Autoimmune Inner Ear Disease (AIED)
Author: Timothy C. Hain, MD
Last edited: 7/15/04
What is Autoimmune Inner Ear Disease?
Autoimmune inner ear disease(AIED) is a syndrome of progressive hearing loss and/or dizziness that is caused by antibodies or immune cells which are attacking the inner ear. In most cases, there is reduction of hearing accompanied by tinnitus (ringing, hissing, roaring) which occurs over a few months. Variants are bilateral attacks of hearing loss and tinnitus that resemble Meniere's disease, and attacks of dizziness accompanied by abnormal blood tests for antibodies. About 50% of patients with AIED have balance symptoms.
The immune system is complex and there are several ways that it can damage
the inner ear. Both allergy and traditional autoimmune disease such as ankylosing
spondylitis, systemic lupus erythematosus (SLE), Sjoegren's syndrome (dry
eye syndrome), Cogan's disease, ulcerative
colitis, Wegener's granulomatosis, rheumatoid arthritis, and scleroderma can
cause or be associated with AIED. Another multisystem disease, Bechet's, commonly
has audiovestibular problems. Allergy is traditionally suspected to be food
related, but there is presently no agreement as to the importance of food allergy.
AIED is rare, probably accounting for less than 1% of all cases of hearing impairment or dizziness. The precise incidence is controversial. About 16% of persons with bilateral Meniere's disease, and 6% of persons with Meniere's disease of any variety may be due to immune dysfunction.
What Causes
Autoimmune Inner Ear Disease?
The cause of AIED is generally assumed to be related to either antibodies or
immune cells that cause damage to the inner ear. There are several theories
as to how these might arise, analogously to other putatative autoimmune disorders:
- Bystander damage: Damage to
the inner ear causes cytokines to be released which provoke (after a delay)
additional immune reactions. This theory might explain the attack/remission
cycle of disorders such as Meniere's disease.
- Cross-reactions: Antibodies or
rogue T-cells cause accidental inner ear damage because the ear shares common
antigens with a potentially harmful substance, virus, or bacteria that the
body is fighting off. This is presently the favored theory of AIED. COCH5B2
has recently been reported to be a target antigen in AIED (Boulassel et al,
2001).
- Intolerance: The ear, like the
eye, may be only a partially immune privileged locus.
This means that the body may not know about all of the inner ear antigens,
and when they are released (perhaps following surgery or an infection), the
body may wrongly mount an attack on the "foreign" antigen. In the eye, there
is a syndrome called sympathetic ophthalmia,
where following a penetrating injury to one eye, the other eye may go blind.
This theory is not presently in favor for the ear.
- Genetic factors : Genetically
controlled aspects of the immune system may increase or otherwise be associated
with increased susceptibility to common hearing disorders, such as Meniere's
disease. Bernstein and associates reported that 44% of patients with Meniere's
disease, otosclerosis and striatal presbyacusis
had one particular extended major histocompatibility complex (MHC) haplotype
(Dqw2-Dr3-c4Bsf-C4A0-G11: 15-Bf:0.4-C2a-HSP70:7.5-TNF), compared to only 7%
of controls.
Sudden hearing loss in Koreans
that does not recover is also associated with HLA-DRB1*04, DQA1 03 and 05
(Yeo et al, 1999; Yeo et al, 2001). The author has also found a strong association
with certain types of HLA-types and vertigo in caucasians (unpublished).
These data suggest that more of Meniere's disease and other progressive
syndromes may be caused by immune dysfunction than is presently generally
thought. It is important to remember that HLA-typing is relevant when considered
in the context of the patient's genetic background. In other words, studies
of Korean subjects for example, such as reported by Yeo, may not cross-apply
to persons of non-Korean ethnicity.
How
is Autoimmune Inner Ear Disease Diagnosed?
- Bilateral progressive hearing loss or progressive
vestibular(balance) loss
- Audiometry
documenting progressive bilateral sensorineural hearing loss
- ABR (if hearing is good enough),
or otoacoustic emission testing
- Rotatory chair test
- ECOG (electrocochleography)
- Blood tests for general autoimmune
disease
- ANA (for lupus)
- Sed-rate (for Cogan's)
- Raji-Cell
- Rheumatoid factor
- Complement C1Q
- Smooth muscle antibody
- Thyroid disease [thyroid stimulating hormone (TSH), anti-microsomal
antibodies]
- Anti-gliadin antibodies (for Celiac disease)
- human leukocyte antigens (HLA) testing
- Blood tests for specific inner
ear disorders
- Anti-cochlear antibody test
- Lymphocyte transformation assay
- Immunofluorescence of animal cochlea (research only)
- Blood tests for disorders
that may imitate AIED
- FTA
- Lyme titer
- Diabetic testing
The diagnosis is based on history, findings on physical examination, blood tests, and the results of hearing and vestibular tests. As auditory neuropathy can present with a progressive bilateral sensorineural hearing loss, ABR testing should be done in persons with enough hearing for the test to be practical. Otoacoustic emission tests can be done in those in whom ABR testing cannot be done due to severely impaired hearing. ECOG (electrocochleography) testing may also be useful.
While specific tests for autoimmunity to the inner ear would be desirable,
at this writing (7/2004) there are none that are commercially available and
proven to be useful. This is an area that is evolving rapidly however. As of
1/2003, It is generally felt that anti-cochlear
antibody (also called anti-HSP70) blood tests are not sensitive or specific
enough to be very useful. Antibodies to HSP-70 can also be found in Lyme disease,
ulcerative colitis, cancers and in about 5% of healthy individuals. Yeom et
al (2003) suggested that all anti-HSP tests are directed against the wrong substrate.
Whether this is true or not, because of the poor specificity of anti-HSP 70
testing, diagnosis is generally based on evidence from broader tests of autoimmunity
or a positive response to steroids. Immunofluorescence of supporting cells of
guinea pig organ of Corti has also been shown to correlate with disease and
steroid responsiveness. According to Gray and others, immunofluorescence is
more sensitive and specific (86%, 41%) than is Western Blot (59%, 29%) (Gray
and others, ARO abstracts, 1999, #246). The specificity of both tests to us
seems unacceptably low.
Although there are some individuals with AIED who appear to have primarily a bilateral vestibular presentation (dizziness, ataxia, oscillopsia), very little is known about mechanism as well as whether or not blood tests are useful in this population. This might be an interesting topic for additional research (see below).
As there are presently no specific tests for AIED, a common approach is to look for other evidence for autoimmune involvement. A large number of these are listed above, and the search is successful between 20 and 30% of the time. It is not generally felt that persons with AIED need every one of these blood tests. Generally a sed-rate and ANA are done in all. The others are selected based on clinical suspicion.
There are also conditions that resemble autoimmune disorders, which it is sometimes
prudent to exclude (see above). Generally an FTA (to rule out syphilis infection)
is done in all instances where there is a reasonable suspicion of AIED and other
tests are done based on clinical suspicion.
How is Autoimmune Inner Ear Disease Treated?
Treatment for AIED seems to be rapidly changing. We recommend
that you do not rely on the information here as current, as it seems quite possible
that there may be advances since this page was last updated.
Steroids
There are several protocols for treatment of AIED. In cases with a classic
rapidly progressive bilateral hearing impairment, a trial of steroids (prednisone
or dexamethasone) for four weeks may be tried. This treatment is inexpensive,
but if effective, it is difficult to maintain because of steroid side effects.
Cytotoxic agents
- Cyclophosphamide (Cytoxan)
- Methotrexate
In persons with response to steroids, in most cases a cytotoxic chemotherapy
type of medication such as Cytoxan or Methotrexate will be used over the long
term (Sismanis et al , 1994; Sismanis et al, 1997). These agents are associated
with considerable toxicity, which limits their use.
Plasmapheresis
It has also been reported recently that plasmapheresis may be beneficial in
AIED (Luetje and Berliner, 1997). Plasmapheresis is expensive, must be done
periodically (usually monthly), and intrinsicially it is only suitable to disorders
mediated by antibodies.
Anti-TNF agents (etanercept)
Etanercept (Enbrel), an anti-TNF drug, is emerging as a promising agent for
treatment of AIED (Rahman et al, 2001). It is given as an injection twice a
week. Enbrel is presently very expensive and in short supply, and the lack of
large studies of its use in AIED presently limit clinician enthusiasm for its
use. Nevertheless, it presently appears to be the most promising agent.
Cochlear implant
Cochlear implantation can be successful in AIED, and is may be indicated when
there is acquired bilateral deafness.
In addition, attempts have been made in animals to treat variants of AIED with
oral collagen (Kim et al, 2001). We know of no similar efforts in humans.
Research Studies on Autoimmune Inner Ear Disease
As of May 2004, a visit to the National Library of Medicine's search engine,
Pubmed,
revealed 265 research articles concerning AIED disease published since 1969.
In spite of this moderate effort by the medical research community, AIED disease
remains a chronic, incurable disorder that causes progressive disability to
both hearing and balance. At the American Hearing
Research Foundation (AHRF), we have funded basic research on similar disorders
in the past, and are interested in
funding research on AIED in the future. We are particularly interested in projects
that might lead to methods of stopping progression of hearing loss and the disabling
attacks of dizziness. Click here if you
would you would like more information about contributing to the AHRF's efforts
to cure AIED.
References
- Bernstein JM, Shanahan TC, Schaffer FM. Further observations on the role
of the MHC genes and certain hearing disorders. Acta Otolaryngologica, 116(5):666-71,
1996
- Boulassel M and others. COCHB5B2 is a target antigen of anti-inner ear antibodies
in autoimmune inner ear diseases. Otol Neurotol 2001:22:614-618
- Garcia Berrocal JR, Ramirez-Camacho R, Arellano B, Vargas JA. Validity of
the Western blot immunoassay for heat shock protein-70 in associated and isolated
immunorelated inner ear disease. Laryngoscope 2002 Feb;112(2):304-9
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of collagen conjugated with cholera toxin induces tolerance to type II collagen
and suppresses chondritis in an animal model of autoimmune ear disease. Ann
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