Autoimmune Inner Ear Disease:
Diagnostic and Therapeutic Approaches in a
Multidisciplinary Setting
Eric L. Matteson*
David A. Fabry**
Scott E. Strome†
Colin L. W. Driscoll†
Charles W. Beatty†
Thomas J. McDonald†
Abstract
Autoimmune Inner Ear Disease (AIED) is a clinical syndrome of uncertain
pathogenesis. It is associated with bilateral rapidly progressive hearing loss.
The hearing loss may be associated with vestibular symptoms. Autoimmunity
has been proposed as the pathogenesis of this sort of hearing loss, although
the mechanism of the disease is poorly understood. It is well accepted that
the endolymphatic sac is an immunocompetent organ and circulating autoantibodies against inner ear antigens have been reported, as have viral antigens
in the endolymph, although the sensitivity, specificity, and roles of those antibodies in a disease process are poorly defined.
We will describe the clinical aspects of the disease, the histopathology, the
immunologic indicators, the types of presentation, both from the audiologic
and vestibular point of view, clinical trials for treatment and the follow-up. One
of our conclusions is that many of these patients respond favorably to the treatment Methotrexate.
Key Words: Autoimmune inner ear disease, Methotrexate, Sensorineural
hearing loss, PET Scan
Abbreviations and Acronyms: AIED =Autoimmune Inner Ear Disease; SNHL
=Sensorineural Hearing Loss; ESR=Erythrocyte sedimentation rate; HSP-70
=Heat shock protein 70; PET Scan=Positron emission tomography;
MTX=Methotrexate; FDG=18-fluoro-2-deoxyglucose; MRI=Magnetic resonance imaging;TNF=Tumor necrosis factor
Sumario:
La enfermedad autoimmune del oído interno (AIED) es un síndrome clínico
de patogénesis incierta. Se asocia con un trastorno auditivo bilateral rápidamente progresivo. La hipoacusia puede asociarse con síntomas vestibulares.
Se ha propuesta la autoinmunidad como la patogénesis de este tipo de trastorno
auditivo, aunque el mecanismo de la enfermedad está pobremente entendido.
Se acepta ampliamente que el saco endolinfático es un órgano inmunocompetente y se ha reportado la existencia de anticuerpos circulantes contra el
oído interno. También se ha reportado la presencia de antígenos virales en
la endolinfa, aunque la sensibilidad, especificidad y el papel de estos anticuerpos en el proceso de la enfermedad aún no ha sido bien definida.
*Department of Internal Medicine, Division of Rheumatology
**Division of Audiology, Department of Otorhinolaryngology
†Department of Otorhinolaryngology, Mayo Clinic and Mayo Graduate School of Medicine Rochester, Minnesota
Corresponding Author: Thomas J. McDonald, M.D., Professor and Chair, Department of Otorhinolaryngology, Mayo Clinic
Rochester, MN 55905, Phone: 507-284-3976 , Fax: 507-284-8855, E-mail: tjmcdonald@mayo.edu
This work is in part supported by grants from the Mayo Clinic Foundation and Immunex Corporation to Dr. Matteson, and an
unrestricted grant from Mr. and Mrs. Jesse Jones.
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Journal of the American Academy of Audiology/Volume 14, Number 4, 2003
Describiremos los aspectos clínicos de la enfermedad, la histopatología, los
indicadores inmunológicos, los tipos de presentación tanto desde el punto de
vista audiológico como vestibular, los estudios clínicos para el tratamiento y
el seguimiento. Una de nuestras conclusiones es que muchos de estos
pacientes responden favorablemente al el tratamiento con Metotrexate.
Palabras Clave: Enfermedad auto-inmune del oído interno; metotrexate,
hipoacusia sensorineural, Prueba de PET.
Abreviaturas y Acronimos: AIED = enfermedad auto-inmune del oído interno;
SNHL = hipoacusia sensorineural; ESR = Tasa de eritrosedimentación; HSP70 = proteína 70 de choque térmico; PET Scan = tomografía de emisión de
positrones; MTX = metotrexate; FDG = 18-fluoro-2-dexosiglucosa; MRI = imágenes por resonancia magnética; TNF = factor de necrosis de tumor.
A
utoimmune inner ear disease (AIED)
is a clinical syndrome of uncertain
pathogenesis. It is often associated
with rapidly progressive sensorineural hearing loss (SNHL) but may be unilateral early
in the disease (McCabe, 1979, Veldman et
al, 1984). The hearing loss may be associated
with vestibular symptoms that have a typical fluctuating course during the active phase
of disease. Atypically, it may present as fluctuating hearing loss in the only ear (where
the opposite ear has profound hearing loss
due to a previous event, e.g., Meniere’s).
Although not well studied, circulating
autoantibodies against inner ear antigens
have been reported, but these are poorly
reproducible and not clinically reliable for
either diagnosis or treatment of this often
devastating disease. AIED is frequently not
recognized by clinicians and results in partial hearing loss in virtually all patients, and
complete hearing loss in about 1/3 of patients
(Alleman et al, 1997, Hughes et al, 1984,
Gottschlisch 1995, Toubi et al, 1997). Even
when AIED is recognized, therapeutic
response to corticosteroids, immunosuppressives, and plasmapheresis is incomplete,
and highlights the need for better diagnostic
and therapeutic modalities for its management (Hughes et al, 1984, McCabe, 1989,
Matteson et al, 2000).
The diagnosis and management of
immune-mediated hearing loss has been traditionally dependent upon history and limited
clinical findings. Laboratory markers of
inflammation such as erythrocyte sedimentation rate (ESR), serologic or autoantibody
measurements, including the heat shock protein 70 (HSP-70), imaging studies such as
226
magnetic resonance imaging (MRI) or the
more invasive arteriogram, and/or histologic
examination of biopsied specimens are usually normal and not very helpful, although of
these the HSP-70 shows the most promise
(Hughes et al, 1984, Harris and Sharp, 1990,
Hirose et al, 1999).
Autoimmunity has been proposed as the
pathogenesis of sudden SNHL characterizing
AIED, although the mechanism of disease is
poorly understood. Clinically, sudden SNHL
has been seen in association with other
autoimmune diseases such as rheumatoid
arthritis, systemic lupus erythematous,
inflammatory bowel disease, and polyarteritis nodosa (Hughes et al, 1984, Summers and
Harker, 1982, Andonopoulos et al, 1995) either
in the patients themselves or in members of
the family. Cogan’s syndrome is accepted as
an autoimmune disease, and it is likely that
at least some cases of Meniere’s disease, especially when bilateral, are autoimmune in
nature (Veldman et al 1984, Hughes et al,
1984, Gottschlich et al, 1995). Circulating
autoantibodies against inner ear antigens
have been reported as have viral antigens in
the endolymph, although the sensitivity, specificity and role of these antibodies in the disease process are poorly defined (Alleman et
al, 1997, Kumagami, 1996). The improvement
in hearing following corticosteroid and
immunosuppressive therapy as well as
plasmapheresis further suggests an autoimmune response as the etiology of the hearing
loss in these conditions (Veldman et al, 1984).
It has been suggested that a nonspecific reactant, heat shock protein 70 (HSP-70), may be
predictive of corticosteroid responsiveness
(Hirose et al, 1999). It has also been sug-
Autoimmune Inner Ear Disease/Matteson et al
gested that disturbance of microcirculation in
the inner ear by thrombosis associated with
antiphospholipid antibodies may lead to sudden deafness, although in our experience
these antibodies are infrequently present
and of uncertain diagnostic or therapeutic significance (Toubi et al, 1997, Kumagami 1996,
Casoli and Tumiati, 1995, Naarendorp and
Spiera, 1998).
High doses of corticosteroids, often in
doses of 40-80 gm/day, may be useful in the
initial management of autoimmune mediated SNHL (Hughes et al 1984, McCabe,
1989). Unfortunately, improvement in hearing is rarely sustained, and unacceptable
side effects from the corticosteroid therapy
soon follow. To improve the outcome of
autoimmune inner ear disease, the use of
cytotoxic therapy with cyclophosphamide has
been proposed. While some success has been
reported with this therapy in slowing or
arresting the hearing loss, cyclophosphamide
use is associated with significant toxicities,
including increased risk of infection, malignancy, and death (Clements 1991). Another
chemotherapeutic agent, methotrexate, has
been successfully used in low doses for the
management of a number of autoimmune
diseases, including rheumatoid arthritis,
inflammatory bowel disease, and Wegener’s
granulomatosis with favorable experience
both from a standpoint of efficacy and toxicity (Hughes et al, 1984, Clements, 1991).
Based on this experience, methotrexate has
also been employed as treatment for autoimmune inner ear diseases, including some
cases of Meniere’s disease and Cogan’s syndrome (Matteson et al, 2000).
At Mayo Clinic, we are actively investigating the pathophysiology, diagnosis and
assessment of AIED. There are very few centers in the world where research into this disorder is conducted. Currently, about 80
patients with this disorder are being followed
at Mayo in a clinic we have established to
evaluate and treat patients with autoimmune hearing loss within the Department of
Otorhinolaryngology and the Divisions of
Rheumatology and Audiology. This clinic
forms the basis of our current research, which
includes study of the utility of several therapeutic agents such as methotrexate and
etanercept for this disease, utility of assays
such as positron emission tomography (PET)
and HSP-70 in diagnosing and treating it. To
better understand AIED, immunologic and
immunogenetic studies are being conducted
in Mayo Clinic laboratories by one of the
authors (SES) with a colleague in Rheumatology/Immunology to better understand the
pathogenesis of this condition.
As part of this effort, we recently completed a one year prospective study of low dose
methotrexate to evaluate the long-term efficacy of this therapy in the management of
autoimmune hearing loss (Matteson, et al
2001). This study included 17 patients with
treatment refractory autoimmune hearing
loss. All patients had ongoing episodic worsening of hearing in one or both ears prior to
enrollment despite traditional medical therapy. The MTX dose was 7.5 - 25 mg/ week.
Hearing loss and vertigo were evaluated at
baseline and at completion of the study. Hearing improvement was defined as an improvement in average pure tone threshold (PT) of
>10 dB or an increase in speech discrimination (SD) of >15%, while worsening was
defined as a decrease of >10 dB in PT or
decrease of >15% in SD in at least one ear.
MTX was well tolerated. Among patients
with Meniere’s, 5 of 9 had improvement or resolution of vertigo. Equilibrium improved in
all 3 patients with Cogan’s and improved in
2/3 patients with idiopathic hearing loss and
this symptom. According to the parameters
defined above, hearing improved in 12
patients (71%), was unchanged in 3 patients
(18%), and worsened in 2 patients (11%). As
a result of this study, we believe that longterm low dose MTX therapy may be a useful
therapy for at least some patients who have
hearing loss with a presumptively autoimmune-mediated component that is refractory
to traditional therapies.
Proper diagnosis and assessment of AIED
remains a significant challenge. In an effort
to better define disease activity, we have carried out a preliminary study of positron emission tomography (PET) in AIED. To our
knowledge, this is the first attempt to utilize
PET in the evaluation and characterization
of AIED. As suggested by studies evaluating
inflammation in other idiopathic inflammatory diseases of the immune system such as
rheumatoid arthritis, inflammatory bowel
disease, systemic lupus, giant cell arteritis
and polymyalgia rheumatica, increased 18fluoro-2-deoxyglucose (FDG) transport across
capillary membranes possibly correlates with
glucose uptake in inflammatory foci (Stoppe
et al, 1990, Takano et al, 1993, Danfors et al,
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Journal of the American Academy of Audiology/Volume 14, Number 4, 2003
1997, Bicik et al, 1997; Blockmans et al,
1999). We hypothesized that FDG can be utilized in PET to assess disease activity in
patients with AIED. The primary outcome
measure of the study was whether PET would
detect any abnormality (hypo- or hypermetabolism of FDG) on the affected inner ears
compared to the controls and whether a difference in FDG uptake would be noted following therapy.
We evaluated ten patients with AIED
and five sex and age matched controls without any history of AIED by limited PET of the
inner ear. Five patients with new or active
AIED underwent serial PET before and after
4-6 weeks of a high dose-tapering course of
prednisone. Five patients with an established
diagnosis of AIED and stable disease under
treatment and 5 controls underwent a single
PET scan of the inner ears. Both the study
and control subjects had head MRI (for
anatomical correlation), audiometric, and
vestibular studies, and the AIED patients
had heat-shock protein (HSP-70) measurements. Limited PET images of the inner ear
using 18-fluoro-2-deoxyglucose (FDG) isotopes were obtained. PET scans were read
by two nuclear medicine consultants blinded
to the identity and the diagnosis of each subject. The PET was normal in 4/5 normal controls, and abnormal in one with normal audiometric and vestibular studies. Of patients
with established and stable AIED, 4/5 had no
PET abnormalities and negative HSP-70;
and the one with abnormal PET shortly thereafter manifested clinically active disease. Of
the 5 patients with active AIED followed
serially, 4 had an initial abnormal PET in at
least one ear which became normal (definitely negative) in all but one patient after
therapy. Only one patient with clinically
active AIED had a normal PET before and
after therapy (the HSP-70 was positive before
therapy and negative after the therapy). We
concluded that PET, especially when combined with HSP-70 determination, may be a
useful technique for assessing disease activity in patients with AIED.
Currently, we are evaluating etanercept
(EnbrelTM), a fusion protein consisting of two
recombinant p75 tumor necrosis factor (TNF)
receptors linked to the Fc portion of human
IgG1 as treatment for active AIED (Mohler
et al, 1993). The molecule is a powerful
antagonist of TNF, binding to and inactivating this cytokine. TNF has been shown to
228
play a critical role in a number of chronic
inflammatory conditions (Smith et al, 1990,
Beutler et al, 1994, Arend et al, 1996). For
the past five years, etanercept has been tested
extensively in human trials, including clinical trials in rheumatoid arthritis (RA), juvenile RA, geriatric (age>65) patients with RA,
Crohn’s disease, human immunodeficiency
virus (HIV) infection, congestive heart failure,
allograft rejection and sepsis syndromes
(Moreland et al, 1999, Weinblatt et al, 1999,
Bathon et al, 2000).
The 40 patients enrolled into this 6
month study are assessed by conventional
methods including clinical examination,
audiometrics, evaluation of vestibular function and HSP-70 testing. In addition, serial
PET scanning is being evaluated as a measure of disease activity. This study should
provide definitive information about the utility of these approaches to AIED.
SUMMARY
A
IED is an unusual, but serious condition that may occur in the absence of an
associated disease, or as a manifestation of
a systemic immune mediated inflammatory
disorder. Both diagnosis and treatment are
imperfect, and many patients become severely
hearing-impaired because of it. While variably effective, agents used in the treatment
of AIED have been associated with serious
and occasionally life-threatening adverse
effects (Clements 1991, Hoffman et al, 1992).
Fortunately, many patients may benefit from
advances in cochlear implant technologies,
and a number of our patients with AIED
have undergone this procedure, with generally excellent results. At the same time, our
goal is to preserve natural hearing by
improved understanding of the pathogenesis,
natural history, early diagnosis, and successful treatment of the disease. This latter
point is particularly important as not only
hearing but balance can be permanently
impaired because of the disease, and because
AIED may be part of an underlying systemic
disorder, the management of which is critical to a satisfactory outcome.
A well integrated, organized multidisciplinary approach is essential to satisfactory
evaluation and treatment of AIED. Many
patients with this disease have an underlying systemic disorder which requires management of skilled internists, as does the
Autoimmune Inner Ear Disease/Matteson et al
proper follow-up of long term therapy with
immunosuppressive agents because of their
many complications. The best outcome for the
patient requires the including involvement of
knowledgeable otorhinolaryngologists, audiologists, neurologists, internists, and immunologists.
ies in patients with rapidly progressive sensorineural
hearing loss. Laryngoscope 100:516-524.
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