Autoimmune inner ear disease (AIED), also known as autoimmune sensorineural hearing loss, is a rare form of bilateral sensorineural hearing loss that responds to immunosuppressive therapy.1 This condition, as first described by McCabe1 in 1979, is usually recognized as a specific pattern of sensorineural hearing loss that is uniquely bilateral, asymmetric, and fluctuating.2 Sensorineural hearing loss attributed to AIED was originally characterized by responsiveness to treatment with systemic corticosteroids and cyclophosphamide. The presentation of AIED-related hearing loss is often sudden. Sudden sensorineural hearing loss (SSNHL) is defined hearing loss of more than 30 dB in less than 3 days.3 AIED is unlike most cases of SSNHL in that it is usually bilateral at the time of presentation. This rare occurrence among cases of SSNHL should prompt clinicians to consider the diagnosis of AIED as well as underlying systemic conditions such as infection (Lyme, cytomegalovirus [CMV], Epstein-Barr virus [EBV], syphilis), vasculitis, paraneoplastic syndrome, drug ototoxicity, or other systemic autoimmune diseases.4,5 Early diagnosis and treatment of this disorder is extremely important as early intervention may result in improved rates of hearing loss reversal.6
AIED is a rare disease with an estimated yearly incidence of less than 5 cases per 100,000.7 However, because there are no standardized criteria or definitive diagnostic tests, the exact prevalence remains unknown.7
AIED typically presents as bilateral asymmetric sensorineural hearing loss that progresses over a period of days to months. This contrasts with pediatric nonautoimmune sudden onset hearing loss, in which most cases are unilateral.4.8 Serial audiometry in AIED patients usually depicts fluctuating hearing thresholds that follow a trend of progressive deterioration. Although 80% of AIED patients have bilateral, asymmetrical SSNHL at initial presentation, a small minority will initially present with hearing loss only in one ear, before later (weeks to months) developing hearing loss on the contralateral side.2 One-half of patients with AIED have associated vestibular symptoms such as imbalance and vertigo.2 Tinnitus is also a common presenting symptom. Data describing AIED specifically in children are sparse. Huang et al.9 presented seven children age 4 to 13 years who were diagnosed with AIED based on the finding of SSNHL and positive antibodies. Five of the seven children presented with bilateral hearing loss, and 5 of 7 complained of tinnitus.9
Pathogenesis and Evidence for Autoimmunity
The precise mechanism of hearing loss in AIED is not fully understood. Numerous clinical observations and animal studies seem to support an autoimmune mechanism for this entity.10
Hearing loss is known to occur at a higher-than-normal rate in patients with several autoimmune diseases such as systemic lupus erythematosus, ulcerative colitis, Sjogren's syndrome, and Cogan's syndrome. Interestingly, children with juvenile idiopathic arthritis (JIA) may have subtle hearing impairment more frequently than is commonly appreciated. Céspedes et al.11 found that 78 of 124 ears in 62 patients with JIA had a mild degree of hearing impairment. Ikiz et al.12 found middle and/or inner ear involvement in 32% of ears in a cohort of 38 patients with JIA. He attributed this finding to rheumatic process in the middle ear joints or to immune-complex mediated vasculitis in the inner ear. Similar results were reported among adults with rheumatoid arthritis. Lidar et al.13 reported three cases of vasculitis that initially presented as sudden hearing loss.13
Harris et al.,14 using guinea pig models, showed that the inner ear can produce antibodies in response to sensitization. They later isolated a 68-kD protein, using Western blot analysis on serum from patients with SSNHL and from animals with experimental autoimmune hearing loss. Inner ear proteins were found to be the target of this 68-kD protein.14 Boulassel et al.15 found several additional antibodies (including 30- and 42-kD protein) that reacted with the guinea pig inner ear. These findings suggest that several populations of antibodies contribute to the enhanced immunologic activity in AIED.
The precise immune pathogenesis of the inner ear injury process is unclear. Type II (cytotoxic), type III (immune complex), and type IV (delayed type) immune response were suggested as potential mechanisms.10
There are no standardized diagnostic criteria for AIED and the diagnostic process may be challenging. A high index of suspicion is recommended when sudden bilateral asymmetric sensorineural hearing loss is encountered. The diagnosis is mainly clinical based on hearing loss pattern and responsiveness to immunosuppressant therapy. Positive serum autoantibodies and exclusion of other potential causes further support the diagnosis. The diagnostic assessment consists of four parts.2,4,9
Audiologic testing demonstrates the presence of acute sensorineural hearing loss (bone-conduction thresholds >30 dB for at least three frequencies); usually present in both ears. Speech audiometry typically demonstrates diminished word recognition scores. Vestibular function testing may depict evidence of unilateral or bilateral peripheral vestibular weakness. Otoscopic examination is usually normal, as is head and neck examination. If the patient is experiencing acute vestibular symptoms, spontaneous jerk nystagmus in the horizontal plane may be observed and gait may be unstable.
Evaluation for Underlying Autoimmune/Infectious Disease
Clinical history of autoimmune disease. Suggested laboratory evaluation includes compete blood count, erythrocyte sedimentation rate, antinuclear antibody, antineutrophil cytoplasmatic antibody, rheumatic factor, anti-Sjögren syndrome-related antigen A, anti-Sjögren syndrome-related antigen B, and angiotensin converting enzyme level. Lyme serology, fluorescent treponemal-antibody absorption for syphilis, and/or anti-CMV and EBV immunoglobulin G (IgG) and IgM, as clinically indicated to rule out infectious etiology, may also be considered. Eye examination to rule out interstitial keratitis/uveitis (Cogan syndrome) or branch retinal artery occlusion (Susac syndrome) could also be another element.
Testing for Specific Inner Ear Autoantibodies
Serologic testing for inner ear antibodies can be helpful as a positive finding supports the suspected diagnosis of AIED, but sensitivity is limited and the significance of a positive versus a negative test is unclear. The most well-known antibody is the heat shock protein 70 against the 68-kDa antigen, which is present on hair cells and supporting cells in the inner ear.16 This antibody was found in 35% of patients with AIED17 and in 92% of patients with Cogan's syndrome, which presents with corneal inflammation and audiovestibular dysfunction that is otherwise similar to AIED.18 Presence of these antibodies has been proposed as a marker for steroid responsiveness, but animal studies have failed to definitively support this assertion, and practically speaking, most patients suspected of having AIED have been treated with a steroid trial well before laboratory test results are known. Other antibodies such as anti-beta tubulin and anti-cochlin have also been suggested as possible markers of AIED.
Magnetic resonance imaging (MRI) with contrast of the brain and internal auditory canals should be considered to rule out rare primary causes such as cranial nerve tumor (bilateral vestibular schwanomma, in type 2 neurofibromatosis), neurodegenerative disease (multiple sclerosis), superficial siderosis, or inner ear developmental malformations. Susac syndrome includes the combination of AIED-like hearing loss, visual loss due to retinal artery occlusion, and encephalopathy due to diffuse vasculitic white matter lesions that are apparent on MRI.19 In the acute phase of AIED, contrasted MRI imaging may reveal enhancement of the cochlea or vestibular labyrinth.
Corticosteroids have remained the standard of care for treatment of AIED since it was first suggested by McCabe;1 however, it is worth noting that this original report included a few cases that did not respond to steroids, but did respond to cyclophosphamide.1 Various dosing regimens and treatment durations have been reported. Reported doses range between 1 mg/kg per day and 60 mg daily9,20,21 and can be given orally or intravenously. Xenellis et al.22 found that intratympanic steroid treatment after 10 days of intravenous solumedrol had a favorable outcome compared to intravenous steroids alone. The duration of treatment varied from a minimum of 14 days to 1 month or longer. The overall reported response to steroid treatment is 60% to 70%, but response was temporary in some cases. A variety of steroid-sparing immunosuppressive treatments have also been tried. Methotrexate, cyclophosphamide, anti-TNF antibody biologics, and rituximab (anti-CD20 antibody) have all been used in small studies, with inconclusive results.23 A randomized control study found that methotrexate was not more effective than placebo in maintaining the hearing improvement achieved in 60 patients with AIED.24
Unfortunately, not all patients with AIED will respond adequately to medical therapy even if applied promptly in the acute setting. Further, some patients that do respond will experience slow deterioration of hearing over time despite maintenance immunosuppressant therapy. Also, some patients who respond to immunosuppressant therapy will later develop intolerable side effects. In each of these instances, it is common for patients to be first treated with hearing aid fitting. Later, as hearing thresholds worsen, many patients with AIED eventually undergo cochlear implantation when the benefit from hearing aids is insufficient with respect to speech understanding.25 In general, cochlear implant outcomes in the AIED patient population are quite good, if not better than, the general cochlear implant recipient population. However, cochlear fibrosis and ossification are possible obstacles if implantation is delayed and, although no contraindications to implantation, these specific findings may portend a worse prognosis in each patient.
Autoimmune hearing loss is a rare, but potentially treatable form of sudden hearing loss in children. Most cases present acutely and involve both ears with differing degrees of hearing impairment. Positive response to corticosteroid or other immunosuppressive treatment supports the diagnosis. Unfortunately, there are no definitive diagnostic criteria or reliable serologic markers. Therefore, a high index of suspicion for the diagnosis is appropriate when acute bilateral asymmetric sensorineural hearing loss is encountered, and other possible etiologies have been ruled out. Consideration of an early trial of corticosteroid therapy is a reasonable approach to suspected cases, whereas cochlear implantation is a viable option for most long-term treatment failures.
- McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol. 1979;88(5):585–589. https://doi.org/10.1177/000348947908800501 doi:10.1177/000348947908800501 [CrossRef]496191
- Ciorba A, Corazzi V, Bianchini C, et al. Autoimmune inner ear disease (AIED): a diagnostic challenge. Int J Immunopathol Pharmacol. 2018;32. https://doi.org/10.1177/2058738418808680 PMID: doi:10.1177/2058738418808680 [CrossRef]30376736
- Stew BT, Fishpool SJ, Williams H. Sudden sensorineural hearing loss. Br J Hosp Med (Lond). 2012;73(2):86–89. https://doi.org/10.12968/hmed.2012.73.2.86 PMID: doi:10.12968/hmed.2012.73.2.86 [CrossRef]
- Pitaro J, Bechor-Fellner A, Gavriel H, Marom T, Eviatar E. Sudden sensorineural hearing loss in children: Etiology, management, and outcome. Int J Pediatr Otorhinolaryngol. 2016;82:34–37. https://doi.org/10.1016/j.ijporl.2015.12.022 PMID: doi:10.1016/j.ijporl.2015.12.022 [CrossRef]26857312
- Tarshish Y, Leschinski A, Kenna M. Pediatric sudden sensorineural hearing loss: diagnosed causes and re-sponse to intervention. Int J Pediatr Otorhinolaryngol. 2013;77(4):553–559. https://doi.org/10.1016/j.ijporl.2013.01.004 PMID: doi:10.1016/j.ijporl.2013.01.004 [CrossRef]23369615
- Ruckenstein MJ. Autoimmune inner ear disease. Curr Opin Otolaryngol Head Neck Surg. 2004;12(5):426–430. https://doi.org/10.1097/01.moo.0000136101.95662.aa PMID: doi:10.1097/01.moo.0000136101.95662.aa [CrossRef]15377956
- Vambutas A, Pathak S. AAO: autoimmune and autoinflammatory (disease) in otology: what is new in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol. 2016;1(5):110–115. https://doi.org/10.1002/lio2.28 PMID: doi:10.1002/lio2.28 [CrossRef]27917401
- Kim JY, Han JJ, Sunwoo WS, et al. Sudden sensorineural hearing loss in children and adolescents: clinical characteristics and age-related prognosis. Auris Nasus Larynx. 2018;45(3):447–455. doi:10.1016/j.anl.2017.08.010 [CrossRef]
- Huang NC, Sataloff RT. Autoimmune inner ear disease in children. Otol Neurotol. 2011;32(2):213–216. https://doi.org/10.1097/MAO.0b013e318204ac01 PMID: doi:10.1097/MAO.0b013e318204ac01 [CrossRef]
- Li G, You D, Ma J, Li W, Li H, Sun S. The role of autoimmunity in the pathogenesis of sudden sensorineural hearing loss. Neural Plast. 2018;2018:7691473. https://doi.org/10.1155/2018/7691473 PMID: doi:10.1155/2018/7691473 [CrossRef]30008743
- Céspedes Cruz AI, Méndez Núñez M, Solís Vallejo E, et al. Frequency of auditory involvement and of associated factors in patients with juvenile idiopathic arthritis. Rheumatol Clin. 2019;15(3):152–155. doi:10.1016/j.reuma.2017.07.003 [CrossRef]
- Ikiz AO, Unsal E, Kirkim G, Erdag TK, Guneri EA. Hearing loss and middle ear involvement in patients with juvenile idiopathic arthritis. Int J Pediatr Otorhinolaryngol. 2007;71(7):1079–1085. https://doi.org/10.1016/j.ijporl.2007.03.017 PMID: doi:10.1016/j.ijporl.2007.03.017 [CrossRef]17482280
- Lidar M, Carmel E, Kronenberg Y, Langevitz P. Hearing loss as the presenting feature of systemic vasculitis. Ann N Y Acad Sci. 2007;1107(1):136–141. https://doi.org/10.1196/annals.1381.015 PMID: doi:10.1196/annals.1381.015 [CrossRef]17804541
- Harris JP, Sharp PA. Inner ear autoantibodies in patients with rapidly progressive sensorineural hearing loss. Laryngoscope. 1990;100(5):516–524. https://doi.org/10.1288/00005537-199005000-00015 PMID: doi:10.1288/00005537-199005000-00015 [CrossRef]2329911
- Boulassel MR, Deggouj N, Tomasi JP, Gersdorff M. Inner ear autoantibodie s and their targets in patients with autoimmune, inner ear diseases. Acta Otolaryngol. 2001;121:28–34. doi:10.1080/000164801300006236 [CrossRef]11270490
- Bloch DB, San Martin JE, Rauch SD, Moscicki RA, Bloch KJ. Serum antibodies to heat shock protein 70 in sen-sorineural hearing loss. Arch Otolaryngol Head Neck Surg. 1995;121(10):1167–1171. https://doi.org/10.1001/archotol.1995.01890100075013 PMID: doi:10.1001/archotol.1995.01890100075013 [CrossRef]7546586
- Yoo TJ, Stuart JM, Kang AH, Townes AS, Tomoda K, Dixit S. Type II collagen autoimmunity in otosclerosis and Meniere's disease. Science. 1982;217(4565):1153–1155. https://doi.org/10.1126/science.7112122 PMID: doi:10.1126/science.7112122 [CrossRef]7112122
- Bonaguri C, Orsoni J, Russo A, et al. Cogan's syndrome: anti-Hsp70 antibodies are a serological marker in the typical form. Isr Med Assoc J. 2014;16(5):285–288. PMID:24979832
- Kleffner I, Dörr J, Ringelstein M, et al. European Susac Consortium (EuSaC). Diagnostic criteria for Susac syn-drome. J Neurol Neurosurg Psychiatry. 2016;87(12):1287–1295. https://doi.org/10.1136/jnnp-2016-314295 PMID: doi:10.1136/jnnp-2016-314295 [CrossRef]
- Berrocal JR, Ramírez-Camacho R. Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol. 2002;111(11):989–997. https://doi.org/10.1177/000348940211101107 PMID: doi:10.1177/000348940211101107 [CrossRef]12450172
- Niparko JK, Wang NY, Rauch SD, et al. Serial audiometry in a clinical trial of AIED treatment. Otol Neurotol. 2005;26(5):908–917. https://doi.org/10.1097/01.mao.0000185081.28598.5c PMID: doi:10.1097/01.mao.0000185081.28598.5c [CrossRef]16151337
- Xenellis J, Papadimitriou N, Nikolopoulos T, et al. Intratympanic steroid treatment in idiopathic sudden senso-rineural hearing loss: a control study. Otolaryngol Head Neck Surg. 2006;134(6):940–945. https://doi.org/10.1016/j.otohns.2005.03.081 PMID: doi:10.1016/j.otohns.2005.03.081 [CrossRef]16730534
- Matteson EL, Fabry DA, Facer GW, et al. Open trial of methotrexate as treatment for autoimmune hearing loss. Arthritis Rheum. 2001;45(2):146–150. https://doi.org/10.1002/1529-0131(200104)45:2<146::AID-ANR167>3.0.CO;2-I PMID: doi:10.1002/1529-0131(200104)45:2<146::AID-ANR167>3.0.CO;2-I [CrossRef]11324778
- Harris JP, Weisman MH, Derebery JM, et al. Treatment of corticosteroid-responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA. 2003;290(14):1875–1883. https://doi.org/10.1001/jama.290.14.1875 PMID: doi:10.1001/jama.290.14.1875 [CrossRef]14532316
- Sakano H, Harris JP. Emerging options in immune-mediated hearing loss. Laryngoscope Investig Otolaryngol. 2018;4(1):102–108. https://doi.org/10.1002/lio2.205 PMID: doi:10.1002/lio2.205 [CrossRef]