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.

Comparative Analysis of the Efficiency of Two Treatment Protocols for Posterior Canal Benign Paroxysmal Positional Vertigo.

BACKGROUND AND OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common vertigo of labyrinthine origin, its social and healthcare impact is remarkable. It has recently been shown that single session treatment is as safe and effective as weekly treatment, which could have impact on direct and indirect costs related to the disease. The objective of this study is to determine whether single session treatment of unilateral posterior canal BPPV canalolithiasis is more efficient than conventional treatment. MATERIALS AND METHODS: A prospective randomized controlled trial was performed in 53 consecutive patients diagnosed with unilateral posterior canal BPPV canalolithiasis previously untreated: 26 patients were assigned to single session treatment and 27 patients to weekly treatment. Average and total cost of care, consultation time and the impact in terms of temporary disability and loss of productivity for the company due to patients' medical visits were compared. RESULTS: Average and total cost of care and loss of productivity for the company due to patients' medical visits were significantly lower in the single session group. Consultation time was also better in this group when travelling time was considered. CONCLUSIONS: The single session protocol is fast, effective and reduces direct and indirect cost of care related to disease justifying high resolution consultations.

Análisis comparativo de la eficiencia de dos protocolos de tratamiento del vértigo posicional paroxístico benigno del conducto semicircular posterior / Comparative Analysis of the Efficiency of Two Treatment Protocols for Posterior Canal Benign Paroxysmal Positional Vertigo

Antecedentes y objetivo: El vértigo posicional paroxístico benigno (VPPB) es la causa más frecuente de vértigo de origen laberíntico; su impacto social y en términos de cuidados de salud es notable. Recientemente se ha demostrado que es clínicamente posible realizar el tratamiento y su comprobación en la misma sesión, lo cual podría tener repercusión en los costes asistenciales directos e indirectos relacionados con la enfermedad. El objetivo de este trabajo es determinar si el protocolo de tratamiento unisesión del VPPB CP unilateral tipo conductolitiasis es más eficiente que el protocolo de tratamiento convencional. Materiales y métodos: Estudio prospectivo controlado y aleatorizado en 53 pacientes consecutivos diagnosticados de un VPPB CP unilateral tipo conductolitiasis no tratados previamente; 26 pacientes fueron asignados al grupo unisesión y 27 al semanal clásico. Se compararon los costes medio y total de la asistencia, el tiempo de consulta y el impacto en términos de incapacidad temporal y pérdida de productividad para la empresa asociada a la visita médica del paciente. Resultados: Los costes medio y total de la asistencia así como la pérdida de productividad para una empresa asociada a la visita médica de los pacientes laboralmente activos fueron significativamente menores en el protocolo unisesión. También el tiempo de consulta cuando se consideró el tiempo de desplazamiento al centro. Conclusiones: El protocolo de tratamiento unisesión es rápido, efectivo y reduce los costes asistenciales directos e indirectos relacionados con la enfermedad justificando consultas de alta resolución. (AU)

Background and objective: Benign paroxysmal positional vertigo (BPPV) is the most common vertigo of labyrinthine origin, its social and healthcare impact is remarkable. It has recently been shown that single session treatment is as safe and effective as weekly treatment, which could have impact on direct and indirect costs related to the disease. The objective of this study is to determine whether single session treatment of unilateral posterior canal BPPV canalolithiasis is more efficient than conventional treatment. Materials and methods: A prospective randomized controlled trial was performed in 53 consecutive patients diagnosed with unilateral posterior canal BPPV canalolithiasis previously untreated: 26 patients were assigned to single session treatment and 27 patients to weekly treatment. Average and total cost of care, consultation time and the impact in terms of temporary disability and loss of productivity for the company due to patients’ medical visits were compared. Results: Average and total cost of care and loss of productivity for the company due to patients’ medical visits were significantly lower in the single session group. Consultation time was also better in this group when travelling time was considered. Conclusions: The single session protocol is fast, effective and reduces direct and indirect cost of care related to disease justifying high resolution consultations. (AU)

Video Head Impulse Test in Darkness, Without Visual Fixation: A Study on Healthy Subjects.

OBJECTIVE: The head impulse test (HIT) is triggered by the vestibulo-ocular reflex (VOR), complemented by the optokinetic and pursuit systems. This study aimed to evaluate the possibility of individualizing the VOR contribution to the HIT. DESIGN: Thirty-six healthy individuals (19 males, 17 females; age 21-64 years, mean 39 years) underwent horizontal video HIT (vHIT). This was first conducted in darkness, without visual fixation, and then visually tracked. RESULTS: Seventy percent of the impulses delivered ocular responses opposite to the direction of the head, matching its velocity to a point where quick anticompensatory eye movements (SQEM) stopped the response (SQEM mean latency 58.21 ms, interquartile range 50-67 ms). Of these, 75% recaptured the head velocity after culmination. Thirty percent of the responses completed a bell-shaped curve. The completed bell-shaped curve gains and instantaneous gains (at 40, 60, and 80 ms) before SQEM were equivalent for both paradigms. Females completed more bell-shaped traces (42%) than males (15%); p = 0.01. The SQEM latency was longer (62.81 versus 55.71 ms, p < 0.01), and the time to recapture the bell-shaped curve was shorter (77.51 versus 92.52 ms, p < 0.01) in females than in males. The gains were comparable between sexes in both paradigms. CONCLUSIONS: The VOR effect can be localized in the first 70 ms of the vHIT response. In addition, other influences may take place in estimating the vHIT responses. The study of these influences might provide useful information that can be applied to patient management.

Comparative analysis of the efficiency of two treatment protocols for posterior canal benign paroxysmal positional vertigo. / Análisis comparativo de la eficiencia de dos protocolos de tratamiento del vértigo posicional paroxístico benigno del conducto semicircular posterior.

BACKGROUND AND OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common vertigo of labyrinthine origin, its social and healthcare impact is remarkable. It has recently been shown that single session treatment is as safe and effective as weekly treatment, which could have impact on direct and indirect costs related to the disease. The objective of this study is to determine whether single session treatment of unilateral posterior canal BPPV canalolithiasis is more efficient than conventional treatment. MATERIALS AND METHODS: A prospective randomized controlled trial was performed in 53 consecutive patients diagnosed with unilateral posterior canal BPPV canalolithiasis previously untreated: 26 patients were assigned to single session treatment and 27 patients to weekly treatment. Average and total cost of care, consultation time and the impact in terms of temporary disability and loss of productivity for the company due to patients' medical visits were compared. RESULTS: Average and total cost of care and loss of productivity for the company due to patients' medical visits were significantly lower in the single session group. Consultation time was also better in this group when travelling time was considered. CONCLUSIONS: The single session protocol is fast, effective and reduces direct and indirect cost of care related to disease justifying high resolution consultations.

Burden of Rare Variants in the OTOG Gene in Familial Meniere's Disease.

OBJECTIVES: Meniere's disease (MD) is a rare inner ear disorder characterized by sensorineural hearing loss, episodic vertigo, and tinnitus. Familial MD has been reported in 6 to 9% of sporadic cases, and few genes including FAM136A, DTNA, PRKCB, SEMA3D, and DPT have been involved in single families, suggesting genetic heterogeneity. In this study, the authors recruited 46 families with MD to search for relevant candidate genes for hearing loss in familial MD. DESIGN: Exome sequencing data from MD patients were analyzed to search for rare variants in hearing loss genes in a case-control study. A total of 109 patients with MD (73 familial cases and 36 early-onset sporadic patients) diagnosed according to the diagnostic criteria defined by the Barany Society were recruited in 11 hospitals. The allelic frequencies of rare variants in hearing loss genes were calculated in individuals with familial MD. A single rare variant analysis and a gene burden analysis (GBA) were conducted in the dataset selecting 1 patient from each family. Allelic frequencies from European and Spanish reference datasets were used as controls. RESULTS: A total of 5136 single-nucleotide variants in hearing loss genes were considered for single rare variant analysis in familial MD cases, but only 1 heterozygous likely pathogenic variant in the OTOG gene (rs552304627) was found in 2 unrelated families. The gene burden analysis found an enrichment of rare missense variants in the OTOG gene in familial MD. So, 15 of 46 families (33%) showed at least 1 rare missense variant in the OTOG gene, suggesting a key role in familial MD. CONCLUSIONS: The authors found an enrichment of multiplex rare missense variants in the OTOG gene in familial MD. This finding supports OTOG as a relevant gene in familial MD and set the groundwork for genetic testing in MD.

Can Benign Paroxysmal Positional Vertigo Be Treated in a One Session?

OBJECTIVE: To determine the reliability and safety of posterior canal BPPV (pc-BPPV) treatment with subsequent assessment of the effectiveness of the maneuver in a single session, compared to the classic weekly procedure. METHOD: A prospective study of two randomized groups of unilateral pc-BPPV was performed: a weekly management group (27 patients) and single-session treatment group (26 patients). The number of maneuvers required to clear pc-BPPV, incidence of side effects (re-entries and canal conversions), and recurrence rates were compared. RESULTS: There were no statistically significant differences in the number of maneuvers needed to resolve pc-BPPV, the incidence of side effects, or the recurrence rate between the two groups. Two re-entries were diagnosed in the single-session group, and both were easily and successfully treated. Three early recurrences were found in the single-session group and one spontaneous recovery was encountered in the weekly group. Time required to discharge patients to follow-up was significantly reduced in the single-session group. CONCLUSION: Managing pc-BPPV in one session is safe and reliable, resulting in fewer visits to outpatient clinics and optimization of treatment strategies.

Rehabilitación vestibular en personas mayores con disfunción vestibular / Vestibular rehabilitation in older people with vestibular dysfunction

INTRODUCCIÓN Y OBJETIVO: El mareo y el desequilibrio son síntomas comunes en el anciano y tienen un gran impacto en su calidad de vida. MÉTODO: Revisión narrativa. RESULTADOS: Se revisan los principales factores que condicionan la inestabilidad en el anciano, el impacto de las caídas y las exploraciones más rentables desde el punto de vista diagnóstico y terapéutico en estos pacientes. Por último, se incide en la necesidad de un abordaje multidisciplinar destacando la importancia de la rehabilitación vestibular en el tratamiento de estos trastornos. CONCLUSIONES: La inestabilidad en el anciano es de origen multifactorial y no obedece solamente a razones fisiológicas. De ahí la necesidad de identificar los factores precipitantes, tratarlos si es posible y realizar un abordaje multidisciplinar que minimice la morbimortalidad asociada a este proceso y mejorando su calidad de vida. La rehabilitación vestibular puede mejorar significativamente el equilibrio de los ancianos con inestabilidad lo cual conduciría a una reducción significativa de las caídas

INTRODUCTION AND OBJECTIVE: Dizziness and imbalance are common symptoms in the elderly and have a great impact on their quality of life. METHOD: Narrative review. RESULTS: Main factors that condition instability in the elderly and the impact of falls are reviewed, as well as the most profitable tests in diagnosis. Finally, the need to perform a multidisciplinary approach was discussed, highlighting the importance of vestibular rehabilitation in the treatment of these disorders. CONCLUSIONS: Instability in the elderly is multifactorial and not only due to physiological reasons. Hence the need to identify precipitating factors, treat them if possible and carry out a multidisciplinary approach that minimizes the morbidity and mortality associated with this process and improve their quality of life. Vestibular rehabilitation can significantly ameliorate balance in the elderly with instability which would lead to a significant reduction in falls

Guía de Práctica Clínica Para el Diagnóstico y Tratamiento del Vértigo Posicional Paroxístico Benigno. Documento de Consenso de la Comisión de Otoneurología Sociedad Española de Otorrinolaringlogía y Cirugía de Cabeza y Cuello / Practice Guidelines for the Diagnosis and Management of Benign Paroxysmal Positional Vertigo Otoneurology Committee of Spanish Otorhinolaryngology and Head and Neck Surgery Consensus Document

El vértigo posicional paroxístico benigno (VPPB) es la causa más frecuente de vértigo vestibular episódico. EL propósito de esta guía, encomendada por la Comisión de Otoneurología de la SEORL CCC, es disponer de un documento de consenso que sirva de guía práctica para el manejo del VPPB en la clínica diaria. El punto de partida es la clasificación elaborada por la Barany Society, con sus variantes clínicas. Incluye una descripción de las pruebas diagnósticas y de las maniobras terapéuticas para cada una de las variantes establecidas, habiéndose seleccionado aquellas con estudios con nivel adecuado de evidencia o con suficientes series de soporte. Se ha incluido también un capítulo de diagnóstico diferencial, así como un apartado de aspectos generales básicos en el manejo de los pacientes con VPPB

Benign Paroxysmal Positional Vertigo is the most frequent episodic vestibular disorder. The purpose of this guide, requested by the committee on otoneurology of the Spanish Society of Otolaryngology and Head and Neck Surgery, is to supply a consensus document providing practical guidance for the management of BPPV. It is based on the Barany Society criteria for the diagnosis of BPPV. This guideline provides recommendations on each variant of BPPV, with a description of the different diagnostic tests and the therapeutic manoeuvres. For this purpose, we have selected the tests and manoeuvres supported by evidence-based studies or extensive series. Finally, we have also included a chapter on differential diagnosis and a section relating to general aspects in the management of BPPV

Practice Guidelines for the Diagnosis and Management of Benign Paroxysmal Positional Vertigo Otoneurology Committee of Spanish Otorhinolaryngology and Head and Neck Surgery Consensus Document. / Guía de Práctica Clínica Para el Diagnóstico y Tratamiento del Vértigo Posicional Paroxístico Benigno. Documento de Consenso de la Comisión de Otoneurología Sociedad Española de Otorrinolaringlogía y Cirugía de Cabeza y Cuello.

Benign Paroxysmal Positional Vertigo is the most frequent episodic vestibular disorder. The purpose of this guide, requested by the committee on otoneurology of the Spanish Society of Otolaryngology and Head and Neck Surgery, is to supply a consensus document providing practical guidance for the management of BPPV. It is based on the Barany Society criteria for the diagnosis of BPPV. This guideline provides recommendations on each variant of BPPV, with a description of the different diagnostic tests and the therapeutic manoeuvres. For this purpose, we have selected the tests and manoeuvres supported by evidence-based studies or extensive series. Finally, we have also included a chapter on differential diagnosis and a section relating to general aspects in the management of BPPV.

Treatment of benign paroxysmal positional vertigo. A clinical review.

Benign paroxysmal positional vertigo (BPPV) is the most frequent episodic vestibular disorder. It is due to otolith rests that are free into the canals or attached to the cupulas. Well over 90% of patients can be successfully treated with manoeuvres that move the particles back to the utriculus. Among the great variety of procedures that have been described, the manoeuvres that are supported by evidenced-based studies or extensive series are commented in this review. Some topics regarding BPPV treatment, such as controlling the accuracy of the procedures or the utility of post-manoeuvre restrictions are also discussed.

Regulation of Fn14 Receptor and NF-κB Underlies Inflammation in Meniere's Disease.

Meniere's disease (MD) is a rare disorder characterized by episodic vertigo, sensorineural hearing loss, tinnitus, and aural fullness. It is associated with a fluid imbalance between the secretion of endolymph in the cochlear duct and its reabsorption into the subarachnoid space, leading to an accumulation of endolymph in the inner ear. Epidemiological evidence, including familial aggregation, indicates a genetic contribution and a consistent association with autoimmune diseases (AD). We conducted a case-control study in two phases using an immune genotyping array in a total of 420 patients with bilateral MD and 1,630 controls. We have identified the first locus, at 6p21.33, suggesting an association with bilateral MD [meta-analysis leading signal rs4947296, OR = 2.089 (1.661-2.627); p = 1.39 × 10-09]. Gene expression profiles of homozygous genotype-selected peripheral blood mononuclear cells (PBMCs) demonstrated that this region is a trans-expression quantitative trait locus (eQTL) in PBMCs. Signaling analysis predicted several tumor necrosis factor-related pathways, the TWEAK/Fn14 pathway being the top candidate (p = 2.42 × 10-11). This pathway is involved in the modulation of inflammation in several human AD, including multiple sclerosis, systemic lupus erythematosus, or rheumatoid arthritis. In vitro studies with genotype-selected lymphoblastoid cells from patients with MD suggest that this trans-eQTL may regulate cellular proliferation in lymphoid cells through the TWEAK/Fn14 pathway by increasing the translation of NF-κB. Taken together; these findings suggest that the carriers of the risk genotype may develop an NF-κB-mediated inflammatory response in MD.

Clasificación de los vértigos periféricos de la Comisión de Otoneurología de la Sociedad Española de Otorrinolaringología: concordancia diagnóstica y actualización (versión 2, año 2011) / Peripheral vertigo classification of the Otoneurology Committee of the Spanish Otorhinolaryngology Society: diagnostic agreement and update (version 2-2011)

Introducción: La Comisión de Otoneurología de la SEORL-PCF publicó en 2008 una clasificación de los vértigos periféricos, basada en criterios clínicos. El objetivo de este estudio es validar esta clasificación mediante el análisis de la concordancia diagnóstica entre múltiples evaluadores. Métodos: Participaron 7 evaluadores con experiencia clínica en el diagnóstico de afección vestibular, pertenecientes a 6 centros diferentes. Uno de ellos seleccionó las historias clínicas de 50 pacientes consecutivos que consultaron por alteraciones del equilibrio (24 varones y 26 mujeres; edad media: 53,5 años). Estas historias, suprimidos los datos que permitiesen identificar a los pacientes, el diagnóstico establecido y el tratamiento pautado, fueron remitidas a los otros 6 investigadores. Cada uno de ellos estableció un diagnóstico, intentando ajustarlo a los epígrafes de la clasificación. Resultados: De los 50 pacientes, existió una coincidencia sustancial en el diagnóstico (4 o más evaluadores alcanzaron el mismo) en 31 (26 con diagnóstico positivo y 5 negativo: no podía ser incluido en ningún epígrafe). El índice kappa, que mide el nivel de concordancia entre tres o más observadores, fue de 0,4198 (lo que indica un grado de acuerdo moderado). La unanimidad solo se alcanzó en 7 pacientes (4 VPPB, dos enfermedades de Ménière y un vértigo asociado a migraña). Conclusiones: La actual clasificación, con los criterios que incluye, solo permite etiquetar con un consenso aceptable al 62% de los pacientes. Se propone una modificación de la clasificación, incluyendo el epígrafe de VPPB probable, y revisando los de vértigo-migraña y vértigo asociado a migraña(AU)

Introduction: In 2008, the Otoneurology committee of the SEORL-PCF published a classification of peripheral vertigo, based on clinical criteria. The objective of this study was to validate this classification through analysing the diagnostic agreement among several medical assessors. Methods: Seven medical assessors, all with clinical experience, from 6 different hospitals, participated in the study. One of them selected the clinical histories of 50 consecutive patients who had consulted as a result of balance disorders (24 men and 26 women) with an average age of 53.5 years. These clinical histories -without any information that would identify the patient, the diagnosis established and the treatment- were sent to another 6 assessors. Each of these investigators established their own diagnosis, trying to adjust it to the epigraphs of the classification. Results: Of the 50 patients, there was substantial agreement as to the diagnosis (4 or more evaluators indicated the same one) in 31 cases (26 with a positive diagnosis and 5 with a negative one, which could not be included in any epigraph). The kappa index, which measures the level of accordance between 2 or more assessors, was 0.4198 (moderate level of agreement). Unanimity was achieved in only 7 cases (4 BPPV, 2 Ménière's disease and 1 vertigo associated with migraine). Conclusions: The current classification, with the criteria it includes, allows labelling with an acceptable consensus to only 62% of the patients. Therefore, a modification in the classification is proposed in relation with the probable BPPV epigraph, as well a revision of the entries for vertigo-migraine and vertigo associated with migraine(AU)

[Peripheral vertigo classification of the Otoneurology Committee of the Spanish Otorhinolaryngology Society: diagnostic agreement and update (version 2-2011)]. / Clasificación de los vértigos periféricos de la Comisión de Otoneurología de la Sociedad Española de Otorrinolaringología: concordancia diagnóstica y actualización (versión 2, año 2011).

INTRODUCTION: In 2008, the Otoneurology committee of the SEORL-PCF published a classification of peripheral vertigo, based on clinical criteria. The objective of this study was to validate this classification through analysing the diagnostic agreement among several medical assessors. METHODS: Seven medical assessors, all with clinical experience, from 6 different hospitals, participated in the study. One of them selected the clinical histories of 50 consecutive patients who had consulted as a result of balance disorders (24 men and 26 women) with an average age of 53.5 years. These clinical histories -without any information that would identify the patient, the diagnosis established and the treatment- were sent to another 6 assessors. Each of these investigators established their own diagnosis, trying to adjust it to the epigraphs of the classification. RESULTS: Of the 50 patients, there was substantial agreement as to the diagnosis (4 or more evaluators indicated the same one) in 31 cases (26 with a positive diagnosis and 5 with a negative one, which could not be included in any epigraph). The kappa index, which measures the level of accordance between 2 or more assessors, was 0.4198 (moderate level of agreement). Unanimity was achieved in only 7 cases (4 BPPV, 2 Ménière's disease and 1 vertigo associated with migraine). CONCLUSIONS: The current classification, with the criteria it includes, allows labelling with an acceptable consensus to only 62% of the patients. Therefore, a modification in the classification is proposed in relation with the probable BPPV epigraph, as well a revision of the entries for vertigo-migraine and vertigo associated with migraine.