Stress in Hearing and Balance in Mnire's

Disease
K.C. Horner and Y. Cazals
Equipe Inserm EPI 9902, Laboratoire Otologie NeuroOtologie, Univ. Mditerrane Aix-Marseille II, Facult de
Mdecine Nord, Marseille, France

Stress is an unavoidable every-day phenomenon. Physiological coping with stress depends on

the appropriate release of stress hormones as well as their alleviation at the termination of the
stress. Despite quite a body of research indicating that stress affects inner ear function, this
concept has found little application in otolaryngology. Today's evidence clearly indicates that
the inner ear is equipped to detect stress hormones and some of these hormones have been
shown to affect the inner ear function.
Major stress control pathways shown to affect the inner ear include several third order axes,
the hypothalamus-pituitary-adrenal axis, the hypothalamus-pituitary-thyroid axis and the
hypothalamus-pituitary-gonadal axis whose functioning are interactive and inter-dependent.
Less well-studied are the second order hypothalamus-pituitary control axis and its interaction
with other hormones. To explore these we carried out a retrospective study on a series of
Mnire's patients who had undergone a neurotomy of the vestibular nerve in the dept of ORL
at the Hpital Nord, Marseille. Mnire's patients were particularly appropriate for this study
since stress has long been recognised as a factor associated with the triggering of the symptoms
of this pathology. Patients with acoustic neuroma and facial spasm were taken as a control
population.
We investigated the level of a battery of stress hormones including prolactin -endorphin and
growth hormone. The blood sample was taken on the morning before surgery. The most
striking observation was the presence of hyperprolactinemia in 30% of the Mnire patients
(more than 20 g/l) with confirmation of prolactinoma in 6 patients. The level of -endorphin
could also be elevated. Horner, K.C., Guieu, R., Magnan, J., Chays, A. and Cazal, Y.
Neuropysychopharmacology, (2001) 26:135-138.
These observations suggest that neuroendocrinological feedback pathways controlling stress
can be disturbed in Mnire's patients and depression of hypothalamic dopaminergic
inhibition of prolactin secretion might be implicated. A further study on non-operated
Mnire's patients presenting hyperprolactinemia and on dopamine agonist treatment, is
needed in order to assess the role of stress in Mnire's patients. Progress in this domain could
open the door towards integration of the stress concept into clinical management of various
inner ear disorders.
Keywords: Mnire, stress, vertigo, hearing, tinnitus, prolactin, dopamine
Mnires disease
The first documentation of Mnires disease can
be dated back to 1861 when the French clinician
Prosper Mnire described a form of inner ear
pathology associated with progressive and
severe fluctuant deafness, vertigo and tinnitus.

another French clinician - George Portmann.

Indeed Portmann, who after extensive
anatomical studies on the endolymphatic sac in
fish, birds and mammals (see Portmann, 1978),
hypothetised that the sac controlled inner ear
fluid pressure and went on to try this operation
on a patient for whom the operation resulted in a
One of the principle land-marks in the history of success (Portmann, 1927). The association of
Mnires disease can be associated with yet endolymphatic hydrops with this pathology was
Noise & Health 2003, 5;20, 29-34

demonstrated only twelve years later (Hallpike

and Cairns, 1938 Yamakawa, 1938) and has led
to various experimental and clinical approaches
aimed at reducing the inner ear endolymph
volume in this pathology. Since the presence of
endolymphatic hydrops can be confirmed only at
post-mortem, the Committee on Hearing and
Equilibrium of the American Academy of
Otolaryngology- Head and Neck Surgery (AAOHNS, 1995) has adopted strict guidelines
concerning the diagnosis and evaluation of
Mnires disease. There is a vast range of
medical treatments including diuretics,
vasoactive drugs, steroids, sedatives and all are
reported to provide some short-term benefit but
there is no cure for this disease. The progressive
nature of the disease often leads to incapacitating
vertigo when surgery is often proposed (reviews:
Merchant et al. 1995; Claes and Van de Heyning,
1997). The publications by Torok (1977) and
Jonkees (1980) provide indispensable and daring
critical reviews on the treatment of Mnires
disease. To cite Torok (1977) Basically no one
knows what one is treating and tries only to
control the symptoms. Unfortunately this same
commentary still applies today.
Mnires disease and stress
The pessimistic therapeutic picture of Mnires
disease today is almost certainly related to the
fact that the cause of this inner ear disease is still
unknown. About the same time that G. Portmann
was investigating the endolymphatic sac
function, the biology underlying stress was in its
embryonic state and was about to undergo a
parallel development. The sympathoadrenal
medullary axis with the release of hormone
under stress (Cannon 1929), different stages in
the development of the stress syndrome (Seyle,
1936) and the hypothalamic control of pituitary
hormones (Harris, 1948) were described. The
possible contribution of stress to Mnires
disease was first proposed to be related to
sympathetic hypertonus in this pathology at that
time (Seymour and Tappin, 1953) and
psychophysiological factors in Mnires disease
patients described (Fowler and Zeckel, 1952).
This was followed by a period of twenty years
during which various forms of sympathectomy
were carried out on Mnires patients with some
30

beneficial results (Golding-Wood, 1973; Torok,

1977; Adams and Wilmot, 1982). More recently
surgical or chemical ablation of the vestibular
sense organs has become the most employed
technique for the relieve of vertigo (see
Merchant et al. 1995). In the last twenty years
selective vestibular nerve section has
increasingly been employed since it is reported
to have highest success rate for controlling
vertigo and in addition hearing is conserved
(Silverstein et al., 1987).
Mnires disease is an excellent patient
population for assessment of the effect of
psychological stress on inner function since the
patients themselves often cite stress as a trigger
for onset of their symptoms (Hinchcliffe, 1967).
Compulsive-obsessional perfectionist individual
appears particularly at risk (Stephens, 1975).
Vertigo attacks can be correlated with
psychological state and the integration of this
kind of information into the assessment of such
patients could lead to improved therapy
(Hagnebo et al. 1998). The association between
psychological state and dizziness is not limited
to Mnires disease but includes patients with
panic disorders and anxiety (Yardley, 2000;
Yardley et al., 2001)
Several physiological mechanisms exist which
can account for the association between
psychological stress and vertigo. The central
vestibular pathways may be modulated by
steroids (Seemungal et al., 2001). At the
periphery, the inner ear is supplied with
substantial sympathetic innervation and
receptors for a series of stress hormones have
been localised.
Inner ear and the sympathetic system
The sympathetic innervation of the inner ear has
been described as being substantial with an
ipsilateral innervation arising from the superior
cervical ganglion and a bilateral innervation
from the stellate ganglion. The sympathetic
innervation is described as being associated with
blood vessels or independent of the vasculature.
(Spoendlin and Lichtensteiger, 1966). Electrical
stimulation of different cochlear turns as well as
local
application
of
adrenergic

agonists/antagonists to the cochlea has indicated

that cochlear blood flow increase is mediated via
adrenergic 2 - receptors (Ohlsen et al., 1991;
Laurikainen et al., 1994). Surgical ablation of the
superior cervical ganglion results in cochlear
protection from temporary threshold shifts
(Borg, 1982; Horner et al. 2001) as well as
permanent threshold shifts (Hildesheimer et al.,
2002).
The endolymphatic sac also is endowed with a
sympathetic innervation (Birgersson et al, 1992;
Hozawa and Takasaka, 1993). This is
particularly interesting since it is within the sac
where the immunocompetent cells of the inner
ear are also specifically localised (RaskAndersen and Stahle, 1980). Stress, via the
sympathetic system and stress hormones, is
known to have a major influence on the immune
system (Madden et al., 1995; Elenkov et al.,
2000; Dorshkind and Horseman, 2001; Webster
et al. 2002). A possible immune-related cause
has recently been proposed in Mnires disease
(Veldman, 1998; Ryan et al., 2002).
Sympathetic innervation of human middle ear
mucus-membrane has also recently been
described (Nagaraj and Linthicum, 1998). Since
sympathetic activity appears to contribute to
complex regional pain syndromes (Baron et al.,
2002) it might also be hypothesised that the
middle ear pain experienced by some Mnires
patients might be associated with the
hyperactivation of the sympathetic activity.
Part of the sympathetic cochlear innervation has
been described as originating in the brainstem.
These centrifugal sympathetic fibres follow the
vestibular nerve, as does the cochlear efferent
fibres, to reach the inner ear (Spoendlin and
Lichtensteiger, 1966; Ross, 1969; Laurikainen et
al., 1994). As pointed out earlier, selective
vestibular nerve section is often employed today
to control episodic vertigo. In addition this
surgical intervention might interfere with the
sympathetic efferent limb and so might induce
other effects apart from suppression of vestibular
afferent activity. Interestingly there is some
indication that vestibular neurotomy might
stabilise hearing in the operated ear and reduce

the probability of developing the pathology in

other ear (Magnan et al., 1999).
Inner ear and stress hormones
The pituitary controls the release of a battery of
hormones and this process is radically modified
under stress conditions. Since the functioning of
each hormone involves control of release at the
target, as well as at the pituitary (second-order)
and at the pituitary and the hypothalamus (thirdorder), the release of each of the hormones is to
some extent dependent on the activity of the
others.
The
hypothalamic
hormone
vasopressin, anti-diuretic hormone, (first-order
feed-back) has often been cited as possibly being
implicated in Mnires disease (Naftalin, 1994).
Plasma vasopressin has been reported to be
elevated in Mnires patients (Takeda et al.,
1995) and chronic administration of vasopressin
induces experimental endolymphatic hydrops in
the guinea pig (Takeda et al., 2000). The
hypothalamus-pituitary-adrenal (third-order)
stress control axis is particularly well addressed
in the literature. Glucocorticoids not only play a
specific essential role in the stress response but
in addition they highly influence the other
adaptive mechanisms and in particular the
immune system (Webster et al., 2002). The
homeostatic control of glucocorticoids in the
stress responses is essential since they provide
protection in an early phase of stress but longterm exposure to glucocorticoid can lead to
neurodegenerative disease. Protein receptor
complexes
for
mineralocorticoid
and
glucocorticoids in cochlear and vestibular tissues
were first identified by Rarey and Luttge (1989).
This has led on to a number of studies, for the
most part carried out by the same group, which
clearly demonstrate that in stress conditions
glucocorticoids are functionally active within the
inner ear. Recent data show that glucocorticoids
probably contribute to cochlear protection in
short-term stress conditions (Wang and
Liberman, 2002). The hypothalamus-pituitarythyroid axis has also a major impact on inner ear
function.
Thyroid
deficiency
during
development results in deafness (Uziel, 1985a,b)
and raised thyroid levels in thyroid-receptor
mutants have also profound deafness (Abel et al.,
1999). Thyroid hormone has recently been
31

shown to be implicated in regulation of the

cochlear motor protein prestin (Weber et al.
2002). The hypothalamus-pituitary-gonadal
axis is likely to have a direct impact on inner ear
function since oestrogen receptors have been
described (Stenberg et al., 1999; 2001) and
oestrogen has been shown to inhibit K+ secretion
in the stria vascularis in-vitro (Lee and Marcus,
2001).
The
hypothalamus-pituitary
hormones
(second-order) have been less well investigated
regarding their effect on the inner ear. Prolactin
is of particular interest in the study of Mnires
disease since prolactin is synthetised in stress
and is implicated in the homeostasis of osmotic
balance (Freeman et al. 2000; Bole-Feysot et al.
1998). In addition prolactin receptors have been
detected in tissues concerned with the immune
system including the thymus, spleen, lymph
nodes, bone marrow. Prolactin receptors have
also been detected in lymphocytes. Since
lymphocyte-macrophage complexes have been
observed within the endolymphatic sac it seems
likely that the sac acts as a site for the immunodefence of the inner ear (Rask-Anderson and
Stahle, 1980) where prolactin might play a role.
Interestingly we have recently reported
hyperprolactinemia in some Mnires patients
which was associated with a prolactinoma in a
few cases (Horner et al. 2002). A publication in
Russian has pointed out that otoneurological
disorders are systematically observed in cases of
pituitary tumours with marked extrasellar
growth (Blagoveshchenskaia and Leushkina,
1988). This is in flagrant contrast with the
occidental publications where otoneurological
symptoms have not been reported in association
with pituitary tumours. It is interesting to note
on the other hand, that serum prolactin levels are
reported to be elevated in hypothyroidism and
significant hypothyroidism has been reported in
17% of Mnires patients (Rybak, 1995). Since
prolactin production is under tonic inhibition
from hypothalamic dopamine, dopamine
deficiency might be involved. Indeed vestibular
compensation
observed
after
hemilabyrinthectomy in the guinea pig is
improved after dopamine treatment (Petrosini
and dellAnna, 1993; Drago et al., 1996). These
32

observations suggest that neuroendocrinological

feedback pathways controlling stress might be
disturbed in some Mnires patients and
depression of hypothalamic dopaminergic
inhibition of prolactin secretion might be
implicated. A further study on non-operated
Mnires
patients
presenting
hyperprolactinemia and on dopamine agonist
treatment, is needed in order to better understand
the cause of the symptoms in Mnires disease.
Conclusion
Fifty years have gone by since the effect of stress
on the inner ear was first reported. A body of
literature available today clearly indicates that
this is not a psychological by-product and that
stress might very well cause inner ear pathology.
Despite this, a patient with vertigo consults
either in otolaryngology or neurology or
psychiatry while an integrated management
scheme might be more appropriate. Pin-pointing
stress-induced inner ear pathology is likely to be
complex since each patient is likely to react
differently to stress, stress hormone release is
stress-type specific, different stress pathways
interact and short/long-term effects are different.
Correspondence Address
K.C. Horner
Equipe Inserm EPI 9902, Laboratoire Otologie
NeuroOtologie, Univ. Mditerrane AixMarseille II, Facult de Mdecine Nord,
Boulevard Pierre Dramard, 13916 Marseille
Cedex 20, France
Tel: 04 91 69 89 46; Fax: 04 91 69 87 31
E-mail: horner.k@jean-roche.univ-mrs.fr
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