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Assessment of dermal water by high-frequency ultrasound: comparative studies with nuclear magnetic resonance

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Assessment of dermal water by high-frequency ultrasound: comparative studies with nuclear magnetic resonance
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    ritishJournalof ermatology 1996;135:218-224 Assessmentafdermalwaterbyhigh frequencyultrasaund camparativestudieswithnuclearmagneticresanance M.GNIADECKAANDB.QUISTORPP* BioengineeringandSkinResearchLaboratary DepartmentafDermatology.UniversityafCapenhagen.BispebjergHospital.Denmark NuclearMagneticResonanceCentre.PanumInstitute.UniversityafCapenhagen.Denmark Acceptedforpublication18December1995 Summary Althoughaprincipalconstituentofhumanskin.cutaneouswaterisdifficulttostudy.andlittleisknownaboutwaterbehaviourinphysiologicalandpathologicalconditionsoftheskin.Ithasbeenproposedrecentlythatchangesindermalechogenicitymeasuredbyhigh-frequencyultrasono-graphyreflectchangesindermalwatercontent.Tovalidateskinultrasonographyforassessmentofdermalwaterchangeswehavestudiedtherelationshipbetweendermalechogenicityandskinwatercontentdeterminedbynuclearmagneticresonancetechnique.TwentyMHzultrasoundscanningofthedorsalandventralforearmskinwasperformedin59healthyvolunteers(age18-65)anddermalechogenicitywasdeterminedbycountinglowechogenicpixels(LEPs)inskinimages.IHmagneticresonancespectrawereobtainedfromthesameregionsandtheratioofareasunderthewater-andfat-specificpeaks(WlP)werecalculatedtomeasurearelativewatercontent.Acutedermaloedema(histamineweal)wasstudiedinthesamewayin40individuals.Baselinedermalechogenicitycorrelatedsignificantlywith WI bothintheventral(r = 0 47)anddorsal(r=O 57)forearm.Intrad~rmalapplicationofhistaminecausedadevelopmentofintradermaloedemawhichcouldbevisualizedbynuclearmagneticresonanceimaging.Inacorrespondingultrasoundimageoedemawasseenasalow-echogenicarea.TheproportionalincreasesinLEPsandWIFafterhistamineapplicationwerecorrelated.buttheelevationinLEPswas25-48 (95 confidenceintervals)higherthanthatforWIF.Theseresultssuggestthathigh-frequencyultras onographyisasensitivemethodforassessmentofchangesindermalhydration.Thistechniquemayfindimportantapplicationsincomparativeandnon-invasiveevaluationsofdermalwaterinphysiologicalconditionsandinskinpathologiesassociatedwithoedemaformation.Waterconstitutesabout70 ofthemassofhumanskin.providesadequateenvironmentformetabolicprocesses.andtoagreatextentdeterminesskinstructure.turgorandotherphysicalproperties.Despitebeingsoabundant.waterisaverydifficultcomponenttostudy.Theassessmentofthechangesintissuevolumeduetotheinfluxofwaterisinsensitiveasswellingisonlyapparentwhenthevolumeofinterstitialfluidisdoubled.1,2Invasiveskinsamplingproceduresinvolvingskinbiopsiesandhistologicalprocessinginvariablycausealterationsinwaterdistributionandcontent.Highresolution20MHzultrasonographyisanon-invasiveprocedurewhichhasbeenincreasinglyusedforstudyingcutaneouswater.3-11Inthedermis. Correspondence:MonikaGniadecka.MD.PhD.FrederiksbergAlle29.3.t.v.1820FrederiksbergC.Denmark. 218 ~ ultrasoundreflectionsaregeneratedonthesurfaceofcollagenbundleswhichhavedifferentacousticpropertiesfromthesurroundinggroundsubstanceandthecells.12Influxofwaterintothedermiscausesseparationanddisarrangementofcollagenbundlesandconsequentlyadropinechogenicity.Ultrasoundmethodseemstobeusefulinclinicalpracticeandinresearchformeasurementofskinoedema.Ithasbeenproposedtoestimatethedegreeofinflammatoryskinreactions.particularlythoseevokedbypatchtesting.byultrasound-basedmeasurementofthedropinecho-genicity.3-6Ultrasonographymaybesuitableformeasurementofskinoedemainlimbswithdeepvenousinsufficiencywhichisofdirectclinicalimportanceinrelationtomonitoringtheefficacyofcompressivetherapyinpatientswithvenouslegulcers.lOEchogenicityofdermis8andotherorganssuchastheliver.changesinacircadianrhythm. iQ1996BritishAssociationofDermatologists  .   ~ probablyreflectingphysiologicaldiurnalvariationsinwatercontentinthetissues.Inallthesestudies,however,therationaleforuseafultrasonographyforskinwatermeasurementshasbeenbasedentirelyantheoreticalassumptionsandnovaIidationstudieshavebeenperformed.IHnucIearmagneticresonance(NMR)isrecognizedasaspeciflcmethadfornon-invasiveandquantitativedeterminationafwaterinbiologicalmaterialsY-17TheIHspectrumcontainstwomajorpeaksderivedfromwaterandfat.1'4-16Therefore,assumingthatthefatcontentinagivenanatomicalsiteintheskinisconstant,watermaybedeterminedbytheratioaftheintensityafwaterandfatsignals.15.16WatercontentcanalsobequantifiedfromNMRimages.lS,18However,thismethodiscumbersomeandconsideredlessr~Iiablethanspectroscopy,ascalibrationagainstphantomsisnecessaryandtimeafscanningissignificantlyprolongedwithariskafmovementartefacts.Inthisstudyweevaluateiftheechogenicityafthedermisiscorrelatedtodermalwaterexpressedasthewater/fatratio(W/P)caIculatedfrom1Hmagneticresonanceskinspectra.  ethods  u jects Pifty-nineheaIthyvolunteers(29men,30women,age18-65,median36)enteredthestudyafterinformedconsent.EthicalapprovalforthestudywasobtainedfromtheEthicsCommitteeafCapenhagenMunicipaIity. SkinuItrasonography Cross-sectional,B-modescansaftheskinwereobtainedwitha20MHzuItrasoundscannerDermascanC(CortexTechnology,Hadsund,Denmark).Thisinstru-menthasbeendescribed,indetai ,previously.7-1ODuringimageacquisitionthegain/compensationcurvewasadjustedinthehorizontalpositionat22dBasatthissettingmaximalA-scanpeakswereobtainedbyscanningthestandardrubberphantom(CortexTechnology).ThevelocityafuItrasoundintheskinis1580m/s.Toobtainauniformimagesize,andtoensurethatimageswereobtainedfromthesamesite,thestudiedareawasmarkedwithanadhesivering(Beiersdorf,Germany).TheuItrasoundgel(Greenscan,Nicomed,Denmark)wasappIiedtotheapertureaftheringandanyexcesswasremoved.TheuItrasoundprobewasgentlyplaced over thering,withtheHIGH-PREQUENCYULTRASONOGRAPHY219transducerdirectedperpendicularlytothesurfaceaftheskin.Ultrasoundimageswererecordedanfloppydiscsandfurtherprocessedbyimageanalysis(GIPS,ImageHouse,Capenhagen,Denmark).Thissystemmeasuresechogenicityafsingleimageelements(pixels)ananumericalscaleextendingfromO(non-echogenic)to255(maximalechogenicity).Ineachimagewecountedthenumberafpixelsafintensities 0-30 (Iowechogenicpixels-LEPs).Thismethodhasbeenusedpreviouslytoquantifythelow-echogeniccomponentoftheuItrasoundimage.3-11ThenumberafLEPsincreaseswiththedecreaseafecho-genicity.LEPsweredeterminedinthedermalregion,betweentheepidermalentranceechoandtheinterfacewiththesubcutaneous..fatlayer.Tomeasureskinthfckness,simultaneausA-andB-modescansaftheskinwereobtainedandthepeaksintheA-scancorre-spondingtotheepidermalentranceechoandtheinterfacebetweentheskinandthesubcutaneousfatwereidentified.Thedistancebetweenthesetwopeakswasthemeasureafthethicknessaftheskinandequalled1.34::I::mean::I::tandarddeviation:SD 0 19 mmanthedorsalsiteaftheforearm,1.16::I:: .17 mmantheventralsite,increasingto1.56::1::O'21mmwithinthehistamineweal.Allultra-soundexaminationswererunindupIicateandtheirmeanswereusedforsubsequentanalyses. NMR investigations Proton-1 e H)NMRspectroscopywasperformedina VivospecTMspectrometer(OtsukaElectronics,Inc.,U.S.A.)equippedwitha2.9Teslahorizontalsuper-conductingmagnet(26cmbore,80cmlang)(MagnexScientificLtd,U.K.).Thesurfaceprobewasameandercai inductivelydrivenandtunedfor1H.19The1Hspectrawereobtainedbyasignal-pulsetechnique.Datawerecollectedin2Kmemory over 205msand10scansweresummedwitha6sinterpulsedelay.Inardertomeasurethedepthafthepenetrationaftheprobe,aPetridishfilledwithaS-mmslapafwaterwasplacedatdifferentdistances over thesurfacecai .Afteracquisitionafthespectratheareaunderthewater-specificpeakwascaIculatedbyacurve-fittingroutine(OtsukaElectronics)andplottedvs.thedistancebetweenthecai andthewaterslap.Theareaunderthewater-specificpeaksharplydecreased over thedistanceaf1.5mmattaining25 aftheinitialvalueat2mmfromthecai . Toacquiremagneticresonancespectra(MRS) nvivo thesubjectsputtheirforearmsintothemagnetsothat ~1996BritishAssociationofDermatologists, BritishJournalofDermatology, 135,218-224 ..  --- 220M.GNIADECKAANDB.QUISTORPP waterpeaks ~ 'c ::::J ~ :§.ti I I II IIII fatpeaks IIti III i II1\ Z iijC<D:s(ijcCl iij ..------  . 10000 0.0 -20000lO000 frequency[p.p.m.] Figure 1.Magneticresonancespectra(MRS) of humanskin in vivo.TypicalMRSofthecontrolskin(C)andafterinjectionofhistamine(H)areshown,Water-andfat-specificpeaksareindicated.Notetheincreaseofamplitudeofthewater-specificpeakafterapplicationofhistamine. theinvestigatedregionoftheskinmarkedwiththeadhesiveringresteddirectlyoverthesurfacecoil.Typicalspectracontainedtwomajorpeaks,represent-ingwaterandfat(Pig.l).Theareasunderthewaterandfatpeaksweredeterminedwiththecurve-fittingsoftware.Therelativeamountofwaterintheskinwascalculatedbydividingtheareaunderthewater-specificpeakbytheareaofthe.fat-specificpeak(WlP).TheadvantageofusingWlPisthattherelativeintensityvariationofindividualcomponentsoftheratio,e.g.duetocoilposition,areeliminated.Patisarelativelystablecomponentoftheskinandtherearenomajorage-relatedchangesinfatcontent,20Theskinimagingmoduleconsistedofagradientsurfacecoilplacedinsideandinthemiddleofamainmagnet.Thefieldofviewwas40mmandthethicknessoftheslicewaslmm.Spin-to-relaxationtime(TR)was500msandtimeofecho(TE)was40ms.Initially,weperformedchemicalselectiveimagingwheretwocomplementaryimageswereobtained:onerelatedtothemobilewaterfractionandtheothertothelipidfraction.21Toobtainbettervisualizationofstructuralelementswaterandfatimagesweresubsequently mixedatastandardratio 2:1.  tu y esign Thesitesontheventralanddorsalsideoftheleftforearm,one-thirdthedistancefromwristtoelbow,weremarkedwithanadhesivering(Beiersdorf).Theultrasoundscanofthedemarcatedskinwasobtained,andMRSofthesameskinregionwasperformedimmediatelyafter.Subsequently,in'40individuals,ahistaminewealwasproducedwithinthemarkedskinontheventralside,asdescribedpreviously.22Thestandardpricktestneedles(Phazet,Pharmacia,Uppsala,Sweden)wereused,whichpuncturetheskintoastandarddepth(mean:iSD)of0.79:i0,05mm.Tenminutesafterhistamineapplication,ultrasono-graphyfollowedbyMRSwereperformed.Inselectedcases,ultrasoundandNMRimagingoftheskinwereperformedbeforeand'afterapplicationofhistamine.Skinoverthemedialmalleoluswaschosenforthispurpose,becausethelengthoftheimagingcoildidnotallowstudiesoftheskinonupperextremities. StatisticaIanalysis Dataarepresentedasmeanswith95 confidenceintervals.TheWlPdatadidnotshowanormaldistributionandalogarithmictransformationwasperformedtonormalizevariations.CorrelationanalysiswasperformedtoevaluatetherelationbetweenLEPnumberandWlP.ToassesstheinfluenceofageandsexontherelationshipbetweenWlPandLEPamultipleregressionanalysiswasperformed.Partialcorrelationcoefficientsandtheirconfidenceintervalswerecalculatedfrompublishedformulae.23TheagreementbetweentheultrasoundandMRSmethodswasassessedbycalculatingthe95 agreementintervals,asproposedbyBlandandAltman.24IntheexperimentwiththehistaminewealtheproportionalincreasesinLEPandWlPratioweredetermined,andthedifferencesbetweenthesevalueswerecalculated.The95 confidenceintervalsofthedifferencebetweenLEPandWlPwerereferredtoaslimitsofagreement.Narrowlimitsofagreement,whencomparedwiththemeanofthemeasuredvalue,indicategoodagreementbetweenthemethods.P<0,05wasconsideredstatisticallysignificant.AllcalculationswereperformedwiththeMinitabstatisticalsoftware(Minitab,Inc.,StateCollege,U.S.A.).  es ults Tomeasurewhetherbaselineechogenicityofthedermisiscorrelatedwiththerelativewatercontentintheskin,LEPswerecountedinthedermalultrasoundimageandtheirnumberplottedagainsttheWlPratioofthesameregion(Pig.2).Thecorrelationcoefficientsattained~ 1996BritishAssociationofDermatologists, British Journalof ermatology 135,218-224 . , o.;:; ' ... u... ..... :i: ti) .2 FigU Janddeter1 repre.resolog varia j womsymb tion ~ data,fema~ p W/P~mad~tian)numdors~ regn(P<(adjldepehavithis.(adjaLEP, ~19  L ---, dorf).The ,obtained. performedviduals.aarkedskinsly.22The'harmacia.-etheskin0,05mm.ultrasono-nselectedskinwerelistamine.IIforthisgcoildiddties. onfidencelnormaltionwaslanalysisveenLEP;eandsexmultiple)rrelationtisweregreement ; assessed 'Vals,asperimentreasesinfferenceshe95 LEPandNarrowmeanofbetweentisticallyNiththeCollege,edermistheskin,lageandhesameattained 218-224 1 .1.5 A1 . 1f o.;:; ~ 1.0 u. ......==   AA.AA///1 .I>.A/// ~ :d / AI>.AI>.I>.  .. iJ 1jI2 ;-5.. ~A . 'AAAA . ~ .. ' .. //7 O' ....~/ o A l>.(')I>. oI>. 061:0. o. ~<i..o. o Cl..20.5 OO40006000800010000000 L P Figure2.Relationshipbetweenthewater-andfat-specific(WlP)ratioandlowechogenicpixel(LEP)numberoftheskin.LEPweredeterminedfromtheultrasoundimagesoftheskinandWlPrepresentingrelativewatercontentwascalculatedfrommagneticresonancespectra,asdescribedin MaterialsandMethads. ThelogarithmictransformationofWlPdatawasperformedtonormalizevariations.Circlesandtrianglesrepresentvaluesobtainedfromwomen'andmen,respectively.Opensymbols:ventralforearm,solidsymbols:dorsalforearm.Solidlineshowsasignificantlinearcorrela-tion(r=0,56,P<0'001)inmalesubpopulation,collectivelyforthedatafromventralanddorsalsites.Thecorrespondinglineforthefemaiesubpopulationisplottedwithadashedline(r=0,42, P<Q.OO1). statisticaIsignificancebothfortheventralanddorsalsiteandequalled0.42(95 confidenceintervals0'16-0'59)and0.31(0'05-0'52).respectively.InpreliminaryexperimentswithNMRimagingwenoticedthatwomenhadathickerandmorecompactfatlayerthanmen.Wehypothesizedthatsex-linkeddifferencesinfatdistributionandcontentmightconstituteaconfoundingfactorinfluenceofwhichcouldexplainwideconfidenceintervalsforregressioncoefficients.AgecouldbeanothervariableaffectingWlP.Therefore.weconstructedamultipleregressionmodelwhereWlPratio(afterlogarithmictransforma-tion)wasregressedagainstthreepredictors:thenumberofLEPs.sexandage.Porbothventralanddorsalsites,weobtainedstatisticallysignificantregressioncoefficientsforLEPs(P<0'0001)andsex(P<0'0001).butnotforage.TheR2parameter(adjusted)equalled45'2 .ThisindicatesthatW/PdependsnotonlyonLEPsbutalsoonsex,menhavinghigherWlPratiothanwomen.Toaccountforthisfactwecalculatedpartialcorrelationcoefficients(adjustedforsex)fortherelationshipbetweenWlPandLEP,whichequalled:0,47(0'21-0'62)fortheventralHIGH-PREQUENCYULTRASONOGRAPHY221site,0'57(0'30-0'68)forthedorsalsite,and0,49(0'30-0'59)cumulativelyforventralanddorsalsites.AfteranintradermalapplicationofhistaminetheintradermaloedemaintheregionofthewealwasimagedwithNMR(Pig.3).Inthecorrespondingultra-soundscantheintradermaloedemawasimagedasalow-echogenicregioninthedermis.InthehistaminewealsnumberofLEPsincreasedsignificantlyby211O(95 confidenceintervals1032-3458,P<0-001)pixelsandthiswasaccompaniedbycorrelatedandsignificantincreaseinWlPratiobyamedianvalueof0'26(0'10-0'51.P<0'005).TocalculatetheagreementbetweentheultrasoundandMRSmethod,proportionalchangesinLEPsandWlPafterinjectionofhistaminewerecalculated.InthehistaminewealsLEPsincreasedby63 (51'3-74'7)andW/Pby8'9 (2'9-14'9).TheproportionalincreaseinLEPswascorrelatedwiththepercentageofW/Pincrease(correlationcoefficientof0,39(0'06-0'61),P=0'01).Todeterminethelimitsofagree-ment,the95 confidenceintervalsofthedifferencebetweenproportionalchangesinLEPsandWlPweredetermined.ThelimitsofagreementbetweentheultrasoundandNMRmethodswere43'1-63,5 (mean54'1 ). Discussion Wehavedocumentedacorrelationbetweenecho-genicityquantitatedfromhigh-frequencyultrasoundskinimagesandWlPratiomeasuringrelativeskinwatercontent.ThissuggeststhatLEPcountinthedermalultrasoundimagedependsontheconcentra-tionofwaterintheskin.However.althoughthecorrelationcoefficientwassignificantlydifferentfromzero,itsconfidenceintervalswerewide.ThissuggeststhattheassociationbetweenWlPandLEPscanexplainonlyafraction(approximately45 )ofthevariabilityofourdata.23Therestcanbeattributedtotheinfluenceofconfoundingfactors,includinginherentdeficienciesinbothMRSandultrasoundmethods.TheMRSmethod,althoughconsideredtobethemostspecificofthecurrentlyavailabletechniquesforwaterquantitation in vivo,cannotserveasagoldstandard.MRSspectraoriginatefromathinlayerofskinpositionedcloselytotheproberatherthanselectivelyfromthedermis,asinultrasoundinvestigations.Thus,thereisapossibilityofcontaminationofMRSspectrawithsignalsoriginatingfromoutsidethedermis.Therefore.weperformedaprobepenetrationtestwhichrevealedthatmost(75 )ofthesignalwasgatheredfromadistanceofO ~ 1996BritishAssociationofDermatologists, BritishJournalafDermatology 135,218-224 ...    222M.GNIADECKAANDB.QUlSTORFFtol.5mmfromthesurfaceoftheprobe,whichmatchedobservedskinthickness.Spectralcomponents.derivedfromthedeeperlayersofthesubcutaneousandmusculartissues,althoughhavinglowintensities,couldconstituteaconfoundingfactorinthemeasure-ments.Moreover,wehaveshownthatsex-linkeddifferencesinsubcutaneousfatdistributionandcon-tentinflueJ)cedWIFand.thus,modulatedarelationshipbetweenWIFandLEPnumber Fig.2).Thedeficiencyoftheultrasoundmethodisthatthechangesinechogenicityarenotentirelyspecificforalterationsinskinhydration.Forexample.changesintheorientationofcollagenfibresmayaffectecho-genicity.Scarsandkeloidspresentashypoechogenicareasontheultrasoundimages.12Incutaneousmalignancies.suchasmalignantmelanomaandbasal Figure3.NMRandultrasoundimagingofhumanskinpeforeandafterinjectionofhistamine.NMRimagebeforeandafterhistamineareshownon a)and b),respectively.Correspondingultrasoundimagesshownon c)and d).E-epidermis,I-interfacebetweendermisandthesubcutaneoustissue,asterisks-membraneoftheultrasoundprobe.Lowechogenicpixels LEPs)arehighlightedingreenon e)and d).Noteaformationofahistamineweal,whichpresentsasawater-richstructureon b)andahypoechogenie LEP-enriehed)areaon d) arrows). cellcarcinoma,thedermaltissuebecomesecholucentduetotheerosionofthecollagenfibrenetwork.25Itisthus,possiblethattheinterindividualvariabilityincollagenarchitecturecausedby,e.g.skinageingandphotodamage,couldinfluenceLEPcountswithoutaffectingskinwatercontent.Toassessdirectlytheusefulnessofultrasonographyforassessmentoftheskinwatercompartment,oedemaofthedermiswasevokedinthehistaminewealexperiment.andchangesinLEPsandWIFweredeter-mined.Two-dimensionalsectionalimagesthroughthehistaminewealdemonstratedaregionofdecreasedechogenicitywithindermiswhichcorrespondedtooedemainNMRimages.TocomparequantitativelyMRSandultrasonography,theproportionalincreaseinWIFratioandLEPnumberwerecalculated.The @1996BritishAssociationofDermatologists,  ritishJournalofDermatology 135,218-224 ..~esobtaine \herindicat J .tsedbyaniIr.thecorrelessrnent01tthispur1~culatedw~ledifferencetreernentv\cludezeroJp.rnberwasI\lents01thE\ltrasound 1 leteetingch jlineweals. putean De\)nMRSsp~tresonance~Istructure? coi\.AshY1doesnoti~1belowerttivelyintlInSull resolutiO I sensitive 1 hisroe,rneasure1 , eornparj tentar1portablEirnportawithde  Q Ackn\ Wetlassist,thesILeo1Fondswit\Refl l   2 3
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