Increased oxidative stress, inflammation, and glutamate: Potential preventive and therapeutic targets for hearing disorders.

Hearing disorders constitute one of the major health concerns in the USA. Decades of basic and clinical studies have identified numerous ototoxic agents and investigated their modes of action on the inner ear, utilizing tissue culture as well as animal and human models. Current preventive and therapeutic approaches are considered unsatisfactory. Therefore, additional modalities should be developed. Many studies suggest that increased levels of oxidative stress, chronic inflammation, and glutamate play an important role in the initiation and progression of damage to the inner ear leading to hearing impairments. To prevent these cellular deficits, antioxidants, anti-inflammatory agents, and antagonists of glutamate receptor have been used individually or in combination with limited success. It is essential, therefore, to simultaneously enhance the levels of antioxidant enzymes by activating the Nrf2 (a nuclear transcriptional factor) pathway, dietary and endogenous antioxidant compounds, and B12-vitamins in order to reduce the levels of oxidative stress, chronic inflammation, and glutamate at the same time. This review presents evidence to show that increased levels of these cellular metabolites, biochemical or factors are involved in the pathogenesis of cochlea leading to hearing impairments. It presents scientific rationale for the use of a mixture of micronutrients that may decrease the levels of oxidative damage, chronic inflammation, and glutamate at the same time. The benefits for using oral administration of proposed micronutrient mixture in humans are presented. Animal and limited human studies indirectly suggest that orally administered micronutrients can accumulate in the inner ear. Therefore, this route of administration may be useful in prevention, and in combination with standard care, in improved management of hearing problems following exposure to well-recognized and studied ototoxic agents, such as noise, cisplatin, aminoglycoside antibiotics, and advanced age.

Autoimmune inner ear disease: clinical and laboratory findings and treatment outcome.

OBJECTIVE: To assess the demographics, clinical presentations, auditory and vestibular findings, value of serologic tests, and treatment outcome in autoimmune inner ear disease (AIED). STUDY DESIGN: Retrospective chart review. SETTINGS: Tertiary care centre. PATIENTS: Sixty patients with confirmed AIED, with and without systemic disease. INTERVENTIONS: Diagnostic auditory, vestibular, and serologic tests and treatment with steroids. OUTCOME MEASURES: Auditory, vestibular, and serologic findings and treatment outcomes. RESULTS: The female to male ratio was 2:1. Forty-nine patients presented with unilateral or bilateral hearing loss; 28 patients also had vestibular symptoms. Eleven patients had vestibular symptoms only. Hearing loss was progressive in most, rapid in onset in one, and of sudden onset in two. Approximately 25% of patients had confirmed systemic autoimmune disease. Patients without systemic disease had serologic tests to confirm the diagnosis of AIED. The level of antinuclear antibodies was high, with a speckled pattern, in 38 patients, and 9 patients had a high rheumatoid factor. The positive yield of other detailed tests was low. Vestibular tests showed a peripheral type of change. Steroid treatment produced an excellent response in 33% and a good response in 16% without systemic disease. Only 25% of those with systemic disease had a similar response. Patients with vestibular symptoms only had an excellent response to steroids. CONCLUSIONS: Patients with AIED present with varied symptoms, and some have only vestibular symptoms. Limited serologic tests used in the diagnosis of systemic autoimmune diseases are valuable in establishing the diagnosis of AIED. Fifty percent of patients with AIED have an excellent response to steroids. Those with systemic disease have a lower response rate. Those with vestibular symptoms only are responsive to steroids.

Causative factors and epidemiology of bilateral vestibulopathy in 255 patients.

OBJECTIVE: To determine the causative factors and epidemiology of bilateral vestibulopathy (BV). METHODS: This is a retrospective review of 255 patients (mean age, 62 +/- 16 years) with BV diagnosed in our dizziness unit between 1988 and 2005. All patients had undergone a standardized neurophthalmological and neurootological examination, electronystagmography with caloric irrigation, cranial magnetic resonance imaging or computed tomography (n = 214), and laboratory tests. RESULTS: Sixty-two percent of the study population were male subjects. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%: The most common causes were ototoxic aminoglycosides (13%), Menière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. Hypoacusis occurred bilaterally in 25% and unilaterally in 6% of all patients. It appeared most often in patients with BV caused by Cogan's syndrome, meningitis, or Menière's disease. INTERPRETATION: The cause of BV remains unclear in about half of all patients despite intensive examinations. A large subgroup of these patients have associated cerebellar dysfunction and peripheral polyneuropathy. This suggests a new syndrome that may be caused by neurodegenerative or autoimmune processes.

[Does the hearing loss affect the child's innate immunity?--preliminary]. / Niedosluch a odpornosc naturalna dziecka? (doniesienie wstepne).

UNLABELLED: Human neutrophiles play a crucial role in inmate immunity. Inmate and aquired immune response depend on their functional condition at the first stage of an inflammation process. Reactive forms of oxygen (RFO) produced by neutrophiles play a significant role in the eradication of pathogens as well as in the regulation of immune response. The aim of this study is question, does the hearing loss affect the inmate immunity? METHOD: The RFO production was directly examined in four systems - without stimulation, after stimulation with fMLP, opsonized zymosan or PMA. Direct RFO measurement was performed chemiluminescency evaluation using the whole blood, which indirectly depend on RFO production. RESULT: In the group of children with hearing loss was observed disturbances in RFO productions. CONCLUSION: This observation is very original and important for general practice.

Identification and characterization of choline transporter-like protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody-induced hearing loss.

The Kresge Hearing Research Institute-3 (KHRI-3) antibody binds to a guinea pig inner ear supporting cell antigen (IESCA) and causes hearing loss. To gain insight into the mechanism of antibody-induced hearing loss, we used antibody immunoaffinity purification to isolate the IESCA, which was then sequenced by mass spectroscopy, revealing 10 guinea pig peptides identical to sequences in human choline transporter-like protein 2 (CTL2). Full-length CTL2 cDNA sequenced from guinea pig inner ear has 85.9% identity with the human cDNA. Consistent with its expression on the surface of supporting cells in the inner ear, CTL2 contains 10 predicted membrane-spanning regions with multiple N-glycosylation sites. The 68 and 72 kDa molecular forms of inner ear CTL2 are distinguished by sialic acid modification of the carbohydrate. The KHRI-3 antibody binds to an N-linked carbohydrate on CTL2 and presumably damages the organ of Corti by blocking the transporter function of this molecule. CTL2 mRNA and protein are abundantly expressed in human inner ear. Sera from patients with autoimmune hearing loss bind to guinea pig inner ear with the same pattern as CTL2 antibodies. Thus, CTL2 is a possible target of autoimmune hearing loss in humans.

[The occurrence of atopic hypersensitivity in children with adenoid hypertrophy]. / Ocena czestosci wystepowania atopii u dzieci z przerostem migdalka gardlowego.

UNLABELLED: Allergic sensitization of the airways occurs in the mucosa. The lymphatic structure closest to the nasal mucosa is the adenoid. Adenoid hypertrophy (AH) may cause significant morbidity in children but its relationship to atopy has not been intensively studied. To examine the influence of atopy on the adenoid hypertrophy we studied 134 children ages 4 to 8 years, with an average age of 5.4 who had AH. In the analysed group 102 children suffered from difficulty in nose breathing, 61 of children from recurrent upper respiratory tract infections, 51 from recurrent otitis and 40 from hearing disorders. On the basis of allergic and immunological examinations, in 30.6% atopy was confirmed--41 out of 134 children showed positive skin test for allergy, mostly to different kinds of pollen or house dust. From these positive patients the respective allergens could be determined by RAST tests in serum of 87%. Increased total IgE level in serum was confirmed only in 17.5%. 8.5% of children showed peripheral blood eosinophilia. Some children were qualified for adenotomy and removed adenoid was examined histopathologically. Pharmacological treatment was also recommended. CONCLUSIONS: The study shows that allergy and sensitivity to different kinds of allergens is an important risk factor for a greater degree of AH in children. Therefore, early prevention of exposure to them may help reduce occurrence of AH.

No evidence of auditory dysfunction in guinea pigs immunized with myelin P0 protein.

Recent data have focused on the peripheral nerve myelin glycoprotein P0 as a putative autoantigen involved in the autoimmune etiology of some cases of Meniere's disease, idiopathic sensorineural hearing loss and sudden deafness. To determine whether antibodies to myelin P0 can alter cochlear function, 13 healthy guinea pigs were immunized with purified porcine myelin P0 while 10 controls were injected with saline water. The animals were then evaluated for evidence of evolving inner ear disease using immunological, electrophysiological and morphological methods. Twenty-six experimental ears were tested weekly with a brainstem auditory evoked potential technique for a period of 4 months and were compared to 20 control ears. Uniformly, all P0-sensitized guinea pigs showed antibodies to myelin protein P0 as evidenced by ELISA. Clinical signs of inflammatory demyelination were not discernible in P0-sensitized guinea pigs and all the animals were qualitatively normal. No significant increase of evoked potential thresholds was found in the P0-sensitized animals when compared to controls (P>0.05). Peak latencies of waves I, II, III, IV and V and inter-peak latencies in P0-sensitized guinea pigs did not significantly differ from those of controls (P>0.05). Histological sections of inner ear and peripheral nerves were free of disease in both groups. These findings indicate that the sole presence of antibodies to myelin P0 in the sera of guinea pigs or patients suspected of having autoimmune inner ear diseases is unlikely to elicit auditory abnormalities and that additional factors are necessary for the pathogenic development of these disorders.

[The importance of IgG auto-antibodies, anti-collagen type II specific in Menière's disease and progressive hearing loss]. / La importancia de los auto-anticuerpos IgG, específicos anticolágeno tipo II en la enfermedad de Menière y pérdida progresiva de la audición.

UNLABELLED: The Meniere's Disease and Progressive Hearing Loss were considered idiopathic. Both entities were produced by endo lymphatic hydrops and disruption of the membrane which contain type II collagen. The inner ear presented widely expression of type II collagen. These pathologies were probably autoimmune diseases. The aim of this work was to study the relationship of specific IgG to type II collagen in Meniere's disease, Progressive hearing loss, and compared with Sudden hearing loss patients, vascular vertigo patients and normal controls. Patients were divided by clinical findings in: 1 degree Meniere's disease (n:27), 2 degrees Progressive Hearing loss (n:20), 3 degrees Sudden hearing loss (n:15), 4 degrees Vascular Vertigo (n:9) and compared with normal controls (n:30) aged and sex matched. We have measured specific IgG to type II collagen by ELISA test. We considered positive the OD two or more SD above the mean of normal controls. RESULTS: 1 degree The Meniere's group presented IgG to type II collagen (+) in 22 out of 27 patients, p < .025; 2 degrees The Progressive Hearing loss presented IgG to type II collagen in all cases (n:20), p < .0005. The Sudden Hearing loss presented IgG to type II collagen (-) in all cases (n:15) p < .00001 and Vascular Vertigo (n:9) presented IgG to type II collagen (-) in 8 out of 9 cases, p < .0005. These results suggest strongly the notion that Meniere's diseases and Progressive hearing loss have specific IgG to type II collagen and these conditions were ascribed with in autoimmune process.

La importancia de los auto-anticuerpos IGG específicos anticolágeno tipo II en la enfermedad de Meniere y pérdida progresiva de la audición / The importance of type II anticollagen specific IGG autoantibodies in the Meniere's disease and progressive hearing loss

La enfermedad de Meniere así como la pérdida progresiva de la audición son consideradas como idiopáticas. Las mismas se deben a un hidrops endolinfático y posterior disrupción de diversas estructuras del oído interno, que conducen al vértigo o a la sordera progresiva. Desde hace algún tiempo estas enfermedades han sido consideradas como autoinmunes. La respuesta inmunológica ataca a variadas estructuras, en el ódio interno está presente el colágeno tipo II. El propósito de este trabajo es correlacionar la presencia de IgG anti colágeno tipo II en pacientes afectados de Meniere, pérdida progresiva de la audición y compararlos con pérdia súbita de la audición, vértigo de orígen vascular y controles normales. Para este trabajo hemos estudiados a 71 pacientes con manifestaciones compatibles con diferentes enfermedades relacionadas con el oído interno. Las mismas se dividieron en: Enfermedad de Meniere (n:27), Pérdia progresiva de la audición (n:2)), Pérdida súbita de la audición (n:15), Vértigo vascular (n:9) y 30 controles normales de similar edad y proporciones de sexo. A todos los pacientes y controles se les praticó dosaje de IgG específica para colágeno tipo II por ELISA. Se consideró determinación positiva cuando era más de 2 DS de la media de los normales. Resultados: 1º El grupo Meniere presentó IgG específica para colágeno II (+) en 22 de 27 casos, p<.025. 2º El grupo con Pérdida Progresiva de la Audición presentó IgG especifica para colágeno II (+) en los 29 casos del grupo p<0005. 3º en la Pérdida súbita de la audición todos los casos (n:15) fueron negativos para IgG específica para colágeno II, p<.00001. 4º Los pacientes con vértigo vascular 1 sobre 9 casos fue (+) para IgG anti colágeno II, p<.0005. Estos resultados sugieren fuertemente que los pacientes con enfermedad de Meniere y/o Pérdida Progressiva de la Audición tienen como mecanismo fisiopatogénico productor de ambas enfermedades a autoanticuerpos para colágeno tipo II.

La importancia de los auto-anticuerpos IGG específicos anticolágeno tipo II en la enfermedad de Meniere y pérdida progresiva de la audición / The importance of type II anticollagen specific IGG autoantibodies in the Menieres disease and progressive hearing loss

La enfermedad de Meniere así como la pérdida progresiva de la audición son consideradas como idiopáticas. Las mismas se deben a un hidrops endolinfático y posterior disrupción de diversas estructuras del oído interno, que conducen al vértigo o a la sordera progresiva. Desde hace algún tiempo estas enfermedades han sido consideradas como autoinmunes. La respuesta inmunológica ataca a variadas estructuras, en el ódio interno está presente el colágeno tipo II. El propósito de este trabajo es correlacionar la presencia de IgG anti colágeno tipo II en pacientes afectados de Meniere, pérdida progresiva de la audición y compararlos con pérdia súbita de la audición, vértigo de orígen vascular y controles normales. Para este trabajo hemos estudiados a 71 pacientes con manifestaciones compatibles con diferentes enfermedades relacionadas con el oído interno. Las mismas se dividieron en: Enfermedad de Meniere (n:27), Pérdia progresiva de la audición (n:2)), Pérdida súbita de la audición (n:15), Vértigo vascular (n:9) y 30 controles normales de similar edad y proporciones de sexo. A todos los pacientes y controles se les praticó dosaje de IgG específica para colágeno tipo II por ELISA. Se consideró determinación positiva cuando era más de 2 DS de la media de los normales. Resultados: 1º El grupo Meniere presentó IgG específica para colágeno II (+) en 22 de 27 casos, p<.025. 2º El grupo con Pérdida Progresiva de la Audición presentó IgG especifica para colágeno II (+) en los 29 casos del grupo p<0005. 3º en la Pérdida súbita de la audici

Antibodies against inner-ear proteins in the sera of patients with inner-ear diseases.

Sera from patients with various inner-ear diseases, especially Ménière's disease, were investigated by Western blot against guinea pig inner-ear proteins. Of 45 patients, 24 (53%) with various inner-ear diseases had antibodies against inner-ear proteins, compared with 0 of 10 (0%) in control subjects without inner-ear diseases. Of the 10 proteins that showed a positive reaction with patient sera, the 28-kD band was unique in that it appeared only in the membranous fraction of the inner ear and was highly positive (28%) in reaction with Ménière's disease patient sera. The results in the present study with proteins extracted from guinea pig inner ear were consistent with our previous study using proteins from human inner ear, suggesting that the 28-kD protein may be a candidate for detecting autoimmune inner-ear disease.

Altered immunoregulations in otosclerosis: presence of autoantibodies in otosclerotic sera samples.

A current concept of the etiopathogenesis of otosclerosis is an immune response. The purpose of this study was to determine if autoantibodies were present in sera samples from patients with known otosclerosis. Organ non-specific total antinuclear antibodies (tANA) were determined in 98 sera samples by the immunofluorescent method in 47.9% of otosclerotic patients versus 5% in controls. The most frequent specific antinuclear antibody was antibody to native deoxyribonucleinic acid and antibody to ribonucleoprotein. Tissue-specific antibodies to native-collagen type II molecule (ACA II) were determined by counter-immunoelectrophoresis in the same sera samples and were detected in 54% versus none in healthy sera. There was no correlation between the presence of these two autoantibodies. In patients with tANA present, a statistically significant depletion of cochlear function was noted. The presence of ACA II showed no connection with hearing loss. The present study showed some alteration in immunoregulatory markers in otosclerotic patients and the possibility that ANA may play a role in the pathogenesis of otosclerosis-induced perceptive deafness.

Use of a screening RAST in a large neuro-otologic practice.

Evidence in the literature emphasizes the role of the immune system in disorders of the inner ear and eustachian tube. We initially investigated the presence of inhalant allergy in selected patients seen for otologic problems by means of a screening radioallergosorbent test (RAST), using either a microscreen or a limited antigen panel. This study analyzed the results of tests performed over a 2-year period on 186 patients seen by one of us (WLM) for treatment of vertigo (66%), tinnitus (63%), hearing loss (49%), aural fullness (48%), Meniere's quadrad (27%), balance disturbance other than true vertigo (21%), and eustachian tube dysfunction (4%). We found an incidence of immunoglobulin E-mediated hypersensitivity of nearly 40% in a patient population selected solely for neuro-otologic symptoms and not for sinonasal symptoms. This figure is more than double that quoted for the general population. We also found a surprisingly high incidence of mold antigen atopy in this selected population. Allergy can contribute to a number of otologic symptoms, including eustachian tube dysfunction, vertigo, tinnitus, hearing loss, aural fullness, and nonspecific balance disturbance. Allergy also has been emphasized as an etiologic factor in a portion of patients diagnosed with Meniere's syndrome. A screening RAST, combined with clinical evaluation, appears to be an excellent tool for evaluating these patients for inhalant allergy as part of a comprehensive workup.

Fluctuating hearing loss following immune reaction in the endolymphatic sac of guinea pigs.

This study has investigated immune injuries to the inner ear auditory system of guinea pigs. Following secondary antigen challenge to the endolymphatic sac, the mean hearing threshold significantly increased in the early phase from day 1 to day 3 and thereafter recovered. In the early phase, hearing threshold significantly increased simultaneously to the elevation of perilymph antibody levels. The size of hydrops was not the only factor that causes an increase in hearing loss as well as in AP/SP ratio. Scale-out hearing loss was seen in 2 animals with severe degeneration of the stria vascularis as well as the organ of Corti associated with the inflammatory cellular infiltration especially in the perilymphatic space, even in the absence of keyhole limpet hemocyanin antigen in the cochlea. On the other hand, control animals did not suffer hearing loss. These results suggest that an immune reaction in the endolymphatic sac is a possible pathogenic etiology of Ménière's disease or sudden deafness.

Mechanisms of hearing disturbance in an autoimmune model mouse NZB/kl.

A subline of the NZB mouse, NZB/kl, was found to develop severe hearing disturbances at high frequency sound at the age of 4 to 6 months. Deposition of IgG was observed on the capillary wall of the stria vascularis of the mice, but the concentration of circulating immune complex did not seem to be correlated to the deposition. Electron microscopic examination revealed that the capillaries had a thick basement membrane, and in severe cases the membrane contained foamy structures of various size. In some cases the base membrane was so thick that the capillary lumen was narrowed, and the intermediate cells seemed to be damaged. No pathological findings were found in other inner ear tissues. These results suggest that the changes in the stria vascularis were possibly caused by an autoimmune mechanism which resulted in hearing disturbance.

Stria vascularis ultrastructural pathology in the C3H/lpr autoimmune strain mouse: a potential mechanism for immune-related hearing loss.

The stria vascularis in the C3H/lpr autoimmune strain mouse was ultrastructurally examined in order to better understand the potential mechanisms by which systemic autoimmune disease affects the ear. The inner ear from C3H/lpr mice before disease onset and C3H/HeJ controls showed no apparent pathology. However, the stria vascularis from older C3H/lpr mice after systemic autoimmune disease onset showed considerable intercellular edema around the stria capillaries and thickening of the capillary basement membrane, compared to controls. These observations suggest that perivascular abnormalities, which are the hallmark of systemic autoimmune diseases, may underlie the stria dysfunction and hearing loss seen in autoimmune diseases in humans.

Immunological disorders and auditory lesions.

The mechanisms by which auto-immune diseases may result in hearing disorders are reviewed. This is followed by a more detailed consideration of specific autoimmune disorders generally associated with auditory dysfunction. Four pilot studies examining the relationship between auto-immune disorders and hearing loss are briefly presented.