Jose A. Lopez-Escamez

Diagnostic criteria for Menière's disease

This paper presents diagnostic criteria for Menières disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menières disease and probable Menières disease. The diagnosis of definite Menières disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 minutes and 12 hours. Probable Menières disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 minutes to 24 hours.

Utilizing Ethnic-Specific Differences in Minor Allele Frequency to Recategorize Reported Pathogenic Deafness Variants

Ethnic-specific differences in minor allele frequency impact variant categorization for genetic screening of nonsyndromic hearing loss (NSHL) and other genetic disorders. We sought to evaluate all previously reported pathogenic NSHL variants in the context of a large number of controls from ethnically distinct populations sequenced with orthogonal massively parallel sequencing methods. We used HGMD, ClinVar, and dbSNP to generate a comprehensive list of reported pathogenic NSHL variants and re-evaluated these variants in the context of 8,595 individuals from 12 populations and 6 ethnically distinct major human evolutionary phylogenetic groups from three sources (Exome Variant Server, 1000 Genomes project, and a control set of individuals created for this study, the OtoDB). Of the 2,197 reported pathogenic deafness variants, 325 (14.8%) were present in at least one of the 8,595 controls, indicating a minor allele frequency (MAF) > 0.00006. MAFs ranged as high as 0.72, a level incompatible with pathogenicity for a fully penetrant disease like NSHL. Based on these data, we established MAF thresholds of 0.005 for autosomal-recessive variants (excluding specific variants in GJB2) and 0.0005 for autosomal-dominant variants. Using these thresholds, we recategorized 93 (4.2%) of reported pathogenic variants as benign. Our data show that evaluation of reported pathogenic deafness variants using variant MAFs from multiple distinct ethnicities and sequenced by orthogonal methods provides a powerful filter for determining pathogenicity. The proposed MAF thresholds will facilitate clinical interpretation of variants identified in genetic testing for NSHL. All data are publicly available to facilitate interpretation of genetic variants causing deafness.

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.

Multiple positional nystagmus suggests multiple canal involvement in benign paroxysmal positional vertigo

Conclusion. Video-oculography demonstrates a higher occurrence of atypical positional nystagmus in patients with benign paroxysmal positional vertigo (BPPV). This includes anterior and horizontal canal variants and multiple positional nystagmus, suggesting combined lesions affecting several canals. Objective. To analyse the video-oculographic findings of positional tests in patients with BPPV. Material and methods. Seventy individuals with symptoms of BPPV and positional nystagmus were included in this study. The diagnosis was based on a history of brief episodes of vertigo and the presence of positional nystagmus as confirmed by video-oculographic examination during the Dix–Hallpike test, the McClure test or the head-hanging manoeuvre. Patients were treated by means of different particle repositioning manoeuvres according to the affected canal (Epleys manoeuvre for the posterior or anterior canals and Lemperts manoeuvre for the lateral canal) and the effectiveness was evaluated at 7 and 30 days. Results. Twenty-nine individuals (41.43%) presented an affected unilateral posterior canal. Fifteen patients (21.43%) presented a pure horizontal direction-changing positional nystagmus consistent with a diagnosis of horizontal canal BPPV. Twelve individuals (17.14%) presented a unilateral down-beating nystagmus, suggesting possible anterior canal BPPV. In addition, 14 patients (20%) showed multiple positional nystagmus during the examination corresponding to simultaneous multi-canal BPPV, 5 had bilateral posterior canal BPPV and 2 presented a positional down-beating nystagmus in both left and right Dix–Hallpike manoeuvres and the head-hanging manoeuvre, which is highly suggestive of anterior canal BPPV. However, seven individuals showed positional horizontal and vertical side-changing nystagmus that could not be explained by single-canal BPPV. These patients with multiple positional nystagmus showed changing patterns of positional nystagmus at follow-up.

Familial clustering and genetic heterogeneity in Meniere's disease

The aims of this study were to estimate the prevalence of familial cases in patients with Menieres disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology‐Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs) and offspring (λo) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16–48 and 4–12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.

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.

Identification of two novel mutations in FAM136A and DTNA genes in autosomal dominant familial Meniere's disease

Menieres disease (MD) is a chronic disorder of the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo, and familial MD is observed in 5-15% of sporadic cases. Although its pathophysiology is largely unknown, studies in human temporal bones have found an accumulation of endolymph in the scala media of the cochlea. By whole-exome sequencing, we have identified two novel heterozygous single-nucleotide variants in FAM136A and DTNA genes, both in a Spanish family with three affected cases in consecutive generations, highly suggestive of autosomal-dominant inheritance. The nonsense mutation in the FAM136A gene leads to a stop codon that disrupts the FAM136A protein product. Sequencing revealed two mRNA transcripts of FAM136A in lymphoblasts from patients, which were confirmed by immunoblotting. Carriers of the FAM136A mutation showed a significant decrease in the expression level of both transcripts in lymphoblastoid cell lines. The missense mutation in the DTNA gene produces a novel splice site which skips exon 21 and leads to a shorter alternative transcript. We also demonstrated that FAM136A and DTNA proteins are expressed in the neurosensorial epithelium of the crista ampullaris of the rat by immunohistochemistry. While FAM136A encodes a mitochondrial protein with unknown function, DTNA encodes a cytoskeleton-interacting membrane protein involved in the formation and stability of synapses with a crucial role in the permeability of the blood-brain barrier. Neither of these genes has been described in patients with hearing loss, FAM136A and DTNA being candidate gene for familiar MD.

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.

Accompanying Symptoms Overlap during Attacks in Menière’s Disease and Vestibular Migraine

Menière’s disease and vestibular migraine (VM) are the most common causes of spontaneous recurrent vertigo. The current diagnostic criteria for the two disorders are mainly based on patients’ symptoms, and no biological marker is available. When applying these criteria, an overlap of the two disorders is occasionally observed in clinical practice. Therefore, the present prospective multicenter study aimed to identify accompanying symptoms that may help to differentiate between MD, VM, and probable vestibular migraine (pVM). Two hundred and sixty-eight patients were included in the study (MD: n = 119, VM: n = 84, pVM: n = 65). Patients with MD suffered mainly from accompanying auditory symptoms (tinnitus, fullness of ear, and hearing loss), while accompanying migraine symptoms (migraine-type headache, photo-/phonophobia, visual aura), anxiety, and palpitations were more common during attacks of VM. However, it has to be noted that a subset of MD patients also experienced (migraine-type) headache during the attacks. On the other hand, some VM/pVM patients reported accompanying auditory symptoms. The female/male ratio was statistically higher in VM/pVM as compared to MD, while the age of onset was significantly lower in the former two. The frequency of migraine-type headache was significantly higher in VM as compared to both pVM and MD. Accompanying headache of any type was observed in declining order in VM, pVM, and MD. In conclusion, the present study confirms a considerable overlap of symptoms in MD, VM, and pVM. In particular, we could not identify any highly specific symptom for one of the three entities. It is rather the combination of symptoms that should guide diagnostic reasoning. The identification of common symptom patterns in VM and MD may help to refine future diagnostic criteria for the two disorders.