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.[1]
See the image below.
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Inner ear.
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-specific tests are as follows:
Migration inhibition assay
Lymphocyte transformation test (LTT)
Western blot analysis for antibodies to inner ear antigen
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 few decades. A key feature of immune-mediated inner ear disease is a positive response to immunosuppressive therapy (ie, corticosteroids) in the form of improved hearing.[2]
Surgery generally is not appropriate for immune-mediated inner ear disease. However, intratympanic therapy performed under local anesthesia has been found to be beneficial for some patients.
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.[3, 4, 5, 6]
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.[7, 8]
Because the existence of autoimmune inner ear disease (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.[9]
Hearing loss: The hallmark of immune-mediated inner ear disease is sensorineural hearing loss (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.
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.
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.[10]
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.[11]
A study by Suchan et al detected antibodies against inner ear antigen in 52% of subjects with idiopathic progressive SNHL, 44% of subjects with Ménière disease, and none of the study’s healthy subjects.[12]
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.
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
A study by Dayal et al discovered that patients with autoimmune ear disease having no systemic autoimmune illness often show high levels of antinuclear antibodies (with a speckled pattern) and also sometimes have high levels of rheumatoid factor. The positive yield of other detailed tests was low.[15]
A study by Svrakic et al indicated that tumor necrosis factor (TNF) levels can be used diagnostically and prognostically in immune-mediated inner ear disease. The study, which involved 85 patients with clinical and audiometric characteristics of immune-mediated SNHL, as well as 11 controls, found that patients with immune-mediated SNHL who were nonresponsive to steroids had a higher mean baseline plasma level of TNF (27.6 pg/mL), as derived from peripheral venous blood, than did those who were responsive to steroids (24.1 pg/mL), and that both had higher TNF levels than did the controls (14.4 pg/mL). According to the investigators, a baseline plasma TNF level of more than 18.8 pg/mL from the peripheral circulation has a positive predictive value for immune-mediated SNHL of more than 97%.[16]
Svrakic and colleagues also found evidence that in non-steroid-responsive patients with immune-mediated SNHL, peripheral blood mononuclear cells (PBMCs) respond differently to in vitro stimulation with dexamethasone than do those of steroid-responsive patients, with the mean TNF level secreted by the PBMCs slightly increasing (from 11.2 pg/mL to 11.7 pg/mL) with stimulation instead of decreasing.[16]
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.[17] 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).[18] 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.[19] 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.[20] The 31 kD protein may be of use in the future for early diagnosis of autoimmune inner ear disease (AIED).
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.
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 few decades. A key feature of immune-mediated inner ear disease is a positive response to immunosuppressive therapy (ie, corticosteroids) in the form of improved hearing.[2]
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.[21]
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.[22] A longitudinal, observational, descriptive study by Mata-Castro et al indicated that in patients with immune-mediated hearing loss, azathioprine can maintain hearing threshold and reduce the risk and slow the rate of relapse. In patients treated with azathioprine for 1 year, the investigators found no statistically significant change between pure-tone average at base line and after 1 year’s treatment, while the annual relative incidence rate of relapse was 0.52.[23]
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).[24] 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.[25] 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.[26] 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.
A study by Pathak et al suggested that the antioxidant N-acetylcysteine (NAC) may be effective against AIED. The investigators found that peripheral blood mononuclear cells (PBMCs) in patients with AIED had higher baseline TNF-α and myeloperoxidase levels than did those of healthy controls. NAC, however, was found to discourage the lipopolysaccharide-mediated release of TNF- α from PBMCs while only minimally affecting the TNF-α pathway’s downstream targets.[27]
In 1989, Luetje studied the use of plasmapheresis in patients with autoimmune inner ear disease.[28] 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.
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 has been found to be beneficial for some patients with immune-mediated inner ear disease.
Improvements in treatment may be facilitated by local delivery for both SNHL and autoimmune 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.[29] 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.[30] 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.
The different inner ear drug delivery methods can be summarized as follows:
Intratympanic drug delivery
Passive intratympanic delivery
Biodegradable polymer intratympanic delivery
Hydrogel-based intratympanic delivery
Nanoparticle delivery
Active intratympanic drug delivery
Round window microcatheter
Silverstein MicroWick
Preclinical Alzet osmotic pump
Other systems
Intracochlear drug delivery
Syringe delivery
Direct injection
Syringe pump delivery
Osmotic pump delivery
Cochlear prosthesis- based delivery
Other delivery devices
As treatment options improve for many inner ear diseases and injuries, methods for delivering precise and controlled doses become vital. Researchers in the field of inner ear drug delivery are constantly in the process of advancing new and existing techniques that support the arrival of better and better therapeutic compounds. Those suffering from hearing related disorders can look forward to improved quality of life as the field progresses.[31]
However, physicians must realize that a potential impact of glucocorticoids on ion homeostasis functions exists in addition to immune suppression. These functions are quite interlinked with regard to maintenance of the endolymphatic potential in fluids around auditory and vestibular hair cells. Therefore, assuming that all steroid-responsive hearing loss is due to immune processes simply cannot be justified in light of our current understanding of other cellular and molecular processes under the control of glucocorticoids.[32]
In a retrospective study of intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy, 39% of patients were found to recover 20 dB or 20% SDS (if treated within 6 weeks). This was higher than the figure of 9.1% in their controls.[33]
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).
Patients with immune-mediated endolymphatic hydrops usually are placed on a low-sodium diet, similar to the diet recommended for patients with Ménière disease.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context:
Chemically related to nitrogen mustards. An alkylating agent; mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Clinical Context:
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.
Fifty percent of patients with Autoimmune ear disease have an excellent response to steroids. Those with vestibular symptoms only are in particular responsive to steroids. Those with systemic disease have a lower response rate.[15]
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.
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 eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Ménière Disease.
Neeraj N Mathur, MBBS, MS, DNB(ENT), MNAMS, FAMS, Principal and Director-Professor (ENT), Vardhman Mahavir Medical College and Safdarjung Hospital; Professor, Guru Gobind Singh Indraprastha University and Delhi University, India
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Peter S Roland, MD, Professor, Department of Neurological Surgery, Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, Director, Clinical Center for Auditory, Vestibular, and Facial Nerve Disorders, Chief of Pediatric Otology, University of Texas Southwestern Medical Center; Chief of Pediatric Otology, Children’s Medical Center of Dallas; President of Medical Staff, Parkland Memorial Hospital; Adjunct Professor of Communicative Disorders, School of Behavioral and Brain Sciences, Chief of Medical Service, Callier Center for Communicative Disorders, University of Texas School of Human Development
Disclosure: Received honoraria from Alcon Labs for consulting; Received honoraria from Advanced Bionics for board membership; Received honoraria from Cochlear Corp for board membership; Received travel grants from Med El Corp for consulting.
Chief Editor
Arlen D Meyers, MD, MBA, Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan;RxRevu;Cliexa;The Physicians Edge;Sync-n-Scale;mCharts<br/>Received income in an amount equal to or greater than $250 from: The Physicians Edge, Cliexa<br/> Received stock from RxRevu; Received ownership interest from Cerescan for consulting; .
Additional Contributors
Robert A Battista, MD, FACS, Assistant Professor of Otolaryngology, Northwestern University, The Feinberg School of Medicine; Physician, Ear Institute of Chicago, LLC
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Drugs & Diseases gratefully acknowledge the contributions of previous authors Shelley Jaquish, MD, and William L Meyerhoff, MD, PhD, to the development and writing of this article.
Hughes GB, Barna BP, Calarese LH. Immunologic Disorders of the Inner Ear. Bailey BJ, ed. Head and Neck Surgery-Otolaryngology. Philadelphia, Pa: Lippincott; 1993. 1833-1842.
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