Patrick Axon

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.

Cranial Nerve Involvement in Malignant External Otitis: Implications for Clinical Outcome

Background: Malignant external otitis is an uncommon, potentially lethal infection of the temporal bone primarily affecting elderly diabetic patients.

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.

Limits of temporal pitch in cochlear implants

A common finding in the cochlear implant literature is that the upper limit of rate discrimination on a single channel is about 300 pps. The present study investigated rate discrimination using a procedure in which, in each block of two-interval trials, the standard could have one of the five baseline rates (100, 200, 300, 400, and 500 pps) and the signal rate was a given percentage higher than the standard. Eight Med-El C40+ subjects took part. The pattern of results was different than those reported previously: six Med-El subjects performed better at medium rates (200-300 pps) compared to both lower (100 pps) and higher (400-500 pps) rates. A similar pattern of results was obtained both with the method of constant stimuli and for 5000-pps pulse trains amplitude modulated at rates between 100 and 500 Hz. Compared to an unmatched group of eight Nucleus CI24 listeners tested using a similar paradigm and stimuli, Med-El subjects performed significantly better at 300 pps and higher but slightly worse at 100 pps. These results are discussed in relation to evidence on the limits of temporal pitch at low and high rates in normal-hearing listeners.

MRI without magnet removal in neurofibromatosis type 2 patients with cochlear and auditory brainstem implants.

Objective To assess the impact on image quality of MRI without magnet removal in cochlear implant (CI) and auditory brainstem implant (ABI) users with neurofibromatosis type 2 (NF2). Study Design Prospective cohort. Setting Tertiary center for cochlear and auditory brainstem implantation. Patients Thirteen patients (10 ABI, 3CI) with NF2 underwent a total of 76 MRI scans. Interventions MRI without magnet removal. Main Outcome measure Ability to visualize the ipsilateral and contralateral cerebellopontine angles (CPAs) and internal auditory meati (IAM) with head MRI. Results Of the 76 scans, 40 were of the head, 28 of the spine and 8 of other regions. Scanning was performed with a tight head bandage and plastic card. There were no cases of altered implant function or demagnetization of the device magnet. A grading system was used to assess the view of the ipsilateral IAM-CPA. In 85% of head scans, the view was unimpaired (Grade 0). In 13%, there was distortion (Grade 1). In 2% (1 case), the view was entirely obscured by artifact (Grade 2). Views of the contralateral CPA and IAM were unimpaired in all cases. The best 3 sequences for the depiction of the ipsilateral IAM-CPA (percent graded as 0) were as follows: axial 3D inversion recovery prepared fast spoiled gradient echo (100%), 2 mm coronal T1W of the IAM-CPA (88.9%), and 2 mm axial T1W of the IAM-CPA (76.9%). Conclusion MRI scanning without magnet removal is safe and well tolerated in NF2 patients with auditory implants. With appropriate MRI sequences, the image quality is not significantly impaired.

Change in tinnitus handicap after translabyrinthine vestibular schwannoma excision.

Objective: To evaluate the change in tinnitus handicap after translabyrinthine vestibular schwannoma excision. Study Design: Prospective administration of the Tinnitus Handicap Inventory (THI) preoperatively and at 3 and 12 months postoperatively. Setting: A tertiary referral neuro-otology clinic. Patients: A total of 149 patients from a series of 170 consecutive patients who had vestibular schwannomas excised between May 1998 and July 2002 and who had completed THIs preoperatively and at 3 and 12 months postoperatively. Interventions: Translabyrinthine excision of a unilateral sporadic vestibular schwannoma. Main Outcome Measures: THI scores. Results: The number of patients with moderate or severe handicap was 21 (14%) in the preoperative group and 21 (14%) in the 12-month postoperative group. No significant differences in group data were found comparing (by Wilcoxon signed rank test) preoperative data with 3 months postoperative data (p = 0.09), preoperative data with 12 months postoperative data (p = 0.09), and 3 months postoperative data with 12 months postoperative data (p = 0.33). Considering group data, tinnitus handicap is neither alleviated nor exacerbated by translabyrinthine surgery. The application of the validated 20-point criteria for significant change in the status of an individual patient indicates that tinnitus handicap was worse in 10 (6.5%), unchanged in 129 (87%), and better in 10 (6.5%). Conclusions: The findings of the current study can be used during preoperative patient counseling. In particular, the clinician is now able to take an informed and positive stance about the tinnitus handicap to be expected postoperatively.

The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double-blind, placebo-controlled, crossover study.

Objective: Intravenous infusion of lidocaine has previously been demonstrated to have a transient inhibitory effect on tinnitus in 60% of individuals. The site of action has variously been proposed as the cochlea, the cochlea nerve, and the central auditory pathways. To determine whether a central site of action exists, this study investigated the effect of intravenous infusion of lidocaine in individuals with tinnitus who had previously undergone translabyrinthine excision of a vestibular schwannoma, which involves division of the cochlear nerve. Study Design: Double-blind, placebo-controlled, crossover study. Setting: University hospital. Patients: Patients who had undergone translabyrinthine removal of a unilateral, sporadic, and histologically proven vestibular schwannoma in the last decade and who had reported postoperative tinnitus at follow-up were identified from a departmental database. Sixteen patients participated (12 men and 4 women). The mean age (± standard deviation) of the patients was 58 ± 8.6 years, and the meantime since operation was 24.3 ± 7.3 months. Intervention: Solutions of 2% lidocaine hydrochloride and sodium chloride 0.9% were prepared in identical randomized vials. The volume required for 1.5 ml/kg body weight lidocaine was calculated, and this volume was given over 5 minutes for either vial. Blood pressure, pulse oximetry, and cardiac monitoring were set up and performed throughout the infusions. All investigators were blinded. Outcome Measures: Patient-completed visual analogue scale measures of tinnitus intensity, pitch, and distress, performed before infusion, 5 minutes after infusion onset, and 20 minutes after infusion onset. Results: A significant difference (Wilcoxon signed-rank test, p < 0.05) between placebo and lidocaine infusion conditions was demonstrated for change in visual analogue scale estimates (preinfusion versus 5 min postinfusion) of tinnitus loudness (p = 0.036), pitch (p = 0.026), and distress (p = 0.04). No significant difference between placebo and lidocaine infusion conditions was demonstrated for change in visual analogue scale estimates (preinfusion versus 20 min postinfusion) of tinnitus loudness (p = 0.066), pitch (p = 0.173), and distress (p = 0.058). The indication is of a short-lasting inhibitory effect on tinnitus of lidocaine infusion compared with saline placebo in patients who have undergone translabyrinthine excision of a vestibular schwannoma. Conclusion: Intravenous infusion of lidocaine has a statistically significant inhibitory effect on tinnitus in patients who have previously undergone translabyrinthine removal of a vestibular schwannoma. The site of action of lidocaine in this instance must be in the central auditory pathway, as the cochlear and vestibular nerves are sectioned during surgery, and this finding has important implications for the task of identifying other agents that will have a similar tinnitus-inhibiting effect.

Clinical and molecular predictors of mortality in neurofibromatosis 2: a UK national analysis of 1192 patients

Background Neurofibromatosis 2 (NF2) is an autosomal-dominant tumour predisposition syndrome characterised by bilateral vestibular schwannomas, considerable morbidity and reduced life expectancy. Although genotype–phenotype correlations are well established in NF2, little is known about effects of mutation type or location within the gene on mortality. Improvements in NF2 diagnosis and management have occurred, but their effect on patient survival is unknown. Methods We evaluated clinical and molecular predictors of mortality in 1192 patients (771 with known causal mutations) identified through the UK National NF2 Registry. Kaplan–Meier survival and Cox regression analyses were used to evaluate predictors of mortality, with jackknife adjustment of parameter SEs to account for the strong intrafamilial phenotypic correlations that occur in NF2. Results The study included 241 deaths during 10 995 patient-years of follow-up since diagnosis. Early age at diagnosis and the presence of intracranial meningiomas were associated with increased mortality, and having a mosaic, rather than non-mosaic, NF2 mutation was associated with reduced mortality. Patients with splice-site or missense mutations had lower mortality than patients with truncating mutations (OR 0.459, 95% CI 0.213 to 0.990, and OR 0.196, 95% CI 0.213 to 0.990, respectively). Patients with splice-site mutations in exons 6–15 had lower mortality than patients with splice-site mutations in exons 1–5 (OR 0.333, 95% CI 0.129 to 0.858). The mortality of patients with NF2 diagnosed in more recent decades was lower than that of patients diagnosed earlier. Conclusions Continuing advances in molecular diagnosis, imaging and treatment of NF2-associated tumours offer hope for even better survival in the future.

Non echo planar, diffusion-weighted magnetic resonance imaging (periodically rotated overlapping parallel lines with enhanced reconstruction sequence) compared with echo planar imaging for the detection of middle-ear cholesteatoma

OBJECTIVES We evaluated use of the periodically rotated overlapping parallel lines with enhanced reconstruction diffusion-weighted imaging sequence, compared with conventional echo planar magnetic resonance imaging, in the detection of middle-ear cholesteatoma. MATERIAL AND METHODS Sixteen patients awaiting second-stage combined approach tympanoplasty and three patients awaiting first-stage combined approach tympanoplasty underwent magnetic resonance imaging with both (1) the periodically rotated overlapping parallel lines with enhanced reconstruction sequence (i.e. non echo planar imaging) and (2) the array spatial sensitivity encoding technique sequence (i.e. echo planar imaging). Two neuroradiologists independently evaluated the images produced by both sequences. Radiology findings were correlated with surgical findings. RESULTS AND ANALYSIS Seven cholesteatomas were found at surgery. Neither of the assessed imaging sequences were able to detect cholesteatoma of less than 4 mm. Rates for sensitivity, specificity, and positive and negative predictive values are presented. CONCLUSION Decisions on whether or not to operate for cholesteatoma cannot be made based on the two imaging sequences assessed, as evaluated in this study. Other contributing factors are discussed, such as the radiological learning curve and technical limitations of the magnetic resonance imaging equipment.

A review on the genetics of otosclerosis.

Background:  The aetiology of otosclerosis is not fully understood despite intensive research. It is, however, certain that a genetic component plays a significant role in the manifestation of otosclerosis, although the precise mode of inheritance is still uncertain.