Mutations in the human alpha-tectorin gene cause autosomal dominant non-syndromic hearing impairment.

The tectorial membrane is an extracellular matrix of the inner ear that contacts the stereocilia bundles of specialized sensory hair cells. Sound induces movement of these hair cells relative to the tectorial membrane, deflects the stereocilia, and leads to fluctuations in hair-cell membrane potential, transducing sound into electrical signals. Alpha-tectorin is one of the major non-collagenous components of the tectorial membrane. Recently, the gene encoding mouse alpha-tectorin (Tecta) was mapped to a region of mouse chromosome 9, which shows evolutionary conservation with human chromosome 11q (ref. 3), where linkage was found in two families, one Belgian (DFNA12; ref. 4) and the other, Austrian (DFNA8; unpublished data), with autosomal dominant non-syndromic hearing impairment. We determined the complete sequence and the intron-exon structure of the human TECTA gene. In both families, mutation analysis revealed missense mutations which replace conserved amino-acid residues within the zona pellucida domain of TECTA. These findings indicate that mutations in TECTA are responsible for hearing impairment in these families, and implicate a new type of protein in the pathogenesis of hearing impairment.

Involvement of T-cell receptor-beta alterations in the development of otosclerosis linked to OTSC2.

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-beta (TCR-beta) mRNA expression and percentage of blood circulating TCR-alphabeta(+) T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28(null) cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.

Auditory speech sounds evaluation (A(section)E): a new test to assess detection, discrimination and identification in hearing impairment.

This paper describes a set of suprathreshold tests, available as a software package (A(section)E((R))), for the auditory evaluation of the hearing impaired. It uses isolated speech sounds as test material for a discrimination, identification and detection test, and is specifically suited to test preverbal children. All tests allow strict analytical interpretation. The test material and procedures are described. Their clinical use is illustrated. The authors claim that suprathreshold tests are feasible in the preverbal child, allowing analytical evaluation of the auditory capacities. These tests are complementary to the routinely used detection tests and add significantly to the hearing evaluation in preverbal children. The authors recommend the phoneme discrimination test for selection of cochlear implant candidates and for the evaluation and fitting of cochlear implants.

Normative data of the A(section)E discrimination and identification tests in preverbal children.

The A(section)E((R)) is a set of suprathreshold tests for the auditory evaluation of the hearing impaired. A particular population of interest is the hearing-impaired preverbal child. This paper reports on normative data of the A(section)E((R)) discrimination test in children aged 10 months and of the A(section)E((R)) identification tests in children aged 2 to 4 years. Normally hearing children of these ages were tested and pass criteria were defined in such a way that 95% of the hearing infants would pass the tests. With these criteria, the A(section)E((R)) discrimination test is feasible at 10 months of age and the A section signE((R)) identification test from 30 months of age.

Validation of the French-language version of the OTOSPEECH automated scoring software package for speech audiometry.

OBJECTIVES: To validate a novel speech audiometry method using customized self-voice recorded word lists with automated scoring. PATIENTS AND METHODS: The self-voice effect was investigated by comparing results with prerecorded or self-recorded CVC (consonant-vowel-consonant) word lists. Then customized lists of 3-phoneme words were drawn up using the OTOSPEECH software package, and their scores were compared to those for reference lists. Finally, the customized list scores were compared on automated (Dynamic Time Warping [DTW]) versus manual scoring. RESULTS: Self-voice did not change scores for perception of CVC words at 10, 20 and 30 dB (ANOVA>0.05). Scores obtained with pre-recorded and self-recorded lists correlated (n=10, R(2)=0.76, P<0.01). Customized list scores correlated strongly with the reference cochlear lists of Lafon in normal-hearing (n=77, R(2)=0.83, P<0.001) and hearing-impaired populations (n=13, R(2)=0.89, P<0.001). Results on the automated and manual scoring methods correlated in both populations (n=77, R(2)=0.71, P<0.01; and n=13, R(2)=0.76, P<0.01, respectively), with DTW scores ranging from 24.17 to 53.24. CONCLUSIONS: Automated scoring of customized self-voice recorded lists for speech audiometry displayed results similar to conventional audiometric techniques.

A genotype-phenotype correlation for GJB2 (connexin 26) deafness.

INTRODUCTION: Mutations in GJB2 are the most common cause of non-syndromic autosomal recessive hearing impairment, ranging from mild to profound. Mutation analysis of this gene is widely available as a genetic diagnostic test. OBJECTIVE: To assess a possible genotype-phenotype correlation for GJB2. DESIGN: Retrospective analysis of audiometric data from people with hearing impairment, segregating two GJB2 mutations. SUBJECTS: Two hundred and seventy seven unrelated patients with hearing impairment who were seen at the ENT departments of local and university hospitals from Italy, Belgium, Spain, and the United States, and who harboured bi-allelic GJB2 mutations. RESULTS: We found that 35delG homozygotes have significantly more hearing impairment, compared with 35delG/non-35delG compound heterozygotes. People with two non-35delG mutations have even less hearing impairment. We observed a similar gradient of hearing impairment when we categorised mutations as inactivating (that is, stop mutations or frame shifts) or non-inactivating (that is, missense mutations). We demonstrated that certain mutation combinations (including the combination of 35delG with the missense mutations L90P, V37I, or the splice-site mutation IVS1+1G>A, and the V37I/V37I genotype) are associated with significantly less hearing impairment compared with 35delG homozygous genotypes. CONCLUSIONS: This study is the first large systematic analysis indicating that the GJB2 genotype has a major impact on the degree of hearing impairment, and identifying mild genotypes. Furthermore, this study shows that it will be possible to refine this correlation and extend it to additional genotypes. These data will be useful in evaluating habilitation options for people with GJB2 related deafness.

Otosclerosis: a genetically heterogeneous disease involving at least three different genes.

Otosclerosis is caused by abnormal bone homeostasis of the otic capsule, resulting in hearing impairment in 0.3%-0.4% of the white population. The etiology of the disease remains unclear and environmental as well as genetic factors have been implicated. We localized the first autosomal-dominant locus to chromosome 15 in 1998 (OTSC1) in an Indian family and, recently, we reported the localization of a second gene for otosclerosis to a 16 cM interval on chromosome 7q (OTSC2). In this study, we recruited and analyzed nine additional families (seven Belgian and two Dutch families with 53 affected and 20 unaffected subjects) to investigate the importance of these loci in autosomal-dominant otosclerosis. We completed linkage analysis with three microsatellite markers of chromosome 15 (D15S652, D15S1004, D15S657) and five microsatellite markers of chromosome 7 (D7S495, D7S2560, D7S684, D7S2513, D7S2426). In two families, results compatible with linkage to OTSC2 were found, but in the seven remaining families OTSC1 and OTSC2 were excluded. Heterogeneity testing provided significant evidence for genetic heterogeneity, with an estimated 25% of families linked to OTSC2. These results indicate that, besides OTSC1 and OTSC2, there must be at least one additional otosclerosis locus.

Aminoglycoside-induced ototoxicity.

One of the major side effects of aminoglycoside antibiotics (AG) is ototoxicity. The authors review the literature revealing many controversies on every aspect of this side-effect. Although epidemiological studies have to face the problem of reliable evaluation techniques, the incidence of cochleo- and vestibulotoxic side-effects has been estimated at 7.5% for each. Netilmicin appears to be less ototoxic. No definite risk factors can be proposed, although age, length of therapy, bacteremia, fever, liver and renal dysfunction are probably very important parameters. Most pathological changes at the cochlear level follow a clear spatial sequence, showing unspecific, degenerative lesions, involving every structure of the cochlea. This makes it impossible to draw etiopathological conclusions. Recent pharmacokinetic studies have rejected the 'accumulation theory' of AGs in perilymph, while also in endolymph no accumulation can be found. Only a few data are available on inner ear tissue levels. Among the different pharmacodynamic hypotheses on the action of AGs, binding of the drug to acidic glycosaminoglycans in the stria vascularis, and interference by the drug with phosphoinositide metabolism in the hair cells seem to be of major importance.

Use of antibiotic prophylaxis in ear surgery.

A prospective, double-blind, randomized, placebo-controlled study was performed to evaluate the effect of antibiotic prophylaxis in ear surgery. The present study reports on the results of 750 patients, half of whom received cefuroxime for 1 day, the other half, placebo. All postoperative infections occurring within 2 weeks after the intervention were recorded, together with several preoperative and perioperative parameters. It is concluded that exploratory tympanoplasties (including stapedotomy) and "dry perforation" tympanoplasties should be considered "clean" operations according to the American National Research Council and do not benefit from antibiotic prophylaxis. On the other hand, tympanoplasties performed on draining ears and on ears with cholesteatoma should be considered "dirty" operations for which antibiotic prophylaxis may decrease the postoperative infection rate by factor 3. All postoperative infections healed without sequels under proper treatment, except for three that resulted in graft necrosis--one in the placebo group and two in the cefuroxime group. In consequence, prophylaxis may not be mandatory in the dirty group, although the authors advocate its use for the sake of patient and surgeon comfort.

Box and whisker plots for graphic presentation of audiometric results of conductive hearing loss treatment.

The Committee on Hearing and Equilibrium of the American Academy of Otolaryngology-Head and Neck Surgery has published guidelines for the reporting of audiometric results of middle ear interventions. It recommends the reporting of several audiometric variables by means of two summary parameters: means and standard deviation. This article advocates the use of other summary statistics, namely the median, quartiles, and extremes, because they do not require a normal distribution of the audiometric data and they are not sensitive to variations of the extreme values. On the basis of the exploratory data analysis, we propose a graphic method to present the Committee's variables in terms of their summary statistics. This "multiple box and whisker plot" offers a detailed and accurate overview of six variables in one graph.

Cochlear implants in aplasia and hypoplasia of the cochleovestibular nerve.

OBJECTIVE: To report on the outcome of four patients with aplasia or hypoplasia of the cochleovestibular nerve who have received a cochlear implant. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Four patients with: 1) type I aplasia; 2) type IIa aplasia; 3) type IIa hypoplasia; and 4) type IIb aplasia received a cochlear implant. All patients had corner audiograms even with hearing aids. INTERVENTION: Three patients received a LAURA multichannel implant, and one patient received a Nucleus 24 implant. MAIN OUTCOME MEASURE: Auditory performance, educational setting. RESULTS: The patients with type I and type IIb aplasia did not have auditive perception with their implant and became non-users. Both are now in a total communication educational setting. The patients with type IIa aplasia and hypoplasia had moderate audiological results with the implant with audiometrical thresholds of approximately 40-60 dB HL (pure tone average), moderate phoneme discrimination, and poor word discrimination. One child is in a total communication educational setting and the other in an oral educational setting, but the preferred mode of communication remains total communication for both. Both appear to benefit from the implant nonetheless. CONCLUSION: Patients with aplasia/hypoplasia of the cochleovestibular nerve should be counseled with caution with respect to cochlear implantation, but particular circumstances may justify the intervention. At present these circumstances seem to be a type IIa aplasia or hypoplasia in which the end organ (cochlea or common cavity) still connects to a neural structure on MRI.

A Two-stage bipodal screening model for universal neonatal hearing screening.

OBJECTIVE: A model is proposed for universal neonatal hearing screening. METHODS: The screening model is two-staged because it consists of a first test and, in case of failure (1.4% of the subjects), of a retest 3 weeks later. It is bipodal because it involves both the hospital audiologic department and a central Well Baby Organization. The idea is to have a maximal number of newborns tested at the maternity by trained audiologists and to have the Well Baby Organization trace and chase the missing subjects. The model has been evaluated during 1 calendar year (1999) in a maternity with 2,012 newborns. RESULT: The result is a coverage of 99.3%. Most newborns (97.3%) were tested at the maternity ward with a total time investment of less than 15 minutes per child. The actual test time is 2 minutes, 12 seconds (median value). The Well Baby Organization keeps track of all the results and has to test no more than 2% of the newborns. Sensitivity and specificity were not the primary outcomes of this evaluation, but they were similar to those of a previous study evaluating the screen procedure on a larger scale, giving a sensitivity of approximately 100% and a false alarm rate of 1/1,000. CONCLUSION: These figures demonstrate that universal neonatal hearing screening is feasible within the existing health care structure, with unprecedented coverage, sensitivity, and specificity.

Contralateral suppression of transient evoked otoacoustic emissions: normative data for a clinical test set-up.

HYPOTHESIS: Contralateral suppression of transient evoked otoacoustic emissions (TEOAEs) can be used in a clinical set-up using a procedure based on a unique and robust parameter to quantify the magnitude of suppression for a subject. BACKGROUND: TEOAEs can be suppressed by delivering contralateral white noise (WN). This suppression is thought to be mediated via the efferent nerve fibers that innervate the outer hair cells. The ipsilateral TEOAE-eliciting click stimulus level and the contralateral WN level have a strong impact on the recorded level of suppression. METHODS: TEOAEs were recorded using the nonlinear stimulation mode in two conditions (with and without contralateral WN). An optimal TEOAE-eliciting click stimulus level and contralateral WN level were defined to obtain a unique and robust parameter to quantify the magnitude of suppression. RESULTS: Suppression of TEOAEs with contralateral WN can be measured in a clinical set-up using nonlinear stimulation, and the level of suppression is of the same order of magnitude as measures using the linear stimulation recording mode. The level of suppression appears to be "locked" to the interaural difference between ipsilateral TEOAE-eliciting broadband click stimulus level and the contralateral WN level. CONCLUSIONS: A procedure is proposed to record contralateral suppression in a clinical set-up, and normative data are given for a normal-hearing population (n = 60).

Allograft tympanoplasty type 1 in the childhood population.

Seventy allograft type 1 tympanoplasties in children under 16 years of age were studied retrospectively. Only patients with a tympanic membrane perforation without cholesteatoma and a normal ossicular chain were included. Short-term and long-term anatomic and functional results were analyzed after a mean follow-up of 40 months. The overall short-term take rate was 97% and the long-term take rate was 88%. A number of variables with alleged prognostic value for surgical outcome were analyzed, but none showed statistical correlation with either anatomic or functional results. A median hearing gain of 10 dB was achieved, which was stable over time. We conclude that allograft tympanoplasty type 1 in this group of children is anatomically and functionally successful regardless of age.

Persistent stapedial artery: does it prevent successful surgery?

Because of the important function of the embryologic stapedial artery, it is taken for granted by many surgeons that the finding of such a persistent artery in postnatal humans during middle ear surgery should urge maximal caution in order not to damage the artery. Often, discontinuation of the surgery is recommended. Yet this attitude is based on theoretic considerations rather than on any clinical evidence of complications following injury to this vessel. The present paper describes the embryology in relation to this specific aspect and reviews the literature on the persistent stapedial artery, emphasizing the papers dealing with injury to this vessel. In addition, we report 4 cases of persistent stapedial artery from the files of almost 20,000 patients in whom tympanotomy was performed. From all these data we conclude that injury to this artery or even complete section probably does not cause major, if any, postoperative sequelae, and that consequently, middle ear surgery is not necessarily hindered by the presence of this vessel.

Tympano-ossicular allografts for cholesteatoma in children.

At the Sint Augustinus Hospital, Antwerp, Belgium, all children with cholesteatoma are operated by a canal wall up approach and immediate reconstruction with a tympano-ossicular allograft. In the majority of the cases, a second stage is performed after 1 year. This paper presents the results of a retrospective review of the charts of 103 consecutive children treated between 1979 and 1995. The mean patient age was 10 years and the mean postoperative follow-up was 4.5 years. In 28 children residual cholesteatoma was found at the second stage operation and 20 developed recurrent cholesteatoma in the course of time. So far no residual cholesteatoma surfaced after the staged procedure, but 11 children needed more than two operations to control recurrent disease. An intact, trouble-free graft was present in 79 children at the latest follow-up. The median postoperative bone-conduction thresholds were equal to the preoperative thresholds. The median postoperative air-conduction thresholds improved in 50% of the cases, remained unchanged in 25%, and deteriorated in 25% of the cases. It is concluded that the tympano-ossicular allograft technique is effective and safe and offers good anatomical and acceptable functional results.

Audiological findings in large vestibular aqueduct syndrome.

An enlarged vestibular aqueduct is a congenital disorder causing early onset and progressive hearing loss in children. This paper presents the audiological findings at first presentation and the audiological evolution in 10 consecutive cases presenting with hearing loss and showing a large vestibular aqueduct on imaging. The reported onset of the hearing loss is within the first few years of life. Most of the cases (80%) showed bilateral involvement. The sex ratio was 1. Patients presented on average at age 5 with a median hearing loss of 62 dB at the speech frequencies. The hearing loss was essentially asymmetrical with an interaural difference, of 33 dB and it was a mixed type of hearing loss in 90% of the cases. The authors claim that the conductive component of this hearing loss is a pure cochlear conductive loss which may be pathognomonic for the disease. The presence of a conductive component in a child is easily misinterpreted as a middle ear ventilation problem or in case of good ventilation as an ossicular problem (type otosclerosis). In addition and in contrast to most literature data, the authors did not find evidence for stabilization of the hearing loss but they found a steady decrease of the hearing at an average rate of 4 dB/year.

Histological study of the thin replacement membrane of human tympanic membrane perforations.

A histological study was done on the thin, nearly transparent replacement membrane of tympanic membrane perforations. Human tympanic membranes that were rejected for transplantation, were studied by light and electron microscopy. The abrupt reduction in thickness at the margin of the covered perforation, is entirely due to the reduction of the lamina propria. Even in the thinnest parts of the replacement membrane, a lamina propria is present, separated by continuous basement membranes from the epithelium and mucosa, and measuring no more than some 2-3 microns in thickness. This lamina propria consists of fibrils and interfibrillar matrix, but fibroblasts appear to be lacking. The epithelial layer does not contain basal cells, confirming the thesis that the upper layers are not generated by in situ proliferation, but that they have migrated from the periphery.

Numerical assessment of TOAE screening results: currently used criteria and their effect on TOAE prevalence figures.

The literature on neonatal hearing screening by means of oto-acoustic emissions (OAE's) presents various prevalence figures, and gives little quantitative information on the procedure used to score the recordings. If the OAE test is to be interpreted by users who do not have the opportunity to develop intuitive interpretation skills through extensive training, a clear numerical decision criterion is needed. The present paper discusses the scoring procedure used by 25 teams, which together screen 22,356 neonates annually. More than 60% of the groups involved in this study use visual interpretation of the recorded OAE response, together with numerical criteria. Amongst the teams, 21 different ways of numerical scoring are used. It is shown that for a given set of OAE recordings, prevalence varies from 61% to 90%, depending on the numerical decision criterion being applied. We conclude that at this moment no consensus exists regarding the numerical criterion to be used when assessing OAE screening results. In view of the strong effect of criteria on the outcome of OAE screening, such consensus is urgently needed, but should be based on sensitivity and specificity figures for each scoring technique.

Basic fitting and evaluation parameters of a newly designed cochlear implant electrode.

OBJECTIVE: To validate a newly designed cochlear implant electrode (TRACE) in the standard monopolar mode and compare it to a patient group implanted with a standard Nucleus Contour cochlear implant electrode. The electrode contacts of the TRACE electrode have the same active surface area for stimulation, but the position in the scala tympani is different from that of the Nucleus Contour electrode. MATERIAL AND METHODS: The following parameters, used in cochlear implant fitting and evaluation procedures, were determined: the threshold and comfort stimulation current levels; the electrode impedances; and the phoneme discrimination and speech recognition scores using the ACE speech algorithm. CONCLUSION: The new electrode does not differ significantly from the standard Nucleus Contour electrode in terms of the investigated parameters within the test group.