Manuela Mazzoli

The relationship between distortion product otoacoustic emissions and extended high-frequency audiometry in tinnitus patients. Part 1: Normally hearing patients with unilateral tinnitus

Summary Background The aim of this study was to evaluate distortion product otoacoustic emissions (DPOAEs) and extended high-frequency (EHF) thresholds in a control group and in patients with normal hearing sensitivity in the conventional frequency range and reporting unilateral tinnitus. Material/Methods Seventy patients were enrolled in the study: 47 patients with tinnitus in the left ear (Group 1) and 23 patients with tinnitus in the right ear (Group 2). The control group included 60 otologically normal subjects with no history of pathological tinnitus. Pure-tone thresholds were measured at all standard frequencies from 0.25 to 8 kHz, and at 10, 12.5, 14, and 16 kHz. The DPOAEs were measured in the frequency range from approximately 0.5 to 9 kHz using the primary tones presented at 65/55 dB SPL. Results The left ears of patients in Group 1 had higher median hearing thresholds than those in the control subjects at all 4 EHFs, and lower mean DPOAE levels than those in the controls for almost all primary frequencies, but significantly lower only in the 2-kHz region. Median hearing thresholds in the right ears of patients in Group 2 were higher than those in the right ears of the control subjects in the EHF range at 12.5, 14, and 16 kHz. The mean DPOAE levels in the right ears were lower in patients from Group 2 than those in the controls for the majority of primary frequencies, but only reached statistical significance in the 8-kHz region. Conclusions Hearing thresholds in tinnitus ears with normal hearing sensitivity in the conventional range were higher in the EHF region than those in non-tinnitus control subjects, implying that cochlear damage in the basal region may result in the perception of tinnitus. In general, DPOAE levels in tinnitus ears were lower than those in ears of non-tinnitus subjects, suggesting that subclinical cochlear impairment in limited areas, which can be revealed by DPOAEs but not by conventional audiometry, may exist in tinnitus ears. For patients with tinnitus, DPOAE measures combined with behavioral EHF hearing thresholds may provide additional clinical information about the status of the peripheral hearing.

An introduction to the genetics of normal and defective hearing.

The recent rapid development of molecular biology techniques applied to the genetics of normal and defective hearing shed a new light on old questions regarding hearing and deafness. Genes are DNA sequences that determine characteristics, normally by specifying the sequence of aminoacids in a protein. The majority of genes is located in the chromosomes (human chromosomes have perhaps 80,000 pairs of genes). In addition there are 37 mithochondrial genes which are inherited only from the mother. One method used to identify candidate genes based on their function or pattern of tissue expression involves the construction of cDNA libraries from the target organ or tissue, in this case from the cochlea. The construction and characterization of cochlear cDNA libraries from humans and other species provide an important resource for rapid identification of cochlear genes involved in normal hearing and hearing disorders. Studies of the molecular genetics of the inner ear are hampered by the relative inaccessibility of the cochlea, by the limited number of cochlear and vestibular cells, and by our inability to maintain many of these cell types in long-term cultures. Several rodent inner-ear cDNA libraries and a human foetal cochlear cDNA library have already been constructed. Human and rodent cochlea-subtracted cDNA libraries are very useful for identifying genes controlling the development and maintenance of hearing. cDNA libraries constructed at different stages of development, and subtracted from each other, could be instrumental in identifying genes important at each stage of cochlear development. In addition, these libraries have the potential of fostering the identification of other proteins unique to the cochlea and will contribute to the identification, characterization, and functional analysis of these cochlea-specific proteins. Another important application of cDNA libraries is in identifying hearing-loss genes. Once the candidate gene for a given type of hearing loss is cloned and decoded, the structure of its protein product can be determined. This will provide insights into the biochemical function of the gene product in normal cochlear tissue, and will show why the genetic mutation results in hearing loss, that is, the recent identification of the myosin VIIa gene in Usher type IB. In addition, through the use of homologous recombination and transgenic technology, in vivo mouse models of inner-ear genetic disorders can be created. To date, 350 different genetic conditions associated with hearing impairment have been described, and during the past five years several of the genes involved in these form have already been mapped and identified.

Audiometric Patterns of Genetic Non-syndromal Sensorineural Hearing Loss

Sixty-five families with non-syndromal sensorineural hearing loss (NS-SNHL) of genetic aetiology were subtyped according to Gorlin et al. Individual audiogram shapes were also classified in order to detect inter- and intra-familial variations. In 48 families with an Autosomal Dominant (AD) inherited form, 26 exhibited the features of (high-frequency) progressive NS-SNHL, 12 those of mid-frequency NS-SNHL, 5 were affected by congenital low-frequency NS-SNHL; 1 kindred showed a progressive low-frequency pattern and another 1 a unilateral NS-SNHL; only 3 kindreds were affected by severe congenital NS-SNHL. Autosomal Recessive (AR) inherited forms were composed of 9 kindreds with severe congenital NS-SNHL, and 7 with moderate congenital NS-SNHL. One X-linked form was identified. AD- and AR-inherited NS-SNHL differed significantly both in severity of hearing impairment and in audiogram shapes. With few exceptions, in each family classified according to Gorlin, most of the affected subjects shared the same audiogram profile. Intrinsic progression of the disease versus ageing was studied in the larger subtype of individuals with the high-frequency loss. Gorlins classification still remains the best system to classify NS-SNHL, and can provide a broad base to separate a very heterogeneous group of disorders. Results obtained in gene mapping in single large human families or in homologous gene search could be tested in our families. For some of them, namely those with high frequency progressive and low-frequency NS-SNHL, testing should already be feasible.

Clinical Applicability of Transient Evoked Otoacoustic Emissions: Identification and Classification of Hearing Loss

The study aimed at the development of a clinically applicable methodology that could: (1) discriminate transient evoked otoacoustic emission (TEOAE) recordings from normal hearing or hearing impaired individuals; (2) classify the nature of the hearing loss as conductive or as cochlear, and (3) define clear-cut TEOAE clinical criteria. A classification algorithm based on a multivariate discriminant analysis of fast Fourier transform data from recordings evoked by click stimuli of 50 ± 2, 62 ± 2, 68 ± 2 and 80 ± 2 dB SPL was used to discriminate 302 normal subjects from 383 subjects suffering from mild to moderate hearing losses. The best discriminant model (QDF80) produced a sensitivity of 93.8% and a specificity of 79.4%. When extra correlation criteria were serially applied to the classification outcome, the specificity was increased to 85.3%, but the sensitivity was marginally decreased to 91.7%. The classification of the correctly identified hearing-impaired cases yielded 93.8% identification of conductive and 75.1% identification of cochlear cases. A sensitivity analysis of the misclassified hearing-impaired cases suggested that the TEOAE spectra are well correlated with the 2-kHz but poorly correlated with the 4-kHz octave frequency.

Identification of Hearing Loss Using TEOAE Descriptors: Theoretical Foundations and Preliminary Results

It was hypothesized that the relationship between transiently evoked otoacoustic emission (TEOAE) signals and the functional status of the outer hair cells provides an opportunity to design a clinical procedure that can evaluate the normality of cochlear function. To discriminate normal subjects from subjects suffering from mild to moderate hearing loss (HL), it was assumed that every subject population has unique and discrete TEOAE signal descriptors. The main classification algorithm was based on a discriminant analysis of raw fast Fourier transform data. When it was applied to a sample set of TEOAE recordings (from 56 normal and 68 HL subjects) elicited from 68-dB SPL click stimuli, it correctly identified 90.2% of the normal and 87.5% of the HL subjects. The same algorithm yielded an 85.5% discrimination between TEOAE recordings from conductive and cochlear HL cases.

Mapping of a new autosomal dominant nonsyndromic hearing loss locus (DFNA30) to chromosome 15q25-26.

Hearing impairment is the most common inherited human sensory defect. Nonsyndromic Hearing Impairment (NSHI) is the most genetically heterogeneous trait known. Over 70 loci have been mapped and a total of 19 genes have been identified. We report here a novel locus (DFNA 30) for autosomal dominant NSHI that we mapped to chromosome 15q25-26 in an Italian four-generation family. The haplotype analysis has identified a critical interval of 18 cM between markers D15S151 and D15S130. This region does not overlap with DFNB16 locus but partially coincides with the otosclerosis (OTS) locus. Localisation of the locus DFNA30 is a first step towards the identification of the gene.

Cochlear Implants in Subjects Over Age 65: Quality of Life and Audiological Outcomes.

Background Cochlear implants (CIs) have been recognized as a safe and effective means for profound hearing loss rehabilitation in children and adults and recently their use has been extended to subjects over 65 years of age. The aim of this paper was to assess indices related to changes in the quality of life (QoL) in elderly CI recipients. Material/Methods A case-control paradigm was used to assess the effects of CIs on the QoL. Forty-two subjects were assigned to the Case group and 15 subjects to the Control group. All 57 subjects were affected by profound hearing loss and had received a CI. Audiological data were collected from both groups at: (i) 1 month pre-implantation [T1]; (ii) 1 day pre- implantation [T2]; (iii) 30 days post-implantation, with CI used in free field [T3]; and (iv) 12 months post-implantation, with CI used in a free field [T4]. The QoL was assessed via a Glasgow Benefit Inventory (GBI) questionnaire, adapted to otolaryngology. To compare subjects across different ages with varying degrees of speech development, a perception parameter was used from the Speech Perception Categories test developed by Geers and Moog. Results Hearing performance was considerably improved after CI. In relation to the hearing performance at time T1, statistically significant threshold gains were observed in both groups in the T3 and T4 observation windows. At time T4, a threshold gain of 70 dB HL in the Case group and a gain of 84 dB HL in the Control group were observed. With speech therapy rehabilitation, a perception level of 6 was reached by 80.0% of patients in the Case group and by 100% of patients in the Control group. In terms of QoL, both groups showed improved post-CI scores. Statistical differences were observed between the 2 groups, with the Control group outperforming the Case group in all but the social section. Conclusions Despite age-related changes in auditory system and prolonged hearing deprivation, CIs offer audiological and QoL benefits in the elderly.

Cerebral Inflow and Outflow Discrepancies in Severe Sudden Sensorineural Hearing Loss

The aim of this study is to evaluate whether cerebral inflow and outflow abnormalities, assessed by the means of a validated ultrasound model, could be associated with Sudden Sensorineural Hearing Loss (SSNHL). According to Clark, a total of 42 patients affected by severe SSNHL and 19 healthy volunteers matched by gender without any history of sudden hearing impairment have been included in this study. Patients and controls underwent EchocolorDoppler assessment of brain hemodynamics. All subjects affected by SSNHL were also assessed with Auditory Brainstem Responses (ABR) and Magnetic Resonance Imaging (MRI) in order to exclude retrocochlear pathology. The head inflow through the common carotid artery was practically equivalent between groups, but at the level of the carotid bifurcation, the external carotid artery showed a highly significant flow rate in SSNHL 5.4±2 vs 3.9±1.1 ml/s in controls (p=0.01). The brain inflow was similar between patients and controls, but interestingly the flow rate of the vertebral artery was significantly reduced in SSNHL 1.6±0.8 vs 2.8±0.9 ml/s (p=0.01). The brain outflow was found significantly restricted at the level of the jugular outlet 6.6±6 vs 9.9±6 ml/s (p=0.002); consequently, the collateral flow index was significantly increased in SSNHL (p=0.001). The present study shows a discrepant distribution of the brain inflow which seems to penalize the posterior segments of the Willis polygon in patients affected by severe SSNHL. In addition, our study confirms the presence of chronic cerebrospinal venous insufficiency in SSNHL with significant activation of venous collateral circulation.

High Resolution M-Mode Evaluation of Jugular Vein Valves in Patients with Neurological and Neurosensory Disorders.

BACKGROUND High prevalence of valve absence was found in the internal jugular vein (IJV) of healthy volunteers by means of M-mode high-resolution Echo Colour Doppler (ECD). However, the prevalence of valve in neurovascular disorders linked to Chronic Cerebrospinal Venous Insufficiency (CCSVI) is still unknown. METHODS A cohort of 83 Healthy Controls (HC), 71 Multiple Sclerosis (MS), 99 Inner Ear Disorders (IED) underwent ECD investigation of the IJV valve, including M-mode evaluation and related hemodynamics. The primary outcome measure was characterization of valve presence, morphology and motility, whereas the secondary outcome was the rate of flow alteration. RESULTS Bilateral valve presence was found in 38% of HC, 58% of MS and 25% of IED, whereas, bilateral valve absence was recorded in 16% of HC, 10% of MS and 31% of IED (p<0.003). Bicuspid morphology was more prevalent in HC 56%, while monocusp was more prevalent in patients: 75% MS and 57% IED (p<0.0001). The main finding was the presence of mobile valve leaflets in 98% of HC, contrarily fixed valve leaflets were recorded in 82% of MS and in 41% of IED, p< 0.0001. Finally, by stratifying the entire cohort according to the presence of mobile and not mobile valve leaflets, normal monodirectional and phasic flow were commonly found in the mobile leaflets subgroup, p<0.0001. CONCLUSION In patients with miscellaneous neurological disorders, a significant higher rate of defective valves was found with respect to HC. The latter condition is strongly associated to brain outflow abnormalities described in CCSVI condition.