The Mechanism of Hearing Loss in Paget's Disease of Bone.

0.3 MB·English

by  Monsell, Edwin M

TheLaryngoscope
LippincottWilliams&Wilkins,Inc.
©2004TheAmericanLaryngological,
RhinologicalandOtologicalSociety,Inc.
The Mechanism of Hearing Loss in Paget’s
Disease of Bone
Edwin M. Monsell, MD, PhD
Objectives/Hypothesis:Themechanismofhearing minimum diameter of the internal auditory canal of
loss(HL)inPaget’sdiseaseofbonewasinvestigated. 68temporalbonesfromsubjectswithPaget’sdisease
Thepresentstudywasasystematic,prospective,con- were found to have no statistically significant rela-
trolledsetofclinicalinvestigationstotestthehypoth- tionshiptohearingthresholds.ThePearsonproduct-
esisthatthereisageneralunderlyingmechanismof moment correlation coefficients (age- and sex-
HLinPaget’sdiseaseofboneandtogainadditional adjusted)inthegroupwithPaget’sdiseaseinvolving
insights into the auditory and otologic dynamics of thetemporalbonewere(cid:1)0.63forleftearsand(cid:1)0.73
this disease. Specific questions were 1) whether the forrightearsforhigh-frequencyairconductionpure-
mechanism is cochlear or retrocochlear and 2) tone thresholds (mean of 1, 2, and 4 kHz) versus co-
whetherthebonemineraldensityofthecochlearcap- chlearcapsuledensity.Correlationcoefficients(age-
suleisrelatedtohearinglevels.StudyDesign:Several and sex-adjusted) between cochlear capsule density
double-blinded, cross-sectional, prospective, correla- and air-bone gap (mean at 0.5 and 1 kHz) for the
tional studies were conducted in a population of el- affectedgroupwere(cid:1)0.67forleftearsand(cid:1)0.63for
derly human subjects with skull involvement with right ears. All correlations between hearing thresh-
Paget’sdiseaseversusacontrolpopulationofelderly oldsandcochlearcapsuledensityinpageticsubjects
subjects free of Paget’s disease. Demographic and were significant at P < .001. The regressions were
clinical data were recorded. Longitudinal observa- consistent throughout the ranges of hearing level.
tions were made in subjects under treatment. Meth- There were no significant correlations between co-
ods: Subjects were recruited from a Paget’s disease chlearcapsulemeandensityandhearinglevelinthe
clinic. Pure-tone auditory thresholds, word recogni- volunteer subjects. Conclusions: The evidence sup-
tion,andauditorybrainstemresponses(ABRs)were portstheexistenceofageneral,underlying,cochlear
recorded.Thedimensionsoftheinternalauditoryca- mechanismofpageticHLthatiscloselyrelatedtoloss
nals were measured using computed tomographic ofbonemineraldensityinthecochlearcapsule.This
(CT)imagesanddigitalimageanalysis.Theprecision, mechanismaccountswellforboththehigh-frequency
accuracy, and temporal stability of methods to mea- sensorineuralHLandtheair-bonegap.Earlyidenti-
surethebonemineraldensityofthecochlearcapsule fication,radiographicdiagnosisoftemporalbonein-
and an adjacent area of nonotic capsule bone were volvement, and vigorous treatment with third-
validated and applied. Correlations were sought be- generationbisphosponatesareimportanttolimitthe
tweenhearinglevelsandcochlearcapsulebonemin- development and progression of pagetic HL. Key
eraldensity.Results:ABRswererecordedin64ears Words: Sensorineuralhearingloss,conductivehear-
with radiographically confirmed Paget’s disease in- ingloss,presbycusis,Paget’sdiseaseofbone,quanti-
volving the skull. Responses were absent in eight tative CT, bone mineral density, auditory evoked
ears,allofwhichhadelevatedhighpure-tonethresh- potentials.
olds. ABRs were interpreted as normal in 56 ears; Laryngoscope,114:598–606,2004
none were abnormal. The mid-length diameter and
INTRODUCTION
Paget’s disease is a disorder of osteoclasts. Its etiol-
Winnerofthe2003MosherAward.
ogyisunknown.Thereisevidenceoftheinvolvementofa
FromtheDepartmentofOtolaryngology–HeadandNeckSurgery,
WayneStateUniversitySchoolofMedicine,Detroit,MI,U.S.A. paramyxovirus1 and genetic factors.2 Pagetic osteoclasts
ThisworkwassupportedbytheNationalInstitutesofHealth,RO1- are larger, and they are more active resorbers of bone by
AR40554 awarded to Henry G. Bone, MD, then at Henry Ford Health
an order of magnitude or more. Progressively enlarging
System,bytheFundforHenryFordHospital,andbyagrantfromthe
PagetFoundation. lytic lesions are formed. Osteoblasts react to the acceler-
Editor’sNote:ThisManuscriptwasacceptedforpublicationNovem- atedosteolysisofpageticosteoclastsbyformingnewbone
ber10,2003. at a greatly accelerated rate. Often, this bone is poorly
SendCorrespondencetoDr.EdwinM.Monsell,DepartmentofOto-
lamellated.Whentherateofboneresorptioniscontrolled
laryngology–HeadandNeckSurgery,WayneStateUniversitySchoolof
Medicine,4201St.Antoine5E-UHC,Detroit,MI48201,U.S.A. by medication, the rate of bone formation is gradually
Laryngoscope114:April2004 Monsell:HearingLossinPaget’sDiseaseofBone
598
reduced. Lytic areas are at least partially repaired, and the auditory nerve would account for hearing levels in
thenewboneformedhasanormallamellarappearance.3 subjectswithPaget’sdiseaseoftheskull.
AbibliographyonPaget’sdiseaseforhealthprofessionals Precise, accurate, stable techniques of quantitative
ismaintainedbytheNationalInstitutesofHealthOsteo- CT(QCT)havebeenusedtomeasurethemineraldensity
porosis and Related Bone Diseases National Resource ofhumanboneinvivo.Forthisstudy,aQCTmethodwas
Centerathttp://www.osteo.org/research.asp. developed and validated to measure the bone mineral
Hearing loss (HL) is a prominent feature of Paget’s densityofsmallvolumesofboneintheskull,specifically
disease of bone when the skull is involved.4–7 In auditory thecochlearcapsule.SubjectswithPaget’sdiseaseinvolv-
studies,themajorityofpatientswerefoundtohaveahigh- ing the temporal bone were scanned. Correlations were
frequency sensorineural HL and a low frequency air-bone sought between density values versus hearing levels. If
gap.5,6,8ThemechanismofHLisnotwellunderstood. statistically significant correlations were found, the hy-
Because of the lack of an animal model for Paget’s pothesiswouldbesupported.
disease of bone, studies of the mechanisms of HL are
limited to postmortem studies and in vivo clinical inves-
METHODS
tigations. Before 1990, efforts to understand the mecha-
nism of HL in many otologic disorders, including Paget’s Experimental Subjects
diseaseofbone,werelimitedtodescriptivehistopathologic Allsubjectsinthisstudygaveinformedconsentaccordingto
studies, usually of a small numbers of cases as they be- proceduresoftheinstitutionalreviewboard(HumanRightsCom-
mittee)andtheprinciplesoftheDeclarationofHelsinki.Forty-
came available for study. The histopathologic findings in
two subjects with Paget’s disease of the skull were evaluated
human temporal bones with Paget’s disease have now
duringthetermofthestudy.ThediagnosisofPaget’sdiseasewas
beendescribedinmorethan50cases,includingsomewith
established using standard clinical criteria, including medical
audiometricdata.7,9,10Severalmechanismsforthesenso-
history, physical examination, laboratory tests, and radiologic
rineural HL were suggested in these studies, including studiesbyanendocrinologistsubspecializinginboneandmineral
compressionoftheauditorynerve11orvascularshunts.7It diseases. The diagnosis was confirmed by clinical evaluation of
wassuggestedthattheair-bonegapmaybecausedbystiff- CTscansbyaneuroradiologist.Thedurationofdisease,severity
nesschangesinthesofttissueelementsofthemiddleear.7 ofdisease,anddegreeofcochlearinvolvementvariedwidely.
Epitympanic spurs and proliferation of fibrous tissue adja- A priori exclusion criteria included systemic bone disease,
centtotheossicleshaveoccasionallybeendemonstrated.5,12 priormiddleearsurgery,andknownextraneouscausesofHL(oto-
In a differing analysis, Khetarpal and Schuknecht9 sclerosis,chronicotitis,classicMenie`re’sdisease,andmastoiditis).
Subjectswithdiabetes,mildhypothyroidismcorrectedbyhormone
were unable to demonstrate histopathologic correlates of
replacement,orwithhistoriesofnoiseexposurewerenotexcluded.
HL in a thorough study of 26 temporal bones. Most re-
Thirty-seven subjects with Paget’s disease involving the
markablewasthefindingthatevenincasesofsevereHL,
skullwererecruitedforstudiesofABRsanddimensionalstudies
there was no correlation between the hearing threshold oftheinternalauditorycanal.Subjectsrangedinagefrom40to
and the number or location of surviving hair cells.9 The 87years.Themeanagewas68years.Therewere23femaleand
authors also showed no evidence of ossicular fibrosis or 14malesubjects.Nine(24%)ofthesesubjectswereblackand28
ankylosis to account for the air-bone gap. Khetarpal and (76%)werewhite.
Schuknecht proposed that “both the conductive and sen- Thirty-threesubjects(66ears)wereavailableforstudiesof
sorineural components of the HL in Paget’s disease are ABRs. Of these, two left ears were excluded from analysis be-
causeofpriormiddleearsurgery,leaving31leftearsand33right
caused by changes in bone density, mass, and form that
ears,or64totalearswithABRdataforanalysis.
dampenthefinelytunedmotionmechanicsofthemiddle
Thirty-seven subjects were available for CT scanning for
andinnerears.”9Theywereunabletoofferdirectevidence
dimensional measurements. The processing of CT images in-
tosupportthissuggestion.
cluded a data reduction step that resulted in inadvertent omis-
Thepresentstudywasasystematic,prospective,con- sionofthemedialportionoftheinternalauditorycanalfromthe
trolled set of investigations to test the hypothesis that image data set of one right and two left ears (total 3 ears).
thereisageneralunderlyingmechanismofHLinPaget’s Dimensionalmeasurementscouldnotbemadefromtheseincom-
disease of bone and to gain additional insights into the pletedatasets,leaving36rightand35leftears(total71ears)for
auditoryandotologicdynamicsofthisdisease.Agroupof analysisofdimensionsinpageticversusnormalsubjects.
elderly subjects with Paget’s disease involving the skull Thirty-fivepatientswithPaget’sdiseaseinvolvingtheskull
wereavailableforbothstudiesofthebonemineraldensityofthe
and a control group of elderly subjects without Paget’s
cochlearcapsule(QCT)andhearinglevels.Therewere21female
diseasewererecruitedforseveralinvestigations.
and 14 male subjects with Paget’s disease involving the skull.
Auditorybrainstemresponses(ABRs)wererecorded
Eight(23%)ofthesesubjectswereblackand27(77%)werewhite.
to search for evidence of retrocochlear disease. The pres-
The35patientsrangedinagefrom40to87years.Themeanage
enceofnormalABRswouldbetakenasevidenceofnormal was 68 years. Data from three ears from three subjects were
retrocochlear function and a cochlear site of lesion. Di- excludedfromtheanalysis,twoearsforahistoryofearsurgery
mensionalmeasurementsweremadeoftheinternalaudi- and another because of chronic mastoiditis. Data from the re-
tory canal using digital image analysis from computed maining67ears(33leftand34rightears)wereanalyzed.
tomographic (CT) images. Correlations were sought be-
tween internal auditory canal dimensions and hearing Volunteer Subjects
levels(bothhigh-frequencyair-conductionthresholdsand A control group of 22 volunteer subjects over age 50 was
the low-frequency air-bone gap) to determine whether recruitedfromamongthespousesofpageticsubjectsandothers.
narrowingoftheinternalauditorycanalorcompressionof Twovolunteerswereexcluded,oneeachforMe´nie`re’sdiseaseand
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599
otosclerosis,leavingatotalgroupof20subjects.Therewere10 of time (approximately 1.2–1.5 ms) to reach the middle- to low-
menand10womeninthecontrolgroup.Onewomanwasofblack frequency portion of the cochlear duct, producing a latency shift,
descent.Theremaining19controlsubjectswerewhite.Themean whichisreflectedintheABRinsubjectswithhigh-frequencysen-
agewas59years. sory HL. Thus, measured latencies that exceeded the reference
Volunteers had no clinical history of Paget’s disease and valuesbythetimeexpectedbasedonthedegreeofhigh-frequency
underwent determination of serum alkaline phosphatase to ex- HLwereinterpretedasnormal(forthedegreeandconfigurationof
cludePaget’sdisease.Aneuroradiologistunawareoftheclinical theHL)andconsistentwithintactauditorynervefunction.15
diagnosisreviewedeachsetofQCTimagestoconfirmthepres-
enceofPaget’sdiseaseineachpageticsubjectanditsabsencein Dimensional Measurements
the volunteers. Other exclusion criteria for volunteers were the Measurement of the dimensions of the internal auditory
sameasforthepageticsubjects. canalwasaccomplishedwithdigitalimageprocessing.Instep1,
aperpendicularpairofplanarCTimages(axialandcoronal)was
Audiometry and Auditory Brainstem Responses selectedfromthethree-dimensionaldatasetusingdigitalimage
Pure-tone behavioral audiometric thresholds for air and analysis software developed for this purpose.16 The axial plane
boneconductionweredeterminedat2.5dBincrements.Because was selected first and included a section of maximal diameter
of reports that a high-frequency sensorineural HL and a low- throughout the internal auditory canal. The vestibule and por-
frequency air-bone gap are characteristic in Paget’s dis- tionsofthecochlearandvestibularlabyrinthswerealsoincluded
ease,5,8,13,14audiometricfrequenciesthatreflectedthesetwoef- inthissectionalimage.Thelineofrotationbetweentheaxialand
fectswereselected.Ahighpure-toneaveragewascalculatedas coronal planes was the line passing through the center of the
thearithmeticmeanofpuretonethresholdsat1,2,and4kHz. internalauditorycanal(Fig.1).
The air-bone gap was calculated as the mean of air-conduction In step 2, the length, the mid-length diameter, and the
thresholdsat0.5and1kHzminusthebone-conductionthresh- minimumdiameteroftheinternalauditorycanalintheaxialand
oldsatthosefrequencies. coronalplanesofeachtemporalboneweremeasured.Tosimplify
TheABRwasrecordedwithacommerciallyavailableclin- dataanalysis,thetwosetsofdata(axialandcoronal)forlength
icalevokedpotentialssystem(Quantum84,Cadwell,Kennewick, andmid-lengthdiameterwereaveraged.Thesmallerofthetwo
WA). Electrodes were applied with a conductant paste to the minimumdiameters(axialandcoronal)wastakentoidentifyall
vertex(noninvertinginputCz),leftandrightmastoids(inverting cases where auditory nerve compression might occur. Left and
inputsM1andM2,respectively),andatthemidfrontallocation rightearswereanalyzedseparately.
(groundFpz).Simultaneousipsilateralandcontralateralrecord- Theprecisionofthedimensionalmeasurementswastested
ingswereconductedtooptimizetheidentificationofcomponent in two ways. Step 2 was repeated for each pair of axial and
waveV.Thebioelectricactivitywasdifferentiallyamplified(105), coronalimagesineighttemporalbonesatleast24hoursafterthe
filtered(100–3000Hz),andaveraged(1,500–4,000samples). initialsetofmeasurements(24pairsofobservations).Steps1and
Stimuli consisted of 0.1 ms unipolar electrical rectangular 2 were also repeated in eight temporal bones each (24 pairs of
pulses. Either condensation or rarefaction clicks were used, de- observations).Duringeachsecondsetofmeasurements,theop-
pending on which yielded the higher quality waveform. The eratorwasunawareof(i.e.,“blinded”to)thefirstresult.Forthe
soundstimuluswasproducedbyapiezoelectrictransducerthat lengthandmid-lengthdiameter,theaveragecoefficientsofvari-
was coupled to the ear by a 26 cm length of silastic tubing ation were less than 3% for the first test of precision described
terminatinginafoamearplug.Thestimulusintensitywas75dB aboveandlessthan5%forthesecondtest.Themeasurementofthe
nHLforthosesubjectswithnormalhearingsensitivityand85dB minimumdiameterwassomewhatlessprecise,withacoefficientof
nHLforthosesubjectswithhearinglosses.Thestimulusrepeti- variationof5%forthefirsttestand11%forthesecond.15
tionratewas21.3pulsespersecond.Eachrecordingwasdupli-
catedatleastonceandwassuperimposedsothatanassessment
ofwaveformstabilitycouldbemade.ThelatenciesofABRcom-
ponentswavesI,II,III,IV,andVweretabulated(whenidenti-
fiable)asweretheamplitudesofwavesI,III,andV.Thewave
V/waveIamplituderatiowascalculated.
Thereisnouniversallyacceptedmethodofinterpretationof
ABRs.Inthisstudy,ABRswereinterpretedasthoughtheywere
diagnostictestsforretrocochleardisease(diseaseoftheauditory
nerveandcentralauditorypathways).Itwasreasonedthatab-
normal ABRs could be taken as evidence of abnormal auditory
nervefunction(asopposedtoabnormalcochlearfunction)asthesite
oftheauditorylesion.ABRfindingswerecomparedwithnormative
dataestablishedforinterpretationforretrocochleardisease.These
dataconsistedoflatencyandamplitudevaluesfrom32clinicsub-
jectswithnormalhearing.ABRswereconsiderednormalifvalues
werewithin2.5SDofthenormalhearinggroup.15
Iflatencyoramplitudevalueswerenotwithin2.5SDofthe
valuesofthenormalhearinggroup,anotherlevelofanalysiswas
applied.Nospecific“correctionfactor”inmillisecondsoflatency
perdBofhighfrequencyHLwasused;however,thedegreeofHL
in the higher frequencies and the steepness of the audiometric
Fig.1. (A)Axialand(B)coronalcomputedtomographyimagesof
slope in these frequencies was assessed. In the presence of a
typical pagetic temporal bone showing placement of lines for di-
high-frequencycochlearHL,theportionofthecochleathatgives mensional measurement.15 (Monsell EM, Bone HG, Cody DD, Ja-
rise to the transduction events that will result in the ABR is cobson GP, Newman CW, Patel SC, Divine GW. Hearing loss in
understoodtobethedomainthatnormallycodesformiddle-and Paget’sdiseaseofbone:evidenceofauditorynerveintegrity.AmJ
low-frequencysounds.Thetravelingwavetakesafiniteamount Otol1995;16:27–33.)
Laryngoscope114:April2004 Monsell:HearingLossinPaget’sDiseaseofBone
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Radiology the mineral density of normal cortical bone (1,850 mg/cm3) were
Muchofthepresentstudydependedonthedevelopmentand consistentwiththeresultsofotherlaboratories.18
validationoftheradiologicmethodofmeasuringbonemineralden-
Image Analysis
sityofthecochlearcapsuleusingaparticulartypeofQCT.17
A custom software package with a trilinear interpolation
The method of measuring bone mineral density of the co-
algorithmwasusedtotranslateandrotatetheimagedatasothat
chlear capsule used in this study was a modification of a tech-
athinsectionofthetemporalboneorientedinastandardplane
niqueoriginallyusedtomeasuretheregionalbonemineralden-
couldbeselectedforanalysisinteractivelyonacomputerwork-
sity in human vertebral bodies in vivo.17 A specific convolution
station. This plane incorporated the lateral semicircular canal
filter (mathematical algorithm to calculate the image from raw
andanearmid-modiolarsectionofthecochlea(Fig.3A).19
data)wasappliedtooptimizetheaccuracyandprecisionofden-
Regionsofinterestwereconstructedfromthesesectionalim-
sity measurements without sacrificing the high quality of the
agestosamplethebonedensityinthecochlearcapsule(Fig.3B).19
images. The technique resulted in a three-dimensional array of
Regionsofinterestweredefinedwithparticularcaretocorrespond
valuesexpressedasphysicaldensity(e.g.,mg/cm3).Theamount
tothestructureofthecochlearcapsuleandtoavoidoverlappingthe
ofradiationexposurewassimilartothatofconventionalCT.
areaofstudywiththeair-containingspaceofthemiddleear.Such
Thescanprotocolusedanx-raytubevoltageof130kVp,100
overlappingcouldresultinerrorscausedbypartialvolumeeffects.
mAcurrent,4secondsexposuretime,anda1mm2focalspot.The
Three-dimensional regions of interest that included the entire co-
headholderincorporatedasolidbone-mineralcalibrationphan-
chlearcapsulewereusedforstudiesoftreatmentresponse.
tommarketedbyImageAnalysis(Irvine,CA).Thisdevicehada
gradedseriesoffivedensitystandardsconsistingofhydroxyap-
atiteembeddedinaplasticresin(Fig.2).Thirtyto50scanswith
aslicethicknessof1mmweretakenthroughthetemporalregion
oftheskullofeachsubjectintheaxialplane.Ascandiameterof
30cmwasreconstructedto512(cid:1)512voxels,producingvoxelsof
dimensions0.585(cid:1)0.585(cid:1)1.0mm.Asubregionof128(cid:1)128
voxelswasselectedforanalysis(Fig.2).Measurementresolution
was determined to be 1.6 mm in each dimension, providing a
sample volume of 0.004 cm3. This method has previously pro-
ducedmeasurementswithnoiseof0.7to1.3%,accuracyof2.7%,
and serial precision in vitro of 0.2%.15 The long-term precision
was monitored by use of a solid calibration standard (Image
Analysis,Irvine,CA).Averystableresultforaperiodofalmost4
yearswasaccomplished.16
Toassessmeasurementaccuracy,fourcochlea-shapedplastic
densitystandardswereinsertedintothetemporalbonesofaskull
phantom.Measurementswereconfirmedtobelinearthroughthe
rangeofdensitiesencounteredinPaget’sdisease.Measurementsof
Fig. 3. (A) Example of a planar quantitative computed tomography
Fig.2. Axialquantitativecomputedtomographyscanimageofthe image from a 66-year-old subject with Paget’s disease moderately
head showing the calibration device beneath the head. White involving the left temporal bone. (B) The same image showing the
squares outline the subregions sampled (128 (cid:1) 128 pixels).16 Re- cochlearcapsuleregionsofinterestdefinedforthistemporalbone.(C)
printedfromHearingResearch,Vol83,MonsellE,CodyD,BoneH,et Airandboneconductionaudiogramfromthesamesubjectandear.19
al.,HearinglossinPaget’sdiseaseofbone:therelationshipbetween (Monsell EM, Cody DD, Bone HG. Measurement of regional bone
pure-tone thresholds and mineral density of the cochlear capsule, mineral density: a new techniqe for the evaluation of the temporal
Pages114–120,Copyright1995,withpermissionfromElsevier. bone.AmJOtol1993;14:455–459.)
Laryngoscope114:April2004 Monsell:HearingLossinPaget’sDiseaseofBone
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Two studies were conducted to assess the consistency of Therewerenosignificantcorrelationsbetweenhear-
imageanalysis.First,asecondregionofinterestwasconstructed inglevelandtheminimumdiameterineitherthepagetic
ontheoriginalimagesectionatleast24hoursafterconstructing or the volunteer subjects. There were significant correla-
thefirstregionofinterest,andthedensitymeasurementsfrom
tions between mid-length diameter and high-tone aver-
eachregionofinterestwerecompared.Inthismanner,theerror
age,butthesewereweakandweresignificantonlyinleft
attributable to selection of the regions of interest was demon-
ears(TableII).Inoneextensivelypagetictemporalbone,
stratedtobe0.7%.16Inthesecondstudy,theimagesectionthat
the minimum coronal diameter was 1.17 mm (pure-tone
passedthroughthelateralsemicircularcanalwasreselected,and
aregionof interestonthissecondsectional imagewasdefined. average at 0.5, 1, 2, and 4 kHz (cid:2) 42 dB), the smallest
Theerrorattributabletothecompleteprocessofimageanalysis diameter measured in this study. The corresponding di-
was found to be 1.5%, including selection of the lateral canal ameter on the opposite side was 1.76 mm (pure-tone av-
planeandconstructionoftheregionsofinterest.16 erage(cid:2)42dB).
Statistical Analysis
Comparison of Left versus Right Ear Cochlear
Therelationshipbetweendimensionsandhearingmeasures
Capsule Density
wasassessedbycorrelations.Internalauditorycanaldimensions
Leftandrightcochlearcapsuledensitieswerehighly
werecomparedbetweenthePageticsubjectsandcontrolsbyuse
ofttestsandanalysisofcovariance.Ineachcase,adjustmentwas correlated (r (cid:2) 0.82, P (cid:3) .001). The regressions were
madeforthecovariatesageandsex. consistentthroughouttherangesofcochlearcapsuleden-
Regressionmethodswereusedtoexaminetherelationship sity (Fig. 4). These findings confirm clinical observations
between hearing thresholds and mean bone mineral density of that pagetic involvement of the skull is most commonly
thecochlearcapsule.LinearregressionrelationshipsandPearson symmetrical.
product-momentcorrelationswerecomputedtoassessthesimple
associations.Analysisofcovariancewasusedtocomputepartial
Relationship of Bone Mineral Density of the
correlationcoefficients,adjustedforthecovariatesofageandsex.
Cochlear Capsule to Hearing Levels
ABonferroniadjustmenttothePvaluesconsideredstatistically
significant([0.05]/2(cid:2)0.025orless)wasperformedtoaccountfor Significant Pearson product-moment correlations
thetwomeasuresofhearingthatweretested. werefoundbetweenhigh-frequencypure-toneairconduc-
tionhearingthresholdsandmeanbonemineraldensityof
RESULTS thecochlearcapsulein33leftearsand34rightearsofthe
35Paget’sdiseasesubjectsbothwithandwithoutcorrec-
Auditory Brainstem Responses
tionforageandsex(TableIII)16(datarepresentingthree
Eightearsinfivesubjectshadnorecordableauditory
earswerenotincludedbecauseofexclusioncriteria).Scat-
evokedresponsescausedbylowhearinglevels.ABRsfrom
ter plots (Fig. 5) illustrate the consistency of the regres-
theremainingearswerenormal,indicatingthattherewas
sionfunctionsthroughouttherangeofthehigh-frequency
no electrophysiologic evidence of impairment of auditory
pure-tone hearing levels. Multiple regressions showed
nervetransmission.
that correlations between cochlear capsule density and
Dimensional Measurements hearing threshold at individual frequencies from 1
Results are summarized in Tables I and II.15 Corre- through4kHzwerenotsubstantiallydifferentfromeach
lationsweresoughtbetweenthelength,mid-lengthdiam- other.
eter, and minimum diameter versus high pure-tone Significant correlations also were found between
threshold average (1, 2, and 4 kHz) and versus the low- meancochlearcapsuledensityandtheair-bonegapinthe
frequency air-bone gap (0.5–1 kHz). No association was pageticsubjects(Fig.5,CandD).Incontrast,therewere
found between internal auditory canal dimensions and nosignificantcorrelationsbetweencochlearcapsulemean
hearinglevelinthevolunteersubjects.Thereweresignif- densityandthehighfrequencypure-tonehearinglevelsin
icantcorrelationsoflengthversusbothhigh-toneaverage the volunteer subjects (Fig. 5, E and F). Because normal
and air-bone gap (Table II). t tests did not demonstrate subjects are not expected to have conductive HL or air-
that any of the dimensions were significantly different bonegaps,itisquestionablewhethercalculationofcorre-
betweenpageticandcontrolgroups. lations involving the air-bone gap in the volunteer sub-
TABLEI.
MeanInternalAuditoryCanalDimensions.
Mid-Length Minimum
Length, Diameter, Diameter,
Side n SD(mm) SD(mm) SD(mm)
Pagetic
Left 35 12.3,2.29 3.92,1.09 3.65,0.95
Right 36 12.2,2.17 4.03,1.26 3.49,0.75
Volunteer
Left 20 12.0,1.91 4.21,0.89 3.81,0.90
Right 20 11.8,1.82 4.04,0.80 3.76,0.73
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602
TABLEII.
InternalAuditoryCanalDimensionalCorrelationsinPageticSubjects.
UnadjustedCorrelations/PValues
35RightEars 33LeftEars
Mid-Length Minimum Mid-Length Minimum
Length(r,p) Diameter(r,p) Diameter(r,p) Length(r,p) Diameter(r,p) Diameter(r,p)
Hightoneaverage 0.49,0.003* 0.26,0.12 (cid:4)0.08,0.65 0.27,0.12 0.39,0.025* 0.12,0.52
Air-bonegap 0.40,0.019* 0.0003,0.99 (cid:4)0.30,0.089 0.34,0.059 0.0066,0.9718 (cid:4)0.085,0.65
AgeandSexAdjustedCorrelations/PValues
35RightEars 33LeftEars
Mid-Length Minimum Mid-Length Minimum
Length(r,p) Diameter(r,p) Diameter(r,p) Length(r,p) Diameter(r,p) Diameter(r,p)
Hightoneaverage 0.55,0.001* 0.25,0.15 (cid:4)0.11,0.54 0.32,0.08 0.41,0.021* 0.14,0.46
Air-bonegap 0.41,0.02* 0.02,0.99 (cid:4)0.29,0.11 0.35,0.066 0.039,0.84 (cid:4)0.06,0.76
*Indicatesstatisticallysignificantcorrelation.
jects would be meaningful. As expected, there were no eitherthehighpure-tonethresholdlevelortheair-bone
significant correlations between cochlear capsule mean gap. There was no apparent relationship between sex
densityandtheair-bonegapinthevolunteersubjects. and high-frequency pure-tone thresholds; however, men
Therobustnessofthecorrelationswasexploredby may have had a smaller air-bone gap by 3.8 dB for left
examiningtheeffectofriskfactorsforHL.Theeffectof ears or 3.7 dB for rightears(P(cid:2).10andP(cid:2).03,respec-
risk factors, including noise exposure (by history) and tively)afteradjustmentforageandmeanbonedensityofthe
diabetes mellitus, was examined by comparing selected cochlearcapsule.16
pagetic subjects without risk factors (n (cid:2) 22) to those
with risk factors (n (cid:2) 13). There were no significant
DISCUSSION
differences between the two groups in correlations of
The ABR results are consistent with intact auditory
nerve function in this group of subjects with Paget’s dis-
ease of the skull. Correlational data in right temporal
bones suggested that the length of the internal auditory
canal might be related to high-tone hearing level. How-
ever, this association was less clear on the left side and
appeared qualitatively weaker for conductive losses com-
paredwithsensorineurallosses(TableII).Thebiologicor
clinicalsignificanceofthesepossibleweakassociationsis
unclear, although it is conceivable that extensive Paget’s
diseaseiscorrelatedwithbossingoftheporusacusticusin
somecasesofmoderatetoadvanceddiseaseandhasbeen
observedhistologically.9
Olivares and Schuknecht20 measured the diameters
of the internal auditory canal in 435 histologically pre-
pared temporal bones. Specimens with evidence of bone
disease, including Paget’s disease, were specifically ex-
cluded. One hundred forty-four ears with sensorineural
HL were purposely included. The authors found no rela-
tionshipbetweenthewidthoftheinternalauditorycanal
andhearinglevel.Tensubjectshadcanalwidthsof3mm
orlessandaveragepuretonethresholdsof30dBorbetter
in frequencies 0.5, 1, and 2 kHz. The authors concluded
thatitisdoubtfulthatnarrowingoftheinternalauditory
canal is associated with HL in nonpagetic sensorineural
HL. The differences between the measurements of the
mid-length diameter of the internal auditory canal from
digital radiographic data (mean of all mid-length diame-
Fig. 4. Scatterplot of cochlear capsule density in subjects with ters in pagetic subjects (cid:2) 3.97 mm) and the 6% smaller
Paget’sdiseaseinvolvingthetemporalbone,leftversusrightears. measurements derived from histologic preparations
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603
TABLEIII.
CorrelationsBetweenHearingThresholdsandMeanDensityoftheCochlearCapsule.
PageticSubjects NotAdjusted* Adjusted
Densityvs. Side n r p r p
High-frequencypure-toneaverage Left 33 (cid:4)0.64 0.0001 (cid:4)0.63 0.0002
High-frequencypure-toneaverage Right 34 (cid:4)0.73 0.0001 (cid:4)0.73 0.0001
Air-bonegap Left 33 (cid:4)0.62 0.0001 (cid:4)0.67 0.0001
Air-bonegap Right 34 (cid:4)0.62 0.0001 (cid:4)0.63 0.0001
*Forageandgender.
(mean of 435 subjects (cid:2) 3.72 mm) by Olivares and The possibility of partial auditory nerve compro-
Schuknecht20maybecausedbyshrinkageoftissueduring mise in occasional instances cannot be excluded abso-
histologicprocessing. lutely; however, our radiologic and electrophysiologic
Fig.5. (A,B)Scatterplotsofthecorrelationsofhigh-frequencypure-tonehearingthresholdsbyairconductionversusmeancochlearcapsule
bone mineral density in pagetic ears. Note the strong correlation for all ranges of hearing and bone density. (C, D) Scatterplots of the
correlations of air-bone gap versus mean cochlear capsule bone mineral density. (E, F) Scatterplots of high-frequency pure-tone hearing
thresholds by air conduction versus mean cochlear capsule bone mineral density in volunteer subjects show no significant relationship.16
ReprintedfromHearingResearch,Vol83,MonsellE,CodyD,BoneH,etal.,HearinglossinPaget’sdiseaseofbone:therelationshipbetween
pure-tonethresholdsandmineraldensityofthecochlearcapsule,Pages114–120,Copyright1995,withpermissionfromElsevier.
Laryngoscope114:April2004 Monsell:HearingLossinPaget’sDiseaseofBone
604
dataindicatethatauditorynervefunctionisintactinmost The idea that an air-bone gap can exist without a
cases of HL associated with Paget’s disease of bone. The conductiveHLinthemannerusuallyunderstoodmaybe
results support the hypothesis that the primary effect of difficulttoaccept.KhetarpalandSchuknecht9originated
Paget’sdiseaseonhearingisonthecochlea. the concept with their report of no fibrosis or ankylosis
The results with QCT show the feasibility of deter- involving the ossicles, their articulations, or suspensory
mining regional bone mineral density in the temporal ligaments.Currently,Paget’sdiseaseistheonlyinstance
bone,includingsmallstructuressuchasthecochlearcap- known of an air-bone gap that does not indicate an im-
sule.Althoughthelinearresolutionofmeasurementis1.6 pairmentofthesoundconductingmechanism.Theimpli-
mm,voxeldimensionsof0.585mmenableaccuratemea- cation is that the air-bone gap is a phenomenon of the
surement of mean density of small regions by sampling acoustical mechanics of hearing by bone conduction. We
multiplevoxels,typically60to100foreachcochlearcap- areledtosuspectthattheair-bonegapmaybecausedin
sule.Errorscausedbyvoxelsthatincludeintheirvolume somewaybyenhancedconductionoflow-frequencysound
different structures of adjacent regions (partial volume energy by pagetic bone. The strong correlations between
effect)wereminimizedbutnotcompletelyeliminated. bonemineraldensityofthecochlearcapsuleandtheair-
A strong and statistically significant relationship was bone gap suggest that the enhancement occurs primarily
demonstrated between the bone mineral density of the co- in the cochlear capsule, although enhancement may also
chlear capsule and both the high-frequency pure-tone air- occurinpageticboneoftheskullbasemoregenerally.
conductionthresholdsandtheair-bonegapinsubjectswith Pageticbonehasbeenobservedtochangeshape.Grad-
Paget’sdiseaseoftheskull.Theredoesnotappeartobean ual bowing of the weight-bearing long bones is common
inflectionintheregressionlineorsuggestionofathreshold whentheyareinvolved.HLinPaget’sdiseasedoesnotseem
phenomenon in this relationship. This consistency of the toberelatedtochangesintheshapeoftheskullorinnerear.
regression throughout its range suggests that the effect of Platybasia,aflatteningandwideningoftheskullbase,oc-
Paget’sdiseaseonhearingisacontinuous,gradedprocess. cursonlyinthemostadvancedcasesofpageticinvolvement
The bone of the normal cochlear capsule is lamellar of the skull, whereas HL occurs with almost any degree of
bone with few haversian canals and vascular elements involvementofthetemporalbone.Thedimensionalanalysis
andthusconsistsofdense,compactbonetissue.21Conse- ofpagetictemporalbonesinthisstudydidnotshowchanges
quently, bone lysis by Paget’s disease would result in in the internal auditory canal. Also, we did not observe
density values less than normal, whereas bone sclerosis qualitativechangesintheshapeofthecochlea.
could only thicken the cochlear capsule, not increase its Treatment with the newer bisphonsponates provides
mineraldensity.Inaccordancewiththisprinciple,inthis rapidarrestofthepageticprocessandlong-termcontrol.22
study, pagetic involvement of the skull was associated Acutespinalneuropathycausedbyinvolvementofthebone
onlywithreductionsincochlearcapsuledensityornormal adjacenttothespinalcordrecoversinhourstodaysduring
values,dependingonthedegreeofthepageticeffect. bisphosphonate treatment, possibly because of a vascular
The findings in the studies reported here strongly stealphenomenonortheeffectsoftoxiccytokinesonneural
supportthehypothesisthatthereisageneralunderlying structures.23Nevertheless,ithasbeenthecommonobserva-
mechanismofHLinPaget’sdiseaseofbone.Thefindingof tion,confirmedinthisstudyandtheauthor’sclinicalexpe-
normal ABRs supports the cochlea as the site of the rience, that pagetic HL does not recover despite vigorous
pageticlesionratherthantheauditorynerve.Thelackof treatment.Consequently,spinalneuropathyisnotasuitable
evidence for nerve compression further supports the co- model for pagetic HL. The possibility that pagetic bone re-
chlear hypothesis and demonstrates that there is very leasestoxiccytokinesthatimpaircochlearfunctionirrevers-
littledistortionofconsequenceintheshapeofthetempo- ibly but without resulting in loss of hair cells was not ad-
ralbone,exceptperhapsinrare,extremecases.Thedem- dressed by the study and cannot be excluded. Also, spiral
onstrated relationship between cochlear capsule mean ligamentatrophy,whichoccursprominentlyinotosclerosis,
density and hearing levels also supports the cochlear hy- isnotatypicalfeatureofpageticHL.
pothesisandthehypothesisofageneralunderlyingmech- Histologic studies show that the pagetic process in-
anism. This relationship also suggests that alteration of volves the entire cochlear capsule in essentially all cases
bonemineraldensitymaybeclosetothemechanismofHL. observed. This finding suggests that the entire capsule is
These correlational findings are not necessarily in involved early. A reasonable inference from the cross-
directconflictwiththefindingsofearlierhistologicstud- sectional data of the study is that bone mineral density is
iesofpagetictemporalbones.Thepossibilityofadditional graduallylostasthediseaseprogresses.Itmaybesuspected
mechanisms,particularlyinadvancedcases,isnotexcluded. thatcontinuousremodelingofpageticoticcapsulebonere-
Audiometricdata,particularlydatainvolvingthedeter- sultsinprogressivesensorineuralHL,predominantlyinthe
mination of bone-conduction thresholds, are subject to con- higherfrequencies.Oneistemptedtospeculatethatperhaps
siderablevariability,especiallyinelderlysubjects.Thesub- Paget’sdiseaserevealsthenormalauditoryfunctionofotic
jects in this study were older than the general population. capsulebone.Thisbonenormallydoesnotundergoremod-
Consequently,itmustbeacknowledgedthatthestrengthof eling.WhenitdoesundergoremodelinginPaget’sdisease,a
thecorrelationsisremarkable.Thepositivefindingofcorre- gradualdeclineoccursinauditoryfunction.
lations between cochlear capsule mineral density versus Sensory transduction in the cochlea is a process of
hearinglevelssupportsthevalidityofthenegativefindingof interaction between mechanical (acoustic) and electrical
no significant correlations between dimensional measure- events. It appears that conformational change in
mentsoftheinternalauditorycanalandhearinglevels. membrane-bound ion channels may be induced by me-
Laryngoscope114:April2004 Monsell:HearingLossinPaget’sDiseaseofBone
605
chanicaldeformation.Theflowofionsacrosshaircellsis Acknowledgments
dependent on the maintenance of the “silent” current.24 Thisthesisisdedicatedtomyfamily,whosustained
Thiscurrentflowmaybereducedinpageticbone.Itisalso methroughtheyearsofthisresearch.
possiblethatacousticenergyisabsorbedbypageticbone,
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