Screening for Circulating Inflammatory Proteins Does Not Reveal Plasma Biomarkers of Constant Tinnitus.

BACKGROUND AND OBJECTIVE: Tinnitus would benefit from an objective biomarker. The goal of this study is to identify plasma biomarkers of constant and chronic tinnitus among selected circulating inflammatory proteins. METHODS: A case-control retrospective study on 548 cases with constant tinnitus and 548 matched controls from the Swedish Tinnitus Outreach Project (STOP), whose plasma samples were examined using Olink's Inflammatory panel. Replication and meta-analysis were performed using the same method on samples from the TwinsUK cohort. Participants from LifeGene, whose blood was collected in Stockholm and Umeå, were recruited to STOP for a tinnitus subtyping study. An age and sex matching was performed at the individual level. TwinsUK participants (n = 928) were selected based on self-reported tinnitus status over 2 to 10 years. Primary outcomes include normalized levels for 96 circulating proteins, which were used as an index test. No reference standard was available in this study. RESULTS: After adjustment for age, sex, BMI, smoking, hearing loss, and laboratory site, the top proteins identified were FGF-21, MCP4, GDNF, CXCL9, and MCP-1; however, these were no longer statistically significant after correction for multiple testing. Stratification by sex did not yield any significant associations. Similarly, associations with hearing loss or other tinnitus-related comorbidities such as stress, anxiety, depression, hyperacusis, temporomandibular joint disorders, and headache did not yield any significant associations. Analysis in the TwinsUK failed in replicating the top candidates. Meta-analysis of STOP and TwinsUK did not reveal any significant association. Using elastic net regularization, models exhibited poor predictive capacity tinnitus based on inflammatory markers [sensitivity = 0.52 (95% CI 0.47-0.57), specificity = 0.53 (0.48-0.58), positive predictive value = 0.52 (0.47-0.56), negative predictive values = 0.53 (0.49-0.58), and AUC = 0.53 (0.49-0.56)]. DISCUSSION: Our results did not identify significant associations of the selected inflammatory proteins with constant tinnitus. Future studies examining longitudinal relations among those with more severe tinnitus and using more recent expanded proteomics platforms and sampling of cerebrospinal fluid could increase the likelihood of identifying relevant molecular biomarkers.

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice.

Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 (Slc17A8), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8-/- mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.

Alterations in auditory brain stem response distinguish occasional and constant tinnitus.

BACKGROUNDThe heterogeneity of tinnitus is thought to underlie the lack of objective diagnostic measures.METHODSLongitudinal data from 20,349 participants of the Swedish Longitudinal Occupational Survey of Health (SLOSH) cohort from 2008 to 2018 were used to understand the dynamics of transition between occasional and constant tinnitus. The second part of the study included electrophysiological data from 405 participants of the Swedish Tinnitus Outreach Project (STOP) cohort.RESULTSWe determined that with increasing frequency of the occasional perception of self-reported tinnitus, the odds of reporting constant tinnitus after 2 years increases from 5.62 (95% CI, 4.83-6.55) for previous tinnitus (sometimes) to 29.74 (4.82-6.55) for previous tinnitus (often). When previous tinnitus was reported to be constant, the odds of reporting it as constant after 2 years rose to 603.02 (524.74-692.98), suggesting that once transitioned to constant tinnitus, the likelihood of tinnitus to persist was much greater. Auditory brain stem responses (ABRs) from subjects reporting nontinnitus (controls), occasional tinnitus, and constant tinnitus show that wave V latency increased in constant tinnitus when compared with occasional tinnitus or nontinnitus. The ABR from occasional tinnitus was indistinguishable from that of the nontinnitus controls.CONCLUSIONSOur results support the hypothesis that the transition from occasional to constant tinnitus is accompanied by neuronal changes in the midbrain leading to a persisting tinnitus, which is then less likely to remit.FUNDINGThis study was supported by the GENDER-Net Co-Plus Fund (GNP-182), the European Union's Horizon 2020 grants no. 848261 (Unification of Treatments and Interventions for Tinnitus [UNITI]) and no. 722046 (European School for Interdisciplinary Tinnitus Research [ESIT]).

The spatial percept of tinnitus is associated with hearing asymmetry: Subgroup comparisons.

The spatial percept of tinnitus is hypothesized as an important variable for tinnitus subtyping. Hearing asymmetry often associates with tinnitus laterality, but not always. One of the methodological limitations for cross-study comparisons is how the variables for hearing asymmetry and tinnitus spatial perception are defined. In this study, data from two independent datasets were combined (n=833 adults, age ranging from 20 to 91 years, 404 males, 429 females) to investigate characteristics of subgroups with different tinnitus spatial perception focusing on hearing asymmetry. Three principle findings emerged. First, a hearing asymmetry variable emphasizing the maximum interaural difference most strongly discriminated unilateral from bilateral tinnitus. Merging lateralized bilateral tinnitus (perceived in both ears but worse in one side) with unilateral tinnitus weakened this relationship. Second, there was an association between unilateral tinnitus and ipsilateral asymmetric hearing. Third, unilateral and bilateral tinnitus were phenotypically distinct, with unilateral tinnitus being characterized by older age, asymmetric hearing, more often wearing one hearing aid, older age at tinnitus onset, shorter tinnitus duration, and higher percentage of time being annoyed by tinnitus. We recommend that careful consideration is given to the definitions of hearing asymmetry and tinnitus spatial perception in order to improve the comparability of findings across studies.

Sex-Dependent Aggregation of Tinnitus in Swedish Families.

Twin and adoption studies point towards a genetic contribution to tinnitus; however, how the genetic risk applies to different forms of tinnitus is poorly understood. Here, we perform a familial aggregation study and determine the relative recurrence risk for tinnitus in siblings (λs). Four different Swedish studies (N = 186,598) were used to estimate the prevalence of self-reported bilateral, unilateral, constant, and severe tinnitus in the general population and we defined whether these 4 different forms of tinnitus segregate in families from the Swedish Tinnitus Outreach Project (STOP, N = 2305). We implemented a percentile bootstrap approach to provide accurate estimates and confidence intervals for λs. We reveal a significant λs for all types of tinnitus, the highest found being 7.27 (95% CI (5.56-9.07)) for severe tinnitus, with a higher susceptibility in women (10.25; 95% CI (7.14-13.61)) than in men (5.03; 95% CI (3.22-7.01)), suggesting that severity may be the most genetically influenced trait in tinnitus in a sex-dependent manner. Our findings strongly support the notion that genetic factors impact on the development of tinnitus, more so for severe tinnitus. These findings highlight the importance of considering tinnitus severity and sex in the design of large genetic studies to optimize diagnostic approaches and ultimately improve therapeutic interventions.

Association between Hyperacusis and Tinnitus.

Many individuals with tinnitus report experiencing hyperacusis (enhanced sensitivity to sounds). However, estimates of the association between hyperacusis and tinnitus is lacking. Here, we investigate this relationship in a Swedish study. A total of 3645 participants (1984 with tinnitus and 1661 without tinnitus) were enrolled via LifeGene, a study from the general Swedish population, aged 18-90 years, and provided information on socio-demographic characteristics, as well as presence of hyperacusis and its severity. Tinnitus presence and severity were self-reported or assessed using the Tinnitus Handicap Inventory (THI). Phenotypes of tinnitus with (n = 1388) or without (n = 1044) hyperacusis were also compared. Of 1661 participants without tinnitus, 1098 (66.1%) were women and 563 were men (33.9%), and the mean (SD) age was 45.1 (12.9). Of 1984 participants with tinnitus, 1034 (52.1%) were women and 950 (47.9%) were men, and the mean (SD) age was 47.7 (14.0) years. Hyperacusis was associated with any tinnitus [Odds ratio (OR) 3.51, 95% confidence interval (CI) 2.99-4.13], self-reported severe tinnitus (OR 7.43, 95% CI 5.06-10.9), and THI ≥ 58 (OR 12.1, 95% CI 7.06-20.6). The association with THI ≥ 58 was greater with increasing severity of hyperacusis, the ORs being 8.15 (95% CI 4.68-14.2) for moderate and 77.4 (95% CI 35.0-171.3) for severe hyperacusis. No difference between sexes was observed in the association between hyperacusis and tinnitus. The occurrence of hyperacusis in severe tinnitus is as high as 80%, showing a very tight relationship. Discriminating the pathophysiological mechanisms between the two conditions in cases of severe tinnitus will be challenging, and optimized study designs are necessary to better understand the mechanisms behind the strong relationship between hyperacusis and tinnitus.

Relationship between headaches and tinnitus in a Swedish study.

The heterogeneity of tinnitus is likely accounting for the lack of effective treatment approaches. Headaches have been related to tinnitus, yet little is known on how headaches impact tinnitus. We use cross-sectional data from the Swedish Tinnitus Outreach Project to i) evaluate the association between headaches and tinnitus (n = 1,984 cases and 1,661 controls) and ii) investigate the phenotypic characteristics of tinnitus subjects with tinnitus (n = 660) or without (n = 1,879) headaches. In a multivariable logistic regression model, headache was significantly associated with any tinnitus (odds ratio, OR = 2.61) and more so with tinnitus as a big problem (as measured by the tinnitus functional index, TFI ≥ 48; OR = 5.63) or severe tinnitus (using the tinnitus handicap inventory, THI ≥ 58; OR = 4.99). When focusing on subjects with tinnitus, the prevalence of headaches was 26% and reached 40% in subjects with severe tinnitus. A large number of socioeconomic, phenotypic and psychological characteristics differed between headache and non-headache subjects with any tinnitus. With increasing tinnitus severity, fewer differences were found, the major ones being vertigo, neck pain and other pain syndromes, as well as stress and anxiety. Our study suggests that headaches could contribute to tinnitus distress and potentially its severity.

Impact of Temporomandibular Joint Complaints on Tinnitus-Related Distress.

There is increasing evidence of associations between the presence of temporomandibular joint (TMJ) disorders and tinnitus. It has been recently proposed that tinnitus patients with TMJ complaints could constitute a subtype, meaning a subgroup of tinnitus patients responsive to specific treatments. Tinnitus patients with TMJ complaints are often young women with somatosensory features of their tinnitus. Here, we investigate the socio-economic factors, phenotypic characteristics and psychological variables of tinnitus subjects from the Swedish Tinnitus Outreach Project, with (n = 486) or without (n = 1,996) TMJ complaints. The prevalence of TMJ complaints was greater in tinnitus subjects with severe tinnitus (36%) when compared to those with any tinnitus (19%), strongly indicating the contribution of TMJ problems to the severity of tinnitus. Comparing subgroups with or without TMJ complaints in the whole sample, differences were found regarding a large number of socioeconomic, phenotypic, and psychological characteristics. Subjects with TMJ complaints were more often women, more often reported stress as the cause of tinnitus, were more severely affected by tinnitus, scored worse in measures of psychological well-being and life quality, and were more often affected by problems tolerating sounds, headache, vertigo/dizziness, and neck pain. In addition, they more often reported pulsating and tonal tinnitus, somatic modulation of tinnitus, and aggravation of tinnitus by loud sounds and stress. When focusing the analysis in subjects with tinnitus as a big problem using the Tinnitus Functional Index cut-off ≥ 48, or with severe tinnitus according to the Tinnitus Handicap Inventory cut-off ≥ 58, the impact of somatosensory modulations and stress on tinnitus were greater in subjects with TMJ complaints in comparison to those without. In light of these results, we hypothesize that stress could contribute to the co-occurrence of TMJ problems and tinnitus and also to the development of severe tinnitus. Our study supports the need of involving dental care and stress management in the holistic treatment of patients with severe tinnitus.

Standardised profiling for tinnitus research: The European School for Interdisciplinary Tinnitus Research Screening Questionnaire (ESIT-SQ).

BACKGROUND: The heterogeneity of tinnitus is substantial. Its numerous pathophysiological mechanisms and clinical manifestations have hampered fundamental and treatment research significantly. A decade ago, the Tinnitus Research Initiative introduced the Tinnitus Sample Case History Questionnaire, a case history instrument for standardised collection of information about the characteristics of the tinnitus patient. Since then, a number of studies have been published which characterise individuals and groups using data collected with this questionnaire. However, its use has been restricted to a clinical setting and to the evaluation of people with tinnitus only. In addition, it is limited in the ability to capture relevant comorbidities and evaluate their temporal relationship with tinnitus. METHOD: Here we present a new case history instrument which is comprehensive in scope and can be answered by people with and without tinnitus alike. This 'European School for Interdisciplinary Tinnitus Research Screening Questionnaire' (ESIT-SQ) was developed with specific attention to questions about potential risk factors for tinnitus (including demographics, lifestyle, general medical and otological histories), and tinnitus characteristics (including perceptual characteristics, modulating factors, and associations with co-existing conditions). It was first developed in English, then translated into Dutch, German, Italian, Polish, Spanish, and Swedish, thus having broad applicability and supporting international collaboration. CONCLUSIONS: With respect to better understanding tinnitus profiles, we anticipate the ESIT-SQ to be a starting point for comprehensive multi-variate analyses of tinnitus. Data collected with the ESIT-SQ can allow establishment of patterns that distinguish tinnitus from non-tinnitus, and definition of common sets of tinnitus characteristics which might be indicated by the presence of otological or comorbid systemic diseases for which tinnitus is a known symptom.

The genetic vulnerability to cisplatin ototoxicity: a systematic review.

Ototoxicity is one of the major side-effects of platinum-based chemotherapy, in particular cisplatin (cis-diammine dichloroplatinum II). To our knowledge, no systematic review has previously provided a quantitative summary estimate of the impact of genetics upon the risk of developing hearing loss. We searched Embase, Medline, ASSIA, Pubmed, Scopus, and Web of Science, for studies documenting the genetic risk of ototoxicity in patients with cancer treated with cisplatin. Titles/abstracts and full texts were reviewed for inclusion. Meta-analytic estimates of risk (Odds Ratio) from the pooled data were calculated for studies that have been repeated twice or more. The search identified 3891 papers, of which 30 were included. The majority were retrospective (44%), ranging from n = 39 to n = 317, some including only patients younger than 25 years of age (33%), and some on both genders (80%). The most common cancers involved were osteosarcoma (53%), neuroblastoma (37%), prostate (17%) and reproductive (10%). Most studies performed genotyping, though only 5 studies performed genome-wide association studies. Nineteen single-nucleotide polymorphisms (SNPs) from 15 genes were repeated more than twice. Meta-analysis of group data indicated that rs1872328 on ACYP2, which plays a role in calcium homeostasis, increases the risk of ototoxicity by 4.61 (95% CI: 3.04-7.02; N = 696, p < 0.0001) as well as LRP2 rs4668123 shows a cumulated Odds Ratio of 3.53 (95% CI: 1.48-8.45; N = 118, p = 0.0059), which could not be evidenced in individual studies. Despite the evidence of heterogeneity across studies, these meta-analytic results from 30 studies are consistent with a view of a genetic predisposition to platinum-based chemotherapy mediated ototoxicity. These new findings are informative and encourage the genetic screening of cancer patients in order to identify patients with greater vulnerability of developing hearing loss, a condition having a potentially large impact on quality of life. More studies are needed, with larger sample size, in order to identify additional markers of ototoxic risk associated with platinum-based chemotherapy and investigate polygenic risks, where multiple markers may exacerbate the side-effects.

Visualization of Global Disease Burden for the Optimization of Patient Management and Treatment.

BACKGROUND: The assessment and treatment of complex disorders is challenged by the multiple domains and instruments used to evaluate clinical outcome. With the large number of assessment tools typically used in complex disorders comes the challenge of obtaining an integrative view of disease status to further evaluate treatment outcome both at the individual level and at the group level. Radar plots appear as an attractive visual tool to display multivariate data on a two-dimensional graphical illustration. Here, we describe the use of radar plots for the visualization of disease characteristics applied in the context of tinnitus, a complex and heterogeneous condition, the treatment of which has shown mixed success. METHODS: Data from two different cohorts, the Swedish Tinnitus Outreach Project (STOP) and the Tinnitus Research Initiative (TRI) database, were used. STOP is a population-based cohort where cross-sectional data from 1,223 non-tinnitus and 933 tinnitus subjects were analyzed. By contrast, the TRI contained data from 571 patients who underwent various treatments and whose Clinical Global Impression (CGI) score was accessible to infer treatment outcome. In the latter, 34,560 permutations were tested to evaluate whether a particular ordering of the instruments could reflect better the treatment outcome measured with the CGI. RESULTS: Radar plots confirmed that tinnitus subtypes such as occasional and chronic tinnitus from the STOP cohort could be strikingly different, and helped appreciate a gender bias in tinnitus severity. Radar plots with greater surface areas were consistent with greater burden, and enabled a rapid appreciation of the global distress associated with tinnitus in patients categorized according to tinnitus severity. Permutations in the arrangement of instruments allowed to identify a configuration with minimal variance and maximized surface difference between CGI groups from the TRI database, thus affording a means of optimally evaluating the outcomes in individual patients. CONCLUSION: We anticipate such a tool to become a starting point for more sophisticated measures in clinical outcomes, applicable not only in the context of tinnitus but also in other complex diseases where the integration of multiple variables is needed for a comprehensive evaluation of treatment response.

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.

Genetic susceptibility to bilateral tinnitus in a Swedish twin cohort.

PURPOSE: Genetic contributions to tinnitus have been difficult to determine due to the heterogeneity of the condition and its broad etiology. Here, we evaluated the genetic and nongenetic influences on self-reported tinnitus from the Swedish Twin Registry (STR). METHODS: Cross-sectional data from the STR was obtained. Casewise concordance rates (the risk of one twin being affected given that his/her twin partner has tinnitus) were compared for monozygotic (MZ) and dizygotic (DZ) twin pairs (N = 10,464 concordant and discordant twin pairs) and heritability coefficients (the proportion of the total variance attributable to genetic factors) were calculated using biometrical model fitting procedures. RESULTS: Stratification of tinnitus cases into subtypes according to laterality (unilateral versus bilateral) revealed that heritability of bilateral tinnitus was 0.56; however, it was 0.27 for unilateral tinnitus. Heritability was greater in men (0.68) than in women (0.41). However, when female pairs younger than 40 years of age were selected, heritability of 0.62 was achieved with negligible effects of shared environment. CONCLUSION: Unlike unilateral tinnitus, bilateral tinnitus is influenced by genetic factors and might constitute a genetic subtype. Overall, our study provides the initial evidence for a tinnitus phenotype with a genetic influence.Genet Med advance online publication 23 March 2017.

Validation of Online Versions of Tinnitus Questionnaires Translated into Swedish.

Background: Due to the lack of objective measures for assessing tinnitus, its clinical evaluation largely relies on the use of questionnaires and psychoacoustic tests. A global assessment of tinnitus burden would largely benefit from holistic approaches that not only incorporate measures of tinnitus but also take into account associated fears, emotional aspects (stress, anxiety, and depression), and quality of life. In Sweden, only a few instruments are available for assessing tinnitus, and the existing tools lack validation. Therefore, we translated a set of questionnaires into Swedish and evaluated their reliability and validity in a group of tinnitus subjects. Methods: We translated the English versions of the Tinnitus Functional Index (TFI), the Fear of Tinnitus Questionnaire (FTQ), the Tinnitus Catastrophizing Scale (TCS), the Perceived Stress Questionnaire (PSQ-30), and the Tinnitus Sample Case History Questionnaire (TSCHQ) into Swedish. These translations were delivered via the internet with the already existing Swedish versions of the Tinnitus Handicap Inventory (THI), the Hospital Anxiety and Depression Scale (HADS), the Hyperacusis Questionnaire (HQ), and the World Health Organization Quality of Life questionnaire (WHOQoL-BREF). Psychometric properties were evaluated by means of internal consistency [Cronbach's alpha (α)] and test-retest reliability across a 9-week interval [Intraclass Correlation Coefficient (ICC), Cohen's kappa] in order to establish construct as well as clinical validity using a sample of 260 subjects from a population-based cohort. Results: Internal consistency was acceptable for all questionnaires (α > 0.7) with the exception of the "social relationships" subscale of the WHOQoL-BREF. Test-retest reliability was generally acceptable (ICC > 0.70, Cohens kappa > 0.60) for the tinnitus-related questionnaires, except for the TFI "sense of control" subscale and 15 items of the TSCHQ. Spearmen rank correlations showed that almost all questionnaires on tinnitus are significantly related, indicating that these questionnaires measure different aspects of the same construct. The data supported good clinical validity of the tinnitus-related questionnaires. Conclusion: Our results suggest that most Swedish adaptations of the questionnaires are suitable for clinical and research settings and should facilitate the assessment of treatment outcomes using a more holistic approach by including measures of tinnitus fears, emotional burden, and quality of life.

Systematic review of outcome domains and instruments used in clinical trials of tinnitus treatments in adults.

BACKGROUND: There is no evidence-based guidance to facilitate design decisions for confirmatory trials or systematic reviews investigating treatment efficacy for adults with tinnitus. This systematic review therefore seeks to ascertain the current status of trial designs by identifying and evaluating the reporting of outcome domains and instruments in the treatment of adults with tinnitus. METHODS: Records were identified by searching PubMed, EMBASE CINAHL, EBSCO, and CENTRAL clinical trial registries (ClinicalTrials.gov, ISRCTN, ICTRP) and the Cochrane Database of Systematic Reviews. Eligible records were those published from 1 July 2006 to 12 March 2015. Included studies were those reporting adults aged 18 years or older who reported tinnitus as a primary complaint, and who were enrolled into a randomised controlled trial, a before and after study, a non-randomised controlled trial, a case-controlled study or a cohort study, and written in English. Studies with fewer than 20 participants were excluded. RESULTS: Two hundred and twenty-eight studies were included. Thirty-five different primary outcome domains were identified spanning seven categories (tinnitus percept, impact of tinnitus, co-occurring complaints, quality of life, body structures and function, treatment-related outcomes and unclear or not specified). Over half the studies (55 %) did not clearly define the complaint of interest. Tinnitus loudness was the domain most often reported (14 %), followed by tinnitus distress (7 %). Seventy-eight different primary outcome instruments were identified. Instruments assessing multiple attributes of the impact of tinnitus were most common (34 %). Overall, 24 different patient-reported tools were used, predominantly the Tinnitus Handicap Inventory (15 %). Loudness was measured in diverse ways including a numerical rating scale (8 %), loudness matching (4 %), minimum masking level (1 %) and loudness discomfort level (1 %). Ten percent of studies did not clearly report the instrument used. CONCLUSIONS: Our findings indicate poor appreciation of the basic principles of good trial design, particularly the importance of specifying what aspect of therapeutic benefit is the main outcome. No single outcome was reported in all studies and there was a broad diversity of outcome instruments. PROSPERO REGISTRATION: The systematic review protocol is registered on PROSPERO (International Prospective Register of Systematic Reviews): CRD42015017525 . Registered on 12 March 2015 revised on 15 March 2016.