Pathophysiology Of Hearing Loss Research Articles

Polymer-Based Nanoparticles for Inner Ear Targeted Trans Differentiation Gene Therapy.

Hearing loss is a significant disability that often goes under recognised, largely due to poor identification, prevention, and treatment. Steps are being made to amend these pitfalls in the investigation of hearing loss, however, the development of a cure to reverse advanced forms remains distant. This review details some current advances in the treatment of hearing loss, with a particular focus on genetic-based nanotechnology and how it may provide a useful avenue for further research. This review presents a broad background on the pathophysiology of hearing loss and some current interventions. We also highlight some potential genes that may be useful in the amelioration of hearing loss. Pathways of cellular differentiation from stem or supporting cell to functional hair cell are covered in detail, as this mechanism represents a key means of regenerating these cell types. Overall, we believe that polymer-based nanotechnology coupled with novel excipients represents a useful area of further research in the treatment of hearing loss, although further studies in this area are required.

Association between the systemic immuno-inflammation index and hearing loss: result from NHANES 2009-2018.

A novel inflammatory marker that measures the degree of systemic immunoinflammation, the systemic immuno-inflammation index (SII) is frequently used to forecast a number of illnesses. According to earlier studies, inflammation may play a role in the pathophysiology of hearing loss (HL). A sample from the National Health and Nutrition Examination Survey (NHANES) covering the years 2009 to 2018 was used in the current cross-sectional survey. Subgroup analysis and weighted multiple linear regression models were used to examine the independent linear correlation between SII and HL. Fitted smoothed curve analyses were also conducted to show the non-linear relationship between the two variables. Among the 8,535 participants, the mean age was 40.92 ± 18.6 years, with 49.01% being male. Notably, individuals with hearing loss demonstrated an SII of 530.00 ± 320.72, while those with normal hearing displayed an SII of 491.21 ± 265.15. The mean ± SD values of low-frequency, speech-frequency, and high-frequency Pure Tone Average (PTA) hearing thresholds were 10.33 ± 9.79, 12.20 ± 11.11, and 22.48 ± 19.49 dB, respectively. A positive dose-response relationship between higher SII and hearing thresholds was observed after adjusting for potential confounders. Furthermore, the interaction analysis did not reveal any significant impact on this positive correlation. The results of our investigation suggest that the Systemic Inflammatory Index may serve as a potential biomarker for the likelihood of hearing loss. However, additional research is required to further elucidate the nature of this association.

Insight into the Pathophysiology of Hearing Loss and Renal Tubular Dysfunction Through Genetic Testing

Insight into the Pathophysiology of Hearing Loss and Renal Tubular Dysfunction Through Genetic Testing

Residual Hair Cell Responses in Electric-Acoustic Stimulation Cochlear Implant Users with Complete Loss of Acoustic Hearing After Implantation.

Changes in cochlear implant (CI) design and surgical techniques have enabled the preservation of residual acoustic hearing in the implanted ear. While most Nucleus Hybrid L24 CI users retain significant acoustic hearing years after surgery, 6-17 % experience a complete loss of acoustic hearing (Roland et al. Laryngoscope. 126(1):175-81. (2016), Laryngoscope. 128(8):1939-1945 (2018); Scheperle et al. Hear Res. 350:45-57 (2017)). Electrocochleography (ECoG) enables non-invasive monitoring of peripheral auditory function and may provide insight into the pathophysiology of hearing loss. The ECoG response is evoked using an acoustic stimulus and includes contributions from the hair cells (cochlear microphonic-CM) as well as the auditory nerve (auditory nerve neurophonic-ANN). Seven Hybrid L24 CI users with complete loss of residual hearing months after surgery underwent ECoG measures before and after loss of hearing. While significant reductions in CMs were evident after hearing loss, all participants had measurable CMs despite having no measurable acoustic hearing. None retained measurable ANNs. Given histological data suggesting stable hair cell and neural counts after hearing loss (e.g., Quesnel et al. Hear Res. 333:225-234. (2016)), the loss of ECoG and audiometric hearing may reflect reduced synaptic input. This is consistent with the theory that residual CM responses coupled with little to no ANN responses reflect a "disconnect" between hair cells and auditory nerve fibers (Fontenot et al. Ear Hear. 40(3):577-591. 2019). This "disconnection" may prevent proper encoding of auditory stimulation at higher auditory pathways, leading to a lack of audiometric responses, even in the presence of viable cochlear hair cells.

Nanoparticle-based inner ear delivery systems for the treatment of hearing loss

Hearing loss has become the most common sensory disorder worldwide. Despite intensive research on the pathophysiology of hearing loss, biological therapeutic approaches are limited by the anatomical and physiological characteristics of the inner ear. Challenges in inner ear drug delivery involve biotherapeutic instability, membrane inaccessibility and delivery non-specificity. With the development of nanotechnology, the nanoparticle-based delivery systems are promising to overcome these limitations. After drugs loading and stabilization, nanoparticles can carry the drugs into the inner ear by crossing round window membrane. The surface bioconjugation of ligand endows nanoparticles with specific targeting capability. Nanoparticles with stimuli-responsive moieties can provide a controlled release manner. Together, these strategies show great potential for hearing loss treatment. Understanding the current advances of nanotechnology in hearing loss treatment will facilitate future therapeutic options and clinical applications.

Cochlear implantation in postirradiated ears: A case-control comparative study.

ObjectivesThe aim of this study is to investigate the hearing outcomes of cochlear implantation (CI) in patients with hearing loss who had received radiotherapy for nasopharyngeal cancer (NPC). The study compared speech perception in patients who had prior radiotherapy with those who did not receive radiotherapy.MethodsEighty‐eight Cantonese speaking adult patients who had profound sensorineural hearing loss and received CI from 1995 to 2015 at the Chinese University of Hong Kong CI‐center were studied. Twenty‐five patients had history of NPC and radiotherapy were determined as the exposed group, while 63 patients of mixed etiologies but with no history of radiotherapy were included in the control group. The Hong Kong Speech Perception Test Manual (HKSPTM) scores preoperatively, at 6, 12, and 24 months postoperatively were used to assess hearing performance. The HKSPTM consisted categories of speech recognition, word recognition, and tone perception.ResultsNo statistical significance differences were found at the four time‐points in the three categories of HKSPTM between the two groups.ConclusionCI is a clinically effective intervention and good rehabilitative option for hearing restoration in NPC patients with hearing impairment. Further studies with greater sample size and additional pathological studies on the pathophysiology of hearing loss in this subgroup of patients may provide supplementary information for clinicians when counseling for CI.Level of evidence4.

Abnormal Tectorial Membranes in Sensorineural Hearing Loss: A Human Temporal Bone Study.

This study evaluates the morphological changes of the tectorial membrane (TM) in conjunction with degeneration of hair cells, interdental cells, and presence of endolymphatic hydrops (EH) in sensorineural hearing loss (HL) in the human using histopathology techniques. The TM plays an important role in mechanical transduction of acoustic energy, and pathology of the TM may result in HL. All temporal bone (TB) specimens from the Massachusetts Eye and Ear Otopathology Laboratory from patients with various causes of sensorineural HL and morphological abnormalities of the TM were evaluated. Cases with a history of cochlear trauma (other than acoustic trauma) and/or severe postmortem artifacts were excluded. The TBs were processed histologically, and the status of hair cells, supporting cells, interdental cells, presence of EH, and postmortem time were tabulated. Two thousand two hundred ninety TBs from 1340 individuals were evaluated, and 164 of 748 TBs from the otological disorders in which the TM were abnormal, met the inclusion criteria. The most common disorders were idiopathic sudden deafness (57.1%), genetic etiology (53.7%), and ototoxicity (40.0%), as compared with cases with presbycusis (2.9%). EH was found in 33.3% of all cases with an identified abnormality of the TM.Abnormalities of the TM were 1) deformed, 2) shrunken, 3) detached from the limbus, 4) encapsulated, or 5) missing. Encapsulated, shrunken and missing patterns (36, 35, 31%, respectively) were the most common. A relative high prevalence of EH among disorders with TM abnormalities suggests a possible common pathophysiology in both. In addition, anatomic abnormalities of the TM may play a role in the pathophysiology of HL in these disorders.

The Role of Glia in the Peripheral and Central Auditory System Following Noise Overexposure: Contribution of TNF-α and IL-1β to the Pathogenesis of Hearing Loss

Repeated noise exposure induces inflammation and cellular adaptations in the peripheral and central auditory system resulting in pathophysiology of hearing loss. In this study, we analyzed the mechanisms by which noise-induced inflammatory-related events in the cochlea activate glial-mediated cellular responses in the cochlear nucleus (CN), the first relay station of the auditory pathway. The auditory function, glial activation, modifications in gene expression and protein levels of inflammatory mediators and ultrastructural changes in glial-neuronal interactions were assessed in rats exposed to broadband noise (0.5–32 kHz, 118 dB SPL) for 4 h/day during 4 consecutive days to induce long-lasting hearing damage. Noise-exposed rats developed a permanent threshold shift which was associated with hair cell loss and reactive glia. Noise-induced microglial activation peaked in the cochlea between 1 and 10D post-lesion; their activation in the CN was more prolonged reaching maximum levels at 30D post-exposure. RT-PCR analyses of inflammatory-related genes expression in the cochlea demonstrated significant increases in the mRNA expression levels of pro- and anti-inflammatory cytokines, inducible nitric oxide synthase, intercellular adhesion molecule and tissue inhibitor of metalloproteinase-1 at 1 and 10D post-exposure. In noise-exposed cochleae, interleukin-1β (IL-1β), and tumor necrosis factor α (TNF-α) were upregulated by reactive microglia, fibrocytes, and neurons at all time points examined. In the CN, however, neurons were the sole source of these cytokines. These observations suggest that noise exposure causes peripheral and central inflammatory reactions in which TNF-α and IL-1β are implicated in regulating the initiation and progression of noise-induced hearing loss.

Pathophysiology of hearing loss : Classification and treatment options

From thetherapeutic perspective, the etiology and pathophysiology of hearing loss can be classified based on the extent of the primary cause. Hearing loss can have very different consequences for cell preservation in the organ of Corti and the spiral ganglion. These not only have implications for prosthetic therapy outcome, but may also influence the potential for future causal molecular therapies. Etiologies leading to deficits that are limited to one or a few molecules without having an effect on cell survival have the greatest potential for future causal therapy using molecular and cellular approaches. Preliminary success for molecular therapy was recently reported in animal experiments. Unfortunately, the incidence of these types of hearing loss is very low and in the future the therapy of hearing loss will therefore also require several different approaches. In addition to peripheral pathophysiology, hearing loss has consequences on the functioning of the brain, which can vary greatly due to individual adaptation to the situation without hearing. The authors therefore argue for individualization of the diagnostics and therapy that focus not only the symptom of hearing loss, but also the individual pathophysiology and consequences. Only with individualized therapy can the success of treating hearing disorders be significantly improved.

Quantification of hearing loss in patients with posterior semicircular canal dehiscence

Conclusion: Patients with posterior semicircular canal dehiscence (PSCD) have low frequency conductive hearing loss similar to patients with superior semicircular canal dehiscence (SSCD) secondary to a pathologic third window. Objectives: PSCD can result in conductive hearing loss, but the magnitude of this hearing loss remains to be quantified. Patients with SSCD have been shown to have low frequency conductive hearing loss. The underlying pathophysiology of hearing loss from PSCD and SSCD is similar and related to a pathologic third window. Method: A PubMed search was completed for a meta-analysis of patients with PSCD. Articles with quality audiograms were obtained. Air conduction thresholds for ears with posterior semicircular canal dehiscence were compared to the opposite ear as well as normal control data. Results: Eight articles with 21 patients with PSCD and quality audiograms were included. Two patients had bilateral PSCD and one of those was excluded because hearing thresholds were at the limit of the audiometer. Patients with posterior semicircular canal dehiscence have statistically significant lower air conduction thresholds in frequencies at and below 2000 Hz.

Gene therapy for sensorineural hearing loss.

Gene therapy is a promising treatment modality that is being explored for several inherited disorders. Multiple human gene therapy clinical trials are currently ongoing, but few are directed at hearing loss. Hearing loss is one of the most prevalent sensory disabilities in the world, and genetics play an important role in the pathophysiology of hearing loss. Gene therapy offers the possibility of restoring hearing by overcoming the functional deficits created by the underlying genetic mutations. In addition, gene therapy could potentially be used to induce hair cell regeneration by delivering genes that are critical to hair cell differentiation into the cochlea. In this review, we examine the promises and challenges of applying gene therapy to the cochlea. We also summarize recent studies that have applied gene therapy to animal models of hearing loss.

NF2 Genetic Alterations in Sporadic Vestibular Schwannomas

NF2 gene alterations may have a clinical impact in non-NF2 vestibular schwannomas (VSs). It has been suggested that NF2 mutations might correlate with clinical expression of VS in NF2 patients. The aim of this study was to analyze the impact of genetic alterations in the NF2 gene on epidemiologic, clinical, and radiologic features of patients with sporadic VS. The association between cigarette consumption and the molecular genetic findings was also studied. The study group consisted of 51 patients who underwent surgery for removal of vestibular schwannoma in our institution between January 2006 and December 2010. Five highly polymorphic microsatellite DNA markers were used to observe the frequency of loss of heterozygosity (LOH) in chromosome 22. The NF2 gene mutations were detected using polymerase chain reaction amplification and denaturing high-performance liquid chromatography analysis (PCR/dHPLC), and direct sequencing of NF2. Multiplex ligation-dependent probe amplification (MLPA) of the NF2 gene was also performed. An NF2 mutation was identified in 49%, 22q LOH in 57%, and MLPA alterations in 13.7% of the cases. One mutational hit was present in 27%, and 2 hits were present in 45% of the tumors. No association was found between the type of NF2 mutation and relevant clinical parameters. The presence of NF2 mutations detected by PCR/dHPLC was associated with no complaint of hearing loss at the time of diagnosis (p = 0.023), with subjective aural fullness (p = 0.022) and with an absence of tumor involvement of the internal auditory canal (p = 0.029). Patients with NF2 mutations had lower mean corrected PTA thresholds compared with those with no NF2 mutation (p = 0.037). Inactivation of the NF2 gene by mutation, MLPA, or LOH was more frequent in smokers when compared with never smokers (p = 0.048). NF2 mutations may play a role in the pathophysiology of hearing loss as well as in the pattern of growth of VS. Cigarette smoking in patients with VS seems to play a role in both the risk of developing the tumor and also in its genetic profile. More studies are needed to corroborate these results and, more broadly, to establish links between molecular and clinical data.

Steroids for Idiopathic Sudden Sensorineural Hearing Loss

IDIOPATHIC SUDDEN SENSORINEURAL HEARING LOSS, OR sudden deafness, is the acute onset of hearing loss of at least 30 dB in 3 connected frequencies occurring instantaneously or over a period of up to 3 days. Sudden hearing loss is thought to be relatively rare, occurs mainly in patients between the ages of 30 and 60 years, and can be devastating for the patient. Therefore, sudden hearing loss should be treated as a medical emergency. The natural course is characterized by spontaneous recovery among approximately 50% of patients. Accurate estimates of incidence are difficult to obtain because a significant number of patients who spontaneously recover do not seek medical attention. As the term idiopathic implies, the etiology and pathophysiology of hearing loss are unknown. Possible causes include infections (especially viruses), autoimmune disease, circulatory problems, and neurological disease, including multiple sclerosis. Treatment options include oral steroids, intratympanic steroid injections, oral antivirals, vasodilators, diuretics, hyperbaric oxygen therapy, and vitamins. As a result of the high rate of spontaneous resolution, multiple potential causes, and absence of validated tests for etiological identification, the evaluation of treatment effectiveness is difficult. In this issue of JAMA, Rauch and colleagues describe the findings from the first multi-institutional study of oral vs intratympanic corticosteroid therapy for hearing loss. In this study, 2443 adult patients were assessed for eligibility at 16 different academic and community-based otology practices. Of these patients, 250 (10%) agreed to participation and were randomized to receive either 60 mg/d oral prednisone for 14 days with a 5-day taper (n=121) or four 1-mL doses of 40 mg/mL of methylprednisolone injected into the middle ear over a 2-week period (n=129). Audiometry and safety monitoring were performed at screening, and after 1 week, 2 weeks, 2 months, and 6 months of treatment. The primary study hypothesis was that intratympanic methylprednisolone is inferior to oral prednisone for the treatment of hearing loss. The investigators established an average of more than 10 dB as the clinically significant amount of audiometric difference between the 2 study groups. Subgroup analyses of patients based on the amount of hearing loss ( 90-dB or 90-dB pure-tone average [PTA]) were specified a priori. The primary finding of the study was a 2.0-dB difference in PTA between the 2 treatment groups at 2 months with a maximum difference (upper limit of the confidence interval) of 6.6 dB. This value of 6.6 dB was below the required value of 10 dB to demonstrate clinical significance and reject the null hypothesis of noninferiority (ie, intratympanic treatment is worse than oral prednisone). Among the patients who presented with hearing loss of 90 dB or greater and dizziness, came for treatment in fewer than 7 days from onset, or had no prior steroid use, the possibility of a clinically meaningful difference in hearing recovery between the 2 groups could not be ruled out. Overall, the 2 treatments were well tolerated, and the number and severity of serious adverse events and adverse events were similar between groups, as had been anticipated from prior studies. However, of the patients randomized to receive intratympanic steroids, 3.1% had persistent tympanic membrane perforation and 4.7% had persistent otitis media vs 0% and 0.8% in the oral group, respectively. At present, the emergency administration of a tapering dose of systemic steroids after hearing loss onset is widely considered standard treatment. Several uncontrolled studies suggested that intratympanic steroids have equivalent efficacy as oral steroids, while minimizing the potential adverse systemic effects of oral steroids. The practice of prescribing a tapering dose of oral steroids is largely based on the results of 1 randomized clinical study and a retrospective study. In the study by Wilson et al, patients in the steroid group had a recovery rate (61%) that was similar (65%) to untreated patients reported by Mattox and Sim-

Hearing Improvement in a Growing Vestibular Schwannoma

Vestibular schwannomas are benign, slow-growing tumors that originate from Schwann cells lining the vestibular nerves, most commonly the superior vestibular nerve. They arise at the neurilemmal/neuroglial junction which is situated within the internal auditory canal. They have an incidence of 1 per 100,000 per year and a prevalence of around 700 per million. A case of a patient undergoing a period of observation for a vestibular schwannoma whose hearing improved despite growth of the tumor is described. This raises interesting questions regarding the pathophysiology of hearing loss in patients with vestibular schwannomas. Possible hypotheses are discussed.

Central role of supporting cells in cochlear homeostasis and pathology

Supporting cells have a crucial role in degenerative and regenerative events of primary sensorial hair cells of the organ of Corti. This new role should determine future studies about pathophysiology of hearing loss and its regenerative treatment. Recent findings suggest an active role of supporting cells in the maintenance of hair cell function and structure. Evidences of high energy consumption and close proximity to auditory nervous fibers suggesting K+ active exchange, preferential expression of specific proteins and antigens, presence of glucocorticoids receptors, affinity for cisplatin and regenerative potential give the supporting cells an important role in homeostasis of the organ of Corti and in some specific diseases affecting this structure. As well as glial cells provide protection and regeneration to neural tissues, supporting cells may provide the necessary metabolic and electrolitic conditions for hair cells mechanical and bioelectrical function. This opens new possibilities for the treatment of apparently "irreversible" destruction of the inner ear.

Reversible hearing loss associated with high-voltage electric shock

Hearing loss associated with high-voltage electric shock is a rare entity and minimal information is available in the current literature about this condition. To our knowledge, this article represents the first case report in the literature of improvement in sensorineural hearing loss sustained due to a high-voltage electric shock. A case report of a patient who incurred various otologic problems, including hearing loss and tinnitus, is presented. An improvement in hearing loss and tinnitus was observed in the subsequent follow up after one month. Audiological findings and possible pathophysiology of hearing loss are discussed. We recommend that further studies be done to investigate the incidence, severity and pathophysiology of hearing loss in such cases.

Oxidative Stress in Aging in the C57B16/J Mouse Cochlea

Presbycusis is a complex of high frequency hearing loss and disproportionate loss of speech discrimination that is seen concomitantly with physical signs of aging. Among the most extensively characterized strains of mice that show an early hearing loss is the C57B16/J strain, a strain that shows early onset of high frequency hearing loss at age 6 months and complete hearing loss by 1 year of age. The histopathology of this strain consists of loss of hair cells and spiral ganglion neurons in the basal turn, with a progression of loss of hair cells and ganglion neurons towards the apical portion of the cochlea as the animal ages. The process of aging has been extensively studied and although details differ in various organisms the consensus today is that oxidative stress, i.e. free radical-mediated tissue damage, is one of the core mechanisms of aging. Aerobic metabolism results in the creation of hydrogen peroxide and reactive oxygen species. These are normally detoxified by a variety of enzymes and free radical scavengers, including superoxide dismutase (SOD), catalase and glutathione. To determine whether oxidative stress plays a role in the pathophysiology of hearing loss in this mouse model of presbycusis we determined the relative change in mRNA production for selected free radical detoxifying enzymes in the C57B16/J mouse cochlea. Using semi-quantitative RT-PCR with tubulin mRNA as a control, relative levels of antioxidant enzyme mRNAs were determined. There was an overall increase in SOD1 mRNA levels when comparing 1 and 9 month time points, and a transient increase in the expression level of catalase mRNA. B6.CAST +Ahl mice, which carry the C57B16/J genome but receive their Ahl gene from CAST mice, do not show these alteractions in antioxidant enzyme production. Our results suggest that at an age of 9 months, at which point significant hearing loss has developed, the C57B16/J mouse cochlea is exposed to increased levels of free radicals and that the Ahl gene of the C57B16/J mouse mediates this decrease in protective enzymes and therefore increase in levels of oxidative stress.