CaseReportsCaseSeriesBrachialplexusmucormycosissecondarytoperineurialspreadLiteraturereviewandcasereportofararemodeofinfectiousspreadAndrewSJackVinilShahWyattLRameyROCMRhinoorbitocerebralmucormycosis ID: 895381
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ContentslistsavailableatInterdisciplinaryNeurosurgeryjournalhomepage:www.elsevier.com/locate/inat CaseReports&CaseSeriesBrachialplexusmucormycosissecondarytoperineurialspread:LiteraturereviewandcasereportofararemodeofinfectiousspreadAndrewS.Jack,VinilShah,WyattL.Ramey ROCM,Rhino-orbitocerebralmucormycosis;CNS,Centralnervoussystem;CT,Computedtomography;ID,Infectiousdisease;MRI,Magneticre-sonanceimagingCorrespondingauthor.E-mailaddress: 2.CasepresentationA66-yearoldfemalewithapastmedicalhistoryofdiabetes,chronickidneydisease,andcirrhosisduetohepatitisCpresentedtoanoutsidehospitalwithanecroticandgangrenousleftupperextremity.Thepatienthadfallen6-weekspriorandsustainedanabrasiontoherleftforearmthatthenprogresseddespiteantibioticsandoutpatientwoundcarenursing.Wheninitiallyseenattheoutsidehospital,shehadanon-healing,ulceratedwoundwithagangrenousforearmuptoherelbow.Withtheexceptionofawhitebloodcellcountof20,000,theremainderofherinfectiouswork-upwasnegativeincludingbloodcultures,urineculture,ultrasoundofherabdomenandpelvis,andcomputedtomography(CT)imagingofherhead,neck,chest,andupperextremitywithcontrast(revealingnoothersourceofinfection).Duetotheopen,drainingwoundandextentoftissuenecrosis,thepatientwastreatedoperativelywithanaboveelbow,mid-humerus,amputation.MicrobiologicalandpathologicalspecimensisolatedRhizopusoryzaethecausativeorganism.Upondiagnosisandinconsultationwiththeinfectiousdisease(ID)serviceatourinstitution,thepatientwasstartedonliposomalamphotericinB,caspofungin,posaconozole,aswellasbroadspectrumantibiotics(vancomycinandertrapenem).TheIDandorthopaedicsurgeryservicethenarrangedforthepa-tienttobetransferredtoourinstitutionforongoingmanagementandfurtherIDwork-up.Atthetimeofarrival,thepatientwasneurologi-callyintact,andstablefromacardiovascularandrespiratorystandpoint.Morespecically,althoughnoneurologicaldecitswerefoundproximally,duetothedistalamputation,completeneurologicalex-aminationoftheinvolvedlimbwasnotpossible.Moreover,thepatientwasfoundtohaveadehiscentdistalamputationsite.Furtherin-vestigationstodeterminetheextentofdiseasewerecompleted,in-cludingMRIofthepatientsshoulder.Thisrevealedadistalabscesswithinvolvementoftheradial,medianandulnarnerves.Duetothepersistentandprogressivefungalinfectionaswellasopensurgicalsite,revisionandmoreproximallimbdisarticulationwasplannedandcar-riedoutinamultidisciplinaryorthopaedic-vascular-plasticsurgeryapproach.Intraoperatively,themoreproximalaxillarynerveandin-fraclavicularcordswerefoundtobegrosslyabnormal.Frozensectionnerveandvascularbiopsiesfromthesectionedaxillaryartery,aswellasaxillarylymphnodesweresenttopathology.Nodalandvascularbiopsieswereallnegative,howevertheplexalnervecordswerefoundtobeinltratedwithfungalorganisms.Adecisionwasmadebythesurgicalteamtostagetheprocedurebyclosingthewoundandob-tainingneurosurgicalperipheralnerveconsultationwithfurthermag-
2 neticresonanceimaging(MRI)investigations
neticresonanceimaging(MRI)investigations.TheperipheralnerveandneuroradiologicalreviewoftheoutsideCTimagingfoundathickenedandabnormaldistalradialnerve,aswellasagrosslyabnormalmoreproximalposteriorcord(Fig.1C).AsubsequentMRIoftheheadandneckwascompletedandnormal,howeveraMRneurogramoftheleftbrachialplexushighlightedthegrosslyabnormalbrachialplexuscordswithmoreproximalextensionoftheinfectionintotheplexalnervedivisions,trunksandC6-T1spinalnerveroots(Fig.1F).TheMRIndingshadrapidlyprogressedfromthatseenontheoutsidehospitalCT.Asecondstageprocedurewasthenplannedwiththegoalofre-sectinganddebridingasmuchoftheproximalnerveinfectionexten-sionaspossibleforsourcecontrol.Theprevioussurgicalsitewasre-openedandincisionextendedsupero-mediallytoexposethesupra/in-fraclavicularbrachialplexus.Theposterior,medialandlateralcordswereadherenttooneanotherinalargeinduratedmass,swollenwithanecroticandpurulentexudate.Furthermore,thebrachialplexusdivi-sionsandtrunkswereexposedandalsofoundtobegrosslyabnormal(pathologicalspecimensshowingperineurialfungalinFig.2andB).Usingbipolarcauteryandsharpdissection,thenerveswereresectedproximallyuntilahealthyfascicularpatternandinter-fascicularbleedingwasseen.Debridementofthegrosslynecroticsofttissuecontinueduntilweweresatisedthatwehadremovedasmuchassafelypossible.Hemostasiswasobtained,andthewoundclosedinDespitesurgicalresectionattemptingtocontroltheinfectiousburden,theinfectioncontinuedtospreadpostoperativelytothepa-slungs.AlthoughaCTscanofthechestdoneinitiallyshowednonidusofinfection,multiplebloodculturesdrawnhadallshownnogrowth,inadditiontoaxillaryvascularspecimensbeingnegativeforfungalinltration,thepatientwentintorespiratoryfailureintheearlypostoperativeperiodandeventuallydiedonpostoperativeday8.3.Discussionisaninvasivefungalinfectionprimarilyaimmunocompromisedpatients.Althoughuncommonindevelopeddeveloped,theincreasingnumberofimmunocompromisedpa-tientswithchronicdiseasessuchasdiabetesdemandsthathealthcareprovidersremainvigilantandawareofthisconditioncondition.Currenttherapyincludesaggressivesurgicaldebridement,antifungalagents,andstrategiesofimprovingpatientimmunestatusstatus.Despitethis,mucormycosisisassociatedwithhighratesofmorbidityandmortality.Infact,pulmonarymucormycosisanddisseminatedmu-cormycosiscarryespeciallypoorprognoseswithmortalityratesre-portedtobeashighas76%and96%,respectivelyrespectively.Here,wereportacaseofupperextremitycutaneousmucormycosisbecomingdis-seminatedthroughperineurialspreadtothemoreproximalbrachialplexusandspinalnerveroots.Althoughfewpreviouscaseshavedocumentedperineurialspecies(spp.)spreadspread–6],nonehavecharacterizeditsoccurrenceinthebrachialplexusandpropensityforperineurialspreadoversuchalongdistance.Infact,onlyonepreviouscasehasdocu-mentedmucormycosisbrachialplexusinvolvementinvolvement.Intheircasereport,Levy,etal.detailapatientwithleftupperlobepulmona
3 rymucormycosis,adrainingchestwalllesion,
rymucormycosis,adrainingchestwalllesion,aswellasbrachialplexusplexus.Theirpatienthadpresentedwithrespiratoryandgeneralizedsystemicsymptoms.Assuch,itislikelythatthepatienthaddevelopedpulmonarymucormycosiswithsecondarybrachialplexusinvolvementthroughcontiguousspread.OthercasereportsdetailingtrigeminalperineurialspreadofmucormycosishaveinvolvedROCMformsofthediseasedisease–6].MRIstudiesfromthesecasesdemonstratefungalorganismsoriginatingintheparanasalsinusesandcavernoussinuswithonlytwoofthestudiespathologicallyconrmingretrogradeperineurialspreadalongthetrigeminalnervetothepons.Althoughthesecaseshighlightapropensityofspp.forneuralinvasioninvasion,unlikeourcase,theyalsoincludefungalinvasionofmajorvascularpathwaysandalongashortdistance.In-keepingwithourcase,cutaneousmucormycosistypicallypre-sentswitherythema,indurationandanecrotic,ulceratedwoundwound.Ifuntreated,thistypicallyprogressestosubcutaneousextension,necro-tizingfasciitis,andpossiblesystemicdisseminationdissemination.Widespreaddisseminationoccursastheorganismsaccomplishcertainkeycriticalstepsincluding:hosttissueinoculationofspores,evadinghostdefensesandgerminatingintohyphae,growthandreplication,attachmentandinvasionofendothelialcells,andhematogenousdisseminationdissemination.Vascularinvasionandmucormycosisdisseminationhasbeenshowntobemediatedbyendothelialcellreceptorglucose-regulatedprotein78thatisupregulatedindiabeticsdiabetics.However,inourcasethediseasewasprimarilypropagatedthroughperineurialspread.Perineurialspreadhasbeensparselyreportedreported.However,onereportbyFrateretal.suggeststhatperineurialinvasionbyspp.maybeun-derrecognizedincomparisontoitspropensityforangioinvasionangioinvasion.Intheirstudy,allpathologicalmucormycosisbiopsyspecimenswithperineurialinvasionalsodemonstratedvascularinvasion.Theauthorsnotethatthismayrepresentanadditionalmethodofspreadforthefungus,howevertherelativeimportanceofthisandmechanismforithasyettobedetermineddetermined.Thelatterispartiallyelucidatedwhentakeninthecontextofmorerecentstudiesshowingtheanityofspp.toattachtoepithelialgrowthfactorreceptor(EGFR)andA.S.Jack,etal. extracellularmatricesinbasementmembranes,specicallylamininandtype4collagenbothfoundinabundanceinperipheralnervesnerves.Aftergermination,theabilityofspp.toadheretoperipheralnervereceptorsandextracellularmatricesmayexplainitspropensityformorelong-distancedisseminationalongperipheralnerves(suchasthatseeninourcase).Themorerecentlyrecognizedproclivitythatspp.demonstratesforperineurialinvasionemphasizestheim-portanceofadetailedneurologicalexaminationofpresentingpatients,aswellasthoroughdiagnosticimagingwork-upincludingMRIandMRneurographyoftheinvolvedareatolookforperineurialspread.4.ConclusionMucormycosisisanuncommonfungalinfectionprimarilyaimmunocompromisedpatients.Here,wepresentanovelcaseofcuta-neousmucormycosisoriginatingintheforearmresultinginper
4 ineurialspreadtothemoreproximalbrachialp
ineurialspreadtothemoreproximalbrachialplexusandspinalnerveroots.Giventhehighrateofmorbidityandmortalityassociatedwithmu-cormycosis,timelydiagnosisandthoroughinvestigativework-upin-cludingMRI/MRneurogramoftheinvolvedareatoinvestigateperi-neurialspreadanddeterminetheextentofinfectionisadvisable. Fig.1.A:CTwithcontrastshowingaxialviewatthedistal-humerusleveloftheleftarmpriortoamputationdemonstratingathickenedradialnerve(denotedbywhitearrow).BandC:Sagittal(B)andcoronal(C)CTdemonstratingathickenedposteriorcord(whitearrow).D:AxialMRneurogramoftheleftbrachialplexusdemonstratingabnormalenhancementofall3cords,withmasslikeenlargementoftheposteriorcord,(whiteasterisk)aswellasabnormalenhancementoftheproximalnervedivisions(whitearrowandarrowhead).EandF:Sagittal(E)andCoronal(F)MRneurogramshowingabnormalenhancementofthemarkedlyenlargedposteriorcord(whiteasterisk),andthickenedlateral(whitearrow)andmedialcords(arrowhead). Fig.2.A:Microscopichaematoxylinandeosin(H&E)stainedpathologicalsectionoftheresectedneuraltissueseenat10xmagnicationshowingfungalinoftheperineurium(staineddarkred/pinkandhighlightedwithblackarrows)ofanerve(blackasterisk).B:PathologicalH&EstainedsectionasshowninA,viewedat20xmagnicationshowingthebroad,pleomorphicandpauci-septateorganisms(blackarrows)inltratingtheperineuriumofanerve(blackasterisk).A.S.Jack,etal. DeclarationofCompetingInterestTheauthorsdeclarethattheyhavenoknowncompetinginterestsorpersonalrelationshipsthatcouldhaveappearedtoinencetheworkreportedinthispaper.FundingdisclosureAppendixA.SupplementarydataSupplementarydatatothisarticlecanbefoundonlineat[1]G.Petrikkos,A.Skiada,O.Lortholary,etal.,Epidemiologyandclinicalmanifestationsofmucormycosis,Clin.Infect.Dis.54(Suppl1)(2012)S23[2]J.L.Frater,G.S.Hall,G.W.Procop,Histologicfeaturesofzygomycosis:emphasisonperineuralinvasionandfungalmorphology,Arch.Pathol.Lab.Med.125(2001)https://doi.org/10.1043/0003-9985(2001)อต&#x:HFO;&#xZ000;125125H.Levy,H.Sacho,C.Feldman,etal.,PulmonarymucormycosispresentingwithHorner'ssyndrome.Reportofamedicalcure,S.Afr.Med.J.70(1986)363363F.M.McLean,L.E.Ginsberg,C.A.Stanton,Perineuralspreadofrhinocerebralmu-cormycosis,AJNRAm.J.Neuroradiol.17(1996)114[5]S.Orguc,A.V.Yuceturk,M.A.Demir,etal.,Rhinocerebralmucormycosis:peri-neuralspreadviathetrigeminalnerve,J.Clin.Neurosci.12(2005)484[6]F.H.Stefani,P.Mehraein,Acuterhino-orbito-cerebralmucormycosis,Ophthalmologica172(1976)38[7]G.Petrikkos,C.Tsioutis,RecentAdvancesinthePathogenesisofMucormycoses,Clin.Ther.40(2018)894[8]M.M.Roden,T.E.Zaoutis,W.L.Buchanan,etal.,Epidemiologyandoutcomeofzygomycosis:areviewof929reportedcases,Clin.Infect.Dis.41(2005)634[9]D.Farmakiotis,D.P.Kontoyiannis,Mucormycoses,Infect.Dis.Clin.NorthAm.30(2016)143[10]M.I.A.Hassan,K.Voigt,Pathogenicitypatternsofmucormycosis:epidemiology,interactionwithimmunecellsandvirulencefactors,Med.Mycol.57(2019)A.S.Jack,etal.