Autoimmune Inner Ear Disease (AIED)
Author: Timothy C. Hain, MD
Last edited: 06/10/08
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 symptoms related to balance (dizziness or unsteadiness).
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, scleroderma, and psoriatic arthritis (Srikumar, 2004) 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 have symptoms 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 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)
- Erythrocyte sedimentation rate
- Raji-Cell
- Rheumatoid factor
- Complement C1Q
- Smooth muscle antibody
- Thyroid disease [thyroid stimulating hormone (TSH), anti-microsomal
antibodies]
- Anti-gliadin antibodies (for Celiac disease)
- Anti-neutrophyil cytoplasmic antibody
- Antiendothelial cell antibody
- Antiphospholipid/anticardiolopin antibody
- human leukocyte antigens (HLA) testing
Doctors may order some or all of these tests, which are not specific for AIED but may give evidence of autoimmune disease in the patient (Garcia-Berrocal, 2005).
- Blood tests for specific inner
ear disorders
- Anti-cochlear antibody test
- Lymphocyte transformation assay
- Immunofluorescence of animal cochlea (research only)
These antibodies are not present in all patients with AIED, and may be present in some patients without evidence of hearing loss.
- Blood tests for disorders
that may imitate AIED
- FTA
- Lyme titer
- Diabetic testing
- Response to oral steroid therapy (Ruckenstein, 2004)
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 (1/2008) there are none that are commercially available and
proven to be consistently useful. This is an area that is evolving rapidly however. 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). Recent studies have questioned the effectiveness of methotrexate in AIED (Ruckenstein, 2004). These agents are associated
with considerable toxicity, which limits their use.
Other medications
A small trial found enoxaparin (low molecular weight heparin) to be beneficial in patients with AIED (Mora, 2005). Larger trials are necessary before this therapy can be widely practiced. Enoxaparin affects the clotting system of the blood, and may place patients at increased risk of bleeding.
Transtympanic delivery of medication may provide better penetration of drug molecules into the inner ear. Transtympanic administration of steroids has been shown to improve hearing and balance symptoms in AIED in a small study (Garcia-Berrocal, 2006). Larger trials are needed to determine the true effectiveness of oral and transtympanic drug delivery (Alles, 2006; Rauch, 2004).
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. Transtympanic application of Enbrel was effective in a pilot study in steroid-dependent patients and when used in combination with methylprednisone (Van Wijk, 2006). 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.
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.
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.
Cell and gene therapy
Cell therapy involves transplantation of individual stem cells capable of developing into inner ear cells in the ear canal. Gene therapy is the introduction of new genes into native cells, allowing the cells to produce new proteins that improve their ability to function. Several laboratories have researched the possibility of cell or gene therapy to replaced damaged ear cells in AIED. Laboratory tests with animal models are promising, but much more research is needed to determine the effectiveness and safety of cell and gene therapies (Nakagawa, 2005; Nakagawa, 2004; Pau, 2004).
Research Studies on Autoimmune Inner Ear Disease
As of January 2008, a visit to the National Library of Medicine's search engine,
PubMed,
revealed 329 research articles concerning AIED disease published since 1964 with eight of these published in the last year.
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
- Agrup C., Luxon LM. Immune-mediated inner-ear disorders in neuro-otology. Curr Op Neurol. 19(1):26-32, 2006.
- Alles MJ, der Gaag MA, Stokroos RJ. Intratympanic steroid therapy for inner ear diseases, a review of the literature. Eur Arch Oto-Rhino-Lyryngol. 263(9):791-7, 2006.
- 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, Ibanez A. et al. Alternatives to systematic steroid therapy for refractory immune-mediated inner ear disease: A psysiopathologic approach. Eur Arch Oto-Rhino-Laryngol. 263(11):977-82, 2006.
- Garcia-Berrocal JR, Trinidad A et al. Immunologic work-up study for inner ear disorders: looking for a rational strategy. Acta Oto-Laryngol. 125(8):814-8, 2005.
- 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
- Gottschlich S, Billings PB, Keithly EM, Weisman MH, Harris JP. Assessment
of serum antibodies in patients with rapidly progressive sensorineural hearing
loss and Meniere's disease. Laryngoscope 105:1995,1347-1352
- Kim N, Cheng KC, Kwon SS, Mora R, Barbieri M, Yoo TJ. Oral administration
of collagen conjugated with cholera toxin induces tolerance to type II collagen
and suppresses chondritis in an animal model of autoimmune ear disease. Ann
Otol Rhinol Laryngol 2001 Jul;110(7 Pt 1):646-54
- Luetje CM, Berliner KI. Plasmaphereis in autoimmune inner ear disease: long-term
follow-up. Am J Otol, 18:572-576, 1997
- Maiorana CR, Staecker H. Advances in inner ear gene therapy: exploring cochlear protection and regeneration. Curr Op Otolaryng Head & Neck Surg. 13(5):308-12, 2005.
- Mora R. Jankowska B. Socium enoxaparin treatment of sensorineural hearing loss: an immune mediated response? Int Tin J. 11(1):38-42, 2005.
- Moscicki RA, San Martin JE, Quintero CH, Rauch SD, Nadol JB, Bloch KJ. Serum
antibody to inner ear proteins in patients with progressive hearing loss.
JAMA 1994,272, 611-61
- Nakagawa T. Ito J. Application of cell therapy to inner ear diseases. Acta Oto-Laryngol Supplement. (551):6-9, 2004.
- Pau H. Clarke RW. Advances in genetic manipulations in the treatment of hearing disorders. Clin Otolaryngol & Al Sci. 29(6):574-6, 2004.
- Rahman MU, Poe DS, Choi HK. Etanercept therapy for immune-mediated cochleovestibular
disorders: preliminary results in a pilot study. Otol Neurotol 22:619-624,
2001
- Rahman MU, Poe DS, Choi HK. Autoimmune
vestibulo-cochlear disorders. Curr Opin Rheumatol 2001 May;13(3):184-9
- Rauch SD. Intratympanic steroids for sensorineural hearing loss. Otolaryng Clin of Nor Am. 37(5):1061-74, 204.
- Ruckenstein MJ. Autoimmune inner ear disease. Curr Op Otolaryngol Head & Neck Surg. 12(5):426-30, 2004.
- Shin SO, Billings PB, Keithley EM, Harris JP. Comparison of anti-heat shock
protein 70 (anti-hsp70) and anti-68-kDa inner ear protein in the sera of patients
with Meniere's disease. Laryngoscope 107(2);222-7, 1997
- Sismanis A, Thompson T, Willis HE. Methotrexate therapy for autoimmune hearing
loss: a preliminary report. Laryngoscope 104:1994, 932-934
- Sismanis A, Wise CM, Johnson GD. Methotrexate management of immune-mediated
cochleovestibular disorders. Otolaryngol HNS 1997:116:146-52
- Street I. Jobanputra P. Proops DW. Etanercept, a tumor necrosis factor alpha receptor agonist and methotrexate in acute sensorineural hearing loss. J Laryng & Oto. 120(12):1064-6, 2006.
- Van Wijk F, Staecker H. Keithley E. Lefebvre PP. Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol & Neuro-Oto. 11(6):357-65, 2006.
- Yeo SW, Chang KH, Suh BD. Typing of human leucocyte antigen in patients
with sudden deafness. ARO abstracts, 1999, #23
- Yeo S. Association of HLA class II genes with sudden sensorineural hearing
loss. ARO abstracts, 2000, #765
- Yeo SW and others. Different distribution of HLA Class-II alleles according
to response to corticosteroid therapy in sudden sensorineural hearing loss.
Arch OHNS 2001:127:945-949
- Yeo
SW, Park SN. Immune-mediated sensorineural hearing loss in a patient with
ankylosing spondylitis: A case report. Otolaryngol Head Neck Surg 2001; 125:
113-4
|
