David M. Baguley

Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell’s apical H+-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in “sporadic” cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.

Specialised treatment based on cognitive behaviour therapy versus usual care for tinnitus: a randomised controlled trial

BACKGROUND Up to 21% of adults will develop tinnitus, which is one of the most distressing and debilitating audiological problems. The absence of medical cures and standardised practice can lead to costly and prolonged treatment. We aimed to assess effectiveness of a stepped-care approach, based on cognitive behaviour therapy, compared with usual care in patients with varying tinnitus severity. METHODS In this randomised controlled trial, undertaken at the Adelante Department of Audiology and Communication (Hoensbroek, Netherlands), we enrolled previously untreated Dutch speakers (aged >18 years) who had a primary complaint of tinnitus but no health issues precluding participation. An independent research assistant randomly allocated patients by use of a computer-generated allocation sequence in a 1:1 ratio, stratified by tinnitus severity and hearing ability, in block sizes of four to receive specialised care of cognitive behaviour therapy with sound-focused tinnitus retraining therapy or usual care. Patients and assessors were masked to treatment assignment. Primary outcomes were health-related quality of life (assessed by the health utilities index score), tinnitus severity (tinnitus questionnaire score), and tinnitus impairment (tinnitus handicap inventory score), which were assessed before treatment and at 3 months, 8 months, and 12 months after randomisation. We used multilevel mixed regression analyses to assess outcomes in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00733044. FINDINGS Between September, 2007 and January, 2011, we enrolled and treated 492 (66%) of 741 screened patients. Compared with 247 patients assigned to usual care, 245 patients assigned to specialised care improved in health-related quality of life during a period of 12 months (between-group difference 0·059, 95% CI 0·025 to 0·094; effect size of Cohens d=0·24; p=0·0009), and had decreased tinnitus severity (-8·062, -10·829 to -5·295; d=0·43; p<0·0001) and tinnitus impairment (-7·506, -10·661 to -4·352; d=0·45; p<0·0001). Treatment seemed effective irrespective of initial tinnitus severity, and we noted no adverse events in this trial. INTERPRETATION Specialised treatment of tinnitus based on cognitive behaviour therapy could be suitable for widespread implementation for patients with tinnitus of varying severity. FUNDING Netherlands Organisation for Health Research and Development (ZonMW).

Tinnitus and cochlear implantation

Tinnitus is a common experience, but there is very marked heterogeneity of aetiology, perception and the extent of distress among individuals who experience tinnitus. In view of this, a modern approach to tinnitus should consider homogeneous groups of individuals. This review considers tinnitus experiences in patients undergoing cochlear implantation, this being of interest because the prevalence of tinnitus in this patient group prior to surgery may shed some light on the link between cochlear dysfunction and tinnitus. Second, any change in tinnitus experience as a result of electrode placement surgery or cochlear implant activation has relevance for patient counselling and informed consent. Finally, in recent tinnitus retraining therapy literature there has been the suggestion that unilateral sound therapy for tinnitus patients may set up an unhelpful asymmetry of input to the auditory system, with possible exacerbation of contralateral tinnitus. Unilateral cochlear implant use represents the most dramatic asymmetry possible and hence is a test of that hypothesis. Relevant papers (n = 32) were identified from literature databases. The standard of reporting tinnitus results was inconsistent. Tinnitus is experienced by up to 86% of adult cochlear implant candidates, but is not universal and is only troublesome in a small proportion (reported as 27% in one study). Electrode insertion may induce tinnitus in a small (up to 4%) number of patients, but this is rare. Cochlear implant device use is associated with reduction of tinnitus intensity and awareness in up to 86% of patients, and rarely with exacerbation (up to 9%). There are some indications in the literature that the more complex the simulation strategy, the larger that effect. Specifically, unilateral cochlear implant use was generally associated with reduction of contralateral tinnitus (in up to 67% of individuals) rather than exacerbation, and so the assertion that unilateral sound therapy for tinnitus is contraindicated is not proven. Sumario El acúfeno es una experiencia común, pero existe una marcada heterogeneidad en cuanto a la etiología, la percepción y el grado de incomodidad experimentado por los individuos que lo padecen. Ante esto, un enfoque moderno para el estudio del acúfeno debe involucrar grupos homogéneos de individuos. Esta revisión considera las experiencias con relación al acúfeno en pacientes sometidos a implantación coclear; hecho que resulta de interés pues la prevalencia del acúfeno en este grupo de pacientes antes de la cirugía puede aportar información sobre el vínculo entre la disfunción coclear y el acúfeno. En segundo lugar, todo cambio sobre la percepción del acúfeno como resultado de la colocación quirúrgica de un electrodo o la activación de un implante coclear tiene relevancia en la asesoría al paciente y para el consentimiento informado. Finalmente, en la literatura reciente sobre terapia de re-entrenamiento en acúfeno, se ha sugerido que la terapia sonora unilateral en estos pacientes puede crear una asimetría en la estimulación de ingreso al sistema auditivo, con una posible exacerbación del acúfeno contra-lateral. El uso de un implante coclear unilateral representa la más dramática asimetría posible, y por lo tanto, se constituye en una prueba para dicha hipótesis. Se identificaron reportes relevantes (n = 32) a partir de bases de datos en la literatura. La norma para reportar el acúfeno fue inconsistente. El acúfeno es experimentado por un 86% de los candidatos adultos para implante coclear, pero este hecho no es universal y resulta molesto solamente para una pequeña proporción de ellos (un estudio reporta un 27%). La inserción del electrodo puede producir un acúfeno en un pequeño número de pacientes (hasta un 4%), pero es raro. El uso del implante coclear se asocia con una reducción en la intensidad y la conciencia del acúfeno en hasta un 86% de los pacientes, y raramente con una exacerbación (hasta 9%). Existen algunas indicaciones en la literatura que aluden a que cuánto más compleja es la estrategia de estimulación mayor es ese efecto. Específicamente, el uso unilateral de un implante coclear se asoció con una reducción en el acúfeno contra-lateral (hasta en un 6% de los individuos) más que con una exacerbación, y por lo tanto, no se demuestra la afirmación de que la terapia sonora unilateral para el acúfeno está contraindicada.

Cochlear implants and tinnitus

The clinical observation that multichannel intra-cochlear cochlear implants have a suppressive effect on tinnitus in profoundly deaf patients is supported by many published studies. Whilst there are problems with that literature, specifically in the way that tinnitus outcomes are reported, the finding of tinnitus benefit is consistent. New developments in this area include the use of functional imaging to investigate tinnitus suppression by cochlear implant stimulation and consideration of a reported worsening effect on tinnitus of binaural implantation. Following work on hearing aids, it is suggested that optimization of the benefit of monaural cochlear implantation on tinnitus in a tinnitus-specific electrode configuration might include the use of a low knee point compression algorithm and disabling directional microphone function: these strategies are potentially also of benefit in patients whose tinnitus results in sleep disturbance. Opportunities for stimulation strategies for tinnitus suppression that bypass speech processing are also identified.

Methodological aspects of clinical trials in tinnitus: A proposal for an international standard

Chronic tinnitus is a common condition with a high burden of disease. While many different treatments are used in clinical practice, the evidence for the efficacy of these treatments is low and the variance of treatment response between individuals is high. This is most likely due to the great heterogeneity of tinnitus with respect to clinical features as well as underlying pathophysiological mechanisms. There is a clear need to find effective treatment options in tinnitus, however, clinical trials differ substantially with respect to methodological quality and design. Consequently, the conclusions that can be derived from these studies are limited and jeopardize comparison between studies. Here, we discuss our view of the most important aspects of trial design in clinical studies in tinnitus and make suggestions for an international methodological standard in tinnitus trials. We hope that the proposed methodological standard will stimulate scientific discussion and will help to improve the quality of trials in tinnitus.

Convergent validity of the tinnitus handicap inventory and the tinnitus questionnaire

For research into tinnitus to be robust and credible, the use of well-validated instruments of self-perceived tinnitus handicap as outcome measures is essential. The tinnitus handicap inventory (THI) and the tinnitus questionnaire (TQ) are two such instruments which are in widespread use. Both questionnaires were administered by mail to 100 consecutive new patients of the Cambridge Tinnitus Clinic, and completed in randomized order. These patients had been referred by the otolaryngology team and had not undergone any tinnitus therapy. The response rate was 78 per cent, neither questionnaire being more acceptable to patients than the other. The convergent validity of the instruments was high, with total and subscale scores all being significantly correlated at the five per cent level (Spearman correlation coefficients). A number of subscale scores were not significantly correlated at the one per cent level however. In particular, the sleep disturbance element of the TQ was demonstrated to have some discriminant validity from the THI and from other elements of the TQ at the one per cent significance level. The THI and TQ have been demonstrated to have high convergent validity and are both suitable for tinnitus outcome studies involving the quantification of self-perceived tinnitus handicap. For research that aims to determine the specific effect of an intervention on tinnitus-related sleep disturbance, the TQ sleep subscale has potential utility. The hypothetical constructs of tinnitus handicap underlying the psychologist-developed TQ and the audiologist-developed THI have been shown to be convergent.

Strategy and benefits of acoustic neuroma searching

Advances in audiological, radiological and microsurgical techniques have enabled otologists to diagnose and excise very small acoustic tumours with a low morbidity and mortality. Is this cost effective? In an attempt to answer this question, an analysis of 66 cases of surgically treated acoustic neuromas is presented. This represents part of a series of skull base procedures carried out at Addenbrookes Hospital over the last five years. As a result of this work an investigative protocol is suggested. By studying the relative morbidity of early and late surgical intervention in these cases, and by costing the exercise, the justification for early diagnosis and treatment is presented both in financial and human terms.

Pitch Comparisons between Electrical Stimulation of a Cochlear Implant and Acoustic Stimuli Presented to a Normal-hearing Contralateral Ear

Four cochlear implant users, having normal hearing in the unimplanted ear, compared the pitches of electrical and acoustic stimuli presented to the two ears. Comparisons were between 1,031-pps pulse trains and pure tones or between 12 and 25-pps electric pulse trains and bandpass-filtered acoustic pulse trains of the same rate. Three methods—pitch adjustment, constant stimuli, and interleaved adaptive procedures—were used. For all methods, we showed that the results can be strongly influenced by non-sensory biases arising from the range of acoustic stimuli presented, and proposed a series of checks that should be made to alert the experimenter to those biases. We then showed that the results of comparisons that survived these checks do not deviate consistently from the predictions of a widely-used cochlear frequency-to-place formula or of a computational cochlear model. We also demonstrate that substantial range effects occur with other widely used experimental methods, even for normal-hearing listeners.

The evidence base for the application of contralateral bone anchored hearing aids in acquired unilateral sensorineural hearing loss in adults

• Acquired unilateral sensorineural hearing loss reduces the ability to localize sounds and to discriminate in background noise.

Cochlear implant failure due to unexpected absence of the eighth nerve - a cautionary tale

We present a case of bilateral absence of the eighth cranial nerve in the internal auditory meatus (IAM). This caused total failure of responses after cochlear implantation in a six-year-old patient with congenital deafness. Pre-operative magnetic resonance (MR) imaging is important to show not only the anatomy of the middle and inner ears but also the structures in the IAM.