The effect of canal diameter on audiologic results in patients with cochlear implantation with large vestibular aqueduct syndrome.

PURPOSE: To compare audiologic results according to vestibular aqueduct (VA) diameter in patients who have undergone cochlear implantation and were diagnosed with LVAS. METHODS: This was a retrospective study detailing the outcomes of 18 patients with LVAS and 18 patients undergone cochlear implants. VA diameter was assessed by magnetic resonance imaging and computed tomography. Categories of Auditory Perception (CAP) and Speech Intelligibility Rating (SIR) were assessed in all patients, and speech audiometry, including speech recognition thresholds (SRT) and word discrimination scores, was applied for all subjects who were able to perform these tests. All audiologic parameters were compared between patients with and without LVAS, and the relationship of these parameters with VA diameter was investigated. RESULTS: The control group consisted of 18 subjects (5 males, 13 females), ranging in age between 2 and 34 years (mean 13.17 ± 8.97 years). The research group consisted of 18 subjects (8 males, 10 females), ranging in age between 2 and 35 years (mean 13.28 ± 8.96 years). There was a statistically significant difference between the groups in terms of SIR and CAP pre-post differences (Mann-Whitney U test, p < 0.05), with higher averages in the LVAS group. No statistically significant correlations were found between VA diameter on computed tomography and magnetic resonance imaging and the audiologic variables collected. CONCLUSIONS: Patients with LVAS benefit from cochlear implant surgery and VA parameters do not affect audiologic parameters.

Implementing the chick embryo model to study vestibular developmental disorders.

Children with congenital vestibular disorders show delayed motor development and challenges in maintaining posture and balance. Computed tomography images reveal that these children have abnormal inner ears in the form of a sac, with the semicircular canals missing or truncated. Little is known about how this inner ear abnormality affects central vestibular development. At present, mice with the chromodomain helicase DNA-binding protein 7 mutation are the most common model for studying congenital vestibular disorders, despite forming multiple diverse inner ear phenotypes and inducing abnormal cerebellar and visual system development. To identify the effects of a sac-like inner ear on central vestibular development, we have designed and implemented a new model, the anterior-posterior axis rotated otocyst (ARO) chick, which forms a sac-like inner ear in 85% of cases. The ARO chick is produced by anterior-posterior rotation of the otocyst at embryonic day 2. Here, we describe for the first time the 15% of ARO chicks that form three small semicircular canals and rename the ARO chicks forming sacs (ARO/s chicks). The basic features of the vestibular sensory organs in ARO/s chicks are similar to those found in patients' sacs, and ARO/s hatchlings experience balance and walking problems like patients. Thus, ARO/s chicks have a reproducible inner ear phenotype without abnormalities in vestibular-related structures, making the model a relatively simple one to evaluate the relationship between the sac-like inner ear pathology and formation of the central vestibular neural circuitry. Here, we describe unpublished details on the surgical approaches to produce ARO chicks, including pitfalls and difficulties to avoid.NEW & NOTEWORTHY This paper describes simple techniques for chick otocyst rotation resulting in a sac-like inner ear (85%), the common phenotype in congenital vestibular disorders. We now describe anterior-posterior axis rotated otocyst chicks, which form three small canals (15%), and rename chicks forming a sac (ARO/s chicks). Basic protocols and potential complications of otocyst rotation are described. With the use of ARO/s chicks, it will be possible to determine how the vestibular neural circuit is modified by sac-like inner ear formation.

A New Model for Congenital Vestibular Disorders.

Many developmental disorders of the inner ear are manifested clinically as delayed motor development and challenges in maintaining posture and balance, indicating involvement of central vestibular circuits. How the vestibular circuitry is rewired in pediatric cases is poorly understood due to lack of a suitable animal model. Based on this, our lab designed and validated a chick embryo model to study vestibular development in congenital vestibular disorders. The developing inner ear or "otocyst" on the right side of 2-day-old chick embryos (E2) was surgically rotated 180° in the anterior-posterior axis, forming the "anterior-posterior axis rotated otocyst chick" or ARO chick. The ARO chick has a reproducible pathology of a sac with truncated or missing semicircular canals. A sac is the most common inner ear defect found in children with congenital vestibular disorders. In E13 ARO chicks, the sac contained all three cristae and maculae utriculi and sacculi, but the superior crista and macula utriculi were shortened in anterior-posterior extent. Also, the number of principal cells of the tangential vestibular nucleus, a major avian vestibular nucleus, was decreased 66 % on the rotated side. After hatching, no difference was detected between ARO and normal chicks in their righting reflex times. However, unlike normal chicks, ARO hatchlings had a constant, right head tilt, and after performing the righting reflex, ARO chicks stumbled and walked with a widened base. Identifying the structure and function of abnormally developed brain regions in ARO chicks may assist in improving treatments for patients with congenital vestibular disorder.

Prevalence Estimates of Rare Congenital Anomalies by Integrating Two Population-Based Registries in Tuscany, Italy.

BACKGROUND/AIMS: Population-based registries play a key role in the epidemiological surveillance of congenital anomalies (CAs). This study is aimed at improving the epidemiological surveillance and providing prevalence estimates of rare CAs using the Registry of Rare Diseases as an added data source to the Registry of Congenital Anomalies. METHODS: Cases of diagnosed rare CAs (2006-2013) were extracted from the Tuscany Registry of Rare Diseases and the Tuscany Registry of Congenital Anomalies in order to set up an integrated dataset. Prevalence (per 100,000 births; 95% confidence interval) was calculated for each rare CA. RESULTS: Overall, 56 rare CAs were analyzed including 656 cases, of whom 121 (18.4%) were retrieved from the Registry of Rare Diseases that provided a major contribution for rare CAs for which a prenatal diagnosis is difficult, or for CAs more easily diagnosed in the postneonatal period. After data integration, an increased prevalence estimate was observed in particular for atresia of bile ducts (6.24; 3.57-10.14), tuberous sclerosis (2.34; 0.86-5.10), Kabuki syndrome (1.95; 0.63-4.55), and some monogenic CAs. CONCLUSIONS: This study represents an example of integration of registries operating in the field of rare diseases. Providing the accurate prevalence of rare CAs is a key point to improving surveillance, supporting public health policies, and planning healthcare.

Congenital vestibular disease in captive Sumatran tigers (Panthera tigris ssp. sumatrae) in Australasia.

The Sumatran tiger (Panthera tigris ssp. sumatrae) is a critically endangered species in the wild. To ensure that demographic and genetic integrity are maintained in the longer term, those Sumatran tigers held in captivity are managed as a global population under a World Association of Zoos and Aquariums Global Species Management Plan (GSMP). A retrospective study, including segregation and pedigree analysis, was conducted to investigate potential cases of congenital vestibular disease (CVD) in captive Sumatran tigers in Australasian zoos using medical and husbandry records, as well as video footage obtained from 50 tigers between 1975 and 2013. Data from the GSMP Sumatran tiger studbook were made available for pedigree and segregation analysis. Fourteen cases of CVD in 13 Sumatran tiger cubs and one hybrid cub (Panthera tigris ssp. sumatrae × Panthera tigris) were identified. Vestibular signs including head tilt, circling, ataxia, strabismus and nystagmus were observed between birth and 2 months of age. These clinical signs persisted for a median of 237 days and had resolved by 2 years of age in all cases. Pedigree analysis revealed that all affected tigers were closely related and shared a single common ancestor in the last four generations. A genetic cause for the disease is suspected and, based on pedigree and segregation analysis, an autosomal dominant mode of inheritance is likely. Further investigations to determine the world-wide prevalence and underlying pathology of this disorder are warranted.

Signaling regulating inner ear development: cell fate determination, patterning, morphogenesis, and defects.

The membranous labyrinth of the inner ear is a highly complex organ that detects sound and balance. Developmental defects in the inner ear cause congenital hearing loss and balance disorders. The membranous labyrinth consists of three semicircular ducts, the utricle, saccule, and endolymphatic ducts, and the cochlear duct. These complex structures develop from the simple otic placode, which is established in the cranial ectoderm adjacent to the neural crest at the level of the hindbrain at the early neurula stage. During development, the otic placode invaginates to form the otic vesicle, which subsequently gives rise to neurons for the vestibulocochlear ganglion, the non-sensory and sensory epithelia of the membranous labyrinth that includes three ampullary crests, two maculae, and the organ of Corti. Combined paracrine and autocrine signals including fibroblast growth factor, Wnt, retinoic acid, hedgehog, and bone morphogenetic protein regulate fate determination, axis formation, and morphogenesis in the developing inner ear. Juxtacrine signals mediated by Notch pathways play a role in establishing the sensory epithelium, which consists of mechanosensory hair cells and supporting cells. The highly differentiated organ of Corti, which consists of uniformly oriented inner/outer hair cells and specific supporting cells, develops during fetal development. Developmental alterations/arrest causes congenital malformations in the inner ear in a spatiotemporal-restricted manner. A clearer understanding of the mechanisms underlying inner ear development is important not only for the management of patients with congenital inner ear malformations, but also for the development of regenerative therapy for impaired function.

Do signs of natural plugging of superior semicircular canal dehiscence exist?

Our experience with 102 patients having superior semicircular canal dehiscence confirm that the clinical manifestations of the disease are very diverse; we also identified 3 patients who showed Meniere-like symptoms. Clinical examination during an acute vertigo attack of a patient with Meniere disease for several years and whom we subsequently diagnosed as having large superior semicircular canal dehiscence on the affected side allowed us to hypothesize that a natural plugging of the superior semicircular canal by the overhanging dura mater could be responsible for the recurrence of symptoms. Clinical and instrumental data were very similar to those recorded in 7 of 9 patients immediately after surgical plugging. The aim of the study was to understand which semiological and instrumental elements could be clinically useful, first in distinguishing Meniere disease from superior semicircular canal dehiscence and, secondly, in understanding if signs of natural plugging are present.

Natural history of hearing loss in children with enlarged vestibular aqueduct syndrome.

OBJECTIVE: To determine the natural history of hearing loss in children with enlarged vestibular aqueduct (EVA) syndrome. DESIGN: (1) Retrospective cohort study and (2) systematic literature review. SETTING: Tertiary pediatric centre. METHODS: (1) Charts of children assessed by one physician between 1993 and 2000 were reviewed. (2) Source articles were identified by a search of Medline, Embase, and the Cochrane Library of the English-language literature through January 2006, with manual review of references. The search was limited to English, human, and age less than 18 years. MAIN OUTCOME MEASURES: Pure-tone average. Hearing was classified as stable, progressive and fluctuating. RESULTS: (1) Twenty-one children (39 ears) with EVA were identified. Eighty-two percent of ears had stable hearing, and 18% of ears demonstrated progressive hearing loss. (2) Seven source articles were identified and combined with the present data for a total of 310 ears with a mean follow-up of 4 years. Bilateral EVA was found to be six times more common than unilateral EVA, and there was an equal male to female ratio. Stable hearing was found in 67% of ears and progressive hearing loss in 33% of ears. Subgroup analysis demonstrated hearing fluctuations in 50% of progressive hearing loss ears and 34% of stable ears. CONCLUSIONS: Stable hearing is observed in 67% of ears with EVA of which 34% will demonstrate fluctuations in hearing. Progression of hearing loss is seen in 33% of ears of which half will demonstrate fluctuations.

CHARGE syndrome: an update.

CHARGE syndrome is a rare, usually sporadic autosomal dominant disorder due in 2/3 of cases to mutations within the CHD7 gene. The clinical definition has evolved with time. The 3C triad (Coloboma-Choanal atresia-abnormal semicircular Canals), arhinencephaly and rhombencephalic dysfunctions are now considered the most important and constant clues to the diagnosis. We will discuss here recent aspects of the phenotypic delineation of CHARGE syndrome and highlight the role of CHD7 in its pathogeny. We review available data on its molecular pathology as well as cytogenetic and molecular evidences for genetic heterogeneity within CHARGE syndrome.

Novel method for homogeneous gene transfer to the inner ear.

Viral vectors are widely used in gene therapy due to their efficiency. In this paper we describe a novel method for transfecting the whole inner ear of a guinea pig using adenoviral vectors. Very small perforations are made in both the cochlea and lateral semicircular canal, into which 50 microl of adenoviral suspension (8.9x10(8) plaque forming unit (PFU)/ml) is gently infused. Any excess suspension flows out through the perforation in the semicircular canal and therefore makes no contact with the central nervous system. Our method can therefore be utilized to perform homogeneous gene transfer and may eliminate any effects on other organs, such as the contralateral ear.

Vestibular-evoked myogenic potentials in three patients with large vestibular aqueduct.

An enlarged vestibular aqueduct (LVA) is a common congenital inner ear anomaly responsible for some unusual vestibular and audiological symptoms. Most of the cases show bilateral early onset and progressive hearing loss in children. The gross appearance on CT scan of the inner ear is generally normal. However, precise measurements of the inner ear components reveal abnormal dimensions, which may account for the accompanying auditory and vestibular dysfunction. Despite extensive studies on hearing and the vestibular apparatus, saccular function is not studied. To our knowledge this is the first report of saccular malfunction in three patients with LVA by means of vestibular evoked myogenic potentials. Conventional audiograms revealed bilateral severe sensorineural hearing loss in two patients and mixed type hearing loss in one patient. Two of the patients complained about vertigo and dizziness but vestibular assessments of the patients showed normal results. The diagnosis had been made by high-resolution CT scans and MR images of the skull that showed LVA in the absence of other anomalies. The VEMP threshold measured from the ear with LVA in two patients with unilateral enlargement of the vestibular aqueduct was 75-80 dB nHL whereas the threshold from normal ears was 95 dB nHL. The third patient with mixed type hearing loss and bilateral LVA had VEMP responses despite a big air-bone gap in the low frequency range. The VEMP in this patient was greater in amplitude and lower in threshold in the operated ear (the patient had a tympanoplasty which did not improve her hearing). These findings and results of other patients with Tullio phenomenon and superior semicircular canal dehiscence, who also showed lower VEMP threshold, confirmed the theory of a 'third window' that allows volume and pressure displacements, and thus larger deflection of the vestibular sensors, which would cause the vestibular organ to be more responsive to sound and pressure changes.

Vestibular compensation in infants and children with congenital and acquired vestibular loss in both ears.

In children with semicircular canal anomalies, vestibular compensation during their development and growth was studied. The damped rotation test elicited 'absence or poor per-rotatory nystagmus and absence of post-rotatory nystagmus in all cases. Development of gross motor and balance function was seriously delayed in each case during the first 2 or 3 years of life. Thereafter, during the pre-school age, all children could achieve most landmarks of motor development, such as head control, independent walking and running. However, balance functions at the age of entrance of the elementary school (6 years old) were variously impaired in each case. The better case could swim under water but the poor case could not maintain static balance with eyes closed. These motor skills due to vestibular compensation presumably depend on integration of the compensatory input from visual, somatosensory and proprioceptive senses, and the maturation of motor control systems in the cerebellum, basal ganglia and motor cortex.

Fetal alcohol syndrome. Hearing, speech, language, and vestibular disorders.

Fetal alcohol syndrome (FAS) refers to a pattern of anomalies that include craniofacial, CNS, growth, and various sensory anomalies. We have observed that FAS is associated with four kinds of hearing disorders: (1) developmentally delayed auditory function, (2) sensorineural hearing loss, (3) intermittent conductive hearing loss owing to recurrent serous otitis media, and (4) central hearing loss. As is the case with other syndromes associated with craniofacial anomalies and hearing impairments, speech and language pathologies also are common in FAS patients. Although auditory and vestibular systems arise from similar embryological tissue, vestibular dysfunction is variable in FAS. Early identification and intervention to treat hearing, language, and speech problems should improve the functional level of FAS in children.

Usher syndrome in the Samaritans: strengths and limitations of using inbred isolated populations to identify genes causing recessive disorders.

We have previously reported significant linkage between markers on 11q13.5 and Usher syndrome type 1 (USH1B) in a large Samaritan kindred. USH1B is an autosomal recessive disease characterized by profound congenital sensorineural deafness, vestibular dysfunction and progressive visual loss. A unique haplotype found only in all USH1B carriers and affected individuals implied that the disease-causing mutation probably entered the community from a single founder. Screening for mutations in a gene called GARP, which was mapped to the same genetic interval as USH1B, revealed a base substitution in the coding region of the gene, in a homozygous state in all affected individuals. This base substitution, which results in an arginine to tryptophane change, is not found in control individuals and occurs at an amino acid residue that is conserved across species, including mouse, gorilla, chimpanzee and macaque. This study emphasizes the strength of using an isolated inbred population for efficient identification of the primary linkage and for narrowing the disease interval, but also demonstrates its limitations in distinguishing between mutations causing the disease and those representing unique and private polymorphisms.

Cochlear implants in children with congenital inner ear malformations.

OBJECTIVE: To describe clinical experiences with multichannel cochlear implantation in children with inner ear malformations, including surgical indications and techniques, imaging findings, and outcomes. DESIGN: A retrospective review of a series of 10 consecutive cases with a mean follow-up of 29 months, as well as a review of the literature. SETTING: Academic referral center. SUBJECTS: Ten children who underwent multichannel cochlear implantation for inner ear malformations. High-resolution computed tomographic scans demonstrated a common cavity deformity in 3, an incomplete cochlear partition in 4, and an enlarged vestibule in 1. Two had membranous anomalies as indicated by cerebrospinal fluid gushers at surgery, but the results of imaging were normal. INTERVENTION: All subjects received multichannel cochlear implants. Two subjects underwent mastoid obliteration at the time of implantation owing to preoperative recurrent meningitis or chronic otitis media with episodes of clinical mastoiditis. MAIN OUTCOME MEASURES: The 10 subjects were evaluated for electrode insertion and stability and auditory function for up to 7 years. RESULTS: All 22 electrodes are functional in each child with an incomplete partition, an enlarged vestibule, or a membranous anomaly. Of 3 subjects with common cavities, 2 had full insertion of electrodes and 1 had 16 electrodes inserted. All subjects had speech awareness thresholds detected at 25 dB or better. Three (75%) of the 4 subjects with at least 30 months of experience, including 1 subject with a common cavity, have developed open-set word recognition. CONCLUSIONS: Electrode insertion and hearing results in children with an incomplete partition, an enlarged vestibule, or a membranous anomaly are similar to those in children with normal cochleas. Specific surgical techniques are effective for children with a common cavity, and the results are less certain. Cerebrospinal fluid gushers were encountered frequently but were not difficult to control.

Large vestibular aqueduct syndrome with high CT density and high MR signal intensity.

We report a case of large vestibular aqueduct syndrome with a markedly dilated endolymphatic sac bilaterally. The density and signal intensity of the extraosseous portion of the sac were higher than those of cerebrospinal fluid on CT and MR studies. The findings may represent protein-rich and hyperosmolar fluid within the endolymphatic sac.

Vestibular function in patients with a large vestibular aqueduct.

Four patients (7 ears) with a large vestibular aqueduct (VA) were examined for history of vertigo and vestibular function. Vertigo was observed in all the 4 patients. The caloric responses were significantly poorer in ears with a large VA than in the controls. On a patient with a large VA who had several attacks of sudden hearing loss and vertigo following minor head trauma, long-time exposure to sunshine, common cold, and exercise, vestibular function tests were performed several times; the caloric responses were found to fluctuate and direction changing apogeotropic positional nystagmus was observed. These findings suggest that in patients with a large VA, not only hearing but also the vestibular function are generally impaired. We believe than direct transmission of intracranial pressure changes to the inner ear or subsequent inner ear fluid movement through the large endolymphatic sac and duct have an influence on the cochlea and vestibule.