33 research outputs found
Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study
Background: tinnitus is a heterogeneous condition associated with audiological and/or mental disorders.
Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to
twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown
since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the
phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme
phenotype.
Methods: for this extreme phenotype study, we used three different cohorts with European ancestry (Spanish
with Meniere disease (MD), Swedes tinnitus and European generalized epilepsy). In addition, four independent control datasets were also used for comparisons. Whole-exome sequencing was performed for the MD
and epilepsy cohorts and whole-genome sequencing was carried out in Swedes with tinnitus.
Findings: we found an enrichment of rare missense variants in 24 synaptic genes in a Spanish cohort, the
most significant being PRUNE2, AKAP9, SORBS1, ITGAX, ANK2, KIF20B and TSC2 (p < 2E 04), when they were
compared with reference datasets. This burden was replicated for ANK2 gene in a Swedish cohort with 97 tinnitus individuals, and in a subset of 34 Swedish patients with severe tinnitus for ANK2, AKAP9 and TSC2 genes
(p < 2E 02). However, these associations were not significant in a third cohort of 701 generalized epilepsy
individuals without tinnitus. Gene ontology (GO) and gene-set enrichment analyses revealed several pathways and biological processes involved in severe tinnitus, including membrane trafficking and cytoskeletal
protein binding in neurons.
Interpretation: a burden of rare variants in ANK2, AKAP9 and TSC2 is associated with severe tinnitus. ANK2,
encodes a cytoskeleton scaffolding protein that coordinates the assembly of several proteins, drives axonal
branching and influences connectivity in neurons
Clinical subgroups in bilateral meniere disease
Meniere disease (MD) is a heterogeneous clinical condition characterized by sensorineural hearing loss, episodic vestibular symptoms, and tinnitus associated with several comorbidities, such as migraine or autoimmune disorders (AD). The frequency of bilateral involvement may range from 5 to 50%, and it depends on the duration of the disease. We have performed a two-step cluster analysis in 398 patients with bilateral MD (BMD) to identify the best predictors to define clinical subgroups with a potential different etiology to improve the phenotyping of BMD and to develop new treatments. We have defined five clinical variants in BMD. Group 1 is the most frequently found, includes 46% of patients, and is defined by metachronic hearing loss without migraine and without AD. Group 2 is found in 17% of patients, and it is defined by synchronic hearing loss without migraine or AD. Group 3, with 13% of patients, is characterized by familial MD, while group 4, that includes 12% of patients, is associated by the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by AD. This approach can be helpful in selecting patients for genetic and clinical research. However, further studies will be required to improve the phenotyping in these clinical variants for a better understanding of the diverse etiological factors contributing to BMD
Corrigendum: Clinical Features of Headache in Patients With Diagnosis of Definite Vestibular Migraine: The VM-Phenotypes Projects
[This corrects the article DOI: 10.3389/fneur.2018.00395.]
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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13063-016-1399-9) contains supplementary material, which is available to authorized users
Relevance of artifact removal and number of stimuli for video head impulse test examination
Objective: To evaluate the effect of artifacts on the impulse and response recordings with the video head impulse test (VHIT) and determine how many stimuli are necessary for obtaining acceptably efficient
measurements.
Methods: One hundred fifty patients were examined using VHIT and
their registries searched for artifacts. We compared several variations
of the dataset. The first variation used only samples without artifacts,
the second used all samples (with and without artifacts), and the rest
used only samples with each type of artifact. We calculated the relative
efficiency (RE) of evaluating an increasingly large number of samples (3
to 19 per side) when compared with the complete sample (20 impulses
per side).
Results: Overshoot was associated with significantly higher speed
(p = 0.005), higher duration (p < 0.001) and lower amplitude of the
impulses (p = 0.002), and consequent higher saccades’ latency (p =
0.035) and lower amplitude (p = 0.025). Loss of track was associated
with lower gain (p = 0.035). Blink was associated with a higher number
of saccades (p < 0.001), and wrong way was associated with lower saccade latency (p = 0.012). The coefficient of quartile deviation escalated
as the number of artifacts of any type rose, indicating an increment of
variability. Overshoot increased the probability of the impulse to lay on
the outlier range for gain and peak speed. Blink did so for the number
of saccades, and wrong way for the saccade amplitude and speed. RE
reached a tolerable level of 1.1 at 7 to 10 impulses for all measurements
except the PR score.
Conclusions: Our results suggest the necessity of removing artifacts
after collecting VHIT samples to improve the accuracy and precision of
results. Ten impulses are sufficient for achieving acceptable RE for all
measurements except the PR score
Clinical Features of Headache in Patients With Diagnosis of Definite Vestibular Migraine: The VM-Phenotypes Projects
Migraine is a common neurological disorder characterized by episodic headaches with specific features, presenting familial aggregation. Migraine is associated with episodic vertigo, named Vestibular Migraine (VM) whose diagnosis mainly rely on clinical history showing a temporary association of symptoms. Some patient refers symptoms occurring in pediatric age, defined "episodic symptoms which may be associated with migraine." The aim of this cross sectional observational study was to assess migraine-related clinical features in VM subjects. For the purpose, 279 patients were recruited in different centers in Europe; data were collected by a senior neurologist or ENT specialist through a structured questionnaire. The age of onset of migraine was 21.8 ± 9. The duration of headaches was lower than 24 h in 79.1% of cases. Symptoms accompanying migrainous headaches were, in order of frequency, nausea (79.9%), phonophobia (54.5%), photophobia (53.8%), vomiting (29%), lightheadedness (21.1%). Visual or other auras were reported by 25.4% of subjects. A familial aggregation was referred by 67.4%, while migraine precursors were reported by 52.3% of subjects. Patients reporting nausea and vomiting during headaches more frequently experienced the same symptoms during vertigo. Comparing our results in VM subjects with previously published papers in migraine sufferers, our patients presented a lower duration of headaches and a higher rate of familial aggregation; moreover some common characters were observed in headache and vertigo attacks for accompanying symptoms like nausea and vomiting and clustering of attacks
Burden of rare variants in synaptic genes in patients with severe tinnitus: An exome based extreme phenotype study
tinnitus is a heterogeneous condition associated with audiological and/or mental disorders. Chronic, severe tinnitus is reported in 1% of the population and it shows a relevant heritability, according to twins, adoptees and familial aggregation studies. The genetic contribution to severe tinnitus is unknown since large genomic studies include individuals with self-reported tinnitus and large heterogeneity in the phenotype. The aim of this study was to identify genes for severe tinnitus in patients with extreme phenotype.This study has been funded by H2020 MSCA-ITN-2016–722046, the H2020-SC1-2019-848261, and the GNP-182 GENDER-Net Co-Plus Fund (JALE and CRC). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434), under agreement LCF/PR/DE18/52010002 (JALE). This project is a part of European School of Interdisciplinary Tinnitus (ESIT) research and Sana Amanat is a PhD student in Biomedicine Program at the University of Granada. CRC received additional funding from Svenska Läkaresällskapet (SLS- 779681 ), Hörselforskningsfonden (503). The data handling for STOP and SweGen cohorts were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX partially funded by the Swedish Research Council through Grant agreement No. 2018-05973 . The time provided by JS was funded by the University of Nottingham, Nottingham Research Fellowship. PM was supported by the BMBF Treat-ION Grant ( 01GM1907 ) and the DFG Research Unit FOR2715 (FNR INTER/DFG/17/ 11583046 ).Ye