Autoimmune Inner Ear Disease

Ravi N. Samy, M.D., F.A.C.S.,1 and Nael M. Shoman, M.D.1

ABSTRACT

Autoimmune inner ear disease (AIED), first reported by

McCabe in 1979, describes a disease process in which cochleovestibular
is compromised by one’s own immune system. Only indirect laboratory

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evidence exists regarding the underlying immune reaction, which can
only be confirmed histopathologically in postmortem studies. Diag-
nosis involves a thorough history and complete head and neck,
otomicroscopic, and audiometric evaluation. AIED classically presents
with bilateral, fluctuating, or rapidly progressive asymmetric sensor-
ineural hearing loss (SNHL), which typically occurs over weeks to
months but can occur suddenly over a period of a few hours or days.
Fifty percent of patients have vestibular symptoms as well, which can be
unilateral or bilateral. A lengthy serological workup is unwarranted
given the absence of a reliable diagnostic laboratory test. Antibodies to
the 68-kDa protein (heat shock protein-70) is marker-specific but not
sensitive for AIED and may correlate with steroid responsiveness. In
cases where the diagnosis remains unclear, a prolonged course of
steroids, with repeat audiometric testing at 1 month, can be undertaken.
Treatment aims to inhibit the detrimental immune response using
immunosuppressant drugs; however, no standardized treatment regi-
men has been found. Cochlear implantation remains a viable last resort
for patients with progressive SNHL.

KEYWORDS: Sensorineural hearing loss, autoimmune inner ear

disease, endolymphatic hydrops, dizziness

Learning Outcomes: As a result of this activity, the participant will be able to (1) list how to diagnose
autoimmune inner ear disease and (2) describe how to treat autoimmune inner ear disease.

1
Department of Otolaryngology, University of Cincinnati/
Cincinnati Children’s Hospital, UC Neuroscience Insti-
tute, Cincinnati, Ohio.
Address for correspondence and reprint requests: Ravi
N. Samy, M.D., F.A.C.S., Department of Otolaryngology,
University of Cincinnati/Cincinnati Children’s Hospital,
UC Neuroscience Institute, 231 Albert B. Sabin Way,
Cincinnati, OH 45267-0528 (e-mail: Ravi.Samy@UC.
edu).
Hearing Loss as a Result of Common and Rare Medical
Conditions: Clinical Findings, Management Options, and
Prevention Strategies; Guest Editor, Julie A. Honaker,
Ph.D.
Semin Hear 2011;32:299–307. Copyright # 2011 by
Thieme Medical Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI: http://dx.doi.org/10.1055/s-0031-1291934.
ISSN 0734-0451.
299
300 SEMINARS IN HEARING/VOLUME 32, NUMBER 4 2011
A lthough sensorineural hearing loss
(SNHL) is a common otologic disorder, it is
typically not reversible. Immune abnormalities
are probably of greater importance in SNHL
than clinicians realize, as numerous patients
with Ménière’s disease and concomitant
SNHL have shown cellular and humoral im-
mune abnormalities.1 As such, a disease process
in which hearing is compromised by one’s own
immune system is autoimmune inner ear dis-
ease (AIED). AIED is important to recognize
and treat, as it represents one of the few
medically treatable or recoverable forms of
SNHL.2 An accurate diagnosis made in a
timely fashion allows for treatment with glu-
cocorticoids that may result in stabilization or
improvement of the hearing loss; treatment
that is delayed beyond 3 months may result in
permanent, bilateral, profound hearing loss.3
The classic presentation of AIED is bilateral,
fluctuating or rapidly progressive asymmetric
SNHL, which typically occurs over weeks to
months but can occur suddenly over a period of
a few hours or days. The SNHL may or may
not be associated with dizziness.4 This article
will review the clinical presentation, diagnosis,
laboratory findings, pathophysiology, and
treatment of patients with presumed AIED.
Although Lehnhardt5 first suggested the
idea of autoimmune disease causing bilateral
hearing loss in the German literature in the
1950s, the first reported series of patients
diagnosed with AIED was by Brian F. McCabe
at the University of Iowa in 1979.4 McCabe
accumulated a series of 18 patients over a 10-
year period. One patient with SNHL also had
postauricular tissue available for pathological
examination, which revealed vasculitis, for
which McCabe postulated an autoimmune eti-
ology. He treated his patients with oral steroids
and intravenous cyclophosphamide, a treat-
ment rarely used today due to the risk of
toxicity and side effects. In McCabe’s series,
the minimum treatment period was 8 months
and the maximum treatment period was 2 years.
Interestingly, in addition to hearing loss and
dizziness, 5 of 18 patients also had facial palsy,
which is typically not associated with AIED.
Since the initial report, numerous animal
models (using primarily mice or guinea pigs)
and clinical studies have been performed to
allow us to better understand this disease proc-
ess.6 However, despite over three decades hav-
ing passed, there is still much we do not
understand about AIED. The actual incidence
and prevalence of AIED as a percentage of all
cases of SNHL is unknown due to two reasons:
(1) an inability to directly examine and biopsy
the membranous labyrinth (without causing
permanent damage) and confirming the pres-
ence of an underlying autoimmune process
and (2) a lack of the presence of a reliable
serological, audiometric, or radiological marker
that indicates the presence of AIED in each
individual patient.7 It is feasible that a
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large proportion of patients with SNHL of
undetermined etiology, including pediatric
and sudden SNHL, may have an immune-
mediated underlying process. In the absence
of a reliable diagnostic marker, however, the
true incidence remains unknown. This can
make AIED difficult to diagnose but should
cause one to consider AIED in the differential
diagnosis of patients with idiopathic, rapidly
progressing unilateral or bilateral cochleoves-
tibular disorders.8
Although autoimmune inner ear disease is
the term most commonly used to describe this
disorder, it may be more appropriate to call this
disease an immune-mediated inner ear disor-
der.6,9 Only indirect laboratory evidence exists
regarding the unknown immune reaction that
is occurring and causing the pathophysiology,
which can only truly be confirmed at autopsy
with histopathologic sections.9 The prevalence
of congenital SNHL due to AIED may be
increased in children born to mothers with
AIED.1 This should not be surprising as anti-
bodies can be transferred from mother to baby
via the placenta, particularly when the blood–
placental barrier is incomplete. This includes
the transmission of maternal antibodies to
inner ear antigens to the fetus. Thus, maternal
immunosuppressant treatment during preg-
nancy may reduce the risk of autoimmune-
induced SNHL in children of affected
mothers. Antibodies to inner ear proteins may
not be responsible for the initial audiovestibular
dysfunction, but this subsequent immune
response after an initial insult (e.g., viral
infection) may further worsen the dysfunction.
The possibility even exists that the immune

system response is just an epiphenomenon and
not the actual cause of the dysfunction.10
Although presenting evidence supporting the
notion that the etiology and pathogenesis of
certain inner ear diseases may be immune-
mediated, those reports have not yet fully con-
firmed an autoimmune disease mechanism be-
cause the majority of the evidence implicating
the immune system is indirect.11 For example,
immune-mediated vascular damage can be de-
tected by anti–endothelial cell autoantibodies,
which is a possible serological marker of vascu-
litis rather than the actual cause.12
Animal and clinical testing has shown
antibodies to several inner ear proteins, includ-
ing 30-, 42-, and 68-kDa proteins. These
proteins correspond to the major peripheral
myelin protein P0, b-actin protein, and the
heat shock stress protein 70, respectively.10
Immunoglobulin G antibodies to P0 have
been found in patients with bilateral Ménière’s
disease and bilateral sudden hearing loss.13 The
development of delayed endolymphatic hy-
drops has shown antibodies against 68-kDa
and 28-kDa proteins, for ipsilateral and con-
tralateral hydrops, respectively. Although some
studies have not shown a high incidence of
Western blot 68-kDa positive testing, one
study showed 90% of patients tested positive.14
Testing positive for the 68-kDa protein may
suggest steroid responsiveness and may portend
a more favorable prognosis.14
CLINICAL PRESENTATION
AND DIAGNOSIS
Any patient with progressive bilateral SNHL
should undergo an evaluation for AIED, and
immunosuppressive therapy should be consid-
ered. A patient with unilateral progressive
SNHL deserves a workup after other causes,
such as acoustic neuroma, have been ruled out.
A team consisting of an otologist, a rheuma-
tologist, and an audiologist is necessary to
properly manage the patient. The otologist is
responsible for the otologic evaluation, the
rheumatologist for the general evaluation, and
the audiologist for performing necessary audio-
metric evaluations. Based on the current liter-
ature review, a reasonable and cost-effective
evaluation should consist of a thorough case
AUTOIMMUNE INNER EAR DISEASE/SAMY, SHOMAN 301
history, physical examination, audiogram, and
serum evaluation. Historical evidence for
known causes of otologic disease and SNHL
is sought, and a history of symptoms of sys-
temic rheumatologic or neurological disorders
is solicited.
The otologic physical examination rules
out evidence of other otologic or neurological
disease, and the general physical examination
searches for evidence of systemic rheumato-
logic disease. The audiogram documents
SNHL and serial audiograms document pro-
gression. Auditory brain stem response testing
or magnetic resonance imaging of the cerebel-
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lopontine angle may be indicated to rule out
retrocochlear pathologies, such as multiple
sclerosis plaques or acoustic neuromas. The
patient should thoroughly understand the po-
tential consequences of current treatment regi-
mens and the near certainty of further hearing
loss if treatment is not initiated.3
A high index of suspicion and clinical
acumen are important to assess if an individual
with SNHL and/or dizziness has AIED. Otol-
ogists typically make the diagnosis first. How-
ever, primary care physicians, neurologists, and
audiologists may all evaluate these patients.
Thus, proper understanding of this disease
entity is important to avoid delaying proper
diagnosis and treatment.8 The primary method
of diagnosis is via history and physical exami-
nation and audiometric testing. Unfortunately,
this can still be inadequate to diagnose a disease
process that is best understood from a histo-
pathologic standpoint, which can only be done
postmortem. The differential diagnosis in-
cludes any condition that can cause rapid or
sudden unilateral/bilateral hearing loss: acous-
tic neuroma (including neurofibromatosis type
2) or other retrocochlear lesions (e.g., menin-
gioma), multiple sclerosis, Ménière’s disease,
genetic hearing loss, luetic labyrinthitis (syph-
ilis), viral infections, and vascular etiolo-
gies.4,10,11 Loveman et al14 performed a
retrospective review of 30 patients diagnosed
with AIED. Although median duration from
onset of symptoms to audiometric testing and
treatment was 25.5 weeks (mean of 144 weeks),
the range was between 3 and 1040 weeks. Of
this group, 50% were steroid-responsive. Their
patients reflected the population of west Texas:
302 SEMINARS IN HEARING/VOLUME 32, NUMBER 4 2011
83% patients were female; primarily white
(60%), 33% were Hispanic, 7% were Asian,
and 0% were African-American.
A thorough history includes assessment for
the following: (1) the rapidity of the hearing
loss; (2) unilaterality versus bilaterality of
symptoms; (3) associated tinnitus and aural
fullness; (4) dizziness; (5) past medical history
of autoimmune diseases, tumors, or syphilis; (6)
past surgical history (particularly surgeries of
the head and neck or skull base); (7) medica-
tions (including herbal medications and over-
the-counter supplements); (8) allergies; (9)
social history (including that of smoking, alco-
hol consumption, transfusions, or illicit drug
use); and (10) family history of autoimmune
diseases, hearing loss, or systemic illnesses.
Although most AIED studies tend to focus
on the hearing loss portion of AIED, 50% of
these patients have vestibular symptoms as
well, which can be unilateral or bilateral and
can present as ataxia, generalized imbalance,
disequilibrium, motion intolerance, positional
vertigo, and Ménière’s type.2,15,16 Some pa-
tients may even have dizziness alone, without
associated SNHL, due to unilateral or bilateral
peripheral vestibulopathy. There also may be
an overlap between AIED and Ménière’s
disease (particularly bilateral Ménière’s).17
Ménière’s disease may in fact have an auto-
immune cause in some patients.3 One study
noted an abnormality of the helper T-cell
balance (ratio of interferon-gamma-producing
helper T cells to interleukin-4-producing
helper T cells) as well as an increased natural
killer cell activity in Ménière’s disease.18
Pursuant to a detailed history, a complete
head and neck examination is performed. This
includes examination for lesions and ulcera-
tions of the oral and nasal cavities, masses of
the head and neck, and skin lesions. A neuro-
logical examination is performed as well, as-
sessing for cranial nerve palsies and cerebellar
dysfunction (e.g., finger to nose, heel to shin,
and gait testing). A systemic examination of the
extremities assessing for joint contractures and
additional skin lesions can be performed as
well. The final and most important portion of
the examination involves close inspection of the
ears including a thorough otomicroscopic ex-
amination. In particular, the clinician must
assess for evidence of inflammatory conditions
of the auricle, such as relapsing polychondritis
as well as psoriasis or other dermatologic con-
ditions that can affect the external auditory
canal. The tympanic membranes should be
assessed for perforations, masses, and otorrhea.
Tuning fork tests and tympanometry can be
used to assess conductive hearing loss due to
effusion. Systemic conditions with local man-
ifestations (including Wegener’s granuloma-
tosis, an autoimmune vasculitis that can cause
a chronic otitis media and concomitant
SNHL) should remain in the differential
diagnosis.
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Besides the history and physical examina-
tion of a patient with suspected AIED, the next
most important part of the evaluation is audio-
metric testing. Pure-tone testing, speech re-
ception testing, and word recognition scores are
the most important testing modalities. How-
ever, there is no pattern or type of hearing loss
pathognomonic for AIED.2 Quaranta et al19
proposed the use of evoked and distortion-
product otoacoustic emissions to monitor the
clinical course of AIED. They felt that the
underlying cochlear pathology was one of en-
dolymphatic hydrops. This raises the question
of whether electrocochleography or vestibular
evoked myogenic potentials could monitor for
progression or prognosis in AIED. Serial
audiograms are performed monthly until hear-
ing loss has stabilized. If the patient notes any
change in hearing or increasing aural fullness,
more frequent audiometric testing can be per-
formed. Vestibular testing (e.g., electronystag-
mography or rotary chair testing) is useful as an
adjunct to establish a baseline to assess for
vestibular end-organ damage. In addition, all
potential AIED patients need to have magnetic
resonance imaging scanning with gadolinium, a
contrast agent, to rule out tumor-related causes
of hearing loss. Occasionally, these scans can be
positive (i.e., enhance with gadolinium) and
show signs of labyrinthitis from the underlying
autoimmune process. A high-resolution tem-
poral bone computed tomography scan may be
helpful as well, particularly if one is having
difficulty assessing for chronic otitis media due
to autoimmune pathology.
Abnormal laboratory testing can help sup-
port the diagnosis of AIED. Laboratory

screening tests often include complete blood
count, chemistry panel, fluorescent treponemal
antibody absorbed (to rule out syphilis), Lyme
titers, immunologic studies (68-kDa, antinu-
clear, antineutrophilic cytoplasmic, antiendo-
thelial cell, antiphospholipid/anticardiolipin
and antithyroid antibodies; lymphocyte inhib-
ition assay; rheumatoid factor; C3 and C4
complement levels; Raji cell assay for circulat-
ing immune complexes; and erythrocyte sed-
imentation rate).4,8,9 However, one needs to
understand that negative laboratory testing
does not rule out AIED as there is no gold
standard, diagnostic test.2 Serological workup
is used to assess for systemic immunologic
involvement but does not correlate with either
the presence of AIED or its severity.2 This lack
of reliable testing has made the diagnostic
criteria for AIED almost arbitrary, as opposed
to other systemic autoimmune diseases.8 The
laboratory testing is helpful only when abnor-
mal or positive, as it can help delineate the
possible etiology of the AIED. However, the
prognostic importance of the autoantibodies is
unclear.8 In one study, positive autoimmune
tests were not even predictive of hearing im-
provement after 1 month of steroid treat-
ment.20 The lack of a rational strategy and
the high cost of laboratory testing have per-
suaded some authors to recommend a more
restricted immunologic workup, such as assess-
ing for 68-kDa protein or antinuclear anti-
body.21 Many laboratories agree that
antibodies to the 68-kDa protein, now known
to be the heat shock protein-70, is a marker
specific but not sensitive for this disease.3 As
one can see, AIED is not a homogeneous
group; there is only circumstantial evidence
about its presence. If after all of the above,
the diagnosis of AIED is still not clear or
certain, a prolonged course of immunomodu-
lating agents (particularly steroids) with repeat
audiometric testing at 1 month is undertaken to
better clarify the diagnosis.
PATHOPHYSIOLOGY
The immune response involved in AIED is
believed to be both humoral and cell-mediated.
There is a possible genetic predisposition to
autoimmune disease. Damage to the inner ear
AUTOIMMUNE INNER EAR DISEASE/SAMY, SHOMAN 303
can cause profound hearing loss by exposing the
immune system to previously sequestered inner
ear proteins, which may result in the production
of antibodies against the inner ear, as the inner
ear contains thousands of proteins.22 Animal
models used to investigate AIED have shown
that there is no anatomic barrier to the systemic
circulation within the cochleovestibular com-
partment.11 The endolymphatic sac contains
immunocompetent tissues capable of immune
responses.3 The inner ear antigens targeted
by the immune system have not yet been iden-
tified, even though numerous reports of pro-
gressive hearing loss associated with systemic
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autoimmune diseases have been published.22
Cogan’s syndrome, Behcet’s disease, relapsing
polychondritis, systemic lupus erythematosus,
rheumatoid arthritis, polyarteritis nodosa, and
inflammatory bowel disease have all been linked
with SNHL and dizziness. Audiovestibular
disease control or management with immuno-
suppressive drugs has been effective in reversing
or stabilizing hearing loss in some of these
patients.3 Nearly 15% of AIED cases have
another autoimmune diagnosis as well, such as
inflammatory bowel disease (ulcerative colitis or
Crohn’s), systemic lupus erythematosus, rheu-
matoid arthritis, and ankylosing spondylitis.2
TREATMENT
Once a patient is believed to have AIED,
rheumatologic consultation is important to
assess for primary versus secondary AIED.
Rheumatologic consultation is also important
to assess for management of complications of
treatment of immunosuppression, because
most clinicians are unfamiliar with the drugs
used in autoimmune diseases. With primary
AIED, the membranous labyrinth is the only
organ affected by an immune-mediated proc-
ess. This is believed to be an inner ear–specific
autoimmune process that involves T-cell tar-
geting of cochleovestibular antigens, such as
cochlin, a 60-kDa protein.6Secondary AIED
refers to a systemic process that subsequently
involves the inner ear, such as systemic
lupus erythematosus, rheumatoid arthritis,
or an autoimmune vasculitis. With secondary
AIED, if a concomitant systemic disease of
autoimmune etiology is not properly diagnosed
304 SEMINARS IN HEARING/VOLUME 32, NUMBER 4 2011
and treated, permanent systemic end-organ
damage and failure can result (e.g., cardiovas-
cular complications such as stroke, renal failure,
etc.).
Treatment of AIED is directed at manag-
ing the underlying disease process by inhibiting
the detrimental immune response.3 Unfortu-
nately, no standardized treatment regimen has
been found. All of the pharmaceutical treat-
ments that are being used for AIED are being
used off-label (i.e., without Food and Drug
Administration approval). Most of the studies
using immunosuppressants other than steroids
have been open-label and of short duration.16
The goal is to taper off the immunosuppressant
once symptoms and hearing have stabilized. To
minimize the incidence and severity of side
effects, typically more evident with higher
doses, a combination of treatments is some-
times used to maintain the lowest dose possible
of each immunosuppressant. The goal is to
restore hearing to normal or make the hearing
serviceable with the use of hearing aids. Re-
garding the prognosis for patients with AIED,
Garcı́a-Berrocal et al9 compared a group of
patients with AIED to those with viral, vascu-
lar, or idiopathic causes of sudden SNHL.
Those with AIED had the best and earliest
recovery of hearing but the highest rate of
recurrence when compared with the other
groups (p < 0.05), as would be expected with
other autoimmune diseases.9
If hearing loss cannot be stopped or pre-
vented, cochlear implants in one or both ears is
an option and may be less of a concern than
the side effects and complications of immu-
nosuppressant medications. The treating
physician needs to avoid certain immunosup-
pressants during pregnancy (and clearly dis-
cuss management with the patient and the
obstetrician). The primary immunosuppres-
sant used is systemic steroids; that is consid-
ered the current gold standard for treatment of
AIED. Other treatments include azathio-
prine, intravenous gamma globulin, metho-
trexate, etanercept, cyclophosphamide, and
plasmapheresis. Potential side effects of ste-
roids include aseptic femoral head necrosis,
osteoporosis, psychiatric changes, weight gain,
cataract formation, elevated blood sugars, ele-
vated blood pressure, sleep disturbances, as
well as other potential systemic side effects.
However, one prospective study showed that
of its 116 patients on a minimum steroid
regimen of 1 month, only seven had any
adverse events, the most common of which
was hyperglycemia. Weight gain was another
common side effect, and no patients suffered
from fractures or osteonecrosis.23 Thus, with
appropriate patient education and selection,
such as avoiding high-dose systemic steroids
in patients with poorly controlled diabetics or
a patient with an active peptic ulcer, and
monitoring for complications, steroids are
safe and effective for AIED.23 Overall steroid
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response is 60% in patients with presumed
AIED. Some patients may have improvement
in hearing, but in others, it may be stabilized.
Hearing loss may, unfortunately, be refractory
to steroids.2 Some patients may have steroid-
dependent hearing, and for those, adding
another immunosuppressant may spare the
patient high-dose steroids, potentially mini-
mizing their side effects. Why some patients
initially respond to steroid treatment and then
become resistant to such treatment remains
unknown.11
Treatment typically starts with prednisone
at 1 mg/kg per day (usually 60 to 80 mg for the
average adult) for 4 weeks. Courses of treat-
ment less than 4 weeks in duration may lead to
a relapse. Patients with total treatment dura-
tion of less than 6 months may be at higher risk
of relapse than those treated for 6 months or
longer.2 However, due to the risk of long-term
side effects, the goal is to slowly taper the
patient off steroids once the hearing has recov-
ered. At the very least, the patient should be on
the lowest possible daily dose of steroids or an
every other day regimen. One should see an
improvement in subjective hearing loss, tinni-
tus, and dizziness. A report of increased tinni-
tus or change in hearing represents early
relapse, and the steroid dosage is generally
increased. Audiometric testing (especially
with symptomatic or treatment changes) at
regular intervals assists the physician with dos-
ing decisions.3 Objective improvement in-
cludes better word recognition scores, and
pure-tone thresholds decreasing 15 dB in one
frequency or 10 dB in two or more frequen-
cies.2 If there is neither subjective improvement

in symptoms or objective audiometric improve-
ment (i.e., the patient is a nonresponder), the
steroids should be slowly tapered off (in about a
month or longer, depending on duration and
dosage of steroid used).
Transtympanic medications, particularly
steroids, are promising (e.g., transtympanic dex-
amethasone or methylprednisolone), parti-
cularly in animal models. There has been
increased use over the past 10 years. Unfortu-
nately, there is no standardization with regard
to type of medication, dosage, and method of
distribution (e.g., one-time versus weekly versus
use of osmotic minipump) and no long-term
data on clinical efficacy.24 However, to date,
there has not been a single study that has shown
efficacy in human clinical trials.25 Intratympanic
injection of infliximab, a tumor necrosis factor-
a antibody, may provide an alternative to
steroids.6 Yang et al26 evaluated the use of
multiple medications in a guinea pig model of
inflammation. Sterile labyrinthitis was created
with keyhole limpet hemocyanin. Dexametha-
sone, cyclosporine, prednisolone, fluorouracil,
and FK506 were administered to the round
window with either a single injection or osmotic
minipumps. Histological evaluation was per-
formed as was auditory brainstem response
(ABR) evaluation of hearing. In none of the
cases was the administered substance beneficial
in suppressing the inflammatory response.26
Etanercept is an inhibitor of tumor ne-
crosis factor-a. It has been approved for use
in inflammatory arthritides, including rheu-
matoid and psoriatic arthritis as well as an-
kylosing spondylitis. Although initially felt to
be promising particularly by working in com-
bination with methotrexate, a more recent
pilot study did not find any positive benefit.16
In this preliminary study, 20 patients with
AIED were enrolled in a blinded, placebo-
controlled randomized clinical trial using
etanercept 25 mg subcutaneously twice
weekly for 8 weeks with a follow-up at
4 weeks off treatment. The primary study
end point was an improvement in pure-tone
average threshold of 10 dB in two consec-
utive frequencies and/or improvement in
word recognition score of >12%. In this
short-duration study, there was no benefit
to etanercept use as compared with placebo
AUTOIMMUNE INNER EAR DISEASE/SAMY, SHOMAN 305
either in fluctuation of hearing loss or im-
provement in vertigo or tinnitus. Limits of
this study include its duration and limited
number of patients. In addition, the authors
felt that because the average duration of
AIED in these patients was over 4 years, it
is possible that a shorter duration of AIED
would benefit from etanercept as well as a
higher dosage (e.g., 100 mg/wk is used for
severe cases of psoriasis). There is also the
possibility of a subset of patients who would
respond. Other tumor necrosis factor inhib-
itors such as infliximab and adalimumab may
be promising.16
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Methotrexate, a folic acid antagonist, has
been used for numerous diseases, including
malignancies (e.g., Burkitt’s lymphoma, me-
ningeal leukemia, osteosarcoma), psoriasis,
and rheumatoid arthritis. It has been used for
AIED as well, with less long-term systemic
side effects than steroids. Doses beginning at
7.5 mg/wk and increasing to 15 to 20 mg/wk
are typically used. Because of a delay until
therapeutic benefit is realized, corticosteroid
therapy is initiated and then tapered while
methotrexate is added. As the slow tapering
of the steroid is continued, the dose of metho-
trexate is increased over time. Potential side
effects/toxicities include myelosuppression,
gastrointestinal upset, oral ulceration, hepatic
fibrosis, and acute pneumonitis.2 Weekly test-
ing includes complete blood count, liver func-
tion tests, blood urea nitrogen, creatinine, and
urinalysis.2 Harris et al27 conducted a random-
ized, double-blinded, placebo-controlled study
from 1998 to 2001 at 10 centers throughout the
United States. Patients were randomized to
either oral methotrexate (15 to 20 mg/wk) or
placebo in combination with an 18-week pre-
dnisone taper. The main outcome studied was
the maintenance of hearing improvement with
steroid treatment. Unfortunately, in this well-
done study, methotrexate was found to be no
better than placebo in maintaining the steroid
hearing improvement.27 Although some still
use methotrexate for AIED, there has been a
significant decline in the use of methotrexate by
neurotologists since this study’s findings were
published in 2003.
Cyclophosphamide administered at doses
of 2 to 5 mg/kg per day can be taken either orally
306 SEMINARS IN HEARING/VOLUME 32, NUMBER 4 2011
or intravenously. It has been used for AIED
for cases resistant to steroids; however, this drug
has a significant toxicity profile, including the
potential for causing malignancy of the urinary
tract or leukemia. As a result of the potential
toxicities, it is used more commonly as a salvage
drug.2 If one contemplates using this medica-
tion, consultation with a rheumatologist is war-
ranted.
Plasmapheresis is a blood purification pro-
cedure. Plasmapheresis removes antibodies
from the blood but does not directly affect
the immune system’s ability to produce more
antibodies. It has been used for Guillain-Barré
syndrome, myasthenia gravis, and thrombotic
thrombocytopenic purpura. It also can be con-
sidered for AIED, especially when hearing
continues to plummet despite maximal medical
therapy.3
For those patients in whom medical treat-
ment fails to prevent progression of SNHL and
hearing aids are no longer useful, cochlear
implantation is an option and may even be
preferable to the potentially significant side
effects caused by the immunosuppressant med-
ications. The primary author of this article has
had patients who have stopped their immuno-
suppressant medications due to interest in be-
coming pregnant or due to side effects and
instead have chosen implantation.
RESEARCH/FUTURE DIRECTIONS
Clearly, much needs to be done to improve our
understanding of AIED. As Loveman et al14
stated about AIED, ‘‘diagnosis . . . is neither
simple nor certain, and optimal management is
not established.’’ Large, multicenter prospec-
tive studies are needed to assess for the best
diagnosis, management, and treatment of
AIED.2 Highly sensitive and specific labora-
tory studies are needed to accurately diagnose
AIED and provide prognosis. Clearly, oral or
transtympanic pharmaceutical treatments with
minimal systemic side effects would also be
desirable.3
ACKNOWLEDGMENTS
The authors thank Cori Birkholz and Gina
Diaz for their assistance with this project.
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