Early-onset severe neuromuscular phenotype associated with compound heterozygosity for OPA1 mutations.

INTRODUCTION: Pathogenic mutations in the OPA1 gene are the most common identifiable cause of autosomal dominant optic atrophy (DOA), which is characterized by selective retinal ganglion cell loss, a distinctive pattern of temporal pallor of the optic nerve and a typical color vision deficit, with variable effects on visual acuity. Haploinsufficiency has been suggested as the major pathogenic mechanism for DOA. Here we present two siblings with severe ataxia, hypotonia, gastrointestinal dysmotility, dysphagia, and severe, early-onset optic atrophy who were found to be compound heterozygotes for two pathogenic OPA1 mutations. This example expands the clinical phenotype of OPA1-associated disorders and provides additional evidence for semi-dominant inheritance. METHODS AND RESULTS: Molecular analysis of the OPA1 gene in this family by Sanger sequencing revealed compound heterozygosity for two mutations in trans configuration, a p.I382 M missense mutation and a p.V903GfsX3 frameshift deletion in both affected siblings. Electron microscopy of a skeletal muscle biopsy of the older sibling revealed dense osmiophilic bodies within the mitochondria. Mitochondrial DNA (mtDNA) content was within normal limits, and electron transport chain analysis showed no deficiencies of the mitochondrial respiratory chain enzymes. Multiple mtDNA deletions were not found. CONCLUSION: Compound heterozygosity of pathogenic OPA1 mutations may cause severe neuromuscular phenotypes in addition to early-onset optic atrophy. While a role for OPA1 in mtDNA maintenance has been discussed, compound biallelic pathogenic OPA1 mutations in our patients did not result in altered mtDNA copy number, mtDNA deletions, or deficiencies of the electron transport chain, despite the severe clinical phenotype.

Neurocognitive functioning of a child with partial trisomy 6 and monosomy 21.

This case study describes the neurocognitive presentation of a child with identified genetic abnormalities of trisomy 6 and monosomy 21 who was evaluated as part of a standard medical protocol for cochlear implantation following diagnosis of profound sensorineural hearing loss. This child received neurocognitive testing prior to cochlear implantation and approximately 12 months post-activation of his cochlear implant. While he has not fully developed oral language, his presentation suggested improvement in overall skills since the activation of the cochlear implant; however, less than would be expected for a typically developing child.

Balance and sound conditions in adults with bilateral cochlear implants.

PURPOSE: Determine if 1) balance is impaired in patients with bilateral cochlear implants compared to healthy controls; 2) the presence of sound, non-speech or speech, affects standing balance. MATERIALS AND METHODS: Four patients with bilateral cochlear implants were tested on three balance conditions on Romberg tests on medium density compliant foam with eyes closed, with head stationary or moving in yaw or pitch, under 5 sound conditions: no sound, ambient background noise, pink noise, foreign language, English language. RESULTS: Dependent measure were duration of standing and kinematics. Three of four subjects performed well with head still and no sound, background noise, or pink noise. All subjects performed poorly during the head movement conditions in the presence of either a foreign language or English words. Subjects could not perform enough head movements during yaw and pitch conditions for accurate kinematic measurements. CONCLUSION: The no-sound condition did not influence standing balance skills. The addition of ambient or pink noise also did not affect their balance. When they were distracted by attending to words, however, regardless whether or not they understood the words, standing balance skills deteriorated. Thus, distracted attention in these patients leads to impaired balance, which may impair functional motor skills.

Cognition in children with sensorineural hearing loss: etiologic considerations.

OBJECTIVES: A considerable amount of literature has documented the impact of hearing impairment on spoken language skills in deaf children referred for cochlear implantation. Critical areas of neurocognitive development in the acquisition of visual (manual) language also appear to be impacted, although the evidence is less robust. The present study focused on the development of visual and fine motor skills in a sample of preschool-age children diagnosed with sensorineural hearing loss with no known neurologic conditions (n=36). STUDY DESIGN: Analysis of data collected as part of a standardized screening process for cochlear implantation at an academic medical center. METHOD: Children underwent a standardized neuropsychological assessment battery. Children were classified into three groups based on the etiology of their deafness (Connexin=15, Structural Malformation=11, and Unknown=10). RESULTS/CONCLUSIONS: Correlational analyses replicated previous research on the reduction in visual reception and fine motor skills as deaf children age. Children with genetic (Connexin) etiology exhibited a significant reduction in fine motor skills with age, whereas those with an etiology of Structural Abnormality exhibited a significant reduction in visual reception skills with age. Results of planned comparisons conducted as part of a multivariate analysis of variance (Skill x Group) indicated that the Connexin group was significantly better than the Unknown group with regard to fine motor skills. Implications for these findings and future studies are discussed.

Dyslipidemia and auditory function.

The relationship between dyslipidemia and hearing is unclear. This study was conducted to investigate whether elevated serum lipid levels impact auditory function in humans and in guinea pigs. In the human study, a cross-sectional study of 40 volunteers with dyslipidemia was conducted. Pure tone thresholds, distortion product otoacoustic emissions, and lipid profiles were analyzed. When controlled for patient age and sex, we found that elevated triglycerides were associated with reduced hearing. In the guinea pig study, a prospective study of animals fed a high-fat diet for 14 weeks was conducted. Although the high-fat diet led to a dramatic elevation in the average weight and total cholesterol in all animals (from 61 to 589 mg/dl), there were no meaningful changes in distortion product otoacoustic emission magnitudes. These results suggest that whereas chronic dyslipidemia associated with elevated triglycerides may reduce auditory function, short-term dietary changes may not.

Endoscopically guided placement of prefabricated cochlear implant electrodes in a common cavity malformation.

OBJECTIVE: To devise a safe and effective method of optimal customized electrode placement in the common cavity of children with cochleovestibular malformations. METHODS: Specialized electrodes were manufactured on the basis of three-dimensional data obtained from the high resolution computed tomography (HRCT) scans of the temporal bones of these two children. Electrode positioning was achieved with direct endoscopic view of the cavity utilizing a three-hole common cavity technique. RESULTS: Optimal electrode positioning in apposition to the medial neuroepithelium in the common cavity was verified visually intraoperatively. Postoperatively, minimal stable electrical current levels were found to be required. CONCLUSIONS: Custom-designed electrodes have the potential to offer improved results in children with common cavity malformations. Intraoperative direct positioning may further improve these results.

Steady-state response audiometry in a group of patients with steeply sloping sensorineural hearing loss.

OBJECTIVES: The purpose of this study was to examine the predictive value of auditory steady-state response (ASSR) evoked potential thresholds and predicted behavioral thresholds in a group of children with steeply sloping sensorineural hearing loss (HL). STUDY DESIGN: Case series. METHODS: Twenty-nine children with sloping sensorineural HL underwent behavioral audiometric evaluation, impedance testing, distortion product otoacoustic emissions, and steady-state response testing. A t test was performed to compare the means of ASSR predicted behavioral thresholds and behavioral responses. Pearson correlation coefficients were calculated at each tested frequency, 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz, using the same data. RESULTS: Bracketed thresholds were obtained at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz. Nineteen ears were used in this evaluation. A comparison of threshold difference as a function of bracketing revealed that the means were statistically different (P < .05). The mean threshold differences were calculated, and Pearson r values were determined between the behavioral thresholds and the predicted thresholds using the Rance 95 algorithm. The results revealed no difference of means at 500 Hz between predicted and measured behavioral thresholds. Linear regression analysis revealed strong correlation at 500 Hz, 1,000 Hz, and 2,000 Hz. CONCLUSIONS: The GSI Audera appears to predict the configuration of HL in children with steeply sloping sensorineural HLs and over-predicts the severity of the loss by 15 to 20 dB above 500 Hz at each test frequency (1,000, 2,000, and 4,000 Hz). Correlation coefficients display a strong correlation at 500 Hz, 1,000 Hz, and 2,000 Hz.

Auditory steady-state response audiometry in profound SNHL: the impact of abnormal middle ear function.

Auditory steady-state response (ASSR) audiometry is a commercially available tool that is used to predict behavioral auditory threshold levels. Its particular value stems from the technology's ability to measure frequency-specific responses in the background electroencephalogram to auditory stimuli presented across a broad range of frequencies and sound pressure levels. It is clearly of benefit when used to assess threshold levels in infants and children with severe-to-profound hearing impairment (i.e., cochlear implant candidates). Although numerous authors have provided evidence of the usefulness of ASSR testing, their reports have concerned patients whose middle ear impedance measures were normal. We report the cases of 2 patients who, following improvement of abnormal middle ear impedance values, experienced a marked improvement in measurable thresholds by ASSR testing.

Neonatal hearing loss in the indigent.

OBJECTIVE: To compare the risk factor profile for neonatal hearing loss (HL), and the follow-up rate of those identified with HL in an indigent population with those in an insured population. STUDY DESIGN: Retrospective review. METHODS: We studied 4526 neonates from the high-risk nursery or neonatal intensive care unit from two adjacent hospitals in Houston, Texas. Ben Taub General Hospital (BTGH) is a county public hospital that serves mainly the indigent. Texas Children's Hospital (TCH) is a private tertiary care center that serves patients with private insurance and Medicaid. RESULTS: Overall, 133 infants failed the screening test. Follow-up diagnostic testing identified 48 patients with definite HL. Although nearly twice as many patients at BTGH failed screening compared with TCH (88 vs. 45), four times as many patients at BTGH did not return for diagnostic testing (43 vs. 10). When a hearing aid was needed, there was a delay in getting one at BTGH (P <.05). There was a higher prevalence of dysmorphic facial features and central nervous system disease and a lower prevalence of long-term ventilatory support at BTGH (P <.05). There were no differences between BTGH and TCH in the prevalence of low birth weight, neonatal asphyxia, syndromic stigmata, neonatal infection, family history of HL, or neonatal transfusion (P >.1). CONCLUSIONS: Significant differences in the risk factor profile for neonatal HL exist between the indigent and the general population. A worrisome problem exists with the timely intervention in hearing-impaired indigent neonates.

Comprehensive diagnostic battery for evaluating sensorineural hearing loss in children.

OBJECTIVE: Selection of diagnostic tests for children with sensorineural hearing loss (SNHL) is influenced by clinical suspicion. Testing results reported in the literature are similarly biased. We evaluate the usefulness of a comprehensive diagnostic battery for each child. STUDY DESIGN: Retrospective review. SETTING: Tertiary care university hospital. PATIENTS: A total of 270 children referred for severe to profound SNHL between January 2002 and June 2009. INTERVENTIONS: Results of the following were reviewed: magnetic resonance imaging, computed tomography, renal ultrasound, electrocardiography, fluorescent treponemal antibody absorption test, connexin 26 sequencing, genetic consultation, and ophthalmologic consultation. MAIN OUTCOME MEASURE: Diagnostic yield of each test was determined. RESULTS: Each diagnostic test or consultation was completed by at least 95% of patients for whom it was ordered. Magnetic resonance imaging revealed abnormalities explaining SNHL in 24% of patients. Computed tomography showed inner ear anomalies in 18% of patients. Biallelic connexin 26 mutations were found in 15%. Renal ultrasound found anomalies in 4% of patients. Electrocardiography found 1% of patients with prolonged QT intervals. Fluorescent treponemal antibody absorption test result was positive in 0.5%. Genetic consultation found a genetic cause for hearing loss in 25%. Ophthalmologic consultation found abnormalities associated with hearing loss in 8%. CONCLUSION: Diagnostic radiologic imaging is the highest yielding test for evaluating children with SNHL. Connexin 26 sequencing identifies a nearly nonoverlapping subset of children compared with imaging. Specialty consultations, particularly from a clinical geneticist, can improve diagnostic yield. Other tests, although of lower diagnostic yield for SNHL, can identify important diseases that significantly affect patient health.

Neuroimaging with near-infrared spectroscopy demonstrates speech-evoked activity in the auditory cortex of deaf children following cochlear implantation.

Cochlear implants (CI) are commonly used to treat deafness in young children. While many factors influence the ability of a deaf child who is hearing through a CI to develop speech and language skills, an important factor is that the CI has to stimulate the auditory cortex. Obtaining behavioral measurements from young children with CIs can often be unreliable. While a variety of noninvasive techniques can be used for detecting cortical activity in response to auditory stimuli, many have critical limitations when applied to the pediatric CI population. We tested the ability of near-infrared spectroscopy (NIRS) to detect cortical responses to speech stimuli in pediatric CI users. Neuronal activity leads to changes in blood oxy- and deoxy-hemoglobin concentrations that can be detected by measuring the transmission of near-infrared light through the tissue. To verify the efficacy of NIRS, we first compared auditory cortex responses measured with NIRS and fMRI in normal-hearing adults. We then examined four different participant cohorts with NIRS alone. Speech-evoked cortical activity was observed in 100% of normal-hearing adults (11 of 11), 82% of normal-hearing children (9 of 11), 78% of deaf children who have used a CI > 4 months (28 of 36), and 78% of deaf children who completed NIRS testing on the day of CI initial activation (7 of 9). Therefore, NIRS can measure cortical responses in pediatric CI users, and has the potential to be a powerful adjunct to current CI assessment tools.

Characteristics of malfunctioning channels in pediatric cochlear implants.

OBJECTIVES/HYPOTHESIS: To examine the characteristics of pediatric cochlear implant channel malfunction preceding device failure. STUDY DESIGN: : Retrospective review. METHODS: All pediatric patients who underwent cochlear implantation at a tertiary academic medical center were reviewed regarding device type, reason for replacement, time to replacement, and timing and pattern of channel faults in failed versus nonfailed devices. RESULTS: Between 1993 and 2008, 264 pediatric cochlear implantations were performed. With an average 894-day follow-up, the replacement rate was 9.5% (25/264). Reasons for replacement were device failure (6.4%), medical/surgical failure (2.3%), and obsolescence (0.8%). Replacement rates were comparable among Advanced Bionics (13.3%), Cochlear Corporation (6.3%), and MED-EL (10.3%) devices. Fifty-two cochlear implants developed at least one channel fault, and 13 eventually progressed to failure requiring replacement. MED-EL devices comprised 12 of these 13 failures. At the 12-month follow-up interval, one, three, and five channel faults predicted 40%, 75%, and 100% probabilities of eventual electrode failure, respectively. Channels destined to fail demonstrated small, yet statistically significant, impedance elevations 12 months before failure and large elevations 3 months before failure. CONCLUSIONS: Replacement of cochlear implants in pediatric patients is common and is due to device malfunction about one half of the time. Earlier initial channel fault, earlier subsequent channel faults, adjacent channel faults, and a greater total number of channel faults were associated with the need for replacement surgery. Elevations in a channel's impedance should raise the concern for an impending failure. These predictors can help the cochlear implant team when considering surgery to replace the device.

Intra-operative monitoring of cochlear function during cochlear implantation.

The objective of this study was to determine if intra-operative auditory monitoring is feasible during cochlear implantation and whether this can be used as feedback to the surgeon to improve the preservation of residual hearing. This prospective non-randomised study was set in a paediatric tertiary referral hospital. Thirty eight consecutive paediatric patients undergoing cochlear implantation who had measurable auditory thresholds pre-operatively were divided into two cohorts. The unmonitored cohort included the first 22 patients and the monitored cohort included the last 16 patients. The main outcome measure(s) were pre-operative, intra-operative and more than one month post-operative average auditory thresholds at 500, 1000 and 2000 Hz measured using auditory steady-state response audiometry. The average pre-operative thresholds were 103.5 dB HL and 99.7 dB HL in the unmonitored and monitored cohorts, respectively. These were not statistically different (p > 0.3). In the monitored cohort, we measured auditory thresholds to assess cochlear function at multiple time points during the operation. Compared to baseline, thresholds were increased 0.7 dB after drilling the mastoidectomy and well, 0.2 dB after opening the cochlea and 4.6 dB after inserting the electrode array. One month post-operatively, the average thresholds were 114.0 dB HL in the unmonitored cohort but only 98.8 dB HL in the monitored cohort (p < 0.001). Both the use of intra-operative auditory monitoring and higher pre-operative thresholds were associated with improved preservation of residual hearing (p