanismsofstrokeinthesechildreninclude dehydrationasaresultoffever,vasculitis,or athromboticprocess.26 Strokeisasequela ofseveremeningitisinchildren,especially infectionsecondaryto Haemophilusinfluenzae,Streptococcuspneumoniae, and Mycobacteriumtuberculosis.Otherinfectionsthat areassociatedwithstrokeinchildren includevaricella-zoster,humanimmunodeficiencyvirus(HIV),cat-scratchfever,and mycoplasma.
Themodeofonsetofneurologicsymptomsstronglycorrelateswiththeunderlying causeofstrokeinchildren6monthsto18 yearsoldaccordingtoonemorerecent study.16 Themodeofonsetwasnonabrupt in68%ofchildrenwitharteriopathicstroke comparedwithanabruptonsetin72%of childrenwithstrokeduetononarteriopathic causes.16
Theremaybeahistoryofheadtrauma, sometimesslight,beforetheonsetofstroke inchildren.27 Severalauthorshavefounda historyofmildheadtrauma,withoutloss ofconsciousnessorepilepsy,andassociated infarctionlocalizedinthebasalganglia.27,28
Strokesinthedistributionofthevertebrobasilarcirculationarelesscommonthan strokesinthecarotidterritoriesandarenot aswellcharacterizedinchildren.Mostchildrenwithposteriorcirculationstrokeare boyswithvertebrobasilararterialabnormalities,morethanhalfofwhicharedissections.29 Postulatedreasonsforamale predominancethathavebeenobservedin severalstudiesincludeanincreasedpotentialfortraumaandanincreaseincervical spinalabnormalitiesinboys.29,30 Another uniquefeatureassociatedwithposteriorcirculationstrokesisthatmostchildrenwere previouslyhealthycomparedwithchildren withstrokesintheanteriorcirculation,of whichhalfhadapreexistingmedical condition.29
StrokeCauses
Strokecausesandriskfactorshavenotbeen studiedaswellininfantswithperinatalstroke asinolderagegroupswithstroke.Several studieshaveidentifiedprothromboticrisk factorsin68%ofinfantswithperinatal strokecomparedwith24%ofcontrols.33 One studyshowedelevatedlipoprotein(a)in20% ofpatients,whereasanotherfound24%of patientshadfactorVLeidenmutation.34
Atpresent,thereisnostrokeclassification systemspecificallytailoredtothemultiplerisk factorsandetiologiesinchildrenandyoung adults.Severalstudiesthathaveuseda validatedclassificationsystem,theTrialof ORG-10172inAcuteStrokeTherapy(TOAST) subtyping,arereviewedhere.35 Inastudycomparingthesubtypesofstrokeinpatients1year toyoungerthan15yearsold,48%wereclassifiedas“otheretiologies,”38%asunknownetiology,and14%ascardioembolic;nocases wereattributedtoatherothrombosisorsmall vesselarterialdisease.36 Inpatients15to18 yearsold,55%wereofotheretiology,18%were ofunknownetiology,and27%werecardioembolic.Althoughthisgroupwassmall(11 patients),investigatorsobservedthatthe causesofstrokeinthisgroupweremoresimilar tothoseinyoungadultsthaninchildren.Inthe groupolderthan18to45yearsold,therewere 44%withotheretiologies,23%withunknown etiologies,16%atherothrombotic,14%cardioembolic,and3%smallvesseldisease.ApplyingtheTOASTsubtypingforotherseriesof childhoodstroke,theresultsshow0%to5% atherothrombosis,3%to65%cardioembolism, 0%to2%smallvessel,0%to46%otheretiologies,and33%to94%unknownetiologies.36
Inamorerecentstudyofpatients18to45 yearsoldusingtheTOASTclassification,the mostcommoncauseswereotherthantraditionalcausesin26.4%,cardioembolismin 22.4%,andidiopathicstrokesin20.7%.37 It alsoisnotablethatfeweryoungerpatients (51.9%)hadacauseofstrokeestablished withhighprobabilitycomparedwitholder
Althoughitisimportanttoreviewthemost commoncausesofischemicstrokeinthe variousagegroups,directcomparison betweenvariousstudiescanbechallenging. Publishedstudiesofstrokeinchildrenand youngadultshaveyieldedvariableresults regardingwhatisthemostcommonsubtype ofstrokebecausethisdependsonthepopulationstudied,thetimeperiodofstudy,the classificationsystemused,andtheextent ofinvestigation.Atherosclerosisandsmall vesseldiseaseplayaminorrolebefore age35inmostindividuals,andthereisa preponderanceofstrokesofnontraditional etiologies(i.e.,prothromboticdisorders,cervicocephalicarterialdissections,moyamoya disease,vasculitis),andstrokesofunknown etiologies(idiopathic).Theonenotable exceptiontothisgeneralizationistheetiologiesinblacks,whicharediscussedsubsequently.Cardioembolismfromcongenital oracquiredheartdiseasecontinuestoplay arole,butitdoesnotseemtobethemost commoncauseinsomemorerecentstudies ofchildrenandyoungadults.11,31,32
patients(70%).UsingtheTOASTsubtypes forotherstudiesofthisagegroup,cardioembolicstrokeoccurredin24%to34%, otheretiologiesoccurredin19%to65%, andidiopathicstrokeoccurredin24%to 33%.38-40
Thecausesofstrokeinyoungblacksaredifferentthaninnon-blacks.Inindividuals15to 44years,thecauseswereatheroscleroticvasculopathyin9%,nonatheroscleroticvasculopathyin4%,lacunarinfarctsin21%, cardioembolismin20%,hematologicin14%, drug-relatedin6%,andundeterminedin 26%.41,42 Thisgreaternumberoflacunar infarctionsislikelyduetoahigherprevalence ofarterialhypertensionamongyoungblacks.41
Strokeismorecommoninboys18years andyoungerthaningirls,regardlessof strokeetiologicsubtypes.43 Themalepredominanceis61%forunderlyingcardiac disease;59%forvasculopathy;61%for underlyingchronicdisease,suchasprothromboticstates,sicklecellanemia,and hematologicmalignancies;and66%forhead andneckdisease,suchasotitismedia,pharyngitis,andheadandnecktrauma.
Althoughischemicstrokesaremorecommonthanhemorrhages,hemorrhagesaccount foradisproportionatenumberofstrokes inyoungerpatients.4 Inadults,ischemic strokeoccursin80%ofcases,andhemorrhagesaccountforapproximately20%of strokes.Inchildren,thedistributionofhemorrhagesisgreater,withischemicstrokes accountingfor55%andhemorrhages accountingfor45%ofstrokes.4,44 Hemorrhagicstrokeisthemostcommonformof strokeamongyoungadultsinsomeseries.45
Strokepatientsyoungerthan45yearshave adisproportionatepercentageofSAHand intracranialhemorrhage(42.7%)compared witholderpatients(15.7%),predominantly attributabletoaneurysmsandarteriovenous malformations.13
RiskFactorsforIschemicStrokein YoungIndividuals General
Therearemultipleriskfactorsforischemic strokeinchildrenandyoungadults,includingmorethan100differentriskfactorsin
childrenalone,andarediscussedatlength insubsequentchapters(seeTables3-1,6-2, 6-3,7-3,9-1,and10-1).Onlythemorecommonriskfactorsarereviewedhere.
Perinatalstrokeisuniquebecausematernalandfetalriskfactorsmustbeconsidered. Factorssuchasmaternalinfertility,oligohydramnios,preeclampsia,prolongedrupture ofmembranes,umbilicalcordabnormality, chorioamnionitis,andprimiparityseemto beimportantasriskfactorsforarterial strokeinnewborns.46,47 Infectionplaysa moresignificantroleinthisagegroup.In addition,theneonatalcoagulationsystem isimmatureandmoresusceptibletoclot formation.47 FactorVLeidenandprothrombingene(G20210A)mutationcancause arterialstrokeintheperinatal/neonatal period,whereasthesearemoreassociated withvenousthromboembolisminadults.47
Thereareethnicdisparitiesintheriskof strokeinchildrenandyoungadults.Black childrenhaveahigherriskofstroke,witha relativeriskof2.59forischemicstroke.42 Hispanicchildrenhavealowerriskofischemic stroke(0.76),whereasAsianchildrenhave asimilarriskaswhites.Amongindividuals 20to44years,Hispanicsandblackshavea higherriskofstrokethannon-Hispanic whites.11
Ischemicstrokeismorecommoninboys, regardlessofstrokesubtype,age,oretiology.48 Inamorerecentlarge,nationalstudy, ischemicstrokewas2.62timesmorelikely tooccurinboysthangirls16to20years old,and1.17timesmorelikelyinboysthan girls0to5yearsold.48 Intermsofrisk,the oddsare50%higherforaboytohavean ischemicstroke.
Afamilyhistoryofischemicstrokeisa riskfactorforstroke,buttherolethatthis playsinstrokesinyoungindividualsis uncertain.TheFraminghamHeartStudy reportedapositiveassociationbetweenverifiedmaternalandpaternalhistoryoftransientischemicattack(TIA)andstrokeand anincreasedriskofstrokeintheoffspring.49 Thereisafivefoldincreaseinstrokeprevalenceamongmonozygotictwinscompared withdizygotictwins.50,51
Tobaccouseisasignificantriskfactorfor strokeinyoungindividuals.Approximately 4000children12to17yearsoldstartsmoking
everydayintheUnitedStates,and1140 becomedailycigarettesmokers. 52 Cigarette smokingincreasestheriskofstrokein youngadultstwofold. 53 Smokingin25-to 37-year-oldsisthemostconsistentpredictorofcarotidintima-mediathickness, amarkerofsubclinicalatherosclerosis. 54
Thepresenceofotherriskfactorswith tobaccousecanactsynergisticallyto increasestrokeriskinyoungadults.One studyshowedthatthepresenceofapolipoproteinEpolymorphismsincombination withsmokingcanincreasetheriskofstroke inyoungadults. 55 Smokingcessation reducestheriskofstroketothatofa nonsmokerwithin2yearsaftercessation. 56
Thereisanassociationbetweenvery recentalcoholintake,particularlydrinking forintoxication,andtheonsetofischemic cerebralinfarctioninyoungadults16to40 yearsoldwithnootherknownetiologyfor stroke.57 Thisassociationisconcerningin lightofthefactthattheaverageageofa child’sfirstdrinkisnow12,andnearly20 percentof12-to20-year-oldsareconsidered bingedrinkers.58
Druguseincreasestheriskofstrokeby6.5 timesthatofnon–drugusers.59 Among patientsyoungerthan35years,oneseries showedthatdrugabusewasthemostcommonlyencounteredriskfactorforstroke, presentin47%,withanoverallrelativerisk forstrokeof11.7.59 Amorerecentstudy showedthat14percentofhemorrhagic strokesand14percentofischemicstrokesin individuals18to44yearswerecausedbydrug abuse,includingamphetamines,cocaine, cannabis(marijuana),andtobacco.60 In manyregionsoftheUnitedStates,useof methamphetamineisincreasingdramatically amongyoungpeople.Amphetamineabuseis associatedwithafivefoldincreasedriskof hemorrhagicstrokeinindividuals18to44 years.60 Cocaineusershavedoubletherisk ofischemicandhemorrhagicstroke.60 Strokeswithuseofmarijuanahavebeenthe subjectofcasereports,andthisassociation hasbeenconfirmedinalargepopulationbasedstudy.60,61 Therealsohavebeenreports ofepisodicmarijuanauseasariskfactor forstrokeinchildhood,particularlyinthe posteriorcirculation.60,62 Strokeswiththe useofstimulantsarethoughttoberelated
tovasospasm,vasculitis,orincreasedblood pressure.
Obesityisnowthemostprevalentdiseasein childrenandyoungadults.Thelateststatistics indicatethat17%ofchildren2to19yearsold areoverweight.63 Thispercentagerepresents anincreaseinprevalenceofoverweightchildrenandadolescentsduringtheperiod1999 to2004.Theprevalencewasevengreater fornon-Hispanicblacks(20%)andMexicanAmericans(19.2%).Theseoverweightchildren areatriskofbecomingoverweightyoung adultswithagreaterriskofhypercholesterolemia,hypertension,diabetes,heartdisease, andstroke.
AtheroscleroticRiskFactors
Atherosclerosisisuncommonasacauseof strokeinindividualsyoungerthan30to35 years.64,65 Only2%ofpatients16to30years oldinoneserieshadatherosclerosisasa causativefactorforstroke.64 Inthesame series,thepercentageofpatients31to45years withatherosclerosisasacauseofinfarction was7%.Mostofthesepatientshaveclassicrisk factors,suchasarterialhypertension,diabetes mellitus,cigarettesmoking,andhyperlipidemia.Otherfactorsthatincreasetheriskof atherosclerosisinchildrenandyoungadults includegeneticmetabolicdisorderssuchas familialhyperlipidemiasandhypercholesterolemias,progeria,familialhypoalphalipoproteinemia,Tangierdisease,andhigh-density lipoprotein(HDL)deficiencystates.Aspreviouslymentioned,atheroscleroticetiologies aremorecommoninyoungadultblacks.
Hypertensionisthemostpowerfulrisk factorforischemicstrokeandintraparenchymalhemorrhage.Inacase-controlstudy, arterialhypertensionwaspresentinapproximately31%ofpatientsyoungerthan50 yearswithstroke,andthiswasstatistically significantcomparedwiththecontrol group.66 Smallarterydiseaseassociatedwith strokewasthemostlikelycauseofischemic infarctioninonly2%,however,ofpatients 31to45yearsanddidnotaccountfor anystrokesinpatients16to30years.64 Strokein15-to44-year-oldblacksismore frequentlyassociatedwitharterialhypertensioncomparedwithnon-blacks,yieldinga higherpercentageoflacunarinfarctionsin
thispopulation.41,42 Somerare,inherited enzymedeficiencies,suchas11b-hydroxylase deficiency,11b-ketoreductasedeficiency,and 17a-hydroxylasedeficiency,areassociated witharterialhypertensionand,rarely,with hypertensivestrokes.Thesesyndromesmay manifestinchildrenandyoungadultsifthe enzymedefectissevere.
Diabetesisaprominentriskfactorfor ischemicstrokeandisreportedbysome investigatorstobesecondonlytohypertensionasariskfactorforstroke.56 Diabetesin combinationwithotherriskfactors,suchas hypertension,hyperlipidemia,alcoholuse, andtobaccouse,cangreatlyincreasethe riskofstroke.67 Withtheepidemicofobesity amongchildren,thisriskfactorislikely toplaymoreofaroleintheyoungadult populationinthefuture.
Thesignificanceofdisordersofcholesterolandlipidsandtherisksoftobaccouse havepreviouslybeendiscussedasriskfactorsforischemicstrokeinyoungindividuals.
OtherRiskFactors
Riskfactorsinthecategoryof“other”are extensive,diverse,andincreasinglyrecognizedascausesforstrokeinchildren.Some oftheseriskfactorsarediscussed,including arterialdissection,fibromusculardysplasia (FMD),vasculitis,postvaricellaarteriopathy, moyamoyadisease,sicklecelldisease,and metabolicandgeneticdisorders.
Spontaneousortraumaticcervicocephalic arterialdissectionsaredescribedin20%to 25%ofcasesofstrokeinyoungadults.64,68 Themeanageforstrokecausedbycervicocephalicarterialdissectionisapproximately 40years.64 Amalepredominancethat isunexplainedbytraumaisnotedin children.30 Spontaneouscarotidcirculation dissectionsaremostcommonlyintracranial, whereaspost-traumaticanteriorcirculation dissectionsaremorecommonlyextracranial inlocationinchildren.30
CervicocephalicFMDisanangiopathyof unknownetiologyinvolvingmedium-sized arteriesthatismorecommoninyoung adultsandwomen.IntheLausanneStroke Registry,cervicocephalicFMDwasthecause ofstrokein4%ofpatients16to30yearsold and1%ofpatients31to45years.64 Although
thisconditionusuallymanifestsinadults,it hasbeendescribedinchildren.69 FMDhas beenassociatedwithcervicocephalicarterial dissections,intracranialaneurysms,and carotidcavernousfistulasandmoyamoya disease.70,71
Vasculitismanifestinginchildhoodcan benoninfectiousorinfectious.Noninfectiouscausesincludemanyconnectivetissue diseases,polyarteritisnodosa,Wegener granulomatosis,centralnervoussystem (CNS)granulomatousangiitis,lymphomatoidgranulomatosis,andTakayasuarteritis. Infectiouscausesincludemanytypesof bacterial,fungal,andviralmeningitisor meningoencephalitis.
Varicellainfectionwithinthepreceding yearisanimportantriskfactorforstroke. Ischemicstrokeisacomplicationofvaricella in1in15,000cases.72 Inchildren6months to10yearsoldwithacuteischemicstroke, thereisathreefoldincreaseinpreceding varicellainfection.72 Mostofthesestrokes occurwithin6monthsofinfection.Some notablecharacteristicsincludealikelihood ofbasalganglionicinfarction,anteriorcirculationstenoticvasculopathy,andrecurrent strokeorTIAintwothirdsofpatients.72 Theexactmechanismbywhichvaricella causesstrokeisunknown,butintraneuronal migrationofvaricellafromthetrigeminal ganglionalongthetrigeminalnerveto thecerebralarteries,causingarteritisand vasospasm,islikely.
Moyamoyadiseaseisanoninflammatory vasculopathyofuncertainetiologythatproducesprogressivenarrowingandobliteration ofthedistalinternalcarotidarteriesandtheir branches,oftenbilaterallyandwithinvolvementofthecircleofWillis.Extensivecollateralnetworksformatthebaseofthebrain, producinganangiographicpatternresemblingapuffofsmoke.Thisconditionis uncommonbutincreasinglyrecognizedin childrenandyoungadultsinNorthAmerica. Itisoneofthemajorcausesofstrokein Japanesechildren.73 Theconditionmaybe congenitalinsomepatients,anditmay befamilialin7%to12%ofpatients.73 Neurologicdisordersinchildhoodincludeischemic strokes,seizures,headaches,andmovement disorders.Patientsolderthan30yearsmay developcerebralhemorrhages.Thereisa
femalepreponderance.74 Moyamoyasyndromehasbeenassociatedwithmanyother systemicconditions,includingsicklecell diseaseandneurofibromatosis1.
Inearlystudies,migrainewasimplicatedas acauseofstrokein1.7%ofcasesofstrokein childrenandin10%to15%ofstrokesinyoung adults.59,75,76 Morerecentstudieshaveconfirmedmigrainewithvisualauraasariskfor ischemicstrokeinwomen15to49years old.77 Concurrentsmokingandtheuseoforal contraceptivesincreasestheriskofstrokesubstantially.Itisimportanttoevaluatethispopulationfullyforothercausesforstroke, especiallybecauseofthepossibleassociation ofmigrainewithpatentforamenovaleand hemostaticabnormalities.78 Certainmetabolicabnormalities,resultingfrominborn errorsofmetabolism,areassociatedwithan increasedriskofstroke.Classichomocystinuriaisduetocystathionine b-synthasedeficiencyandcausesprematurecardiovascular diseaseandvenousthrombosisatayoung age.Moderatehyperhomocysteinemia,owing toadefectinthemethylenetetrahydrofolate reductasegene,isariskfactorforischemic stroke,causingafourfoldincreasedriskfor ischemicstrokeinchildrenandasimilarrisk inadults.79,80 Otherrareconditionsresulting frominbornerrorsofmetabolismthat increasetheriskofstrokeincludeFabry’s disease,organicaciddisorders,ornithine transcarbamylasedeficiency,carbohydratedeficientglycoproteinsyndrome,andmitochondrialencephalomyopathy,lacticacidosis, andstrokelikesymptoms(MELAS).
Geneticdisorderssuchascerebralautosomaldominantarteriopathywithsubcorticalinfarctsandleukoencephalopathy (CADASIL),cerebralautosomalrecessive arteriopathywithsubcorticalinfarctsand leukoencephalopathy(CARASIL),andhereditaryendotheliopathy,retinopathy,nephropathy,andstrokes(HERNS)arerarecausesof ischemicstrokeinyoungadults.Genetic causesofstrokeinchildrenandyoung adultsarediscussedinChapter11.
CardiacDisorders
Approximately15%to20%ofischemicstrokes inindividuals1monthto18yearsoldare attributedtocardiacdisorders.36,81 Inchildren
youngerthanage15,themostcommoncardiacsourcesofstrokearecongenitalheart defects.Childrenwithcyanoticcongenital heartdiseaseareatriskforstrokeowingto manyfactors,includingintracardiacshunts, infectiveendocarditis,polycythemia,anemia, hemoglobinopathies,coagulationdisturbances,preexistingbrainmalformations,perioperativehypoxemiaandlowcardiacoutput states,catheterizationprocedures,sequelae ofcardiopulmonarybypass,deephypothermiccirculatoryarrest,andpostoperative arrhythmias.82,83 Theuseofcardiopulmonary bypasshasariskofgaseousandparticulate microembolization,macroembolization,and hypoperfusion.84 Hypothermicbypasstechniquescancausestrokebecauseofdecreased perfusion.84 Inchildrenandyoungadults olderthanage15,themostcommoncardiac riskfactorsarepatentforamenovale,atrial septaldefect,noninfectiousvalvulardisease, leftatrialorleftventricularthrombus,cardiomyopathy,andatrialfibrillation.
HematologicRiskFactors
Coagulationabnormalitiesareincreasingly recognizedasimportantcausesofstrokein youngindividuals.Prothromboticabnormalitieshavebeenidentifiedin20%to50%of childrenwithischemicstroke.85 Someof theseconditionsareinheriteddisorders, whichmaypredisposetoeitherthrombosis orhemorrhage.Prothromboticdisorders, suchasantithrombindeficiency,proteinC andproteinSdeficiencies,andfactorV Leiden,arecausesofstrokeinyoungindividuals.Inonestudy,mostinfantswithneonatal/perinatalstrokehadatleastone thrombophiliamarker.86 Anticardiolipin antibodiesandlupusanticoagulanthave beenassociatedwithanincreasedriskof ischemicstrokeandcerebralvenousthrombosisinyoungadults.87,88 Inchildren,casecontrolstudieshavereportedanassociation betweenanticardiolipinantibodiesorlupus anticoagulantandfirststroke,butnotfor recurrentstroke.89,90
Sicklecelldiseaseisariskfactorfor thromboticandhemorrhagicinfarcts. Approximately60%to80%ofpatientswith sicklecelldiseasewhoeventuallyhavea strokehaveitbeforeage10years,witha
meanageforfirst-timestrokeofslightly olderthan6years.91-93 TheCooperative StudyofSickleCellDiseaseshowedthat 25%ofpatientswithhomozygoussicklecell anemiaand10%ofpatientswithhemoglobinsicklecelldiseasehadastrokebyage 45years.94 Therealsoarereportsofthepresenceof“silent”infarctionsin23%ofchildrenwithhomozygoussicklecellanemia.95
Oralcontraceptiveuseisinfrequentlythe causeofstroke.Ameta-analysisofstudies indicatesthatitisariskfactorwitharelative riskof1.93forlow-estrogenpreparationsin population-basedstudiesthatcontrolledfor tobaccouseandarterialhypertension.96
Pregnancyisariskfactorforstroke,particularlyinwomenolderthan35yearsand inblackwomen.97 Thehighestriskforstroke isintheperipartumperiodandupto6 weeksafterdelivery.98-100 Numerousfactors contributetothisriskandarereviewed elsewhere.97
MultipleRiskFactors
Twomorerecentstudieshaveemphasized theviewthatischemicstrokeinchildrenis amultifactorialprocess.31,32 Thepresence ofmultipleriskfactorshasbeendescribed in25%ofchildrenwithischemicstroke, andtheirpresenceisassociatedwitha higherriskofstrokerecurrence.32
StrokeofUncertainEtiology
Inapproximatelyonethirdofchildrenand youngadultswithstroke,nocauseisfound afteracompleteworkup.8,36 Itisimportant toperformcomprehensiveevaluationsin childrenandyoungadultsandtoconsider uncommonprothromboticdisorders,antiphospholipidantibodies,andgeneticdisordersascausesforstrokeinthispopulation. Inonestudyofischemicstrokeinchildren inwhichmostpatients(87%)underwenta cerebralarterialimagingstudy(eithercerebralangiographyormagneticresonance angiography),andinwhichtherewas aggressiveevaluationformodifiableriskfactors,suchasanemiaandhyperhomocysteinemia,theproportionofchildrenwith strokeofuncertainetiologywasverylow (1.9%).31
CerebralSinovenousThrombosis
Cerebralsinovenousthrombosis(CSVT) mostcommonlyaffectschildrenandyoung adults.Itisbeingdiagnosedwithincreasing frequencyasaresultofincreasedawareness ofthedisorderandincreaseddetection withmoresensitiveneuroimagingtechniques.TheCanadianPediatricStrokeSurvey, apopulation-basedstudy,foundanincidenceof0.67per100,000children0to18 yearsofageperyear.101 Neonatesaccounted for43%ofthecases,and54%ofcaseswere ininfantsyoungerthan1yearold.Stroke resultingfromCSVTismorecommonin boys(63%)thaningirls0to18years.43 In adults,75%ofcasesoccurinwomen.102 One studyshowedthat61%ofwomenwithCSVT were20to35yearsold.103 Pregnancyandoral contraceptiveusemaycontributetothis finding.
RiskfactorsforCSVTarenumerous(see Table12-3),andthistopicisdiscussedfurtherinChapter12.Despiteextensiveevaluation,nocauseisfoundinapproximately 25%ofchildren.104 Inapproximately75%of children,ariskfactorisidentified,andmultipleriskfactorsmaybeidentifiedin65%of children.105,106
ClinicalfeaturesofCSVTinchildhoodcan besubtle.Neonatesmaypresentwithfever, lethargy,irritability,seizures,andrespiratory distress.Olderchildrenmayhavefever, lethargy,andsignsofincreasedintracranial pressure.Approximatelyhalfofchildren presentwithfocalabnormalitiesorseizures.8 YoungadultswithCSVTmaypresent withsignsofintracranialhypertension (headacheandpapilledema)ifthesuperior sagittalsinusisaffected,asoccursin70% to80%ofcases.Impairedconsciousness, focalsigns,orseizuresmaybepresentwith corticalveininvolvementandassociated venousinfarction.
BrainHemorrhage
Hemorrhagicstrokeaccountsfor20%ofall strokes,butitaccountsforatleasthalfof eventsinchildrenandyoungadultsin someseries.45 Strokepatientsyoungerthan 45yearshaveadisproportionatepercentage ofSAHandintracerebralhemorrhage(42.7%)
comparedwitholderpatients(15.7%), predominantlyattributabletoaneurysmsand arteriovenousmalformations.13
Thereisahigherriskforbrainhemorrhagesinboys.Theoddsare37%higherfor aboytohaveahemorrhagicstroke.48 Black childrenhaveahigherriskofstroke,witha relativeriskof1.59forSAHand1.66for intracerebralhemorrhage.42
Causesforhemorrhagicstrokearelisted inTables14-1and15-1.Therearenumerous causesforhemorrhagicstrokesinchildren. Amongchildrenyoungerthan20years, 46%ofhemorrhagesareduetostructural abnormalities(79%arteriovenousmalformation,37%cavernousmalformation,33% aneurysm,and7%tumor).107 Othercauses aretraumain24%,idiopathicin19%,and medicalin10%.Inadultsyoungerthan49 yearsold,33%havearterialhypertension; 41%haveintracranialaneurysms,arteriovenousmalformations,orothervasculopathies;and20%abusedrugs.108 Inanother reviewofriskfactorsforintraparenchymal hemorrhagein68children,themostcommonriskfactorswerevascularmalformation/fistulain32%,hematologiccausesin 17.6%,coagulopathiesin14.7%,andbrain tumorin13.2%;noriskfactorswerefound in10.3%.Aneurysmsaccountedfor5.9%; cavernousmalformation,2%;hemorrhagic infarct,8.8%;andspontaneousarterialdissection,2.9%.109 Inblacks15to44years old,themostcommoncausesofintracerebralhemorrhagearehypertensivevasculopathyin64.2%;undetermined,22.4%; aneurysm,4.5%;arteriovenousmalformation,4.5%;andthrombolysis/anticoagulation,3%.41 ForSAH,thedistributionin blacksisaneurysmin69.4%,undetermined in21%,andarteriovenousmalformationin 10.5%.41
Alcoholanddrugabusecontributetothe riskforbrainhemorrhage.Thereisadosedependentincreasedriskforsubarachnoid andintracerebralhemorrhageassociated withalcoholabusethatisprobablysecondary tochronicelevationofbloodpressure.110-112 Individualswithheavyalcoholconsumption havea1.9timeshigherriskforhemorrhagic strokecomparedwithindividualswhodo notconsumealcohol.113 TheriskofSAHwith alcoholuseisdose-dependent,increasing
to1.5inindividualsdrinking1to2drinks perdayand3.8timesinindividualsdrinking morethan2drinksperdaycompared withnondrinkers.114
Inastudyofwomen15to44yearsold, theuseofamphetaminesandcocainewas associatedwitha9.6timeshigherriskfor intracranialhemorrhagethaninwomen withnodrugabuse.115 Theprimarymechanismofcocaine-inducedintracranialhemorrhageisprobablyacuteelevationofblood pressure,withorwithoutanunderlying cerebrovascularmalformation.
RiskofStrokeRecurrence
Clinicallyapparentandclinicallysilentrecurrentischemicstrokearecommonafteran initialischemicstrokeinchildren.116 One studyshowedahighrateofrecurrentstroke, withnearly40%ofchildrenexperiencinga recurrence1dayto11.5yearslater(median 267days).116 Anothermorerecentstudy showedamoremodestrateofrecurrence, with1in10childrenhavingarecurrence within5yearsdespitestandardtreatment.117 Clinicallysilentinfarctionsoccurredin19% of103childreninonestudy,whoremained asymptomaticaftertheirinitialinfarction.116 So-calledsilentinfarctionsmayhaveeffects oncognitivefunctioninchildren,however.
Somestudieshaveshownthatthepresenceofmultipleriskfactorsisassociated withahigherriskofrecurrence.31,32 Risk factorsthathavebeenassociatedwith recurrenceincludepreviousTIA;bilateral infarction;leukocytosis;andthepresence ofamedicaldiagnosisbeforethestroke (especiallyimmunodeficiency),suchaselevatedlipoprotein(a),proteinCdeficiency andstrokeofvascularorigin,andmoyamoyadisease.116,117 Theriskfactorsfor recurrenceofCSVTarenotwellstudied.It issuggestedthatindividualswithchronic medicalconditions,suchasanemiaorcongenitalnephroticsyndrome,areatriskof CSVTrecurrence.118 Theriskofrecurrent hemorrhagicstrokeinchildrenis10%within 5years,withahigherriskofrecurrence acutelyforchildrenwithmedicaletiologies andamoreprolongedandhighriskfor recurrencewithstructurallesions. 107
Prognosis
Figure1-1 showstheincidenceofdeathsfrom cerebrovasculardiseaseinchildrenandyoung adults.119 Thepeaksfordeathsareininfants youngerthan1yearandinadults35to44 years.Themortalityratefromstrokehas declined58%overtheperiodfrom1979to 1998.120 Estimatesofthedeathratefromrecurrentstrokeare15%to20%.117 Themortality rateishigherforpatientshavingarecurrent stroke(40%)comparedwithasinglestroke (16%).121 Thereisahigherriskfordeathwith hemorrhageandwithstupororcomaatpresentation.122 Onestudyshowednoethnicdifferencesinstrokeseverityorcase-fatalityrate, butboyshaveahighercase-fatalityratefor stroke.120
Onestudyindicatedthatchildrenwithsubcorticalstrokeshaveabetteroutcomethan childrenwithcorticalstrokes.123 Although 86%ofchildrenwithsubcorticalstrokehad goodoutcomes,only38%withcorticalstrokes hadsimilaroutcomes.123
Childrensurvivinganinitialischemic strokemayhavevaryingdegreesofhemiparesis,learningdisabilities,attention-deficit/ hyperactivitydisorder,mentalretardation, seizuresandmovementdisorders.124,125 Certainclinicalfeaturesorriskfactorsare associatedwithapooreroutcome.Children whopresentwithseizurestendtohavea worseprognosisforintellectualdevelopmentandahigherincidenceofrecurrent seizurescomparedwithchildrenwhodo nothaveseizuresduringtheacutephase.24
Onestudyofyoungadultswithacuteischemiccerebralinfarctionhada30-daymortality of6.6%,whichislessthanmortalityreported
witholderadults.126 Patientswithacardiac sourceofstrokehadthegreatestmortality.126 Afterastrokeinayoungadult,theprognosis isslightlybetterforpatients16to30years oldcomparedwithpatients31to45years. Approximately60%oftheyoungergrouphad eithernoorminordisabilitycomparedwith 51%oftheoldergroup.64 Afterrehabilitation, approximately80%ofyoungadultpatients resumetheirpreviousjobswithin6months afterdischarge.127
TherehavebeenfewstudiesofthelongtermprognosisofCVSTinchildren.Data fromtheCanadianPediatricStrokeSurvey inchildren(0to18years)foundthat8% of160patientsdied. 129 Deathoccurredin 5of42childreninanotherstudyandwas associatedwithcomaatpresentation. 118 Predictorsofagoodcognitiveoutcome includedolderage,lackofparenchymal abnormality,anticoagulation,andlateral orsigmoidsinus(orboth)involvement. 118 ComplicationsofCSVTthatcanpersist includepseudotumorcerebri,cognitive andbehavioraldisabilities,epilepsy,and persistentfocalneurologicabnormalities. 118 Inasmallstudyof17childrenwith CVST,childrenwhosurvivedhadafair prognosis,withmostshowingnormalcognitiveandphysicaldevelopment. 128
Inastudyof56childrenwithhemorrhagic strokeoverameanfollow-upof10.3years, deathoccurredin23%asaresultoftheinitial hemorrhage;rebleedingoccurredin16%, whichresultedindeathin33%;andseizures developedin11%.129 Althoughmostsurvivingchildrenfunctionedindependently,only 25%ofthesechildrenwerefreeofphysical orcognitivedeficits.
FIGURE1-1 Deathsfromcerebrovasculardiseaseinchildrenandyoung adults.(DatafromKungHC,Hoyert DL,XuJQ,MurphySL.Deaths:final datafor2005.InNationalVitalStatisticsReports,vol56,no10.Hyattsville, MD:NationalCenterforHealthStatistics,2008.)
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