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.

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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).