www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
25
(OH)
D3
levels,
incidence
and
recurrence
of
different
clinical
forms
of
benig
paroxysmal
positional
vertigo
夽
Sinisa
Maslovara
a,b,∗,
Silva
Butkovic
Soldo
c,d,
Anamarija
Sestak
a,
Katarina
Milinkovic
a,
Jasna
Rogic-Namacinski
a,e,
Anamarija
Soldo
c,d aCountyGeneralHospital,DepartmentofOtolaryngology,Vukovar,CroatiabUniversityofOsijek,MedicalFaculty,DepartmentofOtorhinolaryngologyandMaxillofacialSurgery,Osijek,Croatia cClinicalHospitalCenter,DepartmentofNeurology,Osijek,Croatia
dUniversityofOsijek,MedicalFaculty,DepartmentofNeurology,Osijek,Croatia eCountyGeneralHospital,DepartmentofLaboratoryDiagnostic,Vukovar,Croatia
Received27February2017;accepted22May2017 Availableonline11June2017
KEYWORDS Benignparoxysmal positionalvertigo; VitaminD3 insufficiency; Recurrence; Clinicalforms Abstract
Introduction:Benignparoxysmalpositionalvertigoisthemostcommoncauseofdizzinessin thegeneralpopulation.ItisaconditionwithpotentialimpactofreducedlevelsofvitaminD onitsrecurrentattacks.
Objectives: Theaimofthisstudywastomeasuretheserum levelsof25-hydroxyvitaminD3 (25-OHD3)inpatientswithbenignparoxysmalpositionalvertigoanddeterminewhetherthere isadifferenceintheserumlevelsofvitaminD3betweenpatientswithandwithoutrecurrence, aswellasbetweenthedifferentclinicalformsofbenignparoxysmalpositionalvertigo. Methods:The study included 40 patients who came to the regular medical examination, diagnosedwithposteriorcanal-benignparoxysmalpositionalvertigobasedonthepositive Dix-Hallpike’s test. All patients underwentEpley manoeuvreafter the diagnosis. Patientswere classifiedaccordingtocurrentguidelinesforlevelsofvitaminD3intheseruminthreegroups: thedeficiency,insufficiencyandadequatelevel.
Results:Theaverageserumlevelof25-OHD3amongrespondentswas20.78ng/mL,indicating alackorinsufficiencyoftheaforementioned25-OHD3.Accordingtothelevelsof25-OHD3, mostpatientssufferfromdeficiency(47.5%).7(17.5%)respondentshadadequatebloodlevel of25-OHD3,and14(35%)respondentssufferfrominsufficiency.Asignificantdifferencewas
夽 Pleasecitethisarticleas:MaslovaraS,ButkovicSoldoS,SestakA,MilinkovicK,Rogic-NamacinskiJ,SoldoA.25(OH)D3levels,incidence
andrecurrenceofdifferentclinicalformsofBPPV.BrazJOtorhinolaryngol.2018;84:453---9.
∗Correspondingauthor.
E-mail:sinisamaslovara@yahoo.com(S.Maslovara).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2017.05.007
1808-8694/©2017Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
wasnotfoundintheserumlevelof25-OHD3betweenpatientswithandwithoutbenign parox-ysmalpositionalvertigorecurrence.Therewasasignificantdifferenceintheserumlevelsof 25-OHD3incomparisontotheclinicalformofthedisease.Lower25-OHD3valueswerefound inpatientswithcanalithiasiscomparedtothosewithcupulolithiasis.
Conclusions:TherewerenosignificantdifferencesinthevitaminD3serumlevelinpatientswith andwithoutrecurrence.ThestudyshowedalowlevelofserumvitaminD3inmostpatients, indicatingtheneedforsupplementaltherapy.
© 2017 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 Vertigemposicional paroxísticabenigna; Insuficiênciada vitaminaD3; Recorrência; Formasclínicas
Níveisde25(OH)D3,incidênciaerecorrênciadediferentesformasclínicasde vertigemposicionalparoxísticabenigna
Resumo
Introduc¸ão: Vertigemposicional paroxística benignaé a causamais comum de tonturasna populac¸ãoem geral. Éumacondic¸ãonoqualníveis reduzidosdevitamina Dpodemter um potencialimpactoparaodesenvolvimentodecrisesrecorrentes.
Objetivos: Oobjetivodesseestudofoimedirosníveisséricosde25-hidroxivitaminaD3(25-OH D3)empacientescomvertigemposicionalparoxísticabenignaedeterminarsehádiferenc¸a nosníveisséricosdevitaminaD3entrepacientescomesemrecorrência,bemcomoentreas diferentesformasclínicasdevertigemposicionalparoxísticabenigna.
Método: Oestudoincluiu 40 pacientessubmetidos a exame médico regular, diagnosticados comvertigemposicionalparoxísticabenignadecanalposteriorbaseadonoresultadopositivo doteste de Dix-Hallpike.Todosospacientes foramsubmetidos àmanobrade Epleyapóso diagnóstico.Ospacientesforamclassificadosdeacordocomasdiretrizesatuaisparaosníveis devitaminaD3séricaemtrêsgrupos:deficiência,insuficiênciaeníveladequado.
Resultados: Onívelséricomédiode25-OHD3entreosindivíduosavaliadosfoide20,78ng/mL, indicandofaltaouinsuficiênciadestavitamina.Deacordocomosníveisde25-OHD3,amaioria dospacientesapresentoudeficiência(47,5%).Seteindivíduos(17,5%)entrevistadostinhamnível sanguíneoadequadode25-OHD3 e14(35%)apresentavaminsuficiência.Nãofoiencontrada diferenc¸a significativano nível séricode 25-OH D3 entrepacientes come semrecidiva de vertigemposicionalparoxísticabenigna.Houveumadiferenc¸asignificativanosníveisséricos de25-OHD3deacordocomaformaclínicadadoenc¸a.Baixosníveisde25-OHD3forammais encontradosempacientescomcanalitíaseemcomparac¸ãocomaquelescomcupulolitíase. Conclusões:Nãohouvediferenc¸as significativasnonívelséricodevitaminaD3empacientes comesemrecorrência.OestudomostrouumbaixoníveldevitaminaD3séricanamaioriados pacientes,indicandoanecessidadedeterapiasuplementar.
© 2017 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
Benignparoxysmalpositionalvertigo(BPPV)isthemost com-mon cause of dizziness in the general population with a lifetimeprevalenceofabout10%.1Thediseaseoccurs
spon-taneously, clinically manifests in short seizures, intensive vertigosthatarecausedbya certainpositionof thehead andareoftenaccompaniedbyvegetativesymptoms.After placingthe head in the incitingposition, typical vertical-torsionalnystagmuscan be seen. The illness usually lasts for a few daysor weeks and then spontaneously ceases,2
butit can alsoprolong toseveral monthsor evenexceed andbecomechronicorrecurrent.
Pathophysiological mechanismsofdisease development compriseoftearingoffcrystalsofcalciumcarbonate, otoco-nia(orotoliths)fromtheotolithicmembraneoftheutricle,
whichthen,duetogravityandcoincidingwiththeposition ofthehead,floatthroughendolymphinoneofthe semicir-cularcanals.Duetotheanatomicalstructureandwidejoint frontandrearducts’parts,otolithsmostfrequentlyendup intherearductwheretheirmassturnscupularsense, oth-erwiseintendedformanagingaccelerationordeceleration ofangularmovement,inonesensitivetogravity.3
Accord-ingtothesite ofaccumulationof otoconia,twoclinically mostprominentformsarecanalithiasisandcupulolithiasis, wheretheformermanifestsastheaccumulationofotoconial debrisinthetubeitself,whileinthelatter,the accumula-tionisdirectlynexttothecupularsense.Thecauseofthe diseaseismostoftenidiopathic,inabout50%ofcases,and itisassociatedwithdegenerativechangesassociatedwith theageingprocess.4Assecondarycauses,headinjurieslead
labyrinthitis(vestibularneuritis)isconsideredthecauseof theBPPVinabout15%ofcases.6
Epleyor Semontmanoeuvresor theirmodifications are mostlyusedinthetreatmentofPC-BPPVandtheirefficiency isreachingalmost100%aftertwoorseveralprocedures.7---10
However, despite the successful repositioning manoeuvre thediseaserecursinsomepatientsafterashortorlonger period,usuallytakingholdof thesamesemicircularduct. According to data from the available literature, recur-rencehappensin30%ofpatientsafteroneyear,11 whereas
whenlongerobservationperiodsareconsideredrelapsesare recordedmorefrequently,inabout50%ofcases.12,13
In 2003 Vibert D. et al. noted the possible connec-tionbetweenosteoporosisandBPPV.14 Additionally,recent
researchindicatedtheimpactofthevitaminDlevelsonthe BPPVwithreducedlevelsbeingassociated withits occur-rence and more frequent recurrence.15---22 We know that
vitamin D deficiency can cause bone diseases --- either as rachitisorosteomalacia.Otoconia,similarlytobones,is a resultofthedepositionofinorganic calciumcarbonate(in thebonesit isthe calciumphosphateform)onpreviously formedorganicglycoproteinmatrix.Althoughallthedetails oftheotoconiaformationarestillunknown,itisclearthat there is a great similarity between the otoconia and the bonein theirmatrixstructureandtheconsequent deposi-tionof calcium crystals.16 Mostexperts acknowledge that
the 25-OH vitamin D3 plasma/serumconcentration is the bestindicatorofthegeneralsupplyofthebodywith vita-min D. While 25-OH D3 form of the vitamin D represents most of the active vitamin D form in plasma/serum, 25-OHD2 formisalsopresent insignificant quantities during the replacement therapy with vitamin D2.23---25 The main
objectivesof thisstudy weretodetermine whetherthere aredifferencesintheserum25-OHD3levelamong respon-dentssufferingfromBPPVregardingage,sex,clinicalform, andsingleepisode/recurrenceofthedisease.Inadditionto measuringthelevelof25-OHD3,totalserumcalciumwas determinedduetotheeffectof25-OHD3onitslevel.
Methods
The study included 40 patients diagnosed with PC-BPPV based onthe positive Dix-Hallpike’s test coming for their regular medical examination.26 All patients underwent
Epleymanoeuvreafterthediagnosis.27 Thestudyexcluded
patients withcomorbidities includinga confirmed diagno-sisofMénière’sdisease,vestibularmigraineorunilateralor bilaterallabyrinthhypofunction,patientstakingvitaminD supplementsandthosewithserumcalciumabnormalities. Exclusioncriteriawereappliedfollowingpatients’medical history andlaboratory findings. Patientswere categorised intogroupsaccordingtothelevelofvitaminD3.Groupswere formedbythenewCroatianguidelinesfortheprevention, detectionandtreatmentofvitaminDdeficiencyinadults. Accordingtothisguideline,theamountthatmarksthe opti-mal serumlevel of 25 (OH)D should be above30ng/mL. Valuesbetween20and30ng/mLindicateinsufficiency,and valuesequaltoorlowerthan20ng/mLindicateadeficiency of25(OH)D.28
QuantitativeanalysisofvitaminDandcalciuminserum andplasmawereperformedbystandardlaboratorymethod
ECLIA(the electrochemiluminescence binding assay). The deviceusedwasCobase411immunoassayanalyser(Roche DiagnosticsGmbH,Penzberg,Germany).Reference labora-toryvaluesforserumvitaminDrangefrom20to50ng/mL, whilethereferencevaluesforserumcalciumrangefrom2to 3mmoL/L.SerumlevelsofvitaminDandcalciumwere mea-suredafterthediagnosisofBPPV,and6monthsafterthat. Afterexaminingthespecialists’medicaldocumentationof thepatients,otherdataneededfortheresearch(age,sex, clinicalformofthediseaseandrecurrencedata)werealso gathered.Thecriteriaforrecurrencearere-occurrenceof symptomsandapositiveDix-Hallpiketestaftersuccessfully implementedEpleyrepositioningmanoeuvre.
Ethics
This study was approved by Ethics Committee of the respectiveinstitution under an approval protocol number EP-09/2016-4,in accordancewiththeethicalstandardsof theinstitutionalandnationalresearchcommitteeand con-sistent with the 1964 Helsinki Declaration and its later amendments,or comparableethical standards.All of the patients included in the study were adequately informed about the methods and objectives of this study. They have voluntarily accepted to participate in the study. Informedconsentwasobtainedfromallindividual partici-pantsincludedinthestudy.
Statistics
Descriptivestatisticalmethodswereusedforthefrequency distributionoftheobservedvariables.Differencesin cate-goricalvariables weretestedby 2 testand,ifnecessary,
byFisher’sexacttest.Thenormalityofthedistributionof numericalvariableswastestedbyKolmogorov---Smirnovtest. Differences in the normally distributed numerical varia-blesbetweenthetwogroupsweretestedbyMann---Whitney
Utest, and according to the diagnoses by Kruskal---Wallis test.29,30 Allp-valuesaretwo-sided.The significancelevel
wasset at ˛=0.05.The statistical program Rwasusedin thestatisticalanalysis(www.r-project.org,version3.2.3.).
Results
Thestudyincluded40respondents,29ofwhomwerewomen (73%)withmeanageof64.In19(47.5%)respondents,the exactclinicalformofthediseasewasdetermined:10(53%) werediagnosedwithPC-BPPV(canalolithiasis)and9(47%) werediagnosedwithPC-BPPV(cupulolithiasis).Recurrence ofthe disease wasidentified in5 (16%) respondents. The averageleveloffreecalciuminthebloodwas2.15mmoL/L andofvitaminD320.78ng/mL(Table1).
Statistically,therewasnosignificantdifferencebetween gender groups regarding age, free calcium and vitamin D3 levels (Table 2). Also,significant correlation of recur-renceandgenderwasnotfound(Table3).Additionally,no significant differences between recurrenceof the disease regarding age, vitamin D3 values and free calcium levels werefound(Table4).
Table1 Characteristicsofrespondents. Number(%)ofrespondents Gender Male 11(28) Female 29(72) Recurrence Yes 5(16) No 26(84) Diagnosis PC-BPPV(cupulolthiasis) 9(47) PC-BPPV(canalolithiasis) 10(53) Mean(standarddeviation)
Age(years) 64(12)
Ca2+(mmoL/L) 2.15(0.38)
VitaminD3(ng/mL) 20.8(7.87)
Table2 Meanage,vitaminD3,andfree calciumlevelin bloodaccordingtoage.
Mean(standarddeviation) pa
Male Female
Age(years) 62(15) 65(11) 0.842
VitaminD3(ng/mL) 21(6) 21(8) 0.832
Ca2+(mmoL/L) 2.16(0.33) 2.14(0.4) 0.299
aMann---WhitneyUtest.
Table3 Correlationofrecurrenceandgender. Numberofrespondents(%) pa
Male Female
Recurrence 0.583
Yes 2(25) 3(13)
No 6(75) 20(87)
aFisher’sexacttest.
Whenanalyzingthedataaccordingtothediagnosisthe followingresultswereobtained:theageofrespondentsand theleveloffreecalciumdidnotshowsignificantdifferences but vitamin D3 level was significantly decreased in PC-BPPVlat.dex.(canalolythiasis),andsignificantlyincreased in PC-BPPVlat. sin. (cupulolithiasis)(Kruskal---Wallis test,
p=0.034)(Table5). 0 2 4 6 8 10 12 14 16 18 20 Adequate level Insufficiency Deficiency Nu m b e r o f r e s pond en ts
Figure1 RespondentsaccordingtothevitaminD3level. AccordingtothelevelsofvitaminD3,mostrespondents sufferedfromitsdeficiency(47.5%).Adequatebloodlevels ofvitaminDarepresentin7(17.5%)patientswhile14(35%) respondentssufferedfromvitaminD3insufficiency(Fig.1). Respondents with canalithiasis had significantly lower values of vitamin D3 when compared to cupulolithiasis (Mann---WhitneyUtest,p=0.013),whereastheleveloffree calciumwassimilarinbothclinicalformgroupsofthe dis-ease(Table6).
Intheanalysesofthediseaseclinical form,in casesof canalolithiasis there were significantly more respondents withvitaminDdeficiency(6/9respondents),whileinmost cases of cupulolithiasis results indicated insufficiency in vitamin D levels (5/10 respondents) (2 test, p=0.036)
(Table7).
Discussion
Theresultsofthisstudyindicatedthattheaverageageof respondentsis64years,whichisconsistentwithdatainthe literature.Previousstudiessuggest thattheoccurrenceof BPPVpeaksinthesixthandseventhdecadeoflife.31 This
study included40 patients,27.5%of whomweremenand 72.5%women.AlthoughitisknownthatBPPVoccurstwiceas ofteninwomen,31 thedifferencebetweenwomenandmen
inthisstudycanbeattributedtotherelativelysmallsample. Also,participationinthestudyisvoluntaryandwomenhave respondedinhighernumbers.
Recentstudieshavedemonstratedthepotentialimpact ofreducedlevelsofvitaminDintheoccurrenceofBPPV15---21
andmorefrequentincidenceofrecurrenceinpatientswith reduced values of the vitamin D.21,22 The role of vitamin
D is well-known in the regulation of serum calcium and phosphorus,therebymaintainingtheproperbonestructure. SimilarlytotheroleofvitaminD inthebonemetabolism,
Table4 Correlationofmeanage,freecalciumandvitaminD3levelandrecurrence.
Median(interquartilerange) pa
Accordingtotheincidenceofrecurrence
Recurrence Withoutrecurrence
Age(years) 58(52---74) 65(57---69) 0.707
VitaminD3(ng/mL) 21.9(14---22) 20.2(16.8---30.5) 0.485
Ca2+(mmol/L) 1.99(1.55---2.20) 2.32(2.16---2.43) 0.068
Table5 Meananddispersionaccordingtothediagnosis.
Median(interquartilerange) pa
PC-BPPVlat.dex. (canalolithias) PC-BPPVlat.dex. (cupulolithiasis) PC-BPPVlat.sin. (canalolithiasi) PC-BPPVlat.sin. (cupulolithiasi) Age 71(67---74) 68(62---69) 66(61---69.5) 55(55---62) 0.059 VitaminD3 (ng/mL) 15(12.8---18) 24(22---32) 20.35(17.75---28) 32(17---37.8) 0.034 Ca2+ (mmoL/L) 2.28(1.7---2.43) 2.32(2.31---2.38) 1.8(1.23---2.38) 2.44(2.37---2.45) 0.500 a Kruskal---Wallistest.
Table6 Meananddispersionaccordingtoclinicalformofthedisease. Median(interquartilerange)
Accordingtoclinicalformofthedisease pa
Canalolithiasis Cupulolithiasis
VitaminD3(ng/mL) 18(15---20.1) 27(22---32) 0.013
Ca2+(mmoL/L) 2.27(1.23---2.39) 2.38(2.31---2.44) 0.650
a Mann---WhitneyUtest.
therearestudies showing theroleof vitamin D inotolith metabolismaswellaspositivecorrelationofreduced vita-min D serum levels and the emergence of BPPV relapse with low vitamin D levels (≤20ng/mL) presenting a con-siderable risk factors for BPPV recurrence.20---22,32 Because
of the influence of vitaminD3 in the regulation of serum calciumlevels,boththevitaminD3andthecalciumlevels weremeasured inallpatients.Theaverageserumcalcium for all respondents amounted to 2.15mmoL/L, which is thelowerlimitofnormalvalues(referenceserumcalcium level is2.14---2.53mmoL/L).The average serumvitaminD was 20.78ng/mL, which is slightly less than the average level of vitaminD3 in the study conductedby Bükiet al. (23ng/mL).15Therewasnosignificantdifferenceinthelevel
ofcalciumandvitaminD3betweenmenandwomen.Kahr etal. conducteda studyin 2016 andfound that 93.5%of patientshavelevelsofvitaminD3lessthan20ng/mL.33
Sim-ilarly,alargepercentageofpatients(80%)withvitaminD3 levellessthan20ng/mLwasfound inastudy byJeongSH etal.18Inourstudy,thelargestpercentageofrespondents
(47.5%)recordedvitaminD3leveloflessthan20ng/mL,i.e.
deficiency,while35%recordedinsufficiencyandonly17%of respondentsrecordedadequatelevelsofvitaminD3(Fig.1). There were differencesin vitamin D3 levelsin various clinical forms of BPPV, as well asin accordance withthe affectedside, wherethe highest median vitaminD3 level wasinPC-BPPVinpatientswithcupulolithiasisontheleft side,32ng/mL,andthelowestinPC-BPPVinpatientswith right canalithiasis, 15ng/mL (Table 5). According to this study, patients with canalithiasis have significantly lower serumlevelsof vitaminD and calciumthan patients with cupulolithiasis.Asignificant differencewasfound in mea-suredvaluesandthecategorizationofthevitaminD3status accordingtotheclinicalformofthedisease,whereas signif-icantdifferencewasnotfoundinthelevelofcalciuminthe samecategorization(Tables6and7).Accordingtothe clin-icalform,incanalithiasis, thereis a vitaminD deficiency (66.7%),while incupulolithiasis resultsindicatevitamin D insufficiency(50%).
Amor-DoradoJ.C.etal.foundthat36.5%ofrecurrence occurswithin48months.34BrandtT.etal.intheir
retrospec-tivestudy of 125 patients,6---17 years afterthe diagnosis
Table7 Meananddispersionaccordingtoclinicalformofthedisease.
Number(%)ofrespondentsaccording
VitaminD3 Toclinicalformofthedisease pa
Canalolithiasis Cupulolithiasis Deficiency 6/9 1 Insufficiency 2/9 5/10 0.036 Adequatelevel 1/9 4/10 Total 9/9 10/10 a 2test.
found 50% of recurrence, of which the largest part (80%) occurred withinthe first year. They also recorded almost twicethe incidenceof recurrencein patientsin the sixth decadeoflifethaninthoseintheseventh,andmuchhigher rate of recurrence in women (58%) than in men (39%).13
In this study, recurrence was, contrary to the findings of thosestudies,13,34reportedinsomewhatlowerpercentage,
i.e. in 16.13% of the respondents, for which there wasa history of recurrence after the repositioning manoeuvre. Furthermore,ahighernumberofrecurrencewasrecorded inwomen,whichisinlinewiththehighernumberofwomen withBPPVincludedinthisstudy(Table3).Themedianage of respondents with recurrencewas 58 years. Given that theaveragevalueofvitaminD3inpatientsincludedinthe studywasinsufficient,itcouldbestatedthatthereisa pos-itivecorrelationbetweenthelowlevelsofvitaminD3and theoccurrenceof BPPV. Talaatetal.reportedtheresults oftheirstudy,wherethereisastatisticallysignificant dif-ference inthe level of vitamin D3 between patients with andwithoutrecurrenceofBPPV, whichwasnotconfirmed in our study.35 This fact can be explained by a relatively
shortperiodofmonitoringpatientsforrecurrence, particu-larlyinthosepatientswhowereincludedintheresearchlast since,aspreviouslyshown,12,13,34thenumberofrecurrences
increaseswithtime.
Conclusion
Therewerenosignificantdifferencesin serumvitaminD3 levelinpatientswithandwithoutrecurrence.Thestudyhas demonstratedalowserumvitaminD3levelinmostpatients, indicatinganecessityofamandatorysupplementaltherapy forallpatientswiththereduced25OHD3.Thepatientswith a clinical canalithiasis form have manifested significantly lower vitamin D3 values than those with cupulolithiasis, which opens up a new perspective on understanding the otolithicmetabolism.
Funding
Thisresearchreceivednospecificgrantfromfunding agen-ciesinthepublic,commercial,ornot-for-profitsectors.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
All authors participated in the research conceptual set up, interpretation and discussion of the data as well as manuscript writing. All authors revised and approved the finalcopyofthemanuscript.
References
1.vonBrevernM,RadtkeA,LeziusF,FeldmannM,ZieseT,Lempert T, et al. Epidemiology of benign paroxysmal positional ver-tigo:apopulationbasedstudy.JNeurolNeurosurgPsychiatry. 2007;78:710---5.
2.ImaiT,ItoM,TakedaN,UnoA,MatsunagaT,SekineK,etal. Nat-uralcourseoftheremissionofvertigoinpatientswithbenign paroxysmalpositionalvertigo.Neurology.2005;64:920---1. 3.SchuknechtHF.Cupulolithiasis.ArchOtolaryngol.1969;90:765. 4.BalohRW,HonubriaV,JacobsonK.Benignpositionalvertigo: clinical and oculographic features in 240 cases. Neurology. 1987;37:371---8.
5.MotinM,KerenO,GroswasserZ,GordonCR.Benign paroxys-malpositionalvertigoasthecauseofdizzinessinpatientsafter severetraumaticbraininjury:diagnosisandtreatment.Brain Inj.2005;19:693---7.
6.KarlbergM, HalmagyiGM, Büttner U,Yavor RA. Sudden uni-lateral hearing loss with simultaneous ipsilateral posterior semicircularcanalbenignparoxysmalpositionalvertigo:a vari-antofvestibulo-cochlearneurolabyrinthitis?ArchOtolaryngol HeadNeckSurg.2000;126:1024---9.
7.FurmanJM,Cass SP.Benignparoxysmal positional vertigo.N EnglJMed.1999;341:1590---6.
8.WolfJS,BoyevKP,ManokeyBJ,MattoxDE.Thesuccessofthe modifiedEpleymaneuverintreatingbenignparoxysmal posi-tionalvertigo.Laryngoscope.1999;109:900---3.
9.RoaCastroFM,DurandeAlbaLM,RoaCastroVH.Experience with Epley’s manoeuvre and vestibular habituation training inbenignparoxysmalpositionalvertigo.ActaOtorrinolaryngol Esp.2008;59:91---5.
10.WaleemSS,MalikSM,UllahS,UlHassanZ.Officemanagement ofbenignparoxysmalpositionalvertigowithEpley’smaneuver. JAyubMedCollAbottabad.2008;20:77.
11.YetiserS, InceD.Diagnostic roleofhead-bendingand lying-downtestsinlateralcanalbenignparoxysmalpositionalvertigo. OtolNeurotol.2015;36:1231---7.
12.NunezRA,CassSP,FurmanJM.Shortandlong-termoutcomesof canalithrepositioningforbenignparoxysmalpositionalvertigo. OtolaryngolHeadNeckSurg.2000;122:647---52.
13.BrandtT,HuppertD,HechtJ,KarchC,StruppM.Benign parox-ysmalpositioningvertigo:along-termfollow-up(6---17years)of 125patients.ActaOtolaryngol.2006;126:160---3.
14.VibertD,KompisM,HauslerR. Benignparoxysmal positional vertigo in older women may be related to osteoporo-sis and osteopenia. Ann Otol Rhinol Laryngol. 2003;112: 885---9.
15.Büki B, Ecker M, Jünger H, Wang Lundberg Y. Vitamin D deficiency and benign paroxysmal positioning vertigo. Med Hypotheses.2013;80:201---4.
16.YangH,ZhaoX,XuY,WangL,HeQ,LundbergYW.Matrix recruit-mentand calcium sequestrationfor spatialspecific otoconia development.PLoSOne.2011;6:e20498.
17.JeongSH,ChoiSH,KimJY,KooJW,KimHJ,KimJS.Osteopenia andosteoporosisinidiopathicbenignpositionalvertigo. Neu-rology.2009;72:1069---76.
18.JeongSH,KimJS,ShinJW,KimS,LeeH,LeeAY,etal.Decreased serumvitaminDinidiopathicbenignparoxysmalpositional ver-tigo.JNeurol.2013;260:832---8.
19.Parham K, Leonard G, Feinn RS, Lafreniere D, Kenny AM. Prospectiveclinicalinvestigationoftherelationshipbetween idiopathic benign paroxysmal positional vertigo and bone turnover:apilotstudy.Laryngoscope.2013;123:2834---9. 20.YamanakaT,ShirotaS,SawaiY,MuraiT,FujitaN,HosoiH.
Osteo-porosisasariskfactorfortherecurrenceofbenignparoxysmal positionalvertigo.Laryngoscope.2013;123:2813---6.
21.SheikhzadehM,LotfiY,MousaviA,HeidariB,MonadiM,Bakhshi E.InfluenceofsupplementalvitaminDonintensityofbenign paroxysmal positional vertigo: a longitudinal clinical study. CaspianJInternMed.2016;7:93---8.
22.TalaatHS, Abuhadied G, TalaatAS, Abdelaal MS. Low bone mineral density and vitamin D deficiency in patients with benignpositionalparoxysmalvertigo.EurArch Otorhinolaryn-gol.2015;272:2249---53.
23.HartGR,FurnissJL,LaurieD,DurhamSK.Measurementof vita-minDstatus:background,clinicaluse,andmethodologies.Clin Lab.2006;52:335---43.
24.HoughtonLA,ViethR.Thecaseagainstergocalciferol(vitamin D2)asavitaminsupplement.AmJClinNutr.2006;84:694---7. 25.HolickMF.VitaminDdeficiency.NEnglJMed.2007;357:266---81. 26.DixMR,HallpikeCS.Pathology,symptomatologyanddiagnosis ofcertaindisordersofthevestibularsystem.ProcRSocMed. 1952;45:341.
27.EpleyJM.Thecanalithrepositioningprocedure:fortreatment ofbenignparoxysmalpositionalvertigo.OtolaryngolHeadNeck Surg.1992;107:399---404.
28.Vraneˇsi´c BenderD, Giljevi´c Z,Kuˇsec V, Laktaˇsi´c ˇZerjavi´c N, BoˇsnjakPaˇsi´cM,VrdoljakE,etal.Guidelinesforthe preven-tion,detectionandtherapyofvitaminDdeficiencyinadults. LijeˇcVjesn.2016;138:1---12.
29.Maruˇsi´cMisur.Uvoduznanstveniradumedicini.In:Udˇzbenik. 4thed.Zagreb:Medicinskanaklada;2008.
30.Ivankovi´c D i sur. Osnove statistiˇcke analize za medicinare. Zagreb:MedicinskifakultetSveuˇciliˇstauZagrebu;1988.
31.BrandtT.Vertigo.2nded.London:Springer;2003.
32.KudlacekS,SchneiderB,PeterlikM,LebG,KlaushoferK,Weber K,etal.AssessmentofvitaminDandcalciumstatusinhealthy adultAustrians.EurJClinInvest.2003;33:323---31.
33.KahramanSS,OzcanO,ArliC,UstunI,ErduranR,AkogluE,etal. Calciumhomeostasisduring attackand remissioninpatients withidiopathicbenignparoxysmalpositionalvertigo.Otol Neu-rotol.2016;37:1388---92.
34.Amor-Dorado JC, Barreira-Fernández MP, Aran-Gonzalez I, Casariego-Vales E,LlorcaJ,González-Gay MA.Particle repo-sitioningmaneuverversusBrandt-Daroffexercisefortreatment of unilateral idiopathic BPPV of the posterior semicir-cular canal: a randomized prospective clinical trial with short- and long-term outcome. Otol Neurotol. 2012;33: 1401---7.
35.TalaatHS,KabelAM,KhalielLH,AbuhadiedG,Abuhadied G, El-Naga HA, et al. Reduction of recurrence rate of benign paroxysmalpositionalvertigobytreatmentofseverevitamin Ddeficiency.AurisNasusLarynx.2016;43:237---41.
