Pathophysiology of Ménière`s Syndrome

Otology & Neurotology
26:74–81 © 2005, Otology & Neurotology, Inc.
Pathophysiology of Ménière’s Syndrome: Are
Symptoms Caused by Endolymphatic Hydrops?
Saumil N. Merchant, Joe C. Adams, and Joseph B. Nadol, Jr.
Otopathology Laboratory, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary,
Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, U.S.A.
Background: The association of Ménière’s syndrome with endolymphatic hydrops has led to the formation of a central hypothesis: many possible etiologic factors lead to hydrops, and
hydrops in turn generates the symptoms. However, this hypothesis of hydrops as being the final common pathway has not
been proven conclusively.
Specific Aim: To examine human temporal bones with respect
to the role of hydrops in causing symptoms in Ménière’s syndrome. If the central hypothesis were true, every case of
Ménière’s syndrome should have hydrops and every case of
hydrops should show the typical symptoms.
Methods: Review of archival temporal bone cases with a clinical diagnosis of Ménière’s syndrome (28 cases) or a histopathologic diagnosis of hydrops (79 cases).
Results: All 28 cases with classical symptoms of Ménière’s
syndrome showed hydrops in at least one ear. However, the
reverse was not true. There were 9 cases with idiopathic hy-
drops and 10 cases with secondary hydrops, but the patients did
not exhibit the classic symptoms of Ménière’s syndrome. A
review of the literature revealed cases with asymptomatic hydrops (similar to the current study), as well as cases where
symptoms of Ménière’s syndrome existed during life but no
hydrops was observed on histology. We also review recent
experimental data where obstruction of the endolymphatic duct
in guinea pigs resulted in cytochemical abnormalities within
fibrocytes of the spiral ligament before development of hydrops. This result is consistent with the hypothesis that hydrops
resulted from disordered fluid homeostasis caused by disruption of regulatory elements within the spiral ligament.
Conclusion: Endolymphatic hydrops should be considered as a
histologic marker for Ménière’s syndrome rather than being
directly responsible for its symptoms. Key Words: Endolymphatic hydrops—Ménière’s syndrome—Temporal bone.
Otol Neurotol 26:74–81, 2005.
In 1861, Prosper Ménière (1) described a syndrome
consisting of continuous or intermittent head noises accompanied by diminution of hearing and intermittent attacks of vertigo; uncertain gait and falling; accompanied
by nausea, vomiting, and syncope. The essence of
Ménière’s hypothesis was that the association of auditory
and vestibular symptoms suggested the ear as the anatomical location of the disorder, as opposed to the central
nervous system as previously thought. By extension of
Flourens’ (2) experiments on pigeons, he hypothesized
the site of lesion to be the semicircular canals. In 1938,
Yamakawa (3) in Japan and Hallpike and Cairns (4) in
England independently reported the finding of endolymphatic hydrops in temporal bones from patients with
Ménière’s syndrome. Hallpike and Cairns regarded the
hydrops as an essential morbid anatomy of a specific
disease of the labyrinth. Other investigators described
similar temporal bone findings over the next decade (5–
9). The hydrops seen in temporal bones was described as
“idiopathic” in that there was no obvious abnormality
in the temporal bones that could be considered causal.
With the identification of a pathologic lesion (i.e., hydrops), the term “Ménière’s disease” came to be applied
to the syndrome.
A large number of factors have been proposed as leading to the development of endolymphatic hydrops. The
list includes excessive endolymph production, decreased
endolymph absorption by the endolymphatic sac, ionic
imbalance, genetic abnormalities, viral infection, autonomic imbalance, dietary factors, autoimmune reactions,
vascular irregularities, allergic responses, and others
(10–13). In the majority of cases of Ménière’s disease,
light microscopy of temporal bone sections has failed to
demonstrate losses of sensory or neural structures within
the inner ear such as hair cells, neuronal cells, stria vascularis, dark cells, and so forth, that can be correlated
with the premortem loss of auditory and vestibular function (3–9,11). Because hydrops is the only consistent
pathologic abnormality observed at light microscopy, a
central hypothesis has been articulated regarding the
pathophysiology of Ménière’s disease: although many
Presented at the Annual Meeting of the American Otological Society, May 1–2, 2004, Phoenix, Arizona, U.S.A.
Address correspondence and reprint requests to Saumil N. Merchant,
M.D., Department of Otolaryngology Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114-3096; U.S.A.; Email:
[email protected]
74
PATHOPHYSIOLOGY OF MÉNIÈRE’S SYNDROME
possible etiologic factors can lead to endolymphatic hydrops, it is the hydrops that generates the symptoms of
Ménière’s disease (10) (Fig. 1). The central hypothesis
has not been conclusively proven. If the hypothesis were
true, every case of Ménière’s syndrome should have endolymphatic hydrops and every case of hydrops should
show the clinical symptoms, unless the chain of neural
events is interrupted. A temporal bone study from our
laboratory in 1989 to assess the correlation between case
histories and postmortem histopathology in Ménière’s
syndrome raised questions about the validity of this central hypothesis (14). Since this 1989 study, we have
added over 250 new temporal bone specimens to our
collection. One goal of this study was to reexamine the
relationship between hydrops and symptoms of
Ménière’s syndrome by including the new specimens.
In 1965, Kimura and Schuknecht (15) reported that
obliteration of the endolymphatic duct in the guinea pig
consistently produced endolymphatic hydrops. This was
the first description of a reliable animal model of endolymphatic hydrops. Guinea pigs with hydrops did not
demonstrate signs of episodic vestibular disturbances,
but they showed shifts in auditory thresholds, as determined by electrophysiologic studies (16,17). Light microscopic studies revealed partial degeneration of hair
cells, stria vascularis, and neurons, especially in the apical turn, but this was insufficient to account for the shifts
in auditory thresholds (16,17), a finding analogous to
observations in human temporal bones. New light was
shed on the histopathology of hydrops in the guinea pig
by the findings of Ichimiya et al. (18) and Nadol et al.
(19), who demonstrated cytochemical and ultrastructural
lesions affecting the fibrocytes within the spiral ligament, hair cells, and cochlear neurons. However, it was
not known which came first—the hydrops or the cytopathologic changes—raising the question as to whether
hydrops had induced the observed abnormalities or vice
versa. Another unanswered question was the mechanism
of development of hydrops after blockage of the en-
75
dolymphatic duct. It had been traditionally assumed that
the hydrops was the result of blockage of longitudinal
flow of endolymph from the cochlea to the endolymphatic sac (11,15). However, measurements of endolymph flow in the guinea pig showed the rate of longitudinal flow to be exceedingly small and therefore
insufficient to account for the development of hydrops
on the basis of blockage of flow (20,21). Some answers
to these questions have emerged by the recent work of
Shinomori et al. (22), who demonstrated that obliteration
of the endolymphatic duct resulted in disruption of enzymes within the spiral ligament, indicating dysregulation of inner ear fluids. Remarkably, these changes occurred before the development of hydrops. A second goal
of this article is to discuss the implications of these recent
observations with respect to experimental hydrops and
Ménière’s syndrome.
METHODS
The human temporal bone collection at the Massachusetts
Eye and Ear Infirmary currently contains 1,750 specimens from
963 individuals. These temporal bones were prepared in the
standard manner for light microscopic study including fixation
in 10% formalin, decalcification with ethylene diamine tetraacetic acid, embedment in celloidin, serial sectioning at a thickness of 20 ␮m, and staining of every 10th section with hematoxylin and eosin (11). A search of the database containing the
records of our temporal bones was conducted in two ways: 1)
searching for cases with a clinical diagnosis of Ménière’s syndrome (a clinical diagnosis of Ménière’s syndrome was made
when the case history included both episodic vertigo and sensorineural hearing loss (23)) and 2) searching for cases with a
histopathologic description of endolymphatic hydrops in at
least one ear. Endolymphatic hydrops was defined for the purpose of this study as hydrops present in any part of the membranous labyrinth with the exception of apical cochlear hydrops. This was based on the observations of Yamashita and
Schuknecht (24) that apical endolymphatic hydrops occurs in
approximately 15% of temporal bones, that it cannot be correlated with any type of ear disease, and that it is probably of no
pathologic or functional significance. The extent and severity
of hydrops was characterized in each sense organ of the inner
ear (cochlea, saccule, utricle, and the three canals) by examining serial sections using the same criteria as we have in the past
(14). The hydrops was characterized as idiopathic when there
was no obvious abnormality in the temporal bone that could be
considered causal or as “secondary,” based on the coexistence of
other pathologic changes in the inner ear such as surgical
trauma, temporal bone fracture, labyrinthitis, syphilis, Cogan’s
syndrome, and a variety of neoplasms affecting the labyrinth
(11). The case histories and histologic slides of specimens that
met the above criteria were reviewed to examine the relationship between hydrops and symptoms.
RESULTS
FIG. 1. Central hypothesis for Ménière’s syndrome (modified
after Kiang (10)). Many possible etiologic factors can lead to
endolymphatic hydrops, which in turn generates the clinical
symptoms.
Searching for a clinical diagnosis of
Ménière’s syndrome
Twenty-eight cases had a clinical diagnosis of
Ménière’s syndrome (Fig. 2). Every patient with this
diagnosis had endolymphatic hydrops on histopathologic
Otology & Neurotology, Vol. 26, No. 1, 2005
76
FIG. 2.
S. N. MERCHANT ET AL.
Results of searches of database containing temporal bone records.
examination in the affected ear. The hydrops was idiopathic in 26 cases and considered secondary in 2 cases.
All 26 cases with idiopathic hydrops showed dilatation
of the cochlear duct and the saccule, and the majority (17
cases [65%]) also had hydrops involving the utricle
and/or the ampullae. The two cases with secondary hydrops consisted of 1) a 55-year-old woman with episodic
vertigo and sensorineural hearing loss after a right stapedectomy whose temporal bone showed cochlear hydrops, collapse of the wall of the saccule, and disruption
with atrophy of the saccular macula (a case of posttraumatic hydrops); and 2) a 63-year-old man with episodic
vertigo, bilateral progressive sensorineural hearing loss,
and intractable urticaria whose temporal bones showed
bilateral cochlear hydrops, collapse of the utricular and
ampullary walls, degeneration of the auditory and vestibular end organs, focal areas of fibrous proliferation
and new bone formation within the labyrinth, and scattered aggregates of inflammatory cells within the endolymphatic and perilymphatic spaces (a case of presumed autoimmune inner ear disease).
Searching for a histopathologic description of
endolymphatic hydrops
Seventy-nine cases were identified as having endolymphatic hydrops in at least one ear, of which 35
cases were idiopathic and 44 were considered to be secondary (Fig. 2). Of the 35 cases with idiopathic hydrops,
26 cases had a clinical history of Ménière’s syndrome
and 9 cases did not. Additional details of the nine cases
with idiopathic hydrops are shown in Table 1. None of
the nine individuals had a history of episodic vertigo,
despite hydrops of the cochlea and/or the vestibular apparatus. One case (Case 1) had normal hearing, and the
Otology & Neurotology, Vol. 26, No. 1, 2005
temporal bones showed saccular hydrops on both sides.
The remaining eight cases had varying degrees of sensorineural hearing loss, which was fluctuating, sudden,
or progressive in nature. The audiometric pattern of the
loss was variable, and included low tone, flat, and downsloping patterns. The hydrops was limited to the cochlea
in one case, whereas the other seven cases had hydrops
affecting the cochlea, saccule, and utricle (with or without the ampullae). The severity and extent of hydrops in
these 7 cases was similar to that observed in the 26 cases
with Ménière’s syndrome. Many specimens with idiopathic hydrops also demonstrated premortem rupture of
the membranous labyrinth. Some of the nine cases with
idiopathic hydrops showed partial loss of hair cells
and/or afferent neurons within the cochlear and vestibular end organs. However, none of the ears showed severe
or total degeneration of the end organs (such degeneration would confound the interpretation of the role of
hydrops in causing symptoms). An analysis of the 44
cases with secondary hydrops revealed the following
breakdown:
1. Only two individuals had the Ménière’s symptom
complex during life; brief descriptions of both
cases are given above.
2. There were 10 cases without a history of episodic
vertigo. The hydrops involved only the cochlea in
two cases, whereas the remaining eight had cochleosaccular hydrops (with or without hydrops affecting the utricle and ampullae). The extent and
severity of hydrops in these eight cases was similar
to that observed in bones from individuals with
Ménière’s syndrome, including the presence of
ruptures affecting the membranous labyrinth in
several bones. All 10 cases exhibited varying de-
PATHOPHYSIOLOGY OF MÉNIÈRE’S SYNDROME
77
TABLE 1. Cases with idiopathic hydrops without the classic Ménière’s symptom complex
Hydrops
Case
Sex/age
(yr)
Side
Episodic
vertigo
1
M/6
2
Sensorineural
hearing loss
Audiometric pattern
and severity
M/34
Right
Left
Right
No
No
No
No
No
Yes, fluctuating
Normal hearing
Normal hearing
35-dB low-tone loss
3
4
F/42
M/62
Left
Left
No
No
Yes, fluctuating
Yes, fluctuating
5
F/87
Left
No
Yes, progressive
6
M/78
Left
No
Yes, progressive
7
8
9
F/86
M/77
M/91
Right
Right
Right
No
No
No
Left
No
Yes, progressive
Yes, progressive
Yes, initially sudden,
then progressive
Yes, severe loss
since childhood
50 to 70-dB flat loss
30 to 50-dB
down-sloping loss
75 to 105-dB
down-sloping loss
70 to 90-dB loss,
greater in low tones
90 to 100-dB flat loss
Profound loss
80 to 95-dB flat loss
70 to 95-dB flat loss
Lat
Post
Ruptures of
membranous
labyrinth
Co
S
U
Sup
+
+
+
+
+
+
+
+
+
+
Between saccule
and utricle
Reissner’s saccule
+
+
+
+
Vestibular cecum
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Lat ampulla, saccule,
common crus
Saccule
Reissner’s saccule
Lat, post ampullae
All three ampullae,
utricle
M, male; F, female; +, presence of hydrops; Co, cochlea; S, saccule; U, utricle; Sup, superior canal; Lat, lateral canal; Post, posterior canal.
grees of sensorineural hearing loss in the hydropic
ear. However, none of the 10 cases had severe or
complete atrophy of the auditory or vestibular
end organs.
3. There were an additional 32 cases without an accompanying history of symptoms of Ménière’s
syndrome, but no firm conclusions could be drawn
about the relationship between hydrops and the absence of symptoms in these cases because of confounding factors such as degeneration of the end
organs, inadequate medical records, or young age
of the subject (which might preclude reporting of
vertigo or hearing loss). Two representative case
histories of individuals with idiopathic hydrops but
without the Ménière’s symptom complex are presented below along with the histopathologic findings (Cases 5 and 6 from Table 1).
Case 5
A 56-year-old woman underwent bilateral myringotomies for middle ear effusions. An audiogram at age 58
revealed good hearing for air conduction in both ears
(Fig. 3A). She developed a bilateral progressive, downsloping, sensorineural hearing loss that was worse in the
left ear. Audiometric evaluations were performed at ages
73 and 81 (Fig. 3A). She wore a hearing aid with success
in her right ear. She did not experience episodic vertigo.
At the age of 81, she was given radioactive iodine for
hyperthyroidism. She developed diabetes mellitus at age
82 and malignant lymphoma at age 83, for which she
received therapy with cyclophosphamide for 6 months.
She fell at the age of 87, breaking her hip, which was
corrected by surgery. At age 87, she stated that the hearing aid was working well in her right ear and that she had
“difficulties with balance.” She was using a cane and
walker. She died at the age of 87.
Histologic findings
The left inner ear shows endolymphatic hydrops affecting all turns of the cochlea (Fig. 3B). There is severe
dilatation of the vestibular cecum that has expanded to
fill the bony vestibule. There is a fistula between the
hydropic vestibular cecum and the saccule (Fig. 3B).
There is hydrops involving the saccule, the utricle, and
the ampulla of the superior semicircular canal. The organ
of Corti is intact in all turns. The basilar membrane is
thickened in the basal 5 to 6 mm of the organ of Corti.
There is moderate to severe atrophy of the stria vascularis in the middle and apical turns. The cochlear neuronal population appears normal for age. All vestibular
sense organs show good populations of hair cells, supporting cells, and nerve fibers. There is a granular basophilic deposit on the cupula of the posterior canal. In the
right inner ear, the cochlea is similar to the opposite side
but there is no endolymphatic hydrops. The saccule
shows degenerative changes involving the otolithic
membrane associated with cytoarchitectural irregularities of the sensory epithelium. The utricular macula and
all three cristae appear normal. There is a clump of amorphous basophilic granular material in the nonampullated
end of the duct of the lateral canal.
Comment
This patient had bilateral, progressive, down-sloping
sensorineural hearing loss, worse in the left ear, without
episodic vertigo. Although there is extensive endolymphatic hydrops of the cochlear and vestibular apparatus
in the left ear, she did not experience episodic vertigo
or fluctuating hearing loss. The down-sloping sensorineural hearing loss cannot be fully explained on the basis
of the observed otopathologic findings and is consistent
with a diagnosis of “cochlear conductive presbycusis”
(11). The “difficulties with balance” at the end of her life
may have been multifactorial in nature, associated with
Otology & Neurotology, Vol. 26, No. 1, 2005
78
S. N. MERCHANT ET AL.
90-dB sensorineural hearing loss that was worse on the
left. Speech discrimination was 92% on the right and
60% on the left.
Histologic findings
The left inner ear shows moderate to severe endolymphatic hydrops in all cochlear turns along with severe
hydrops of the saccule (Fig. 4A). Although there is compression artifact, the hair cells and stria vascularis appear
to be intact. There is a partial loss of cochlear neurons in
the basal turn. The macula of the saccule appears normal.
The utricle and its macula appear normal. There is hydrops of the posterior ampulla and hydrops with a premortem rupture of the lateral ampulla (Fig. 4B). There
are ruptures involving the saccule and common crus. All
three cristae, the vestibular nerves, and the bony labyrinth appear normal. The right inner ear shows a normal
organ of Corti and stria vascularis with a partial loss of
FIG. 3. Case 5 from Table 1, an 87-year-old woman. (A) Audiograms at ages 58, 73, and 81 showing a bilateral, progressive,
down-sloping sensorineural hearing loss, which was worse on
the left. (B) Photomicrograph of the left inner ear. There is moderate to severe endolymphatic hydrops affecting the middle and
apical turns of the cochlea. There is severe dilatation of the vestibular cecum that has expanded to fill the bony vestibule. There
is also a fistula between the hydropic vestibular cecum and the
saccule. IAC, internal auditory canal.
hip replacement surgery, degenerative vestibulopathy involving the saccule in the right ear and cupulolithiasis of
the posterior canal in the left ear, and possible diabetic
peripheral neuropathy.
Case 6
A 78-year-old man was hospitalized for squamous cell
carcinoma of the right maxillary sinus. He reported having progressive hearing loss in both ears for several years
and that it was worse on the left. He had occasional
tinnitus. He denied vertigo. He had a history of exposure
to noise as a factory worker. An audiogram 6 days before
death showed a bilateral, moderate to profound, 70- to
Otology & Neurotology, Vol. 26, No. 1, 2005
FIG. 4. Case 6 from Table 1, a 78-year-old man. (A) Photomicrograph of left inner ear showing severe endolymphatic hydrops
affecting the cochlea and saccule. There is an artifactual tear of
the basilar membrane in the lower middle turn (*). IAC, internal
auditory canal. (B) Photomicrograph of ampulla of the lateral
semicircular canal of the left ear, showing hydrops, areas of thinning of the wall of the membranous labyrinth, and an area of outpouching/rupture. The smooth outline of the area of the rupture
and the lack of torn membranes suggest that the rupture was
premortem in nature. The sensory epithelium of the crista and
nerve fibers appears normal.
PATHOPHYSIOLOGY OF MÉNIÈRE’S SYNDROME
cochlear neurons in the basal turn. There is no endolymphatic hydrops. The utricular and saccular maculae and
the ampullae of all three canals including hair cells, supporting cells, and vestibular nerve fibers appear normal.
Comment
This patient did not experience vestibular complaints
or fluctuating hearing loss, despite having moderately
severe endolymphatic hydrops in the left ear involving
the auditory and vestibular end organs.
DISCUSSION
The finding that endolymphatic hydrops was present
in every individual with a clinical diagnosis of Ménière’s
syndrome establishes the correlation between Ménière’s
syndrome and hydrops. Such a correlation, however,
does not imply a cause-and-effect relationship. If the
central hypothesis (Fig. 1) were true, every case of
Ménière’s syndrome should have endolymphatic hydrops and every case of hydrops should show the clinical
symptoms. We identified nine cases of idiopathic hydrops from patients who did not have the classic symptoms of Ménière’s syndrome during life. One of the nine
cases who had saccular hydrops had normal hearing and
no vertigo (Case 1), whereas the remaining eight cases
had sensorineural hearing loss without vertigo. The hearing loss was fluctuant in only three of the eight cases.
The audiometric pattern varied and included low tone,
and flat and down-sloping losses. With the exception of
Case 1, the extent and severity of the hydrops in these
cases were similar to that observed in the temporal bones
of individuals with the Ménière’s symptom complex.
Furthermore, we found a number of cases of secondary
hydrops who also did not suffer from the classic symptom complex of Ménière’s syndrome.
Our results indicate that 1) endolymphatic hydrops of
the cochlea is invariably associated with a sensorineural
hearing loss, but not necessarily a fluctuating type or a
low-tone pattern; and 2) hydrops of the cochlea and/or
vestibular system is not necessarily associated with a
history of episodic vertigo. Therefore, these results are
not consistent with the central hypothesis of hydrops as
the final common pathway for production of symptoms
in Ménière’s syndrome. The results are more consistent
with hydrops being a marker for disordered homeostasis
of the labyrinth, in which some factor (as yet unknown)
produces both the clinical symptoms of Ménière’s syndrome and endolymphatic hydrops.
The results of the current study are similar to those of
the previous temporal bone study from our laboratory in
1989 regarding the relationship between hydrops and
symptoms (14). The current study included the additional
temporal bone cases accrued over the past 15 years as
well as cases with secondary hydrops. A review of the
literature reveals reports of cases with asymptomatic hydrops (25–28) as well as cases of Ménière’s syndrome
diagnosed during life without demonstrable hydrops at
histologic examination (27,29–33). The central role of
hydrops in mediating the pathophysiology of the
79
Ménière’s symptom complex has also been questioned
by other authors (34,35).
We point out that temporal bone studies have some
inherent limitations that prevent an unequivocal rejection
of the central hypothesis. For example, the lack of vestibular symptoms in patients with hydrops can be explained on the basis that symptoms were present but not
documented in the medical history. Although we cannot
discount such an explanation, they appear unlikely in at
least some of our cases (e.g., Cases 5, 7, and 9 in Table
1) who had multiple otolaryngologic evaluations during
life. It has also been suggested that the lack of vertigo in
cases with hydrops might be explained on the basis that
these bones did not have ruptures of the membranous
labyrinth or that the hydrops was nonprogressive (11,25).
Many of the cases in the current study showed clear
examples of membrane ruptures, but there was no history
of vertigo, which brings into question the rupture theory
as an explanation for the episodic vertigo in Ménière’s
syndrome. We have no way of establishing whether the
hydrops in asymptomatic cases was progressive or not.
However, the hydrops was quite severe in many of our
asymptomatic cases, with the dilated membranous labyrinth having reached the limits of expansion within the
bony confines of the cochlea or the vestibule. Thus, the
hydrops must have been progressive at some point in
time. A more direct way to confirm or refute the central
hypothesis is to visualize the endolymphatic space in
living subjects by imaging techniques (10). Indeed, magnetic resonance imaging has been recently used to diagnose hydrops in vivo in the guinea pig (36,37). These
studies demonstrate the potential of in vivo imaging to
permit a systematic assessment of the dynamic events
over time in patients with and without Ménière’s syndrome.
Much research has focused on the pathology and
pathophysiology of hydrops in the guinea pig model in
an attempt to better understand Ménière’s syndrome. Hydrops starts to develop within a few days after obliteration of the endolymphatic duct in the guinea pig and is
consistently observed by 1 week postoperatively (15,16,
37). Although it had been traditionally assumed that the
hydrops was the result of blockage of longitudinal flow
of endolymph from the cochlea to the endolymphatic sac
(11,15), measurements of the rate of endolymph flow in
the guinea pig showed the rate of longitudinal flow to be
exceedingly small and inadequate to account for the development of hydrops (20,21). Thus, the mechanism of
how hydrops occurred after blockage of the endolymphatic duct remained unknown. The cause of auditory
threshold shifts in hydropic animals also remained obscure and was attributed to being the result of the hydrops (11,16).
New light was shed on the histopathology of hydrops
in the guinea pig by the findings of Ichimiya et al. (18)
and Nadol et al. (19), who demonstrated cytochemical
and ultrastructural lesions at the level of hair cells, cochlear neurons, and the spiral ligament. The essence of
their investigations was that the Type I fibrocytes of the
spiral ligament were the most severely affected cochlear
Otology & Neurotology, Vol. 26, No. 1, 2005
80
S. N. MERCHANT ET AL.
cells, although Type II fibrocytes were also clearly affected in animals with long-term survival. However, it
was not known which came first—the hydrops or the
cytopathologic changes—raising the question as to
whether hydrops had induced the observed abnormalities
or vice versa. More recently, Shinomori et al. (22) extended these findings to show that the cytochemistry of
fibrocytes and other nonsensory cells changed before the
induction of hydrops. Shinomori et al. (22) blocked the
endolymphatic duct to induce hydrops in 22 guinea pigs
and studied the cytochemistry of the inner ear at various
postoperative survival times ranging from 1 day to 3
months. A striking finding was that there were changes
in the cytochemistry of Type I and Type II fibrocytes and
of nonsensory epithelial cells 1 day after surgery, before
the development of hydrops. The Type I fibrocytes
showed increased immunostaining for the NaK2Cl cotransporter (NKCC1), along with decreased immunostaining for taurine and C-Jun-N-terminal kinase (JNK).
These results are interesting because the fibrocytes of
the spiral ligament, which contain a variety of gap junctions, enzymes, and proteins, are known to play crucial
roles in maintaining fluid homeostasis within the cochlea
(38–41). For example, the Type I and Type II fibrocytes
are involved in the transport of K+ ions from the root
cells to the stria vascularis, thus enabling the recycling of
K+ ions within the scala media (38,40). NKCC1 is involved in regulation of cellular volume in response to
osmotic stresses (42). Taurine is an amino acid that
widely serves as an osmolyte (43). JNK is known to be
a critical player in many forms of cellular stress responses (44). The increased immunostaining for NKCC1
and decreased staining for taurine in the Shinomori et al.
(22) study suggest that the Type I fibrocytes were osmotically stressed and that the cytochemical changes reflected compensatory mechanisms for regulation of cell
volume. The decrease in staining for JNK indicates that
the fibrocytes were under stress, probably because of a
change in perilymphatic conditions induced by the surgical procedure. The connective tissue surrounding the
endolymphatic duct is in communication with the perilymphatic fluid spaces of the vestibular and cochlear end
organs (45). We hypothesize that surgical obstruction of
the endolymphatic duct altered the cytochemistry of the
perilymph (in some unknown manner), resulting in cellular stress and dysfunction of fibrocytes of the spiral
ligament. In turn, this may have interfered with the recycling of K+ ions, resulting in an osmotic imbalance and
expansion of the endolymphatic compartment (i.e., endolymphatic hydrops). In other words, the findings suggest that hydrops is the result (rather than the cause) of
disordered cochlear homeostasis. There is another line of
evidence to support the hypothesis that dysfunction of
the spiral ligament results in endolymphatic hydrops.
Transgenic mice with deletion of the Brn-4 transcription
factor, which is expressed in fibrocytes of the spiral ligament, develop endolymphatic hydrops (46,47). These
animals also suffer from a hearing loss and show decreased immunoreactivity for NaK-ATPase, NKCC1,
Otology & Neurotology, Vol. 26, No. 1, 2005
and connexin-31 within the Type II fibrocytes of the
ligament (47).
It has long been a practice to consider endolymphatic
hydrops as a sign of excessive endolymph production
with respect to its absorption (11). This conceptual
framework has contributed to misconceptions concerning the cause of hydrops. It should be remembered that
the fluid volume within the bony labyrinth remains constant (21). Changes in the volumes of the endolymphatic
and perilymphatic compartments are responses to osmotic gradients between the compartments. In the cochlea, the major potential for creation of abnormal osmotic gradients is associated with the flux of K+ ions into
the endolymphatic compartment from the stria vascularis, a flux that reflects the current flow underlying the
endolymphatic potential (21). This current flow is continuous and is largely independent of levels of soundinduced activity of the sensory cells (48). For osmotic
pressure to remain constant in the presence of this constant inward flux of potassium ions, there must be an
equal efflux from the scala media via a return pathway.
Zidanic and Brownell (48) measured current flow in the
cochlea and concluded that return paths of K+ ions included sensory and nonsensory cells on the basilar membrane, as well as Reissner’s membrane. Chiba and Marcus (49) reported a potential K+ return pathway through
cells in the region below the spiral prominence. Irrespective of the exact return paths, delineation of cochlear gap
junctional pathways together with considerations of tight
junction barriers and specializations for ionic uptake led
Kikuchi et al. (38) to conclude that Type II fibrocytes are
the major site of uptake of K+ ions from the perilymphatic space for their return to the stria vascularis. Type
I fibrocytes are part of that return pathway. The results of
Ichimiya et al. (18) and Nadol et al. (19) indicated that
spiral ligament fibrocytes and other cells are profoundly
affected in the hydropic guinea pig. The results of Shinomori et al. (22) show that Type I fibrocytes and other
cells are affected before the onset of hydrops, which
indicates that spiral ligament abnormality is not a
byproduct of the processes that induce the hydrops.
Clearly, much remains to be clarified regarding the underlying cytologic changes that lead to the induction of
hydrops. The key point of the present publication is that
there is a pressing need for a search for the cellular and
molecular bases of the various symptoms of Ménière’s
syndrome, because the evidence indicates that hydrops
per se is not the cause. Therefore, therapeutic strategies
whose main goal is the reduction of hydrops (e.g., endolymphatic sac shunting, sacculotomy) are unlikely to
control the disorder. A better understanding of the syndrome at a cellular level may uncover targets for novel
therapeutic interventions.
CONCLUSION
Endolymphatic hydrops should be considered as a histologic marker for Ménière’s syndrome rather than being
directly responsible for its symptoms.
PATHOPHYSIOLOGY OF MÉNIÈRE’S SYNDROME
Acknowledgments: The authors thank Mr. Axel Eliasen for
support of this work and the NIDCD National Temporal Bone,
Hearing and Balance Pathology Resource Registry for identifying temporal bone cases with Ménière’s syndrome or endolymphatic hydrops.
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