Autoimmune Inner Ear Disease (AIED)

Author: Timothy C. Hain, MD

Last edited: 10/2012

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 et al 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 (Bovo et al 2009). The precise incidence is controversial.

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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. CTL2 has recently been reported to be a target antigen in AIED (Kommareddi et al 2009).
  • 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: GGenetically controlled aspects of the immune system may increase or otherwise be associated with increased susceptibility to common hearing disorders, such as Meniere’s disease. A systematic review of literature from 1861 to 2011 concluded that up to one-third of Meniere’s disease cases can be linked to immunological causes based on clinical data and positive response to steroids. Genetic factors can also have a positive effect on hearing (Greco et al 2012). Gazquez and associates reported that Meniere’s disease patients with the allelic variant MICA*4, a major histocompatibility complex (MHC), had a slower progression of hearing loss than those with a different MHC. In confirmed cases of autoimmune-related sudden hearing loss, the most prominent inner ear protein, cochlin, can produce T-cell responsiveness, and has been implicated as the antigen responsible for inflammation and damage to the inner ear (Baek et al 2006). These data suggest that more of Meniere’s disease and other progressive syndromes may be caused by immune dysfunction than is presently generally thought.

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How is Autoimmune Inner Ear Disease Diagnosed?

  • Bilateral progressive hearing lossor 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 et al 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, as of 7/2012, 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. One study suggested that all anti-HSP tests are directed against the wrong substrate (Yeom et al 2003).

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.

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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 (Alexander et al 2009, Sismanis et al 1994, Sismanis et al 1997). Studies have questioned the effectiveness of methotrexate in AIED (Ruckenstein 2004). These agents are associated with considerable toxicity, which limits their use.

Other medications

Small trials found enoxaparin (low molecular weight heparin) and rituximab to be beneficial in patients with AIED (Cohen et al 2011, Mora et al 2005). Larger trials are necessary before these therapies 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 et al 2006). Larger trials are needed to determine the true effectiveness of oral and transtympanic drug delivery (Alles et al 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 et al 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 (Bianchin et al 2010). 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 antigen administration (Cai et al 2009). 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 & Ito 2004, Pau & Clarke 2004, Zhou et al 2012, Zhou et al 2011).

Research Studies on Autoimmune Inner Ear Disease

As of July 2012, a visit to the National Library of Medicine’s search engine, PubMed, revealed 497 research articles concerning AIED disease published since 1964 with eleven 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. Get more information about contributing to the AHRF’s efforts to detect and treat acoustic neuroma.

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References

  • Alexander TH, Weisman MH, Derebery JM, Espeland MA, Gantz BJ, et al. 2009. Safety of high-dose corticosteroids for the treatment of autoimmune inner ear disease. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 30: 443-8
  • Alles MJ, der Gaag MA, Stokroos RJ. 2006. Intratympanic steroid therapy for inner ear diseases, a review of the literature. Eur Arch Otorhinolaryngol 263: 791-7
  • Baek MJ, Park HM, Johnson JM, Altuntas CZ, Jane-Wit D, et al. 2006. Increased frequencies of cochlin-specific T cells in patients with autoimmune sensorineural hearing loss. J Immunol 177: 4203-10
  • Bianchin G, Russi G, Romano N, Fioravanti P. 2010. Treatment with HELP-apheresis in patients suffering from sudden sensorineural hearing loss: a prospective, randomized, controlled study. The Laryngoscope 120: 800-7
  • Bovo R, Ciorba A, Martini A. 2009. The diagnosis of autoimmune inner ear disease: evidence and critical pitfalls. Eur Arch Otorhinolaryngol 266: 37-40
  • Cai Q, Du X, Zhou B, Cai C, Kermany MH, Yoo T. 2009. Induction of tolerance by oral administration of beta-tubulin in an animal model of autoimmune inner ear disease. ORL; journal for oto-rhino-laryngology and its related specialties 71: 135-41
  • Cohen S, Roland P, Shoup A, Lowenstein M, Silverstein H, et al. 2011. A pilot study of rituximab in immune-mediated inner ear disease. Audiology & neuro-otology 16: 214-21
  • Garcia-Berrocal JR, Ibanez A, Rodriguez A, Gonzalez-Garcia JA, Verdaguer JM, et al. 2006. Alternatives to systemic steroid therapy for refractory immune-mediated inner ear disease: A physiopathologic approach. Eur Arch Otorhinolaryngol 263: 977-82
  • Garcia-Berrocal JR, Trinidad A, Ramirez-Camacho R, Lobo D, Verdaguer M, Ibanez A. 2005. Immunologic work-up study for inner ear disorders: looking for a rational strategy. Acta oto-laryngologica 125: 814-8
  • Greco A, Gallo A, Fusconi M, Marinelli C, Macri GF, de Vincentiis M. 2012. Meniere’s disease might be an autoimmune condition? Autoimmunity reviews
  • Kommareddi PK, Nair TS, Vallurupalli M, Telian SA, Arts HA, et al. 2009. Autoantibodies to recombinant human CTL2 in autoimmune hearing loss. The Laryngoscope 119: 924-32
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  • Rahman MU, Poe DS, Choi HK. 2001. Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 22: 619-24
  • Rauch SD. 2004. Intratympanic steroids for sensorineural hearing loss. Otolaryngologic clinics of North America 37: 1061-74
  • Ruckenstein MJ. 2004. Autoimmune inner ear disease. Current opinion in otolaryngology & head and neck surgery 12: 426-30
  • Sismanis A, Thompson T, Willis HE. 1994. Methotrexate therapy for autoimmune hearing loss: a preliminary report. The Laryngoscope 104: 932-4
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  • Van Wijk F, Staecker H, Keithley E, Lefebvre PP. 2006. Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiology & neuro-otology 11: 357-65
  • Yeom K, Gray J, Nair TS, Arts HA, Telian SA, et al. 2003. Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients. The Laryngoscope 113: 1770-6
  • Zhou B, Kermany MH, Cai Q, Cai C, Zhou Y, et al. 2012. Experimental autoimmune hearing loss is exacerbated in IL-10-deficient mice and reversed by IL-10 gene transfer. Gene therapy 19: 228-35
  • Zhou Y, Yuan J, Zhou B, Lee AJ, Ghawji M, Jr., Yoo TJ. 2011. The therapeutic efficacy of human adipose tissue-derived mesenchymal stem cells on experimental autoimmune hearing loss in mice. Immunology 133: 133-40