罕见病例一例－－Whipple病 | 丁香园

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NeurologicPresentationofWhippleDisease:Reportof12CasesandReviewoftheLiterature
WhipplediseaseisararemultisystemicinfectiousdiseasecausedbyTropherymawhippelii.Thisbacteriaisprobablyacommensalorganismofthegastrointestinaltractbutmaycauseinfectionifunderlyingimmunologicabnormalitiesarepresent,especiallyofmacrophages（6,30,34）.Thediseaseismultifocalbutusuallyaffectsthegastrointestinaltract,andduodenalbiopsyremainsthestandarddiagnosticprocedure.T.whippeliicannotbeculturedbytraditionalmethods（38,39,46）,sothediagnosisisbasedontypicalhistologiclesionsandidentificationofthecausativeorganismbypolymerasechainreaction（PCR）.Thediseasecanbecuredwithprolongedantibiotictreatment.

InvolvementofthecentralnervoussystemisaclassicalfeatureofWhippledisease（20%–40%）（17,31,52）butclinicalsymptomsusuallydevelopinthelaterstageofthedisease.Neurologicinvolvementhasbeenreportedparticularlyinpatientswhopreviouslyreceivedantibiotictreatmentsthatcouldnotcrosstheblood-brainbarrier.WeconductedthepresentstudytodescribeneurologicaspectsofWhippledisease,basedontheanalysisof12originalcasesandareviewofthepublishedliterature.

Case1
Mrs.M.wasbornin1955.Hermedicalhistorybeganin1975,withthesuddenonsetoflefthemiparesissparingtheface.NeithersensitivitydisordersnorBabinskisignwasnoticed.Examinationoftheocularfunduswasnormal.Theerythrocytesedimentationrate（ESR）was11mm/h.Cerebrospinalfluid（CSF）wasnormal.Computedtomography（CT）ofthebrainshowedanexpansivelesionintheposteriorpartoftherightfrontallobe.Aneurosurgicalresectionofthetumorwasperformed.Thehistologicanalysisshowedanecroticlesionwithnoevidenceofmalignancybutwithinflammatorygranulomatoustissueinfiltratedbynumerouscells.ThemacrophagespresentedonlyafewperiodicacidSchiff（PAS）-positivegranules.InAugust1998,thepatientpresentedwithagitation,behaviordisorders,andconfusionassociatedwithclonicmovementsontherightsideanddecreasedbilateralvisualacuity.Physicalexaminationrevealedbilateraluppermotorneurondisorder.Biologicinvestigationsshowedahemoglobinof107g/LandanESRof25mm/h.ThebrainCTscanrevealedprominentedemaofthelefthemisphereassociatedwithahypodenselesionintheleftoccipitallobewithamasseffect（Figure1）.ThepatientwastransferredtotheneurosurgerydepartmentinSeptember1998withtotaldementiawithmutism.Stereotacticbiopsyoftheleftoccipitallobewasperformed.Thehistologywassimilartothatobservedin1975.Thelesionsinvolvedbothwhiteandgraymatter,mimickingencephalitis.TherewerealsoassociatedperivascularandintraparenchymatousmacrophagesexhibitingPAS-positiveinclusionssuggestiveofWhippledisease（Figure2）.AnalysisoftheCSFdidnotshowanycellwithPAS-positivecytoplasm.ThespecificsearchforT.whippeliiwithDNAextractionandspecificPCRcontrolledwithhybridizationintheCSFwasnegative.AttheendofOctober1998,becauseofdelirium,agastroscopywasperformed.Thegastroscopydidnotrevealanymacroscopicabnormality.Duodenalandjejunalbiopsieswerenormal.Treatmentwithtrimethoprim-sulfamethoxazole（TMP-SMX）320+1,600mg/dwasintroducedandsignificantneurologicimprovementwasnoticed.Thedeficitintherightpartofthebodydecreased,deliriumdisappeared,andthepatientwasabletotalkandperformdailyactivitiesagain.ACTscanofthebrainwasperformedforfollow-upinDecember1998:thehypodenseedematouslesionshadclearlyshrunk,especiallyintheleftpartofthebrain

Fig.1.CerebralCTscanwithcontrastmedium（Case1,September1998）.ProminentedemainthelefthemispherewithoutdeepSylviantumorouslesion;leftSylvianfissureheterogeneousinappearance,associatedwithhypodenselesionintheleftoccipitallobewithamasseffectbutwithoutspecificcontrastenhancement.
Fig.2.CerebralCTscanwithcontrastmedium（Case1,October1999）.Clearregressionofhypodenseedematouslesions,notablyontheleft.
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http://www.google.com/search?hl=zh-CN&q=Whipple+disease+&btnG=Google+%E6%90%9C%E7%B4%A2&lr=
Whipple'sdiseasecausesweightloss,incompletebreakdownofcarbohydratesorfats,andmalfunctionsoftheimmunesystem.Whenrecognizedandtreated,Whipple'sdiseasecanusuallybecured.Untreated,thediseasemaybefatal....

A68-year-oldmanwasadmittedforwalkingdifficulties,memoryloss,andincontinencethathadbeenprogressingfor5months.For12years,hehadcomplainedofarthralgiasofthehandsandwrists.Thediagnosisofrheumatoidpolyarthritishadbeenmade.

Aneurologicexaminationrevealedatetrapyramidalsyndromeassociatedwithapathyandmemoryloss.Bloodtestsindicatedaninflammatorysyndromewithanelevationoftheerythrocytesedimentationrate（80mmatthefirsthour）andanincreaseofproteins.Theresultsofantinuclearantibody,HIV,BandChepatitis,latex,andWalerRosetestswerenegative.TheCSFtestshowedanincreaseintheproteinrate（1.95g/L）withanabsoluteincreaseofimmunoglobulinG（205mg/L）,butthecellcountandglucoselevelwerenormal.PolymerasechainreactionforTropherymawhippeliiwasnegative.

MRimagesofthebrain（Fig1A–DandF）hadareasofT2hyperintensityintherightandleftmediobasaltemporallobe,anteriorcommissure,rightandleftmamillarybodies,leftcerebralpeduncle,rightmiddlecerebellarpeduncle,bulb,rightlobeofthecerebellum,andopticchiasm.Theselesionsshowednomasseffect.AfterIVinfusionofacontrastagent,mildenhancementoftherighttemporallesioncouldbeseen.MRimagingofthespinalcordwasalsoperformed,showingT2panmedullarycentralhyperintensity.

FIG1.Imagesfromthecaseofa68-year-oldmanwhowasadmittedforwalkingdifficulties,memoryloss,andincontinencethathadbeenprogressingfor5months.
A,AxialT2-weightedMRimage（4347/100/4）ofthebrainshowshyperintensityinthemediobasalpartoftherightandlefttemporallobes（arrows）,inthemamillarybodies（star）,andintheopticchiasm（arrowhead）.

B,AxialT2-weightedfluid-attenuatedinversionrecoveryMRimage（11000/140/2[TR/TE/excitaitons]）ofthebrainshowsdiffusehyperintensityinvolvingtherightmediobasalandleftmediotemporallobes（arrows）,aswellasinvolvementoftheleftcerebralpeduncle（arrowhead）.Notethelackofmasseffectdespitethesizeofthelesion.

C,Coronalfluid-attenuatedinversionrecoveryMRimage（11000/140/2）ofthebrainshowshyperintensityinthemediobasalpartofrightandlefttemporallobes（arrows）,brainstem（star）,andrightmiddlecerebellarpeduncle（arrowhead）.

D,CoronalT1-weightedMRimage（535/14/2）ofthebrainshowsmildenhancementoftherighttemporallesionsaftertheIVadministrationofacontrastagent（arrow）.

E,SagittalT2-weightedMRimage（2745/120/6）ofthespineshowshyperintensityinthecentralpartofthespinalcord（arrow）.

F,CoronalT2-weightedfluid-attenuatedinversionrecoveryMRimage（11000/140/2）ofthebrain,obtainedafter1yearoftreatment,showsnearlycompleteresolutionoftherighttemporallesion（arrow）.

Thepatientunderwentaduodenalbiopsy,whichshowedmacrophagesthatstainedpositivelywithperiodicacid-Schiffstain（Fig2）.PolymerasechainreactionforTropherymawhippeliiwaspositiveontheduodenalbiopsy.
FIG2.Duodenalbiopsywasperformed.Notethecharacteristicfoamymacrophagescontainingperiodicacid-Schiffstain-positiverod-shapedstructuresinthesubmucosalregion
reviewof84casesdescribedintheliterature（4）revealedthatclinicallydetectableinvolvementoftheCNSrangesfrom6%to43%ofpatientssufferingfromWhippledisease.In43ofthe84reportedcases,CTorMRimagingoftheheadwasperformed,andin23,focalabnormalitieswerefound（4）.

However,Dobbins（1）postulatesthatallpatientssufferingfromWhipplediseasehaveanatomic-pathologicCNSinvolvement（13）.Itconsistsofmultiplesmallcircularorovallesions,measuringanaverageof2mmindiameter,disseminatedthroughoutthegraymatterandcharacterizedbytheaccumulationofmacrophages,stainingveryintenselywithperiodicacid-Schiffstain,asshowninpostmortemstudies.Electronmicroscopyshowsthatthemacrophagescontainabacilliformorganism,namedTropherymawhippeliibyRelmanetal（3）,revealingthebacterialcauseofthedisease（2,6）.Thesamelesionsarefoundinotherorganswhentheyareaffectedbythedisease（2,6）.Recently,molecularbiologyallowedthedetectionofthepresenceofTropherymawhippeliiintheaffectedorgansbyusingpolymerasechainreaction（3）.Previousstudieshaveshownagoodcorrelationbetweenpreferentialsitesofanatomic-pathologiclesionsandthelesionsrevealedbyMRimagingandCT（5,8,9,14）.

ThefirstneuroradiologicdescriptionsofCNSinvolvementwerereportedasseenonCTscans（8,14）,andtheypresentednospecificcharacteristics（2）.TheCTscancanbenormal,regardlessoftheclinicalfeatures,orcanrevealfocalizedlesions,whichcanbehypo-orhyperdense,contrastenhancedornot,andwithorwithoutmasseffect（2）.However,MRimaginghasproveditssuperiorityforthedetectionofsmalllesions（3）.InareviewoftheliteraturepresentedbyLouisetal（4）,43patientshadundergoneCTorMRimagingandthreepatientswithnormalCTfindingshadfocalabnormalitiesontheirMRimages（4）.

Theselesions,whichoccurin53%ofthecases（4）,oftenconsistofT1hypointensityandT2hyperintensity,shownomasseffect,andarelocatedinthemedialpartofthetemporallobes,inthehypothalamicregion,orinthepons（9,10）.Theselesionsaresometimesenhancedafterinfusionofcontrastmedia（4,8,9,14）.Moreover,associatedmoderateatrophyoccursin42%ofthecases（4）.

Multiplemasslesionshaverarelybeendescribed.TheyusuallyappearhypointenseonT1-weightedimagesandhyperintenseonT2-weightedimagesandenhanceafterinfusionofcontrastmedia（12）.However,asmallnumberofpatientshavenormal-appearingMRimages（4）.

Theinvolvementofthespinalcordhasrarelybeenreported.WefoundonlyonereportofmyelopathysecondarytoWhippledisease,diagnosedbyusingMRimaging（11）.Itwaslocatedinthecervicalregion,anditappearedhyperintenseonT2-weightedimagesafterIVinjectionofgadolinium.

Involvementoftheopticchiasmhasalsorarelybeenrevealedbyneuroradiologicexamination,althoughitismoreoftendiscoveredduringpostmortemstudies（9）.WefoundonlyonereportwithanincreasedT2signalintensitylocatedintheoptictracts（9）.However,clinicalopticalmanifestationsarecommonincasesofWhippledisease（4,5）.

EarlytreatmentofWhipplediseaseleadstoimprovementofthelesionsrevealedbyneuroradiologicexamination（4,9,12）,asshowninourcase,butdiagnosisisoftendifficult.Diagnosisisoftendifficulttodetermineonthebasisofpolymerasechainreactionorhistologicfindings（98%）;moreprecisely,63%ofpatientsunderwentbiopsy（88%ofwhichwereobtainedfromthesmallbowel（4）.Morerarely,thediagnosisismadebasedonlymphnodebiopsyorcerebralbiopsy.However,polymerasechainreactionhasshownsensitivityandspecificitytoconfirmadiagnosisofWhippledisease（15）,andrecentstudieshaverevealedgeneticmaterialofTropherymawhippeliiinperipheralbloodmononuclearcellsandincellsofpleuraleffusion（16）,suggestingthatthediagnosiscansometimesbemadeonthebasisofpolymerasechainreactionofperipheralblood（17）.ThediagnosiscanalsobeobtainedbyconductingananalysisoftheCSFforperiodicacid-Schiffstain-positivecells（2）,butthevalueofpolymerasechainreactioninCSFhasnotyetbeenevaluatedbecauseoftherarityofthedisease.

Treatmentisoftendelayed,however,resultingindeathorirreversiblecerebrallesions,suchasatrophy（9,13）.Moreover,relapseofthediseaseisfrequent,leadingtothereappearanceoftheCNSlesionsonMRimages（4）.

Inconclusion,thiscasereportshowstheimportanceofneuroradiologicexaminations,particularlyMRimaging,forthedetectionofCNSlesionsintheinitialevaluationofpatientssuspectedofhavingWhipplediseaseandforthelong-termfollow-upofthesepatients.ItisnecessarytoperformMRimagingofthebrainandspinalcordtoascertainthedifferentlocationsoftheselesions

InAugust1994,a65-year-oldwomanpresentedwitha2-monthhistoryofupperandlowerlimbparesthesiasand1-weekparaparesisandsphincterdysfunction.Onclinicalexamination,sensorymotormyelopathywithanuppercervicallevelwasconfirmed.
FIG1.August1994.Sagittalfastspin-echoT2-weighted（5000/112/2）（TR/TE/excitations）imageshowsenlargedandinhomogeneouslyhyperintensespinalcordfromthecervico-occipitaljunctiontotheupperdorsalregion（A）.Sagittalspin-echoT1-weighted（460/17/2）imageswithgadopentatedimeglumineshowperiphericalenhancement（.Aftersevendaysofcorticosteroidtherapy,spinalcordenlargementhasdecreased（C）.Eightmonthslater（April1995）,thecordisnormal（D）
FIG2.November1995.SagittalT2-weighted（5000/112/2）imageshowsenlargedandinhomogeneouslyhyperintensespinalcordfromdistalcervicaltoupperthoraciccord（A）.Onemonthlater,thecordisnormal
FIG3.May1997.Coronalfast-FLAIR（9002/137/2000）（TR/TE/TI）imageshowsnodularsignalhyperintensitywithslightmasseffectinleftmiddlecerebellarpeduncle.
January2000（5monthsafterstartofantibiotictherapy）.Coronalfast-FLAIR（8802/105/2200）imagesshowregression:onlyslightsignalabnormalitiesinthestructurespreviouslyinvolved,andnonewlesions
March1998.Coronalfast-FLAIR（9002/137/2000）imagesshowpersistenceofthelesionsobservedpreviously（A）,increasedinvolvementofmiddleandnewinvolvementofsuperiorrightcerebellarpeduncles
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