A mouse model of autoimmune inner ear disease without endolymphatic hydrops.

Autoimmune inner ear disease (AIED) is an organ-specific disease characterized by irreversible, prolonged, and progressive hearing and equilibrium dysfunctions. The primary symptoms of AIED include asymmetric sensorineural hearing loss accompanied by vertigo, aural fullness, and tinnitus. AIED is divided into primary and secondary types. Research has been conducted using animal models of rheumatoid arthritis (RA), a cause of secondary AIED. However, current models are insufficient to accurately analyze vestibular function, and the mechanism underlying the onset of AIED has not yet been fully elucidated. Elucidation of the mechanism of AIED onset is urgently needed to develop effective treatments. In the present study, we analyzed the pathogenesis of vertigo in autoimmune diseases using a mouse model of type II collagen-induced RA. Auditory brain stem response analysis demonstrated that the RA mouse models exhibited hearing loss, which is the primary symptom of AIED. In addition, our vestibulo-oculomotor reflex analysis, which is an excellent vestibular function test, accurately captured vertigo symptoms in the RA mouse models. Moreover, our results revealed that the cause of hearing loss and vestibular dysfunction was not endolymphatic hydrops, but rather structural destruction of the organ of Corti and the lateral semicircular canal ampulla due to an autoimmune reaction against type II collagen. Overall, we were able to establish a mouse model of AIED without endolymphatic hydrops. Our findings will help elucidate the mechanisms of hearing loss and vertigo associated with AIED and facilitate the development of new therapeutic methods.

Immune-Mediated Inner Ear Disease: Diagnostic and therapeutic approaches.

INTRODUCTION: Immune Mediated Inner Ear Disease (IMIED) is a rare form of sensorineural bilateral hearing loss, usually progressing in weeks to months and responsive to immunosuppressive treatment. Despite recent advances, there is no consensus on diagnosis and optimal treatment. METHODS: A review of articles on IMIED from the last 10 years was conducted using PubMed® database. RESULTS: IMIED is a rare disease, mostly affecting middle aged women. It may be a primary ear disease or secondary to autoimmune systemic disease. A dual immune response (both cellular and humoral) seems to be involved. Cochlin may be the inner ear protein targeted in this disease. Distinction from other (core common) forms of neurosensory hearing loss is a challenge. Physical examination is mandatory for exclusion of other causes of hearing loss; audiometry identifies characteristic hearing curves. Laboratory and imaging studies are controversial since no diagnostic marker is available. CONCLUSION: Despite recent research, IMIED diagnosis remains exclusive. Steroids are the mainstay treatment; other therapies need further investigation. For refractory cases, cochlear implantation is an option and with good relative outcome.

Update on Vertigo in Autoimmune Disorders, from Diagnosis to Treatment.

The prevalence of autoimmune diseases has been increasing over the last 20 years. The clinical presentation of this large and heterogeneous group of disorders depends on whether the involvement is organ-specific or non-organ-specific. Dizziness, vertigo, and disequilibrium are common symptoms reported by patients with vestibulocochlear involvement. The association of vertigo and autoimmune diseases has been largely documented, suggesting that autoimmune disorders could be overrepresented in patients with vertigo in comparison to the general population. The aim of this review is to present the recent literature findings in the field of autoimmune-mediated diseases with cochleovestibular involvement, focusing on the clinical presentation, diagnosis, and treatment of immune-mediated inner ear diseases including autoimmune inner ear disease (AIED), Meniere's disease, and bilateral vestibulopathy, as well as of systemic autoimmune diseases with audiovestibular disorders, namely, Behçet's disease, Cogan's syndrome, sarcoidosis, autoimmune thyroid disease, Vogt-Koyanagi-Harada syndrome, relapsing polychondritis, systemic lupus erythematosus, antiphospholipid syndrome, IgG4-related disease, and ANCA-associated vasculitides.

¿Puede la tomografía por emisión de positrones ayudar en la caracterización de la enfermedad inmunomediada del oído interno? / Can positron emission tomography support the characterization of immune-mediated inner ear disease?

Introducción: Evaluar la utilidad de la PET/TC con 18F-FDG en la caracterización de la enfermedad inmunomediada del oído interno primaria (EIOI) aportando datos que ayuden a valorar la actividad inflamatoria y la existencia o ausencia de enfermedad sistémica asociada. Material y métodos: Estudio prospectivo sobre 28 pacientes con sospecha de EIOI o EIOI primaria diagnosticada y 4 controles ajustados por edad y sexo, sin enfermedad ótica conocida, a los cuales se había realizado una PET con 18F-FDG por otro motivo. Dieciocho pacientes presentaban EIOI primaria y 10EIOI secundaria. A todos se les realizó una PET/TC con 18F-FDG para valorar la actividad metabólica en el oído interno y la presencia de afectación sistémica. La interpretación del resultado de la PET fue realizada por 2médicos nucleares sin conocimiento de la clínica del paciente. Para valorar la reproductibilidad de las medidas se realizaron análisis Bland y Altman y correlación de coeficientes intraclase. Resultados: Se encontraron hallazgos sospechosos de afectación sistémica en 13 pacientes. Cuatro de ellos correspondieron a pacientes diagnosticados previamente de EIOI primaria que mostraron actividad inflamatoria (tiroidea y aórtica). En cuanto al análisis semicuantitativo de la actividad metabólica en el oído interno, la variabilidad interobservador fue muy alta y no fue posible establecer diferencias adecuadas entre grupos. Conclusiones: Este estudio demuestra que la PET/TC con 18F-FDG puede tener un papel en la evaluación de pacientes con sospecha de EIOI primaria descartando la presencia de datos que sugieran inflamación sistémica. Consideramos que no es adecuado tratar de cuantificar la actividad metabólica del oído interno probablemente por el pequeño tamaño del mismo

Introduction: To evaluate the utility of 18F-FDG PET/TC as an imaging tool for the characterization of immune-mediated inner ear disease (IMIED), providing measurements of the inner ear region activity as well as detecting possible involvement of other organs. Material and methods: The study included 28 patients with IMIED and 4 sex-matched and age-matched control subjects with no history of ear disease. Eighteen patients were considered to be suffering from primary IMIED and 10 patients from secondary. PET/CT scans with 18F-FDG were performed to assess systemic involvement as well as inner ear region activity. Interpretation of PET/CT scans was performed independently by 2nuclear medicine physicians blinded to clinical history. In order to assess inter-rater agreement before performing the analysis of the inner ear, different Bland & Altman plots and the intraclass correlation coefficients were estimated. Results: Different metabolically active foci findings were reported in 13 patients. Four patients diagnosed as primary IMIED showed thyroid and aorta activity. Regarding the inner-ear semiquantitative analysis, the inter-rater agreement was not sufficiently high. Comparisons between groups, performed using Mann-Whitney test or Kruskal-Wallis tests, showed no differences. Conclusions: The study showed 18F-FDG PET/TC could be an important tool in the evaluation of IMIED as it can support the characterization of this entity providing the diagnosis of unknown or underestimated secondary IMIED. Nevertheless, we consider PET is not an adequate tool to approach the inner ear because of the small size and volume of the cochlea which makes the assessment very difficult

Can positron emission tomography support the characterization of immune-mediated inner ear disease? / ¿Puede la tomografía por emisión de positrones ayudar en la caracterización de la enfermedad inmunomediada del oído interno?

INTRODUCTION: To evaluate the utility of 18F-FDG PET/TC as an imaging tool for the characterization of immune-mediated inner ear disease (IMIED), providing measurements of the inner ear region activity as well as detecting possible involvement of other organs. MATERIAL AND METHODS: The study included 28 patients with IMIED and 4 sex-matched and age-matched control subjects with no history of ear disease. Eighteen patients were considered to be suffering from primary IMIED and 10 patients from secondary. PET/CT scans with 18F-FDG were performed to assess systemic involvement as well as inner ear region activity. Interpretation of PET/CT scans was performed independently by 2nuclear medicine physicians blinded to clinical history. In order to assess inter-rater agreement before performing the analysis of the inner ear, different Bland & Altman plots and the intraclass correlation coefficients were estimated. RESULTS: Different metabolically active foci findings were reported in 13 patients. Four patients diagnosed as primary IMIED showed thyroid and aorta activity. Regarding the inner-ear semiquantitative analysis, the inter-rater agreement was not sufficiently high. Comparisons between groups, performed using Mann-Whitney test or Kruskal-Wallis tests, showed no differences. CONCLUSIONS: The study showed 18F-FDG PET/TC could be an important tool in the evaluation of IMIED as it can support the characterization of this entity providing the diagnosis of unknown or underestimated secondary IMIED. Nevertheless, we consider PET is not an adequate tool to approach the inner ear because of the small size and volume of the cochlea which makes the assessment very difficult.

N-Acetylcysteine attenuates tumor necrosis factor alpha levels in autoimmune inner ear disease patients.

Autoimmune inner ear disease (AIED) is a poorly understood disease marked by bilateral, rapidly progressive hearing loss triggered by unknown stimuli, which is corticosteroid responsive in 60 % of patients. Although the mechanism of the disease is not precisely understood, a complex interaction of cytokines is believed to contribute toward the inflammatory disease process and hearing loss. Previously, we showed the role of TNF-α in steroid-sensitive and IL-1ß in steroid-resistant immune-mediated hearing loss. N-Acetylcysteine (NAC), a broad spectrum antioxidant, has been effective in other autoimmune disorders. Other studies have shown NAC to have a protective adjunct role in human idiopathic sudden hearing loss, where the addition of NAC resulted in better hearing recovery than with steroids alone, although the mechanism of this protection was not elucidated. In the present study, we observed PBMCs from AIED patients exhibited higher baseline TNF-α and MPO levels compared with normal healthy controls. NAC effectively abrogates LPS-mediated TNF-α release from PBMC of both AIED patients and controls. We demonstrated that in AIED patients, the TNF-α downstream signaling pathway appears aberrantly regulated, influencing both MPO and IL-8 expression. Given that NAC effectively abrogated LPS-mediated TNF-α release and exerted minimal effects on the downstream targets of this pathway, we feel NAC may be a rational adjunct therapy for this enigmatic disease, worthy of clinical exploration.

Current understanding of the pathogenesis of autoimmune inner ear disease: a review.

BACKGROUND: Autoimmune inner ear disease (AIED) is a poorly understood form of sensorineural hearing loss that causes bilateral, asymmetric, progressive hearing loss, sometimes with vestibular symptoms, often associated with a systemic autoimmune disease, which is noteworthy as the only sensorineural loss responsive to medical therapy. Despite much research interest of the past 25 years, its aetiopathogenesis is still unproven. OBJECTIVE OF REVIEW: To succinctly consolidate research and opinion regarding the pathogenesis of autoimmune inner ear disease, in ongoing efforts to elucidate the molecular and intracellular pathways that lead to inner ear damage, which may identify new targets for pharmacotherapy. TYPE OF REVIEW: Systematic review SEARCH STRATEGY: PubMed/MEDLINE search using key terms to identify articles published between January 1980 and Apr 2014. Additionally, any landmark works discussed in this body of literature were obtained and relevant information extracted as necessary. EVALUATION METHOD: Inclusion criterion was any information from animal or human studies with information relevant to possible aetiopathogenesis of AIED. Studies that focused on diagnosis, ameliorating symptoms or treatment, without specific information relevant to mechanisms of immune-mediated injury were excluded from this work. Articles meeting the inclusion criteria were digested and summarised. RESULTS: A proposed pathogenic mechanism of AIED involves inflammation and immune-mediated attack of specific inner ear structures, leading to an excessive Th1 immune response with vascular changes and tissue damage in the cochlea. Studies have identified self-reactive T cells and immunoglobulins, and have variously implicated immune-complex deposition, microthrombosis and electrochemical disturbances causing impaired neurosignalling in the pathogenesis of AIED. Research has also demonstrated abnormalities in the cytokine milieu in subjects with AIED, which may prove a target for therapy in the future. CONCLUSION: Ongoing research is needed to further elucidate the aetiopathogenesis of AIED and discern between various mechanisms of tissue injury. Large-cohort clinical studies employing IL-1 receptor blockade are warranted to determine its potential for future therapy.

COGAN'S SYNDROME.

OBJECTIVES: The objective of our study was to review the current knowledge on Cogan's syndrome, including etiology, diagnosis and treatment. Systematic review methodology: Relevant publications on Cogan's syndrome from 1945 to 2014 were studied. CONCLUSIONS: Cogan's syndrome is a rare autoimmune vasculitis, with unknown pathogenesis. Infection was thought to have played a role in the pathogenesis of the disease, but now the autoimmunity hypothesis is considered more likely to be true. Cogan's syndrome is characterized by ocular and audiovestibular symptoms similar to those of Meniere's syndrome. Approximately 70% of the patients have systemic disease, of which vasculitis is considered the pathological mechanism. Corticosteroids are the first line of treatment; multiple immunosuppressive drugs were also used with varying degrees of success. The novelty in the treatment of the disease is tumor necrosis factor (TNF)-alpha-blockers, but more studies are necessary to establish their efficacy.

Endolymphatic sac involvement in bacterial meningitis.

The commonest sequelae of bacterial meningitis are related to the inner ear. Little is known about the inner ear immune defense. Evidence suggests that the endolymphatic sac provides some protection against infection. A potential involvement of the endolymphatic sac in bacterial meningitis is largely unaccounted for, and thus the object of the present study. A well-established adult rat model of Streptococcus pneumoniae meningitis was employed. Thirty adult rats were inoculated intrathecally with Streptococcus pneumoniae and received no additional treatment. Six rats were sham-inoculated. The rats were killed when reaching terminal illness or on day 7, followed by light microscopy preparation and PAS-Alcian blue staining. The endolymphatic sac was examined for bacterial invasion and leukocyte infiltration. Neither bacteria nor leukocytes infiltrated the endolymphatic sac during the first days. Bacteria invaded the inner ear through the cochlear aquaduct. On days 5-6, the bacteria invaded the endolymphatic sac through the endolymphatic duct subsequent to invasion of the vestibular endolymphatic compartment. No evidence of direct bacterial invasion of the sac through the meninges was found. Leukocyte infiltration of the sac occurred prior to bacterial invasion. During meningitis, bacteria do not invade the endolymphatic sac through the dura, but solely through the endolymphatic duct, following the invasion of the vestibular system. Leukocyte infiltration of the sac occurs prior to, as well as concurrent with bacterial invasion. The findings support the endolymphatic sac as part of an innate immune defense system protecting the inner ear from infection.

Cochlin in autoimmune inner ear disease: is the search for an inner ear autoantigen over?

DEFINITION: Autoimmune inner ear disease (AIED) is characterised by a rapidly progressive, often fluctuating, bilateral sensorineural hearing loss over a period of weeks to months. It is an uncommon disease accounting for less than 1% of all cases of hearing impairment or dizziness. The diagnosis is often missed and this impacts on the prognosis as the condition responds well to steroids and immunosuppressants if recognised early. LACUNA IN KNOWLEDGE: No useful specific test for autoimmunity affecting the inner ear exists. OBJECTIVE OF STUDY: To gather evidence regarding cochlin in AIED. METHODOLOGY: Systematic review of human studies and animal experimental studies on inner ear antigens was undertaken. SEARCH STRATEGY: We searched MEDLINE (1965-2012), and Pubmed for relevant studies. A combination of key words for inner ear, autoimmunity (autoimmune, immune mediated) and cochlin were used. RESULTS: A number of antigens have been implicated in autoimmune inner ear disease. Cochlin is a major component of the extracellular matrix in the inner ear and a promising candidate. We present evidence in literature on the role of this protein in the pathogenesis of autoimmune inner ear disease.

Mining immune epitopes in the inner ear.

Etiologies for many inner ear disorders, including autoimmune inner ear disease, sudden sensorineural hearing loss, and Meniere's disease, remain unknown. Indirect evidence suggests an immune-mediated process involving an allergic or autoimmune mechanism. We examined whether known immunogenic proteins share sequence similarity with inner ear proteins, which may lead to cross-reactivity and detrimental immune activation. Comprehensive bioinformatic analyses of primary sequences of intact and mutated proteins associated with human hearing loss and all proteins known to be expressed in the human inner ear were compared with all immune epitopes in the Immune Epitope Database. The exact match and basic local alignment search tool computational algorithms identified 3036 and 106 unique epitope matches, respectively, the majority of which were infectious epitopes. If validated in future clinical trials, these candidate immune epitopes in the inner ear would be potential novel targets for diagnosis and treatment of some inner ear disorders and the resulting hearing loss.

Innate immune recognition of molds and homology to the inner ear protein, cochlin, in patients with autoimmune inner ear disease.

Autoimmune Inner Ear Disease (AIED) is characterized by bilateral, fluctuating sensorineural hearing loss with periods of hearing decline triggered by unknown stimuli. Here we examined whether an environmental exposure to mold in these AIED patients is sufficient to generate a pro-inflammatory response that may, in part, explain periods of acute exacerbation of disease. We hypothesized that molds may stimulate an aberrant immune response in these patients as both several Aspergillus species and penecillium share homology with the LCCL domain of the inner ear protein, cochlin. We showed the presence of higher levels of anti-mold IgG in plasma of AIED patients at dilution of 1:256 (p = 0.032) and anti-cochlin IgG 1:256 (p = 0.0094 and at 1:512 p = 0.024) as compared with controls. Exposure of peripheral blood mononuclear cells (PBMC) of AIED patients to mold resulted in an up-regulation of IL-1ß mRNA expression, enhanced IL-1ß and IL-6 secretion, and generation of IL-17 expressing cells in mold-sensitive AIED patients, suggesting mold acts as a PAMP in a subset of these patients. Naïve B cells secreted IgM when stimulated with conditioned supernatant from AIED patients' monocytes treated with mold extract. In conclusion, the present studies indicate that fungal exposure can trigger autoimmunity in a subset of susceptible AIED patients.

Autoimmune inner ear disease: a retrospective review of forty-seven patients.

The purpose of this retrospective study was to characterize and further define autoimmune inner ear disease (AIED) using the Harris AIED classification. A retrospective review was conducted at two tertiary medical centers for 47 patients who were diagnosed with AIED. The overall patient response rate to oral prednisone treatment was 69.7%. The sensitivity of the test for a serum antibody against heat-shock protein 70 (HSP70) was 54.5% and the specificity was 42.9%. Therefore, the clinical utility of the HSP70 antibody test appeared to be limited with respect to the diagnosis of AIED. Vertigo, tinnitus and aural fullness improved significantly with both of the newly developed adalimumab (Humira®) and rituximab (Rituxan®). However, hearing loss did not improve in the present study.

Review of the biologic agents used for immune-mediated inner ear disease.

INTRODUCTION AND OBJECTIVES: Immune-mediated inner ear disease (IMIED) is one of the few reversible forms of sensorineural hearing loss. Treatment is based on high-dose corticosteroids, although long-term therapy is associated with serious adverse effects; this has led to the use of other agents or different routes of administration such as transtympanic delivery. This study analyses the role of biological agents in IMIED management. MATERIAL AND METHODS: We searched PUBMED for studies that examined the response to treatment with different biological agents in patients with IMIED. The following data were extracted from the selected studies and entered into a standardised database: exclusion and inclusion criteria, characteristics of the patients studied, treatment, outcome measures and response rates achieved. RESULTS: Thirteen studies were included in this review. A TNF alpha inhibitor (etanercept, infliximab, adalimumab) was used in 8 studies, an IL-1 antagonist (anakinra) was used in 3 studies and rituximab, an antibody directed against the CD20 surface antigen on B lymphocytes, was evaluated in 2 studies. Most studies achieved a hearing improvement or stabilisation in more than 70% of treated patients. CONCLUSIONS: Biological agents can play a role in the management of patients with IMIED, at least in those patients who do not respond to conventional therapy or whose hearing is not stabilised. However, specially-designed randomised controlled clinical trials are needed to assess their effectiveness.

[Peripheral vestibular syndrome intricated pathogenic issues. A case report]. / Sindromul vestibular--aspecte patogenice intricate. Prezentare de caz.

BACKGROUND: Ménière's syndrome appears to be the final common pathway of the mechanisms the inner ear responds to almost any injury. Although the autoimmune disease seems to play a major role, exposure to intense noise can also be a trigger in the appearance and/or aggravation of the disease. MATERIAL AND METHODS: The case of 41 years old musician with a history of ankylosing spondylitis, diagnosed with Ménière's syndrome 5 years ago, is presented. Recently the symptoms became more polymorphic, revealing the association between benign paroxysmal positional vertigo (BPPV), Ménière's syndrome and high frequency hearing loss in an autoimmune background. Besides general, neurological and ENT examination, the diagnostic workup comprised of tonal audiogram, brain stem auditory evoked potentials, computerized dynamic posturography and videonistagmography. RESULTS: The final diagnosis was acute noise trauma, Ménière's syndrome, left horizontal semicircular canal BPPV, bilateral sensorineural sudden aggravated hearing loss in high frequencies (above 9 kHz) and allegedly autoimmune inner ear disease. Treatment with an association of corticosteroids, vasodilators and vitamins combined with Vannucchi's maneuver were followed by a significant relief of the symptoms. CONCLUSION: Although no causal relationship was found between acoustic trauma and increased endolymphatic pressure, both literature data and the case presented show that intense and prolonged noise exposure may aggravate peripheral vestibular syndrome.

High dose combination pertussis toxin induces autoimmune inner ear disease in Sprague-Dawley rats.

CONCLUSION: A better animal model of autoimmune inner ear disease (AIED) in Sprague-Dawley rats has been developed by combination with high dose of pertussis toxin. This study also indicated that inner ear-specific antigens can be involved in autoimmune reactions. Cell-mediated immune injury can play an important role in the induction of AIED, at least in the earlier stage. OBJECTIVES: The purpose of this study was to develop a more suitable rat model that demonstrated closer resemblance to the pathophysiological process in AIED. METHODS: Ninety-six female Sprague-Dawley rats were divided into four groups. They were subcutaneously immunized with crude inner ear antigen/complete Freund's adjuvant (CIEAg/CFA), or intraperitoneal injection of 500 ng pertussis toxin (PT), or injection of CIEAg/CFA+PT, or phosphate-buffered saline (PBS) alone. The auditory function, histopathology of the inner ear, and autoantibodies were examined. RESULTS: Significant differences in the time course of auditory brainstem response (ABR) threshold and mean score of cellular infiltration were demonstrated in the CIEAg/CFA+PT group of animals. Missing hair cells, degeneration of the spiral ganglion cells, endolymphatic hydrops, and autoantibodies were all noted after immunization. There were no significant differences in ABR threshold or histopathology in any other group of animals.

A pilot study of rituximab in immune-mediated inner ear disease.

Immune-mediated inner ear disease (IMED) is a cause of rapidly progressive auditory dysfunction. Patients are often responsive to high-dose corticosteroids and the disease is believed to be mediated by an antibody to inner ear proteins. To date, no therapies have proven effective as corticosteroid-sparing agents. Rituximab is a monoclonal antibody that depletes B cells, resulting in a reduction in autoantibody production. For that reason, rituximab was evaluated in a small pilot study in patients with IMED to see if there was a signal suggesting benefit. In all, 5/7 patients met the primary endpoint of an improvement in pure tone average (500-3000 Hz) by 10 dB in at least one ear, or an improvement in word identification score by at least 12% at 24 weeks, both relative to screening precorticosteroid values after 1 course of treatment. No significant adverse events were reported. The results of this study suggest further evaluation of rituximab as a treatment for IMED is indicated.

Extraintestinal Crohn's disease mimicking autoimmune inner ear disease: a histopathological approach.

Patients with autoimmune inner ear disease develop rapidly progressive sensorineural hearing loss over a period of several weeks or months, often accompanied by vestibular loss. This disease can occur as a distinct clinical entity or in association with an underlying autoimmune disorder. Treatment comprises immunosuppression by corticosteroids, cytostatic drugs or tumor necrosis factor-α antagonists. We report histopathological and immunohistochemical findings of the inner ear of a patient with a granulomatous inner ear disease suffering from Crohn's disease that was nonresponsive to treatment and who underwent surgery for bilateral cochlear implants.