Autoimmune Inner Ear Disease Patients Research Articles

Cochlear implantation in patients with autoimmune hearing loss

Autoimmune inner ear disease (AIED) manifests with recurrent fluctuating sensorineural hearing loss and vestibular symptoms. Treatment includes steroids and avariety of immunosuppressants. Despite adequate treatment, sensorineural hearing loss can be progressive to the point of deafness. In these patients, acochlear implant (CI) is indicated. We present the case of a25-year-old male who underwent cochlear implantation in the left ear. After implantation we noticed brisk variations in impedances which were related to application of the previously prescribed tumor necrosis alpha (TNFα) inhibitor adalimumab. Can immunomodulatory therapy in AIED patients after CI fitting affect the quality of hearing rehabilitation? We documented impedances and speech intelligibility (Freiburg monosyllable test) of our patient for 1year in dependence on adalimumab therapy. Directly after implantation, impedances were within the normal range. During the further course, impedances started to rise, and recurrent adjustments of the implant were needed. Adalimumab therapy was reinitiated, which resulted in asubsequent reduction of impedances. Cochlear implantation can be necessary in some AIED patients and poses asufficient method for hearing rehabilitation. Depending on the activity of the underlying disease, arise in impedances may occur. Immunomodulatory treatment may therefore be necessary to maintain adequate hearing results with the CI.

Disease-Modifying Antirheumatic Drugs in the Treatment of Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis of Auditory and Vestibular Outcomes.

To answer the following question: In patients with primary autoimmune inner ear disease (AIED), (population) what impact do disease-modifying antirheumatic agents (DMARDs) (intervention) when compared with no treatment or corticosteroids (comparison) have on auditory and vestibular outcomes (outcome)? Systematic review and meta-analysis. According to PRISMA guidelines, PubMed, Scopus, CINAHL, and Cochrane Library databases were searched from inception to March 10, 2022. Studies of patients receiving DMARDs for the treatment of AIED were selected for review. Case reports, phase I/II trials, studies of patients with secondary AIED, and studies of AIED patients receiving solely corticosteroids were excluded. Primary outcomes were pure-tone audiometry and speech discrimination scores at baseline and after DMARD treatment. Secondary outcomes were rates of subjective audiovestibular complaints and rates of adverse reactions. No objective vestibular outcomes underwent meta-analysis. Mean differences were calculated using RevMan 5.4. Heterogeneity was assessed with the Q test and I2 statistic. Pooled prevalence rates of audiovestibular symptoms were expressed as a percentage with 95% confidence intervals. Ten studies with a total of 187 patients were included. Treatments included methotrexate, etanercept, azathioprine, anakinra, cyclophosphamide, rituximab, and infliximab. Mean treatment duration was 10.8 ± 22.2 months and mean follow-up was 13.7 ± 8.1 months. The pure-tone audiometry and speech discrimination scores mean differences between baseline and post-DMARD were -2.1 [-4.1, -0.1] dB and 13.9 [8.5, 19.4] %, respectively. Seven studies reported 38 adverse events, four of which were classified as serious. DMARDs showed statistically significant improvement in auditory outcomes, as well as subjective symptoms, with relatively low rates of adverse events. They warrant further exploration to better compare with corticosteroids.

NaCl exposure results in increased expression and processing of IL-1\u03b2 in Meniere\u2019s disease patients

Meniere’s disease (MD) is a chronic disease that causes episodic vertigo, fluctuating hearing loss, and aural fullness, initially managed by dietary salt reduction, and use of diuretics. Our prior research in autoimmune inner ear disease (AIED) demonstrated that in peripheral blood mononuclear cell (PBMC) from corticosteroid-resistant AIED patients, increased production, processing and release of interleukin-1β (IL-1β) is observed and hearing could be improved with use of anakinra, an interleukin-1 receptor antagonist. We have further identified that in these AIED patients, IL-1β is uniquely processed to a 28 kDa pro-inflammatory product by caspase-7. In the present study, we characterize the production, processing and release of the pro-inflammatory cytokines IL-1β and IL-6 from PBMC of MD (n = 14) patients in response to sodium chloride (NaCl), and determined the effect of the diuretic triamterene-hydrocholothiazide (T-HCTZ), or anakinra in these patients. We observed that PBMC cultured with NaCl from MD patients show processing of IL-1β to the 28 kDa product, and that this product is abrogated with T-HCTZ. Our observations are consistent with other autoimmune diseases where high concentrations of NaCl caused release of pro-inflammatory cytokines and may provide further insight as to the mechanism of disease progression in MD patients.

Cochlear Implantation and Perioperative Management in Autoimmune Inner Ear Disease: A Systematic Review and Meta-Analysis.

To assess outcomes in autoimmune inner ear disease (AIED) after cochlear implantation (CI) through systematic review and meta-analysis. PubMed, MedLine, Embase, and CINAHL. Databases were queried for inclusion of AIED patients who underwent CI with outcomes recorded ≥3 months postoperatively. We examined demographics, pure-tone average (PTA), speech perception, preoperative imaging, intraoperative management, and postoperative complications. Twenty-six articles encompassing 124 patients met inclusion criteria. Mean implantation age was 26.2 years (range 4-65 years) with average length of follow-up at 28.2 months (range 3-120 months). Meta-analysis demonstrated significant improvement in speech perception following CI. There was a statistically significant improvement in speech recognition score (SRS) (standard mean difference [SMD] = 6.5, 95% confidence interval [CI], 4.8-8.0, P < 0.0001) as well as word recognition score (WRS) (SMD = 5.5, 95% CI, 4.2-6.8, P < 0.0001) after CI. Anomalous preoperative radiologic manifestations were reported by 57.7% (15/26) studies. Disease activity-related intraoperative adjustment was noted in 57.7% (15/26) studies; common consequences were cochlear drill-out (53.3%), difficult round window insertion (26.7%), and scala vestibuli insertion (26.7%). Frequent postoperative complications noted in 26.9% (7/26) studies included systemic AIED flares (71.4%) and wound healing delay (42.9%). Findings of this systematic review of AIED cochlear implant literature demonstrate a lack of consistent reporting standards for PTA and speech perception as well as a lack of long-term follow-up. Despite these findings, meta-analysis suggests that CI is a viable treatment for improving speech perception in AIED patients.

The Correlation of Clinical Corticosteroid Responsiveness With Expression of IL-6 in Peripheral Blood Immune Cells (PBMC) in Patients With Autoimmune Inner Ear Disease (AIED).

Autoimmune inner ear disease (AIED) patients will differentially express interleukin (IL)-6 based on corticosteroid responsiveness. AIED is characterized by periods of acute sensorineural hearing loss (SNHL). In a majority of patients corticosteroid responsiveness is lost over time. The mechanisms that control corticosteroid responsiveness have not been fully elucidated. Thirty-five AIED patients and 13 age-matched control subjects were enrolled in this study. Steroid responsive (n = 15) and steroid nonresponsive AIED patients (n = 20) were characterized based on audiometry before and after treatment for acute SNHL. Plasma and peripheral blood mononuclear cells (PBMC) were obtained at the time of acute SNHL to quantify plasma IL-6, soluble IL-6 receptor (sIL-6R), and C-C Motif Chemokine Ligand 3 (CCL3). PBMCs were stimulated with dexamethasone and release of soluble IL-6, sIL-6R, and CCL3 protein into conditioned supernatants was measured. Plasma IL-6 was also correlated to serum c-reactive protein (CRP), cardiac CRP, erythrocyte sedimentation rate. Statistically significant differences were observed in the plasma IL-6 between AIED patients and controls (2.37 versus 2.03 pg/ml, p < 0.01), plasma IL-6, and CCL3 between responders and nonresponders (0.136 versus 3.84 pg/ml, p < 0.005; 30.5 versus 32.4, p < 0.05) and released IL-6 from dexamethasone stimulated PBMC in AIED patients compared with controls (0.54 versus 1.12 pg/ml, p < 0.001). There was a correlation between plasma IL-6 levels of AIED patients to both serum CRP and cardiac CRP (R2 = 0.83, R2 = 0.88). We observed AIED patients, specifically nonresponders expressed greater levels of IL-6. Elevated IL-6 levels in AIED patients correlated with CRP levels, providing a commonly available laboratory test that may aid in rapid clinical decision-making in these patients.

Hearing loss in inner ear and systemic autoimmune disease: A systematic review of post-cochlear implantation outcomes.

ObjectivesTo assess outcomes following cochlear implantation (CI) in patients with hearing loss secondary to primary or secondary autoimmune inner ear disease (AIED).MethodsA systematic review and narrative synthesis was completed according to PRISMA guidelines. Databases searched included MEDLINE, PubMed, EMBASE, Web of Science, Cochrane Collection, and ClinicalTrials.gov. No limits were placed on year of publication or language.ResultsA total of 551 studies were identified, of which 29 were included after removal of duplicates, and screening the title, abstract, and full text. All except one study were OCEBM grade IV. 114 of 115 patients displayed improvement in hearing following cochlear implantation. With implant use, roughly a third of these patients had hearing that improved over time, a third improved and plateaued, and a third remained stable. There was no additional risk of perioperative complications found in AIED patients compared what is generally accepted in general cochlear implantation, although two episodes of device failure after 6 months were noted, and four patients with secondary AIED displayed poor initial audiological outcomes.ConclusionCI in both primary and secondary AIED provides marked improvement in hearing. Early CI may be a valid management option, provide long‐lasting hearing in patients and reduce the side effects of long‐term systemic immunosuppressants. However, patients should be counseled residual hearing may be lost if there is cochlear ossification or fibrosis which may make implant insertion more traumatic.Level of EvidenceNA.

Autoimmune Inner Ear Disease among Patients with Selective IgA Deficiency

Objectives: Autoimmune inner ear disease (AIED) is a distinct clinical entity from sudden sensorineural hearing loss. The purpose of this study was to investigate the clinical characteristics of AIED in patients with selective IgA deficiency (sIgAD). Materials and Methods: This retrospective observational study was based on data from the Leumit Healthcare Services database in Israel. We searched all subjects aged ≥12 years who had undergone serum total IgA measurements during 2004–2014 for any reason. The sIgAD patients included all subjects with serum IgA of ≤7 mg/dL (0.07 g/L). A control group was randomly sampled from the full study population (n ≈ 730,000) with a case-control ratio of 10 controls for each case (1:10). Results: Among 347 subjects with sIgAD, we identified 9 patients with concomitant AIED (sIgAD + AIED group). This group was characterized by a higher prevalence of allergic diseases (8 patients; 88.9%) than sIgAD patients without AEID (sIgAD + AIED group; 153 patients; 45.2%; p = 0.014). Both systemic diseases (3 patients; 33.3%) and organ-specific autoimmune diseases (7 patients; 77.8%) were more prevalent in the sIgAD + AIED group (sIgAD + AIED group: 19 patients 5.5%, p = 0.015; sIgAD − AEID group: 76 patients, 21.9%, p < 0.001), with an OR of 8.39 (1.94–36.19; p = 0.004). sIgAD patients with and without AIED were characterized by a higher prevalence of documented episodes of acute otitis media, allergic diseases, and autoimmune diseases than the control group. Conclusion: The study exposes a significant association between AIED and sIgAD. We believe that sIgAD has to be excluded in AIED patients.

Monocytes, Macrophages, and Microglia and the Role of IL-1 in Autoimmune Inner Ear Disease (AIED)

Purpose of Review Autoimmune inner ear disease (AIED) is a rare disease of unknown etiology characterized by a sudden decline in hearing. Although AIED is initially responsive to corticosteroid therapy, this response is lost over time. We recently demonstrated in a small cohort of corticosteroid-resistant AIED patients that IL-1 was overexpressed in the plasma and that IL-1 antagonism led to hearing improvement and reduction in circulating IL-1. Autoinflammatory diseases, such as Muckle-Wells syndrome (MWS), are diseases of the innate immune system whose phenotype includes sensorineural hearing loss. Monocytes are the primary cells orchestrating the inflammatory response in this family of diseases, due to a gain-of-function mutation that causes excessive IL-1 release.

The Balance of Tissue Inhibitor of Metalloproteinase-1 and Matrix Metalloproteinase-9 in the Autoimmune Inner Ear Disease Patients.

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein implicated in the control of inflammation in a number of autoimmune diseases. We hypothesized that the balance of TIMP-1 and matrix metalloproteinase-9 (MMP-9) may influence the control or perpetuation of inflammation in corticosteroid-responsive (RES) and corticosteroid-resistant (NR) autoimmune inner ear disease (AIED) patients. In the present study, we observed that plasma from AIED patients exhibited greater levels of TIMP-1 values compared with normal healthy controls. TIMP-1 abrogates lipopolysaccharide-mediated interleukin (IL)-1β release from peripheral blood mononuclear cells in a dose-dependent manner. RES AIED patients have higher basal TIMP-1 levels and produce more TIMP-1 in response to IL-1β. Conversely, consistent with our previous studies, we found that NR patients have higher basal MMP-9 levels and produce more MMP-9 levels in response to IL-1β.

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-1β 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.

Paediatric autoimmune inner ear disease: A case series

Objective: Autoimmune inner ear disease (AIED) is an uncommon cause of sensorineural hearing loss which may present differently in paediatric patients. The fluctuating nature of the hearing loss and the inherent challenges of audiological assessment of children can make this disease difficult to diagnose and treat. We present our experience of diagnosis and management of AIED in children in this case series. Study design: This is a retrospective case series review of paediatric AIED patients. Diagnosis was made through clinical presentation, audiometric evaluation, and serological testing. Patients were treated with corticosteroids and/or methotrexate. An improvement in pure tone averages (PTA) or speech reception threshold (SRT) of 10dB or greater was considered a clinically significant improvement. Results: The clinical history of four patients is presented. We observed significant differences in disease presentation and progression in these patients. Patients were largely responsive to steroid therapy in patients with both primary AIED and secondary AIED. Conclusion: Children with AIED fall into primary and secondary disease classifications; however, the disease presentation may be vastly different. These patients seem to benefit from corticosteroid and methotrexate therapy. Close collaboration between otolaryngologists and paediatric rheumatologists can result in timely diagnosis and treatment.

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-1β mRNA expression, enhanced IL-1β 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.

Cochlear implantation in patients with autoimmune inner ear disease including cogan syndrome: A comparison with age‐ and sex‐matched controls

Evaluate the characteristics and outcomes of patients with autoimmune inner ear disease (AIED) who have undergone cochlear implantation (CI) and compare post-CI performance in AIED to matched controls. Retrospective case control study. Study cohort was comprised of 25 adult implantees (AIED [n = 18], Cogan syndrome [n = 7]). The AIED group was defined by rapidly progressive bilateral sensorineural hearing loss leading to unusable hearing within weeks to months. Patients with Cogan syndrome, the archetypal inner ear autoimmune disease, were also examined and used for within-cohort comparison. Clinical and operative records were reviewed. Post-CI performance was assessed using open-set sentence tests. Age- and sex-matched individuals deafened by other postlingual causes were used as controls. Of 25 patients, 24 had uneventful, full electrode insertions. One AIED patient had partial insertion due to cochlear ossification and did not achieve open-set speech perception post-CI. Mean open-set sentence scores for study patients with uneventful insertions were 92.8%, 97.3%, and 96.4% at 6 months, 1 year, and ≥ 2 years, respectively. Compared to matched controls, patients deafened by autoimmune causes had significantly higher post-CI performance at all postoperative test intervals (P < .05). There was no significant difference in postimplantation performance between Cogan syndrome and AIED patients. To our knowledge this was the largest study of cochlear implantation in AIED and Cogan syndrome patients. In our experience, both groups generally attained high levels of post-CI speech perception and performed above average. Cochlear ossification affecting implantation in Cogan syndrome patients was not observed in our series, contrary to some reports.

Cochlear Implantation Outcomes in Patients With Autoimmune and Immune-Mediated Inner Ear Disease

To compare hearing outcomes in patients with autoimmune inner ear disease (AIED) undergoing cochlear implantation to a group of controls, postlingually deafened by non-immune-mediated causes. Hearing performance in AIED patients who receive unilateral or bilateral cochlear implants is comparable to similarly treated postlingually deafened adults without AIED. Retrospective chart review. Academic neurotologic tertiary referral center. Ten patients with AIED with 12 implanted ears who met the audiological criteria for cochlear implantation were compared with 12 randomly selected controls, postlingually deafened by non-immune-mediated causes. Cochlear implantation using commercially available devices. Preoperative and postoperative hearing thresholds, words, and sentence scores. A note was made regarding the presence or absence of ossification or fibrosis noted within the scala tympani at the time of implant. The mean age was 49.6 ± 14 years in the AIED group and 56.8 ± 17 years in the control group (p = 0.31). The mean duration of deafness was 14 ± 26 months in the AIED group and 6.5 ± 4 months in the control group (p = 0.34). In the AIED group, 42% were men and 58% were women. In the control group, 33% were men and 67% women. Five patients in the AIED group (6 implanted ears) were found to have cochlear fibrosis and variable degrees of ossification. Two patients in that group required drill-out procedures. All patients had full insertion. The mean preoperative pure-tone averages in the AIED and control groups were 102 ± 18 and 90 ± 13 dB, respectively (p = 0.13). In the AIED, the mean short-term (≤12 mo of follow-up) postoperative word and sentence scores were 74.8% ± 15% and 94% ± 6%, respectively. In the control group, the mean short-term postoperative words and sentence scores were 72% ± 12% and 96% ± 4%, respectively. No statistical difference was present in the short-term postimplantation words (p = 0.7) and sentence scores (p = 0.49) between both groups. The mean long-term (after 12 mo of follow-up) postoperative word and sentence scores in the AIED group were 87.2% ± 11% and 96.8% ± 4%, respectively. In the control group, the long-term words and sentence scores were 77.2% ± 14% and 77.2% ± 7%, respectively. No statistical significance was found in the long-term postimplantation words (p = 0.17) and sentence scores (p = 0.7) between both groups. Cochlear implantation is a safe and viable option for hearing rehabilitation in patients deafened by progressive AIED. Hearing outcomes in AIED patients are excellent and support transition to implantation when hearing is lost or long-term steroid therapy becomes undesirable. Cochlear fibrosis or ossification seems to affect nearly 50% of implanted ears (41.6% of patients) in this study and implies that the cochlea is at risk for ossification changes long term. In appropriate candidates, earlier implantation may be indicated before postinflammatory obliterative changes in the cochlea.

Alternate Splicing of Interleukin-1 Receptor Type II (IL1R2) In Vitro Correlates with Clinical Glucocorticoid Responsiveness in Patients with AIED

Autoimmune Inner Ear Disease (AIED) is poorly characterized clinically, with no definitive laboratory test. All patients suspected of having AIED are given glucocorticoids during periods of acute hearing loss, however, only half initially respond, and still fewer respond over time.We hypothesized that AIED is a systemic autoimmune disease characterized by dysfunctional peripheral blood mononuclear cells (PBMC) responses to a unique cochlear antigen(s). To test this hypothesis, we examined end-stage AIED patients undergoing cochlear implant surgery and compared autologous perilymph stimulated PBMC from AIED patients to controls. We determined that autologous perilymph from AIED patients was unable to induce expression of a long membrane-bound Interleukin-1 Receptor Type II (mIL1R2) transcript in PBMC as compared with controls, despite similar expression of the short soluble IL1R2 (sIL1R2) transcript (p<0.05). IL1R2 is a molecular decoy that traps interleukin-1β (IL-1β) and does not initiate subsequent signaling events, thereby suppressing an inflammatory response. IL1R2 transcript length is regulated by alternate splicing, and the major inhibitory function is attributed to the full-length mIL1R2. In addition, IL1R2 expression is induced by dexamethasone.Separately, we prospectively examined patients with newer onset glucocorticoid-responsive AIED. Immediately prior to clinical treatment for acute deterioration of hearing thresholds, their PBMC demonstrated a robust induction of mIL1R2 in PBMC in response to dexamethasone in vitro that correlated with a clinical response to prednisone in vivo (p<0.0001) as measured by hearing restoration. In contrast, clinically steroid unresponsive patients demonstrated high basal levels of mIL1R2 in their PBMC and only minimally augmented expression in response to dexamethasone. Thus, induced expression of mIL1R2 appears to be a protective mechanism in hearing homeostasis and warrants further investigation in a large prospective clinical trial to determine if IL1R2 can be used as a specific biomarker for AIED.

Etanercept Treatment for Autoimmune Inner Ear Disease: Results of a Pilot Placebo-Controlled Study

Autoimmune Inner Ear Disease (AIED) is an idiopathic progressive, often bilateral, sensironeural hearing loss that occurs over weeks to months, generally resulting in significant auditory disability. Response to treatment with immunomodulators other than corticosteroids has been poor. Data from a guinea pig model of AIED and a recent open label trial of etanercept suggested potential treatment benefit. Based on these preliminary results, we conducted a pilot placebo controlled trial of etanercept in AIED patients. Twenty AIED patients were enrolled in a 12-week blinded placebo (PLA) controlled randomized clinical trial of etanercept (ETA) with 25 mg SC twice weekly. Patients received treatment for 8 weeks with a 4-week follow-up off-treatment. The primary study endpoint was an improvement in pure tone threshold (PTA) of 10 Db in two consecutive frequencies and/or improvement in speech discrimination of >12% at week 8. Patient demographics were similar for the ETA and PLA patients. Seventeen subjects (8 ETA, 9 PLA) completed the trial. The 3 dropouts were due to lack of efficacy. One ETA and 2 PLA subjects achieved the primary endpoint (p > 0.999). One ETA and 1 PLA pt demonstrated improved in hearing loss and vertigo severity by VAS and hearing disability. No safety issues were observed. The results of this pilot trial demonstrate that etanercept 25 mg twice weekly for 8 weeks was no better than placebo for treatment of AIED in this patient population.