Andrés Soto-Varela

High Prevalence of Systemic Autoimmune Diseases in Patients with Meniere's Disease

Background Autoimmunity appears to be associated with the pathophysiology of Menieres disease (MD), an inner ear disorder characterized by episodes of vertigo associated with hearing loss and tinnitus. However, the prevalence of autoimmune diseases (AD) in patients with MD has not been studied in individuals with uni or bilateral sensorineural hearing loss (SNHL). Methods and Findings We estimated the prevalence of AD in 690 outpatients with MD with uni or bilateral SNHL from otoneurology clinics at six tertiary referral hospitals by using clinica criteria and an immune panel (lymphocyte populations, antinuclear antibodies, C3, C4 and proinflammatory cytokines TNFα, INFγ). The observed prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and ankylosing spondylitis (AS) was higher than expected for the general population (1.39 for RA, 0.87 for SLE and 0.70 for AS, respectively). Systemic AD were more frequently observed in patients with MD and diagnostic criteria for migraine than cases with MD and tension-type headache (p = 0.007). There were clinical differences between patients with uni or bilateral SNHL, but no differences were found in the immune profile. Multiple linear regression showed that changes in lymphocytes subpopulations were associated with hearing loss and persistence of vertigo, suggesting a role for the immune response in MD. Conclusions Despite some limitations, MD displays an elevated prevalence of systemic AD such as RA, SLE and AS. This finding, which suggests an autoimmune background in a subset of patients with MD, has important implications for the treatment of MD.

Efficacy of a vibrotactile neurofeedback training in stance and gait conditions for the treatment of balance deficits: a double-blind, placebo-controlled multicenter study.

Objective Vestibular rehabilitation strategies mostly require a long-lasting training in stance conditions, which is finally not always successful. The individualized training in everyday-life conditions with an intuitive tactile neurofeedback stimulus seems to be a more promising approach. Hence, the present study was aimed at investigating the efficacy of a new vibrotactile neurofeedback system for vestibular rehabilitation. Study Design Double-blinded trial. Patients One hundred five patients who experience one of the following balance disorders for more than 12 months were included in the study: canal paresis, otolith disorder, removal of an acoustic neuroma, microvascular compression syndrome, Parkinson’s disease, and presbyvertigo. Interventions Vibrotactile neurofeedback training was performed daily (15 min) over 2 weeks with the Vertiguard system in those 6 tasks of the Standard Balance Deficit Test with the most prominent deviations from the normative values. Main Outcome Measures Trunk and ankle sway, dizziness handicap inventory, and vestibular symptom score were measured in the verum and placebo group before the training, on the last training day and 3 months later. Results A significant reduction in trunk and ankle sway as well as in the subjective symptom scores were observed in the verum group. Such an effect could not be found in any of the outcome parameters of the placebo group. Conclusion The vibrotactile neurofeedback training applied in the present study is a highly efficient method for the reduction of body sway in different balance disorders. Because the rehabilitation program is easy to perform, not exhausting, and time saving, elderly patients and those with serious, long-lasting balance problems also can participate successfully.

Vibrotactile neurofeedback balance training in patients with Parkinson's disease: Reducing the number of falls

The aim of this study was to assess effectiveness of balance training with a vibrotactile neurofeedback system in improving overall stability in patients with Parkinsons disease (PD). Ten patients diagnosed with idiopathic PD were included. Individualization of the rehabilitation program started with a body sway analysis of stance and gait tasks (Standard Balance Deficit Test, SBDT) by using the diagnostic tool of the applied device (Vertiguard(®)-RT). Those tasks with the poorest outcome as related to age- and gender-related controls were included in the training program (not more than six tasks). Improvement of postural stability was assessed by performing SBDT, Sensory Organization Test (SOT) of Computerized Dynamic Posturography (CDP), Dizziness Handicap Inventory (DHI), activity-specific balance confidence scale and recording the number of falls over the past three months. Furthermore, scores of SOT and DHI of 10 PD patients previously trained in an earlier study (by using CDP) were compared with results of those in the present study. After neurofeedback training (NFT), there was a statistically significant improvement in body sway (calculated over all training tasks), number of falls, and scores of SOT, DHI and ABC. In comparison with CDP-training, a statistically significant higher increase of SOT score was observed for patients after NFT with the Vertiguard-RT device compared to CDP training. Our results showed that a free-field vibrotactile NFT with Vertiguard(®)-RT device can improve balance in PD patients in everyday life conditions very effectively, which might led in turn to a reduction of falls.

Vestibular rehabilitation with computerised dynamic posturography in patients with Parkinson's disease: Improving balance impairment

Purpose. In patients with Parkinsons disease (PD), balance impairment involves considerable morbi-mortality from the numerous falls that may result. In an earlier postural study, we detected that a deteriorated processing of vestibular input is implicated. The aim of the present study is to assess the effectiveness of vestibular rehabilitation in improving overall stability in patients with PD. Method. Out of an initial group of 45 patients with PD, we chose those presenting a high risk of falls, based on their score on the timed up and go test (TUG). Rehabilitation was performed on 10 patients using computerised dynamic posturography (CDP). Improvement was assessed using the dizziness handicap inventory (DHI), the TUG and the CDP. Results. We found statistically significant improvement in the sensorial organisation test (SOT) and the limits of stability and rhythmic weight shift tests measured by the CDP, the DHI and the TUG. These improvements continue to be statistically significant 1 year post-treatment. Conclusion. Vestibular rehabilitation in PD has shown to be effective in improving the activities of daily life, gait velocity and balance, as well as in reducing the risk of falls. Moreover, these benefits persist over time.

HLA-DRB1*1101 allele may be associated with bilateral Méniére's disease in southern European population.

Objective: To analyze the associations of HLA-DRB1* and DQB1* Class II alleles in patients with bilateral Méniéres disease (MD). Patients and Methods: Eighty patients from two ethnically defined groups with definite bilateral MD, according to the diagnostic scale of the American Academy of Otolaryngology-Head and Neck Surgery, were compared with normal controls from the same origin in a prospective multicenter study. We performed an allele-specific amplification for HLA-DRB1* and DQB1* genes of the major histocompatibility complex. Results: The allele HLA-DRB1*1101 was associated with bilateral MD in the Mediterranean population (odds ratio, 3.65 [95% confidence intervals, 1.5-9.1], corrected p = 0.029); however, this allele was not associated in the group from Galicia (northwest of Spain). No differences were found in the distribution of alleles for the gene HLA-DQB1* between patients and controls. Conclusion: The allele HLA-DRB1*1101 and the allelic group HLA-DRB1*11 may determine an increased susceptibility to develop bilateral MD in a southern European population.

What is the most effective vestibular rehabilitation technique in patients with unilateral peripheral vestibular disorders

Vestibular rehabilitation has been found to be effective and safe in patients with instability. There is insufficient evidence, however, for distinguishing between the efficacies of different rehabilitation techniques. The objective of this study is to verify whether there are differences between two instrumental vestibular rehabilitation techniques, computerised dynamic posturography (CDP) and optokinetic stimulation (OKN), in order to establish the optimal strategy for each patient. We conducted a prospective, comparative study of the two techniques (CDP and OKN) in patients with instability due to chronic unilateral peripheral vestibular disorder. We randomly included 12 patients in each group, performing the evaluation with the Dizziness Handicap Inventory and the CDP with the sensorial organisation test (SOT), rhythmic weight shift and limits of stability (LOS). We found a statistically significant improvement in both groups in average balance score according to the SOT. In the OKN group, however, improvement was greater in visual preference. The CDP group showed greater benefits in the visual and vestibular input and LOS. Patients with poor vestibular and visual input or with reduced LOS will benefit more from an exercise protocol with CDP. Patients with poor visual preference, however, are ideal candidates for rehabilitation with OKN.

Polymorphisms of CD16A and CD32 Fcγ receptors and circulating immune complexes in Ménière's disease: a case-control study

BackgroundAutoimmune diseases with elevated circulating autoantibodies drive tissue damage and the onset of disease. The Fcγ receptors bind IgG subtypes modulating the clearance of circulating immune complexes (CIC). The inner ear damage in Ménières disease (MD) could be mediated by an immune response driven by CIC. We examined single-nucleotide polymorphism (SNPs) in the CD16A and CD32 genes in patients with MD which may determine a Fcγ receptor with lower binding to CIC.MethodsThe functional CD16A (FcγRIIIa*559A > C, rs396991) and CD32A (FcγRIIa*519A > G, rs1801274) SNPs were analyzed using PCR-based TaqMan Genotyping Assay in two cohorts of 156 mediterranean and 112 Galicia patients in a case-control study. Data were analyzed by χ2 with Fishers exact test and Cochran-Armitage trend test (CATT). CIC were measured by ELISA for C1q-binding CIC.ResultsElevated CIC were found in 7% of patients with MD during the intercrisis period. No differences were found in the allelic frequency for rs396991 or rs1801274 in controls subjects when they were compared with patients with MD from the same geographic area. However, the frequency of AA and AC genotypes of CD16A (rs396991) differed among mediterranean and Galicia controls (Fishers test, corrected p = 6.9 × 10-4 for AA; corrected p = 0.02 for AC). Although genotype AC of the CD16A receptor was significantly more frequent in mediterranean controls than in patients, [Fishers test corrected p = 0.02; OR = 0.63 (0.44-0.91)], a genetic additive effect for the allele C was not observed (CATT, p = 0.23). Moreover, no differences were found in genotype frequencies for rs396991 between patients with MD and controls from Galicia (CATT, p = 0.14). The allelic frequency of CD32 (rs1801274) was not different between patients and controls either in mediterranean (p = 0.51) or Galicia population (p = 0.11).ConclusionsElevated CIC are not found in most of patients with MD. Functional polymorphisms of CD16A and CD32 genes are not associated with onset of MD.

MICA-STR A.4 is associated with slower hearing loss progression in patients with Ménière's disease.

Hypothesis Immune response may influence hearing outcome in Ménière’s disease (MD). Background Major histocompatibility complex class I chain–related A (MICA) encodes a highly polymorphic stress-inducible protein, which interacts with NKGD2 receptor on the surface of NK, &ggr;&dgr; T cells and T CD8 lymphocytes. We investigated the association of MICA gene with hearing outcome in MD and its linkage disequilibrium (LD) with human leukocyte antigen (HLA)–B. Methods MICA short tandem repeat polymorphism (MICA-STR) was genotyped using a polymerase chain reaction-based method in a total of 302 Spanish patients with MD and 420 healthy controls. Genotyping of HLA-B was performed using polymerase chain reaction and detected with reverse sequence-specific oligonucleotide probe system in 292 patients and 1,014 controls. Results Hearing loss was associated with the duration of MD (p = 0.001). We found that MICA*A5 alelle was significantly associated in the Mediterranean set (Pc = 0.04, odds ratio = 0.51 [95% confidence interval, 0.30–0.84]), but this finding was not replicated in the Galicia population. However, median time to develop hearing loss greater than 40 dB was 16 years (95% confidence interval, 9–23) for patients with the MICA*A.4 allele and 10 years (95% confidence interval, 9–11) for patients with another MICA-STR allele (log-rank test, p = 0.0038). We did not find statistical differences in the distribution of B locus between the MD and the control group. In the LD analysis, MICA*A5.1-HLA-B*07 (8.8%), MICA*A6-HLA-B*44 (8.3%), and MICA*A6-HLA-B*51 (8.3%) were the most common haplotypes, and the stronger LD was found for haplotypes MICA*A.4-HLA-B*18 (r2 = 0.41) and MICA*A.4-HLA-B*27(r2 = 0.29). Conclusion The allelic variant MICA*A.4 is significantly associated with slower progression of hearing loss in patients with MD. This suggests that the immune response influence hearing level in MD.

A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere’s disease

Menieres Disease (MD) is a complex disorder associated with an accumulation of endolymph in the membranous labyrinth in the inner ear. It is characterized by recurrent attacks of spontaneous vertigo associated with sensorineural hearing loss (SNHL) and tinnitus. The SNHL usually starts at low and medium frequencies with a variable progression to high frequencies. We identified a novel missense variant in the PRKCB gene in a Spanish family with MD segregating low-to-middle frequency SNHL. Confocal imaging showed strong PKCB II protein labelling in non-sensory cells, the tectal cells and inner border cells of the rat organ of Corti with a tonotopic expression gradient. The PKCB II signal was more pronounced in the apical turn of the cochlea when compared with the middle and basal turns. It was also much higher in cochlear tissue than in vestibular tissue. Taken together, our findings identify PRKCB gene as a novel candidate gene for familial MD and its expression gradient in supporting cells of the organ of Corti deserves attention, given the role of supporting cells in K+ recycling within the endolymph, and its apical turn location may explain the onset of hearing loss at low frequencies in MD.

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.