Portuguese Version

Year:  2002  Vol. 68   Ed. 5 - (20º)

Artigo de Revisão

Pages: 730 to 734

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Immunomediated sensorineural hearing loss

Author(s): Norma de Oliveira Penido 1,
Mariana Dantas Aumond 2,
Fernando Danelon Leonhardt 3,
Carlos Eduardo Cesário de Abreu 4,
Ronaldo Nunes Toledo 5

Keywords: sensorineural hearing loss, autoimmune inner ear disease, Western Blot

Abstract:
The immunomediated sensorineural hearing loss (ISHL) is characterized as an asymmetric and progressive sensorineural hearing loss. Tree patients with ISHL were studied, regarding clinical aspects, diagnostic tests, treatment options and disease evolution. They presented whether positive response to immunosuppressive therapy or positiviness to Western Blot test for hsp 70-68kD. Two patients presented rapidly progressive sensorineural hearing loss, associated to vestibular symptoms and the other presented unilateral sudden deafness. No patient reacted to rheumatological testes, and one presented increased erythrocyte sedimentation rate. None satisfactorily responded to corticotherapy, but two presented clinical improvement with other immunosuppressive therapies. The ISHL diagnosis is based on clinical aspects and on the positive response to therapeutic testes with immunosupressor drugs. The Western Blot test for hsp 70-68 kD, with 42% sensitivity and 90% specificity, is the only specific laboratorial exam for ISHL. One patient presented positiviness to this exam and did not responded to immunosuppressive therapy. Two patients with negative tests satisfactorily responded to immunosuppressive therapy. The low sensitivity and high costs of Western Blot test represent difficulties to the spread use of it. The early introduction of treatment has a major importance in the diagnosis of ISHL and to increase the auditory prognosis.

Introduction

Immune-mediated sensorineural hearing loss (ISHL) is generally manifested as a rapidly progressive bilateral asymmetrical sensorineural loss (RPISHL), followed or not by inner ear symptoms, and it is up to today a challenging disease. It may initially manifest as unilateral hearing loss and only later, after various years, manifests itself in the other ear. Pathophysiology of this condition remains unknown but positive response to immnunosuppressant treatment reinforced the need to redefine and develop highly specific diagnostic tests to prevent their effects in patients that do not benefit from the treatment.
In 1958, Lehnhardt1 was the first one to consider that a RPISHL could be the result of autoimmune processes against the inner ear. Schiff and Brown2, in 1974, speculated that owing to sudden deafness after use of adrenocorticotrophic hormone, its etiology should be autoimmune vasculitis. In 1979, McCabe3 reported various cases of RPISHL successfully treated with immunosuppressant therapy and introduced the clinical entity of ISHL.

The clinical picture of ISHL is characterized as sensorineural loss, normally bilateral, progressive and associated with vestibular symptoms (vertigo and instability) and reduced vestibular response in otoneurological tests. In some cases, tinnitus and ear fullness can be present. Affection of middle and external ear is not frequent. The hearing loss is seldom presented as sudden deafness or fluctuating pattern.

The age of the affected patients is normally between the 4th and 5th decades of life, more common in women4. An important characteristic is quick progression and in some days or weeks it may cause severe bilateral sensorineural hearing loss. ENT examination normally does not present significant findings, but the anamnesis is important to provide data concerning the existence of associated systemic diseases. Pure tone audiometry does not reveal a typical curve, which may be ascending or descending, and vocal discrimination is normally not proportional to pure tone audiometry. At electronystagmography we can find reduction in caloric test.

Immune-mediated sensorineural hearing loss is associated with autoimmune systemic diseases (ASD). This association is well characterized in the following affections: systemic lupus erythematosus, polyarteritis nodosa, rheumatoid arthritis, giant cell arthritis, Wegener's granulomatosis, ulcerative colitis, Sjögren's syndrome, Behcet's syndrome, amyloidosis, sarcoidosis, Cogan's syndrome and Berger's disease. However, the incidence of inner ear impairment in ASD is very variable.

The studied patients were prospectively followed up in the Division of Otology at Escola Paulista de Medicina-UNIFESP in the period between 1999 and 2001, and we assessed clinical history and physical examination, lab tests (complete blood count, erythrocyte sedimentation rate, anti-nucleus factor, serology for Treponema pallidum and anti hsp 70-68kD antibody), audiological assessment and otoneurological test. We initially started therapy with corticoids (prednisone 1mg/kg/day) and replaced them with other immunosuppressant drugs (cyclophosphamide or methotrexate) depending on clinical and/or audiometric progression.

Response to immunosuppressant therapy was defined as a sustained response for four weeks, including: improvement in pure tone means of 15dBHL or greater, improvement in vocal discrimination in 20% or greater, or stabilization of hearing with complete improvement of vertigo.

The anti-cochlea specific antibody which is currently known can be detected using Western Blot against hsp-70 (heat shock protein) 68kD antigen. This antigen, collected from animal inner ear macerated cells (bovine or rodents), is placed in contact with the patients' serum using a Western Blot panel.

Case Report

Case Report 1

O.M., 63-year-old male Caucasian patient, born and living in Dracena/SP, pharmacist, reported history of left eye itching for 15 days after contact with cleaning products, associated with upper airway infection. Seven days before, he had experienced episode of sudden loss of balance, vertigo, nausea, vomiting, tinnitus and daily night fever. He did not report hearing loss.

Upon the ENT examination, he presented imbalance to the left with closed eyes and horizontal rotation nystagmus to the right. Initial ophthalmic examination revealed at biomicroscopy significant conjunctival hyperemia and puntate keratitis on the right eye, and ocular fundus with no signs of vasculitis (diagnostic hypothesis of superficial keratitis medicamentosa).

Initial audiometry showed bilateral and symmetrical mild to moderate hearing loss and discrimination of one-syllable words at 84% on the right and 96% on the left. The otoneurological test showed hyporeflexia on the left. Initial lab test showed increase in erythrocyte sedimentation rate (110 mm/h).

We started anti-vertigo therapy and corticoid therapy with prednisone 1mg/Kg/day . After one week, he manifested progressive hearing loss on the left, with worsening of ocular and vertigo manifestations. A new ophthalmologic test revealed at biomicroscopy superficial and deep conjunctival hyperemia with reaction of the anterior chamber and positive test for phenilephrine (hypothesis: non-granulomatous anterior sclero-uveitis). A new audiometry showed bilateral and asymmetrical sensorineural loss with mild to moderate loss on the right and severe loss on the left, with one-syllable word discrimination of 76% on the right and 20% on the left. We performed head MRI (magnetic resonance imaging) and it was compatible with small vessel vasculitis. We diagnosed him as having Cogan's syndrome and started pulse therapy with solumedrol 1g IV for 3 days and monthly pulse therapy with cyclophosphamide 1g IV with improvement of clinical, vertigo and ophthalmic manifestations.

Serology for syphilis and Lyme's disease and rheumatological tests (anti-nucleus factor) were negative. Anti-hsp 70 68kD antibody test was negative. Doppler echocardiogram showed a slight increase of the left atrium and minimal aorta and tricuspid insufficiency. We performed monthly audiometry with progressive improvement of pure tone thresholds and vocal discrimination. Audiometry after 3 months of treatment showed mild sensorineural hearing loss on the right and moderate on the left, with one-syllable word discrimination of 92% on the right and 64% on the left.

Case Report 2

FOS, 24-year-old female Caucasian patient, born and living in São Paulo, licensed practical nurse, reported tinnitus on the left for 10 years and significant hearing loss on the left for seven days. She reported arthritis at the age of 5 years, treated with benzathine penicillin and retina detachment one year before, treated with corticosteroid.

At general, ENT and visual physical examination, she did not manifest any abnormalities. Initial audiometry showed sensorineural hearing loss on the left with moderate to severe loss and the discrimination of one-syllable and two-syllable words on the left was 36%. Initial lab tests were normal (erythrocyte sedimentation rate was 20 mm/h).

We started therapy with pentoxiphyilline 40mg/day and prednisone 1mg/kg/day, and the patient reported improvement of hearing loss; audiometry ten days after onset of treatment showed improvement in pure tone thresholds, especially in high frequencies (mild to moderate hearing loss, ascending curve) and vocal discrimination of one and two-syllable words was 68%. We started to tamper the dose of PO prednisone and the patient reported increase in tinnitus, vertigo, nausea and ear fullness. A new audiometry revealed worsening of audiometry pure tone thresholds and electrocochleography (transtympanic electrode and clicks at 90dB HL) showed hydrops on the left (SP/AP ratio of 43%). Otoneurological test was normal. By increasing corticoid therapy dosage, there were clinical and audiometric improvements that were not sustained after a new attempt to tamper the therapy. Serology for syphilis, anti-nucleus factor and anti hsp 70-68kD antibodies were negative.

The patient then suffered from the side effects of the corticoid therapy (Cushing's syndrome) and we decided to interrupt the medication. She used azathioprine 100mg/day and intra-tympanic corticoid instillation (depomedrol 0.4ml) using an otological tubing, with no improvement of the clinical picture. She started treatment with methotrexate 10mg/week with significant improvement of tinnitus and total remission of vertigo. The audiometry still showed severe sensorineural hearing loss on the left and voice detection threshold at 90dB. We increased the dose of methotrexate to 20mg/week and there was a slight improvement in speech detection threshold to 70dB.

Case Report 3

VA, 38 year-old Asian male patient, born in Japan and living in São Paulo, reported history of sudden deafness on the right with associated tinnitus five years before. He did not report vertigo. The patient was hospitalized at the time and took hydrocortisone and mannitol, with no improvement. Three months before, he experienced strong tinnitus on the left and hearing loss on the same side after the tinnitus disappeared. He did not report hearing fluctuation.

When we started the follow up of the patient, there were no physical abnormalities and the audiometry showed bilateral and symmetrical moderate sensorineural hearing loss and one-syllable word discrimination of 76% on the right and 80% on the left. Electrocochleography with transtympanic electrode and clicks at 90dB showed SP/AP ratio of 33% on the right and 14% on the left, with P1 and P2 waves over the baseline (the result was abnormal bilaterally). Otoacoustic emissions were absent on both ears, compatible with bilateral cochlear damage.

Lab tests showed erythrocyte sedimentation rate of 13mm/h, serology tests for syphilis and anti-nucleus were negative. Anti hsp 70-68kD antigen test was positive.

The patient took prednisone 1mg/Kg/day for three weeks, plus diet with low sodium and fat, and used of hydrocortisone 25mg/day for three months with no hearing improvement.

Discussion

Immune-mediated hearing loss, which has been widely studied in the past two decades concerning its etiological and pathophysiological mechanisms, is still a complex disease that is difficult to diagnose and treat. The main clinical characteristics of ISHL are: rapidly progressive or sudden, asymmetrical bilateral sensorineural hearing loss, normally affecting low frequencies. In some cases, tinnitus and ear fullness can be present. The hearing loss rarely fluctuates.

Approximately 60% of the patients report vertigo5, which coincides with our study, in which 66% (N=2) of the patients presented such symptom. At electronystamograghy, we can detect reduction of caloric response. Patients who have hearing fluctuation, vertigo and tinnitus should be investigated for endolymphatic hydrops. If the patients present results compatible to endolymphatic hydrops at electrocochleography (SP/AP ratio > 0.33) and do not present response to immunosuppressant therapy, they are classified as having Meniere's disease. However, if the patients present hydrops and positive response to immunosuppressant therapy they should be classified as having immune-mediated hearing loss, manifested by endolymphatic hydrops 5. The patient reported in case 2 is classified under this category.

The incidence is greater among women, and in the age rage 30 to 50 years, which is similar in patients with systemic AID; in our study, the gender distribution was 2 male patients to one female patient. The association with systemic AID is reported in 29% of the patients with ISHL and one of our patients (33%) presented association with systemic AID (Cogan's syndrome)5. AID is characterized by the likelihood of the subject to interact against autologous antigens and they are classified into organ-specific and non organ-specific diseases. The inner ear is capable of presenting humoral immune response when facing antigenic stimuli, be them local or not, which is the case of the endolymphatic sac recognized as the most capable region to have immune processing owing to the presence of type II collagen structures. Various pathophysiological mechanisms can explain ISHL: immediate hypersensitivity (IgE against cochlear and immune-complex antigens); direct action of cytotoxic T cells; hypersensitivity mediated by antigen-antibody complex; late hypersensitivity (possible exposure to non-expressed cochlear antigen from traumatic or infectious damage, sensitizing the circulating T lymphocytes and damaging the organ); classical auto-immune mechanism (formation of auto-antibodies or cross antibodies between different organs - kidney and cochlea, mainly)6. Cogan's syndrome is a rare disease that affects predominantly young Caucasian adults with no gender predominance. The etiology can be considered as a hypersensitivity response to one or more infectious agents, associated with vasculitis. The clinical characteristics of Cogan's syndrome are: non-luetic interstitial keratitis associated with vertigo, tinnitus and sensorineural hearing loss. Evidence of systemic vasculitis can be found in 50% of the patients7; the studied case 1 presented signs of systemic vasculitis in head magnetic resonance imaging. The atypical forms of Cogan's syndrome comprise more severe inflammatory affections. The exclusion diagnosis is based on clinical suspicion since there are no specific lab tests. The investigation for antibodies against inner ear specific antigens by Western Blot method (anti hsp 70- 68kD) is negative8, and it was investigated in our first patient. MRI can show hyper-signal T1 in the inner ear structures after injection of contrast (gadolinium).

Among lab tests that can support diagnosis of ISHL, we can include Western Blot against hsp-70-68kD, erythrocyte sedimentation rate, complete blood count (CBC), anti-cytoplasm antibody (ANCA), complement, anti-nucleus factor and serology for Treponema pallidum. However, only erythrocyte sedimentation rate was useful for the screening of systemic diseases. The increased rate proved to be sensitive to detect the need for further specific tests5. Patients with negative Western Blot can, however, benefit from corticoid therapy since the test is not very sensitive because 58% of the patients that respond positive to corticoid therapy present negative result in the test9, 10, 11. Only 1 patient in this study presented positive result to Western Blot against hsp70-68kD and did not respond to immunosuppressant therapy, however the two patients with negative result responded satisfactorily to the treatment.

MRI can support diagnosis of ISHL through cochlear hyper-signal after infusion of paramagnetic contrast (gadolinium) in images obtained at T1, when in the presence of inflammatory process6. In the case of AID, MRI can evidence other systemic abnormalities of the central nervous system, such as small vessel vasculitis, present in case 1.

Immunosuppressant treatment based on prednisone 1mg/kg/day is the first line treatment for ISHL and the maximum dose duration depends on the evolution of the case, but the patient should remain under maintenance dose (10-20mg/day) for at least 3 months. If the satisfactory response is not reached or when the patient presents contraindications to corticoid therapy, the substitution for immunosuppressant drugs, such as cyclophosphamide or methotrexate is recommended. During the administration period of the drugs, we should monitor the side effects and assess the cost-benefit deriving from the treatment. Adverse effects to prednisone include: hydroelectrolytic abnormalities, osteomuscular, gastrointestinal (peptic ulcer, pancreatitis), and dermatological abnormalities, neurological, psychiatric and hormonal affections (Cushing's state, diabetes mellitus and supra-renal failure), among others. Cyclophosphamide has as the main side effects, myelosuppression, reproductive abnormalities, nausea and vomiting, phlebitis and thrombosis. Methotrexate has as the main toxic effect myelosuppression and gastrointestinal abnormalities and its prolonged use can cause chronic hepatic toxicity12.

Positive response to immunosuppressant therapy was defined as the sustained response for four weeks to it, including improvement in pure tone means of 15dB HL or greater, improvement in vocal discrimination index of 20% of greater, or stabilization of hearing and complete remission of vertigo. In our study, no patient had the appropriate sustained response to corticoid therapy but two of them improved after introduction of other immunosuppressant therapies. The patient reported in case 1, after use of cyclophosphamide, presented total remission of vertigo and 220% improvement on the left (from 20 to 64%) and 21% on the right (76% to 92%) for vocal discrimination. The patient reported in case 2 presented total remission of vertigo and stabilization of the hearing picture after beginning of treatment with methotrexate.

closing remarks

Immune-mediated sensorineural hearing loss, widely studied for the past 20 years, is still a complex disease concerning diagnosis and treatment. The diagnosis is mainly clinical and based on positive response to therapeutic tests with immunosuppressant drugs. Currently the investigation with Western Blot for anti-hsp 70-68kD antibody is the only specific lab test for diagnosis of ISHL. However, the low sensitivity of the test and its high cost hinder its routine use in practice. The early introduction to treatment is fundamental to support the diagnosis and provide better hearing prognosis.

REFERENCES

1. Lehnhardt E. Plötzliche Hörstörungen auf beiden Seiten gleichzeitig oder nacheinander aufgetreten. Z Laryngol Rhinol Otol 1958;37:1-17.
2. Schiff M and Brown M. Hormones and sudden deafness. Laryngoscope 1974;84:1959-1981.
3. McCabe BF. Autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1979;88:585-589.
4. Hughes GB et al. Practical versus theoretical management of autoimmune inner ear disease. Laryngoscope 1984;94:758-767.
5. Hirose K, Wener MH, Duckert LG. Utility of laboratory testing in autoimmune inner ear disease. Laryngoscope 1999;109:1749-1754.
6. Cruz OLM, Alvarenga EL, Costa SS. In: Cruz OLM, Costa SS. Otologia clínica e cirúrgica.1ª ed. Rio de Janeiro: Revinter; 2000. p.307-313.
7. Chynn EW, Jakobiec FA. Cogan's syndrome: ophthalmic, audiovestibular, and systemic manifestation and systemic therapy. Int Ophthalmol Clin 1996;36(1):61-72.
8. Davis LE. In Cummings CW et al. Otolaryngology Head and Neck Surgery. 3rd ed. Mosby Inc.; 1999.
9. Billings PB, Keithley EM, Harris JP. Evidence linking the 68 kilo Dalton antigen identified in progressive sensorineural hearing loss patient sera with heat shock protein 70. Ann Otol Rhinol Laryngol 1995;104:181-188.
10. Gottshlich S, et al. Assessment of serum antibodies in patients with rapidly progressive sensorineural hearing loss and Ménière's disease. Laryngoscope 1995;105:1347-1352.
11. Veldman JE. Immune-mediated sensorineural hearing loss with or without endolymphatic hydrops: a clinical and experimental approach. Ann N Y Acad Sci 1997;830:179-186.
12. Machado RCL, Piva DRS, Koike CT. In: Fonseca SM et al. Manual de quimioterapia antineoplásica. 1ª ed. Rio de Janeiro: Reichmann & Affonso Editores; 2000. p. 93-134.

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1 Ph.D. in Medicine, UNIFESP-EPM.
2 Physician, Master studies in Otorhinolaryngology under course, UNIFESP-EPM.
3 4 Physician, Master studies in Otorhinolaryngology under course, UNIFESP-EPM.
5 Physician, Master studies in Otorhinolaryngology under course, UNIFESP-EPM.
6 Physician, Master studies in Otorhinolaryngology under course, UNIFESP-EPM.

Study presented as poster at II Congresso Triológico de Otorrinolaringologia, held on August 22 - 26, 2001 in Goiânia, GO.

Affiliation: Federal University of São Paulo Paulo - Escola Paulista de Medicina.
Department of Otorhinolaryngology and Human Communication Disorders.

Address correspondence to: Fernando Danelon Leonhardt - R. Bandeira Paulista, 142 - apto. 22
04532-000 - São Paulo - SP - Tel. (55 11) 3168-0103 - E-mail: fernandodanelon@uol.com.br

Article submitted on September 6, 2001. Article accepted on April 25, 2002

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