Tinnitus, biomarkers and quality of life in an older population

Tinnitus is a symptom involving the perception of sound in the ears or head, without a corresponding external acoustic stimulus. It is related to many different conditions and has a major impact on quality of life of the affected person. Currently, its diagnosis and monitoring are based on subjective audiometric and psychometric measures. There are no objective methods for tinnitus identification. In addition, the pathophysiological mechanisms underlying tinnitus remains unknown. The purpose of this thesis was to study the mechanisms underlying tinnitus and their relationship to hearing loss, being that hearing loss is the comorbidity most frequently associated with tinnitus. It also aimed to evaluate the contribution of genetic, audiological and immunological factors to the etiology of tinnitus. For this purpose, systematic reviews (SR) were performed, in order to account the state of art, the perspectives of the patient and their relatives, and previous clinical trials of tinnitus treatments. SRs contributed to the identification of a pool of tinnitus-related complaint domains used by COMIT’ID (Core outcome measures in tinnitus international Delphi) in a 3-round internet-based Delphi survey to identifying core outcome sets (COS), i.e., which complaints related to tinnitus are essential for evaluation in clinical trials. These recommendations are specific to the three main therapeutic modalities: sound, psychological, and pharmacological. In order to contribute to the standardization of tinnitus clinical evaluation and treatment, TINNET, a European network for scientific tinnitus research, was created. Among the different activities carried out in were a systematic review of existing national clinical practice guidelines for the diagnosis and treatment of tinnitus. This review contributed to the development of a multidisciplinary European guideline for tinnitus: diagnosis, evaluation and treatment. This guideline was presented at TINNET final meeting and it is being disseminated widely. Another aim of the present thesis was to review work on somatosensory tinnitus (pathophysiology, diagnosis, treatment and the participation in an international Delphi consensus group on the diagnosis of this subtype of tinnitus), to contribute to a better understanding of this subtype of tinnitus. In order to achieve the objectives of this PhD study, 114 participants aged 55 to 75 years were recruited from the Portuguese population. Participants were divided into four groups according to the presence/absence of tinnitus and hearing loss. The completion of the study protocol gave rise to four original research articles, including a demographic characterization, relevant psychological and quality of life aspects comparing the studied population and the published literature, audiologic markers of tinnitus, and immunological profile of population and biomarkers of presbycusis and tinnitus. The results point to hearing loss as a risk factor for the development of tinnitus and psychological complaints as a risk factor for more severe tinnitus and consequently less quality of life in patients with this symptom. In characterizing audiological markers, the presence of previous noise exposure and the hearing loss increased the probability of developing tinnitus. Also, participants with an abrupt onset of tinnitus and who had a negative effect or rebound on residual inhibition were more likely to develop severe or catastrophic tinnitus. For the population with tinnitus, a reduction in amplitude of auditory evoked potentials wave I and a higher values in the 'Ratio of Waves V/I for both ears' were associated with a greater probability of developing severe or catastrophic tinnitus. The inflammatory profile of the study population showed significant differences in IL10 levels between the group with and without tinnitus. IL1α was significantly higher in patients with tonal tinnitus, while IL2 was higher in participants who reported negative or rebound effect on residual inhibition of tinnitus. A negative correlation was also found between IL10 and tinnitus duration, and between HSP70 and tinnitus intensity. Biomarkers were explored in this thesis. A systematic review was performed to synthesize evidence for the existence and clinical usefulness of biomarkers. GRM7 and NAT2 were evaluated in the thesis population. The results indicate a higher prevalence of the T allele in the GRM7 gene (60.3% T/T and 33.3% A/T). Participants with a T/T genotype appeared to be at a higher risk for ARHL development, and 33% have a lower risk of developing tinnitus compared to participants with A/A and A/T genotype. Regarding the NAT2 phenotype, the slow acetylator (53%) was most common, followed by the intermediate acetylator (35.9%). These results suggest that the AT allele of GRM7 and the slow acetylating phenotype of Nat2 are potential biomarkers of tinnitus severity. The results in this thesis are very interesting and original, showing us the need for future research in larger samples, and employing rigorous methodological design in order to control for confounding variables. On the other hand, translational studies may be the key to clarifying the pathophysiologic dilemmas of tinnitus.O acufeno é um sintoma referente à perceção de um som nos ouvidos ou na cabeça, sem que exista um estímulo acústico externo correspondente. Está presente em diferentes patologias (otológicas ou não) e tem um impacto importante na qualidade de vida da pessoa afetada. Atualmente, o seu diagnóstico e monitorização são baseados em medidas subjetivas audiométricas e psicométricas, sendo que não existem métodos objetivos para a identificação do acufeno. Além disso, os mecanismos fisiopatológicos subjacentes ao acufeno subjectivo permanecem desconhecidos. O objetivo da presente tese é estudar os mecanismos subjacentes ao acufeno subjectivo e a sua relação com a surdez, visto que a surdez é a co-morbilidade mais frequentemente associada ao acufeno. Pretende-se também avaliar a contribuição dos fatores genéticos, audiológicos e imunológicos na etiologia do acufeno. Para isso, foram realizadas revisões sistemáticas (RS) sobre esta temática de forma a conhecer o estado de arte, primeiramente em relação à forma como os pacientes e os familiares percecionam o acufeno e também sobre os ensaios clínicos existentes acerca da eficácia do tratamento do acufeno. Ambas as RS contribuíram para a identificação de um conjunto de domínios relacionados com o acufeno, usado pelo COMIT’ID (Core outcome measures in tinnitus international Delphi), num método de consensos Delphi, baseado na Internet, com o objetivo de identificar um ‘Core Outcome Set’ (ou seja definir quais as queixas relacionadas com o acufeno que são imprescindíveis para a sua avaliação) recomendado para ensaios clínicos de eficácia terapêutica para o acufeno assim como para o seu diagnóstico. Estas recomendações são específicas para as três modalidades terapêuticas principais: sonora, psicológica e farmacológica uma vez que cada modalidade tem fundamentos específicos e por isso visam avaliar diferentes aspetos do acufeno. Com o objetivo de contribuir para a padronização da avaliação e do tratamento clínico do acufeno, foi constituída a TINNET, uma rede europeia para a investigação científica do acufeno. Considerando o objetivo do presente estudo e a hipótese de integrar esta rede europeia, foram desenvolvidas um conjunto de atividades que em muito contribuíram para o conhecimento sobre o acufenos. Entre as diferentes atividades realizadas com o apoio da TINNET destaca-se a realização de uma revisão sistemática sobre as ‘guidelines’ clínicas existentes para o diagnóstico e tratamento do acufeno. Esta revisão foi uma das bases que conduziu ao desenvolvimento das ‘guidelines’ europeias multidisciplinares para o acufeno: diagnóstico, avaliação e tratamento. Estas ‘guidelines’ foram apresentadas na conferência final do TINNET e estão atualmente em fase de disseminação. Outro foco de interesse da presente tese foi a realização de trabalhos de revisão sobre o acufeno somatosensorial (nomeadamente sobre a fisiopatologia, diagnóstico e tratamento), bem como a participação num grupo de consenso internacional sobre o diagnóstico deste subtipo do acufeno, de forma a contribuir para uma melhor compreensão deste subtipo do acufeno. Também estas atividades contribuíram para o desenvolvimento de competências cientificas essenciais ao desenvolvimento do presente estudo, dado que permitiram uma melhor compreensão deste subtipo do acufeno, demonstrando-se a heterogeneidade e diversidade do acufeno. De forma a alcançar os objetivos deste estudo de doutoramento, recrutaram-se 114 voluntários da população portuguesa com idade dos 55 aos 75 anos. Os indivíduos desta amostra permitiam a realização de diferentes estudos nomeadamente os laboratoriais, tendo a analise dos resultados envolvido a amostra dividida em quatro grupos consoante a presença/ausência do acufeno e de surdez. Dos resultados desta tese fazem parte quatro artigos originais que e incluem uma caracterização demográfica, aspetos relevantes a nível psicológico e de qualidade de vida, marcadores audiológicos do acufeno, perfil imunológico da população e biomarcadores da presbiacusia e do acufeno. Os resultados obtidos sugerem a perda auditiva como fator de risco para o desenvolvimento do acufeno e as queixas a nível psicológico como fator de risco para o acufeno mais grave e consequentemente associado a menor qualidade de vida nos pacientes com este sintoma. A nível da caracterização dos marcadores audiológicos, verificou-se que a presença de antecedentes de exposição ao ruído e a perda auditiva aumentam a probabilidade de desenvolver acufeno. Também, os participantes com um início abrupto do acufeno e que apresentam um efeito negativo ou ‘rebound’ na inibição residual têm maior probabilidade de desenvolver acufeno grave ou catastrófico. Encontrou-se nos Potenciais Evocados Auditivos, uma redução da amplitude na onda I em pacientes com acufeno, bem como valores maiores no ‘Ratio de amplitude das ondas V e I de ambos ouvidos’ estando associados a maiores probabilidades de desenvolver acufeno severo ou catastrófico. O perfil inflamatório da nossa população mostra diferenças significativas entre o grupo com e sem acufeno quando comparados para a IL10. Quanto à relação entre os parâmetros imunológicos e a acufenometria, verificou-se uma correlação entre o aumento da IL1α e acufeno tonal, bem como entre o aumento da IL2 e a inibição residual do acufeno. Foi também encontrada uma correlação negativa para a IL10 e a duração do acufeno e para o HSP70 e a intensidade do acufeno. Estes resultados são muito originais e suscitam a necessidade de estudos futuros que permitam esclarecer os mecanismos subjacentes às correlações encontradas. Em relação aos biomarcadores, foi efetuada uma revisão sistemática com a finalidade de sintetizar evidências para a existência e utilidade clínica dos biomarcadores para o desenvolvimento ou gravidade do acufeno. Foi também realizado um estudo acerca do papel do GRM7 e do NAT2 na nossa amostra. Os resultados apontam para uma maior prevalência do alelo T no gene GRM7 (60,3% T/T e 33,3% A/T). Os participantes com um genótipo T/T parecem ter um maior risco para o desenvolvimento de ARHL e 33% apresentam menor risco para o desenvolvimento do acufeno, em comparação com indivíduos com A/A e genótipo A/T. Em relação ao fenótipo NAT2, o acetilador lento (53%) foi o mais comum seguido pelo intermediário acetilador (35,9%). Os nossos resultados sugerem que o genótipo A/T de GRM7 e o fenótipo acetilador lento de NAT2 como potenciais biomarcadores da severidade do acufeno. Os resultados obtidos são originais e no seu conjunto são muito interessantes, apontando para a necessidade de estudos futuros em larga escala de forma a aprofundar as conclusões aqui obtidas. Por outro lado, os estudos translacionais poderão ser a chave para esclarecer os dilemas da fisiopatologia do acufeno

Neurotological consequences of long COVID

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protocol for a systematic review

Introduction In Europe alone, over 70 million people experience tinnitus. Despite its considerable socioeconomic relevance, progress in developing successful treatments has been limited. Clinical effectiveness is judged according to change in primary outcome measures, but because tinnitus is a subjective condition, the definition of outcomes is challenging and it remains unclear which distinct aspects of tinnitus (ie, ‘domains’) are most relevant for assessment. The development of a minimum outcome reporting standard would go a long way towards addressing these problems. In 2006, a consensus meeting recommended using 1 of 4 questionnaires for tinnitus severity as an outcome in clinical trials, in part because of availability in different language translations. Our initiative takes an approach motivated by clinimetrics, first by determining what to measure before seeking to determine how to measure it. Agreeing on the domains that contribute to tinnitus severity (ie, ‘what’) is the first step towards achieving a minimum outcome reporting standard for tinnitus that has been reached via a methodologically rigorous and transparent process. Methods and analysis Deciding what should be the core set of outcomes requires a great deal of discussion and so lends itself well to international effort. This protocol lays out the first-step methodology in defining a Core Domain Set for clinical trials of tinnitus by establishing existing knowledge and practice with respect to which outcome domains have been measured and which instruments used in recent registered and published clinical trials. Ethics and dissemination No ethical issues are foreseen. Findings will be reported at national and international ear, nose and throat (ENT) and audiology conferences and in a peer-reviewed journal, using PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analysis) guidelines. Trial registration number The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525

Treatment of patients with somatic tinnitus attributed to temporomandibular disorder: a case report

Communication abstract: Proceedings of the 5th International Congress of CiiEM - Reducing inequalities in Health and Society, held at Egas Moniz’ University Campus in Monte de Caparica, Almada, from June 16th to 18th, 2021.This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Tinnitus is a common symptom described in patients with temporomandibular disorders (TMDs), affecting quality of life and frequently causing distress. Somatic or somatosensory tinnitus can be attributed to the somatic system of the temporomandibular or cervical spine. Due to the multifactorial etiology of TMD, its management should be based on a multidisciplinary approach. Dentists and physical therapists may play a role in the individual and multimodal management of such patients. The aim of this case study is to analyse the effects of the conservative multidisciplinary management of tinnitus in patients with coexisting tinnitus, TMD and bruxism.info:eu-repo/semantics/publishedVersio

Biomarkers of presbycusis and tinnitus in a Portuguese older population

Trabalho apresento em TRI / TINNET Conference 2018, 14-16 março de 2018, Regensburg, GermanyN/

Evidence for biological markers in tinnitus: a systematic review

Trabalho apresento em TRI / TINNET Conference 2018, 14-16 março de 2018, Regensburg, GermanyN/

Audiological biomarkers of tinnitus in an older Portuguese population

Copyright © 2022 Haider, Ribeiro, Ribeiro, Trigueiros, Caria, Borrego, Pinto, Papoila, Hoare and Paço.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.publishersversionpublishe

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-β 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

Pathophysiology of Subjective Tinnitus: Triggers and Maintenance

Tinnitus is the conscious perception of a sound without a corresponding external acoustic stimulus, usually described as a phantom perception. One of the major challenges for tinnitus research is to understand the pathophysiological mechanisms triggering and maintaining the symptoms, especially for subjective chronic tinnitus. Our objective was to synthesize the published literature in order to provide a comprehensive update on theoretical and experimental advances and to identify further research and clinical directions. We performed literature searches in three electronic databases, complemented by scanning reference lists from relevant reviews in our included records, citation searching of the included articles using Web of Science, and manual searching of the last 6 months of principal otology journals. One-hundred and thirty-two records were included in the review and the information related to peripheral and central mechanisms of tinnitus pathophysiology was collected in order to update on theories and models. A narrative synthesis examined the main themes arising from this information. Tinnitus pathophysiology is complex and multifactorial, involving the auditory and non-auditory systems. Recent theories assume the necessary involvement of extra-auditory brain regions for tinnitus to reach consciousness. Tinnitus engages multiple active dynamic and overlapping networks. We conclude that advancing knowledge concerning the origin and maintenance of specific tinnitus subtypes origin and maintenance mechanisms is of paramount importance for identifying adequate treatment

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 healthcare 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 are 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 in the database of the Core Outcome Measures in Effectiveness Trials (COMET) initiative