Auditory neuropathy: endocochlear lesion or temporal processing impairment? Implications for diagnosis and management

BACKGROUND/OBJECTIVE: Auditory neuropathy/dys-synchrony, characterized by absent auditory brainstem responses, normal otoacoustic emissions or cochlear microphonics, and word discrimination disproportional to the pure-tone audiogram, may be accompanied by perceptual consequences that could jeopardize language acquisition in affected children. However, the related evidence is constantly changing leading to a serious debate. The aim of the present paper is to review the current knowledge on auditory neuropathy/dys-synchrony, and to present the therapeutic strategies that can be employed in its management, taking into account the potentially underlying pathophysiology. MATERIALS/METHODS: Literature review from Medline and database sources. Related books were also included. STUDY SELECTION: Controlled clinical trials, prospective and retrospective cohort studies, nested-based case-control and analytical family studies, laboratory and electrophysiological studies, animal models, case-reports, joint statements and review articles. DATA SYNTHESIS: Auditory neuropathy/dys-synchrony, in contrast to what is widely believed, is a very frequent disease, responsible for approximately 8% of newly diagnosed cases of hearing loss in children per year. Hyperbilirubinemia and hypoxia represent major risk factors, whereas generalized neuropathic disorders, or a genetic substrate involving the otoferlin gene, are responsible for the phenotype of auditory neuropathy/dys-synchrony in certain cases. Auditory nerve myelinopathy and/or desynchrony of neural discharges are the most probable underlying pathophysiologic mechanisms. Genetic testing may be helpful in cases of non-syndromic prelingual children. Auditory neuropathy/dys-synchrony management aims at restoring the compromised processing of auditory information, either through conventional amplification and/or alternative forms of communication, or by cochlear implantation (combined with intensive speech and language therapy). CONCLUSION: Auditory neuropathy/dys-synchrony is more frequent than considered in the past, especially amongst hearing-impaired children. Accurate diagnosis, based on subjective and objective hearing assessment techniques (including the various electrophysiological assessment measures), and timely treatment of the affected children is of paramount importance, with hearing aids, intensive speech and language therapy (and sign language when indicated) providing the mainstay of habilitation, and cochlear implantation representing a valid therapeutic alternative.     

ALDH3A1: a corneal crystallin with diverse functions

Aldehyde dehydrogenase 3A1 (ALDH3A1) comprises a surprisingly high proportion (5-50% depending on species) of the water-soluble protein of the mammalian cornea, but is present little if at all in the cornea of other species. Mounting experimental evidence demonstrates that this abundant corneal protein plays an important role in the protection of ocular structures against oxidative damage. Corneal ALDH3A1 appears to protect against UV-induced oxidative stress through a variety of biological functions such as the metabolism of toxic aldehydes produced during the peroxidation of cellular lipids, the generation of the antioxidant NADPH, the direct absorption of UV-light, the scavenging of reactive oxygen species (ROS), and the possession of chaperone-like activity. With analogies to the abundant, multifunctional, and taxon-specific lens crystallins, mammalian ALDH3A1 has been considered a corneal crystallin, suggesting that it may contribute to the optical properties of the cornea as well. Recent studies have also revealed a novel role for ALDH3A1 in the regulation of the cell cycle. ALDH3A1-transfected HCE cells have increased population-doubling time, decreased plating efficiency, and reduced DNA synthesis, most likely due to a profound inhibition of cyclins and cyclin-dependent kinases. We have proposed that the ALDH3A1-induced reduction in cell growth may contribute to protection against oxidative stress by extending time for DNA and cell repair. Taken together, the multiple roles of ALDH3A1 against oxidative stress in addition to its contributions to the optical properties of the cornea are consistent with the idea that this specialized protein performs diverse biological functions as do the lens crystallins.     

Familial bipolar disorder and multiple sclerosis: a three-generation HLA family study

The coexistence of bipolar disorder (BD) and multiple sclerosis (MS) is well known. Manic symptoms may represent initial symptoms of MS, at least in some cases, and follow the MS-HLA phenotype frequencies. The purpose of this study was to examine the possible relation of BD and MS based on an HLA family study of a woman with BD and comorbid MS, with family history of BD. Five members of the family from three generations (the patient, her mother, her brother, and her two daughters) were examined regarding the two disorders and the HLA class I and II specificities, performed by serology and molecular techniques. Her deceased father, her brother, and her older daughter suffered from BD. Moreover, in her brother, BD and MS comorbidity was diagnosed. The three affected members and the nonaffected grandmother share the same class I and II, HLA-A2, B18, CW8, DR2, DQ1 haplotype. The shared class II, HLA-DR2, DQ1 haplotype among affected individuals, which is well known to be associated with MS in Caucasians, suggests a possible susceptibility locus for BD, mapped on chromosome 6, very close to the HLA region, underlying the clinical comorbidity of the two disorders.     

Metastatic breast carcinoma confined to bone: portrait of a clinical entity

BACKGROUND: The current study was performed to study metastatic breast carcinoma that remains confined to bone. METHODS: The medical notes of 2514 breast carcinoma patients who were treated in 2 academic units over a 20-year period were screened and patients who fulfilled the following criteria were selected: 1) clinical manifestation and imaging confirmation of bone metastases, and 2) metastatic disease remaining confined to bone for a minimum of 24 months. Available clinical and pathologic data were recorded and analyzed. The objective of the current study was to describe this clinical entity and investigate possible correlations between clinicopathologic parameters and clinical outcome. RESULTS: A total of 104 patients (4% of the total screened patient population) fulfilled the study criteria. The majority of patients were postmenopausal, with a median age of 58 years; 44 of the patients were found to have metastases at the time of presentation (M1) and 60 patients developed metastases at a median of 38 months (range, 8-160 months) after surgery for the primary tumor. Metastases remained confined to bone for a median of 50 months. Survival after the diagnosis of bony metastases was 72 months and was similar in the 2 groups (66 months vs. 78 months). Of the patients treated, 80% responded to hormonal therapy, and 76.5% responded to chemotherapy. There was no association noted between survival and tumor grade, anatomic distribution, or disease extension. CONCLUSIONS: Bone-confined metastatic breast carcinoma has an indolent clinical course that alleviates the need for vigorous follow-up and calls into question aggressive therapeutic approaches in these patients. Translational studies are warranted to map the molecular profile, leading to the development of targeted therapies in this group of patients.     

Familial occurrence of hyperdynamic circulation status due to intrahepatic fistulae in hereditary hemorrhagic telangiectasia

The cases of two brothers with intrahepatic arterio-venous shunt causing hyperdynamic circulation in hereditary hemorrhagic telangiectasia are presented. There was a strong family history of fatal liver involvement in all members of the previous generation. The first patient had embolization of the right hepatic artery with symptomatic relief, but developed cirrhosis with portal hypertension seven years later. The second patient developed cirrhosis with portal hypertension, and died following rupture of esophageal varices, within a year. It is suggested not only that hereditary hemorrhagic telangiectasia is transmitted as a dominant trait, but that there is also a hereditary transmission of hepatic involvement in this disease.     

Kidney development in the first year of life in small-for-gestational-age preterm infants

Background: Small-for-gestational-age (SGA) infants have been reported to have a significantly reduced number of nephrons that could be a risk factor for development of hypertension later in life. Objective: To evaluate kidney size prospectively in relation to other anthropometric parameters during the first year of life in SGA babies. Materials and methods: The babies in the study were 31–36 weeks gestational age (GA) at birth and were matched with control preterm infants of similar GA, but appropriate for gestational age (AGA). The SGA infants were further classified as symmetrical and asymmetrical according to the anthropometric parameters. Results: The total number of measurements in symmetrical SGA preterm infants was 324, in asymmetrical SGA preterm infants 295, and in AGA infants 536. In symmetrical SGA preterm infants (31–36 weeks GA) mean kidney length (± SD) of 56±4 mm was significantly different from the controls (58.9±4.6 mm) up to 6 months chronological age (P < 0.05). In the asymmetrical SGA preterm infants, mean kidney length (45.3±4.0 mm) was significantly different from the controls (48.2±4.4 mm) up to 40 weeks corrected age. At 1 year chronological age, all preterm infants (symmetrical and asymmetrical SGA and AGA) had similar mean kidney length (61.6±4.6, 62.8±4.3, and 62.3±4.0 mm, respectively). The ratio of kidney length to crown-to-heel length was similar in all preterm groups. Conclusions: Kidney length in preterm SGA infants (symmetrical and asymmetrical) follows closely the other auxological parameters during the first year of life.     

The effect of initial stimulus type for visual reinforcement audiometry

Visual reinforcement audiometry (VRA) is routinely used with infants to assess hearing level. It is an operant procedure based on the association of auditory and visual stimuli. There are several recommended test procedures for VRA. One clinical VRA procedure involves presenting the initial auditory stimulus without activation of the visual reward. If the infant generates a head orientation response, the visual reward is then activated. The aim of this study was to investigate the unconditioned response rates (head orientation towards loudspeaker) to two different sound-field-presented stimuli, 1000-Hz narrowband noise (NBN) and 1000-Hz frequency-modulated tones (FMTs), using this VRA procedure. For each stimulus type, 100 infants presenting for VRA were assessed (age range 6-30 months, mean age 13 months). Of the infants presented with NBN, 69% responded, compared to 25% of infants presented with FMTs. Chi-squared analysis revealed a highly significant statistical difference in favour of NBN. In conclusion, this study demonstrated the effectiveness of using a 1000-Hz NBN stimulus over a 1000-Hz FMT stimulus in securing an unconditioned head orientation response in infants presenting for VRA.     

Young deaf children with hearing aids or cochlear implants: early assessment package for monitoring progress

BACKGROUND: Very few assessment measures exist for evaluating progress in young deaf children with hearing aids and cochlear implants. OBJECTIVE: To introduce and describe an early assessment package that covers auditory perception, communication/language development, and speech production in very young deaf children. MAIN OUTCOME MEASURES: Seven of the assessment measures (Listening Progress Profile, Categories of Auditory Performance, Tait Video Analysis, Stories-Narratives Assessment Procedure, Profile of Actual Linguistic Skills, Speech Intelligibility Rating, and the Profile of Actual Speech Skills) have been specifically developed at the Nottingham Cochlear Implant Programme, and a further one (Meaningful Auditory Integration Scale) was modified for use within the package. Moreover, two commercially available tests (Pragmatics Profile of Everyday Communication Skills and Preschool Language Scale) are included to complete the package. METHODS: The present paper describes each measure, how to use it, and its time frame. In addition, two case studies demonstrate the usefulness of the package as a whole. RESULTS AND CONCLUSIONS: The Nottingham Early Assessment Package (NEAP) offers a framework with which to assess in young deaf children the use of audition and language and communication in real-life situations. Being simple, reliable, and time effective can be used in everyday clinical practice. NEAP is innovative in design and offers a structured approach to monitor very young deaf children, both in short and long term. In addition, it allows the identification of additional problems and areas of difficulty as well as specific abilities and skills. This enables the clinician to determine appropriate intervention strategies.