www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Gadolinium-enhanced
MRI
reveals
dynamic
development
of
endolymphatic
hydrops
in
Ménière’s
disease
夽
Xuanyi
Li
a,b,1,
Qianru
Wu
a,1,
Yan
Sha
c,
Chunfu
Dai
a,∗,
Ru
Zhang
daNationalHealthCommissionKeyLaboratoryofHearingMedicine(FudanUniversity),DepartmentofOtologyandSkullBase Surgery,Shanghai,China
bHospitalofXuzhouMedicalUniversity,DepartmentofOtolaryngology,Xuzhou,China
cEye,Ear,NoseandThroatHospital,FudanUniversityDepartmentofRadiologyShanghai,Shanghai,China dShanghaiEastHospital,DepartmentofOtorhinolaryngologyShanghai,Shanghai,China
Received21August2018;accepted24October2018 Availableonline20December2018
KEYWORDS Endolymphatic hydrops; Menieredisease; Magneticresonance imaging; Gadolinium; Injection; Intratympanic Abstract
Introduction:Meniere’s disease is associated with impaired hearing, tinnitus, vertigo, and auralfullness.Manyanatomicalstudieshavesuggestedidiopathicendolymphatichydrops as thepathologicalbasisofMeniere’sdisease,whichnowcanbevisualizedbyusinggadolinium -enhancedmagneticresonanceimagingoftheinnerear.
Objective: ToinvestigatethedevelopmentofendolymphatichydropsinMeniere’sdiseaseby monitoringthevestibulesandcochleaeofaffectedpatients.
Methods:Innerearsof178patientswithdefiniteunilateralMeniere’sdiseasediagnosiswere visualized by 3-dimensional fluid-attenuated inversion recovery andthree-dimensional real inversion recoverymagnetic resonanceimagingfollowing bilateralgadolinium intratympanic injection.Thescanswereusedtoevaluatethepresenceanddegreeofendolymphatichydrops inthevestibulesandcochlearstructures,includingthecochlearapicalturn,thecochlear mid-dleturn,andthecochlearbasalturn.Thecorrelationofendolymphatichydropsoccurrence betweenthevariouspartsoftheinnerearwasdetermined.
Results:Symptomatic endolymphatic hydrops was detected on the affected side in all patients, whereas asymptomatic endolymphatic hydrops was detected on the unaf-fected contra-lateral side in 32 patients (18.0%). On the affected side, the cochlear apical turn and the cochlear middle turn demonstrated significantly higher rates of endolymphatic hydrops than the cochlear basal turn and the vestibule. The sever-ity of endolymphatic hydrops gradually decreased from the cochlear apical turn to the cochlear basal turn. On the contra lateral side, the incidence and degree
夽 Pleasecitethisarticleas:LiX,WuQ,ShaY,DaiC,ZhangR.Gadolinium-enhancedMRIrevealsdynamicdevelopmentofendolymphatic
hydropsinMénière’sdisease.BrazJOtorhinolaryngol.2020;86:165---73.
∗Correspondingauthor.
E-mail:cfdai66@126.com(C.Dai).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologia1XuanyiLiandeQianruCirurgiaWuCérvico-Facial.areco-firstauthors. https://doi.org/10.1016/j.bjorl.2018.10.014
1808-8694/©2018Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
ofthedetectedasymptomaticendolymphatichydropsweresignificantlygreaterinthecochleae thaninthevestibules(p<0.05),withnosignificantdifferencedetectedbetweenthecochlear turns.
Conclusion:Progressionofendolymphatichydropsappears tobedirectional,initiatedinthe cochlea.Theorderofendolymphatichydropsseveritygraduallydecreasesfromthecochlear apicalturntothecochlearbasalturnandthentothevestibule.Endolymphatichydropsinthe vestibuleisassociatedwithsymptomaticMeniere’sdisease.
© 2018 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE Hidropsia
endolinfática; Doenc¸adeMénière; Imagemde ressonância magnética; Gadolínio; Injec¸ão; Intratimpânica
Ressonânciamagnéticacomgadolíniorevelaodesenvolvimentodinâmicoda hidropsiaendolinfáticanadoenc¸adeMénière
Resumo
Introduc¸ão:A doenc¸adeMénièreestáassociadaadeficiênciaauditiva,zumbido,vertigeme plenitudeauricular.Muitosestudosanatômicossugeremhidropsiaendolinfáticaidiopáticacomo abasepatológicadadoenc¸a,queagorapodeservisualizadaatravésdeestudoporimagemda orelhainternaporressonânciamagnéticacomgadolínio.
Objetivo:Investigarodesenvolvimentodahidropsiaendolinfáticanadoenc¸adeMénièrecom monitoramentodosvestíbulosedascócleasdospacientesafetados.
Métodos: Orelhasinternasde178pacientescomdiagnósticodefinitivodedoenc¸adeMénière unilateral foramvisualizados atravésde imagem derecuperac¸ão deinversão atenuada por fluidosemressonânciamagnéticatridimensional,3-DFLAIR,eporinversãorealapósinjec¸ão intratimpânicabilateraldegadolínio.Osexamesforamusadosparaavaliarapresenc¸aeograu dehidropsiaendolinfáticanosvestíbulosenasestruturascocleares,inclusive ogirococlear apical,ogirococlearmédioeogirococlearbasal.A correlac¸ãodaocorrênciadehidropsia endolinfáticaentreasváriaspartesdaorelhainternafoideterminada.
Resultados: Hidropsia endolinfáticasintomática foi detectadano lado afetadoem todos os pacientes,enquantohidropsiaendolinfáticaassintomáticafoidetectadanoladocontralateral nãoafetadoem32pacientes(18,0%).Noladoafetado,ogiroapicaldacócleaeogirococlear médiodemonstraramtaxassignificativamentemaisaltasdehidropsiaendolinfáticadoqueo girobasaleovestíbulo.Agravidadedahidropsiaendolinfáticadiminuiugradualmentedogiro apicaldacócleaparaogirobasal.Noladocontralateral,aincidênciaeograudahidropsia endolinfáticaassintomáticadetectadaforamsignificantementemaioresnascócleasdoquenos vestíbulos(p<0,05),semdiferenc¸asignificanteentreosgiroscocleares.
Conclusões:A progressão da hidropsia endolinfática parece ser direcional, iniciando-se na cóclea.Asuaordemdagravidadediminuigradualmentedogiroapicaldacócleaparaogiro basale,emseguida,paraovestíbulo.Ahidropsiaendolinfáticanovestíbuloestáassociadaà doenc¸adeMénièresintomática.
© 2018 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Meniere’s disease (MD), first reported in 1861 by Pros-perMénière,isassociatedwithimpairedhearing,tinnitus, vertigo,andauralfullness.1Thesyndromeiscausedby
dis-turbances in the homeostasis of the inner ear, resulting in impaired cochlear and vestibular functions. Since the firstreportsofendolymphatichydrops(EH)inthetemporal bonesofpatientswithMD,manyanatomicalstudies, lack-ingidentification of causal abnormalities, have suggested idiopathicEHasthepathologicalbasisofMD.2---5Various
fac-tors,including viralinfections,6,7 autoimmune disorders8,9
andendocrinemalfunctions,10havebeenassociatedwithEH
development.However,some studies have suggested that EHisnotadirectetiologicalfactorinthedevelopmentof MDandtheemergenceofMDsymptoms.11,12Investigations
of the role of EH in MD are still hampered by a limited understandingofEHdevelopmentinvivo.
The current gold standard for EH detection is autopsy analysis of temporal bones, which generally detects developed EH and fails to analyze the progression of EH. Nakashima etal.13 firstvisualized the endolymphatic
space in living patients using Gadolinium (Gd)-enhanced 3-Dimensional Fluid-Attenuated Inversion Recovery
(3D-FLAIR) magnetic resonance imaging (MRI) of the innerear.Sincethen,3D-FLAIRMRIand3-Dimensionalreal Inversion Recovery (3D-real IR) MRI have been commonly usedforEHanalysis.14,15Humanandanimalstudiesrevealed
that3D-realIRimagingprovidesmoreclearandconsistent histopathological observations than 3D-FLAIR imaging.15,16
However, 3D-FLAIR imaging outperforms 3D-real IR under conditionsofinsufficientGddeliveryintotheperilymphatic spacefollowinganintratympanicinjection.16
ThisstudyutilizedGd-enhancedinnerearMRIto investi-gatethedevelopmentofEHinpatientswithMD.Specifically, 3D-FLAIR and 3D-real IR MRI scans were used to analyze theoccurrenceanddegreeofEHinthevestibuleandeach cochlearturnoftheinnerearsofMDpatients.
Patients
and
methods
Patients
This study evaluated 178 patients (110 males and 68 females) with definite unilateral MD diagnosis according to the 1995 American Academy of Otolaryngology-Head and Neck Surgery guidelines.17 Median patient age was
52 years (23---74 years),and median MDduration was 3.7 years(2months,20years).Theenrollmentcriteriaforthe presentstudywere:unilateraldisease,twoormore defini-tiveepisodesofvertigowithhearingloss,tinnitus,oraural fullness and nohistory of middle earor neurological dis-orders. All individuals complained of hearing loss on the affected side. All patients were diagnosed by the corre-spondingauthorintheDepartmentofOtologyandSkullBase SurgeryoftheEye,Ear,NoseandThroatHospitalatFudan UniversitybetweenJuly2013andMay2017.MDstagewas determinedbasedontheworstaudiograminthe6months prior toMRIscanning, usingthe pure-toneaverage calcu-latedatthethresholdsof0.5,1,2,and3kHz.17
Thestudywasapprovedbythemedicalethicscommittee oftheEye,Ear,NoseandThroatHospitalatFudanUniversity (2014007),andallpatientssignedinformedconsentforms.
MRI
Thepatientsreceivedbilateralintratympanicinjectionsof Gddilutedinsaline(v/v1:7)usinga22gaugespinalneedle anda 1mLsyringe.Gadopentetate dimegluminewas cho-sen in this research as the Gd contrast agent. Following the injections, thepatients maintained an upright seated position for 30min without speaking or swallowing. After 24h MRIscanswereperformed usinga3TMR unit(Verio,
SiemensHealthcare,Erlangen,Germany)witha32channel phased-arrayreceive-onlyheadcoil.
T2-space,3D-realIR,and3D-FLAIRsequenceMRIimages werecollectedaspreviouslydescribed.14Briefly,the
param-etersforthe3D-realIRsequencewereasfollows:voxelsize of0.4×0.4×0.8mm,scantimeof14min,repetitiontime (TR)of9000ms,echotime(TE)of181ms,inversiontime(TI) of1730ms,slicethicknessof0.80mm,fieldofview(FOV) of160×160mm,andmatrixsizeof3300×918.The param-etersfor3D-FLAIRsequencewereasfollows:voxelsizeof 0.7×0.7×0.6mm, scantimeof 6min, TRof 6000ms,TE of387ms,TIof2100ms,slice thicknessof 0.60mm, echo trainlengthof173,FOVof220×220mm,andmatrixsizeof 1701×810.
Imageevaluation
Afterintratympanic injection,Gdpermeatesintothe per-ilymph through the oval and round windows to the inner ear.Therefore,perilymphaticspacewithaccumulatedGdis detectableasacontrast-enhancedsignal,whereas endolym-phaticspacedemonstratesanegativesignal.Analysisofthe boundarybetweentheperilymphaticandtheendolymphatic spacesfacilitatesdetectionofEH,evidencedasanenlarged negativesignalexpandingintothepositivesignalofthe per-ilymphaticspaceconfinedtothebonylabyrinth.
An experienced radiologist, withno information about theclinicaldiagnosis,assessedtheMRIscansforEHdegree asnone, mild, or significant according tothe three-stage grading criteria18 (Table 1). Adobe Photoshop CS5 (Adobe
Systems,Inc.,SanJose, CA)wasutilizedtocalculate the ratio of the endolymphatic space to the vestibular fluid space.
Statisticalanalysis
Statistical analysis was performed using SPSS 20.0 (IBM, Armonk, NY). McNemar’s test, Wilcoxon matched-pairs signed-rankstest,andSpearman’srankcorrelationtestwere usedtoanalyzethedata.The levelofsignificancewasset atp<0.05.
Results
DetectionofEH
Cochleae and vestibules were detectable on MRI scans obtained24hfollowingbilateralintratympanicinjectionsof
Table1 Three-stagegradingofendolymphatichydropsusingmagneticresonanceimaging.
Hydropsstage Vestibulea Cochlea
None Arearatio≤1/3 NodisplacementofReissner’smembrane.
Mild 1/3<Arearatio<1/2 DisplacementofReissner’smembrane,withendolymphatic
spaceareanotexceedingscalavestibulearea.
Significant Arearatio>1/2 Endolymphaticspaceareaexceedsscalavestibulearea.
a Theratiooftheareaoftheendolymphaticspacetotheareaofthevestibularfluidspace(sumoftheareasoftheendolymphatic andtheperilymphaticspaces).
Right Symptomatic EH Asymptomatic EH in CAT & CMT in cochlea in vestibule Saccule Utricle Left
A
B
C
D
Figure1 Bilateralendolymphatichydrops(EH)wasdetectedinapatientdiagnosedwithleftunilateralMeniere’sdisease(MD). Three-dimensionalfluid-attenuatedinversionrecovery(3D-FLAIR)(A,B)andthree-dimensionalrealinversionrecovery(3D-realIR) (C,D) magneticresonanceimaging(MRI)wasperformed24hoursfollowingabilateralintratympanicgadolinium (Gd)injection. 3D-FLAIRMRIshowedbilateralperilymphaticspacepermeatedwithGd(A,B).EHwaspresentinbilateralcochleae(C,D)andthe leftvestibule(A,C),butabsentintherightvestibule(B,C,D).SymptomaticEHwaspresentinallturnsofleftcochlea,while asymptomaticEHwasonlypresentinapicalandmiddleturn(CAT&CMT)(C,D).ThedegreeofsymptomaticEHintheleftcochlea (affectedside)was greaterthanthatoftheasymptomaticEHintherightcochlea(unaffectedside) (C,D).SignificantEH was observedintheleftvestibule,inwhichtheboundarybetweenthesacculeandtheutriclecouldnotbedetectable(C).Thesaccule andutriclecouldbedetectedrespectivelyintherightvestibule,inwhichnoEHwaspresent(C).
thecontrastagent.3D-FLAIRand3D-realIRsequenceswere usedforthedetectionandevaluationofEHinthevestibules andcochlearstructures,includingtheCochlearApicalTurn (CAT), the Cochlear MiddleTurn (CMT), andthe Cochlear Basal Turn (CBT) of the MD patients (Fig. 1). Among the 178 patients diagnosed with unilateral MD, asymptomatic EHwasdetectedinthecontralateralunaffectedinnerear of32patients(18.0%)
EHcommonlyoccurredinallanalyzedanatomical struc-turesinthe affectedinner ears(Table2). Specifically,EH wasdetected in CATs, CMTs, CBTs, and vestibules on the affectedsidein97.2%,97.2%,94.9%,and95.5%ofthe178 patients,respectively.Amongthe32unilateralpatientsof MDwithbilateralEH,incontrast,theasymptomaticEHon theasymptmaticsidewasdetectedin96.9%,96.9%,90.6%, and31.3%ofCATs,CMTs,CBTsandvestibules,respectively (Table3).
Onbothsides,theprevalenceofEHintheCATwassimilar withthatin theCMT(p=1.000).On theaffectedside,EH occurredmorefrequentlyin theCAT andtheCMT thanin thevestibuleor theCBT(McNemar’stest,p<0.05).There wasnostatisticalsignificanceintheratesofEHdetection betweenthevestibulesandtheCBTs(Table2).
Onthecontra-lateralunaffectedside,asymptomaticEH wassignificantlyless commoninthevestibulethanin the cochlea (Table 3) (vestibule vs. CAT, vestibule vs. CMT, vestibule vs. CBT, p=0.000). No significant differences in EHratesweredetectedbetweenthecochlearturns. More-over,vestibularEHwasdetectedatsignificantlyhigherrates ontheaffectedside(95.5%)thanonthecontralateralside (31.3%).
DegreeofEH
To examine the relationship between disease progression anddegree of EH(Table1), weclassified theMDstage of eachpatientaccordingtopuretonethresholdcalculations. Thus,eightpatientswereclassifiedasStage1,20patientsas Stage2,109patientsasStage3,and41patientsasStage4. Consideringthesmallnumberofindividualswithearlystage MD,wecombinedStages1and2fortheanalysis.In addi-tion,weperformedseparateanalysesforthesymptomatic andthecontralateralasymptomaticsidesofthe32patients withbilateralMD.
Table2 Endolymphatichydrops(EH)invariouspartsofthesymptomaticinnerearsof178patientswithunilateralMénière’s disease.
Vestibule+ Vestibule− Total CAT+ CAT− Total
CAT+ 165(92.7%) 8(4.5%) 173(97.2%) CAT− 5(2.8%) 0(0.0%) 5(2.8%) Total 170(95.5%) 8(4.5%) 178(100%)a CMT+ 165(92.7%) 8(4.5%) 173(97.2%) 173(97.2%) 0(0.0%) 173(97.2%) CMT− 5(2.8%) 0(0.0%) 5(2.8%) 0(0.0%) 5(2.8%) 5(2.8%) Total 170(95.5%) 8(4.5%) 178(100%)a 173(97.2%) 5(2.8%) 178(100%)c CBT+ 162(91.0%) 7(3.9%) 169(94.9%) 168(94.4%) 1(0.6%) 169(94.9%) CBT− 8(4.5%) 1(0.6%) 9(5.1%) 5(2.8%) 4(2.2%) 9(5.1%) Total 170(95.5%) 8(4.5%) 178(100%)b 173(97.2%) 5(2.8%) 178(100%)a
CAT,Cochlearapicalturn;CMT,Cochlearmiddleturn;CBT,Cochlearbasalturn;+,representsdetectionofEHinindicatedstructure;−, representsabsenceofEHinindicatedstructure.
a CATvs.Vest,CMTvs.Vest,CBTvs.CAT,p=0.000. b CBTvs.Vest,p=0.188.
c CMTvs.CAT,p=1.000.
Table3 Endolymphatichydrops(EH)invariouspartsofthecontra-lateralasymptomaticearsof32patients withbilateral Ménière’sdisease.
Vestibule+ Vestibule− Total CAT+ CAT− Total
CAT+ 9(28.1%) 22(68.8%) 31(96.9%) CAT− 1(3.1%) 0(0.0%) 1(3.1%) Total 10(31.3%) 22(68.8%) 32(100%)a CMT+ 9(28.1%) 22(68.8%) 31(96.9%) 31(96.9%) 0(0.0%) 31(96.9%) CMT− 1(3.1%) 0(0.0%) 1(3.1%) 0(0.0%) 1(3.1%) 1(3.1%) Total 10(31.3%) 22(68.8%) 32(100%)a 31(96.9%) 1(3.1%) 32(100%)c CBT+ 7(21.9%) 22(68.8%) 29(90.6%) 29(90.6%) 0(0.0%) 29(90.6%) CBT− 3(9.4%) 0(0.0%) 3(9.4%) 2(6.3%) 1(3.1%) 3(9.4%) Total 10(31.3%) 22(68.8%) 32(100%)a 31(96.9%) 1(3.1%) 32(100%)b
CAT,Cochlearapicalturn;CMT,Cochlearmiddleturn;CBT,Cochlearbasalturn;+,representsdetectionofEHinindicatedstructure;−, representsabsenceofEHinindicatedstructure.
a CATvs.Vest,CMTvs.Vest,CBTvs.Vest,p=0.000. b CBTvs.CAT,p=0.125.
c CMTvs.CAT,p=1.000.
In patients withbilateralEH, thecochleaeof the con-tralateralasymptomatic sidesdemonstrated thepresence ofpredominantlymildEH,withverylowratesofsignificant EHdetected(Fig.2A).Thevestibulesoftheasymptomatic sideswere predominantly freeof detectable EH, withno significant EH observed. Thus, although nodifferences in EHdegreeweredetectedbetweenthecochlearturns,the EHdegree profilesof thevestibulesandthecochlea were significantlydifferent(Table4).
Incontrasttotheasymptomaticcontralateralsides,the symptomaticsidesofearlystageMDdemonstrated substan-tial rates of both mild and significant EHin the vestibule (Fig.2B).Inaddition,symptomaticearsalsodemonstrated less differences in EH degree profiles of the cochlear turns and the vestibules than did the asymptomatic ears (Fig.2A---D)(Table4).TheprogressionofMDfromStage1to Stage4correspondedwithincreasingseverityofEHineach partoftheinnerear(Fig.2B---D).ForallclassifiedMDstages, significantEHwastheleastcommonintheCBTrelativeto theothercochlearturns(Fig.2A---D).However,patientswith Stage4MDexhibitedsignificantEHinallpartsoftheinner
ear,withnosignificantdifferencesdetectedamonganytwo parts(Fig.2D)(Table4).Inaddition,weconfirmedthatthe degree ofsymptomatic EH ontheaffected side of the32 patientswithbilateral EHwasnotoverall milderand was similartothesymptomatic EH ontheaffected sideof all 178patients.
ThecorrelationofEHoccurrence
Onthesymptomaticsideofthepatientsdiagnosedwith uni-lateralMD,asignificant correlation of EHoccurrence was observedbetweenanytwopartsoftheinnerear.The corre-lationbetweenthedifferentcochlearturnswashigherthan that between the vestibuleand the cochlea. The highest coefficient wasobservedfor thecomparisonbetween the CATandtheCMT.Onthecontra-lateralasymptomaticside ofthe32patientswithbilateralEHdetectedinthisstudy, the correlation of asymptomatic EH among the cochlear turnswas consistent withthat observed for the affected side.Specifically,thecorrelationbetweentheCATandthe
100
A
D
E
B
C
80 60 40 20 0 CAT CMT CBT P ercentage (100%)unaffected side of 32 patients with bilateral EH
affected side of 32 patients with bilateral EH
stage 1 and stage 2 stage 3
significant mild none stage 4 P ercentage (100%) P ercentage (100%) P ercentage (100%) P ercentage (100%) Vest
CAT CMT CBT Vest CAT CMT CBT Vest
CAT CMT CBT Vest CAT CMT CBT Vest
100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0
Figure2 Percentdistributionofendolymphatichydrops(EH)degreesindifferentgroupsclassifiedaccordingtoMeniere’sdisease (MD)stagesandlateralsymptoms.(A)AsymptomaticEHoncontra-lateralunaffectedsideof32patientswithbilateralEH.(B)EH ontheaffectedsideof28patientswithStage1andStage2MD.(C)EHontheaffectedsideof109patientswithStage3MD.(D)EH ontheaffectedsideof41patientswithStage4MD.(E)EHontheaffectedsideof32patientswithbilateralEH.EHwasclassified asundetectable(none),mild,orsignificant.DataarepresentedaspercentagesofEHdetectedatacertaindegree.CAT,Cochlear apicalturn;CMT,Cochlearmiddleturn;CBT,Cochlearbasalturn;Vest,Vestibule.
Table4 ComparisonofendolymphatichydropsdegreeatdifferentMénière’sdiseasestages(p-value).
Anatomicalstructure Asymptomaticcontra-lateralEH Stage1+2 Stage3 Stage4
n=32 n=28 n=109 n=41 CATvs.CMT 0.317 1.000 0.083 0.317 CATvs.CBT 0.180 0.059 0.000a 0.059 CATvsVest 0.000a 0.978 0.234 0.317 CMTvs.CBT 0.157 0.059 0.000a 0.102 CMTvs.Vest 0.000a 0.978 0.499 0.527 CBTvs.Vest 0.000a 0.197 0.009a 0.593
CAT,Cochlearapicalturn;CMT,Cochlearmiddleturn;CBT,Cochlearbasalturn;Vest,Vestibule. ap<0.05.
CMTwasgreaterthanthat betweentheCMT andtheCBT (Spearman’s rank correlation test, p<0.05). On the con-trary,nosignificantcorrelation betweenthevestibuleand anyofthecochlear turnswasdetected ontheunaffected side(Table5).
Discussion
MD is associated with recurrent episodic vertigo, tinni-tus, aural fullness, and fluctuating hearing loss.19 It is
Table5 Correlationbetweenendolymphatichydrops(EH)occurrenceinthevestibulesandcochlearturns. SymptomaticsideofMD
patients(n=178)
Contra-lateralasymptomaticsideof patientswithbilateralEH(n=32)
CAT CMT CBT Vest CAT CMT CBT Vest
CAT 1 0.949a 0.674a 0.447a 1 0.903a 0.628a 0.234
CMT 1 0.686a 0.424a 1 0.863a 0.155
CBT 1 0.442a 1 −0.065
Vest 1 1
MD,Ménière’sdisease;CAT,Cochlearapicalturn;CMT,Cochlearmiddleturn;CBT,Cochlearbasalturn;Vest,Vestibule. a p<0.01
by endolymphatic hydrops, or a distended endolymphatic space,whichisdetectableintemporalbonesuponautopsy analysis. Animal models have been used to explore the mechanismsunderlyingMDandEH.20,21 However,evidence
regarding the role of EH as a causative factor of MD or an epiphenomenon during MD progression has remained inconclusive.22 Toourknowledge,theinvivodevelopment
ofEHinMDpatientsremainspoorlyunderstood.Temporal boneautopsy,consideredagoldstandardforthedetection ofEH,cannotbeusedtomonitorthepathogeneticprocess ortocontrolforsuchvariablesasdiseaseonset.
By enabling the visualization ofthe boundarybetween theendolymphaticandperilymphaticspaces,MRIscanning followingintratympanic orintravenous Gdinjection facili-tatesthedetectionofEHinlivingpatients.23---25Inthisstudy,
weperformedGd-enhancedMRItovisualizeoccurrenceand degreeofEHindifferentpartsofinnerear,andalsorelated thestagesofpatientswiththeseverityofEHtoanalyzeand deducethedynamicdevelopmentofEHinpopulation.
All178patientswithdefiniteunilateralMDtestedinthis studyhadEHinthevestibuleorthecochleaoftheaffected symptomatic ear. Asymptomatic EH was also detected in the contralateral unaffected ears of 32 patients. Asymp-tomaticEHappearedmorefrequentlyinthecochleaethan inthe vestibules.Previousstudies utilizingtemporalbone autopsyortemporalboneGd-enhanced MRIhavesimilarly reportedasymptomaticEH.Followingtemporalbone analy-sisinchildren,BachorandKarmody26reportedlowratesof
sacculeandutricledilationbuthighincidenceofbulgingin thecochlearduct,with65.6%occurringintheapicalturn. Recentstudieshavealsoreportedasymptomatic EHinthe vestibulesandcochleaeofunaffectedears,thoughatrates differentfromthoseobservedinourstudy.25,27 These
stud-ies have suggested that bilateral EH does not necessarily correlatewithclinicalsignsofMDonbothsides. Evidence ofasymptomaticEHhasbeenusedtosupporttheviewthat EHis afeature,ratherthana cause,ofMD.11,12 However,
thedetectionof EHviatemporalbone autopsyin100%of patientswithahistoryofMDsupportsthehypothesis that EHcausesMD.22
Thus,wesoughttoinvestigatetherelationshipbetween EH and the symptoms of MD. Our results emphasized the differences between EH in the symptomatic ear and the contralateral asymptomatic ear. Although cochlear EH was prevalent on both sides, differences in EH rates between the cochlea and the vestibule were more
substantialontheasymptomaticsidethanontheaffected side. Asymptomatic EH was detected in 31.3% of the vestibules on the unaffected side, whereas 95.5% of the symptomatic side vestibules exhibited signs of EH. The degree ofEH wasalsosignificantly differentbetween the twosides. The degreeof asymptomaticEHonthe contra-ateralsidewasmuchmilderthanthatofthesymptomatic EHontheaffectedside.Inparticular,thedifferenceinEH degree in the vestibules of asymptomatic ears and those of symptomatic early-stage MD earsunderscored therole ofvestibularEHinthe clinicalsymptomsof MD.Based on theanalysisabove,presenceofEHinanypartofinnerear, especiallyincochlearturns,wasnotnecessaryforonsetof MDsymptoms,soEHshouldbeidentifiedasthe pathologi-calbasisofMD,insteadofthecausalanddefinitivefactor. However,as the severity of EH in vestibule progressively worsened,potentiallyinconjunctionwithotherfactors,the onsetof MD symptoms was more likelyto occur.21,28 This
resultwasmuchconsistentwithYoshidaTetal.,29in2018.
YoshidaTreportedthat EHwaspresent in thecochlea of 45/52affectedearsofpatientswithMD(87%)andin16/42 controlearswhichwerenotassociatedwithMD(38%). How-ever,inthevestibule,symptomaticEHwaspresentin49/52 affectedears (94%) and asymptomatic EHin 3/42 control ears(7%). Consequently, YoshidaT et al.,regarded EH in thevestibuleasamorespecificpredictorofdefiniteMDthan EHin thecochlea.Similarly,theresultsinthismanuscript wouldalsoemphasizetheimportanceofEHinvestibuleto theonsetofMDsymptoms,especiallytheseverityofEHin vestibule.
AsforthesusceptibilityofEH,ourobservationsrevealed that, on both sides, EH occurred more commonly and at a higher degree of severity in the cochlea, especially in theapicalturn,thaninthevestibule.Thisresultis consis-tentwiththetemporalboneautopsyfindingsofOkunoand Sando,demonstratingthatEHismorecommonlyobserved intheparsinferior(cochlea andsaccule)than inthepars superior(utricle andsemicircular canals) of thetemporal bone.30AstothehighersusceptibilityofEHincochlea,we
couldreferit tothedistributionof darkcells intheinner ear.KimuraRS31reportedthatdarkcellsinthevestibuleare
mainlylocalizedintheampullae,utricleandcommoncrus, whichwasnotdetectedinthesaccule,saccularduct,ductus reuniensandmainpartsofthecanalsbythecombineduse ofmacroscopicobservations,lightmicroscopyandelectron microscopy.Duetothecharacteristicsofthedistributionof
vestibulardarkcells, andthemorphology and functionof Bast’svalve,theendolymphinhesacculeshouldbe gener-atedmostlikelyfromthedarkcellsofthestriavascularisin cochlea.Thus,weemphasizedtheimportanceofthestria vascularisincochleainthepathogenesisofMD,whichmay produceredundantendolymph.
Multiplestudieshaveprovidedevidenceforthe suscep-tibilityoftheapicalturntosignificantEH.32,33Nagerisetal.
reportedthatvaryingdegreesofdisplacementofthe basi-larmembranetowardsthescalatympaniintheapicalturn, whichwasnotobservedinotherturnsofthecochlea,may berelatedtoatrophy of thespiral ligament.32 Valketal.
reported that, in the guinea pig, a rupture of Reissner’s membraneinresponsetodestructiveacuteendolymphatic hydropsmostoftenoccursintheapicalturnofthecochlea.33
AsforthehighersusceptibilityofsignificantEHin apexin thecochlea,wearenotsurethatitisthecauseofhearing lossinearlyMD,whichtypicallystartswithlow-frequency tones,eventhoughlow-frequencytonesareconsistentwith thelocationofthebasilarmembraneinapexturn.19
Basedonthe observedrelationships betweenMDstage andEHdistributionanddegree,weproposethatEH under-goesdynamicdevelopmentinpatientswithMD.Considering that the incidence of asymptomatic EH was much lower in thevestibule than inthe cochlea and wasvery similar between the cochlear turns, we propose that EH initially developsinthecochlea.Duringtheasymptomaticstage,EH is likelymild in both thecochlea and thevestibule.With diseaseprogression,theseverityofEHgraduallyincreases, especiallyinthevestibule,andtheclinicalsymptomsofMD becomeapparent.ConsideringtheprevalenceofEHinthe apicalandmiddleturnsofthecochleaandthehighEH cor-relationobservedforeverytwoadjacentanatomicalparts, weproposethatEHoriginatesintheCAT,withEHseverity decreasingfromtheapicaltothebasalturn,andthenfrom thecochleatothevestibule.
Limitationsshouldbenotedintheinterpretationofthis study.Althoughthisstudydemonstratedtheoccurrenceand thedistinctfeaturesofasymptomaticEHontheunaffected sideofsomeMDpatients,ithasnotassessedtheincidenceof asymptomaticEHinthegeneralpopulationandthepotential progressionofasymptomaticEHintoMD.
Conclusion
DynamicdevelopmentofEHappearstobedirectional,likely beinginitiated in the cochlea. The degree of EH severity graduallydecreasesfromtheCATtothevestibule,with sig-nificantEHmorelikelytoappearinthe CATandtheCMT. Moreover,occurrenceofEHinthevestibuleissignificantly correlatedwithsymptomaticMD.
Funding
National Natural Science Foundation of China, 81570917, 81600802,81771009.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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