REVIEW
Wha is Menie
` e’s disease? A con empo a y e-e alua ion
o endolympha ic hyd ops
R. Gu
¨ ko
1
•I. Pyyko
¨
2
•J. Zou
3
•E. Ken ala
4
Recei ed: 19 July 2015 / Re ised: 4 Oc obe 2015 / Accep ed: 5 Oc obe 2015
The Au ho (s) 2015. This a icle is published wi h open access a Sp inge link.com
Abs ac Menie
` e’s disease is a ch onic condi ion wi h a
p e alence o 200–500 pe 100,000 and cha ac e ized by
episodic a acks o e igo, luc ua ing hea ing loss, inni-
us, au al p essu e and a p og essi e loss o audio es ibula
unc ions. O e 150 yea s ago, P ospe Menie
` e was he
i s o ecognize he inne ea as he si e o lesion o his
clinical synd ome. O e 75 yea s ago, endolympha ic
hyd ops was disco e ed as he pa hologic co ela e o
Menie
` e’s disease. Howe e , his pa hologic inding could
be asce ained only in pos -mo em his ologic s udies. Due
o his diagnos ic dilemma and he a iable mani es a ion
o he a ious audio es ibula symp oms, diagnos ic clas-
si ica ion sys ems based on clinical indings ha e been
epea edly modi ied and ha e no been uni o mly used in
scien i ic publica ions on Menie
` e’s disease. Fu he mo e,
he highe le el measu es o impac on quali y o li e such
as i ali y and social pa icipa ion ha e been neglec ed
hi he o. Recen de elopmen s o high- esolu ion MR
imaging o he inne ea ha e now enabled us o isualize
in i o endolympha ic hyd ops in pa ien s wi h suspec ed
Menie
` e’s disease. In his e iew, we summa ize he
exis ing knowledge om empo al bone his ologic s udies
and om he eme ging e idence on imaging-based e alu-
a ion o pa ien s wi h suspec ed Menie
` e’s disease. These
indica e ha endolympha ic hyd ops is esponsible no only
o he ull-blown clinical iad o simul aneous a acks o
audi o y and es ibula dys unc ion, bu also o o he
clinical p esen a ions such as ‘‘ es ibula ’’ and ‘‘cochlea
Menie
` e’s disease’’. As a consequence, we p opose a new
e minology which is based on symp oma ic and imaging
cha ac e is ics o hese clinical en i ies o cla i y and sim-
pli y hei diagnos ic classi ica ion.
Keywo ds Menie
` e’s disease Endolympha ic hyd ops 
Magne ic esonance imaging Diagnosis Classi ica ion
In oduc ion
P ospe Menie
` e epo ed in 1861 ha e igo, balance and
hea ing diseases e lec ed a lesion o he inne ea [1].
P e iously, dizziness and balance diseases had been
a ibu ed o ‘‘apoplec i o m ce eb al conges ion’’, and he
ana omical s uc u es o he inne ea we e only conside ed
wi h espec o sound pe cep ion. As a di ec o o he i s
school o he dea -mu e in Pa is, P ospe Menie
` e
undoub edly saw many pa ien s wi h he combina ion o
dea ness and e igo. Howe e , he ole o he inne ea in
main aining balance and o ien a ion was la gely unknown
a ha ime. The combina ion o his clinical expe ience
wi h his pa ien g oup and his knowledge o Flou ens’
seminal wo k on he e ec s o semici cula canal abla ion
This manusc ip is pa o a supplemen sponso ed by he Ge man
Fede al Minis y o Educa ion and Resea ch wi hin he unding
ini ia i e o in eg a ed esea ch and ea men cen e s.
&R. Gu
¨ ko
[email p o ec ed]
1
Depa men o O o hinola yngology Head and Neck Su ge y,
Uni e si y o Munich, Ma chioninis . 15, 81377 Munich,
Ge many
2
Ge man Cen e o Ve igo and Balance Diso de , Uni e si y
o Munich, Ma chioninis . 15, 81377 Munich, Ge many
3
Hea ing and Balance Resea ch Uni , O ola yngology, School
o Medicine, Uni e si y o Tampe e, 33520 Tampe e,
Finland
4
Depa men o O o hinola yngology, Helsinki Uni e si y
Cen al Hospi al, Haa maninka u 4E, 00290 Helsinki,
Finland
123
J Neu ol (2016) 263 (Suppl 1):S71–S81
DOI 10.1007/s00415-015-7930-1
in pigeons allowed him o ecognize he inne ea as he
si e o lesion.
The ca dinal symp oms o Menie
` e’s disease (MD) o m
a disease en i y consis ing o episodic e igo, luc uan
hea ing loss and inni us. The pa ien s also complain o
ullness in he ea , gai p oblems, pos u al ins abili y, d op
a acks and nausea. MD is a ch onic illness a ec ing abou
190 pe 100,000 pa ien s in a US heal h claims da abase,
bu in popula ion-based s udies a p e alence o as high as
513/100,000 has been epo ed [2]. In 1937, he disco e y
o endolympha ic hyd ops (EH) in human empo al bones
by B i ish and Japanese esea che s [3,4] e ealed he
pa hologic coun e pa o he clinical synd ome desc ibed
by P ospe Menie
` e. EH is a dis ension o he endolym-
pha ic space o he inne ea in o a eas ha a e no mally
occupied by he pe ilympha ic space. I mos o en occu s
in he cochlea duc and he sacculus bu may also in ol e
he u icle and he semici cula canals [5]. Analysis o
empo al bone specimens has shown a iabili y o he
p esence o EH [6] and Sal and Plon ke [7] ques ioned
whe he he p esence o pos -mo em EH is ei he essen ial
o speci ic o MD. Recen de elopmen s o gadolinium
chela e (GdC)-enhanced MRI a e ans ympanic injec ion
o he con as agen p o ide a ool o sepa a ely isual-
izing endolympha ic and pe ilympha ic spaces wi h
gadolinium chela e (GdC) as he con as agen [8]. Wi h
hese new imaging echniques, EH can be demons a ed
in i o and can be used o con i m he diagnosis.
In his a icle, we shall summa ize impo an ecen
de elopmen s in he e alua ion o EH in MD and discuss
he u u e impac o hese insigh s on i s classi ica ion.
E idence om human empo al bone s udies
Mo i a e al. [9] examined 53 empo al bones and quan i-
ied endolympha ic hyd ops in pa ien s wi h Menie
` e’s
disease: he collec i e endolympha ic olume o he
cochlea duc , saccule and u icle amoun ed o 64 llin
compa ison o 20 ll in heal hy subjec s. The e o e, he
e y igh ly con olled minuscule endolympha ic luid
space o he inne ea is enla ged by mo e han 200 % in
MD! O all he hi he o known pa hologic changes in MD
pa ien s, his change clea ly has he highes magni ude.
Howe e , in o de o ob ain clues ha help us o
unde s and (1) wha is he pa hophysiologic consequence
o EH? and (2) wha e en s lead o he de elopmen o
EH?, o he pa hologic changes ha a e ound in MD
pa ien s ha e o be conside ed as well.
Nage is e al. [10] desc ibed a ela ed phenomenon: he
displacemen o he basila memb ane owa ds he scala
ympani in he apical cochlea egions. In MD pa ien s’
empo al bones, he e was a signi ican co ela ion be ween
he se e i y o EH and he basila memb ane displacemen .
The eason why his phenomenon was ound only in he
apical po ion o he cochlea is p obably he la ge wid h
and highe elas ici y o he basila memb ane compa ed o
he basal cochlea egions and he lack o a suppo ing
bony s uc u e o he apical Lamina spi alis. This ea u e is
a consequence o EH ha has se e e unc ional conse-
quences, since he basila memb ane and i s speci ic
biomechanic p ope ies a e an essen ial pa o he
mechanoelec ical ans e unc ion o he hea ing sys em.
O he mo phologic changes ha ha e been obse ed in
MD gi e no such a clea pic u e. Un o una ely, he
esea ch on inne ea pa hology has no been sys ema ically
p omo ed o a long ime. Un il 1995, examina ions o only
100 cases o MD ha e been published wo ldwide, and
many o hose we e based on insu icien clinical in o -
ma ion. O en, a es ibula ib osis is obse ed, wi h he
o ma ion o band-like ib ous s uc u es. These may c ea e
a connec ion be ween he s apes oo pla e and he u icula
macula, which in u n could be an explana ion o he
Hennebe sign (occu ence o e igo when s a ic p essu e
is applied o he ea canal) [11]. Wi hin he endolympha ic
sac (ELS), an inc eased amoun o in aluminal p ecipi a e,
consis ing o glycop o eins sec e ed by he ELS, has been
demons a ed [12]. Fu he mo e, ul as uc u al e idence
sugges s ha glycop o ein syn hesis in he ough endo-
plasma ic e iculum and Golgi complexes is hype ac i e in
MD pa ien s [13]. Accumula ion o Glycop o eins in he
ELS could by i s osmo ic e ec in e e e wi h inne ea
homeos asis and con ibu e o EH o ma ion.
Elec on mic oscopy s udies e ealed minimal changes o
he cochlea hai cells: usion o s e eocilia and displacemen
o ou e hai cells owa ds he basila memb ane, wi h loss o
con ac o he cu icula pla e [14,15], a phenomenon, which
by i sel may disable he cochlea ampli ie unc ion o he
ou e hai cells and, he e o e, lead o hea ing loss.
Fu he indings a e a neu al ibe loss in he spi al
osseus lamina [16] and a educed numbe o a e en ne e
endings and a e en synapses a he basis o inne and
ou e hai cells [15]. Tsuji e al. could show a signi ican
educ ion o ype II hai cells in all i e es ibula end
o gans and o es ibula ganglion neu ons [17]. Ano he
ecen s udy on 39 empo al bones ound a ma ked loss o
neu ons o he spi al ganglion, in bo h he ipsila e al and
con ala e al ea in pa ien s wi h unila e al MD [18]. A
simila magni ude o loss o cochlea inne and ou e hai
cells was ound (abou 70 %). The s ia ascula is, which
can be ega ded as he ‘‘powe plan ’’ o inne ea home-
os asis, was ound o be a ophic ( educed in a ea) and
su e ing om a educed blood essel densi y [19].
In summa y, besides EH, se e al degene a i e changes
could be obse ed in he audio es ibula pe iphe y o MD
pa ien s, especially in he a e en es ibula and cochlea
S72 J Neu ol (2016) 263 (Suppl 1):S71–S81
123
ganglia and ne es. Howe e , hese indings do no ye allow
o de ini i e conclusions on he sequence o pa hophysiologic
e en s du ing he de elopmen and p og ess o he disease.
Rela ionship be ween his ologically p o en EH
and clinical de ini e Menie
` e’s disease
Despi e he de elopmen o se e al animal models o EH,
none o hese models displays he ypical pheno ype
obse ed in human MD pa ien s: pa oxysmal
audio es ibula e en s plus ch onic-p og essi e loss o
inne ea unc ions. The e o e, we shall concen a e on
e idence om human pa ien s when conside ing he ela-
ionship be ween EH and clinical MD in pa ien s.
In a ecen e iew, Fos e e al. [20] analyzed all pub-
lished a icles ha ha e epo ed on empo al bones wi h
EH and/o on empo al bones o pa ien s wi h clinically
suspec ed MD. This esul ed in a o al o 3707 empo al
bone specimens. O hese, 165 cases had been epo ed o
ul ill he AAO-HNS 1995 c i e ia. Two o hese s udies
we e speci ically designed o explo e he ela ionship o EH
o MD ha mee s he AAO-HNS 1995 c i e ia, and ound
EH in 100 % o MD cases [6,21]. 163 o he empo al
bones om de ini e MD pa ien s in his e iew (98.8 %) had
EH in a leas one ea . Only wo o 165 cases had been
classi ied as MD wi hou EH, and hese cases we e men-
ioned inciden ally in a single s udy o s ial changes in he
con ala e al ea o MD pa ien s. Fos e e al. communica ed
wi h he au ho s o ha s udy [18] and epo ha bo h cases
we e diagnosed be o e he AAO-HNS 1995 c i e ia, and
ha hei clinical p esen a ion was no desc ibed so i is
impossible o e i y whe he hey ul illed he AAO-HNS
c i e ia du ing hei li e ime. None o hese cases can be
used o e u e he p ima y inding o he Me chan s udy ha
EH and MD a e ound in associa ion wi h 100 % o cases
when he cu en de ini ion o MD is s ic ly applied.
This indica es ha i is i ually ce ain ha EH is p e-
sen in a leas 1 empo al bone in a pe son who mee s
cu en MD c i e ia. The au ho s conclude ha EH is
unlikely o be jus an epiphenomenon o MD, because he
associa ion is pe ec : e e y case wi h MD acco ding o he
AAO-HNS c i e ia showed EH. I seems, he e o e, ha
EH is necessa y bu no su icien o he display o he ull
symp om iad o MD.
Diagnos ic c i e ia: e olu ion o he cu en
c i e ia o assessmen o Menie
` e’s disease
Symp om-based classi ica ion me hods ha e been used o
make he diagnosis [22]. In he diagnos ic wo k up, mainly
e igo cha ac e and ype, associa ed hea ing loss and
inni us o au al ullness a e aken in o conside a ion.
Indeed, in a axonomic in es iga ion o pa ien s wi h e -
igo, a e exclusion o neu ological and middle ea con-
di ions, head auma and o o oxici y, Hinchcli e [23]
ound ha hose wi h ‘classical’ Menie
` e’s disease (mee -
ing he ‘‘de ini e MD’ de ini ion below) ell in a single
nosological en i y wi h all he o he cases o e igo. He
la e a gued ha MD included ‘ o mes us es’, whe e he
iad o symp oms is no comple e [24]. Diagnos ically
con i med cases ep esen only a limi ed p opo ion o
indi iduals wi h he disease, as e lec ed in he a iabili y
be ween p e alence s udies [2,25].
The nomencla u e o ‘‘cochlea ’’ o ‘‘ es ibula ’’ MD
was coined by he Ame ican Academy o O ola yngology-
Head and Neck Su ge y (AAO-HNS) in 1972 [26] and was
abandoned wi h he 1985 [27] and 1995 [22] upda es o he
AAO-HNS c i e ia as he e was insu icien e idence ha
hese mono-symp oma ic diseases sha e he same pa ho-
physiology wi h MD. The e ised AAO-HNS c i e ia [22]
de ine ‘Possible MD’ as episodic e igo o luc ua ing
hea ing loss. ‘P obable MD’ consis s o one a ack o
o a o y e igo las ing a leas 20 min oge he wi h in-
ni us and documen ed hea ing loss. ‘De ini e MD’ consis s
o wo o mo e spon aneous episodes o e igo 20 min o
longe wi h inni us and documen ed hea ing loss. ‘Ce ain
MD’ is diagnosed by addi ional his ological e i ica ion o
EH in he inne ea . To de ine he condi ion clinically, he
exis ing AAO-HNS classi ica ion is o en unhelp ul as he
la ency o join p esen a ion o he ca dinal complain s may
ake up o 10 yea s [28]. Gene al p ac i ione s, o ola yn-
gologis s and audio- es ibula physicians ace a challenge
in making he diagnosis o MD. The symp oms can be
a iable, occu o e di e en ime spans and he hea ing
loss can eco e be o e audiome ic measu emen s a e
made [22].
Recen ly, he Classi ica ion Commi ee o he Ba
´ a
´ny
Socie y o mula ed diagnos ic c i e ia o MD join ly wi h
se e al na ional and in e na ional o ganiza ions [29]. The
classi ica ion includes wo ca ego ies: de ini e MD and
p obable MD. The diagnosis o de ini e MD is based on
clinical c i e ia and equi es he obse a ion o an episodic
e igo synd ome associa ed wi h low- o medium- e-
quency senso ineu al hea ing loss and luc ua ing au al
symp oms (hea ing, inni us and/o ullness) in he a ec ed
ea . Du a ion o e igo episodes is limi ed o a pe iod
be ween 20 min and 12 h. P obable MD is a b oade
concep de ined by episodic es ibula symp oms ( e igo
o dizziness) associa ed wi h luc ua ing au al symp oms
occu ing in a pe iod om 20 min o 24 h. These de ini-
ions un o una ely do no help he clinician in de ining
MD. One in e es ing di e ence is ha he p oposed de i-
ni ion does no include endolympha ic hyd ops ha was he
o iginal inding in he disease.
J Neu ol (2016) 263 (Suppl 1):S71–S81 S73
123
Recen no el imaging me hods ha e made i possible o
isualize EH wi h gadolinium con as ed 3T MRI. The
AAO-HNS (1995) c i e ia [22] include EH as landma k o
de ine ce ain MD. Recen ly, Nakashima e al. [30] sug-
ges ed ha he inne ea o all pa ien s wi h suspec ed MD
should be imaged and he classi ica ion as de ini e MD
should include MRI e idence o EH. The au ho s p opose
ha also monosymp oma ic ea s wi h EH could be ea ed
as MD in he same way as in he 1972 AAO-HNS classi-
ica ion, which ecognized es ibula MD and cochlea MD
as one disease en i y among he umb ella o MD [26].
Suppo ing his idea, Pyykko
¨e al. [28] epo ed ha in
abou 20 % o he pa ien s wi h MD i can ake mo e han
5 yea s and in 10 % e en mo e han 10 yea s be o e
cochlea and es ibula symp oms will coincide.
To conclude, we p opose ha diagnosis o MD should
be based on he p esence o EH in addi ion o symp oms
and ha also monosymp oma ic pa ien s wi h EH be
ega ded as ‘ce ain’ MD cases. MRI in es iga ions should
be made mo e equen ly in assessing MD han hi he o.
Clinical ea u es o Menie
` e’s disease
Al hough he ca dinal symp oms o e igo, hea ing loss
and inni us a e gene ally well acknowledged by physi-
cians, MD pa ien s o en complain also o p essu e o
ullness in he ea , gai p oblems, pos u al ins abili y,
Tuma kin a acks and nausea [31,32]. To de e mine he
se e i y o he impac on he pa ien s’ quali y o li e,
se e al symp om-speci ic sco ing ins umen s ha e been
de eloped. Such a ing scales a e, e.g., he Hea ing Dis-
abili y and Handicap Scale [33,34], he Ve igo Handicap
Index [35], and he In e na ional Tinni us In en o y [36].
A MD-speci ic indica o is he MD Pa ien O ien ed
Se e i y Index (MDPOSI) [37]. Some o hese ha e been
de eloped o e alua e changes in he na u al cou se o
he apeu ic e ec s, such as MDPOSI. The symp om-
speci ic ins umen s seem o mo e accu a ely e lec chan-
ges in con ol o e igo in MD o e ime han do, e.g.,
gene al Quali y o Li e (QoL) ins umen s [32]. These
indica o s seem o be capable o desc ibing changes in he
ac i i y o he disease and a e used in he alida ion o he
e icacy o he ea men [38,39]. In addi ion, i seems ha
pe sonal ai measu ed as sense o cohe ence, a i ude and
mood a e impo an de e minan s o he impac o MD
[32,39,40]. S ephens e al. [41] poin ed ou ha anxie y, as
a mood diso de , will e lec expec a ions, en i onmen al
demands and a i udes. They showed ha he le el o
anxie y co ela ed wi h he Sense o Cohe ence [40].
Howe e , he pe sonal ac o s, unce ain y o li e and
en i onmen al ac o s ha e no been included in he di -
e en complain -o ien ed impac classi ica ions. In his
ega d, he In e na ional Classi ica ion o Func ion g oup
(ICF, WHO 2001) [42] has de eloped a sys em encom-
passing many di e en aspec s o he disease, which can be
used as explana o y amewo k. This amewo k allows a
be e unde s anding o he impac o he illness and wha
consequences i has on gene al well-being and, he e o e,
may help o alle ia e hese impac s. Social pa icipa ion
which is included in he ICF is a i al pa o li e in human
beha io ha o ms he co e cons uc o he le el o
ac i i ies enabling goal-di ec ed beha io . When es ab-
lishing ea men s a egies, ICF includes wo mos
impo an addi ional opics: own a i udes and pe sonal
con ex ual ac o s, as poin ed ou by Wade [43].
In MD, ICF b ings in some impo an elemen s o
ac i i y limi a ions such as a igue and ca d i ing ha
we e epo ed only in an open-se ques ionnai e. I also
b ings in he wo k- ela ed i ems ha can be se e e and
impac g ea ly on he quali y o li e in MD, as well as
speci ic pa icipa ion es ic ions, such as p oblems in
shopping, doing household wo k, pe o ming spo ac i i-
ies and ga dening [44]. Among pe sonal con ex ual ac-
o s, he es ic ions in li e and unce ain y a e also
impo an [44]. These i ems we e e lec ed in anxiousness
which was one o he mos signi ican ac o s co ela ing
wi h he quali y o li e [32].
In se e al ins umen s measu ing quali y o li e such as
15-D, SF-36 as well as in he pe cep ion o ‘wellness’
changes in i ali y has been epo ed in MD [45]. Abou
70 % o he subjec s wi h MD had educed i ali y [46].
Reduc ion o i ali y co ela ed wi h inc eased anxie y,
educ ion o quali y o li e and wi h se e al i ems
desc ibing pa icipa ion es ic ions. The educ ion in
i ali y seems o be a consequence o he condi ion (in his
case es ibula dys unc ion) a he han a causa i e ac o
o MD [32,47,48]. Al hough pe sonali y ai was asso-
cia ed wi h anxie y and i ali y, he pe sonali y ai was
ega ded as a modi ying ac o o he condi ion. The el-
a i ely mino ole o he pe sonali y ai in quali y o li e
and disease-speci ic impac has been documen ed ea lie
[39,48,49]. Van C uissen e al. [47] indica ed ha he
psychological p o ile o MD pa ien s seems compa able o
pa ien s wi h o he ch onic condi ions.
To summa ize, MD causes es ic ions in a e y b oad
spec um o pe sonal ac i i ies as well as in con ex ual
ac o s and is cha ac e ized by educed i ali y and
unce ain y o con ol o li e. The es ic ed o mula ion o
complain s in cu en classi ica ions does no explain he
indi idual cons ain s caused by he illness. The condi ion
may lead o es ic ions and limi a ions ha a e no di ec ly
ela ed o he disease a i s glance [44]. The e a e e y
ew epo s in he li e a u e desc ibing he complain s
associa ed wi h a igue and especially social isola ion [38,
48]. The assump ion ha healing an impai ed unc ion
S74 J Neu ol (2016) 263 (Suppl 1):S71–S81
123
alone would es o e he ull heal h in pa ien s wi h MD is
e oneous, since he social pa icipa ion o ms he co e
cons uc o achie e any goal-di ec ed beha io [40,50].
We, he e o e, encou age u u e s udies in MD o include
he abo e-men ioned measu es o heal h (Fig. 1), espe-
cially i ali y and i s associa ion wi h social and pe sonal
isola ion and o apply holis ic he apeu ic e o s in MD.
E idence om MR imaging in humans
Recen de elopmen s o 3 T MR imaging p o ide a ool o
isualizing EH wi h gadolinium chela e (GdC) as he
con as agen . Following he de elopmen o sepa a e
isualiza ion o he endo- and pe ilympha ic compa men s
by Zou e al. [8], Naganawa e al. [51] and Nakashima e al.
[52,53] de eloped speci ic algo i hms using Fluid A en-
ua ion In e sion Reco e y sequences (FLAIR) ha will
demons a e minu e amoun s o con as agen in he inne
ea [54]. La e , hey demons a ed ha 3-D eco e y u bo
spin echo wi h eal econs uc ion (3D- eal IR) showed
highe con as be ween he non-enhanced endolymph and
he su ounding bone [55]. Wi h he new imaging ech-
niques, EH can be demons a ed in i o and can con i m
he diagnosis. Recen ly, i has been demons a ed ha EH
can di e en ly a ec cochlea and es ibula compa men s
and cause di e en complain s [28]. The alue o EH
imaging in he di e en ial diagnosis has been shown o
he example o pa ien s wi h clinically suspec ed es ibula
mig aine [56]. Fu he mo e, EH could be demons a ed o
p og ess o e ime [57] du ing he disease cou se, and o be
co ela ed wi h he de e io a ion o cochlea , saccula and
hSCC unc ion [58–61]. Howe e , he associa ion be ween
clinical symp oms and EH is no uni o m in each pa ien , as
hea ing can be ela i ely well p ese ed despi e p ominen
endolympha ic hyd ops. Nakashima e al. [62] and Fio ino
e al. [63] ha e demons a ed, wi h MRI, ha EH was
p esen in all li ing pa ien s wi h de ini e MD.
The classi ica ion o he deg ee o endolympha ic
hyd ops is pe o med sepa a ely o he es ibulum and he
cochlea, based on p e iously documen ed c i e ia [64]. The
no mal limi o a io o he endolympha ic a ea o e he
es ibula luid space (sum o he endolympha ic and pe -
ilympha ic a ea) is 33 % and any inc ease in he a io
would be indica i e o EH. Acco ding o hese c i e ia,
mild EH in he es ibule co e s he a io o 34–50 % and
signi ican EH co e s he a io o mo e han 50 % in he
es ibule. Examples o mild and signi ican es ibula EH
a e gi en in Fig. 2. The espec i e e alua ion o he a io o
he endolympha ic a ea in he cochlea is co ela ed o he
displacemen o Reissne ’s memb ane. No mally, he
Reissne ’s memb ane emains in si u and is shown as a
s aigh bo de be ween he endolymph con aining scala
media and he pe ilymph con aining scala es ibuli. Mild
EH displays an ex usion o he Reissne ’s memb ane
owa ds he scala es ibuli and esul s in an a ea enla ge-
men o he scala media while no exceeding he a ea o he
scala es ibuli. Signi ican EH causes an inc ease o he
scala media wi h an a ea la ge han ha o he scala
es ibuli. Based on p e ious MRI s udies in no mal sub-
jec s, Nakashima e al. sugges ed 33 % as he uppe limi
o he enla gemen o endolympha ic space o he es i-
bule [64]. The no mal alues ha we use ha e been
ecen ly con i med by o he esea che s [63,65].
Fo clinical MR imaging o endolympha ic hyd ops, wo
al e na i e ou es o GdC applica ion may be used: in a-
enous (i. .) o in a ympanic (i. .). A e mic oscopically
con olled applica ion o GdC in o he middle ea ca i y, i
en e s he inne ea ia he ound and o al windows (Fig. 3).
The bene i in i. . deli e y is ha i achie es highe GdC
concen a ions—wi h a signi ican ly lowe o al adminis a-
ion dosage— han i. . deli e y and he pa hology is easie o
ecognize. Howe e , he i. . applica ion is o -label, and in
ou hands abou 5–10 % o pa ien s ha e insu icien GdC
up ake om he middle ea . I. . adminis a ion o GdC
educes he isk o sys emic oxici y, al hough i may
po en ially cause local i i a ion and oxici y [66,67]. Cu -
en clinical da a, howe e , e eal no e idence o o o oxici y
a e i. . applica ion [68–70]. I he clinical p esen a ion
sugges s a dis u bance o he blood–laby in h ba ie , e.g.,
due o in lamma o y p ocesses, his equi es i. . applica ion
o GdC o isualize his pa hology. In hei mos ecen
imaging echniques o he inne ea , Naganawa and Naka-
shima [70–72] used i. . adminis a ion o GdC wi h sub-
ac ion echnique in 3T MRI. Wi h a single dose o i. .
GdC, EH was isualized a 4 h pos -injec ion in humans.
The de elopmen o dynamic imaging echniques o he
inne ea has p o ided wo impo an new insigh s in o
MD: (1) he cochlea and es ibula compa men s can be
Fig. 1 Di e en app oaches used o analyze he impac s o Menie
` e’s
Diso de all o which in luence gene ic measu es o quali y o li e
(QoL). The disease-speci ic model can be buil om impai men s
caused by symp oms, open-ended ques ions, ac i i y limi a ions o
pa icipa ion es ic ion (modi ied om [32]). All hese di e en
measu es display speci ic aspec s o QoL bu a e no in e changeable
wi h he ou come o gene ic QoL ins umen s
J Neu ol (2016) 263 (Suppl 1):S71–S81 S75
123

di e en ly a ec ed. (2) EH is e y o en p esen in he
‘‘asymp oma ic con ala e al ea s’’ [28,53]. I has been
well known since long ha in ypical unila e al MD, he
incidence o symp oma ic and unc ional in ol emen o
he con ala e al ea inc eases almos linea ly wi h he
leng h o obse a ion, esul ing in bila e ali y a e o almos
50 % a 30 yea s a e onse o unila e al MD [92]. Ini ial
clinically bila e al p esen a ions o MD, howe e , a e a e.
Wi h he ad en o endolympha ic hyd ops imaging, we
now ind ha e en in clinically unila e al MD, he p o-
po ion o con ala e al hyd opic changes o he inne ea is
su p isingly high, and was epo ed o each 65 % o
clinically ‘‘asymp oma ic con ala e al ea s’’ in an a e age
MD popula ion [28]. This would indica e ha MD is a
sys emic disease. In a ecen s udy, EH was p esen in 190
ou o 205 ea s (93 %) wi h symp oms a ibu able o MD
[28]. Table 1demons a es ha EH occu s mo e equen ly
in he es ibule han he cochlea bu mos commonly he
EH was ound in bo h cochlea and es ibule.
O equally g ea in e es a e he indings on EH in o he
disease en i ies o he inne ea . The g ea ad an age o
hese imaging da a o e he au opsy da a is he much mo e
de ailed clinical desc ip ion and he pe ec empo al
associa ion be ween he EH and he clinical symp oms.
Table 2summa izes he cu en ly published imaging
da a on pa ien s ha ha e no been clinically classi ied as
de ini e MD cases. This eme ging new body o e idence
allows o some i s obse a ions:
The pa ien s wi h luc ua ing low equency hea ing loss
e y o en ha e EH, and he e is a endency owa ds mo e
apically loca ed cochlea EH. These a e analogous o he
‘‘cochlea MD’’ en i y as de ined by he AAO-HNS 1972
guidelines. On he o he hand, a pu e sudden senso ineu al
hea ing loss (no a ec ing he low equencies) seems no
o be clea ly associa ed wi h EH. Fo he o he pa ien
g oups, wi h less ypical p esen a ions, howe e , he e a e
wo di e en en i ies eme ging: hose wi h EH and hose
wi hou EH (Table 3).
In con as o he ‘‘cochlea MD’’, he pa ien s wi h
‘‘ es ibula MD’’ show mo e a iabili y, bu s ill a signi -
ican po ion o hem has EH. A p obable explana ion o
Fig. 2 Assessmen o es ibula endolymph space in a igh inne ea
using egions o in e es (ROI). The ou e ROI de ines he c oss-
sec ional a ea o he es ibulum a he le el o he ho izon al
semici cula canal (‘‘ es ’’). The inne ROI de ines he endolympha ic
space inside he es ibulum (‘‘hyd’’). aThe es ibula endolymph
a io in his pa ien is 0.35, co esponding o mild EH. bThe
es ibula endolymph a io in his pa ien is 0.64, co esponding o
signi ican EH (Figu e ep oduced om [61])
Fig. 3 En y o in a ympanically applied d ugs in o he inne ea
pe ilymph space (whi e) ia he ound and o al windows. Endolymph
space is ma ked in ed
S76 J Neu ol (2016) 263 (Suppl 1):S71–S81
123
Table 1 Endolympha ic hyd ops in pa ien s wi h symp oms associa ed wi h Menie
` e’s diso de classi ied wi h he AAO-HNS as possible,
p obable and de ini e Menie
` e’s diso de (205 ea s wi h symp oms) and also in 45 con ala e al ea s wi hou symp oms a e included
Symp om/diagnosis EH in cochlea only EH in es ibule only EH in bo h To al wi h EH
Possible MD (n=122) 8 43 57 108
P obable MD (n=15) 2 4 8 14
De ini e MD (n=68) 1 4 63 68
To al (n=250) 11 51 136 219
Cochlea and es ibule a e analyzed sepa a ely. Table modi ied om Pyykko e al. [28]
Table 2 Summa y o published epo s o EH in pa ien s ha we e no clinically classi ied as de ini e Menie
´ e’s disease
En i y NWi h EH (%) Rema ks Re e ences
FLFSNHL 1 1 (100 %) [73]
8 6 (80 %) [74]
56 ea s 38 cochlea EH,
44 es ibula EH
No. o pa ien s wi h EH no gi en [75]
1 1 (100 %) [76]
1 1 (100 %) [77]
3 3 (100 %) [78]
43 40 (93 %) [28]
8 8 (100 %) All had EH in Cochlea and Ves ibulum.
The wo cases wi h se e e es ibula EH had absen VEMP
[79]
5 5 (100 %) [80]
ALFSNHL 1 1 (100 %) [81]
2 2 (100 %) Bo h had EH in he apical cochlea egions [82]
RPV 64 31 (48 %) All pa ien s had ho izon al Nys agmus du ing a acks [83]
3 0 (0 %) [74]
1 0 (0 %) [84]
56 29 cochlea EH,
47 es ibula EH
No. o pa ien s wi h EH no gi en [75]
2 1 (50 %) [85]
2 2(100 %) EH was mo e p onounced in Ves ibulum in all 3 cases [78]
17 15 (88 %) [28]
SSNHL?V 7 4 (57 %) A e age hea ing loss was 90 dB. [86]
SSNHL 8 2 (25 %) EH in Cochlea and Ves ibulum. MRI a 2 and
11 mon hs a e SSNHL. In e p e ed as DEH cases
[87]
4 0 (0 %) [74]
1 0 (0 %) HL was 68 dB [85]
hSCC mal o ma ion 11 9 (82 %) 6 cases had se e e EH [88]
DEH 11 8 [74]
7 7 (100 %) Mos had EH in bo h Cochlea and Ves ibulum [89]
2 2 (100 %) [82]
1 1 (100 %) [85]
5 5 (100 %) [90]
2 2 (100 %) [80]
VS 13 4 (31 %) Only he es ibulum could be analyzed [91]
LVAS 1 1 (100 %) [85]
Nnumbe o pa ien s, FLSNHL Fluc ua ing low equency senso ineu al hea ing loss, ALFSNHL acu e low equency senso ineu al hea ing loss,
RPV ecu en pe iphe al es ibulopa hy, SSNHL?Vsudden senso ineu al hea ing loss wi h e igo, SSNHL sudden senso ineu al hea ing loss,
hSCC ho izon al semici cula canal, DEH delayed endolympha ic hyd ops, VS es ibula schwannoma, LVAS la ge es ibula aquaeduc
synd ome
J Neu ol (2016) 263 (Suppl 1):S71–S81 S77
123
his obse a ion is he ac ha —in con as o he
‘‘cochlea MD’’ g oup which is de ined by he e y speci ic
audiome ic inding o luc ua ing hea ing le els p edomi-
nan ly in he low equencies—in his ‘‘ es ibula MD’’
g oup he e has no ye been iden i ied a dis inc i e
es ibula pheno ype. In analogy o he ‘‘cochlea MD’’, i
is possible ha a p edominan ly es ibula EH pheno ype
could be a ce ain pa e n o abno mali ies wi hin he di -
e en es ibula unc ion es s. A simila phenomenon
linked o EH is well desc ibed in de ini e MD pa ien s:
whe eas he calo ic es ibula esponse is declining ela-
i ely ea ly in he disease cou se, he es ibuloocula e lex
as assessed by he head impulse es is ema kably well
p ese ed un il he a he la e s ages o he disease. This
cons ella ion is in s a k con as wi h, e.g., he en i y o
es ibula neu i is, whe e bo h es s a e egula ly pa ho-
logic. Whe he a dis inc i e es ibula pheno ype pa e n is
also p esen in ‘‘ es ibula MD’’ s ill emains o be de e -
mined. La ge-scale s udies in his only ecen ly ecognized
speci ic clinical and mo phological en i y a e no ye
a ailable, bu will likely p omo e ou unde s anding o MD
and EH in he u u e.
P oposed new e minology based on clinical
and imaging indings
Based on he abo e-men ioned e idence, in o de o simpli y
and cla i y he e minology o pa ien s wi h symp oms
o me ly desc ibed in a ious ways, e.g., ‘‘cochlea MD’’,
‘‘ es ibula MD’’, ‘‘ o me us e’’, ‘‘a ypical MD’’,
‘‘monosymp oma ic MD’’, and in o de o enable a desc ip-
ion mo e closely ela ed o he unde lying pa hology, we
p opose a new e minology o hese clinical en i ies.
In his sys em, wo main ca ego ies o inne ea disease
wi h unde lying EH a e ecognized: P ima y Hyd opic Ea
Disease (PHED) and Seconda y Hyd opic Ea Disease
(SHED). PHED includes no only he de ini e MD pa ien s,
bu also he o he clinical en i ies wi h he clinical pheno-
ype o me ly desc ibed as ‘‘cochlea MD’’ o ‘‘ es ibula
MD’’. The indi idual symp oma ologic di e en ia ion is
desc ibed by he addi ion o ‘‘cochlea ’’ o ‘‘ es ibula ’’ o
‘‘cochleo es ibula ype’’. This ca ego y (PHED) is cha -
ac e ized by he absence o any e iden cause o he EH,
i.e., a condi ion o p eceding e en ha is likely o ha e a
signi ican con ibu ion o he o ma ion o EH. I , in
con as , such a condi ion, e.g., umo s, mal o ma ions,
in ec ions, noise o o he aumas ha a ec he inne ea
can be iden i ied in he pa ien , hen he second ca ego y o
SHED should be used. We a e awa e ha high- esolu ion
inne ea imaging is p esen ly no a ailable in all ins i u-
ions. The e o e, he anno a ions o ‘‘suspec ed’’ and
‘‘ce ain’’ should be used, depending on he con i ma ion o
EH in he indi idual pa ien by MR imaging.
Examples would be: ‘‘a 45-yea -old pa ien wi h ce ain
PHED o he es ibula ype.’’ O ‘‘a 20-yea -old pa ien
wi h suspec ed SHED o he audio es ibula ype associ-
a ed wi h LVAS’’.
Especially o he en i y o so-called ‘‘ ecu en
pe iphe al es ibulopa hy’’/‘‘ es ibula MD’’, which is s ill
Table 3 P oposed e minology
o inne ea diseases ela ed o
endolympha ic hyd ops, based
on clinical and imaging indings
P oposed new e minology Old e minology O he e ms
P ima y hyd opic ea disease (PHED)
Cochleo es ibula ype De ini e MD Typical MD
SSNHL?V
Cochlea ype Cochlea MD FLFSNHL
ALFSNHL
Ves ibula ype Ves ibula MD RPV, Fo me us e
Seconda y hyd opic ea disease (SHED)
Cochlea / es ibula /cochleo es ibula ype, associa ed wi h: Seconda y MD Menie
` e synd ome
VS
LVAS
Laby in hi is, meningi is
Noise induced hea ing loss
T auma
Congeni al hea ing loss DEH
Inne ea mal o ma ion
…
FLSNHL luc ua ing low equency senso ineu al hea ing loss, ALFSNHL acu e low equency sen-
so ineu al hea ing loss, RPV ecu en pe iphe al es ibulopa hy, SSNHL?Vsudden senso ineu al hea ing
loss wi h e igo, DEH delayed endolympha ic hyd ops, VS es ibula schwannoma, LVAS la ge es ibula
aquaeduc synd ome
S78 J Neu ol (2016) 263 (Suppl 1):S71–S81
123
an only aguely de ined clinical p esen a ion, we expec
ha he addi ion o EH o he desc ip ion o hese pa ien s
will add impo an pa hological in o ma ion and help o
de ine he es ibula pheno ype o hese pa ien s. Fu he -
mo e, and e en mo e impo an o he de elopmen o new
he apeu ic s a egies, his p oposed new classi ica ion may
lead o an ea lie iden i ica ion o EH du ing he disease
cou se, since heal h p ac i ione s will likely be mo e awa e
o EH as he po en ial unde lying pa hology in pa ien s ha
do no (ye ) display he ull-blown iad o MD symp oms.
The e o e, he apeu ic in e en ions may be possible ea lie
in he disease cou se, hope ully inc easing he chance o
hal ing o e en e e sing he u he p og ession o EH.
Conclusion
Recen s udies ha e shown ha he desc ip ion o unc-
ional impai men s in MD es ic ed o e igo, hea ing loss
and inni us as pu e symp oms do no su icien ly e lec he
wide- anging impac on quali y o li e ha MD pa ien s a e
acing. The e o e, pe sonal ac o s and measu es o ac i i y
and i ali y should be included in u u e s udies.
The miles one de elopmen o MR imaging o endolym-
pha ic hyd ops suppo s he cen al ole o endolympha ic
hyd ops in he pa hology o MD, and con i ms he same
esul om empo al bone s udies. I has imp o ed he di -
e en ial diagnosis in suspec ed MD and wa an s he dis-
cussion abou a new pa hology-based desc ip ion o clinical
en i ies ha display a ious symp oms o inne ea dys-
unc ions due o endolympha ic hyd ops.
Acknowledgmen s This wo k was suppo ed by he Ge man Min-
is y o Resea ch and Educa ion.
Compliance wi h e hical s anda ds
Con lic s o in e es The au ho s decla e ha hey ha e no con lic
o in e es .
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made.
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