Phenotypic spectrum of tinnitus patients bearing rare ANK2 gene variants.

PURPOSE: To describe the clinical, audiological, and psychometric features observed in patients with chronic tinnitus and rare variants in the ANK2 gene. METHODS: We report a case series of 12 patients with chronic tinnitus and heterozygous variants in the ANK2 gene. Tinnitus phenotyping included audiological (standard and high-frequency audiometry, Auditory Brainstem Responses (ABR) and Auditory Middle Latency Responses (AMLR)), psychoacoustic and psychometric assessment by a Visual Analog Scale (VAS) for tinnitus annoyance, the Tinnitus Handicap Inventory (THI), the test on Hypersensitivity to Sound (THS-GÜF), the Patient Health Questionnaire (PHQ-9), the Hospital Anxiety and Depression Scale (HADS) and the Montreal Cognitive Assessment (MoCA). RESULTS: All patients reported a persistent, unilateral noise-type tinnitus, mainly described as white noise or narrowband noise. Seven patients (58%) were considered to have extreme phenotype (THI score > 76), and all patients reported some degree of hyperacusis (THS-GÜF score > 18 in 75% of patients). Seven patients scored MoCA < 26, regardless of the age reported, suggesting a mild cognitive disorder. ABR showed no significant differences in latencies and amplitudes between ears with or without tinnitus. Similarly, the latencies of Pa, Pb waves, and NaPa complex in the AMLR did not differ based on the presence of tinnitus. However, there were statistical differences in the amplitudes of Pa waves in AMLR, with significantly greater amplitudes observed in ears with tinnitus. CONCLUSION: Patients with ANK2 variants and severe tinnitus exhibit an endophenotype featuring hyperacusis, persistent noise-like tinnitus, high-frequency hearing loss, and decreased amplitudes in AMLR. However, anxiety, depression, and cognitive symptoms vary among individuals.

The statistical analysis plan for the unification of treatments and interventions for tinnitus patients randomized clinical trial (UNITI-RCT).

BACKGROUND: Tinnitus is a leading cause of disease burden globally. Several therapeutic strategies are recommended in guidelines for the reduction of tinnitus distress; however, little is known about the potentially increased effectiveness of a combination of treatments and personalized treatments for each tinnitus patient. METHODS: Within the Unification of Treatments and Interventions for Tinnitus Patients project, a multicenter, randomized clinical trial is conducted with the aim to compare the effectiveness of single treatments and combined treatments on tinnitus distress (UNITI-RCT). Five different tinnitus centers across Europe aim to treat chronic tinnitus patients with either cognitive behavioral therapy, sound therapy, structured counseling, or hearing aids alone, or with a combination of two of these treatments, resulting in four treatment arms with single treatment and six treatment arms with combinational treatment. This statistical analysis plan describes the statistical methods to be deployed in the UNITI-RCT. DISCUSSION: The UNITI-RCT trial will provide important evidence about whether a combination of treatments is superior to a single treatment alone in the management of chronic tinnitus patients. This pre-specified statistical analysis plan details the methodology for the analysis of the UNITI trial results. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663828 . The trial is ongoing. Date of registration: December 11, 2020. All patients that finished their treatment before 19 December 2022 are included in the main RCT analysis.

Rare Deletions or Large Duplications Contribute to Genetic Variation in Patients with Severe Tinnitus and Meniere Disease.

Meniere disease (MD) is a debilitating disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. Severe tinnitus, which occurs in around 1% of patients, is a multiallelic disorder associated with a burden of rare missense single nucleotide variants in synaptic genes. Rare structural variants (SVs) may also contribute to MD and severe tinnitus. In this study, we analyzed exome sequencing data from 310 MD Spanish patients and selected 75 patients with severe tinnitus based on a Tinnitus Handicap Inventory (THI) score > 68. Three rare deletions were identified in two unrelated individuals overlapping the ERBB3 gene in the positions: NC_000012.12:g.56100028_56100172del, NC_000012.12:g.56100243_56101058del, and NC_000012.12:g.56101359_56101526del. Moreover, an ultra-rare large duplication was found covering the AP4M1, COPS6, MCM7, TAF6, MIR106B, MIR25, and MIR93 genes in another two patients in the NC_000007.14:g.100089053_100112257dup region. All the coding genes exhibited expression in brain and inner ear tissues. These results confirm the contribution of large SVs to severe tinnitus in MD and pinpoint new candidate genes to get a better molecular understanding of the disease.

Unification of Treatments and Interventions for Tinnitus Patients (UNITI): a study protocol for a multi-center randomized clinical trial.

BACKGROUND: Tinnitus represents a relatively common condition in the global population accompanied by various comorbidities and severe burden in many cases. Nevertheless, there is currently no general treatment or cure, presumable due to the heterogeneity of tinnitus with its wide variety of etiologies and tinnitus phenotypes. Hence, most treatment studies merely demonstrated improvement in a subgroup of tinnitus patients. The majority of studies are characterized by small sample sizes, unstandardized treatments and assessments, or applications of interventions targeting only a single organ level. Combinatory treatment approaches, potentially targeting multiple systems as well as treatment personalization, might provide remedy and enhance treatment responses. The aim of the present study is to systematically examine established tinnitus therapies both alone and in combination in a large sample of tinnitus patients. Further, it wants to provide the basis for personalized treatment approaches by evaluating a specific decision support system developed as part of an EU-funded collaborative project (Unification of treatments and interventions for tinnitus patients; UNITI project). METHODS/STUDY DESIGN: This is a multi-center parallel-arm randomized clinical trial conducted at five different clinical sites over the EU. The effect of four different tinnitus therapy approaches (sound therapy, structured counseling, hearing aids, cognitive behavioral therapy) applied over a time period of 12 weeks as a single or rather a combinatory treatment in a total number of 500 chronic tinnitus patients will be investigated. Assessments and interventions are harmonized over the involved clinical sites. The primary outcome measure focuses on the domain tinnitus distress assessed via the Tinnitus Handicap Inventory. DISCUSSION: Results and conclusions from the current study might not only provide an essential contribution to combinatory and personalized treatment approaches in tinnitus but could also provide more profound insights in the heterogeneity of tinnitus, representing an important step towards a cure for tinnitus. TRIAL REGISTRATION: ClinicalTrials.gov NCT04663828 . Registered on 11 December 2020.

Towards a unification of treatments and interventions for tinnitus patients: The EU research and innovation action UNITI.

Tinnitus is the perception of a phantom sound and the patient's reaction to it. Although much progress has been made, tinnitus remains a scientific and clinical enigma of high prevalence and high economic burden, with an estimated prevalence of 10%-20% among the adult population. The EU is funding a new collaborative project entitled "Unification of Treatments and Interventions for Tinnitus Patients" (UNITI, grant no. 848261) under its Horizon 2020 framework. The main goal of the UNITI project is to set the ground for a predictive computational model based on existing and longitudinal data attempting to address the question of which treatment or combination of treatments is optimal for a specific patient group based on certain parameters. Clinical, epidemiological, genetic and audiological data, including signals reflecting ear-brain communication, as well as patients' medical history, will be analyzed making use of existing databases. Predictive factors for different patient groups will be extracted and their prognostic relevance validated through a Randomized Clinical Trial (RCT) in which different patient groups will undergo a combination of tinnitus therapies targeting both auditory and central nervous systems. From a scientific point of view, the UNITI project can be summarized into the following research goals: (1) Analysis of existing data: Results of existing clinical studies will be analyzed to identify subgroups of patients with specific treatment responses and to identify systematic differences between the patient groups at the participating clinical centers. (2) Genetic and blood biomarker analysis: High throughput Whole Exome Sequencing (WES) will be performed in well-characterized chronic tinnitus cases, together with Proximity Extension Assays (PEA) for the identification of blood biomarkers for tinnitus. (3) RCT: A total of 500 patients will be recruited at five clinical centers across Europe comparing single treatments against combinational treatments. The four main treatments are Cognitive Behavioral Therapy (CBT), hearing aids, sound stimulation, and structured counseling. The consortium will also make use of e/m-health applications for the treatment and assessment of tinnitus. (4) Decision Support System: An innovative Decision Support System will be implemented, integrating all available parameters (epidemiological, clinical, audiometry, genetics, socioeconomic and medical history) to suggest specific examinations and the optimal intervention strategy based on the collected data. (5) Financial estimation analysis: A cost-effectiveness analysis for the respective interventions will be calculated to investigate the economic effects of the interventions based on quality-adjusted life years. In this paper, we will present the UNITI project, the scientific questions that it aims to address, the research consortium, and the organizational structure.