Herminio Pérez-Garrigues

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.

Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere's disease.

Bilateral Menieres disease (BMD) is a severe disease that usually results in bilateral severe or profound sensorineural hearing loss and chronic disequilibrium with loss of vestibular function. We examined single nucleotide polymorphisms (SNPs) in the PTPN22 and CTLA4 genes in Caucasian patients with BMD to assess the possible association between these polymorphism and the predisposition and clinical expression of this disease.

Time Course of Episodes of Definitive Vertigo in Ménière’s Disease

OBJECTIVE To evaluate the frequency and duration of episodes of definitive vertigo in Ménières disease. DESIGN Prospective longitudinal study. SETTING Multiple tertiary referral centers. PATIENTS Five hundred ten individuals from 8 hospitals that met the American Academy of Otolaryngology-Head and Neck Surgery diagnostic criteria for definitive Ménières disease. INTERVENTION Conservative treatment. MAIN OUTCOME MEASURE Frequency and duration of episodes of definitive vertigo during follow-up. RESULTS Ménières disease affects both sexes and both ears equally, with onset generally in the fourth decade of life. The number of episodes of vertigo is greater in the first few years of the disease. Although episodes of vertigo that last longer than 6 hours are less frequent than shorter episodes, they occur with similar frequency throughout the natural course of the disease. The percentage of patients without episodes of vertigo increases as the disease progresses, and 70% of patients who did not have an episode of vertigo for 1 year will continue to be free of episodes during the following year. Thus, there is a relationship between the frequency of episodes in consecutive years, although this association decreases rapidly as the number of years increases. CONCLUSION The frequency of definitive episodes of vertigo in Ménières disease decreased during follow-up, and many individuals reached a steady-state phase free of vertigo.

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.

Poly(ADP-ribose) polymerase-1 (PARP-1) longer alleles spanning the promoter region may confer protection to bilateral Meniere's disease.

Conclusion: The longer alleles (CA)17–20 of the promoter region of PARP-1 gene may confer some protection against bilateral Menieres disease (BMD). Objective: To analyze microsatellite (CA)n polymorphisms in the promoter region of PARP-1 gene and seek out risk and protective variants for BMD. Subjects and methods: Eighty patients from two ethnically defined groups with definite BMD, according to the diagnostic scale of the American Academy of Otolaryngology Head and Neck Surgery, were compared with a group of 371 normal controls from the same origin in a prospective multicenter study. We developed a specific amplification protocol to determine the PARP1-promotor CA microsatellite polymorphisms. Results: We found that the longer alleles (CA)17–20 had a very low frequency in BMD (2/160, 1.3%, OR=7.33 (1.77–30.37, 95% CI), corrected p=0.012), suggesting that it may confer some protection against BMD.

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 Ménières 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.

Screening of the USH1G Gene among Spanish Patients with Usher Syndrome. Lack of Mutations and Evidence of a Minor Role in the Pathogenesis of the Syndrome

The Usher syndrome (USH) is an autosomal recessive hereditary disorder characterized by the association of sensorineural hearing loss, retinitis pigmentosa (RP) and, in some cases, vestibular dysfunction. The USH1G gene, encoding SANS, has been found to cause both Usher syndrome type I and atypical Usher syndrome. 109 Spanish unrelated patients suffering from Usher syndrome type I, type II, type III and unclassified Usher syndrome were screened for mutations in this gene, but only eight different changes without a clear pathogenic effect have been detected. Based on these results as well as previous studies in other populations where mutational analysis of this gene has been carried out, one can conclude that USH1G has a minor involvement in Usher syndrome pathogenesis.

Expresión clínica de las alteraciones del equilibrio en pacientes con síndrome de latigazo cervical

Introduccion y objetivo: Entre las enfermedades que pueden producir trastornos del equilibrio, el sindrome de latigazo cervical (LC) adquiere cada vez mayor relevancia, al aumentar su frecuencia por los accidentes de trafico. Hay varias hipotesis en cuanto a la generacion de mareos y vertigos en relacion con el LC. El objetivo de este estudio es describir y analizar la sintomatologia clinica que refieren estos pacientes. Material y metodo: Estudio prospectivo de 36 pacientes, con LC por accidente de trafico, que fueron remitidos a la unidad de otoneurologia por afeccion relacionada con el equilibrio. Ningun paciente habia sufrido traumatismo craneoencefalico ni afeccion vestibular previamente al accidente. Se practico anamnesis exhaustiva, videonistagmografia y resonancia magnetica cervical. Se clasificaron los casos de acuerdo con el tipo de sintomatologia del equilibrio y el grado de lesion cervical. Resultados: El 55,5 % de los pacientes presentaron sensacion de mareo fugaz, en su mayoria en relacion con cambios posturales y movimientos cefalicos. Un 38,8 % presento sensacion de inestabilidad continua; 6 (16,7 %) casos tuvieron vertigo, 3 de ellos compatible con vertigo posicional paroxistico benigno, 2 con conmocion laberintica y un caso no pudo filiarse a ningun diagnostico. Conclusiones: En el sindrome de LC el sintoma mas frecuente, en relacion con el equilibrio, es la sensacion de mareo fugaz asociado a movimientos cefalicos; solo un pequeno grupo padece vertigo. Aunque las pruebas vestibulares son normales en la mayoria de los pacientes, no podemos descartar que haya una lesion otolitica.

Audiological Findings in Charcot–Marie–Tooth Disease Type 4C

OBJECTIVE Charcot-Marie-Tooth disease type 4C (CMT4C) is a hereditary demyelinating early onset neuropathy with prominent unsteadiness and occasional cranial nerve involvement. Vestibulopathy caused by the dysfunction of cranial nerve VIII has been demonstrated in a high percentage of these patients, but the presence and degree of auditory neuropathy are unknown. The aim of the study was to characterize the hearing abnormalities of a series of patients with CMT4C and to determine the presence and severity of auditory neuropathy (AN) in these patients. MATERIALS AND METHODS Ten patients with genetically confirmed CMT4C underwent comprehensive clinical and audiological testing. The results were compared among patients in different age groups and also to the results of vestibular testing that had already been performed. RESULTS Only 3 patients had hearing problems, but 9 had hearing abnormalities on ancillary testing that were compatible with different degrees of auditory nerve dysfunction. In the mildest cases, only the abnormality of the stapedial reflex and distortion of wave I in auditory brainstem responses could be detected. In the more severe cases, tonal audiometry revealed asymmetric hearing loss. These findings were more severe in older patients, even after correcting for age-related hypoacusia. In these patients, vestibular dysfunction could also be detected and seemed to be more profound and symmetric than hearing loss. CONCLUSION This report confirms and defines the presence of different degrees of auditory neuropathy in all patients with CMT4C, being detectable, usually unilaterally, during infancy, and worsening with disease progression.