AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1979, McCabe first described a cohort of patients with idiopathic, rapidly progressive bilateral sensorineural hearing loss (SNHL). These patients' hearing improved after treatment with corticosteroids, thereby suggesting an autoimmune pathogenesis. The hallmark of this clinically diagnosed condition is the presence of a rapidly progressive, often fluctuating, bilateral SNHL over a period of weeks to months. The progression of hearing loss is too rapid to be diagnostic for presbycusis and too slow to conclude a diagnosis of sudden SNHL. Vestibular symptoms, such as true vertigo, generalized imbalance, and ataxia, may be present.

Pathophysiology

The term autoimmune inner ear disease (AIED) implies a direct attack of the immune system upon an endogenous inner ear antigen. Most of the evidence linking the immune system to cochleovestibular dysfunction is indirect; therefore, immune-mediated inner ear disease may be a preferred term. AIED is a clinical diagnosis based on its distinct clinical course, immune test results, and treatment response. The most important diagnostic finding is improvement in hearing observed with a trial of immunosuppressants.

Specific criteria for idiopathic progressive bilateral sensorineural hearing loss (IPBSNHL) include bilateral SNHL of at least 30 dB at any frequency with progression in at least one ear, defined as a threshold shift that is greater than 15 dB at any frequency or 10 dB at 2 or more consecutive frequencies or a significant change in discrimination score. This definition excludes patients with sudden SNHL occurring in less than 24 hours, which more likely is due to a microvascular or viral etiology.

A certain subset of patients with presumed Ménière disease (idiopathic endolymphatic hydrops) actually may have Ménière syndrome, in which the underlying pathophysiology is immune mediated. Typically, Ménière disease is initially diagnosed in these patients; however, fluctuating hearing loss in the contralateral ear develops later. This change may prompt a workup for AIED. Hughes et al found that approximately one half of their patients with AIED have manifestations of autoimmune Ménière syndrome.

Frequency

United States

Because the existence of AIED has been recognized only since 1979, incidence is difficult to determine. Recent studies in the literature from large referral centers are based on relatively small sample sizes of patients who fit the criteria for diagnosis of AIED. As diagnostic tests for the condition become more specific and more is known about AIED, more patients will be identified who have an autoimmune basis for inner ear symptoms.

Sex

The condition has been suggested to be more common in female patients who may or may not have concomitant systemic autoimmune disease than in male patients.

Age

In most patients, initial onset of symptoms occurs at age 20-50 years. Cases in pediatric patients are uncommon.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Hearing loss: The hallmark of immune-mediated inner ear disease is SNHL, which usually is bilateral and occurs rapidly over weeks to months.
• Fluctuation: Sensorineural loss can fluctuate and stabilize at a certain level, or it can progress without fluctuation.
• Laterality: Bilateral hearing loss occurs in most patients (79%). Occasionally, only one ear is involved initially, with the contralateral ear developing hearing loss later. In bilateral cases, audiometric thresholds can be symmetric or asymmetric.
• Speech discrimination scores: Discrimination scores often are poor in immune-mediated inner ear disease. Therefore, in cases of unilateral or bilateral-asymmetric disease, include diagnostic imaging and serologic studies in the workup to exclude retrocochlear disease and syphilitic inner ear disease.
• Vestibular symptoms: Approximately 50% of patients complain of vestibular symptoms typical of Ménière disease. Vestibular symptoms can include disequilibrium, ataxia, motion intolerance, positional vertigo, and episodic vertigo.
• Tinnitus and aural fullness: As many as 25-50% of patients also have symptoms of tinnitus and aural fullness, which can fluctuate in severity.
• Systemic autoimmune disease: Coexisting systemic autoimmune disease occurs in 15-30% of patients. Diagnoses include rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and polyarteritis nodosa.

Physical

Findings from physical examination of the ear usually are normal in patients with immune-mediated inner ear disease. Occasionally, associated systemic autoimmune diseases can affect the external ear skin or middle ear mucosa.

Causes

• Association with type I immune reaction involving immunoglobulin E (IgE)–mediated response
• • Solimon postulated that histamine-induced vasodilation of endolymphatic sac vasculature may result in endolymphatic hydrops because of impaired fluid transport.
  • A large percentage of patients treated with immunotherapy for inhalant allergies demonstrated improvement in vertigo and other symptoms of Ménière disease, which suggests an association between IgE-mediated disease and inner ear dysfunction.
• Production of autoantibodies to inner ear antigen
• • Yoo et al reported that rodents injected with type II collagen developed new-onset SNHL and pathologic cochlear changes that appear to be immune mediated.
  • Harris and Sharp used Western-blot analysis to identify a 68-kd antibody present in the serum of 35% of their patients with idiopathic progressive SNHL. This antibody targeted a bovine inner ear antigen, suggesting an autoimmune basis for hearing loss.
• Production of immune complexes
• • In a series of 30 patients with Ménière disease, 96% had elevated levels of circulating immune complexes compared with 20% of control subjects.
  • Patients with systemic lupus erythematosus have evidence of circulating immune complexes and multiple autoantibodies. Reports exist of SNHL associated with systemic lupus erythematosus. Likewise, reports of patients with Wegener granulomatosis cite SNHL in association with vasculitis of the cochlear and endolymphatic sac arteries.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Ménière disease
Syphilis
Sudden sensorineural hearing loss
Acoustic neuroma
Other neoplasms

Systemic immunologic disorders with otologic symptoms
Cogan syndrome
Polyarteritis nodosa
Rheumatoid arthritis
Systemic lupus erythematosus
Wegener granulomatosis
Sarcoidosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Antigen-nonspecific tests are useful in routine screening for evidence of systemic immunologic dysfunction, yet specifically are not known to correlate with a diagnosis of immune-mediated inner ear disease. Antigen-nonspecific tests are as follows:
• • Levels of circulating immune complexes
  • Complement levels (C3, C4)
  • Antinuclear antibody levels
  • Rheumatoid factor
  • Acute phase reactants - Erythrocyte sedimentation rate, C-reactive protein
• Antigen specific tests are as follows:
• • Migration inhibition assay: The patient's lymphocytes are placed in a capillary tube with serum containing inner ear antigens present on one end. If the patient's lymphocytes previously have been sensitized to the inner ear antigen, migration inhibition factor is released and impedes dispersion of lymphocytes from the tube. This assay is a gross test of immune reactivity.
  • Lymphocyte transformation test (LTT): The LTT measures the response of the patient's sensitized lymphocytes to known inner ear antigens. The patient's lymphocytes are exposed to serum containing inner ear antigens. A proliferative response occurs and is compared to that of known negative control lymphocytes. Measurement is made by recording the incorporation of tritiated thymidine into new DNA as cell synthesis occurs. Sensitivity of the LTT is reported to be 50-80% when symptoms are active in an immunocompetent patient.
  • Western blot analysis for antibodies to inner ear antigen
    • Harris and Sharp used bovine inner ear extract as antigen in Western blot assays and detected antibody to a 68-kd inner ear antigen in 19 of 54 patients (35%) with progressive SNHL. Recent update includes a cohort of 279 patients with rapidly progressive SNHL, of whom 90 (32%) had positive results of Western blot analysis for the 68-kd antibody.
    • Animals with experimentally induced SNHL possessed autoantibodies to the identical component of the inner ear antigenic isotope to which patients' sera reacted.
    • Moscicki et al confirmed the finding of circulating antibodies against a 68-kd protein, which was found in 42 of 72 patients (58%) with IPBSNHL. Patients with positive test results for the antibody were more likely than those with negative results to have hearing loss that responded to steroid treatment (75% vs 18%). This study is the first to show a correlation between Western blot 68-kd positivity and steroid responsiveness.
    • Rauch subsequently identified the 68-kd protein as heat shock protein 70 (HSP 70). Heat shock proteins are constitutively produced by host and pathogens and usually are up-regulated in response to infection or other stresses.
    • Antibodies to HSP 70 were detected in 47% of 30 patients with Ménière disease, thus identifying a subset of patients with Ménière disease with an immune basis for their symptoms.
    • The LTT and Western blot immunoassay must be performed in specialized immunology laboratories, often on a send-out basis.
    • Control populations vary from persons with normal hearing to those with systemic autoimmune diseases. The 68-kd positivity in these control populations averages 5%. This specificity of approximately 95% appears fairly high but is rather insensitive when used in the general population.
    • Gong et al found that 2 subcomponents of crude inner ear antigen (the 31 kD protein and the 60 kD protein) may induce autoimmune inner ear disease independently in the guinea pig cochlea. The 31 kD protein may correspond to the 30 kD protein identified by Cao et al as myelin protein zero (P0), which is derived from the acoustic nerve and spiral ganglion. The 31 kD protein may be of use in the future for early diagnosis of autoimmune inner ear disease (AIED).

Histologic Findings

Histopathologic human temporal bone studies of patients with immune-mediated inner ear disease rarely are reported in the literature. Further studies may help elucidate the pathophysiology involved in this condition.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The natural history of untreated immune-mediated inner ear disease is unknown; much of the current therapy is based on empiric clinical data gathered during the past 20 years. A key feature of immune-mediated inner ear disease is a positive response to immunosuppressive therapy (ie, corticosteroids) in the form of improved hearing.

• Consider aggressive treatment for every patient, assuming no contraindications to steroid therapy are present, including peptic ulcer disease, diabetes mellitus, glaucoma, hypertension, and history of tuberculosis. Short-term bursts of steroids usually are insufficient (except as an aid in diagnosis) and may result in relapse.
• No standardized regimens for corticosteroid therapy exist, yet many recommend a trial of high-dose prednisone (1 mg/kg/d) for 1 month, followed by a slow taper over several weeks to a maintenance dose of 10-20 mg/d or every other day. Occasionally, higher doses are needed to maintain hearing as disease activity waxes and wanes. Patients often learn what maintenance dose is sufficient, below which their hearing deteriorates.
• Not all patients respond to corticosteroid therapy in the same manner. Some show improvement in threshold, discrimination scores, or both. Others with fluctuation and progression before therapy stabilize without actually improving. Still others actually lose hearing despite immunosuppressive therapy.
• In some patients, hearing loss becomes refractory to steroids, or patients develop adverse effects of chronic steroid administration. These patients may be candidates for cytotoxic therapy.
• Overall steroid response rates are approximately 60%, defined as an improvement in threshold of 15 dB at 1 frequency, 10 dB at 2 consecutive frequencies, or a significant improvement in discrimination score.
• Cytotoxic drugs generally are used for steroid-intolerant patients or those who fail to demonstrate a continued response to steroid therapy. However, McCabe recommends cyclophosphamide in addition to steroids as a first-line treatment.
• Cyclophosphamide is a cytotoxic drug with adverse effects, including myelosuppression, hemorrhagic cystitis, infertility, and increased risk of malignancy.
• Other cytotoxic agents are used to treat immune-mediated inner ear disease, including methotrexate and azathioprine (Imuran). Sismanis et al used low-dose methotrexate to treat a small group of patients with autoimmune SNHL. Significant improvement in speech discrimination, but not pure-tone averages, was observed.
• Harris et al performed, from 1998-2001 and across 10 tertiary care centers, a randomized, double-blind, placebo-controlled study of 67 patients with rapidly progressive, bilateral sensorineural hearing loss (SNHL). Patients who had a response to a one-month prednisone challenge were randomized to receive either placebo or methotrexate (15-20 mg/wk). The authors found that methotrexate was not able to maintain the hearing improvements obtained by high-dose prednisone over time better than placebo. The authors mention, however, that patients may have benefitted from fewer hearing fluctuations over time, but this was not specifically measured by the study.
• Several recent studies studied etanercept (Enbrel) in the treatment of AIED. Etanercept is a potent tumor necrosis factor (TNF) antagonist often used in the treatment of rheumatoid arthritis. Cohen et al enrolled 20 patients in a 12-week blinded placebo-controlled randomized trial of etanercept (25 mg SC twice weekly) versus placebo. They found that etanercept was no better than placebo for the treatment of AIED. Similarly, Harris et al found no benefit of methotrexate over placebo in a 12-month placebo-controlled randomized trial. Finally, Matteson et al studied 23 steroid-responsive patients who received etanercept, 25 mg twice weekly for 24 weeks in an open-label pilot study. Although a significant improvement of hearing loss in these patients was not evident, the previously progressive hearing loss in 87% of these patients appeared to stabilize or improve. Of the patients with symptoms of vertigo, 50% noted improvement.
• In 1989, Luetje studied the use of plasmapheresis in patients with autoimmune inner ear disease. Improvement in auditory function occurred in 6 of 8 patients, 3 of whom were able to discontinue immunosuppressive medication.
• Plasmapheresis involves filtering a patient's whole blood, which removes antibody, antigen, and immune complexes and other immune mediators. Albumin and normal saline are used as replacement fluids. The procedure is expensive and is considered an adjunctive therapy until further controlled studies determine its role in the treatment of immune-mediated inner ear disease.

Surgical Care

Immune-mediated inner ear disease usually is bilateral and often responds to medical management. Surgery generally is not appropriate. However, intratympanic therapy performed under local anesthesia recently has been found beneficial for some patients with immune-mediated inner ear disease.

• Intratympanic administration of corticosteroids results in higher inner ear levels compared with systemic steroid administration.
• Intratympanic administration avoids the blood-labyrinthine barrier and systemic adverse effects observed with oral or intravenous steroids.
• Parnes et al used intratympanic steroids to treat 37 patients with a variety of inner ear disorders causing SNHL. Patients with immune-mediated hearing loss showed promising results, as did several patients who presented with sudden SNHL.
• Steroids initially are administered through a myringotomy placed over the round window region. A tympanostomy tube is left in place for continued treatments.
• Otoendoscopy of the middle ear may be performed to confirm the location of the round window and identify any mucosal adhesions that may impede drug penetration.
• Silverstein developed a drug delivery system that involves placing a small wick through a tympanostomy tube directly into the round window niche. This allows a patient to self-administer the medication into the ear canal, where the drug is absorbed by the wick and directly transported to the round window membrane.

Consultations

Consultation with a rheumatologist or hematologist often is necessary if steroid therapy fails to help the patient and he or she requires treatment with cytotoxic drugs, which requires close hematologic monitoring. Occasionally, patients may require treatment with plasmapheresis (see Medical Care).

Diet

Patients with immune-mediated endolymphatic hydrops usually are placed on a low-sodium diet, similar to the diet recommended for patients with Ménière disease.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to prevent complications and reduce morbidity.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Cytotoxic agents

These agents inhibit cell growth and proliferation and are useful in the treatment of autoimmune diseases.

Drug Name	Methotrexate (Folex PFS, Rheumatrex)
Description	Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response.
Adult Dose	7.5-15 mg PO qwk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
Interactions	Oral aminoglycosides may decrease absorption and blood levels; charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response to MTX Coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels Probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or in presence of risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Prognosis

• Patients who demonstrate improvement in hearing in response to immunosuppressive therapy have a better prognosis than those who do not improve. The natural history of untreated immune-mediated inner ear disease is unknown at this time.

Patient Education

• Inform patients with immune-mediated inner ear disease that regular follow-up care with their otolaryngologist is necessary to correlate subjective hearing fluctuations with objective audiometric data. This information helps guide immunosuppressive therapy, which needs to be monitored closely by a rheumatologist or immunologist.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Ménière Disease.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Informed consent about the possible risks of immunosuppressive therapy in the management of immune-mediated inner ear disease is necessary before treatment.
• Perform workup on patients with a history consistent with bilateral Ménière disease to evaluate for an autoimmune etiology before considering surgery for vestibular symptoms. A workup with results that are positive for an autoimmune etiology may lead to a trial of immunosuppressive therapy and, thereby, avoid the potential morbidity associated with surgery.
• Perform workup such as serologic or imaging studies to exclude conditions such as otosyphilis or acoustic neuroma before immunosuppressive therapy is instituted.
• Patient counseling may be helpful regarding the variable and often poor response to medical therapy for AIED. Patients need to know that immune-mediated inner ear disease is not a uniform disease with a simple diagnosis and treatment. The disease often results in long-term disability due to progressive and often permanent hearing loss. The response to aggressive immunosuppressive therapy can also be disappointing because of variable response rates and high risk of side effects.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bowman CA, Linthicum FH Jr, Nelson RA, et al. Sensorineural hearing loss associated with systemic lupus erythematosus. Otolaryngol Head Neck Surg. Feb 1986;94(2):197-204. [Medline].
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• Cao MY, Deggouj N, Gersdorff M, Tomasi JP. Guinea pig inner ear antigens: extraction and application to the study of human autoimmune inner ear disease. Laryngoscope. Feb 1996;106(2 Pt 1):207-12. [Medline].
• Cohen S, Shoup A, Weisman MH, Harris J. Etanercept treatment for autoimmune inner ear disease: results of a pilot placebo-controlled study. Otol Neurotol. Sep 2005;26(5):903-7. [Medline].
• Derebery MJ, Rao VS, Siglock TJ, et al. Meniere''s disease: an immune complex-mediated illness?. Laryngoscope. Mar 1991;101(3):225-9. [Medline].
• Dornhoffer JL, Arenberg JG, Arenberg IK, Shambaugh GE Jr. Pathophysiological mechanisms in immune inner ear disease. Acta Otolaryngol Suppl. 1997;526:30-6. [Medline].
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• Harris JP, Ryan AF. Fundamental immune mechanisms of the brain and inner ear. Otolaryngol Head Neck Surg. Jun 1995;112(6):639-53. [Medline].
• Harris JP, Sharp PA. Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope. May 1990;100(5):516-24. [Medline].
• Harris JP, Weisman MH, Derebery JM, et al. Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA. Oct 8 2003;290(14):1875-83. [Medline].
• Hughes GB, Barna BP, Calarese LH. Immunologic Disorders of the Inner Ear. In: Bailey BJ, ed. Head and Neck Surgery-Otolaryngology. Philadelphia, Pa: Lippincott;1993:1833-1842.
• Luetje CM. Theoretical and practical implications for plasmapheresis in autoimmune inner ear disease. Laryngoscope. Nov 1989;99(11):1137-46. [Medline].
• Matteson EL, Choi HK, Poe DS, et al. Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center, open-label, pilot study. Arthritis Rheum. Jun 15 2005;53(3):337-42. [Medline].
• McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol. Sep-Oct 1979;88(5 Pt 1):585-9. [Medline].
• Moscicki RA, San Martin JE, Quintero CH, et al. Serum antibody to inner ear proteins in patients with progressive hearing loss. Correlation with disease activity and response to corticosteroid treatment. JAMA. Aug 24-31 1994;272(8):611-6. [Medline].
• Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope. Jul 1999;109(7 Pt 2):1-17. [Medline].
• Rauch SD. Clinical management of immune-mediated inner-ear disease. Ann N Y Acad Sci. Dec 29 1997;830:203-10. [Medline].
• Rauch SD, San Martin JE, Moscicki RA, Bloch KJ. Serum antibodies against heat shock protein 70 in Ménière''s disease. Am J Otol. Sep 1995;16(5):648-52. [Medline].
• Silverstein H. Use of a new device, the MicroWick, to deliver medication to the inner ear. Ear Nose Throat J. Aug 1999;78(8):595-8, 600. [Medline].
• Sismanis A, Thompson T, Willis HE. Methotrexate therapy for autoimmune hearing loss: a preliminary report. Laryngoscope. Aug 1994;104(8 Pt 1):932-4. [Medline].
• Soliman AM. Immune-mediated inner ear disease. Am J Otol. Nov 1992;13(6):575-9. [Medline].
• Tomiyama S, Harris JP. The role of the endolymphatic sac in inner ear immunity. Acta Otolaryngol. Mar-Apr 1987;103(3-4):182-8. [Medline].
• Yoo TJ, Tomoda K, Stuart JM, et al. Type II collagen-induced autoimmune sensorineural hearing loss and vestibular dysfunction in rats. Ann Otol Rhinol Laryngol. May-Jun 1983;92(3 Pt 1):267-71. [Medline].

Article Last Updated: Apr 10, 2006