www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
CASE
REPORT
Waldenström’s
macroglobulinemia
presenting
with
bilateral
vestibular
loss:
a
case
report
夽
Macroglobulinemia
de
Waldenström
com
perda
bilateral
da
func
¸ão
vestibular:
relato
de
caso
Andrea
Castellucci,
Gianluca
Piras,
Cristina
Brandolini,
Giovanni
Carlo
Modugno,
Gian
Gaetano
Ferri
∗DepartmentofExperimental,Diagnostic,andSpecialtyMedicine(DIMES),S.Orsola-MalpighiUniversityHospital,Bologna,Italy
Received26January2015;accepted17March2015 Availableonline26July2015
Introduction
Waldenström’smacroglobulinemia(WM)isalow-grade lym-phoma originally described in 1944.1 It is a malignant
lymphoproliferative disease characterized by the clonal expansionofBcellswithlymphoplasmacyticdifferentiation thatsecretemonoclonalimmunoglobulinM(IgM). Diagnos-tic criteria are based on specific clinical, morphological, and immunophenotypic parameters,besides the evidence ofpathologicplasmacytoidcellsinthebonemarrow. Symp-toms canbe relatedeither totumor infiltration or tothe amount andproperties of thecirculating monoclonal pro-tein:cardiacandrenalfailure,mucosalbleeding,headache, visualdisturbances,ataxia,andeventuallycomahavebeen described aspart ofthe clinical spectrumof WM. Periph-eralneuropathy occursin nearly half of the patients and is mostlyrelatedtothe reactivityofthe IgMproteinwith differentneuralantigens.Frequently,itrepresentsthe ini-tialpresentationofthedisease;sometimesitcouldprecede the diagnosis of macroglobulinemia by several years.2
夽
Please cite thisarticle as: Castellucci A, Piras G, Brandolini C,ModugnoGC,FerriGG.Waldenström’smacroglobulinemia pre-senting with bilateral vestibular loss: a case report. Braz J Otorhinolaryngol.2015;81:571---5.
∗Correspondingauthor.
E-mail:[email protected](G.G.Ferri).
Conversely, the onset of audio-vestibular symptoms and signs as a presenting phenomena of WM is unusual. This reportpresentsanoriginalcase,thefirsteverdisclosedin literature,ofbilateralvestibularloss(BVL)asthepresenting symptomofWM,andtherelevantliteratureisreviewed.
Case
report
A 57-year-old woman presented at the hospital with the onsetof asthenia,fatigue, progressive dizziness, and dis-equilibrium for a few months. Immediately before the symptoms began, she had already experienced positional vertigo spells while laying down or getting up from bed. Rightposterior canalbenignparoxysmal positionalvertigo was diagnosed and treated successfully with two cycles of repositioning maneuvers at another institution. Since then,shehadstartedtofeelprogressivelyunsteady, light-headed, and even experienced oscillopsia while walking, becomingseverelydisabledduringherdailyactivities.She alsonoticedarapidlyprogressivebilateralhearing impair-ment and recurrent nasal bleedings. Surprisingly, she did notshow any spontaneous or positional nystagmusat the infraredvideo-oculography,whileaudiometrictestrevealed amoderate-to-severebilateral high-frequency sensorineu-ralhearingloss(Fig.1a).Subsequently,shewassubmitted toanextensiveneuro-otologicassessment:standard bither-malcalorictest showed minimal/absent caloricresponses
http://dx.doi.org/10.1016/j.bjorl.2015.03.010
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Figure1 Pure-toneaudiometrictestshowingmoderate-severebilateralsensorineuralhearinglossforhighfrequencieswithnearly symmetricalinvolvement,before(a)andaftertherapy(b).
bilaterally. Noresponse waselicitedeven after ice-water stimulation, proving bilateral deficient vestibulo-ocular reflex(VOR) at low-frequency range. High-frequencyVOR gain for all six semicircular canals was tested with the video head impulse test (vHIT). VOR gain for each canal showed to be extremely deficient (Fig. 2). Saccular and utricular function was measured using air-conducted cer-vical vestibular evoked myogenic potentials (VEMPs) and bone-conducted ocular VEMPs, respectively. No reliable response could be detected bilaterally (Fig. 3). Tempo-ral bone high-resolution computed tomography (CT) scan wasnegativeandgadolinium-enhancedbrainmagnetic res-onance imaging (MRI) excluded central nervous system (CNS)involvements.Allprincipalcauses ofbilateral vesti-bularfailurewereexcludedthroughanaccurateanamnesis. Thepatientwassubmittedtoaparallel internalmedicine assessment, which detected signs of pulmonary arterial hypertension. Peripheral blood analysis revealed pancy-topenia(WBC2.78×109/L,RBC3.32×1012/L,Hemoglobin
96g/L, HCT 30.1%, Platelets 94×109/L). Thus, she was
submittedtotheHematologicUnitoftheinstitutionfor fur-therinvestigation.Serumproteinelectrophoresis revealed
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Figure2 Videoheadimpulsetest(vHIT)withanICSVideo-oculographicsystem(GNOtometricsA/S---Denmark)forallsemicircular canals(LH:lefthorizontal,RH:righthorizontal,LA:leftanterior,RP:rightposterior,LP:leftposterior,RA:rightanterior).Passive, unpredictable5◦---20◦,50◦---250◦/s,and750◦---5000◦/s2headimpulsesweredeliveredmanuallyontheplaneofthehorizontaland
verticalcanalswhilethepatientwasaskedtokeeplookingatanearth-fixedtarget.Ontheright,bluelinesrepresentheadimpulses excitingleftcanals,redlinescorrespondtoheadimpulsesexcitingrightcanals,andgreenlinesrepresenteyemovementsinduced bytheactivationofthevestibulo-ocularreflex(VOR)followingeachheadimpulse.Foreachcanal,thecorrespondingmeanvalueof VORgainswithrelatedstandarddeviation()isreported.Overtsaccadescanbeeasilydetected.Ontheleft,eachdotrepresents
theVORgain(eyevelocity/headvelocity)foreachimpulse.VORshowedtobeextremelydeficientforallcanals.
analysis(WBC4.45×109/L,RBC3.66×1012/L,Hemoglobin
104g/L, HCT 33.1%, Platelets 114×109/L, IgM 32.5g/L,
albumin/globulins ratio of 1.42). She felt relieved from fatigueandasthenia,andheraudiometrictestsurprisingly showedaconsistentimprovementinhigh-frequencyhearing thresholdsbilaterally(Fig.1b).Nevertheless,afurther oto-neurologicassessmentconfirmedapersistentdeficiencyin hervestibularfunction.
Discussion
BVL is a rare condition. Though its etiology often remains unknown, as in most studies the idiopathic form
coincideswiththe largest groupof patients,3,4 this
disor-deristhoughttorepresentthefinalcommonexpressionof differentpathologicconditions,includingototoxicity, bilat-eralendolymphatichydrops,infections,tumors(cerebellar tumors,neurofibromatosistype2), surgicalprocedures on theinnerearorontheVIIIcranialnerves,andautoimmune disease.3,4 BLV typically manifests with chronic
disequili-brium, gait ataxia, and oscillopsia while walking. Only a fewcase seriesandliterature reviewsreporthematologic pathologies as a possible cause of BVL3,4 and, similarly,
cochleo-vestibularsymptomsappeartobean unusual pre-sentationofhematologicaldisorders.5Nevertheless,several
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Figure3 Vestibularevokedmyogenicpotentials(VEMPs)evaluatedusinganEpicPlussystem(Labats.r.l.---Mestre,Italy)witha two-channelaveragingcapacity.(a)Airconducted(AC)cervicalVEMPswereevokeddeliveringtoneburst(TB)viaheadphoneswith frequency500Hz,duration8ms,intensity120dBSPL,andstimulationrate5Hz.Upperbluelinescorrespondtomyogenicresponses recordedontheleftsternocleidomastoidmuscle(SCM),lowerredlinesrepresentresponsesrecordedontherightSCM.(b)Bone conducted(BC)ocular VEMPswereassessedusingthreedifferentsagittal (Fz)stimulations:TB250Hz(duration8ms,intensity 1.5V),TB500Hz(8ms,1.5V),andclick(0.5ms,1.0V),alldeliveredbyahand-heldminishakerwithanattachedPerspexrod(type 4810--- Bruel andKjaerP/L,Denmark),withintensityamplificationmodifiedthroughapoweramplifier(type2718---Brueland Kjaer).Bluelinesrepresentresponsesrecodedunderpatient’slefteye;redlinescorrespondtoresponsesrecordedundertheright eye.NoreliablepotentialscouldbedetectedattheSCMnorundertheeyes,besidesuncertainlateresponsesafterclickstimuli.
Figure4 Serumelectrophoresisshowingahomogeneous nar-rowpeakandadensebandinthegammaregion.
nystagmushasbeen explainedthroughtheeffectofheavy globulinsonthecupulaeofthecanals,resultingina buoy-ancymechanism.6Conversely,hearinglossandvariouslevels
of vestibular impairment have been related to different pathologicprocessesoccurringinWM,suchasmultiple hem-orrhagicphenomena,7smallvesselthrombosissecondaryto
sudden release of clotting factors,5 and increased blood
viscosityresultingin the obstruction oflabyrinthine small vessels.8 Moreover, some reports have also described a
symptomaticimprovementwithareductionofblood hyper-viscosity,mainlyafterplasmapheresis.5,6Indeed,oneofthe
most important consequences related to the rheological propertiesof circulatingIgMpentametersishyperviscosity syndrome (HS), which is a distinguishing feature of WM.
Nevertheless,itisobservedinonly10%---30%ofpatientswith WManditcanbealsoseeninpatientswithother hemato-logical disorders.9 It is the consequence of the abnormal
sizeand increasedblood concentrationofthe monoclonal protein, leading to an aggregation of red cells and an increasedvascularresistance.Thisconditionisresponsible fortheonsetoftypicalsymptoms,suchasskinandmucosal bleeding,visualdisturbance,ahugevarietyofneurological disorders,andcardiovascularmanifestations.1,9Once
diag-nosed,itmustbetreated,asitmayleadtolife-threatening consequences.Thereasonwhyparticularorgansites,such astheeyesandtheCNS,aremorefrequentlyinvolvedthan othersinHSmaybeexplainedbythesluggishflowoccurring incertainvascularbeds,resultingin furtherenhancement ofbloodviscosity.Moreover,itiswellknownthattheinner earandthe retinaaresimilarinterms of vascularization, consideringtheirperipherallocationandtheirbloodsupply of terminal type. Therefore, it could be easily hypothe-sizedthatthesametypicalpathologicfindingsdocumented in the retina of patients with HS can likely occur in the labyrinthofthesamesubjects.8Onthebasisofthe
to an ischemic lesion of the utricular macula could have resultedincanalolithiasisofthestillfunctionallyactive pos-teriorcanal.Itcouldhaverepresentedthefirstpremonitory signofanincipientprogressivevestibularanoxia,reinforcing the hypothesisof hyperviscosity asthebasis of vestibular loss.
In contrastwith most of the literature in which hear-inglossusuallyprevailsonvestibularsymptomsinpatients affected by WM,5,7 in the present case cochlear function
waspartiallysparedbyhypoxia,withonlyabilateral high-frequencyhearingimpairment.
Besidessubjectiveanatomo-physiologicfactors privileg-ingcochlearversusvestibularmicrocirculation,thereason why mainly vestibular receptors have been affected by ischemia,withonlyapartialinvolvementofthebasalturn ofthecochlea,couldbeexplainedconsideringtheanatomy ofvascularinnerearsupply.Onthebasisofscanning elec-tronmicroscopicstudies,amodelforthevascularpathways inthelabyrinthhasbeendescribed,andthereforedifferent clinicalscenarioshavebeen proposeddepending onwhich arterialorvenousbranchcouldbeinvolvedbyischemia.10
According to this model, selective combined ischemia at thelevel ofboth vestibularanteriorartery(supplying lat-eralandsuperiorcanalampullaeandutricularmacula)and vestibulo-cochlearartery(feedingposteriorcanalampulla, saccularmacula,andcochlearbasalturn)mayrepresentthe pathologic eventresponsible for the onsetof the present symptoms,sparingvascularsupplytotheupperpartofthe cochlea.Similarly,bloodstagnationatthelevelofthe audi-tory internal vein in association with a blockage of the venousdrainage fromthe lowerpartofthe cochleacould resultinthesameclinicalpicture.
Finally,evenmoreparticularcombinationsamong insuf-ficientarterialflowsandspecificinterruptionsofthevenous returncouldleadtoanoxiaofthesamelabyrinthine com-partmentsandthereforetodamageofthesamereceptors.
Conclusion
InpatientswithaclinicalpictureconsistentwithBVL,even withoutevidentsystemicinvolvement,hematological disor-derssuchasWMshouldalwaysbeconsideredasunderlying causative factors. It is important for neuro-otologists to considerHS in differentialdiagnosis of cochleo-vestibular
symptomsandsigns,asitcouldleadeventolife-threatening consequences.Similarly, hematologistsshouldbeawareof thepossibly of irreversibledamages onsensorineural end organs,suchastheinnerear,causedbytheextremelyhigh levelsofIgMandHS.Infact,thankstoitsparticularlyhigh sensitivity,theinnerearcouldbeanearlydetectorof sys-temicpathological manifestationsasshownin thisunique case report. Moreover, subclinical alterations of cochleo-vestibularfunctioncouldoccurmorefrequentlyinpatients with WM. Therefore, a systematic neuro-otologic assess-mentshouldbepromptlysuggestedinsuchcases,inorderto preventlabyrinthinehypoxiaandeventuallytoadopt appro-priatetherapeuticstrategies.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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