Tinnitus, hearing loss and inflammatory processes in an older Portuguese population.

Objective: Tinnitus is associated with various conditions such as presbycusis, infectious, autoimmune and many other diseases. Our study aims to identify an association between inflammatory markers and the presence of tinnitus or hearing loss (HL).Design: Exploratory study including a structured interview, complete ENT observation, audiological and inflammatory markers evaluation.Study Sample: Sixty women and 54 men (55 to 75 years) from the Portuguese population, with or without sensory presbycusis and/or tinnitus.Results: IL10 levels were significantly lower in participants with tinnitus than in those without tinnitus. Moreover, TGF-ß was lower in older participants (p = 0.034), IL1α was higher in participants with tonal tinnitus (p = 0.033), and IL2 was lower in participants who reported partial or complete residual inhibition (p = 0.019). Additionally, we observed a negative correlation between tinnitus duration and IL10 levels (r= -.281), and between HSP70 levels and tinnitus loudness (r= -.377). TNF-α and HSP70 levels appears to be sensitive to the time when samples were collected (morning or afternoon).Conclusions: The results of our study showing fluctuations in inflammatory markers along the hearing loss process, reinforce the idea that inflammatory mechanisms are involved in hearing loss pathogenesis but also in tinnitus. IL10 levels appear significantly altered in tinnitus but not in hearing loss.

A narrative synthesis of research evidence for tinnitus-related complaints as reported by patients and their significant others.

BACKGROUND: There are a large number of assessment tools for tinnitus, with little consensus on what it is important to measure and no preference for a minimum reporting standard. The item content of tinnitus assessment tools should seek to capture relevant impacts of tinnitus on everyday life, but no-one has yet synthesised information about the range of tinnitus complaints. This review is thus the first comprehensive and authoritative collection and synthesis of what adults with tinnitus and their significant others report as problems in their everyday lives caused by tinnitus. METHODS: Electronic searches were conducted in PubMed, Embase, CINAHL, as well as grey literature sources to identify publications from January 1980 to June 2015 in which participants were enrolled because tinnitus was their primary complaint. A manual search of seven relevant journals updated the search to December 2017. Of the 3699 titles identified overall, 84 records (reporting 86 studies) met our inclusion criteria and were taken through to data collection. Coders collated generic and tinnitus-specific complaints reported by people with tinnitus. All relevant data items were then analyzed using an iterative approach to narrative synthesis to form domain groupings representing complaints of tinnitus, which were compared patients and significant others. RESULTS: From the 86 studies analyzed using data collected from 16,381 patients, 42 discrete complaints were identified spanning physical and psychological health, quality of life and negative attributes of the tinnitus sound. This diversity was not captured by any individual study alone. There was good convergence between complaints collected using open- and closed-format questions, with the exception of general moods and perceptual attributes of tinnitus (location, loudness, pitch and unpleasantness); reported only using closed questions. Just two studies addressed data from the perspective of significant others (n = 79), but there was substantial correspondence with the patient framework, especially regarding relationships and social life. CONCLUSIONS: Our findings contribute fundamental new knowledge and a unique resource that enables investigators to appreciate the broad impacts of tinnitus on an individual. Our findings can also be used to guide questions during diagnostic assessment, to evaluate existing tinnitus-specific HR-QoL questionnaires and develop new ones, where necessary. TRIAL REGISTRATION: PROSPERO registration number: CRD42015020629 . Protocol published in BMJ Open. 2016;6e009171.

Audiological biomarkers of tinnitus in an older Portuguese population.

Tinnitus is a phantom sound perceived in the absence of external acoustic stimulation. It is described in a variety of ways (e.g., buzzing, ringing, and roaring) and can be a single sound or a combination of different sounds. Our study evaluated associations between audiological parameters and the presence or severity of tinnitus, to improve tinnitus diagnosis, treatment, and prognosis. Our sample included 122 older participants (63 women and 59 men), aged 55-75 years from the Portuguese population, with or without sensory presbycusis and with or without tinnitus. All participants underwent a clinical evaluation through a structured interview, Ear, Nose, and Throat observation, and audiological evaluation (standard and extended audiometry, psychoacoustic tinnitus evaluation, auditory brainstem responses, and distortion product otoacoustic emissions). The Tinnitus Handicap Inventory was used to measure tinnitus symptom severity. Our data confirmed that the odds of developing tinnitus were significantly higher in the presence of noise exposure and hearing loss. Also, participants who had abrupt tinnitus onset and moderate or severe hyperacusis featured higher odds of at least moderate tinnitus. However, it was in the ABR that we obtained the most exciting and promising results, namely, in wave I, which was the common denominator in all findings. The increase in wave I amplitude is a protective factor to the odds of having tinnitus. Concerning the severity of tinnitus, the logistic regression model showed that for each unit of increase in the mean ratio V/I of ABR, the likelihood of having at least moderate tinnitus was 10% higher. Advancing knowledge concerning potential tinnitus audiological biomarkers can be crucial for the adequate diagnosis and treatment of tinnitus.

Quality of Life and Psychological Distress in Portuguese Older Individuals with Tinnitus.

Tinnitus is the perception of a sound without an external source, often associated with adverse psychological and emotional effects leading to impaired quality of life (QoL). The present study investigated QoL and psychological distress in tinnitus patients and analysed the effects of associated comorbidities. Tonal and speech audiometry, tinnitus assessment, and clinical interviews were obtained from 122 Portuguese individuals (aged from 55 to 75). Portuguese versions of the Brief Symptoms Inventory (BSI), the Medical Outcomes Study Short Form Health Survey (MOS SF-36) and Tinnitus Handicap Inventory (THI) were used to evaluate psychological distress, health-related QoL, social difficulties and tinnitus severity. The presence of tinnitus was significantly associated with hearing loss. The increases in tinnitus severity were associated with decreases in QoL, particularly regarding MOS SF-36 subscales "perception of health", "social functioning", and "mental health". Regarding BSI, patients with greater tinnitus severity had more severe psychopathology symptoms, measured with scales "Obsessive-compulsive", "Depression", "Anxiety", "Hostility" and "Phobic Anxiety". Our study supports the notion of the negative impact of increased tinnitus severity on QoL and psychological distress in older adults. Presented data strengthen the importance of a multidisciplinary approach to tinnitus assessment and treatment.

Evidence for biological markers of tinnitus: A systematic review.

Subjective tinnitus is a phantom sound heard only by the affected person and may be a symptom of various diseases. Tinnitus diagnosis and monitoring is based on subjective audiometric and psychometric methods. This review aimed to synthesize evidence for tinnitus presence or its severity. We searched several electronic databases, citation searches of the included primary studies through Web of Science, and further hand searches. At least two authors performed all systematic review steps. Sixty-two records were included and were categorized according the biological variable. Evidence for possible tinnitus biomarkers come from oxidative stress, interleukins, steroids and neurotransmitters categories. We found conflicting evidence for full blood count, vitamins, lipid profile, neurotrophic factors, or inorganic ions. There was no evidence for an association between tinnitus and the remaining categories. The current review evidences that larger studies, with stricter exclusion criteria and powerful harmonized methodological design are needed. Protocol published on PROSPERO (CRD42017070998).

One Size Does Not Fit All: Developing Common Standards for Outcomes in Early-Phase Clinical Trials of Sound-, Psychology-, and Pharmacology-Based Interventions for Chronic Subjective Tinnitus in Adults.

Good practice in clinical trials advocates common standards for assessing and reporting condition-specific complaints ("outcome domains"). For tinnitus, there is no common standard. The Core Outcome Measures in Tinnitus International Delphi (COMiT'ID) study created recommendations that are relevant to the most common intervention approaches for chronic subjective tinnitus in adults using consensus methods. Here, the objectives were to examine why it is important to tailor outcome domain selection to the tinnitus intervention that is being evaluated in the clinical trial and to demonstrate that the COMiT'ID recommendations are robust. The COMiT'ID study used an online three-round Delphi method with three separate surveys for sound-, psychology-, and pharmacology-based interventions. Survey data were analyzed to assess quality and confidence in the consensus achieved across surveys and stakeholder groups and between survey rounds. Results found participants were highly discriminatory in their decision-making. Of the 34 outcome domains reaching the prespecified consensus definition in the final round, 17 (50%) were unique to one intervention, while only 12 (35%) were common to all three. Robustness was demonstrated by an acceptable level of agreement across and within stakeholder groups, across survey rounds, across medical specialties (for the health-care practitioners), and across health-care users with varying tinnitus duration. There were few dissenting voices, and results showed no attrition bias. In conclusion, there is compelling evidence that one set of outcomes does not fit all therapeutic aims. Our analyses evidence robust decisions by the electronic Delphi process, leading to recommendations for three unique intervention-specific outcome domain sets. This provides an important starting point for standardization.

The COMiT'ID Study: Developing Core Outcome Domains Sets for Clinical Trials of Sound-, Psychology-, and Pharmacology-Based Interventions for Chronic Subjective Tinnitus in Adults.

Subjective tinnitus is a chronic heterogeneous condition that is typically managed using intervention approaches based on sound devices, psychologically informed therapies, or pharmaceutical products. For clinical trials, there are currently no common standards for assessing or reporting intervention efficacy. This article reports on the first of two steps to establish a common standard, which identifies what specific tinnitus-related complaints ("outcome domains") are critical and important to assess in all clinical trials to determine whether an intervention has worked. Using purposive sampling, 719 international health-care users with tinnitus, health-care professionals, clinical researchers, commercial representatives, and funders were recruited. Eligibility was primarily determined by experience of one of the three interventions of interest. Following recommended procedures for gaining consensus, three intervention-specific, three-round, Delphi surveys were delivered online. Each Delphi survey was followed by an in-person consensus meeting. Viewpoints and votes involved all stakeholder groups, with approximately a 1:1 ratio of health-care users to professionals. "Tinnitus intrusiveness" was voted in for all three interventions. For sound-based interventions, the minimum set included "ability to ignore," "concentration," "quality of sleep," and "sense of control." For psychology-based interventions, the minimum set included "acceptance of tinnitus," "mood," "negative thoughts and beliefs," and "sense of control." For pharmacology-based interventions, "tinnitus loudness" was the only additional core outcome domain. The second step will next identify how those outcome domains should best be measured. The uptake of these intervention-specific standards in clinical trials will improve research quality, enhance clinical decision-making, and facilitate meta-analysis in systematic reviews.

Diagnostic Criteria for Somatosensory Tinnitus: A Delphi Process and Face-to-Face Meeting to Establish Consensus.

Since somatic or somatosensory tinnitus (ST) was first described as a subtype of subjective tinnitus, where altered somatosensory afference from the cervical spine or temporomandibular area causes or changes a patient's tinnitus perception, several studies in humans and animals have provided a neurophysiological explanation for this type of tinnitus. Due to a lack of unambiguous clinical tests, many authors and clinicians use their own criteria for diagnosing ST. This resulted in large differences in prevalence figures in different studies and limits the comparison of clinical trials on ST treatment. This study aimed to reach an international consensus on diagnostic criteria for ST among experts, scientists and clinicians using a Delphi survey and face-to-face consensus meeting strategy. Following recommended procedures to gain expert consensus, a two-round Delphi survey was delivered online, followed by an in-person consensus meeting. Experts agreed upon a set of criteria that strongly suggest ST. These criteria comprise items on somatosensory modulation, specific tinnitus characteristics, and symptoms that can accompany the tinnitus. None of these criteria have to be present in every single patient with ST, but in case they are present, they strongly suggest the presence of ST. Because of the international nature of the survey, we expect these criteria to gain wide acceptance in the research field and to serve as a guideline for clinicians across all disciplines. Criteria developed in this consensus paper should now allow further investigation of the extent of somatosensory influence in individual tinnitus patients and tinnitus populations.

Core Outcome Domains for early phase clinical trials of sound-, psychology-, and pharmacology-based interventions to manage chronic subjective tinnitus in adults: the COMIT'ID study protocol for using a Delphi process and face-to-face meetings to establish consensus.

BACKGROUND: The reporting of outcomes in clinical trials of subjective tinnitus indicates that many different tinnitus-related complaints are of interest to investigators, from perceptual attributes of the sound (e.g. loudness) to psychosocial impacts (e.g. quality of life). Even when considering one type of intervention strategy for subjective tinnitus, there is no agreement about what is critically important for deciding whether a treatment is effective. The main purpose of this observational study is, therefore to, develop Core Outcome Domain Sets for the three different intervention strategies (sound, psychological, and pharmacological) for adults with chronic subjective tinnitus that should be measured and reported in every clinical trial of these interventions. Secondary objectives are to identify the strengths and limitations of our study design for recruiting and reducing attrition of participants, and to explore uptake of the core outcomes. METHODS: The 'Core Outcome Measures in Tinnitus: International Delphi' (COMIT'ID) study will use a mixed-methods approach that incorporates input from health care users at the pre-Delphi stage, a modified three-round Delphi survey and final consensus meetings (one for each intervention). The meetings will generate recommendations by stakeholder representatives on agreed Core Outcome Domain Sets specific to each intervention. A subsequent step will establish a common cross-cutting Core Outcome Domain Set by identifying the common outcome domains included in all three intervention-specific Core Outcome Domain Sets. To address the secondary objectives, we will gather feedback from participants about their experience of taking part in the Delphi process. We aspire to conduct an observational cohort study to evaluate uptake of the core outcomes in published studies at 7 years following Core Outcome Set publication. DISCUSSION: The COMIT'ID study aims to develop a Core Outcome Domain Set that is agreed as critically important for deciding whether a treatment for subjective tinnitus is effective. Such a recommendation would help to standardise future clinical trials worldwide and so we will determine if participation increases use of the Core Outcome Set in the long term. TRIAL REGISTRATION: This project has been registered (November 2014) in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative.

Biomarkers of Presbycusis and Tinnitus in a Portuguese Older Population.

Introduction: Presbycusis or age-related hearing loss (ARHL) is a ubiquitous health problem. It is estimated that it will affect up to 1.5 billion people by 2025. In addition, tinnitus occurs in a large majority of cases with presbycusis. Glutamate metabotropic receptor 7 (GRM7) and N-acetyltransferase 2 (NAT2) are some of the genetic markers for presbycusis. Objectives: To explore patterns of hearing loss and the role of GRM7 and NAT2 as possible markers of presbycusis and tinnitus in a Portuguese population sample. Materials and Methods: Tonal and speech audiometry, tinnitus assessment, clinical interview, and DNA samples were obtained from patients aged from 55 to 75 with or without tinnitus. GRM7 analysis was performed by qPCR. Genotyping of single nucleotide polymorphisms (SNPs) in NAT2 was performed by PCR amplification followed by Sanger sequencing or by qPCR. Results: We screened samples from 78 individuals (33 men and 45 women). T allele at GRM7 gene was the most observed (60.3% T/T and 33.3% A/T). Individuals with a T/T genotype have a higher risk for ARHL and 33% lower risk for tinnitus, compared to individuals with A/A and A/T genotype, respectively. Being a slow acetylator (53%) was the most common NAT2 phenotype, more common in men (55.8%). Intermediate acetylator was the second most common phenotype (35.9%) also more frequent in men (82.6%). Noise exposed individuals and individuals with 'high frequency' hearing loss seem to have a higher risk for tinnitus. Our data suggests that allele AT of GRM7 can have a statistically significant influence toward the severity of tinnitus. Conclusion: For each increasing year of age the chance of HL increases by 9%. The risk for ARHL was not significantly associated with GRM7 neither NAT2. However, we cannot conclude from our data whether the presence of T allele at GRM7 increases the odds for ARHL or whether the A allele has a protective effect. Genotype A/T at GRM7 could potentially be considered a biomarker of tinnitus severity. This is the first study evaluating the effect of GRM7 and NAT2 gene in tinnitus.

Pathophysiology, Diagnosis and Treatment of Somatosensory Tinnitus: A Scoping Review.

Somatosensory tinnitus is a generally agreed subtype of tinnitus that is associated with activation of the somatosensory, somatomotor, and visual-motor systems. A key characteristic of somatosensory tinnitus is that is modulated by physical contact or movement. Although it seems common, its pathophysiology, assessment and treatment are not well defined. We present a scoping review on the pathophysiology, diagnosis, and treatment of somatosensory tinnitus, and identify priority directions for further research. Methods: Literature searches were conducted in Google Scholar, PubMed, and EMBASE databases. Additional broad hand searches were conducted with the additional terms etiology, diagnose, treatment. Results: Most evidence on the pathophysiology of somatosensory tinnitus suggests that somatic modulations are the result of altered or cross-modal synaptic activity within the dorsal cochlear nucleus or between the auditory nervous system and other sensory subsystems of central nervous system (e.g., visual or tactile). Presentations of somatosensory tinnitus are varied and evidence for the various approaches to treatment promising but limited. Discussion and Conclusions: Despite the apparent prevalence of somatosensory tinnitus its underlying neural processes are still not well understood. Necessary involvement of multidisciplinary teams in its diagnosis and treatment has led to a large heterogeneity of approaches whereby tinnitus improvement is often only a secondary effect. Hence there are no evidence-based clinical guidelines, and patient care is empirical rather than research-evidence-based. Somatic testing should receive further attention considering the breath of evidence on the ability of patients to modulate their tinnitus through manouvers. Specific questions for further research and review are indicated.

Different Teams, Same Conclusions? A Systematic Review of Existing Clinical Guidelines for the Assessment and Treatment of Tinnitus in Adults.

Background: Though clinical guidelines for assessment and treatment of chronic subjective tinnitus do exist, a comprehensive review of those guidelines has not been performed. The objective of this review was to identify current clinical guidelines, and compare their recommendations for the assessment and treatment of subjective tinnitus in adults. Method: We systematically searched a range of sources for clinical guidelines (as defined by the Institute of Medicine, United States) for the assessment and/or treatment of subjective tinnitus in adults. No restrictions on language or year of publication were applied to guidelines. Results: Clinical guidelines from Denmark, Germany, Sweden, The Netherlands, and the United States were included in the review. There was a high level of consistency across the guidelines with regard to recommendations for audiometric assessment, physical examination, use of a validated questionnaire(s) to assess tinnitus related distress, and referral to a psychologist when required. Cognitive behavioral treatment for tinnitus related distress, use of hearing aids in instances of hearing loss and recommendations against the use of medicines were consistent across the included guidelines. Differences between the guidelines centered on the use of imaging in assessment procedures and sound therapy as a form of treatment for tinnitus distress respectively. Conclusion: Given the level of commonality across tinnitus guidelines from different countries the development of a European guideline for the assessment and treatment of subjective tinnitus in adults seems feasible. This guideline would have the potential to benefit the large number of clinicians in countries where clinical guidelines do not yet exist, and would support standardization of treatment for patients across Europe.