A Retrospective Study of Clinical Profile of Patients with Autoimmune Inner Ear Disease

Abstract

Bilateral sensorineural hearing loss can be a very distressing symptom and can affect the efficiency of a person and one’s quality of life. Conditions causing bilateral hearing loss are very few and autoimmune aetiology is one of them. Autoimmune ear disease is characterised by bilateral, mostly fluctuating audiovestibular symptoms and symptoms which respond to steroids. Diagnosis of AIED presents a unique challenge to clinicians due to the lack of standardized diagnostic criteria or reliable pathognomonic tests. The purpose of the study is to evaluate the patients who fit into criteria of autoimmune inner ear disease and understand the clinical features and response to medications for the same. A retrospective chart review of patients presenting with rapidly progressive bilateral hearing loss was done. The clinical presentation including detailed history and examination findings along with the blood investigation reports and audiograms were recorded in a tabular form. The study included 6 patients – 3 male and 3 female patients. Age of the patients at onset of hearing loss varied between 24–35 years. 3 of 6 patients presented with primary autoimmune ear disease and other 3 had hearing loss secondary to systemic autoimmune disease. All patients were treated with systemic steroids, but however showed a varied response. Patients with primary AIED were administered inner ear steroid therapy as well. AIED is thus a diagnosis of exclusion done with high index of suspicion. Patients with bilateral progressive sensorineural hearing loss should be evaluated for autoimmune etiology. Oral steroids with intratympanic steroids are currently the mainstay of treatment for AIED. Guarded prognosis of hearing improvement is noted in these patients. Hence, emphasis should be placed on early hearing rehabilitation for better quality of life.

Introduction

Sensorineural hearing loss (SNHL) is caused by various disorders including sudden sensorineural hearing loss, presbycusis, hereditary hearing loss, drug-induced hearing loss, and Meniere’s disease [1]. Bilateral sensorineural hearing loss can be a very distressing symptom and can affect the efficiency of a person and one’s quality of life. Conditions causing bilateral hearing loss are very few and autoimmune aetiology is one of them.

Autoimmune diseases are a group of clinical disorders caused by the activation of cellular or humoral immunity or both without the presence of any infection or any other causative agent [2]. Inner ear involvement can present in systemic autoimmune disorders as audiovestibular symptoms, of which hearing loss is the most common and have to differentiated from primary autoimmune ear disorder, condition where immune system attacks the inner ear primarily. Autoimmune inner ear disease encompasses a group of disorders characterised by an autoimmune process which affects the inner ear. It is characterised by bilateral, mostly fluctuating audiovestibular symptoms that respond to steroids [3].

In this study, we report cases of rapidly progressive bilateral SNHL and further analyse the clinical presentation of immune diseases of the ear, along with review of literature. Despite recent advances in detecting immune-mediated inner ear disease, the number of patients who fit the criteria for such a diagnosis remains relatively small, even at large referral centres. The clinical manifestations of immune-mediated inner ear disease only recently have been well described. There exists a need to further investigate the clinical profiles, demographic features, and treatment response of such a population of patients [4]. The purpose of this retrospective study is therefore to review the clinical and laboratory manifestations of a group of patients with a diagnosis of immune-mediated audio - vestibular inner ear disease.

Materials and Methods

A retrospective chart review of patients presenting with rapidly progressive bilateral hearing loss was done. We had 6 patients – 3 male and 3 female patients. The clinical presentation including detailed history and examination findings along with the blood investigation reports and audiograms were taken from the case records. Findings were recorded in a tabular form (Table 1).

Table 1.

Clinical Characteristics of the patients

Case no	Age at onset	Sex	Presenting complaints	Onset and Progression of hearing loss	Ear findings	Other Clinical features	Surgical Procedures done	Investigations
								Histopathology	Relevant Blood investigations
1	24	F	Bilateral Hearing loss, ear discharge, bilateral facial weakness	Sudden progressive	Granulations in middle ear	Developed stridor on post operative day 6, X ray -Subglottic narrowing	Right mastoid exploration	Granulomatous response with areas showing ill-defined granulomata	C ANCA - positive PR3 ANCA – 117.80
2	24	F	Bilateral eyes congestion, sudden onset hearing loss bilateral ear, vertigo, multiple joint pain	Rapidly progressive	Normal	Redness over pinna	Nil	Nil	ESR - 130
3	34	M	Left ear hearing loss, tinnitus and vertigo with tinnitus and followed by right ear hearing loss, tinnitus	Fluctuating progressive	Normal	Left side audiovestibular symptoms progressed later to right side hearing loss	Nil	Nil	All immunological tests were negative
4	34	F	Bilateral ear hearing loss, facial palsy, giddiness, dysphagia	Rapidly Progressive	Granulations in middle ear and mastoid	Grade 4 facial palsy bilaterally	Bilateral mastoidectomy	Inflammation with granulation tissue	Blood reports including ESR normal
5	35	F	Hearing loss, tinnitus in left ear followed by hearing loss, tinnitus in right ear	Sudden	Normal	Nil	Nil	Nil	All immunological tests were negative
6	24	M	Hearing loss, tinnitus bilateral ear	Sudden	Normal	Nil	Nil	Nil	All immunological tests were negative

Clinical evaluation included a thorough history regarding.

• i.length of time over which the hearing loss has developed.
• ii.associated aural symptoms (tinnitus, vertigo, pain, discharge and pressure).
• iii.predisposing factors for hearing loss (i.e., noise exposure, chemotherapy, antibiotic treatment, previous ear surgery, trauma, meningitis or family history of hearing loss).
• iv.Features of systemic autoimmune disease (joint involvement, skin involvement, eye symptoms, dysphagia and gland involvement).

Examination of the ear and vestibular system was done. Audiometric evaluation including pure-tone audiometry and speech audiometry was done.

The following blood investigations was done.

• Complete blood count with differential counts

• Erythrocyte sedimentation rate (ESR)

• Blood tests for autoimmune disorders

  • ANA
  • Immunological Profile

• Anti-HSP 70 antibody

The various treatment strategies were recorded. 4 patients are on regular follow up. One patient was followed up on telephonic conversation. One patient was lost to follow up.

The current study was approved by the Institutional Ethical Committee.

Results

The study included 6 patients – 3 male and 3 female patients. Age of the patients at onset of hearing loss varied between 24 and 35 years. Few observations in clinical features are as given below.

In the present study, 3 patients had audiological symptoms only and 3 had audiovestibular symptoms. 2 patients had facial paralysis in addition to inner ear features. 2 patients underwent mastoid exploration that revealed granulations in the middle ear and biopsy of which showed granulomatous response in one and inflammation with granulation tissue in the other. 2 patients had systemic features – one had subglottic narrowing (diagnosed with Wegener’s granulomatosis) and the other had redness of pinna suggestive of relapsing polychondritis.

In our series, audiological profile of the patients revealed one of 6 had progressive bilateral hearing loss with no underlying cause, and 2 of 6 had sudden onset, rapidly progressive bilateral sensorineural hearing loss suggestive of primary autoimmune inner ear disease. 3 of 6 patients presented with hearing loss secondary to systemic autoimmune disease. The associated systemic autoimmune conditions included Wegener’s granulomatosis, relapsing polychondritis, IgG4 disease.

In the present series, all patients were treated with systemic steroids, but however showed a varied response. Patients with primary AIED were administered inner ear steroid therapy as well. One of the patient with primary AIED initially presented with audiovestibular symptoms typical of Meniere’s disease on the left side and hence treated with antivertigo medications and intratympanic therapy in the left ear. He later developed auditory symptoms in the right ear and he showed some improvement to oral steroids. The remaining two patients with primary AIED showed improvement in hearing loss with serviceable hearing. One of them was rehabilitated with hearing aid and was able to get back to her workplace. Among the patients with secondary AIED, 2 showed dramatic response to oral steroids – facial paralysis improved in both patients. However the hearing remained the same. The other patient was lost to follow up (Table 2).

Table 2.

Details of treatment and response

CASE NO	AGE AT ONSET	SYSTEMIC DISORDER	TREATMENT	RESPONSE
1	24	Wegener’s granulomatosis	Oral steroid, Cyclophosphamide	Facial paralysis and breathing difficulty responded to steroids
2	24	Relapsing polychondritis	Oral steroid	Minimal response to steroids – lost to follow up
3	34	Nil	Oral steroid, IT steroid left ear	Vestibular symptoms responded well, progression of auditory symptoms
4	34	IgG4 disease	Bilateral mastoidectomy and biopsy, Oral steroid	Good response to oral steroids – facial palsy improved. SNHL same
5	35	Nil	Oral steroid, IT steroid	1. Response to oral and IT steroids 2.Hearing rehabilitation with aid
6	24	Nil	IT steroid	Response to IT steroids

Discussion

Autoimmune inner ear disease (AIED) is an uncommon inner ear disorder characterized by progressive and often fluctuating sensorineural hearing loss (SNHL) [5].

AIED is defined as primary when the pathology is restricted to the inner ear. In one-third of cases, AIED occurs in association with a systemic autoimmune disease and is defined as secondary AIED [6].

In 1958, it was Lehnhardt who first postulated that an autoimmune disorder may cause bilateral hearing loss. In 1979, McCabe further renewed the interest in this disorder by presenting a series of patients with steroid-responsive sensorineural hearing loss (SNHL), thereby suggesting an autoimmune pathogenesis [7].

Few suggestions put forward are :

• Endolymphatic sac may be the site of immunological processing as suggested by Rask-Anderson and Stahle. The pathway of entry into the inner ear is suspected to be via the spiral modiolar vein with entry of inflammatory cells into the scala tympani. The cells then proliferate and release inflammatory mediators that initiate a cascade of events leading to hearing loss.

• Some studies that suggest that autoantibodies are produced against inner ear protein through molecular mimicry in response to viral or bacterial infection [8].

Most studies adhere to the diagnostic criteria defined by the following:

1. progressive, bilateral SNHL of at least 30 dB at one or more frequencies.

2. SNHL determined to be idiopathic based on clinical evaluation, blood tests and MRI imaging [5].

AIED has been classified into five types by Harris et al. [7] (Table 3). In our study, we had 3 patients with type 5 organ specific AIED, 2 patients with type 2 AIED with systemic autoimmune disease and one patient with immune mediated Meniere’s disease.

Table 3.

Harris AIED classification

Type	Features
1:Organ-specific (ear)	Rapidly progressive bilateral SNHL All ages, although middle age most common No other clinical evidence of autoimmune disease Negative serology as evaluated by antinuclear antibody, erythrocyte sedimentation rate, rheumatoid factor, and C1q binding assay >50% of patients respond to high-dose corticosteroids
2: Rapidly progressive bilateral SNHL with systemic autoimmune disease	Rapidly progressive bilateral SNHL Other autoimmune condition present, such as systemic lupus erythematosus, ulcerative colitis, polyarteritis nodosa, vasculitis, rheumatoid arthritis, and Sjögren’s disease Hearing loss often worse with flare-up of autoimmune condition Serologic studies positive in accordance with systemic autoimmune disease Steroid responsive, might be managed with targeted therapies for underlying illness
3: Immune-mediated Meniere’s disease	Bilateral fluctuating SNHL with predominant episodic vestibular symptoms Subset of patients with contralateral delayed endolymphatic hydrops or recent instability of better hearing ear in a patient with burned out Meniere’s disease Steroid responsive, might require long-term immunosuppression due to relapses
4: Rapidly progressive bilateral SNHL with associated inflammatory disease, such as chronic otitis media, Lyme disease, and otosyphilis	Evidence of profound drop in hearing with longstanding chronic otitis media Might show inflammation and perforations of tympanic membrane Hearing loss progresses despite treatment of the infectious agent Serological tests might be positive for underlying disease, patients should be evaluated for granulomatous disease and vasculitis by biopsy of tissue available Steroid responsive, might require long-term immunosuppression
5: Immune-mediated SNHL with other discrete organ system disease, such as Cogan’s syndrome, Wegener’s granulomatosis, and relapsing polychondritis	Serologic tests may be positive in accordance with associated disease Initially responsive to high-dose steroid, but tends to become resistant over time and with each relapse
6: Nonimmune rapidly progressive SNHL (ototoxic or paraneoplastic syndrome)	Young to elderly patients with idiopathic rapidly progressive SNHL leading to deafness Severe ear pain, pressure, tinnitus, and some imbalance Negative serology Inciting event common; drug-related (e.g., oxycodone), paraneoplastic syndrome No response to corticosteroids or antiviral treatment

Patients should be screened for predisposing factors of SNHL as up to 30% of patients with AIED have a coexisting systemic autoimmune disease [5]. In the present study, 3 out of 6 patients (that is 50%) had systemic autoimmune disease.

Yoo and Yazawa identified lists of ear diseases with probable immunological features and autoimmune diseases affecting hearing [9] (Tables 4 and 5).

Table 4.

Ear diseases with immunological features

Region of ear	Disease
External ear	Auricular chondritis, Relapsing polychondritis
Tympanic membrane	Tympanosclerosis
Eustachian tube	Autoimmune salpingitis
Middle ear	Otosclerosis; Secretory otitis media; Necrotizing otitis media; Cholesteatoma
Inner ear	Autoimmune sensorineural hearing loss; Meniere’s disease; Otosclerosis; Cochlear vasculitis; Sudden hearing loss
Retrocochlear	Autoimmune central nervous system disease

Table 5.

Autoimmune diseases affecting hearing

Relapsing polychondritis Systemic lupus erythematosus Disseminated vasculitis Rheumatoid arthritis Sjögren’s syndrome Systemic sclerosis

Myasthenia gravis Hashimoto’s thyroiditis Goodpasture’s syndrome Vogt-Koyanagi-Harada syndrome Cogan’s syndrome Behçet’s disease Sarcoidosis Wegener’s granulomatosis

Clinical history and examination pertaining to the audiovestibular systems and systemic involvement should be carried out. Audiometric evaluation is a crucial part of both the initial diagnostic evaluation and all subsequent follow-ups of patients with hearing loss i.e.pure-tone audiometry and word discrimination [6]. A pure tone threshold shift of at least 15 dB at 1 test frequency or 10 dB at 2 or more consecutive test frequencies, or a greater than 12% drop in word recognition within a 3-month period could point to a diagnosis of AIED [10]. In the present study, all patients had sensorineural hearing loss.

In addition to causing SNHL, autoimmune diseases can lead to conductive hearing impairment. Conditions include :

• Granulomatosis with polyangiitis - secondary to effusions from granulomatous involvement of the middle ear and eustachian tube mucosa

• Relapsing polychondritis – due to eustachian tube dysfunction

• Rheumatoid arthritis - ossicular chain can be affected [6]

The blood investigations recommended in a patient with suspected AIED would include Complete blood count, ESR, Anti-HSP 70 antibody, [5] blood tests for autoimmune disorders [11].

However, García-Berrocal et al. does not recommend an exhaustive immunologic work up if financial resources are limited. Instead ANA and immunophenotype of peripheral blood lymphocytes (PBL) can be done as these have demonstrated similar efficiency [12].

Imaging is essential for middle ear disease and to rule out retrocochlear pathology. In our study, none of the patients had any retrocochlear pathology [5].

The current standard AIED treatment is an initial course of high-dose prednisone (60 mg/day), generally for 4 weeks. Responding patients are slowly tapered to the lowest dose that maintains hearing [13].

Intratympanic (IT) steroid injections have been used to treat AIED in patients who do not respond to oral steroids or cannot tolerate long-term treatment. Matsuoka et al. reported a 50% response rate among patients treated with IT steroids [7]. Garcia Berrocal used IT methylprednisolone to treat 11 patients who responded poorly to oral steroids, three of which also did not improve with methotrexate. Six patients (68.75%) showed an improvement in hearing with weekly IT steroids and all patients affected by vestibular symptoms improved [5, 12]. In our study, 2 patients with primary AIED showed mild improvement in hearing to oral steroid following which one of them was rehabilitated with hearing aid. Non – auditory symptoms of pain, vertigo and facial paralysis showed good response to oral steroids.

Methotrexate is used as an alternative treatment for refractory AIED which works by inhibiting the enzyme dihydrofolate reductase, preventing the synthesis of nucleotides necessary for DNA and RNA formation. Methotrexate has better long-term tolerability than cyclophosphamide. The side effects include nausea, vomiting, mucosal ulcers and hepatotoxicity, which can be prevented with folic acid supplementation. Treatment outcomes have varied with hearing improvement ranging from 0 to 70%. Methotrexate appears to be more efficacious in treating vestibular symptoms with reported subjective improvements in 80–100% of patients [5].

Another development in the last decade has been the introduction of biologic agents for the treatment of autoimmune disease. These are engineered antibodies that target specific molecules of the immune system.

There are generally three types that are being investigated in AIED:

• target TNFα (e.g., infliximab [Remicade], adalimumab [Humira], golimubab [Simponi], and etanercept [Enbrel])

• targets B-cells (e.g., rituximab [Rituxan])

• target IL-1beta (e.g., anakinra [Kineret])

Side effects include upper respiratory tract infections, neutropenia, and infusion site reactions due to immunosuppression [8]. Cochlear implantation is an important option in those patients who are unable to tolerate the side effects of immunomodulating drugs and go on to develop bilateral deafness. In the series reported by Sakano and Harris, all ears were implanted and the outcomes on word and sentence scores were not significantly different between AIED and postlingually deaf patients [8].

Conclusion

AIED is a diagnosis of exclusion done with high index of suspicion. Patients with bilateral progressive sensorineural hearing loss should be evaluated with blood tests for evidence of autoimmune etiology. Screening with ESR and ANA is done and if positive, is an indication to evaluate with immune panel and an immunologist consultation. Evidence of disease in middle ear or mastoid on imaging should be considered for biopsy and histopathology. Oral steroids with intratympanic steroids are currently the mainstay of treatment for AIED. Guarded prognosis of hearing improvement is noted in these patients. Hence, emphasis should be placed on early hearing rehabilitation for better quality of life.

Funding

None.

Declarations

Conflict of Interest

None.