Braz. j. . vol.83 número4

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www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

Aging

and

wave-component

latency

delays

in

oVEMP

and

cVEMP:

a

systematic

review

with

meta-analysis

夽

Ysa

Karen

dos

Santos

Macambira

a

_,

_Aline

_Tenório

_Lins

_Carnaúba

b

_,

Luciana

Castelo

Branco

Camurc

¸a

Fernandes

c,d

,

Nassib

Bezerra

Bueno

e,f

,

Pedro

de

Lemos

Menezes

c,g,∗

a_Universidade_Estadual_de_Ciências_da_Saúde_de_Alagoas_(UNCISAL),_Audiologia,_Maceió,_AL,_Brazil

b_Universidade_Federal_de_Alagoas_(UFAL),_Rede_Nordeste_de_{Biotecnologia}_(RENORBIO),_{Biotecnologia}_em_Saúde,_Maceió,_AL,

Brazil

c_Universidade_Estadual_de_Ciências_da_Saúde_de_Alagoas_(UNCISAL),_Maceió,_AL,_Brazil d_Universidade_Federal_de_São_Paulo_(UNIFESP),_Distúrbio_da_{Comunicac¸ão,}_São_Paulo,_SP,_Brazil

e_Universidade_Federal_de_Alagoas_(UFAL),_Maceió,_AL,_Brazil

f_Universidade_Federal_de_São_Paulo_(UNIFESP),_Ciências,_São_Paulo,_SP,_Brazil

g_Universidade_de_São_Paulo_(USP),_Física_aplicada_à_Medicina,_São_Paulo,_SP,_Brazil

Received10October2016;accepted7December2016 Availableonline2February2017

KEYWORDS

Cervicalvestibular evokedmyogenic potential; Ocularvestibular evokedmyogenic potential; Elderly

Abstract

Introduction:Thenaturalagingprocessmayresultinmorphologicalchangesinthevestibular systemandintheafferentneuralpathway,includinglossofhaircells,decreasednumbersof vestibularnervecells,andlossofneuronsinthevestibularnucleus.Thus,withadvancingage, thereshouldbeadecreaseinamplitudesandanincreaseinlatenciesofthevestibularevoked myogenicpotentials,especiallytheprolongationofp13latency.Moreover,manyinvestigations havefoundnosignificantdifferencesinlatencieswithadvancingage.

Objective: Todetermineifthere aresignificant differencesinthelatencies ofcervicaland ocularevokedmyogenicpotentialsbetweenelderlyandadultpatients.

Methods:Thisisasystematicreviewwithmeta-analysisofobservationalstudies,comparing thedifferencesoftheseparametersbetween elderlyandyoungadults,withoutlanguageor daterestrictions,inthefollowingdatabases:Pubmed,ScienceDirect,SCOPUS,WebofScience, SciELOandLILACS,inadditiontothegrayliteraturedatabases:OpenGrey.euandDissOnline, aswellasResearchGate.

夽 _Please_cite_this_article_as:_Macambira_YK,_Carnaúba_AT,_Fernandes_LC,_Bueno_NB,_Menezes_PL._Aging_and_{wave-component}_latency_delays inoVEMPandcVEMP:asystematicreviewwithmeta-analysis.BrazJOtorhinolaryngol.2017;83:475---87.

∗_{Corresponding}_author.

E-mail:pedrodelemosmenezes@gmail.com(P.L.Menezes).

PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial.

http://dx.doi.org/10.1016/j.bjorl.2016.12.006

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Results:Then1oVEMP latencieshadameandelayintheelderlyof2.32mswith95%CIof 0.55---4.10ms.Theoveralleffecttestshowedp=0.01,disclosingthatsuchdifferencewas sig-nificant.The heterogeneityfound wasI2₌_96% ₍_p_<_0.001)._Evaluation _of_p1_latency _was_not

possibleduetothelownumberofarticlesselectedforthiscondition.cVEMPanalysiswas per-formedin13articles.Forthep13component,themeanlatencydelayintheelderlywas1.34ms with95%CIof0.56---2.11ms.Theoveralleffecttestshowedap<0.001,withheterogeneityvalue

I2₌_92%₍_p_<_0.001)._For_the_n23_component,_the_mean_latency_delay_for_the_elderly_was_2.82_ms

with95%CIof0.33---5.30ms.Theoveralleffecttestshowedp=0.03.Theheterogeneityfound wasI2₌_99%₍_p_<_0.001).

Conclusion:The latencyofoVEMP n1wave componentandlatencies ofcVEMPp13 andn23 wavecomponentsarelongerintheelderlyaged>60yearsthaninyoungadults.

© 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-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

Potencialevocado miogênicovestibular cervical;

Potencialevocado miogênicovestibular ocular;

Idosos

EnvelhecimentoeosatrasosnaslatênciasdascomponentesdeondanooVEMPeno

cVEMP:umarevisãosistemáticacommetanálise

Resumo

Introdução:Oprocessonaturaldeenvelhecimentopoderesultaremmudançasmorfológicasno sistemavestibularenavianeuralaferente,incluindoperdadecélulasciliadas,diminuiçãodo númerodecélulasdonervovestibulareperdadeneurôniosnonúcleovestibular.Dessaforma, comoavançodaidade,deveria ocorrerdiminuiçãonasamplitudeseaumentonaslatências dospotenciaisevocadosmiogênicosvestibulares(VEMP),principalmenteoprolongamentoda latênciap13.Alémdisso,muitosartigosnãoencontraramdiferençassignificativasnaslatências doVEMP,comoavançodaidade.

Objetivo:Analisar se existem diferenc¸as significativas para as latências do VEMP cervical (cVEMP)edoVEMPocular(oVEMP)entreidososeadultos.

Método: Revisão sistemática com metanálise de estudos observacionais que comparam diferenc¸asdessesparâmetrosentreidososeadultosjovens,semrestric¸õesdeidiomasoudatas, nasseguintesbasesdedados:Pubmed,ScienceDirect,Scopus,WebofScience,SciELOeLilacs. Alémdasbasesdeliteraturacinzenta:OpenGrey.eueDissOnline,eaindanoResearchGate.

Resultados: Aslatênciasn1dooVEMPtiveramumatrasomédionosidososde2,32mscomIC 95%0,55---4,10ms.Otesteparaoefeitogeralobtevep=0,01erevelouquetaldiferenc¸afoi significativa.AheterogeneidadeencontradafoiI2₌_96%₍_p_<_0,001)._Avaliac_¸ão_da_latência_de_p1

nãofoipossíveldevidoaobaixonúmerodeartigosselecionadosparaessacondic¸ão.Aanálise docVEMPfoirealizadacom13artigos.Paraocomponentep13,oatrasomédioparaaslatências dosidososfoide1,34mscomIC95%0,56---2,11ms.Otesteparaoefeitogeralobtevep<0,001; comvalordaheterogeneidadeI2₌_92%₍_p_<_0,001)._Para_o_componente_n23,_o_atraso_médio_para

aslatênciasdosidososfoide 2,82mscomIC95%0,33---5,30ms. Otesteparaoefeitogeral obtevep=0,03.AheterogeneidadeencontradafoiI2₌_99%₍_p_<_0,001).

Conclusão:Alatênciadocomponentedeondan1dooVEMPeaslatênciasdoscomponentes deondap13en23docVEMPsãomaisprolongadasemidososcomidade>60anosdoqueem adultosjovens.

© 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Publicado por Elsevier Editora Ltda. Este é um artigo Open Access sob uma licença CC BY (http:// creativecommons.org/licenses/by/4.0/).

Introduction

The vestibular evoked myogenic potential (VEMP) is an objective, non-invasive examination with high-intensity auditorystimulithat assessesvestibularfunction integrity throughthemusclereflexresponse.1---3

Recentadvancesintechnologyhaveallowedcliniciansto assessthe vestibularfunctioncapacitythroughthe ocular

(oVEMP)andcervicalvestibularevokedmyogenicpotential (cVEMP).1,2

OVEMP is a short-latency potential that evaluates the utriculo-ocular reflex (upper vestibular nerve),3 _whereas

cVEMP is a medium-latencypotential1 _that _evaluates _the

saccular-colicreflex(lowervestibularnerve).1---6_Thus,

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thesecondmotorneuron,mayinterferewiththeresponse. Inviewofthis,theVEMPevaluatesthefinalreflex; there-fore, it cannot be used for the topographical diagnosis, but confirmsor rulesout theinvolvementof theaffected pathway.7---10

As a basic evaluation principle of any evoked poten-tial, the time between the stimulus and the response is measured,classifyingitasnormalor alteredbasedonthe durationtimeandthemorphologyofthegeneratedelectric waves.11---13

Thetracingobtainedconsistsoftwobiphasicwave com-plexes. In the cVEMP, the first biphasic potential has a positive peak (P) with a mean latency of 13 milliseconds (ms),followedbyanegativepeak(N)withameanlatency of23ms,anditiscalledP13-N23;whereastheoVEMPshows anegativepeak(N)withameanlatencyof10ms,followed byapositivepeak(P)withameanlatencyof15ms,being called N10-P15.4,14---16 _The _interaural _difference _of _peak

latency is associatedwith theneuronal conduction veloc-ity,andtheincreasein thisdifferencecouldbeexplained bytheasymmetryinthisvelocity,commoninneurological diseases.17,18

Latencyistheclinicalparametermostoftenusedinthe analysisofVEMPresponses,sinceitdoesnotdependon stim-ulus intensity or the muscular tension level and has high reproducibility.1,19

With the natural agingprocess, morphological changes mayoccurinthevestibularsystemandtheafferentneural pathway,includinglossofhaircells,decreasednumbersof vestibularnervecellsandlossofneuronsinthevestibular nucleus.19---22_Therefore,_with_advancing_age,_there_should_be

adecreaseinamplitudes andanincrease inlatencies22 _of

thesepotentials,especiallytheprolongationofp13latency. However, some authors report that VEMP latency cannot beaffectedbytheotolyticfunction,butbytheactivation of the organreceptor.22 _{Additionally,} _many _{investigations}

didnot findsignificant differencesin VEMPlatencies with advancingage.21,23---27 _Therefore,_the_aim_of_this_study_was

todetermineiftherearesignificantdifferences regarding cVEMPandoVEMPlatenciesbetweentheelderlyandyoung adults.

Methods

Thedevisingofthissystematicreviewsoughttoanswerthe following question: Do the elderly have different latency values of cervical and ocular vestibular evoked myogenic potentialsthanadults?Basedonthisquestion,thereviewis reportedaccordingtotheitemsofthePreferredReporting Items for Systematic Reviews and Meta-Analyses State-ment(PRISMA).AprotocolwaspublishedinthePROSPERO database28 ₍_{http://www.crd.york.ac.uk/PROSPERO}_),_under

registrationnumberCRD42016046991.

Searchstrategy

Thestrategyincludesthedescriptors(DECsandMESH)and Free terms (TL), based on the two first elements of PIC (Population,Interest,Context) present in thetitle,which consisted of: (senile OR Age-related OR Aged OR Aging OR Ageing Effect OR Ageing OR older) AND (vestibular

Table1 Literaturesearchstrategy,usedforalldatabases.

MEDLINE(viaPubMed)

#1E#2

#1(Cervicalvestibularevokedmyogenicpotential)OR (myogenicpotential)OR(vestibularpotential)OR (Cervicalevokedpotential)OR(Ocularevokedpotential) OR((Vestibular)AND(Evokedpotential)

#2(senile)OR(relatedtoaging)OR(elderly)OR(Aging)OR (Effectofaging)OR(Aging)OR(Elderly)OR(50years old)OR(60yearsold)OR(65yearsold)OR(70yearsold)

ScienceDirect/ClinicalTrials.gov/LILACS/Scopus/Webof Scienceandotherbases

(VestibularevokedmyogenicpotentialORvestibular potentialORVEMPORCervicalevokedpotentialOR OcularevokedpotentialOR(VestibularPotentialand evoked)AND(senileORRelatedtoagingORElderlyORL AgingOREffectofagingORAgingORElderly)

evokedmyogenicpotentialORvestibularpotentialORVEMP ORCervical evokedpotentialOR Ocularevokedpotential OR [Vestibular AND evoked AND Potential]). The com-pletestrategycanbefoundinthesupplementarymaterial (Table1).

The searches werecarried outbetween themonths of July and August of 2016, and were revised in September ofthesameyear.Thefollowing databasesweresearched: Pubmed,ScienceDirect,BVS(LILACS),SCOPUS,Circumpolar HealthBibliographicDatabase,SciELOandEMBASE,aswell asthegrayliteraturedatabases:OpenGrey.eu,DissOnline, TheNewYorkAcademyofMedicine,aswellas Reasearch-Gate.Therewasnomanualsearchoftheincludedarticles andexpertsintheareawerenotcontactedtoavoidtherisk ofcitationbias.29

Eligibilitycriteria

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Table2 Newcastle-OttawaScale(adapted)forqualityassessmentofcross-sectionalstudies.

Selection:(Maximumof5stars)

1.Samplerepresentativeness:

a)Trulyrepresentativeofthemeaninthetargetpopulation.*(Allsubjectsorrandomsampling). b)Alittlerepresentativeofthemeaninthetargetpopulation.*(Non-randomsampling). c)Groupofselectedusers.

d)Descriptionofthesamplingstrategy. 2.Samplesize:

a)Justifiedandsatisfactory.* b)Notjustified.

3.Non-responses:

a)Comparabilitybetweenresponsesandnon-responsesisestablished,andtheresponserateissatisfactory.* b)Theresponserateisnotsatisfactory,orthecomparabilitybetweenresponsesandnon-responsesisunsatisfactory. c)Descriptionofresponserateorcharacteristicsofresponsesandnon-responses.

4.Exposurecalculation(riskfactor): a)Validatedmeasurementtool.**

b)Measurementtoolnotvalidated,butthetoolisavailableordescribed.* c)Descriptionofthemeasurementtool.

Comparability:(Maximumof2stars)

1.Theobjectsindifferentresultgroupsarecomparable,basedonthestudydesignoranalysis.Confoundingfactorsare controlled.

a)Thestudyconsidersthemostimportantfactor(selectone).* b)Studycontrolforanyadditionalfactor.*

Result:(Maximumof3stars)

1.Resultassessment:

a)Independentblindevaluation.** b)Recordassociation.**

c)Study’sownreport.* d)Nodescription. 2.Statisticaltest:

a)Thestatisticaltestusedtoanalyzethedataareclearlydescribedandadequate,andtheassociationmeasurementis presented,includingconfidenceintervalsandtheprobabilitylevel(p-value).*

b)Thestatisticaltestisnotappropriate,notdescribedorincomplete

ThisscalewasadaptedfromtheNewcastle-OttawaQuality AssessmentScalefor cohortstudiestoperformaqualityassessmentof cross-sectionalstudiesforthesystematicreview,‘‘Arehealthcareworkers’intentionstovaccinaterelatedtotheirknowledge,beliefs, andattitudes?Asystematicreview.’’

Dataextraction

During the selection process, the titles and abstracts of theobtainedarticleswereindependentlyevaluatedbytwo researcherswhowerenotblindedtotheauthorsorjournal title.Disagreementswereresolvedby discussion.Incases wheretherewasnoconsensus,athirdauthorwasaskedto makethefinaldecision.Thefulltextsofpotentiallyeligible articleswereacquiredandanalyzedinfull.

Theoutcomesoughtinthestudieswasthemeanlatency valuesofthebiphasiccomponentsforcVEMPand/oroVEMP andinthesecondassessment,associatedwithadispersion measure.

Datawereanalyzedfrompublishedarticlesandauthors werecontactedforadditionalinformation.Inadditiontothe outcomedata,wealsoobtainedthenamesoftheauthors, title,yearofpublication,country,agerangesofthegroups, numberofsubjectsineach group,monitoredmusclesand auditoryexaminations.Astandardformfordatastoragewas createdbasedonthemodelusedbyCochran.30

Assessmentofbiasrisk

The riskof biaswasassessedaccording tothe recommen-dations of the ‘‘Newcastle-Ottawa’’ manual and scale,31

adaptedforcross-sectionalobservationalstudies.The qual-ity of the study was independently evaluated by two researchersandthedivergenceswereresolvedby consen-sus. The maximum score to be reached was ten points and the evaluated scale items were: (1) representative-ness of the sample; (2) sample size; (3) management of non-responses; (4) exposure calculation (risk factor); (5) comparability,toinvestigatewhetherindividualsin differ-ent groups of outcomes are comparable, based on study designoranalysis,controlofconfoundingfactors;(6) eval-uationofresultsand(7)statisticaltest(Table2).

Data

analysis

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Articles identified through search in databases

(n=7544)

Additional articles identified through other sources

(n=0)

Excluded articles (n=4967) Articles identified after duplicate removal

(n=7189)

Identificationr

Screening

Eligibility

Included

Assessed article (n=7189)

Summaries assessed (n=322)

Full-texts assessed (n=61)

Studies included in the quantitative synthesis

(n=16)

Full-texts excluded (n=45): Inadequate age-range (n=16), Did not analyze latency (n=4), Incomplete data (n=4), Review articles (n=4), Analyzed vestibular pathologies (n=2), Used bone-conduction stimulation (n=2), Assessed galvanic stimulation (n=1), Did not analyze cVEMP or oVEMP (n=1), and does not have a control group (n=1),

Excluded articles (n=4645)

Figure1 Flowchartofarticlesearchandselection.

group) wascompared by meta-analysis. Forthis purpose, a random effects model was used as a measure of the effectof themeandifferencebetween thegroups andas astatisticalmethodofanalysis.An˛valueof0.05was

con-sideredstatisticallysignificant.Whenitwasnotpossibleto obtainadequatedataforanalysis,Cochran’s recommenda-tionswerefollowed.

Thestatisticalheterogeneitybetweenstudieswastested using the Cochran’s Q test and inconsistency was tested using the I2 _test. _A _value _of _p_<_0.10 _was_considered

sta-tisticallysignificant.Whennecessary,studycharacteristics consideredpotentialsourcesofheterogeneitywereincluded inasubgroupanalysis.Furthermore,inthecaseof hetero-geneity,studieswereremoved,onebyone,toinvestigate whetherthatparticularstudywasthesourceof heterogene-ity.

AllanalyseswereperformedusingRevMan5.3software (CochraneCollaboration).

Results

Includedstudies

Theflowdiagramthatillustratesstudysearchandselection is shown in Fig.1. Of the7544 titles considered relevant fromthesearches inthese databases,322abstracts were readand,ofthose,61fulltextswereselectedforreadingin full.Afterreading,41articleswereexcluded,astheydidnot meettheeligibilitycriteriaandfourbecausetheydidnot havesufficientdataandtheirauthorsdidnotrespondtothe requestforadditionalinformation(Table3).Therefore,16

fulltextswereincludedinthequalitativeandquantitative analysis(Table 4).Thelatency means ofyoungadultsand elderlyindividualsofthemeta-analyzedarticlesareshown inTable5(oVEMP)andTable6(cVEMP).

Amongtheselectedstudies,onlythreeassessedoVEMP. However,one of them didnot have p1latency dataand, thus,themeta-analysisofthiscomponentwasvery compro-mised.Ontheotherhand,13articleshadmeanandstandard deviationdataforthecVEMPlatencycomponents,p13and n23, for the control group and for the elderly group. Of these,fourstudies founda significantdifferencebetween thegroups,oneof themfounda significantdifferencefor p13andnon-significantforn23,threestudieswerenotclear whetherthereweredifferencesandfiveaffirmedthatthere werenodifferencesbetweengroups.

Atotalof120subjectswerestudiedfortheassessment ofn1andp1latenciesof oVEMP,60ofwhichwereelderly and60wereyoungadults,and326subjects,ofwhich296 elderlyand326youngadults,wereevaluatedforcVEMPp13 andn23latencies.

In Table 6, all data on means and standard deviations wereprovidedexceptthestandarddeviationsofp13andn23 latenciesoftheelderlyofoneofthestudies,whenevoked byClicks.Inthiscase,thestandarddeviationswere calcu-latedbyapplyingan internationalconventioninwhichthe quotient:mean/2.5isusedtofindthestandarddeviation.

Biasriskassessment

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Table3 Fulltextsexcludedfromtheanalysis.

Name Location Year Reason Name Location Year Reason

Agrawaletal. USA 2013 Agerange Maheuetal. Canada 2015 Reviewarticle Agrawaletal. USA 2012 Agerange McCaslin

etal.

USA 2016 Agerange

BastaeErnst Germany 2007 Didnot analyze latency

Meltem etal.

Turkey 2012 Agerange

Beyazpınaretal. Turkey 2016 Bone-conduction stimulation

Murofushi etal.

Japan 2010 Agerange

Bigelowetal. USA 2016 Vestibular pathology

Nguyen etal.

USA 2010 Agerange

Bigelowetal. USA 2015 Agerange Ochiand Ohashi

Japan 2003 Incomplete dataa Brantbergetal. Norway 2007 Incomplete

dataa

Papathanasiou Greece 2016 Reviewarticle

Changetal. Taiwan 2012 Galvanic

stimulation

Papathanasiou Greece 2013 Reviewarticle

Colebatchetal. Australia 2013 Agerange Pikeretal. USA 2015 Didnotanalyze

latency

Cosietal. Italy 1982 Didnot

analyze cVEMP/oVEMP

Pikeretal. USA 2013 Didnotanalyze

latency

Dennisetal. Australia 2014 Agerange Pikeretal. USA 2011 Agerange

Derinsuetal. Turkey 2009 Agerange Rosengren

etal.

Australia 2011 Agerange

Eleftheriadou etal.

Greece 2009 Agerange Sunetal. USA 2014 Agerange

Erbeketal. Turkey 2014 Agerange Tourtillott

etal.

Canada 2010 Agerange

González-García etal.

Spain 2007 Incomplete

dataa

Tsengetal. Taiwan 2010

Bone-conduction stimulation Halmagyiand

Curthoys

Australia 1999 Agerange Versino etal.

Italy 2015 Agerange

Hongetal. Korea 2008 Vestibular

pathology

Walther etal.

Germany 2010 Agerange

Isaradisaikuletal. Thailand 2012 Agerange WaltherLE etal.

Germany 2011 Agerange

Iwasakiand Yamasoba

Japan 2015 Systematic

review

Welgampola and Colebach

Australia 2001 Didnotanalyze latency

Kurtaranetal. Turkey 2016 Nocontrol Zahang

etal.

China 2014 Agerange

Laymanetal. USA 2015 Agerange Zapalaand

Brey

USA 2004 Agerange

Lietal. USA 2015 Incomplete

dataa

Zunigaetal. USA 2012 Agerange

Maesetal. Belgium 2010 Agerange

a_The_authors_were_contacted_but_did_not_provide_additional_information_until_the_submission_of_this_article.

Allincludedstudiesarecharacterizedasobservationaland cross-sectionalstudies.Inaddition,inthefinalevaluation, allhadapercentageofqualityequaltoorsuperiorto50% (5/10),whereastwoofthemobtainedamaximumscoreof 70%(7/10).

Onlyonestudyassessedthesamplerepresentativeness,25

as it was a normative study and analyzed all available

subjectsinacertainperiod.Allotherstudiesmadechoices perconveniencegroup.

Thesatisfactorysamplesizeof theelderlygroupwasa concernoffourstudies,33---36 _which_conform_to_the_central

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Table4 Characteristicsofincludedstudies.

Authors Year Place Groupsofadults(years) N(Elderly) Intensity Stimulus Assessment

Akinetal.23 ₂₀₁₁ _USA _Group_I_(22---31),_Group_II (61---86)

24 90dBNAn TB500Hz cVEMP

Asal39 ₂₀₁₆ _Egypt _Group_II_(25---35),_Group V(>55)

10 95dBNAn TB500Hz oVEMP

Bastaetal.20 ₂₀₀₅ _Germany _Group_I_(20---40),_Group III(60---76)

20 90dBNAn Tb500Hz cVEMP

Guillénetal.24 ₂₀₀₅ _Spain _Group_I_(11---30),_Group III(>60)

10 100dBNAn Click cVEMP

Jankyand Shepard32

2009 USA GroupII(20---29),Group V(>60)

10 98dBNAn TB

500Hz/Click

cVEMP

Feietal.36 ₂₀₁₅ _China _Group_I_(20---40),_Group III(>60)

20 95dBNAn TB500Hz Botha

Khanetal.25 ₂₀₁₄ _India _Group_II_(16---35),_Group IV(>55)

Kumaretal.33 ₂₀₁₅ _India _Young_adults_(21---40), Elderly(>60)

30 100dBNAn TB500Hz oVEMP

Kumaretal.34 ₂₀₁₀ _India _Group_I_(21---30),_Group_V (>60)

Leeetal.37 ₂₀₀₈ _Korea _Group_II_(20---29),_[Group VI(60---69),GroupVII (>70)]b

[21] 95dBNAn Click cVEMP

Malekietal.35 ₂₀₁₄ _Iran _Group_I_(19---26),_Group_II (>60)

Mandaland Barman26

2009 India GroupI(20---30),[Group IV(60---70),GroupV (70---80)]2

[21] 105dBNAn TB500Hz cVEMP

Sardaetal.40 ₂₀₁₆ _India _Group_I_(20---30),_Group_V (60---70)

10 95dBNAn TP500Hz cVEMP

Singhetal.38 ₂₀₁₄ _Germany _Group_II_(20---30),_[Group VI(60---70),GroupVII (>70)]2

Suetal.21 ₂₀₀₄ _Taiwan _Group_II_(21---40),_Group IV(>60)

Tourtillott27 ₂₀₀₉ _USA _Young_adults_(20---30), Elderly[(65---74), (75---85)]2

a _cVEMP_and_oVEMP_latencies_were_assessed.

b _The_groups_were_analyzed_together,_as_the_criterion_chosen_for_the_group_was_>55_years_or_>60_years.

Table5 MeanandstandarddeviationofoVEMPn1andp1latencies,foryoungadultsandfortheelderly,perstudy.

Authors Meann1latency(±SD)ms Meanp1latency(±SD)ms Stimulus

Youngadultgroup Elderlygroup Youngadultgroup Elderlygroup

Asal(2016)39 _11.6_±_0.7 _11.8_±_0.1 _--- _--- _TB₅₀₀_Hz

Feietal.(2015)36 _16.0_±_1.1 _20.0_±_3.1 _25.5_±_3.6 _26.6_±_3.9 _TB₅₀₀_Hz

Kumaretal.(2015)33 _12.0_±_1.2 _14.6_±_2.1 _16.1_±_1.3 _19.4_±_2.2 _TB₅₀₀_Hz

The non-response rate was satisfactory in 50% of all studies using validated tools for data collection and the comparability between the control group and the elderly groupwasalsopossiblefor allofthem. Theevaluationof theresultswascarriedoutinallthestudiesthroughtheir ownreports, exceptinthetwostudies,33,34 _in_which_wave

analysiswascarriedoutbytwoindependentprofessionals. Finally,allstudiesusedappropriatestatisticaltests.

Dataanalysis

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Table6 MeansandstandarddeviationsofcVEMPp13andn23latencies,foryoungadultsandfortheelderly,perstudy.

Authors Meanp13latency(±SD)ms Meanp23latency(±SD)ms Stimulus

Youngadultgroup Elderlygroup Youngadultgroup Elderlygroup

Akinetal.(2011)23 _15.6_±_0.8 _16.0_±_1.6 _23.2_±_1.7 _23.2_±_2.0 _TB₅₀₀_Hz

Feietal.(2015)36 _16.0_±_1.1 _20.0_±_3.1 _25.5_±_3.3 _26.6_±_3.9 _TB₅₀₀_Hz

Guillénetal.(2005)24 _11.1_±_0.1 _12.1_±_0.7 _17.6_±_1.2 _20.7_±_1.9 _Click

JankyandShepard(2009)32 a _17.6_±_3.3 _15.2_±_2.0 _23.6_±_2.3 _22.6_±_2.0 _TB₅₀₀_Hz JankyandShepard(2009)32 a _14.5_±_2.5 _17.4_±_6.692 _20.7_±_2.2 _25.3_±_10.12b _Click

Khanetal.(2010)25 _11.0_±_0.9 _11.3_±_1.7 _17.3_±_2.1 _17.6_±_2.2 _TB₅₀₀_Hz

Kumaretal.(2010)34 _11.4_±_1.2 _13.4_±_1.5 _19.2_±_2.3 _22.3_±_2.0 _Click

Leeetal.(2008)37 _13.1_±_1.6 _16.2_±_2.4 _18.8_±_1.8 _21.7_±_2.8 _Click

Malekietal.(2014)35 _15.5_±_1.2 _16.4_±_1.7 _24.7_±_1.8 _24.0_±_2.0 _TB₅₀₀_Hz

MandalandBarman(2009)26 _14.3_±_1.6 _14.4_±_2.3 _21.0_±_1.6 _20.8_±_2.9 _TB₅₀₀_Hz

Sardaetal.(2016)40 _16.5_±_2.4 _21.8_±_2.9 _25.1_±_2.7 _29.1_±_5.0 _TP₅₀₀_Hz

Singhetal.(2014)38 _14.4_±_0.7 _17.8_±_1.2 _23.7_±_0.6 _27.3_±_1.3 _TB₅₀₀_Hz

Suetal.(2004)21 _11.4_±_0.8 _11.9_±_0.7 _18.2_±_1.3 _19.2_±_1.4 _Click

Tourtillott(2009)27 _16.2_±_1.3 _16.0_±_1.4 _24.6_±_1.1 _23.9_±_2.6 _TB₅₀₀_Hz

a_It_is_the_same_study,_which_analyzed_TB₅₀₀_Hz_and_clicks. b _Standard_deviation_was_not_provided_and_calculated.

Study or subgroup Mean SD

Elderly Young adults Mean difference

Total Mean SD Total Weight IV, Random, 95%CI

Mean difference IV, Random, 95%CI

Study or subgroup 1.1.1 New subgroup

Mean SD

Asal 2016 11.8

20 20

30 10

20 30

10 0.70 [0.61, 0.79] 4.00 [2.56, 5.44] 2.60 [1.99, 3.21] 29.2% 34.7% 36.1% 16 12 11.1 1.1 1.1 0.1 14.6 0.1 3.1 13 Fei et al. 2015

Fei et al. 2015 Guillén et al. 2005 Janky and shepard 2009 Janky and shepard 2009 Khan et al 2005 Akin et al. 2011 Basta et al. 2016 Kumar et al. 2015

Kumar et al. 2010 Lee et al. 2008

Sarda et al. 2016 Singh et al. 2014 Su et al. 2004 Tourtillot 2009 Maleki et al. 2016 Mandal andbarman 2009

Test for overall effect: Z=2.56 (P=0.01)

Heterogeneity. Tau2=2.27; Chi2=56.18, df=2 (P<0.00001); I2=96%

Test for subgroup differences: Not applicable

Total (95% CI)

Subtotal (95% CI) 296 326 100.0%

60 60 100.0% 2.32 [0.55, 4.10]

16 16.1 20 20 24 23 20

24 0.40 [–0.32, 1.12] –0.10 [–1.34, 1.14] 4.00 [2.56, 5.44] 6.8% 6.4% 7.6% 16.2 16 15.6 2.5 1.1 0.8 20 1.6 1.6 3.1 12.1 17.4 10 10 10 10 10

11 1.00 [0.56, 1.14]

–2.90 [–1.26, 7.06] –2.40 [–4.79, –0.01] 0.30 [–0.85, 1.45] 2.4% 4.6% 8.0% 14.5 17.6 11.1 1.2 3.3 0.1 15.2 0.7 6.6 2 11.3 13.4 30 21 9 30 17 37

2.00 [1.33, 2.67] 3.10 [2.13, 4.07] 0.90 [0.17, 1.63] 7.7% 7.2% 6.9% 11.4 13.1 11 1.1 1.6 0.9 16.2 1.7 1.5 1.4 31 31

0.10 [–1.03, 1.23] 7.6% 15.5 1.2 16.4 1.7 14.4 21.8 10 40 21 10 40 31

5.30 [2.97, 7.63] 3.40 [2.97, 3.83] 0.50 [0.03, 0.97] 4.7% 8.0% 6.9% 16.5 14.4 14.3 2.4 0.7 1.6 17.8 2.3 2.9 1.2 11.9 16 20 20 12 20

–0.20 [–1.16, 0.76]

1.34 [0.56, 2.11]

7.3% 7.9% 16.2 11.4 1.3 0.8 0.7 1.4 –10 –5

Elderly young adults

0 5 10

–10 –5

0 5 10

A -

n1 oVEMP.

B -

p13 cVEMP.

Figure2 Meta-analysis:comparisonofn1oVEMPandp13cVEMPlatencies.(A)n1oVEMP.(B)p13cVEMP.

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and

wave-component

latency

delays

in

oVEMP

and

cVEMP

483

Table7 Qualityofincludedarticles,accordingtothe‘‘Newcastle---Ottawa’’qualityassessmentscale.

Authors Sample repre-sentativeness

Justified samplesizea

Non-response rate

Exposure calculation

Comparability Result assessment

Appropriate statisticaltest

Final assessmentb

Akinetal.(2011)23 _Not

representative

No 8.4% Validatedtool Yes Theirown

report

Yes 6/10

Asal(2016)39 _Not

representative

No 40%

(non-satisfactory)

Validatedtool Yes Theirown

report

Yes 5/10

Bastaetal.(2005)20 _Not

representative

No 0% Validatedtool Yes Theirown

report

Yes 6/10

Guillénetal.(2005)24 _Not

representative

report

Yes 6/10

JankyandShepard (2009)32

Not

representative

No 46.7%

(non-satisfactory)

report

Yes 5/10

Feietal.(2015)36 _Not

representative

No cVEMP10%,

oVEMP5%

report

Yes 6/10

Khanetal.(2014)25 _Little

representative

No Unclear(per

group)

report

Yes 6/10

Kumaretal.(2015)33 _Not

representative

Yes 40%

(non-satisfactory)

Validatedtool Yes Two

independent assessments

Yes 7/10

Kumaretal.(2010)34 _Not

representative

Yes 43%

(non-satisfactory)

Validatedtool Yes Two

independent assessments

Yes 7/10

Leeetal.(2008)37 _Not

representative

report

Yes 6/10

Malekietal.(2014)35 _Not

representative

Yes Unclear(per

group)

report

Yes 5/10

MandaleBarman (2009)26

Not

representative

No 7.2% Validatedtool Yes Theirown

report

Yes 6/10

Sardaetal.(2016)40 _Not

representative

No 40%

(non-satisfactory)

report

Yes 5/10

Singhetal.(2014)38 _Not

representative

Yes 40%

(non-satisfactory)

report

Yes 6/10

Suetal.(2004)21 _Not

representative

No 40%

(non-satisfactory)

report

Yes 5/10

Tourtillott(2009)27 _Not

representative

report

Yes 6/10

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Study or subgroup 1.6.1 cVEMP p13 click

Mean SD

Elderly Young adults Mean difference Total Mean SD Total Weight IV, Random, 95%CI

Guillén et al. 2005 Janky and shepard 2009 Kumar et al. 2010 Lee et al. 2008 Su et al. 2004

Test for subgroup differences: Not applicable Test for subgroup differences: Not applicable

Subtotal (95% CI) 91 88 100.0% 12.1

15.2 10

10

11 1.00 [0.56, 1.14] –2.90 [–4.79, 0.01] 9.9% 23.9% 17.6 11.1 3.3 0.1 0.7 2 13.4 30 21 30 17

2.00 [1.33, 2.67] 3.10 [2.13, 4.07] 22.4% 20.1% 11.4 13.1 1.1 1.6 16.2 1.5 1.4

0.50 [0.03, 0.97]

11.9 20 20

1.19 [0.23, 2.16] 23.7% 11.4 0.8 0.7 –10 –10 –5

–5 0 5 10

Elderly young adults Elderly young adults

0 5 10

A -

p13 cVEMP (sub-group evoked only by 500 Hz Toneburst).

B -

p13 cVEMP (sub-group evoked only by Click). Study or subgroup

1.7.1 cVEMP p13 TB 500 Hz Mean SD

Elderly Young adults Mean difference Total Mean SD Total Weight IV, Random, 95%CI

Fei et al. 2015 Janky and shepard 2009 Khan et al 2005 Akin et al. 2011 Basta et al. 2016

Sarda et al. 2016 Singh et al. 2014 Tourtillot 2009 Maleki et al. 2016 Mandal andbarman 2009

Subtotal (95% CI) 205 238100.0% 16 16.1 20 20 24 23 20

24 0.40 [–0.32, 1.12] –0.10 [–1.34, 1.14] 4.00 [2.56, 5.44] 6.8% 6.4% 7.6% 16.2 16 15.6 2.5 1.1 0.8 20 1.6 1.6 3.1

17.4 10 10 –2.90 [–1.26, 7.06]

0.30 [–0.85, 1.45] 2.4%

14.5 1.2 6.6

11.3 9 37

0.90 [0.17, 1.63] 6.9%

11 0.9 1.7

31 31

0.10 [–1.03, 1.23] 7.6% 15.5 1.2 16.4 1.7 14.4 21.8 10 40 21 10 40 31

5.30 [2.97, 7.63] 3.40 [2.97, 3.83] 4.7% 8.0% 6.9% 16.5 14.4 14.3 2.4 0.7 1.6 17.8 2.3 2.9 1.2

16 20 12 –0.20 [–1.16, 0.76]

1.53 [0.33, 2.72] 7.3%

16.2 1.3 1.4

Figure3 Meta-analysis:comparisonofn13cVEMPlatencies,sub-groupsevokedby500HzToneburstandonlybyClick.(A)p13 cVEMP(sub-groupevokedonlyby500HzToneburst).(B)p13cVEMP(sub-groupevokedonlybyClick).

oVEMP:n1andp1latencies

Thenumberofarticlestobemeta-analyzedforoVEMP n1 latencieswassmall,astherewereonlythreeofthem.33,37,38

Themeandelayofthiscomponentforthelatenciesofthe elderlywas2.32mswith95%CIof0.55---4.10ms.Theoverall effecttestshowedp=0.01;disclosingthatsuchdifference wassignificant. However, the heterogeneity I2₌_96%, _with

ap value <0.001(Fig.2A).Finally, duetothesmall num-berofselectedstudies,itwasnotpossibletoanalyzethe subgroupstounderstandtheoriginsofthisheterogeneity.

Ontheotherhand,onlytwoarticleswerefoundforthep1 component,37,38 _which_considerably_affected _the_analyses,

aspreviouslydescribed,andmadeitsstudyimpossible.

cVEMP:p13andn23latencies

Thenumberofarticlestobemeta-analyzedforcVEMP com-ponentsp13andn23latencieswasquiteencouraging.Thus, 13wereselected(describedinTable7).

Forthep13component,themeandelayforthelatencies intheelderlywas1.34mswith95%CIof0.56---2.11ms.The overalleffecttestshowedp<0.001;disclosingthatsucha

differencewassignificant.However,aheterogeneityvalue ofI2₌_92%_was_found,_with_p_<_0.001₍_Fig.₂_B).

Theattemptstoanalyzethesubgroupswerenot success-ful in explainingheterogeneity. When dividing the groups byusedstimulitoevokecVEMP,ToneburstorClick,inboth cases,itremainedhighandwithp<0.001,ascanbeseen inFig.3.Thesamewasdoneforthestimulusintensity(up to95dBNAnand>95dBNAn)andfortheageranges ofthe controlgroups(20---30yearsanddifferent<20---30years),yet bothevaluationswereunsuccessful.

Forcomponentn23,themeandelayforthelatenciesin theelderlywas2.82mswith95%CIof0.33---5.30ms.Thetest fortheoveralleffectshowedap=0.03;disclosingthatthe difference wassignificant. However,a high heterogeneity valueofI2₌_99%_was_found,_with_p_<_0.001₍_Fig.₄_A).

Discussion

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Fei et al. 2015 Guillén et al. 2005 Janky and shepard 2009 Janky and shepard 2009 click Khan et al 2005

Akin et al. 2011 Basta et al. 2016

Kumar et al. 2010 Lee et al. 2008

Sarda et al. 2016 Singh et al. 2014 Su et al. 2004 Tourtillot 2009 Maleki et al. 2016 Mandal andbarman 2009

Total (95% CI) 296 326100.0%

23.2 23.4 20 20 24 23 20

24 –0.01 [–1.03, 1.01] 20.80 [19.53, 22.07] 1.10 [–1.14, 3.34] 6.9% 6.6% 6.9% 2.6 25.5 23.21 26.6 2 1.6 3.9 20.7 22.6 10 10 10 10 10

11 4.00 [2.63, 5.37] –1.00 [–2.89, 0.89] 4.60 [–1.81, 11.01] 0.30 [–1.29, 1.89] 6.7% 4.8% 6.9% 23.6 20.7 16.7 25.3 1.9 2 10.1 17.6 22.3 30 21 9 30 17 37

3.10 [2.01, 4.19] 2.90 [1.43, 4.37] –0.70 [–1.65, 0.25] 6.9% 6.8% 6.8% 19.2 18.8 17.3 21.7 2.2 2 2.8 31 31

–0.20 [–1.56, 1.16] 6.9% 24.7 24 2 20.8 29.1 10 40 21 10 40 31

4.00 [0.48, 7.52] 3.60 [3.16, 4.04] 1.00 [0.16, 1.84] 6.1% 7.0% 6.9% 25.1 23.7 21 27.3 2.9 5 1.3 19.2 23.9 20 20 12 20

–0.70 [–2.00, 0.60]

2.82 [0.33, 5.30]

6.9% 6.9% 24.6 18.2 2.6 3.3 1.6 2.3 2.2 1.2 2.3 1.8 1.8 2.1 1.6 0.6 1.3 2.7 1.1 1.4 2.6

Fei et al. 2015 Janky and shepard 2009 Khan et al 2005 Akin et al. 2011 Basta et al. 2016

Sarda et al. 2016 Singh et al. 2014 Tourtillot 2009 Maleki et al. 2016 Mandal andbarman 2009

Test for overall effect: Z=3.98 (P<0.00001)

Heterogeneity. Tau2=1.62; Chi2=18.33, df=4 (P=0.001); I2=78%

Total (95% CI)

100.0% 100.0% 238 205 91 88 23.2 23.4 20 20 24 23 20

24 –0.01 [–1.03, 1.01] 20.80 [19.53, 22.07] 1.10 [–1.14, 3.34] 10.1% 9.9% 10.1% 2.6 25.5 23.21 26.6 2 1.6 3.9

22.6 10 10 –1.00 [–2.89, 0.89]

0.30 [–1.29, 1.89] 10.0%

23.6 2

17.6 9 37

–0.70 [–1.65, 0.25] 10.0%

17.3 2.2

31 31

–0.20 [–1.56, 1.16] 10.2% 24.7 24 2 20.8 29.1 10 40 21 10 40 31

4.00 [0.48, 7.52] 3.60 [3.16, 4.04] 9.4% 10.2% 10.1% 25.1 23.7 21 27.3 2.9 5 1.3

23.9 20 12 –0.70 [–2.00, 0.60]

2.72 [0.99, 6.42]

2.76 [1.40, 4.12]

10.1% 24.6 2.6 3.3 1.6 2.3 1.8 2.1 1.6 0.6 2.7 1.1 2.6

4.00 [2.63, 5.37]

10 11

4.60 [–1.81, 11.01] 22.7% 16.7 20.7 1.9 25.3 22.3 30 21 10 30 17 10

3.10 [2.01, 4.19] 2.90 [1.43, 4.37] 24.8% 22.0% 3.9% 19.2 18.8 20.7 21.7 10.1 2 2.8

19.2 20 18.2 20 26.6% 1.00 [0.16, 1.84] 1.2 2.2 1.8 2.3 1.3 1.4 –20 –10

Elderly Young adults

0 10 20

–20 –10

0 10 20

–20 –10

0 10 20

Guillén et al. 2005

Janky and shepard 2009 click Kumar et al. 2010

Lee et al. 2008 Su et al. 2004

A –

n23 cVEMP latencies.

B –

n23 cVEMP latencies, sub-grou p evoked only by 500 Hz Toneburst.

C –

n23 cVEMP latencies, sub-group evoked only by Click.

Figure4 Meta-analysis:comparisonofn23cVEMPlatencies,n23cVEMPsub-groupevokedonlyby500HzToneburstandn23cVEMP sub-groupevokedonlybyClick.(A)n23cVEMPlatencies.(B)n23cVEMPlatencies,sub-groupevokedonlyby500HzToneburst.(C) n23cVEMPlatencies,sub-groupevokedonlybyClick.

reflexinthe1990s.21 _Studies_published_at_that_time_mostly

reportedonthe methodsusedand studiesin guineapigs. Fromtheyear2000articlesstartedtobepublishedaboutthe clinicalapplications,studiesthatinvolvedpathologies aim-ingtoassesstheeffectivenessofvestibularevokedmyogenic potentials.21

Regarding the test protocols, thearticles studied used strongintensitystimuli,rangingfrom90to105dBNAn; how-ever, only two studies usedthe lowest intensity.20,23 _Most

chose to evoke VEMP with Toneburst stimuli, corroborat-ingthe literaturethat recommends the use ofToneburst, because the threshold of saccular excitability is smaller whencomparedtotheclick,beingmorecomfortableforthe assessedsubject,inadditiontohavingabetterdefinitionof wavesand greater responseamplitude.23---27 _Regarding_the

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The methodologicalqualityofthe studieswas satisfac-tory,attainingatleast50%ofthemaximumscore.Thefact thatonlyone study25 _did _not_use_convenience _sampling_is

afactofconcernandverycommoninscientificstudies,as theydonotallowthecreationofrepresentativesamples.On theotherhand,allstudiesusedvalidatedtoolsfordata col-lectionandappropriatestatisticaltests,20,21,23---27,32---40_which

shows a greaterconcern withthe qualityof their quanti-tative analyses. A simple methodological adjustment can be observed in the studies, such as those performed in two articles32,33 _with _wave _analysis _by _two _independent

researchers,whichhelpedthemtoincreasethequalityto themaximumfoundinthepresentsystematicreview.

Accordingtothefindings,thenVlatencycomponentof oVEMPandthep13andn23componentsofcVEMPweremore delayed in the elderly than in young adults, as reported by all selected oVEMP studies33,37,38 _and _in _five _cVEMP

studies,34,36,38---40_showing_that_it_may_be_associated_with_the

reduction in the number of neurons with advancing age, especially for subjects older than 60 years. In addition, advancedage and itsassociation withthe changesin the latency ofthe studied component due toaforementioned loss of neurons would have significant implications in the vestibularnucleus,whichcouldbeassociatedwithbalance deteriorationintheelderly.Finally,itisquitereasonableto affirm,basedontheresultsoftheothercomponents stud-iedandifthereweresufficientarticles,thatthep1wave componentofoVEMPwillmostlikelyalsobedelayedinthe elderly.33,37,38

Conclusion

ThelatencyofoVEMPn1wavecomponentandthelatencies ofcVEMPp13andn23 wavecomponentsarelongerinthe elderlyaged60yearsorolderthaninyoungadults.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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