cerebral venous thrombosis: measuring thrombi and sinuses

1

Cerebralvenousthrombosis:Measuring

thrombiandsinuses

HeikkiHannikainen,medicalstudent

FacultyofMedicine,UniversityofHelsinki

E‐mail:heikki.hannikainen@helsinki.fi

Tel:+358415376585

Supervisors:

TurgutTatlisumak,MD,PhD,DepartmentofNeurology

JukkaPutaala,MD,PhD,DepartmentofNeurology

OiliSalonen,MD,PhD,DepartmentofRadiology

HelsinkiUniversityCentralHospital

Helsinki,Finland

2

ListofContents

TitlePage 1

ListofContents 2

ListofAbbreviations 3

Abstract 4

Reviewoftheliterature 6

Anatomy 6

Pathophysiology 7

Epidemiology 8

Riskfactorsandetiology 8

Symptoms 10

Diagnostics 11

Treatment 13

Prognosis 14

Aimsofthestudy 15

Patientsandmethods 15

Results 20

Discussion 24

Acknowledgments&funding 27

References 27

3

Listofabbreviations

CSFCerebrospinalfluid

CTComputedtomography

CTAComputedtomographyangiography

CVTCerebralvenousthrombosis

ICPIntracranialpressure

IIHIsolatedintracranialhypertension

LMWHLow‐molecular‐weight‐heparin

MRIMagneticresonanceimaging

MRAMagneticresonanceangiography

ROIRegionofinterest

SSSSuperiorsagittalsinus

rSTrighttransversesinus

lSTlefttransversesinus

4

UNIVERSITYOFHELSINKI

Faculty

FacultyofMedicine

Department

DepartmentofNeurology

Author

HeikkiHannikainen

Title

Cerebralvenousthrombosis:Measuringthrombiandsinuses

Subject

Medicine

Level

Thesis

Monthandyear

10/2013

Numberofpages

29

5

Abstract

Backgroundandpurpose:Cerebralvenousthrombosis(CVT)isarare,butseriousdisease,

commonlyoccurringinyoungtomiddle‐agedwomen.Itisnotyetknownwhethersinussize

andshapeconfersariskforthrombosisandwhetherclotsizeiscorrelatedwith

recanalizationrates,andbecausethereisnoestablishedmethodformeasuringsinusorclot

size,wedecidedtodevelopone.

Patientsandmethods:CVTpatientswith3‐Dmagneticresonanceimagingdoneearlyfor

diagnosisandfollow‐upimagingaround6monthsorlaterwererecruited.Ageandsex‐

matched(1:2)controlsubjectswerepatientswithvariousbenignheadacheproblemswho

underwent3DMRIforexcludingCVTorotheracutestructuraldisease.Allmajorsinuses

weremeasuredinsize(areaanddiameter).Alldetectedclotsunderwentsimilar

measurement(volume,areaandlength).MeasurementsweredonewithOsirix‐software.

Results:25CVTpatients(17femalesand8males)and50controlsubjectsweremeasured.

Volumeofthethrombuswaseitherdissolvedorreducedinallexceptonecase.Sinusareain

CVTpatientsinfollow‐upimagingwasslightlysmallercomparedtohealthysubjects(

P=0.052‐0.170).Thrombusvolumeswerebigger(P=0.009)butalsodissolvedmore

effectivelyinwomen,withnodifferenceinsex‐groupsinfollow‐upimaging.Residualclot

volumewasbiggerinolderpatients(P=0.007).Otherfactorsdidnotstronglycorrelatewith

thrombusvolume.Measurementreproducibilitywithtwoindividualinvestigatorswasgood,

withbestinterratercorrelationofover95%involumemeasures.

Conclusions:Thisisthefirstattemptinestablishingavolumetricmeasurementofcerebral

sinusesandclots.Themethodologymayhelpinestimatingprobabilityofrecanalizationand

intrialswithinterventionssuchaslocalthrombolysisandthrombectomy.

Keywords

cerebralvenousthrombosis,clot,clotsize,sinus,sinussize,measurement

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Reviewoftheliterature

Anatomy

Cerebralvenousthrombosis(CVT)occurswhenthecerebralveinsorduralvenoussinuses

ofthebrainareoccludedwiththromboticmaterial.Cerebralveinsemergefromthebrain,

runinthesubarachnoidspaceandpiercethearachnoidmembraneandmeningeallayer

ofduraintotheduralsinuses.Thesesinusesarelocatedbetweenthelayersofduramater

andcontainnovalvesortunicamuscularis.Theyalsoreceivebloodfromdiploic,

meningeal,andemissaryveins.Cerebrospinalfluidisabsorbedfromthesubarachnoid

spacetothesinusesviaarachnoidgranulations.Thevenousdrainageofthebraincanbe

dividedintosuperficialanddeepsystems.Superficialsystemincludesthesuperiorand

inferiorsagittalsinusesandcorticalveins,drainingmostlythesuperficialsurfacesof

cerebralhemispheres.Deepsystemincludesthetransversesinuses,sigmoidsinuses,

straightsinus,andthedeepercorticalveins.Itdrainsthedeepwhiteandgraymatter

surroundingthelateralandthirdventriclesandbasalcisterns.Venousbloodusuallydrains

intothenearestsinus,orinthedeeperstructures,tothedeepveins.Straightsinusis

formedbytheinferiorsagittalsinusandthegreatveinofGalenandendsinthe

confluenceofsinuseslocatedattheinternaloccipitalprotuberance.Superiorsagittalsinus

beginsjustbehindthefrontalsinusesandcoursesallthewaytotheconfluenceofsinuses

runningintheshallowgrooveonthemidlineofthecranium.Rightandlefttransverse

sinusesleavetheconfluencerunningbetweentheattachmentsofthetentorium,then

draintobilateralsigmoidsinuseswhichconvergewiththeinferiorpetrosalsinusesand

ultimatelythebloodleavesthebrainmostlyviainternaljugularveins.(1,2)Theanatomy

oftheduralsinusesissubjecttogreatdealofvariation.Forexamplethetransverse

sinusesarenotequalinsize,therightoneusuallybeinglargerandreceivingmajorityof

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thedrainagefromthesuperiorsagittalsinus.Thelefttransversesinusconverselyreceives

predominantlythedrainagefromthestraightsinus.(1,3)

Figure1.Anatomyofthecerebralvenoussystem(4).

Pathophysiology

Venousflowofthebrainisimpairedbothlocallyandsystemicallywhenthecerebralveins

ortheduralsinusesareoccludedwiththromboticmassleadingtocongestionwithinthe

venousvasculature.Localizedvenousinfarctionandedema,bothcytotoxicandvasogenic,

maybepresent.Petechialhemorrhagesmaydevelopintolargerhematomasand

complicatethesituation.Withocclusionofthemajorduralsinusesintracranial

hypertensionisexplainedbytheimpairedabsorptionofthecerebrospinalfluidand

increasedvenouspressure.(5)

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Epidemiology

Cerebralvenousthrombosisisarareevent,theincidencebeing3‐4per1million

populationannually.Youngadultsandchildrenaremostoftenaffectedandabout75%of

thepatientsarewomen.Meanageofthepatientsis~35‐40years.(5‐7)SSSandthe

transversesinusesarethemostcommonlyaffectedsinuses.Oftenmorethanonesinusis

occluded.(8)

Riskfactorsandetiology

TheriskfactorsfortheCVTaremostlysimilartoothervenousthrombosesandthereare

numeroussuggestedetiologiesforsinusthrombosis(Table1).Thegender‐specificrisk

factorssuchasuseoforalcontraceptives,hormonereplacementtherapy,pregnancy,and

puerperiumaremarkedlyassociatedwithCVT.(9)Ashighas76%ofwomenin

reproductiveagewithsinusthrombosismayhavethesedefinablegender‐specificrisk

factors.(10)Themostcommonacquiredriskfactorsaremalignancies,localandsystemic

infections,hematologicconditions,andmechanicalinjury.(5,8)Severalcongenitalrisk

factors,suchasprothrombinG20210Amutation,activatedproteinCresistance,FactorV

Leiden,andhyperhomocysteinemiaarealsoassociatedwithsinusthrombosis.(11)In10‐

15%ofpatientsnoriskfactorcanbeidentified.(5,8)

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Table1.Riskfactorsandetiology

GeneticthrombophiliasAntithrombinIIIdeficiencyProteinCandSdeficiencyFactorVLeidenmutation(FVR506Q)Prothrombingenemutation(G20210A)Hereditaryhomocyteinemia/homocysteinuriaFactorXIIgenepolymorphism

AcquiredthrombophiliasAntiphospholipidantibodiesHyperhomocysteinemiaNephroticsyndromePregnancyandpuerperiumIncreasedFactorVIIIconcentration

HematologicaldisordersPrimaryandsecondarypolycytemiaEssentialthrombocytosisLeukemiasLymphomasAnemias(irondeficiency,Sicklecell,thalassemia,andothers)ParoxysmalnocturnalhemoglobinuriaUseoferythropoietinHighaltitude

InfectionsMeningitisandbrainabscessOtitis,mastoiditis,sinusitis,tonsillitis,anddentalinfectionsSepsis

SystemicinflammatorydiseasesSystemiclupuserythematosisSarcoidosisWegener’sgranulomatosisBehcet’sdiseaseInflammatoryboweldisease(ulcerativecolitis,Crohn’sdisease)

DrugsandnaturalproductsOralcontraceptivesSteroidsCytostaticsTalidomideTamoxifenL‐AsparaginaseEstrogen‐likesubstanceincludingphytogenics

LocalandmechanicalcausesBraintumorsArteriovenousmalformationsNeurosurgicaloperationsLumbarpuncture

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Traumatoface,maxillarysinuses,andcervicalveinsCatheterizationofcervicalveinsHypoxia

OthersSpontaneousintracranialhypotensionMalignanciesDehydrationThyrotoxicosisDownsyndrome

Symptoms

Themostcommonsymptomisheadache,whichispresentin70‐90%ofpatients.Thereis

nospecificuniformpatternofheadacheforCVTbutitisusuallyacuteorsubacuteslowly

progressingoverafewdays.However,anacutethunderclap‐likeheadacheispossible,

too.(12)SometimesheadachecanbetheonlysignofCVT.(13)Inapproximatelyhalfof

thepatientstherearefocalneurologicalsigns.(14)Seizuresarepresentin40%ofthe

patientsofwhich7%inacutephase.(15)Inpatientswithisolatedintracranial

hypertension,themostimportantsymptomsareheadache,papilledema,nausea,and

visionimpairments.IsolatedintracranialhypertensionmaybetheonlysignoftheCVTin

somecases.(16)

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Diagnostics

Diagnosisofsinusthrombosisischallengingasclinicalsymptomsvaryandneuroimaging

maysometimesbedifficulttointerpret.UnenhancedCT‐scanmayshowso‐calledcord

sign(hyperdensethrombosedvein)ordenseduralsinussign(Figure2).Theseare,

however,relativelyinsensitivesignsofsinusthrombosis.Theemptydeltasign,amore

sensitivesignofCVTseenoncontrastenhancedCT,maybemoreuseful.(17)Theindirect

signsofCVTcanalsobeseenonCT‐scan,suchasedema,decreasedventricularsizeor

venousinfarction(hemorrhagicornonhemorrhagic).Overall,incasesofconfirmedCVT,

somesignsofthrombusmasscanbeseeninunenhancedCTin73%ofthepatientswith

nofalse‐positivereadings.(18)CT‐venographyisasignificantlybetterwayforCVT‐

diagnosticsandcandirectlyvisualizesinusthrombiasfillingdefects.(19)

MRIandMR‐venographyare,however,usuallythepreferredinitialdiagnostictestswhen

CVTissuspected.InregularMRI,thrombusmaybedirectlyvisualizedandnormaldural

sinuses(Figure1)areoftenseenasflowvoids.Theemptydeltasignisoftenvisiblein

contrast‐enhancedMRI.TheindirectsignsarealsousuallybetterseeninMRIcomparedto

CT.(19)InMRIthrombus,missingflow,andparenchymalchangesareofteneasilyseen.

(19)MR‐venographyandCT‐venographyareprobablyequallysensitiveindiagnosisof

CVT.MRI‐basedtechniquesareoftenbettersuitedfordifferentialdiagnosticsand

evaluatingtheparenchymalchanges.Further,MRIismorehelpfulinexcludingotherbrain

pathologies.(14)

MeasuringD‐dimermaybeusefulfordiagnostics.D‐dimerlevelshavebothhighspecificity

andsensitivityindiagnosingCVTandalsocorrelatewiththeextentofthedisease.

However,normalD‐dimercannotbeusedsafelytoruleoutDSTincasesoflowclinical

probability,asisthecaseine.g.deepveinthrombosis.(20)

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Figure2.ExamplesofCVT‐diagnostics.A.Bilateraldenseduralsinussignintransverse

sinusesinunenhancedCT.B.Emptydeltasigninsuperiorsagittalsinusincontrast‐

enhancedCT.C.ThrombusmassseeninsuperiorsagittalsinusinCT‐venography.D.

Thrombosedtransversesinusincontrast‐enhancedT1multiplanarreconstructionMRI‐

image.E.CorticalveinthrombusinT2*‐MRI.F.MR‐venographywiththrombosedSSS.

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Treatment

Immediateanticoagulationmustbeemployedastheprimarytreatmenttopromote

dissolvingofthethrombus,topreventrethrombosisorthrombuspropagation,andto

preventpulmonaryembolismevenincaseswithhemorrhagicchangesinthebrain.

AnticoagulationtreatmentforCVTiswidelyconsideredsafeandpotentiallyeffective.No

newsymptomaticintracerebralhemorrhageswerereportedinarecentCochranereview

includingtwostudies.(21)Unfractionedintravenousdose‐adjustedheparinand

subcutaneousfixeddoselow‐molecular‐weightheparin(LMWH)canbothbeused.LMWH

shouldbepreferredasitismoreeasilyadministeredinpracticeandhasfewerbleeding

complications.Advantagesofintravenousheparinincludepossibilityofrapid

discontinuationifneeded.Theexactdurationoftheanticoagulationtreatmentafterthe

acutephaseisalsocontroversial.IftheCVTisduetoaclearlytransientriskfactor,suchas

pregnancy,oralanticoagulationmaybegivenfor3months.Inidiopathiccasestreatment

of6‐12monthsisrecommendedandcontinuousoralanticoagulationwhenasignificant

persistentriskfactorcanbeidentifiedorCVTrecurs.(22)

Incaseswithpoorerprognosisamoreaggressivetreatmentmaybebeneficial.Local

thrombolysisusingmicrocatheterandrecombinanttissueplasminogenactivatoror

urokinasehasshownsomeeffectinclinicalstudiesbutalsocarriesahigherriskof

bleedingcomplications.Ithasbeenrecommendedforpatientsatahighriskorclinically

deterioratingdespiteanticoagulationtreatmentandwithoutintracranialhemorrhageor

impendingherniation.(22)Mechanicalthrombectomyhasalsobeenusedinselected

cases.(23)

Antiepileptictreatmentisusedforpatientswithseizures.Prophylacticantiepileptic

treatmentmayalsobeusedinpatientswithcertainriskfactors,suchasfocaldeficits,

thrombosisoftheSSSorcorticalveins,andsupratentorialparenchymallesions.(15)A

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prolongedtreatmentof1yearcanbeusedaftertheacutephaseforpatientswithearly

seizuresandhemorrhagiclesions.(22)

Othertreatmentincludessufficientfluidtreatment,analgeticsandtreatmentofelevated

intracranialpressure.WhenanticoagulationtreatmentdoesnotdecreaseelevatedICP,

generalprinciplesoftherapyshouldbeapplied(headelevation,hyperventilation,and

osmoticdiuretics).Acetazolamide,lumbarpuncturewithCSFremoval,shunts,andoptic

nervefenestrationmaybeusedwhenvisionisimpaired.(22)Inmoreseriouscaseswith

threateningherniation(majorcauseofdeathinCVT),decompressivecraniectomyand/or

hematomaevacuationcanoftenbelifesavingandmayresultingoodrecovery.(24)

Prognosis

Prognosishasimprovedduringthelastdecades:totalmortalityrateisunder10%and

below6%duringacutephase.(25)Overhalfofthepatientshavenoresidualsymptomsat

allandlessthan5%aremoderatelyimpairedorseverelyhandicapped.Mostcommon

residualsymptomsarefocaldeficits,residualheadache,andmildcognitiveimpairment.

(8,26)RecurrenceofCVTisrare,occurringinlessthan3%ofthecases.Incidenceofother

thromboembolicevents(outsidecerebralvenoussystem)isunder4%amongCVT‐

patients(25).

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Aimsofthestudy

1. Todevelopmethodologyformeasuringsizeofcerebralveinsandsizeofthrombus

residingincerebralveins;

2. Toanalyzewhethersizeofthrombuspredictsrecanalizationandseverityof

symptoms;and

3. ToanalyzewhethersizeofcerebralveinsinpatientswithCVTdifferfromthosein

healthysubjects.

Patientsandmethods

ThisstudywasapprovedbytherelevantauthoritiesandcarriedoutattheDepartmentof

Neurology,HelsinkiUniversityCentralHospital.Wesearchedallpatientswith

angiographicallyverifieddiagnosisofCVTbetween1990‐2010.Onlypatientswithhigh

qualityMRI‐imagesinbothacuteandfollow‐upphase(usually6months)wereincludedto

ensureprecisemeasurements.Controlpopulationconsistsofage‐andsex‐matched

patientsimagedforheadacheorotherneurologicalsymptomsforexcludingCVTbutwith

nofindingsrelatedtoCVT.TheMRI‐imagesofthepatientsandcontrolsubjectswere

transferredtoDVDsinDICOM‐formatfromthehospital'selectronicimagearchives.All

themeasurementsweremadewithOsirixprogram(version3.8.1)inMacOsX‐

environment(http://www.osirix‐viewer.com/)andusuallyfrommultiplanar

reconstruction(MPR)images.Measuringthecorticalthrombuswasespeciallychallenging

andtheyweresometimesbettervisualizedinT2*‐images.MR‐imagesoftheacutephase

andthefollow‐upimages(usuallycollectedsixmonthsaftertheacutephase)wereboth

measuredforallpatients.Allthemeasurementsweremadebythesameresearcher.To

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assessinterraterreproducibility,blindedmeasurementsusingthesamemethodwere

performedbyasecondinvestigatorforarandomsetof10patients.

VolumesofthethrombiweremeasuredinCVT‐patientsinSSS,sinustransversus,straight

sinus,andcorticalveins.AreaandlengthofthethrombiweremeasuredinSSS,sinus

transversusandstraightsinus.InCVT‐patientsandincontrolsubjectsareaoftheactual

sinuswasmeasuredinSSS,sinustransversus,andstraightsinus.ThediameteroftheSSS

wasmeasuredincontrolsubjectsandinthefollow‐upimagesoftheCVT‐patients.

AllthemeasurementsregardingSSSandstraightsinusweremadefromsagittalslices.

Transversesinuses,sigmoidsinusesandinternaljugularveinsweremeasuredfrom

transverseslices.Whencorticalthrombiwerepresent,theywereusuallymeasuredfrom

transverseslices.Confluenceofthesinuseswasinthesemeasurementsconsideredas

partoftheSSS.Volumeofthethrombusintransversesinusesalsoincludesthrombus

massinthesinussigmoideusandinternaljugularvein.Areaandlengthofthethrombusin

sinustransversus,however,onlyincludesthepartofthethrombusintheactualsinus

transversus.

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Figure3.Thrombusmassinrighttransversesinusoutlinedinoneslice.

Volumesofthethrombiweremeasuredbymanuallyoutliningtheareaoftheactual

thrombusmassineachindividualsliceusingthe“Closedpolygon”tool(Figure3).

Subsequently,volumeofthethrombuswascomputedwith“ROIVolume”toolbythe

program.Areaofthethrombusandtheareaoftheactualsinusweremeasuredusingalso

the“Closedpolygon”toolbymanuallyoutliningthedesiredarea(Figure5),andwhen

needed,constructedfromseveralslices(forexampleinthecaseofSSSusuallyfrom1‐3

adjacentsagittalslices).Lengthofthethrombiweremeasuredusingthe“Length”toolby

drawingseveralstraightlinesrunningapproximatelyinthemiddleofthethrombusmass

andwhenneededmeasuredfromadjacentslicesaswhenmeasuringthearea.The

diameteroftheactualSSSwasmeasuredwith“Length”toolatthehighestpointofthe

SSS,inthemiddlebetweenthehighestpointandthestartingpointoftheSSSandinthe

middlebetweenthehighestpointandtheconfluenceofsinuses(Figure4).

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Figure4.DiametersoftheSSSinthreeestablishedmeasurementpoints

Figure5.Areaofthesuperiorsagittalsinusoutlinedinahealthycontrolsubject.

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SPSSstatistics20wasusedforstatisticalanalyses(IBMCorporation,2011).Mann‐

Whitney‐UandKruskal‐Wallistestswereusedtoanalyzedifferencesofsinus

measurementsbetweenpatientsandcontrols,anddifferencesofthrombusvolumein

patientsubgroups.Wilcoxonsignedranktestwasusedforrelatedsamples.Measurement

reproducibilitywasassessedbycomparingmeansofthetwoindividualinvestigators,

correlationover95%wasdesired.Two‐sidedvaluesofP<0.05wereconsidered

statisticallysignificant.

Theroleoftheresearcher(H.H)inthisstudywastodevelopmethodologytomeasure

duralsinusesandthethrombiresidinginthemastherewasnoexistingmethodologyto

dothis.MRI‐imagesweretransferredandevaluatedbytheresearchertodetermine

whethertheywereofgoodenoughqualitytomakeaccuratemeasurements.Radiologist's

MRI‐reportsoftheimagesandconsultationsfromaneuroradiologistwereusedasanaid

whenneeded.Allthemeasurementsweremadebythesameresearcherwithsame

equipmentandapplyingsamemethods.

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Results

Measurementsweredoneforatotalof25CVT‐patientsinbothacuteandlatephase.

Meanageofthepatientswas43.6,andmeanageforwomen(17intotal)was40.6and

formen(8intotal)50.0.Wehave50controlpatientswiththemeanageof44.1.Mean

ageforwomen(34intotal)was41.7andformen(16intotal)49.2,e.g.2age‐andsex‐

matchedcontrolsubjectsforeveryCVTpatient.

Measuredsinusareasinpatients(follow‐upimages)andcontrolsubjectsarecomparedin

table2.Thecontrolpatientshadaslightlylargersinussize,however,thedifferencewas

notstatisticallysignificant.AreaofthesinusesinCVTpatientswassignificantlybiggerin

acutephasethaninthefollow‐upimaging(Table3).

Table4representsthethrombusvolumesindifferentpatientgroupsinboththeacute

andfollow‐upphase.Thrombusvolumeswereeitherreducedortotallydissolvedinall

patientswithoneexceptionwherethethrombusvolumewasbiggerinfollow‐upphase.

Womenhadsignificantlylargerthrombusvolumesintheacutephase.However,inthe

follow‐upimagestherewasnodifferenceinthethrombusvolume.Intheolderagegroup

(cut‐point44years)theresidualthrombusvolumeinfollow‐upphasewassignificantly

biggerwithnodifferenceintheacutephasecomparedtoyoungeragegroup.Otherwise

theriskfactors,clinicalpresentation,theparenchymallesionsinMRIimagingorthe

outcomedidnotcorrelatewiththrombusvolume.

Measurementreproducibilitywasinvestigatedwithtwoindividualinvestigators,interrater

correlationofthrombusvolumeandsinusvolumemeasureswasover95%inall

measurementpoints.Inthrombuslengthandthrombusareameasurementsinterrater

correlationwasover95%.Sinusareameasurementcorrelationwas87%inright

transversesinus,88%instraightsinusand95%inlefttransversesinus.Lowercorrelation

wasachievedinSSSdiametermeasurements;anterior54%,superior87%andposterior

77%.

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Table2Sinussizeincerebralvenousthrombosispatientsandincontrolsubjects

Case Control P

mean range mean range

Area(cm2)

Superiorsagittalsinus 17.16 12.39‐22.82 18.20 12.35‐24.19 0.170

Rightsinustransversus 5.39 3.72‐8.55 5.74 2.17‐8.47 0.052

Leftsinustransversus 4.23 1.76‐6.39 4.73 2.63‐7.95 0.124

Rectus 2.54 1.44‐3.86 2.75 1.55‐4.32 0.126

Superiorsagittalsinusdiameter(cm)

Anterior 0.42 0.30‐0.57 0.44 0.23‐0.68 0.238

Middle 0.90 0.56‐1.49 0.97 0.64‐1.39 0.108

Posterior 0.69 0.52‐0.96 0.70 0.49‐1.01 0.590

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Table3Sinusandthrombusareaandthrombusvolumechangesintheacuteandfollow

upimaging

Acute Follow‐up P

SinusArea(Cm2) mean range mean range

Superiorsagittalsinus 19.67 14.2‐2.1 17.16 12.4‐22.8 <0.001

Transversesinus,right 6.07 3.4‐9.4 5.35 3.7‐8.6 0.009

Transversesinus,left 4.84 2.2‐8.0 4.23 1.8‐6.4 0.002

Straightsinus 3.21 2.0‐5.9 2.54 1.4‐3.9 0.005

TrombusArea(Cm2)

Superiorsagittalsinus,n=15 4.12 0.3‐11.1 0.79 0.0‐6.4 0.006

Transversesinus,right,n=17 2.43 0.0‐6.1 0.42 0.0‐1.7 0.001

Transversesinus,left,n=10 2.49 0.6‐4.3 0.33 0.0‐1.1 0.005

Straightsinus,n=5 1.64 0.5‐3.1 0 0.0‐0.0 0.043

Thrombusvolume(Cm3)

Total,n=25 4.59 0.6‐15.7 0.54 0.0‐3.0 <0.001

Superiorsagittalsinus,n=15 2.23 0.1‐7.0 0.35 0.0‐2.5 0.002

Transversesinus,right,n=17 3.32 0.2‐14.7 0.31 0.0‐1.2 <0.001

Transversesinus,left,n=10 1.81 0.5‐2.7 0.27 0.0‐1.1 0.004

Straightsinus,n=5 0.56 0.1‐1.3 0 0.0‐0.0 0.043

Corticalveins,n=6 0.69 0.3‐1.2 0 0.0‐0.0 0.028

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Table4.Thrombusvolumemeasurementsindifferentpatientgroupsintheacuteandfollow‐upimaging

Thrombusvolumeintheacutephase(cm³)

Thrombusvolumeatfollowup(cm³)

Mean P Mean P

Gender 0.009 0.475

Male 1.93 0.76

Female 5.84 0.43

Age 1.00 0.007

<44years 4.77 0.24

≥44years 4.31 0.98

Modeofonset 0.543 0.690

Acute 8.84 0.34

Subacute 6.15 0.73

Chronic 2.78 0.66

MRIImaging 0.156 0.780

Noparenchymallesions 5.24 0.56

Parenchymallesion(s) 2.43 0.45

Clinicalpresentation 0.584 0.975

Isolatedheadache 5.87 0.4

Focalsymptoms 3.04 0.62

Impairedconscioussness 1.46 0.36

RiskFactors 0.723 0.128

≥1identifiedriskfactor(s)(n=14) 5.43 0.69

Noidentifiedriskfactor(n=1) 5.45 0.45

Outcome 0.254 0.359

Goodrecovery(mRS0‐1)(n=16) 4.69 0.62

Incompleterecovery(mRS<2)(n=3) 1.84 0.12

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Discussion

Cerebralvenousthrombosisisararediseasewithvariousmanifestationsandisusually

difficulttodiagnose.Withimprovedearlydiagnosisandquicklystartedtreatments,the

prognosisofthediseasehasclearlyimprovedandmortalityratesarealreadybelow10%.

However,consideringthatmostpatientsareratheryoungandmanysurvivewith

significantmorbidities,thereisstillroomforenhancingbothdiagnosticsandtreatment

modalities.

ThereexistsnopreviousworkattemptingatmeasuringclotsizeinCVTpatients.

Therefore,therearenodatadescribingwhetherlargethrombiremainwithout

recanalization,leadtomoresevereconsequences,andlong‐termdisabilities.Iflarge

thrombiareassociatedwithdismaloutcomes,then,novelapproachese.g.local

thrombolysisorsurgicalremovalofthrombusfromsuperficialsinusesmaybewarranted.

Thesehigh‐riskinterventionsoftenrequireanearlyestimateoflikelihoodofspontaneous

recanalizationandmeasurementofclotsize.

Onepreviousstudyinvestigatedthecerebralvenousvolumeinpatientswithidiopathic

intracranialhypertension(27).Inthatstudyvolumemeasurementsweretakenfrom

reconstructed3DimagesfromMRVimageswithoutcontrast.Thereforethemethodology

differedfromours.Inourmethodmanuallyapproximatingthethrombusmatterinsinuses

doesnotsufferfrombiascausedbyslowbloodflowandnoncontinuousthrombusmatter.

Anotherunexploredissueiswhetherthesizeofthecerebralsinusesdifferssignificantly

amongadultindividualsandwhethersizeofthesinusesmightbeafactorpredisposingto

thrombosis.Becausethesinussizecannotbemeasuredreliablyuponpresenceof

thrombusinit,weconsideredonlypatientswithrecanalizationat6or12monthspost‐

thrombosispresumingthatsinussizereturnedtoitsoriginalsizeatthispointoftime.For

thispartofthestudy,werecruitedage‐andsex‐matchedpatientswhounderwentbrain

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MRIforvariousheadachesandimagingexcludedCVTaswellasotherseriousbrain

pathology.

ThetrendofCVTpatientshavingsmallersinussizeincontrolimagingcomparedtohealthy

controlsubjectscouldbeanundiscoveredriskfactorforCVTcombinedwithother

prothromboticfactors.However,itdidnotreachastatisticalsignificanceandcouldreflect

reactiveshrinkageinexposingtheseindividualstodifferentvenousbloodflowconditions,

ormerelyachancefinding.Significanceofthisisfindingshouldbestudiedmore

extensively.

Thrombosedsinuseswereclearlyengorgedintheacutephasefollowedbysignificant

reductioninsinussizeaftertotalorpartialrecanalization.Theoreticallythiscouldbe

explainedbyrecanalizationoftheoccludedsinusresultinginlesseningtheflow

obstructionandvenouscongestion.

Themoreeffectivedissolvingofthethrombusinwomenmayberelatedtothefactthat

gender‐specificriskfactorsplayabiggerroleinwomenwithCVT,namelycontraceptive

pill,HRT,pregnancy,andpuerperium.Theseareoftentransientandeasilytreated

comparedtootherriskfactors.Similarlythefindingofgreaterresidualvolumeofthe

thrombusinolderagegroupmayreflectthesmallerroleofthesetransientriskfactorsin

thesepatients.

Inpreviousstudiesthecorrelationbetweenoutcomeandrecanalizationhasbeenunclear.

Somestudieshavefoundnocorrelation(28)andsomehavereportedhigherfrequencyof

residualsymptomsorworseoutcomewithnorecanalization(29,30).Inthisstudythere

wasnocorrelationbetweenoutcomeandresidualthrombusvolumeorvolumechange.

Thelackofcorrelationbetweenthrombussizeandriskfactorsorclinicalfactorsinthis

studymaybeduetoasmallsamplesizeandshouldbeinvestigatedinalargerpopulation.

Ourworkhascertainlimitations.Firstly,thenumberofpatientsisrathersmall.Secondly,

sinussizeat6or12monthspost‐CVTmaystillbedifferentfromitsoriginalsize.Thirdly,

26

thereisnowell‐establishedgoldstandardmethodologyformeasuringthrombusorsinus

size.Theseresultsshouldthereforebeconsideredashypothesis‐generating.Volumetric

studiesdonemanuallyarenaturallyalsopronetoerrors,butinthisstudythecorrelation

betweenindividualmeasurersusingthesamemethodologywasgood,thehighest

reproducibilityfoundinvolumemeasurements.Thesevolumemeasurementshavemore

dimensionsandattempttomeasuretheactualreal‐lifeclotsizecomparedtomorerater‐

dependentandlessobjectiveareaandlengthmeasurements.However,thisstudyalso

hascertainstrengths.Firstly,itbringsanovelapproachinevaluatingCVTpatients.

Secondly,allcalculationsweredoneonstate‐of‐the‐artMRimages.

Largerstudiesinvestigatingthesinusandthrombusvolumesandthepossible

implementationtoclinicalpracticearewarrantedtorevealsignificanceofourmethodand

findings.Manualmeasurementsusedinthisstudyaretime‐consumingbutalsolikely

morereliablecomparedtoautomatedcalculations,especiallywhenimplementinganovel

method.Onepossibilitycouldbeauser‐supervisedreliableautomatedsoftware

developedformeasuringthesinusesandtheclots.

27

Acknowledgments&funding

IgratefullythankmysupervisorsTurgutTatlisumak,JukkaPutaalaandOiliSalonenforall

theirexcellenthelpandsupport.SpecialthanksalsogotoSiniHiltunen,SamiCurtze,and

AnuEräkantoforessentialsupportandadvices.

HeikkiHannikainenwassupportedbytheHelsinkiUniversityCentralHospitalResearch

Funds(EVO).

References

(1)RhotonAL,Jr.Thecerebralveins.Neurosurgery2002Oct;51(4Suppl):S159‐205.

(2)KilicT,AkakinA.Anatomyofcerebralveinsandsinuses.FrontiersofNeurology&Neuroscience2008;23:4‐15.

(3)StrydomMA,BriersN,BosmanMC,SteynS.Theanatomicalbasisofvenographicfillingdefectsofthetransversesinus.ClinAnat2010Mar;23(2):153‐159.

(4)PutaalaJ,HiltunenS,CurtzeS,SalonenO,TatlisumakT.Aivojensinustromboosindiagnostiikkajahoito.2011;127(LääketieteellinenAikakauskirjaDuodecim):1656‐1666.

(5)StamJ.Thrombosisofthecerebralveinsandsinuses.NEnglJMed2005Apr28;352(17):1791‐1798.

(6)CoutinhoJM,FerroJM,CanhaoP,BarinagarrementeriaF,CantuC,BousserMG,etal.Cerebralvenousandsinusthrombosisinwomen.Stroke2009Jul;40(7):2356‐2361.

28

(7)AgnelliG,VersoM.Epidemiologyofcerebralveinandsinusthrombosis.FrontNeurolNeurosci2008;23:16‐22.

(8)FerroJM,CanhaoP,StamJ,BousserMG,BarinagarrementeriaF,ISCVTI.Prognosisofcerebralveinandduralsinusthrombosis:resultsoftheInternationalStudyonCerebralVeinandDuralSinusThrombosis(ISCVT).Stroke2004Mar;35(3):664‐670.

(9)McBaneRD,2nd,TafurA,WysokinskiWE.Acquiredandcongenitalriskfactorsassociatedwithcerebralvenoussinusthrombosis.ThrombRes2010Aug;126(2):81‐87.

(10)MartinelliI,BattaglioliT,PedottiP,CattaneoM,MannucciPM.Hyperhomocysteinemiaincerebralveinthrombosis.Blood2003Aug15;102(4):1363‐1366.

(11)DentaliF,CrowtherM,AgenoW.Thrombophilicabnormalities,oralcontraceptives,andriskofcerebralveinthrombosis:ameta‐analysis.Blood2006Apr1;107(7):2766‐2773.

(12)WasayM,KojanS,DaiAI,BobustucG,SheikhZ.HeadacheinCerebralVenousThrombosis:incidence,patternandlocationin200consecutivepatients.JHeadachePain2010Apr;11(2):137‐139.

(13)CumurciucR,CrassardI,SarovM,ValadeD,BousserMG.Headacheastheonlyneurologicalsignofcerebralvenousthrombosis:aseriesof17cases.JNeurolNeurosurgPsychiatry2005Aug;76(8):1084‐1087.

(14)PutaalaJ,HiltunenS,CurtzeS,SalonenO,TatlisumakT.[Diagnosisandtreatmentofcerebralsinusthrombosis].Duodecim2011;127(16):1656‐1666.

(15)FerroJM,CanhaoP,BousserMG,StamJ,BarinagarrementeriaF,ISCVTI.Earlyseizuresincerebralveinandduralsinusthrombosis:riskfactorsandroleofantiepileptics.Stroke2008Apr;39(4):1152‐1158.

(16)BiousseV,AmeriA,BousserMG.Isolatedintracranialhypertensionastheonlysignofcerebralvenousthrombosis.Neurology1999Oct22;53(7):1537‐1542.

(17)ProvenzaleJM,KranzPG.Duralsinusthrombosis:sourcesoferrorinimageinterpretation.AJRAmJRoentgenol2011Jan;196(1):23‐31.

(18)RolandT,JacobsJ,RappaportA,VanhesteR,WilmsG,DemaerelP.UnenhancedbrainCTisusefultodecideonfurtherimaginginsuspectedvenoussinusthrombosis.ClinRadiol2010Jan;65(1):34‐39.

(19)PoonCS,ChangJK,SwarnkarA,JohnsonMH,WasenkoJ.Radiologicdiagnosisofcerebralvenousthrombosis:pictorialreview.AJRAmJRoentgenol2007Dec;189(6Suppl):S64‐75.

(20)HaapaniemiE,TatlisumakT.IsD‐dimerhelpfulinevaluatingstrokepatients?Asystematicreview.ActaNeurolScand2009Mar;119(3):141‐150.

(21)CoutinhoJ,deBruijnSF,DeveberG,StamJ.Anticoagulationforcerebralvenoussinusthrombosis.CochraneDatabaseSystRev2011(8):002005.

29

(22)EinhauplK,StamJ,BousserMG,DeBruijnSF,FerroJM,MartinelliI,etal.EFNSguidelineonthetreatmentofcerebralvenousandsinusthrombosisinadultpatients.EurJNeurol2010Oct;17(10):1229‐1235.

(23)StamJ,MajoieCB,vanDeldenOM,vanLiendenKP,ReekersJA.Endovascularthrombectomyandthrombolysisforseverecerebralsinusthrombosis:aprospectivestudy.Stroke2008May;39(5):1487‐1490.

(24)FerroJM.CrassardI.CoutinhoJM.CanhaoP.BarinagarrementeriaF.CucchiaraB.DerexL.LichyC.MasjuanJ.MassaroA.MatamalaG.PoliS.SaadatniaM.StolzE.Viana‐BaptistaM.StamJ.BousserMG.SecondInternationalStudyonCerebralVeinandDuralSinusThrombosis(ISCVT2)Investigators.Decompressivesurgeryincerebrovenousthrombosis:amulticenterregistryandasystematicreviewofindividualpatientdata.Stroke2011Oct;42(10):2825‐2831.

(25)DentaliF,GianniM,CrowtherMA,AgenoW.Naturalhistoryofcerebralveinthrombosis:asystematicreview.Blood2006Aug15;108(4):1129‐1134.

(26)BreteauG,Mounier‐VehierF,GodefroyO,GauvritJY,Mackowiak‐CordolianiMA,GirotM,etal.Cerebralvenousthrombosis3‐yearclinicaloutcomein55consecutivepatients.JNeurol2003Jan;250(1):29‐35.

(27)RohrA,BindeballeJ,RiedelC,vanBaalenA,BartschT,DoernerL,etal.Theentireduralsinustreeiscompressedinpatientswithidiopathicintracranialhypertension:alongitudinal,volumetricmagneticresonanceimagingstudy.Neuroradiology2012Jan;54(1):25‐33.

(28)StolzE,TrittmacherS,RahimiA,GerrietsT,RottgerC,SiekmannR,etal.Influenceofrecanalizationonoutcomeinduralsinusthrombosis:aprospectivestudy.Stroke2004Feb;35(2):544‐547.

(29)PutaalaJ,HiltunenS,SalonenO,KasteM,TatlisumakT.Recanalizationanditscorrelationtooutcomeaftercerebralvenousthrombosis.JNeurolSci2010May15;292(1‐2):11‐15.

(30)StruppM,CoviM,SeelosK,DichgansM,BrandtT.Cerebralvenousthrombosis:correlationbetweenrecanalizationandclinicaloutcome‐‐along‐termfollow‐upof40patients.JNeurol2002Aug;249(8):1123‐1124.