Autoimmune inner-ear disease refers to a progressive, bilateral, although often asynchronous, sensorineural hearing loss, and vestibular function presumed autoimmune condition in which there is sudden or rapidly progressive fluctuating sensorineural hearing loss in the absence of any other neurologic or systemic immunologic abnormalities.
The autoimmune inner ear disease is a clinical syndrome with uncertain pathogenesis that is often associated with rapidly progressive hearing loss that, especially at the early stages of the disease, maybe at monoaural localization, although more often it is at binaural localization. It usually occurs as sudden deafness, or a rapidly progressive sensorineural hearing loss.
These include, but are not limited to, Vogt‐Koyanagi‐Harada syndrome, Cogan’s syndrome, Susac’s syndrome, systemic lupus erythematosus, rheumatoid arthritis, granulomatosis with polyangiitis (ie, Wegener’s granulomatosis), Behçet’s disease, systemic sclerosis, inflammatory bowel disease (eg, Crohn’s, ulcerative colitis), relapsing polychondritis, and temporal arteritis.
Causes of Autoimmune Inner-Ear Disease
The causes of AIED can include:
- The body’s uncontrolled immune system attacks the inner ear protein, forming immune complexes and antibodies and causing progressive hearing loss in both ears.
- Cochlin is a protein located in the inner ear that is attacked by the immune system.
- The Endolymphatic sac, a structure of the inner ear, can become dilated as the immune response of the inner ear.
Symptoms of Autoimmune Inner-Ear Disease
Common symptoms of AIED can include:
- Progressive SNHL in both ears that occurs over weeks to months that is not always the same in both ears
- Fluctuating hearing
- Dizziness or imbalance (approximately 50 percent of AIED cases)
- Ringing in the ears, or tinnitus
- Ear fullness (approximately 25 to 50 percent of AIED cases)
- Conductive hearing loss may be present due to Eustachian tube obstruction from inflamed middle ear lining and/or if AIED is because of systemic autoimmune diseases
- Symptoms of systemic autoimmune diseases, such as fatigue, achy muscles, swelling and redness, low-grade fever, and more
- Dizziness or problems with your balance
- Fullness in your ear
- Tinnitus (ringing, roaring, or hissing in your ear)
- Vertigo (a sense that you’re spinning)
Diagnosis of Autoimmune Inner-Ear Disease
Because of the difficulty in the differential diagnosis of AIED, many have proposed the use of lab tests to assist in the medical diagnosis. McCabe originally recommended an “immune screen” to include
- Erythrocyte sedimentation rate, which is a general indicator of inflammation;
- Rheumatoid factor, which is a marker for rheumatoid arthritis and other autoimmune diseases;
- Anti-nuclear antibody titer, to check for lupus and other autoimmune diseases;
- quantitative immunoglobulin determination; and
- A leukocyte migration inhibition test.
Later, Campbell and Klemens (2000) listed other medical tests they commonly use to detect AIED:
- CBC (complete blood count) to check for leukemia or other hemolytic disorders;
- FTA/ABS blood screen for syphilis;
- MRI, with contrast, of the brain and cerebellopontine angle to check for MS, vascular lesions, and space-occupying lesions;
- Lymphocyte blast transformation to check for inner ear antigen, which may underlie AIED (the efficacy of this test is controversial);
- Rheumatoid factor and antinuclear antibody, as mentioned above;
- Lipid panel to check for dyslipidemias; and
- Steroid trial.
The diagnosis is based on history, findings on physical examination, blood tests, the results of the hearing and vestibular tests, MRI scans, and response to immunosuppressive medications. The usual clinical picture is a subacute bilateral progressive sensorineural hearing loss.
Steroid responsiveness is the most useful method of making the diagnosis, and ordinarily, the diagnosis is made by observing a bilateral progressive sensorineural hearing loss that responds to steroids. This is a rather difficult criterion to meet, as it requires three features — bilateral, progression, and steroid responsiveness. There might be few people where steroid responsiveness has been established, as this generally requires contact with a subspecialty physician. The observation of progression requires a time series of audiograms, quite different from the “point of service” type audiograms used in most settings.
Other tests may be proposed based on the clinical situation.
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 should be done in those in whom ABR testing cannot be done. MRI scans of the brain is useful to diagnose Susac’s syndrome (see above), as well as to exclude possible confounding disorders, such as acoustic neuroma.
While specific tests for autoimmunity to the inner ear would be desirable, at this writing (2020) we know of none that are both commercially available and proven to be useful. (Garcia Berrocal et al, 2002).
Having an autoimmune disease, per se, combined with hearing loss is not a good way of establishing that hearing loss is autoimmune, as both autoimmune disease and hearing loss are very common. In other words, coincidence is not the same as cause. Here is a partial list of blood tests.
- Immunofluorescence of supporting cells of guinea pig organ of Corti (cochlea) 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).
- Western Blot is helpful in some hands (Garcia et al, 2003). Yeom et al (2003) recently reported that immunofluorescence is more sensitive and specific than anti-HSP 70. The specificity of both tests to us seems unacceptably low.
- The lymphocyte transformation assay, like the anti-cochlear antibody test, is present of uncertain value.
- Antiendothelial antibodies may be associated with some cases of AIED (Cadoni et al, 2003). At this writing, there is no commercially available test.
- Several studies have reported an association between autoimmune thyroid disease and ear disease (Brenner et al, 2004; Medugno et al, 2000), which is the rationale for testing for anti-microsomal or thyroid peroxidase antibodies.
- It has recently been reported that antibodies to sulfoglucuronosyl glycolipids are common in autoimmune inner ear disease. (Yamawaki M, 1998). It remains to be seen if this finding will be confirmed and whether a commercial assay will be developed.
- At this writing (2011), it is clear that anti-cochlear antibody (also called anti-HSP70) blood tests are not useful. Antibodies to HSP-70 can also be found in Lyme disease, ulcerative colitis, cancers, and in about 5% of healthy individuals. In Meniere’s disease, Hornibrook et al (2011) found no significant difference between 80 subjects with definite Meniere’s disease and controls. 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 testings, diagnosis is generally based on evidence from broader tests of autoimmunity, or a positive response to steroids.
A small study suggested that FDG PET scans may be useful in AIED. (Mazlumzadeh et al, 2003). More investigation of this modality is needed before its role in diagnosis can be defined. The cost is clearly prohibitive.
As there are no specific tests for AIED, a common approach is to look for other evidence for autoimmune involvement.
- ANA, ANCA, Sed Rate, and CRP
- Thyroid (anti-microsomal and thyroglobulin antibodies)
- Rheumatoid Factor
- Complement C1Q
- Smooth Muscle Antibody
- anti-gliadin and anti-endomysial antibodies (for Celiac disease)
- HLA testing, especially for HLA-B27
As commented above, positives on these blood tests do not prove that hearing loss is caused by autoimmune disease — some of them simply document inflammation. Response of hearing to steroids is far more specific. It is best to get these tests done prior to starting immunosuppressive drugs.
- FTA (for Syphilis) as of 2020, syphilis is on the upswing again.
- HBA1C (for diabetes, which is often autoimmune-mediated also)
- HIV (HIV is associated with auditory neuropathy as well as syphilis)
- Lyme titer (we are dubious that this is helpful as Lyme has very little to do with hearing loss)
Recently it has been suggested that blood levels of TNF, tumor necrosis factor, are both diagnostic and predictive of treatment response (Svarkic, 2012). As TNF is a nonspecific inflammatory cytokine, we are dubious as we think that TNF should logically be elevated in many conditions.
MRI testing is mainly done to exclude other entities, but occasionally enhancement is seen of the cochlea.
Treatment of Autoimmune Inner-Ear Disease
- Autoimmune inner ear disease (AIED) is a reversible form of sensorineural hearing loss when immunosuppressive treatment is given.
- AIED is described as progressive, bilateral although asymmetric sensorineural hearing loss that responds to treatment with corticosteroids.
- Primary AIED exists in the absence of systemic disease and is probably an inner ear-specific autoimmune disease involving T-cell targeting of inner ear-specific antigens such as cochin.
- Secondary AIED may be the consequence of systemic immune abnormalities that involve the inner ear.
- Corticosteroids administered prior to the development of AIED in mice lead to retained cochlear function, although no changes in cochlear histopathology could be noted.
- High-dose corticosteroids for 2–4 weeks are recommended for patients with suspected AIED.
- Treatment with low-dose methotrexate was not found to be efficacious in AIED.
Animal models with keyhole limpet hemocyanin-induced labyrinthitis treated with etanercept, a TNF-α inhibitor, found decreased cochlear inflammation with reduction of hearing loss.
- Clinical studies on the treatment of AIED with etanercept are mixed but promising, and a randomized controlled trial has yet to be conducted.
- Treatment with cyclophosphamide remains an option, but toxic risks often deter clinicians and patients from its use.
- Other treatment options include combination cytotoxic agents and plasmapheresis for potential use in patients with AIED.
- In animal models, it was found that medications can be delivered to the inner ear through the round window and intratympanic administration.
- Intratympanic steroids for the treatment of AIED have produced mixed results.
- Intratympanic injection of infliximab, a humanized TNF-α monoclonal antibody, may provide a steroid-sparing treatment option.
The treatment most widely used for AIED is corticosteroids therapy. The initial dosage regimen is 60 mg or 1 mg/kg per day of prednisone or 6-methylprednisolone for a month. Shorter courses or lower doses have proved to be ineffective and increase the risk of relapse[rx]. In rapidly progressive forms 1 mg/kg per day is maintained for 4 wk until the audiogram is stable and the dose is then tapered over 8 wk to 10-20 mg per day, which is maintained for another 6 wk. In cases of sudden hearing loss, 1 mg/kg per day of 6-methylprednisolone is administered for four weeks. In severe hearing loss (over 70 dB) three pulses of 500 mg are administered, and then the above-mentioned dosage regimen is applied. When patients receive high doses of corticosteroids, active tuberculosis must be ruled out, and glycemia, potassium and blood pressure must be monitored. Tapering must be gradual, slower if glucocorticoids have been given at higher doses or for a longer time.
methotrexate was offered to these patients at a dose of 15 mg/week. If the patient refused methotrexate treatment or if methotrexate therapy failed (as evidence of no response or hearing loss relapse), then they were offered two intratympanic injections of methylprednisolone 0.3–0.5 ml at 40 mg/ml given 1 week apart.
Plasmapheresis is typically reserved in severe cases of autoimmune disorder that progress rapidly with vasculitis, leukopenia, thrombocytopenia or organ involvement despite immunosuppression.[rx] It has been reported to help stabilize hearing when it has been used.[rx, rx]
Some patients do not respond to corticoids or require high doses to control the disease, and other immunosuppressants such as methotrexate or cyclophosphamide have been tried. The empirical basis for using these drugs is the observation that in certain cases their effect enhances that of the corticosteroids, thus obtaining remission of one or more symptoms that are not achieved with corticosteroids alone, or allowing reduction of the required dose of corticosteroids to maintain the patient symptom-free.
Methotrexate: A meta-analysis showed that there was no benefit with methotrexate compared with corticosteroids alone[rx]. However, vertigo or instability can improve with long treatments.
The most frequently employed regimen is 7.5 mg weekly administered in one single dose. Once the response is achieved, the drug is given orally (15 mg weekly) for 12 mo. Methotrexate is associated with blood toxicity (leukopenia, thrombocytopenia), liver toxicity (elevated liver enzymes, periportal fibrosis, cirrhosis), and gastrointestinal toxicity (nausea, vomiting, mucositis). Folic acid supplements reduce the adverse effects, preserve their efficacy, and are, therefore, recommended.
Cyclophosphamide: This drug was used by McCabe[rx], who advocated its use as the treatment of choice, in his original series of cases. However, because of its adverse effect profile (gonadal, bladder, and bone marrow toxicity), it is not frequently used and is limited to those patients who do not respond to corticosteroids or do not maintain their response after dose tapering. The oral dose is 1-2 mg/kg per day for 4-6 wk. Intravenously, the starting dose is 0.75 g/m2 or 0.5 g/m2 if the glomerular filtration rate is lower than a third of the normal value, and this is repeated every 1-3 mo. The white cell count should not be lower than 2000/mm3 and neutrophils should remain over 1000/mm3. When both cyclophosphamide and high doses of corticosteroids are employed trimethoprim/sulphamethoxazole or dapsone is administered to prevent Pneumocystis carinii pneumonia.
NOVELTIES IN AIED THERAPY
The overall response rate to corticosteroids is 60%, but the response rate varies considerably. In most responders, the dose can be lowered or corticosteroids can be withdrawn without relapse, but some patients can present a corticosteroid-dependant hearing loss. Hearing loss may become refractory to corticosteroids, and other immunosuppressants should be considered in these cases. Finally, treatment can result in unacceptable adverse reactions (gastritis, peptic ulcer, fluid retention, glucose intolerance, avascular necrosis of the femoral head, psychiatric problems, sleep disorders, cataracts, osteoporosis, cushingoid habitus) and this has prompted the search for new drugs or different modes of administration such as the intratympanic route.
The use of intratympanic corticosteroids is an attractive therapeutic approach because it is minimally invasive and, since the drug is applied directly to the affected ear, side effects are minimized. However, there is no consensus regarding the doses and length of treatment. Moreover, it is not easy to control the dose that actually enters the inner ear (part of it is absorbed in the middle ear and part is eliminated through the Eustachian tube); as a result, its efficacy has so far not been fully determined[rx].
Biological therapy agents
Biological therapy agents are fusion proteins (made from a fusion gene, which is created by joining parts of two or more genes) or monoclonal antibodies designed to block specific components of the inflammatory cascade. Tumor necrosis factor α inhibitors and lymphocyte CD20 receptor antagonists have recently been tested on AIED patients
Among the biological therapy agents, the most frequently used are tumor necrosis factor alpha-blockers. Tumor necrosis factor (TNF) is a proinflammatory cytokine produced by multiple cells, especially macrophages, that stimulates the maturation and migration of dendritic cells, activates neutrophils and NK cells, and increases vascular permeability. It was isolated by Carswell et al[rx] in 1975 when they were seeking to identify the factors responsible for Meth A sarcoma necrosis. It is expressed early in the inflammatory response in different inner ear structures. Of the different TNF-α blockers that have been developed, etanercept, infliximab, and adalimumab have been tested on AIED patients. X-ray or Mantoux screening is recommended before initiating treatment with TNF-α blockers because TNF-α is a key component in the body’s defense against M. tuberculosis and other granulomatous diseases.
Etanercept: The results obtained so far are promising but not conclusive, as very few studies have been performed. Anecdotally, it has been used together with methotrexate with good results, allowing corticosteroid therapy to be withdrawn[rx]. The usual dose is 25 mg administered by subcutaneous injection twice a week or 50 mg once a week for an indefinite period of time. Side effects that have been a concern are infections including tuberculosis and sepsis, tumors such as lymphomas, anemia, and pancytopenia, demyelinating diseases, congestive heart failure, and hypersensitivity. However, a meta-analysis that examined the adverse reactions with etanercept and other biologic therapies in 163 randomized controlled studies with 50010 participants and 46 extension studies with 11954 participants reported that the severe adverse reactions rate for the biological products was not different from that of the control therapy (e.g., corticosteroids)[rx].
Adalimumab – It is administered by subcutaneous injection of 40 mg every two weeks for an indefinite period of time. The dose can be increased to 40 mg weekly if a decrease in the response is observed. It has been employed successfully in one patient with autoimmune sensorineural hearing loss and rheumatoid arthritis[rx].
Infliximab – The usual regimen is a slow intravenous infusion (2 h) of 3 mg/kg at the start of treatment, and at 2 and 6 wk, followed by maintenance therapy every 8 wk indefinitely. Intratympanic administration of infliximab can help to reduce corticosteroids doses in patients with AIED[rx].
B lymphocyte CD20 receptor antagonist – Apart from TNF-α blockers other biological therapy agents such as rituximab have been recently tested on patients with AIED. Rituximab is a chimeric monoclonal antibody that binds to the CD20 receptor of B lymphocytes, thereby inducing apoptosis and reducing their number. The few studies that have used rituximab in AIED patients have yielded encouraging results[rx,rx]. However, more studies are needed for reliable conclusions to be reached. The recommended dose is 1000 mg in intravenous injection, followed by second injection perfusion of 1000 mg 2 wk later. The most common side effect associated with rituximab is a reaction to the injection (low blood pressure, nausea, eruption, fever, itching, urticaria, throat irritation, tachycardia, peripheral edema). Infections of the upper airway and urinary tract have also been reported (but not in AIED patients).
TNFα is a pro‐inflammatory cytokine and is an indicator of steroid responsiveness in AIED.[rx] Using an established mouse model of AIED immunized with KLH antigen, etanercept has been found to decrease the number of infiltrating cells in the cochlea in response to TNFα.[rx] Several open‐pilot studies show variable hearing results with etanercept in steroid-responsive patients. In one reported study of 12 patients, 58% had hearing improvement.[rx] In another with 23 patients, 30% had improved hearing and 58% had a stable hearing.[rx] However, a pilot placebo‐controlled study of steroid-responsive AIED patients found no difference in the hearing improvement between etanercept and placebo.[rx]
Yet another TNF αantagonist, infliximab, delivered by local intratympanic (IT) infusion once weekly for 4 weeks has been found to stabilize hearing and allow 4 of 5 steroid‐dependent patients to wean off steroids, or improve hearing loss in 3 of 4 steroid‐responsive patients who relapsed after steroid cessation.[rx] Another study of 10 steroid‐dependent AIED patients who underwent IT golimumab therapy found that 6 had stable thresholds in the injected ear and 7 patients were able to wean off steroids.[rx]
TNFα antagonist is not useful in steroid-refractory AIED. In a study of 8 patients who did not respond to steroids, systemic treatment with infliximab was not helpful in hearing improvement.[rx]
One of the challenges of AIED is the treatment of steroid non-responders. While steroids are known to suppress IL‐1β through indirect pathways, one study suggests that the IL‐1β pathway is abnormally upregulated in steroid-resistant patients.[rx] They also showed that IL‐1β antagonist anakinra can decrease IL‐1β in otherwise steroid‐nonresponsive monocytes. This is promising for the potential use of anakinra for steroid‐nonresponsive patients. A phase I/II study showed that in an intention to treat analysis, 58% response rate with anakinra injection in steroid‐nonresponsive AIED.[rx] The drug was well tolerated, aside from the risk of injection site reaction rate of 70%.
Rituximab is a B‐cell inhibitor targeting CD20. A small open pilot study of 7 patients tolerated rituximab without significant side effects and 5 were able to maintain the post‐steroid hearing improvement.[rx] There is one case report of a Cogan’s syndrome patient who did not respond to prednisone, methotrexate, cyclophosphamide, cyclosporine, and adalimumab (TNFα inhibitor), but did have hearing improvement after rituximab.[rx] In a retrospective study, hearing improved in only 2 of 5 treated with rituximab, but all patients improved tinnitus, aural fullness, and vertigo.[rx]
For those patients whose hearing could not be salvaged, cochlear implantation is an excellent rehabilitative option.[rx, rx, rx] Although neo‐ossification (which required drill out) and intraluminal fibrosis was seen in 50% of implanted ears, all ears were implanted and the outcomes on word and sentence scores were not significantly different between AIED and postlingually deaf control patients.[rx] This option is especially important for those patients unable to tolerate the side effects of immunomodulating drugs and go on to develop bilateral deafness.