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Autoimmune Inner Ear Disease (AIEDs): Autoimmune Diseases with Audio-Vestibular Involvement

Autoimmune Inner Ear Disease (AIEDs): Autoimmune Diseases with Audio-Vestibular Involvement
Eric W. Sargent, MD, FACS
August 26, 2002

Systemic illnesses linked with sensorineural hearing loss and dizziness include polyarteritis nodosa (PAN), Cogan's syndrome, relapsing polychondritis, systemic lupus erythematosus (SLE), Wegener's granulomatosis, polyarteritis nodosa, (PAN), Sjögren's syndrome, and Behçet's disease. Interestingly, rheumatoid arthritis has never been conclusively linked with hearing loss. Some infectious conditions, such as Lyme disease and syphilis can cause hearing loss by triggering autoantibody production.

Historical perspective:

As early as 1958, Lehnhardt speculated that cases of recurrent bilateral deafness were due to anticochlear antibodies.

In 1979, McCabe reported a series of 18 patients that he felt represented cases of autoimmune-mediated hearing loss. The case he described in detail was that of a 25-year old man with sudden loss in one ear and progressive loss in the other as well as a unilateral facial paralysis. Treated with Decadron and Cytoxan (a suppressor of cellular immunity), the man's hearing loss and facial paralysis improved. Of the 18 patients, 5 had facial paralysis and a number had destructive vasculitic granulomatous lesions. It is possible that many of the patients described by McCabe had PAN or other autoimmune diseases and not single organ AIED.

McCabe noted that autoimmune hearing loss was typically bilateral. Among the clinical entities he listed in the differential diagnosis of fluctuating or rapidly progressive hearing loss are several that are now considered to be related to autoimmunity in a significant number of patients, such as cochlear Meniere's and sudden sensorineural hearing loss.

'Post-traumatic hydrops' - a Meniere's like syndrome that occurs some time after a head injury - is now thought by many to be an autoimmune condition similar to sympathetic ophthalmia (bilateral granulomatous panuveitis in the contralateral eye after penetrating injury involving the uvea of the other eye). In the same way, patients who suffer progressive or fluctuating loss in one or both ears after inner ear surgery presumably do so because of immune sensitization by the surgical or temporal bone trauma.

Disease & Syndrome Review:
Cogan's Syndrome:

Cogan's syndrome, the prototypical autoimmune inner ear disease (AIED), was first described in 1945. The hallmarks are ocular inflammation and associated vestibulo-auditory dysfunction. Interstitial keratitis presenting with subepithelial corneal opacities is typical along with sensorineural hearing loss and vestibular Meniere's-like symptoms. Audiologic symptoms may precede ocular inflammation by years in atypical cases, complicating diagnosis. Ear involvement in 70% of cases results in bilateral deafness despite early corticosteroid treatment. Despite this, ocular prognosis is good and corneal transplant is rarely necessary. Temporal bone histology reveals severe hair cell degeneration without inflammatory infiltrates or vasculitis. The inciting cause remains unknown.

Relapsing Polychondritis:

AIED is common in relapsing polychondritis: 20% have SNHL and 75% who have SNHL have vestibular dysfunction (15% of all patients with relapsing polychondritis). It is estimated that sudden or gradual hearing loss occurs at some point in the course of nearly half of patients with relapsing polychondritis. The hearing loss may be sensorineural, conductive, or mixed. Although the suspected cause is vasculitis of the labyrinthine artery, little objective temporal bone evidence exists to support this hypothesis.

Systemic Lupus Erythematosus (SLE):

Generally considered to represent several diseases that result from multiple genetic factors interacting with one or more environmental agents. While one prospective study suggested that subclinical SNHL affects 58% of patients with SLE, the fact that many of the drugs (e.g., antimalarials and non-steroidal anti-inflammatory medications) may cause SNHL makes the real incidence difficult to determine. One study found an apparent association between hearing loss associated with SLE and anti-cardiolipin antibodies.

Wegener's Granulomatosis:

Believed to represent the exaggerated hypersensitivity reaction to an unknown antigen that enters through the respiratory tract, Wegener's is characterized by: A) necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, B) Glomerulonephritis, and C) varying degrees of disseminated small vessel vasculitis. Cellular immune response, antilysosomal antibodies, and immune complex formation cause the condition. Testing for C-ANCA (an antibody directed at a 29kDa serine proteinase, termed proteinase 3) is usually positive. Ear involvement may take several forms, although it is most commonly conductive and due to granulomatous nasopharyngeal involvement. SHNL, usually in association with conductive loss, occurs in 8 - 15% of patients with Wegener's Granulomatosis.

Polyarteritis Nodosa (PAN):

Patients with AIED may have small vessel vasculitis and/or glomerulonephritis along with medium-sized arterial involvement (microscopic polyangitis). Others have medium sized vessel involvement consistent with PAN. The condition does not involve the lung and has a predilection for bifurcations of vessels, with some distal involvement of arterioles and adjacent veins. 70% have renal disease. In these vasculitides, hearing loss is often fairly rapid, consistent with a vascular pathogenesis. Facial nerve palsy resulting from vasculitis within the facial canal is a well-described manifestation of PAN.

Sjögren's Syndrome Syndrome:

Although not commonly thought of as a cause of hearing loss, at least 1 well-done study suggests an association with Sjögren's Syndrome syndrome (dry mouth and dry eye due to destruction of salivary and lacrimal glands). In a group of 30 patients with primary Sjögren's Syndrome Syndrome, 46% had SNHL compared with 40 age-matched controls. Investigators found that 64% of subjects with Sjögren's Syndrome and SNHL had anti-cardiolipin antibodies compared to 18% of controls.

Behçet's Disease

The leading cause of endogenous uveitis in Japan and Turkey and one of the major causes of blindness in these countries, Behçet's disease is a systemic inflammatory illness characterized by intraocular non-granulomatous inflammation, oral and mucosal ulcers, skin lesions, variety of other disorder that affect joints, the intestine, the epididymis, and the vascular and nervous systems. It is believed caused by a cellular immune response and may have immune complex formation. It has been associated with SNHL.

Lyme Disease

Although caused by the spirochete Borrelia burgdorferi, many of its symptoms may be mediated by autoimmunity through production of anti-phospholipid antibodies (APLA). Other infections associated with production of APLA include HIV, EBV, parvovirus, Hepatitis A, B, and C, rubella, and mumps, syphilis.

Diagnostic work-up for Inner Ear Autoimmunity:

The diagnosis of AIED is ascertained by the history, clinical findings, response to immunosuppressive medication, and an immunologic evaluation of the patient's serum.

Because the variety of conditions that potentially cause progressive hearing loss is so wide, patients may undergo a large number of tests. Most of these tests will be of extremely low yield.

Hirose, et al, in reviewing 82 patients with progressive hearing loss found only the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) were needed to detect the need for further testing. They report that the test with the best predictive value for corticosteroid responsiveness was the anti-heat shock protein-70 (HSP70) antibody test. They also noted that 50-60% of steroid-responsive patients are Western blot-negative.

The utility of the HSP70 test has been questioned recently. The use of heat shock protein as the antigen for the test is based on the similar molecular weight of HSP70 with a protein extracted from inner ear tissues. The inner ear antigen that may - or may not - be HSP70 reacts with antibodies in the sera of many patients with AIED. However, recent work suggests that the inner ear antigen is not HSP70 and clinicians have found the sensitivity of the HSP70 test at detecting AIED very low.


Glucocorticoids (dexamethasone, prednisone, prednisolone) are commonly used for the treatment of sudden and idiopathic hearing loss as well as hearing loss associated with systemic autoimmune disease, such as Wegener's granulomatosis, PAN, and SLE. Little is known about the specific mechanism of action steroids have on cochlear function. While steroid-mediated hearing improvement has traditionally been attributed to anti-inflammatory and immunosuppressive activity of these medications, steroid treatment appears to be effective in some cases in which no immune disorder is demonstrated. There is no evidence that direct inflammatory responses in the ear are responsible for AIED, particularly in autoimmune disease mice.

The duration of steroids required to ascertain true steroid responsiveness remains uncertain. While very brief courses (e.g., Medrol Dosepack) are sometimes effective, many consider less than one month too brief to allow breakdown of immunoglobulin. Harris and Ryan recommended a 1-month trial of steroid, which could be continued for an additional 1 - 2 months depending on response.

Steroids may also be administered transtympanically. Parnes, et al., reported the use of dexamethasone or methylprednisolone administered to 37 patients. He found notable improvement in several cases of sudden deafness, but no benefit in patients with cochlear hydrops or those with a sudden deterioration of a pre-existing hearing loss. 8% developed a transient otitis media but none developed treatment-induced hearing loss or permanent tympanic perforations.

The choice of steroid remains unclear, although recent data from Trune and Kempton stands the conventional wisdom on its head. They studied autoimmune mice (a 'lupus mouse'; MRL/MpJ-Faslpr), comparing the function of prednisolone with that of aldosterone in retarding the progression of hearing loss. The ABR was used to determine hearing thresholds. After 2 months, untreated controls had elevated ABR thresholds while the thresholds of most mice treated with prednisolone or aldosterone were unchanged or improved. Both steroids improved stria vascularis morphology, although aldosterone seemed more effective. Interestingly, prednisolone had a dose-dependent reduction in circulating immune complexes while aldosterone did not. Trune suggests that it is the change in strial sodium transport that is responsible for the improvement in autoimmune-related hearing loss and not suppression of systemic autoimmune response.

A follow-up study showed that prednisolone (a steroid with both gluco- and mineralocorticoid effects) did not protect hearing in MRL/MpJ-Faslpr when administered with spironolactone, a competitive antagonist of aldosterone at the mineralocorticoid receptor. When spironolactone was administered with aldosterone (which has a higher affinity for the receptor than spironolactone), hearing was preserved.

The site of cochlear damage in autoimmune mice (and probably humans) is thought to be the stria vascularis and no hair cell damage has been observed in the mouse model. Inflammation is never observed, despite leakage of immunoglobulin into pericapillary spaces. The same may be true in the human.

These observations suggest that endolymph sodium-potassium imbalances underlie AIED. As noted in temporal bone histopathology of Cogan's syndrome, no cellular infiltrate or vasculitis is observed. The loss of hair cells seen in this syndrome may be due to loss of the endocochlear potential from damage to the stria.

For patients in whom steroids are contraindicated (e.g., diabetics), other drugs can be used. Of these medications, methotrexate is currently most popular because of its relatively safe side-effect profile. Sismanis, et al., treated 23 patients with AIED with methotrexate and found that 69.6% responded favorably. Side effects were mild and reversible.

Anti-metabolites, such as methotrexate and cyclophosphamide are used to spare patients the risk of long-term steroid use. However, these drugs present their own risks and should be monitored carefully, usually with the assistance of a rheumatologist. A few of the risks of methotrexate include anemia and thrombocytopenia, hepato- and nephrotoxicity, and pulmonary problems. A few of the risks of cyclophosphamide (Cytoxan) include marrow suppression, sterility, hemorrhagic cystitis, bladder cancer, and increased risk of lymphoma.

The role of plasmapheresis is not clear. Outside a small series reported by Luetje, its use in AIED has not been described.

Suggested Diagnostic/Treatment Protocol:

Patients who may have autoimmune inner ear disease include those with fluctuating unilateral or bilateral hearing loss, patients with Meniere's syndrome, rapidly progressive hearing loss, sudden deafness, and a history of temporal bone/head trauma with loss of hearing. In addition to the usual questions about the onset and nature of hearing loss/vertigo, patients should be questioned about rashes, joint pain, visual/ocular symptoms, symptoms of Lyme disease, risk factors for HIV, and treatment for STDs. The examination should include examination of mucosal surfaces (Behcet's disease). Patients are asked to bring any old audiograms they may have had for comparison to new audiograms.

Laboratory work-up may include CBC, Sedimentation Rate, ANA and/or C-reactive protein, 68kDa antibody (see below). If treatment with an antimetabolite is contemplated, U/A and liver enzyme testing should be performed.

In non-diabetic patients, my treatment protocol is to treat with a minimum of 2 weeks of prednisone at a dose of up to 1mg/kg. I encourage patients to take a one-month course and generally taper the prednisone over the last 2 weeks of the course. The prednisone is given as a single morning dose. An oral antacid is generally prescribed and patients are warned of possible side effects of the medication, including aseptic necrosis of the femoral head and adrenal suppression. Patients who have objective response (>10db on PTA and >15% on WRS score) are maintained on prednisone at the minimum dose required to maintain stable hearing (generally about 10mg/day). For many patients I will try to have them change to an alternate day schedule (e.g., 20mg qod). After 2 months, I will try to wean their steroid.

For diabetics or those with other contraindications to steroids, I will use methotrexate. For patients without contraindications, methotrexate is prescribed at 7.5mg/week as a single dose. Folic acid, 1mg/day is also given to minimize stomatitis. Liver enzymes and blood counts are monitored frequently. An alternative in these patients may also be transtympanic steroid administration.

Patient Outcomes:

The charts of 122 patients in our practice who had been tested over the past 2 years for the 68kDa antibody were reviewed. Only patients treated with a minimum of 2 weeks of steroids were included in the analysis.

The 57 patients that met study criteria were divided into the following categories: 1) Unilateral fluctuating hearing loss (UFSNHL); 2) Unilateral Meniere's syndrome (MD); 3) Bilateral fluctuating hearing loss (BFSNHL); 4) Bilateral Meniere's syndrome (Bilateral MD); 5) Rapidly progressive hearing loss (RPSNHL); and 6) Sudden hearing loss (SSHL). Patients were judged to be steroid-responsive if improvement in PTA was >10dB and/or improvement in WRS was >15% on serial audiograms.

Our experience with AIED revealed:
  1. The sensitivity of the HSP70 antibody test for steroid responsive hearing loss is 0.32 - quite low; however, the positive predictive value is high - 0.83. Thus, the HSP70 test does predict response to steroids. In our series, all 68kDa-positive patients (except one) with a history of SSHL in one ear and progressive loss in the opposite ear who were treated with steroids had objective improvement in their hearing.

  2. The 68kDa-negative patients with UFSNHL tend to do better with steroids than 68kDa-negative patients with Meniere's syndrome (i.e., patients with both fluctuating hearing loss and episodic vertigo). 67% of UFSNHL patients improved while only 40% (2 of 5) of Meniere's patients improved. This may represent the effect observed anecdotally by others that patients early in the course of AIED tend to respond better than those treated later in the course.

  3. Pre-existing deafness in an ear contralateral to the fluctuating ear before treatment may predict poorer response to steroids. 17% of responders were deaf in one ear before treatment versus 28% of non-responders.

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