GadoliniumDepositionintheBrain:
SummaryofKnownScienceandRecommendationsfromtheInternationalSocietyforMagneticResonanceinMedicine
VikasGulani,MD,PhD1-4*,FernandoCalamante,PhD5,6,FrankG.Shellock,PhD7-9,
EmanuelKanal,MD10,ScottB.Reeder,MD,PhD11-15
1Radiology,2Urology,3BiomedicalEngineering,4CaseComprehensiveCancerCenter,CaseWesternReserveUniversityandUniversityHospitalsCaseMedicalCenter,Cleveland,Ohio,USA5FloreyInstituteofNeuroscienceandMentalHealth,Heidelberg,Victoria,Australia
6FloreyDepartmentofNeuroscienceandMentalHealth,UniversityofMelbourne,Melbourne,Victoria,Australia
7Radiology,8Medicine,9NationalScienceFoundationEngineeringResearchCenter,UniversityofSouthernCalifornia,LosAngeles,California,USA
10Radiology,UniversityofPittsburghMedicalCenter,Pittsburgh,Pennsylvania,USA11Radiology,12MedicalPhysics,13BiomedicalEngineering,14Medicineand15EmergencyMedicine,
UniversityofWisconsinSchoolofMedicineandPublicHealth,Madison,Wisconsin,USA
*AddressCorrespondenceto:VikasGulani,MD,PhDDirectorofMRIDepartmentsofRadiology,Urology,andBiomedicalEngineeringCaseComprehensiveCancerCenterCaseWesternReserveUniversityUniversityHospitalsofCleveland11100EuclidAve.,BolwellB120Cleveland,OH44106-0500
Abstract:
EmergingevidencehaslinkedMRIsignalchangesindeepnucleiofthebrainwithrepeated
administrationsofgadoliniumbasedcontrastagents.Gadoliniumdepositshavebeenconfirmedinbrain
tissue,mostnotablyinthedentatenucleiandglobuspallidus.Whilesomeagentsofaparticular
chemicalstructure(termedlinear)appeartocausegreatersignalchanges,thedepositionphenomenon
hasalsobeenobservedwithother(macrocyclic)agents.Thereisvariabilityamongtheagentsinthe
degreetowhichthisphenomenonhasbeenobserved.Thechemicalstateofdepositedgadoliniumhas
notbeendetermined,andnolinktorenalfailureorotherdiseasestateshasbeenestablished.The
clinicalsignificanceoftheretainedgadoliniuminbrain,ifany,remainsunknown,astherearenodatain
humansoranimalsdemonstratingarelationshipbetweenbraingadoliniumdepositionandadverse
clinicaleffects.Recommendationsareprovidedandwillevolveasnewstudiesareperformedand
disseminated.
SearchandStudyCriteria:
Anextensiveliteraturereviewwasconductedinordertogeneratethismanuscript.Thisconsistedof
Pubmed,GoogleScholar,andISIWebofSciencesearchesonbraingadoliniumdepositionand
gadoliniumdeposition,withextensivesearchesofpapersreferencingalreadypublishedliteratureand
alsofollowingallreferencesinthepublicationsfound.Duetothelargenumberofpublishedpaperson
thistopic,thoseofmostimportancetothecommunitywereselectedforreference.Excludedfromthe
manuscriptwere“research”manuscriptswhichprovidedonlyanecdotalevidenceforconclusions.
Paperswithquantitativedatawereprioritizedforinclusion,aswerepaperswhichsoughttoprovide
comparisonsbetweenagents.
A.Introduction
Magneticresonance(MR)imagesignalintensityisaffectedbyMR-specifictissuepropertiescalledT1and
T2relaxationtimes.Thesearecharacteristicphysicalpropertiesofeachtissue,relatedtothebehavior
ofthetissueinamagneticfield.Gadoliniumbasedcontrastagents(GBCAs)shortentheT1ofwater
protonsneartheagent,andthisphenomenonisexploitedtoproduceimagesinwhichtissueswithhigh
concentrationofGBCAarebrighterthanareaswithlowerGBCAconcentration.Over30milliondoses
areadministeredworld-wideannually,andover300milliondoseshavebeenadministeredsincethe
introductionoftheseagentsin19871.GBCAsareindispensablefordiagnosisandtreatmentmonitoring
ofmanydiseases,andinmanyresearchapplications.DefinedrisksofGBCAsincludeallergicreactions,
adversereactions,andinpatientswithrenalfailure,nephrogenicsystemicfibrosis(NSF).Allergicand
adversereactionsareinfrequentbutcanbeserious2,3.NSFisararescleroderma-likeillnessthatoccurs
inpatientswithsevererenaldiseaseandexposuretocertainGBCAs.NSFhasbeeneffectivelyeliminated
bycurtailingtheadministrationofGBCAsmostcloselyassociatedwithNSFinhigh-riskpatient
populations,andbyminimizingGBCAdose.
Multiplerecentreportsdetailedbelowindicatethatthereisresidualbrightnessoftissueindeepbrain
nucleiofthebrain,particularlytheglobuspallidusanddentatenucleus,inpatientswhohavereceived
gadoliniumcontrast,andadditionalreportsshowingthatthesesignalchangesarerelateddirectlyto
depositionofgadoliniumintheseregions.Thisraisesconcernsaboutthecontextinwhichgadolinium
depositsinthebrain,andwhetherthisdepositionisaccompaniedbyharmtopatients.Onbehalfofthe
InternationalSocietyofMagneticResonanceinMedicine(ISMRM),wesummarizetheknownliterature
onthissubject,placethematerialincontextofexperiencewithNSF,andproviderecommendationsfor
futureuseoftheagentsinresearchandclinicalpractice.
B.GadoliniumDepositionintheBrain
ThepresenceofhighsignalonunenhancedT1-weightedimagesinthedentatenucleusandglobus
pallidusofpatientswhohadundergonemultipleGBCAenhancedMRIexamswasfirstdescribedin
20144.Increasedrelativesignalintensitycorrelatedtothetotalnumberofgadoliniumadministrations.A
comparisonofsignalintensitiesinasubgroupofpatientswhohadundergoneatleastsixcontrast-
enhancedexamswitheithergadopentetatedimeglumineorgadodiamidetopatientswhohad
undergoneonlynon-contrastMRI,showedhighersignalinthesenucleiinpatientswhohadundergone
repeatedGBCAinjections.Thesefindingswereconfirmedinasimilarstudyinvolvinggadodiamide5and
inmultiplesubsequentstudies6-8.Emergingcase-reportevidencesuggeststhatthisphenomenonalso
occursinchildren,withadepositionpatternsimilartothatobservedinadults9,10.
DuetotheassociationofNSFwithrenalfailure,anaturalquestioniswhethergadoliniumdepositionin
thebrainisalsorelatedtorenalfailure.Signalintensitiesandpostmortemtissuefrombrainsof13
patientswhounderwentatleast4gadiodiamideenhancedexamswerecomparedwith10patientswho
didnotreceivegadolinium7.Gadoliniumwasconfirmedindeepbrainnucleiinpatientswhohad
undergonepriorGBCAenhancedMRIexams,usinginductivelycoupledplasmamassspectroscopy(ICP-
MS).Thesignalintensityratioshadapositivecorrelationwiththetissueconcentrationofgadolinium,
definitivelylinkingincreasedsignalintensityratioswithgadoliniumdepositionandrelativegadolinium
concentration.X-Raymicroanalysisalsodemonstratedgadoliniumdepositsinneuronaltissue.
Gadoliniumwasobservedinendothelialwalls,buttheauthorsalsostatedthat“…gadoliniumappears
tohavecrossedtheblood-brainbarrierandbeendepositedintotheneuraltissueinterstitium.”Sinceall
patientshadnormalrenalfunction,gadoliniumdeposition(innon-diseasedandnon-irradiatedbrain
tissue)appearstobeunrelatedtorenalfunction.
Autopsyspecimensfrombrainsoffivesubjectswithoutsevererenalcompromisewhohadundergoneat
leasttwoadministrationsoflinearGBCAswerecomparedtopatientsnotreceivingGBCAs,usingICP-
MS11.Twosubjectsalsoreceivedgadoteridol,oneofwhomhadalsoreceivedadoseofgadodiamide.
GadoliniumwasdetectedinallspecimensfromtheGBCAgroupandinsomespecimensfromthenon-
GBCAgroupatamuchsmallerconcentration.ThehighestconcentrationintheGBCAgroupwasinthe
dentatenucleusandglobuspallidus.Gadoliniumdepositioninthebrainwasagainconfirmedinsubjects
withnormalornear-normalrenalfunction.
Quantitativemeasurementsweremadeaspartofanindustry-sponsoredstudyexaminingbrainsofrats
afterrepeateddosesofgadodiamide.Thisstudydemonstratedretentionof0.00019%ofthedoseat
oneweek,andinterestingly,clearanceof45%ofthedepositedgadolinium20weeksafterdeposition12.
Noneurotoxicitywasobserved.
Animportantquestioniswhetherthechoiceofcontrastagentoragentclassarefactorsingadolinium
deposition.GBCAscanbeclassifiedasnonionicandionic,withionicagentshavinggreater
thermodynamicstabilitythoughwithanunclearrelationshiptorelativesafety.Whilethermodynamic
stabilityandpH-correctedconditionalstabilityaresometimesused,abetterpredictorofdissociation
rateswouldlikelybethekineticstability,whichprovidesthedissociationhalf-lifeofthegadoliniumfrom
itsligand13.GBCAsarealsocommonlyclassifiedaslinearormacrocyclic,basedonthechemicalstructure
ofthechelatingagentboundtothegadoliniumion.Tables114and2providesummarizecharacteristics
ofvariouscontrastagents,andcomparativestudiesregardingthedepositionphenomenon.
Investigatorshaveattemptedtocomparetheeffectofsomelinearandmacrocyclicagentson
gadoliniumdeposition.Patientswhounderwentsixormoreexamswithgadopentetatedimeglumine
(linear)werecomparedwithpatientsgivengadoteratemeglumine(macrocyclic),showingthatincreases
insignalintensityratiosindentatenucleusrelativetothepons,andglobuspallidusrelativetothe
thalamus,weregreaterwithgadopentetatedimeglumine,andtherewasnostatisticalincreaseinsignal
intensityratiousinggadoteratemeglumine6.Asimilarstudycomparedgadobenatedimeglumine(linear)
withgadopentetatedimeglumine15.Therewasanincreaseinsignalintensityratioofdentatenucleusto
pons,anddentatenucleustoCSFwithgadobenatedimeglumine,butthechangeindentatenucleusto
CSFratiowassmallerforgadobenatedimeglumine,comparedtogadopentetatedimeglumine,
suggestingloweramountsofgadoliniumdeposition.Arecentstudyofsignalintensityratiosinthe
dentatenuncleustoponsormiddlecerebellarpeduncleincluded33patientswhounderwent20
consecutiveadministrationsofmacrocyclicagentsgadoteratemeglumineandgadobutrol,showedno
significantincreaseinthesignalintensitiesinthedentatenucleus16.
Theseauthorshypothesizedthatdifferencesinsignalintensityratiosbetweenlinearversusmacrocyclic
agentswerelikelyduetorelativechemicalstabilitiesofthetwoclassescontributingdifferential
amountsofunchelatedgadolinium.Thiswasbasedontheobservationthatgadoliniumdeposits
measuredinautopsystudiescorrelatedwiththeobservedsignalintensitychanges7,andthatsome
linearagentshavelowerthermodynamicstabilitythanthemacrocyclicagentscurrentlyinuse.Thus,
linearagentsmayreleasemoregadolinium.Subsequently,itwasreportedthatincreasedbrainsignal
intensityratiochangeswereobservedinasubsetofpatientsgivengadopentetatedimeglumine,butnot
inpatientsgivengadoteridol(macrocyclic)17.
Anindustry-sponsoredpreclinicalstudyinvestigatedgadoliniumdepositioninratmodelsimagedserially
whilereceivingover20injectionsofvariousGBCAs.Threegroupswerestudied,includingthose
administeredgadodiamide(linear),gadoteratemeglumine(macrocyclic),orhyperosmolarsaline18.
Repeatedinjectionsofgadodiamideresultedinprogressivelyincreasedsignalintensityratiobefore
reachingaplateau.Theauthorsalsomeasuredpost-mortemgadoliniumconcentrationsinthebrain,
andfoundthatratsexposedtogadodiamidehadhighergadoliniumdepositionthanratsexposedto
gadoteratemeglumine.However,thegadoliniumconcentrationinthesubcorticalbrainwasalso
significantlyhigherforthemacrocyclicgroupthancomparedtocontrolrats.Notably,theauthors
administeredrepeatedbehavioralexamsfoundnoabnormalitiessuggestiveofneurologicaltoxicity.
Thesameindustrygroupstudiedgadoteratemeglumine,gadopentetatedimeglumine,gadobenate
dimeglumineandgadodiamide,andcontrolanimalsinjectedwithsaline,usingthepreviouslydescribed
methodologywiththeadditionofT1mapping19.Signalintensitychangesinthedeepcerebellarnuclei
wereseenforgadodiamideandgadopentetatedimeglumine,butnotgadoteratemeglumine.
Gadobenatedimeglumineshowedatrendofincreasedsignalbutthiswasnotsignificant.Quantitative
measurementsofgadoliniumwerehighestforgadodiamide,followedbygadopentetatedimeglumine,
gadobenatedimeglumine,andgadoteratemeglumine,followedbysaline.Concentrationsinrats
exposedtoallthreelinearagentsweresignificantlygreaterthanbothsalineandgadoteratemeglumine.
Thoughtherewasatrend,nosignificantdifferencewasobservedbetweengadoteratemeglumineand
saline,pointingtoadifferenceinthedepositionofgadoliniumbetweenlinearandmacrocyclicagents.
Thefactthattheconcentrationsofdepositedgadoliniumarehigherforlessthermodynamicallyand
kineticallystableagents,supportsthehypothesisthatdechelationmayplayaroleingadolinium
deposition.Theauthorsalsostatethat,“noobviousbehavioralabnormalitiesweredetectedinrats,
regardlessoftheGBCAadministered.”
Humanstudiesshowconsiderablevariationinobservedsignalchangesamongagents,withinconsistent
dataevenforthesameagent.Forexample,gadobenatedimegluminehasbeenassociatedwithsignal
intensitychangesindeepbrainnuclei15.However,astudyseekingtocomparegadodiamideand
gadobenatedimeglumine,indicatedthatgadiodiamideisassociatedwithsignalintensitychanges,while
gadobenatedimeglumineisnot,althoughtherewasatrendtowardsintensitychangesinthedentate
nucleusonlyandnotintheglobuspallidus8.Thepatientsinthelatterstudyreceivedfewerdosesof
gadobenatedimeglumineonaverage.Recentworkcomparedsubjectswhounderwentatleastthree
examswithgadobenatedimeglumineandwhohadpriorexposuretomultipledosesofgadodiamide,to
agroupwhoonlyunderwentrepeatedgadobenatedimeglumineenhancedexamswithoutprior
exposure20.Thegroupwithpriorgadodiamideexposurehadhigherbaselineandfollow-upsignal
intensityratioofthedentaterelativetothemiddlecerebralpeduncle,andshowedatrendtowardsan
increasedeffectinpatientswhohadpriorgadodiamideexposure.Theauthorshypothesizeda
potentiatingeffectbygadodiamide,withamechanismnotyetunderstood.
Directmeasurementsofgadoliniumdepositionhavebeenobtainedinautopsyderivedtissuefrom
patientswhohadreceivedvariouscombinationsofgadoteridol(macrocyclic),gadobutrol(macrocyclic),
gadobenatedimeglumine,andgadoxetatedisodium21.Gadoliniumwasfoundinallsampledbrain
regions,withallagents.Thisstudyshowedthatgadoliniumfrommacrocyclicagents,aswellasthat
fromlinearagentsconsideredtobelowNSFrisk,doesdepositinthebrain.Thisphenomenonwas
documentedafterevenasingledose.Whilethenumberofsubjectswassmall,theworkpointedto
potentialdifferencesinlevelsofdepositionbetweenthemacrocyclicagentsinvestigated,withahigher
rateofgadobutroldepositionthangadoteridol.Further,thedegreeofdepositionobservedforthetwo
linearagentsstudiedwaslessthanthatobservedforagentspreviouslyimplicatedascarryinggreater
riskofNSF14.Bothfindingsindicatethatagent-specificcharacteristicssuchasproteininteractionsand
chelatestabilitymayplayaroleinthedegreeofdepositionofgadolinium.Directmappingshowed
Gadoliniumdepositioninapatientwhohadreceived4dosesofGadolinium[linearagents]overa
lifetime,andshowednomeasureablesignalintensitychange22.Thisraisesthequestionwhetherthe
signalchangeswereabsentsimplyduetoconcentration(thoughobservedconcentrationsweresimilar
tootherstudies),oriftheformofdepositedGadoliniumplaysaroleinthesignalchange.Itisquite
plausiblethatthechemicalformofdepositedagentmaybedifferentforlinearandmacrocyclicagents.
Basedonthetotalityofdata,weconcludethatasimpledivisionofagentsintomacrocyclicandlinear
classesisinsufficienttoclassifythepharmacokineticbehaviorofGBCAswithregardtogadolinium
depositionandfailstotakeintoaccountdemonstratedclinicallysignificantdifferencesinrelaxivity
amongthevariousGBCA,bothlinearandmacrocyclicinnature23.
Disruptionofthebloodbrainbarrierresultingfromdiseaseprocessesand/ortreatment(e.g.radiation,
chemotherapy)isapotentialconfounder,sincemostpatientsundergoingrepeatedbrainMRIstypically
haveknownorsuspectedneurologicaldiseases.Signalintensitychangesinthedentatenucleusand
globuspallidushavebeenreportedinpatientswithrelapsingremittingmultiplesclerosiswho
underwentrepeatedinjectionsofgadobutrol24.Repeatedinjectionsoverashorterperiodresultedin
greatersignalintensitychanges.Interestingly,astudyfrom2009showeddentatenucleussignal
intensityincreaseswithdiseaseprogressioninsecondaryprogressivemultiplesclerosis25.Thisraisesthe
questionwhetherdiseaseprogressionisaconfoundingfactorfor,orpotentiates,gadolinium
deposition26,andwhetherthediseasesubtypeisimportantfortheobservedfindings.
Astudyinpatientswithrelapsing-remittingmultiplesclerosisindicatedthattheobservedphenomenon
isindependentofdisease;relaxationtimesinthedentatenucleiwereshortenedevenwhencontrolling
fordiseaserelatedfactors27.Anotherissueiswhetherthesignalintensitychangesinthedentatethat
correlatewithdiseaseprogressionoccurinpatientswhounderwentrepeatedMRIexaminations.The
authorsnotethatchangespersistevenaftercontrollingfordiseaseprogression,andthatgadolinium
depositionfrommacrocyclicagentscontributedtotheobservedsignalchanges28.However,two
groups29,30reportanincreaseinT1-weightedsignalratiobetweendentateandponswithgadopentetate
dimegluminebutnotwithgadobutrol.Anothergroupalsofoundnosignificantincreaseinsignal
intensityinpatientswhohadundergonerepeatedexamswithgadobutrol31,contradictingStojanovet
al.24
Finally,anindustrysponsoredgroupstudiedwhetherdepositedgadoliniumcanbeclearedafter
deposition,usingaratmodel32.Theinvestigatorsstudiedtheratbrainapproximately1weekand20
weeksafterupto20repeatdosesofgadiodiamideorgadopentetatedimeglumine.Theresultsshowed
thedepositionofgadoliniumasexpectedandgadodiamidedepositedmorethangadopentetate
(0.00019%oftheinjecteddoseofgadodiamidewasdetectedoneweekafterdosing).Thedepositionof
gadiodiamidedecreasedbyapproximately43%,indicatingalikelyclearingphenomenon,withno
indicationofasaturationofthismechanism.Histopathologicalstudiesshowednoneurotoxicity.The
degreetowhichtheseresultscanbeextrapolatedtohumansisunclear,butpotentialclearanceofthe
alreadysmallamountofdepositedgadoliniumwouldbeanimportantconsiderationifalsotruein
humans.
C.IsThereEvidenceofHarm?
Theclinicalandbiologicalsignificanceoftheretainedgadoliniuminbrain,ifany,remainsunknown.No
harmhasbeendemonstratedinanimalmodelsofgadoliniumexposure.Nobehavioralchangeswere
reportedinsmallanimalsundergoingrepeatedexaminationswithgadoliniumagentsoveraveryshort
period18.Burkeetal.havereportedalistofnon-specificsymptomsfromasurveyofpatientswho
believetheysufferfromgadoliniumtoxicity,thoughthereisnocorrespondingcontrolledstudy33.
Otherthananecdotalreports,therearecurrentlynopeer-revieweddatalinkingadversebiologicalor
neurologicaleffectstogadoliniumdepositioninthebrain.Theprincipalphysiologicalrolesofthe
dentatenucleus,thesiteofdepositionmostoftennoted,includeplanning,initiation,andcontrolof
voluntarymovements.Noclinicalconditionsrelatedtodysfunctionoftheseroleshaveeverbeen
associatedwithimagingfindingsintheretrospectivestudiespublishedtodate6-8,11,15,17,20,24,27,29,31,34,35.
Specifically,noneurologicalsymptomshavebeenreportedthatcouldrelatetodamagetothoseor
otherbrainstructures.Prospectivecontrolledstudieswouldbevaluabletohelpdrawmoredefinitive
conclusions,thoughverylongperiodsofstudymayberequiredtodrawconclusionsregardingsubtle
neurologicaldeficits.
D.LimitationsoftheAvailableEvidence
Allclinicalstudieshavebeensingle-centerandretrospectiveindesign6-8,11,15,17,20,24,27,29,31,34,35.Patients
wereselectedfromhospitaldatabasesusingavarietyofselectioncriteria,andthusselectionand
informationbiasarepossible.SomestudiesincludedpriorscanswithotherGBCAspriortostudies
acquiredusingthespecificGBCAunderinvestigation6,15,31.Thehypothesizedpotentiationeffect
underscorestheneedforcarefulassessmentofexposurehistorytovariousagents20.
Withsomeexceptions27,investigatorsusesignalintensityratiosbetweentargetandreferenceareasof
thebrainforquantitativeanalysis.Thevalueofthisratiodependsonavarietyofphysicaland
acquisitionparametersthataresystemandsite-dependent.UseofquantitativeT1mappingtechniques
ratherthansignalintensityratiosmaybehelpfultoreducevariabilitybetweensites.
Freeelementalgadoliniumisknowntobetoxic,whilechelatedgadoliniumisregardedasrelativelysafe.
Manystudiesoperatefromtheunderlyingassumptionthatgadoliniumisdepositedinanunchelated
form,becausesomelinearagentswithlowerthermodynamicstabilityaremorestronglyassociatedwith
thisphenomenon.However,thechemicalformofgadoliniumdepositsinbrainremainsunknown,and
postmortemstudieshavebeenunabletoaddressthisissue7,11,21,22.Moreover,thepresenceand/or
concentrationofothersubstanceswithT1-shorteningproperties(eg.iron)hasyettobeendetermined.
Recentlydevelopedmethodologytohelpdeterminespeciationofgadoliniumhasnotyetbeenapplied
tobraintissue36.
E.GovernmentStatements
TheU.S.FoodandDrugAdministration(FDA)isevaluatingthepotentialriskofbraindepositswith
repeatedGBCAuse14.TheFDAstatedthatinorderto“reducethepotentialforgadolinium
accumulation,healthcareprofessionalsshouldconsiderlimitingGBCAusetoclinicalcircumstancesin
whichtheadditionalinformationprovidedbythecontrastisnecessary.Healthcareprofessionalsare
alsourgedtoreassessthenecessityofrepetitiveGBCAMRIsinestablishedtreatmentprotocols.”
RecentlythePharmacovigilanceRiskAssessmentCommitteeoftheEuropeanMedicinesAgencyhas
recommendedprecautionarysuspensionofmarketingauthorizationsforfourlinearagentsgadobenate
dimeglumine,gadodiamide,gadopenteticacid,andgadoversetamide,citingthefactthatthelinear
structuremakestheseagentsmorelikelytoreleasegadolinium37.
F.RecommendationsandConclusions
Thedatadescribedabovearerepresentativeofcurrentknowledge.Basedonthesedata,thecurrent
recommendationsfromtheISMRMSafetyCommitteeareasfollows:
1. TheISMRMurgescautionintheutilizationofanymedication,includingGBCAs.Perstandard
practice,GBCAsshouldbeavoidedwhennotrequired.Thedataongadoliniumdeposition
emphasize,butdonotalterthispractice,andGBCAsshouldnotbewithheldfrompatientswith
aclinicalindicationforgadoliniumenhancedMRI.Thephysicianresponsibleforthe
administrationofcontrastshouldunderstandthebenefitsandrisksoftheagent.
2. Theclinicalindication,specificagent,dose,andotherpertinentinformationshouldbe
documentedinthemedicalrecord.
3. Whilemanystudiesindicatethatatleastsomemacrocyclicagentsonthemarketcurrentlymay
exhibitlessdepositionthanatleastsomelinearagentsavailabletoday,thedatadocumentthat
gadoliniumdepositioninthebraindoesoccurwithmacrocyclicagentsaswell.Therearedata,
someofwhicharediscordant,thatsuggestdifferencesingadoliniumdepositionratesamong
themacrocyclicagentsandamongthelinearagents.Relaxivitydifferencesbetweenagentsand
betweenpotentialdepositedspeciesmaycomplicateinterpretationofsignalintensity
differencestudies.Inlightofnoknownharmfromthedepositionphenomenon,itisunclear
thatallmacrocyclicagentsshouldbefavoredoveralllinearagentsbasedoncurrentdata.There
aremanyfactorsthatshouldbeconsideredwhenchoosingacontrastagent,including
pharmacokinetics,relaxivity,efficacy,potentialorrealside-effectsincludingallergicreactions,
patientage,probabilityoftheneedforrepeatedexams,andcost.Institutionsmustweighthese
factorsandthefactthatsomeagentsmayexhibitagreaterpropensityfordeposition,when
choosingtouseaspecificagent.
4. GiventheimportanceofGBCAsforadvancingscientificdiscoveryandforimprovingclinicalcare
throughresearchstudies,theISMRMSafetyCommittee,liketheNIH38,supportstheviewthatit
isappropriatetoadministerGBCAsforresearchundertheguidanceofIRBapprovedprotocols
thatincludeinformedconsent.Becausetherearenoknownrisksassociatedwithgadolinium
depositioninthebrainatthistime,theISMRMisunabletomakeanoverarching
recommendationregardingdisclosureofthisphenomenontoresearchsubjects.Therefore,each
institutionmustdecidewhetherinclusionofadescriptionofthisphenomenoninconsentform
materialsisnecessaryand,ifso,whatcontenttouse.Factorssuchasthecircumstancesunder
whichtheGBCAisbeingadministered,unknownrisksofgadoliniumdeposition,andtheneedto
explainthisphenomenontosubjectsinappropriatelanguagemustbetakenintoaccount.Inthe
eventthatnewdataarediscovereddescribingadversebiologicalorclinicaleffectsrelatedto
gadoliniumdepositionsubsequenttothispublication,itmaybeappropriatetoincludethat
informationaspartoftheconsentprocess.
5. Investigatorspublishingonthistopicshouldexercisecarefuldisclosureoffinancial,consulting,
oradvisingrelationshipswithindustrythatpertaintopotentialconflictsofinterest(COI).While
properdisclosureofCOIshouldbeperformedforallpublications,thisisparticularlyrelevantfor
thegadoliniumdepositionphenomenon.
6. Duetopossibleconfoundingofdiseaserelatedsignalintensitychangeswithgadolinium
depositionrelatedchanges,futurestudiesshouldexplicitlydescribeallrelevantclinicalhistory,
includingtreatment,ofthepatientsincludedinthestudy.
7. TheISMRMsupportsrigorousdata-drivenresearchinallaspectsofmagneticresonance,and
willcontinuetourgeandpromoteresearchanddiscussiononthissubjectatscientificmeetings,
workshops,journalsandthroughpilotgrantfundingopportunities.Ascanbeseenthroughout,
severalissuesremainunresolved.Theseincludebutarenotlimitedto:
(a) Isthedepositedgadoliniumaccompaniedbyclinicaladverseeffects,andarethese
theoreticaleffectsdosedependent?Whatarethefrequenciesandseveritiesofadverse
events(orperceivedadverseevents)?
(b) Whatisthechemicalstateandstructureofthedepositedgadolinium?
(c) Whataretherelativerateswithwhichthephenomenonoccurswitheachgadolinium
chelate?Whatistheroleofdoseorrelaxivityintheseverityofthephenomenon?
(d) Aretheobserveddifferencesbetweenagentsclassoragentdependent?Howdofield
strength,sequencesandsettingsutilizedandagentdependentdifferencesinT1
relaxivityimpactourabilitytopoollargedatasets?
(e) Whichgroupsofpatientsaremoreorlesssusceptibletothegadoliniumdeposition
phenomenon?
(f) Howdotreatmentssuchasradiationorchemotherapyimpactgadoliniumdeposition?
(g) Whatisthemechanismofgadoliniumdepositionintothebrain?
Theexistingdataprovidestrongevidenceforthedepositionofgadoliniumindeepnucleiofthebrain,
particularlyafterrepeatedexposuresofGBCAs.Whilethereareapparentdifferencesamongtheagents
andsomedifferencesbyclass,somedataarecontradictory.Additionally,thereareagentswithno
reporteddataonthisphenomenon.Whiletheobservationofgadoliniumdepositioninthebrainshould
betakenveryseriously,reliabledataregardingclinicalorbiologicalsignificance,ifany,arelacking.
Basedontheavailabledata,therecommendationsaboveattempttobalancethepotential(yet
unknown)harmofgadoliniumdepositionwiththeprovenclinicalandresearchbenefitofGBCAs.
Furtherresearchisneededtoelucidatethemechanismsandrelevanceofgadoliniumdeposition.As
suchdataemerge,recommendationsontheclinicalandresearchuseofGBCAsareexpectedtoevolve.
Contributors
AninitialdraftwasgeneratedbyDrs.Gulani,Calamante,andReeder.Allauthorscontributedto
literaturesearch,editingandthegenerationofrecommendations.Alongerformofthemanuscriptwas
reviewedbytheISMRMSafetyCommitteeandafterthosecommentswereincorporated,theBoardof
Trusteesoftheorganizationreviewedthedocument,providedadditionalfeedback,andeventually
approvedthedocument.Thedocumentwaseditedandshortenedduringthereviewandpublication
process.Nofundingwasreceivedforthegenerationofthismanuscript.Therelevantandnon-relevant
conflictsofinterestsoftheauthorsandtheISMRMhavebeendisclosed.
G.References1. RungeVM.CommentaryonT1-WeightedHypersignalintheDeepCerebellarNucleiAfterRepeatedAdministrationsofGadolinium-BasedContrastAgentsinHealthyRats:DifferenceBetweenLinearandMacrocyclicAgents.InvestRadiol2015;50(8):481-2.2. PrinceMR,ZhangH,ZouZ,StaronRB,BrillPW.Incidenceofimmediategadoliniumcontrastmediareactions.AJRAmJRoentgenol2011;196(2):W138-43.3. HuntCH,HartmanRP,HesleyGK.Frequencyandseverityofadverseeffectsofiodinatedandgadoliniumcontrastmaterials:retrospectivereviewof456,930doses.AJRAmJRoentgenol2009;193(4):1124-7.4. KandaT,IshiiK,KawaguchiH,KitajimaK,TakenakaD.HighsignalintensityinthedentatenucleusandglobuspallidusonunenhancedT1-weightedMRimages:relationshipwithincreasingcumulativedoseofagadolinium-basedcontrastmaterial.Radiology2014;270(3):834-41.5. ErranteY,CirimeleV,MallioCA,DiLazzaroV,ZobelBB,QuattrocchiCC.ProgressiveincreaseofT1signalintensityofthedentatenucleusonunenhancedmagneticresonanceimagesisassociatedwithcumulativedosesofintravenouslyadministeredgadodiamideinpatientswithnormalrenalfunction,suggestingdechelation.InvestRadiol2014;49(10):685-90.6. RadbruchA,WeberlingLD,KieslichPJ,etal.Gadoliniumretentioninthedentatenucleusandglobuspallidusisdependentontheclassofcontrastagent.Radiology2015;275(3):783-91.7. McDonaldRJ,McDonaldJS,KallmesDF,etal.IntracranialGadoliniumDepositionafterContrast-enhancedMRImaging.Radiology2015;275(3):772-82.8. RamalhoJ,CastilloM,AlObaidyM,etal.HighSignalIntensityinGlobusPallidusandDentateNucleusonUnenhancedT1-weightedMRImages:EvaluationofTwoLinearGadolinium-basedContrastAgents.Radiology2015;276(3):836-44.9. RobertsDR,HoldenKR.ProgressiveincreaseofT1signalintensityinthedentatenucleusandglobuspallidusonunenhancedT1-weightedMRimagesinthepediatricbrainexposedtomultipledosesofgadoliniumcontrast.BrainDev2016;38(3):331-6.10. MillerJH,HuHH,PokorneyA,CornejoP,TowbinR.MRIBrainSignalIntensityChangesofaChildDuringtheCourseof35GadoliniumContrastExaminations.Pediatrics2015;136(6):e1637-40.11. KandaT,FukusatoT,MatsudaM,etal.Gadolinium-basedContrastAgentAccumulatesintheBrainEveninSubjectswithoutSevereRenalDysfunction:EvaluationofAutopsyBrainSpecimenswithInductivelyCoupledPlasmaMassSpectroscopy.Radiology2015;276(1):228-32.12. SmithAP,MarinoM,RobertsJ,etal.ClearanceofGadoliniumfromtheBrainwithNoPathologicEffectafterRepeatedAdministrationofGadodiamideinHealthyRats:AnAnalyticalandHistologicStudy.Radiology2016.13. PortM,IdeeJM,MedinaC,RobicC,SabatouM,CorotC.Efficiency,thermodynamicandkineticstabilityofmarketedgadoliniumchelatesandtheirpossibleclinicalconsequences:acriticalreview.Biometals2008;21(4):469-90.14. MediaACoRCoDaC.ACRManualonContrastMediaVersionv10.1.2015;Availableathttp://www.acr.org/Quality-Saftety/Resources/Contrast-Manual.2015(accessedMarch1,20162016).15. WeberlingLD,KieslichPJ,KickingerederP,etal.IncreasedSignalIntensityintheDentateNucleusonUnenhancedT1-WeightedImagesAfterGadobenateDimeglumineAdministration.InvestRadiol2015;50(11):743-8.16. RadbruchA,HaaseR,KieslichPJ,etal.NoSignalIntensityIncreaseintheDentateNucleusonUnenhancedT1-weightedMRImagesafterMorethan20SerialInjectionsofMacrocyclicGadolinium-basedContrastAgents.Radiology2017;282(3):699-707.17. KandaT,OsawaM,ObaH,etal.HighSignalIntensityinDentateNucleusonUnenhancedT1-weightedMRImages:AssociationwithLinearversusMacrocyclicGadoliniumChelateAdministration.Radiology2015;275(3):803-9.
18. RobertP,LehericyS,GrandS,etal.T1-WeightedHypersignalintheDeepCerebellarNucleiAfterRepeatedAdministrationsofGadolinium-BasedContrastAgentsinHealthyRats:DifferenceBetweenLinearandMacrocyclicAgents.InvestRadiol2015;50(8):473-80.19. RobertP,ViolasX,GrandS,etal.LinearGadolinium-BasedContrastAgentsAreAssociatedWithBrainGadoliniumRetentioninHealthyRats.InvestRadiol2016;51(2):73-82.20. RamalhoJ,SemelkaRC,AlObaidyM,RamalhoM,NunesRH,CastilloM.SignalintensitychangeonunenhancedT1-weightedimagesindentatenucleusfollowinggadobenatedimeglumineinpatientswithandwithoutpreviousmultipleadministrationsofgadodiamide.EurRadiol2016;26(11):4080-8.21. MurataN,Gonzalez-CuyarLF,MurataK,etal.MacrocyclicandOtherNon-Group1GadoliniumContrastAgentsDepositLowLevelsofGadoliniuminBrainandBoneTissue:PreliminaryResultsFrom9PatientsWithNormalRenalFunction.InvestRadiol2016;51(7):447-53.22. RobertsDR,WelshCA,LeBelDP,2nd,DavisWC.DistributionMapofGadoliniumDepositionwithintheCerebellumFollowingGBCAAdministration.Neurology2017.23. WhiteGW,GibbyWA,TweedleMF.ComparisonofGd(DTPA-BMA)(Omniscan)versusGd(HP-DO3A)(ProHance)relativetogadoliniumretentioninhumanbonetissuebyinductivelycoupledplasmamassspectroscopy.InvestRadiol2006;41(3):272-8.24. StojanovDA,Aracki-TrenkicA,VojinovicS,Benedeto-StojanovD,LjubisavljevicS.IncreasingsignalintensitywithinthedentatenucleusandglobuspallidusonunenhancedT1Wmagneticresonanceimagesinpatientswithrelapsing-remittingmultiplesclerosis:correlationwithcumulativedoseofamacrocyclicgadolinium-basedcontrastagent,gadobutrol.EurRadiol2016;26(3):807-15.25. RoccatagliataL,VuoloL,BonzanoL,PichiecchioA,MancardiGL.Multiplesclerosis:hyperintensedentatenucleusonunenhancedT1-weightedMRimagesisassociatedwiththesecondaryprogressivesubtype.Radiology2009;251(2):503-10.26. AgrisJ,PietschH,BalzerT.WhatEvidenceIsThereThatGadobutrolCausesIncreasingSignalIntensitywithintheDentateNucleusandGlobusPallidusonUnenhancedT1WMRIinPatientswithRRMS?EuropeanRadiology2015;26(3):816-7.27. TedeschiE,PalmaG,CannaA,etal.InvivodentatenucleusMRIrelaxometrycorrelateswithpreviousadministrationofGadolinium-basedcontrastagents.EurRadiol2016.28. StojanovDA.ReplytoLettertotheEditorre:IncreasingsignalintensitywithinthedentatenucleusandglobuspallidusonunenhancedT1Wmagneticresonanceimagesinpatientswithrelapsing-remittingmultiplesclerosis:Correlationwithcumulativedoseofamacrocyclicgadolinium-basedcontrastagent,gadobutrol.EurRadiol2016;26(3):818-9.29. CaoY,HuangDQ,ShihG,PrinceMR.SignalChangeintheDentateNucleusonT1-WeightedMRImagesAfterMultipleAdministrationsofGadopentetateDimeglumineVersusGadobutrol.AJRAmJRoentgenol2016;206(2):414-9.30. SchlemmL,ChienC,Bellmann-StroblJ,etal.Gadopentetatebutnotgadobutrolaccumulatesinthedentatenucleusofmultiplesclerosispatients.MultScler2016:1352458516670738.31. RadbruchA,WeberlingLD,KieslichPJ,etal.High-SignalIntensityintheDentateNucleusandGlobusPallidusonUnenhancedT1-WeightedImages:EvaluationoftheMacrocyclicGadolinium-BasedContrastAgentGadobutrol.InvestRadiol2015;50(12):805-10.32. SmithAP,MarinoM,RobertsJ,etal.ClearanceofGadoliniumfromtheBrainwithNoPathologicEffectafterRepeatedAdministrationofGadodiamideinHealthyRats:AnAnalyticalandHistologicStudy.Radiology2017;282(3):743-51.33. BurkeLMB,RamalhoM,AlObaidyM,ChangE,JayM,SemelkaRC.Self-reportedgadoliniumtoxicity:Asurveyofpatientswithchronicsymptoms.MagneticResonanceImaging2016;34(8):1078-80.
34. QuattrocchiCC,MallioCA,ErranteY,etal.GadodiamideandDentateNucleusT1HyperintensityinPatientsWithMeningiomaEvaluatedbyMultipleFollow-UpContrast-EnhancedMagneticResonanceExaminationsWithNoSystemicIntervalTherapy.InvestRadiol2015;50(7):470-2.35. RamalhoJ,RamalhoM,AlObaidyM,NunesRH,CastilloM,SemelkaRC.T1Signal-IntensityIncreaseintheDentateNucleusafterMultipleExposurestoGadodiamide:IntraindividualComparisonbetween2CommonlyUsedSequences.AJNRAmJNeuroradiol2016;37(8):1427-31.36. BirkaM,WentkerKS,LusmollerE,etal.Diagnosisofnephrogenicsystemicfibrosisbymeansofelementalbioimagingandspeciationanalysis.AnalChem2015;87(6):3321-8.37. AgencyEM.PRACconcludesassessmentofgadoliniumagentsusedinbodyscansandrecommendsregulatoryactions,includingsuspensionforsomemarketingauthorisations.10March2017.Availableat:http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2017/03/WC500223209.pdf.2017(accessedMarch10,20172017).38. MalayeriAA,BrooksKM,BryantLH,etal.NationalInstitutesofHealthPerspectiveonReportsofGadoliniumDepositionintheBrain.JAmCollRadiol2016;13(3):237-41.39. KahnJ,PoschH,SteffenIG,etal.IsThereLong-termSignalIntensityIncreaseintheCentralNervousSystemonT1-weightedImagesafterMRImagingwiththeHepatospecificContrastAgentGadoxeticAcid?ACross-sectionalStudyin91Patients.Radiology2017;282(3):708-16.
References Reporting Gadolinium
Deposition
Generic Brand Manufacturer
Chemical Ionic vs
ACR NSF
Signal Intensity T1 Gadolinium
Name Name Structure Non-ionic Safety Group Changes Changes Detection
gadopentatate dimeglumine Magnevist Bayer linear Ionic I 4,6,9,17,19,29,30 19,27† 11,12,19
gadoversetamide Optimark Mallinckrodt linear Non-Ionic I
gadodiamide Omniscan GE Healthcare linear Non-Ionic I 4,5,7,8,18,19,34 19 7,11,12,18,19 *
gadoteridol Prohance Bracco macrocyclic Non-Ionic II 11,21 *
gadoterate meglumine Dotarem Guerbet macrocyclic Ionic II 27† 18,19
gadobutrol Gadovist and Gadavist
Bayer macrocyclic Non-Ionic II 24 27† 21
gadobenate dimeglumine Multihance Bracco linear Ionic II 8,15,19,20 # 19 19,21
gadoxetate disodium Eovist Bayer linear Ionic III 39 21
gadofosveset trisodium Ablavar Lantheus linear Ionic III
Table1:ContrastAgent,manufacturer,chemicalstructure,ACRdesignationforNSFrisk,andreportsassociatedwithgadoliniumdepositioninthebrain.TheACRdesignatesthreecategoriesofcontrastagentgroupingsbyriskofNSF.Group1agentshavebeenassociatewiththegreatestnumberofNSFcases.GroupIIagentsareassociatedwithfew,ifany,unconfoundedcasesofNSF.GroupIIIagentshaveonlyrecentlyappearedonthemarket.*Patientsreceivinggadodiamideandgadoteridolin(11)alsoreceivedgadopentetateandthusresultsareconfounded.#(8)showsatrendforsignalchangesingadobenatedimeglumineexposedpatients†(27)reportedT1changesbutpatientsreceivedcombinationsofthreeagents,andthustheresultsareconfounded.Inaddition,onepapershowsdirectevidenceofgadoliniumdepositionwiththepatientreceiving2dosesofgadopentetatedimeglumineand2dosesofeithergadopentetatedimeglumineorgadodiamide22.Sincetheseareconfounded,thisreferenceisnotincludedinthelastcolumn.
Generic Name gadopentatate dimeglumine gadoversetamide gadodiamide gadoteridol gadoterate
meglumine gadobutrol gadobenate dimeglumine
gadoxetate disodium
gadofosveset trisodium
gadopentatate dimeglumine * 19,32
gadoversetamide *
gadodiamide * 21
gadoteridol
17,21
21 * 21 21 21
gadoterate meglumine 6,19 18,19 * 15,19
gadobutrol 29,30 *
gadobenate dimeglumine
15,19 8,19,21 21 *
gadoxetate disodium 21 21 *
gadofosveset trisodium *
Table2:Studieswithcomparisonsofgadoliniumdepositioninmultiplegadoliniumbasedcontrastagents.Foreachentry,theagentdepositingtoalesserdegree(ornotatall)isidentifiedontheleft(inred),andtheagentdepositingtoagreaterdegreeisidentifiedabove(inblue).
