Congenital cytomegalovirus (CMV) for the pediatric otolaryngologist.

Cytomegalovirus (CMV) is a double-stranded DNA virus and a member of the herpesvirus family. It is the most common congenital viral infection. For symptomatic infections, symptoms can vary widely but tends to have a predilection for the central nervous system and for the reticuloendothelial system. Sensorineural hearing loss (SNHL) is by far the most common sequelae of congenital CMV infection. For this reason, it is imperative to understand the screening, diagnosis, and possible treatment options for congenital CMV induced SNHL. This literature review explores the association of CMV with hearing loss, screening for congenital CMV infections, possible treatments options, and the development of a possible vaccine.

International Pediatric Otolaryngology Group (IPOG) Consensus Recommendations: Congenital Cholesteatoma.

OBJECTIVE: To provide recommendations to otolaryngologists and allied physicians for the comprehensive management of children who present with signs and symptoms of congenital cholesteatoma. METHODS: A two-iterative Delphi method questionnaire was used to establish expert recommendations by the members of the International Pediatric Otolaryngology Group, on the preoperative work-up, the perioperative considerations, and follow-up. RESULTS: Twenty-two members completed the survey, in 14 tertiary-care center departments representing 5 countries. The main consensual recommendations were: a precise otoscopic description of the quadrants involved, extensive audiological workup (bilateral tonal, vocal audiometry, and BERA), and a CT scan are required. Facial nerve monitoring and a combination of microscope and telescope are recommended for surgical removal. Clinical and audiological follow-up should be pursued yearly for at least 5 years. First MRI follow-up should be done at 18 months postoperatively if the removal violated the matrix. MRI follow-up duration depends on the initial extent of the cholesteatoma. CONCLUSION: The goal of preoperative and follow-up consensus from International Pediatric Otolaryngology Group participants is to help manage infants and children with congenital cholesteatoma. The operative techniques may vary, and experienced surgeons must perform these procedures.

Advanced practice providers and children's hospital-based pediatric otolarynology practices.

INTRODUCTION: Advanced practice providers (APPs), including nurse practitioners and physician assistants, have been deployed in children's hospital-based academic pediatric otolaryngology practices for many years. However, this relationship in terms of prevalence, roles, financial consequences and satisfaction has not been examined. The objective of this study is to explore how APPs impact healthcare delivery in this setting. METHODS: Pediatric otolaryngology chiefs of all academic children's hospitals in the US were electronically surveyed about the ways APPs intersected clinically and financially in their respective practice. RESULTS: A total of 29 of 36 children's hospital-based pediatric otolaryngology practices completed the survey, of which 26 practices (90%) utilized APP. There were large variances within the APP practice cohort in faculty size (mean/median/range = 9.4/8.5/3-29); annual patient visits (mean/median = 18,373/17,600); number of practice site (mean/median/range = 4.3/4/2-9) and number of outpatient APP (mean/median/range = 6.3/5/1-30). No factors (faculty size, annual visits and number of practice sites) differentiated between the APP and non-APP practices. Among APP practices, significant correlation (p<.00001) was observed between size of APP cohort to faculty size and annual visits. 69% of the practices did not differentiate job functions of nurse practitioners and physician assistants. 85% of the practices utilized APPs in all practice sites and 19% utilized APPs in the operating room. 77% of APPs billed independently and 46% had on-site supervision. The most prevalent APP salary bracket based on 0-5, 6-10 and > 11 years of tenure were $76-100K (65%), $100-150K (77%) and $100-150K (86%), respectively. In 46% of the practices, APPs were able to generate enough revenue to cover more than 75% of their salary and 23% of practices generated a profit. 81% of the chiefs ranked the effectiveness of APPs as high (4 and 5) on a 5-point Likert scale. DISCUSSION: The majority of academic pediatric otolaryngology practices employed APPs. Despite the diversity seen in practice complexity, APP functionality and financial impact, most found the APP model to be beneficial in improving patient care, patient access and faculty productivity.

Relative Preservation of Superior Semicircular Canal Architecture in CHARGE Syndrome.

OBJECTIVES: (1) Describe common patterns of semicircular canal (SCC) anomalies in CHARGE syndrome (CS) and (2) recognize that in CS, the architecture of the superior SCC may be relatively preserved. STUDY DESIGN: This is a retrospective review of temporal bone imaging studies. SETTING: Quaternary care center. SUBJECTS AND METHODS: A sample of 37 patients with CS. All subjects met clinical diagnostic criteria for CS. The presence/absence of anomalies of the middle ear, mastoid, temporal bone venous anatomy, inner ear, and internal auditory canal was recorded. Anomalies of each SCC were considered separately and by severity (normal, dysplasia, aplasia). RESULTS: Thirty-seven subjects (74 temporal bones) were reviewed. Thirty-four (92.0%) patients demonstrated bilateral SCC anomalies. Three (8.0%) had normal SCCs. In patients with SCC anomalies, all canals demonstrated bilateral abnormalities. Thirty-two (86.5%) patients had bilateral horizontal SCC aplasia. These 32 patients also demonstrated posterior SCC aplasia in at least 1 ear. Of 74 temporal bones, 37 (50.0%) had superior SCC dysplasia. All dysplastic superior SCCs showed preservation of the anterior limb. Complete superior SCC aplasia was found in 28 (37.8%) temporal bones. CONCLUSION: SCC anomalies occur with high frequency in CS. Complete absence of the horizontal and posterior canals is typical and usually bilateral. By contrast, the superior SCC often demonstrates relative preservation of the anterior limb.

Language Underperformance in Young Children Who Are Deaf or Hard-of-Hearing: Are the Expectations Too Low?

OBJECTIVE: (1) To examine language performance in the context of cognitive abilities in young children who are deaf or hard-of-hearing and (2) to identify factors associated with having a language underperformance, defined as a gap between the language standard score and the nonverbal IQ (NVIQ) standard score. METHODS: Children 6 to 82 months of age with bilateral hearing loss were enrolled. Language performance was defined as a ratio of language skills relative to cognitive abilities with language underperformance defined as a ratio of language scores to NVIQ <0.85. RESULTS: Among 149 children, approximately half had hearing loss that was clinically classified as mild or moderate, and over one-third received a cochlear implant. Participants had a mean NVIQ in the average range (95.4 [20.3]). Receptive language scores were significantly lower than their NVIQ by 10.6 points (p < .0001). Among children with NVIQs 80 to 100, 62.5% had receptive scores <85 and 50% had a language underperformance (ratio <0.85). Among children with NIVQs >100, 21.1% had receptive scores <85 with 42% having a language underperformance. Children with language underperformance (n = 61, 41.5%) were more likely to have more severe levels of hearing loss, lower socioeconomic status, and be nonwhite. CONCLUSION: Many children early identified with hearing loss continue to demonstrate language underperformance, defined using their cognitive potential. Language deficits have a cascading effect on social functioning in children who are deaf or hard-of-hearing. This study highlights the need to understand a child's cognitive potential to adequately address language needs in existing intervention models.

Pediatric acute mastoiditis in the era of pneumococcal vaccination.

OBJECTIVES/HYPOTHESIS: The objective was to describe trends in the annual prevalence of hospitalization for pediatric acute mastoiditis since introduction of the 7-valent pneumococcal vaccine in 2000 and the 13-valent vaccine in 2010. STUDY DESIGN: Cross-sectional retrospective data analysis. METHODS: The Kids' Inpatient Database from years 2000 to 2012 was analyzed. To determine the annual prevalence of hospitalization for acute mastoiditis, nationally weighted frequencies of hospitalization for children <21 years with acute mastoiditis diagnoses were collected. Trend analysis of hospitalization rates from 2000 to -2012 was performed. RESULTS: From 2000 to 2012, there was no significant trend in hospitalization rates for acute mastoiditis overall (1.38 and 1.43 per 100,000 persons in 2000 and 2012, respectively; P = .86) or by age group. When comparing hospitalization rates at time points 2000 and 2012, children <1 year (4.65 and 3.27 per 100,000 persons, P = .0023) and 1 to 2 years of age (3.95 and 3.18 per 100,000 persons, respectively; P = .0107) demonstrated declines in hospitalization over time. Between 2009 and 2012, hospitalization rates also significantly declined for children aged <1 year (4.50 to 3.27 per 100,000 persons, P = .0056) and 1 to 2 years (4.30 to 3.18 per 100,000 persons, P = .0002) but increased for children 5 to 9 years (1.10 to 1.81 per 100,000 persons, P < .0001) and 10 to 20 years of age (0.41 to 0.72 per 100,000 persons, P < .0001). CONCLUSIONS: Despite introduction of two pneumococcal vaccines, rates of hospitalization for pediatric acute mastoiditis did not decline between 2000 and 2012. Between 2009 and 2012, however, children 0 to 2 years of age showed declining hospitalization rates, possibly reflecting the protective benefit of the 13-valent pneumococcal vaccine. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1480-1485, 2018.

Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures.

The inner ear contains the sensory organs for hearing and balance. Both hearing and balance are commonly affected in individuals with CHARGE syndrome (CS), an autosomal dominant condition caused by heterozygous pathogenic variants in the CHD7 gene. Semicircular canal dysplasia or aplasia is the single most prevalent feature in individuals with CHARGE leading to deficient gross motor skills and ambulation. Identification of CHD7 as the major gene affected in CHARGE has enabled acceleration of research in this field. Great progress has been made in understanding the role of CHD7 in the development and function of the inner ear, as well as in related organs such as the middle ear and auditory and vestibular neural pathways. The goals of current research on CHD7 and CS are to (a) improve our understanding of the pathology caused by CHD7 pathogenic variants and (b) to provide better tools for prognosis and treatment. Current studies utilize cells and whole animals, from flies to mammals. The mouse is an excellent model for exploring mechanisms of Chd7 function in the ear, given the evolutionary conservation of ear structure, function, Chd7 expression, and similarity of mutant phenotypes between mice and humans. Newly recognized developmental functions for mouse Chd7 are shedding light on how abnormalities in CHD7 might lead to CS symptoms in humans. Here we review known human inner ear phenotypes associated with CHD7 pathogenic variants and CS, summarize progress toward diagnosis and treatment of inner ear-related pathologies, and explore new avenues for treatment based on basic science discoveries.

Pediatric Acute Otitis Media in the Era of Pneumococcal Vaccination.

Objectives (1) Describe longitudinal trends in annual prevalence of hospital admission for pediatric acute otitis media (AOM) and complications of AOM (CAOM) since introduction of pneumococcal vaccination in 2000 and (2) describe the longitudinal trend of prevalence of hospital admission for pneumococcal meningitis in children with AOM-related diagnoses in the postvaccination era. Study Design Retrospective analysis of Kids' Inpatient Database from 2000 to 2012. Setting Community, nonrehabilitation hospitals. Subjects and Methods To determine annual prevalence of admission for AOM/CAOM, nationally weighted frequencies of children aged <21 years with acute suppurative otitis media, acute mastoiditis, suppurative labyrinthitis, and/or acute petrositis were collected. The frequency of coexisting pneumococcal meningitis diagnoses among these patients was also collected. Trend analysis of prevalences of admission for AOM/CAOM and for pneumococcal meningitis occurring in the setting of AOM/CAOM from 2000 to 2012 was performed. Results Between 2000 and 2012, annual prevalence of admission for AOM/CAOM decreased from 3.956 to 2.618 per 100,000 persons ( P < .0001) (relative risk reduction 34%). Declines in admission prevalence were most pronounced in children <1 year of age (from 22.647 to 8.715 per 100,000 persons between 2000 and 2012, P < .0001) and 1 to 2 years of age (from 13.652 to 5.554 per 100,000 persons between 2000 and 2012, P < .0001). For all ages, the admission prevalence for pneumococcal meningitis and concomitant AOM/CAOM decreased (from 1.760 to 0.717 per 1,000,000 persons, P < .0001) over the study period. Conclusions The prevalence of hospital admission for pediatric AOM/CAOM has declined since the advent of pneumococcal vaccination. Admission rates for pneumococcal meningitis with AOM/CAOM have similarly declined.

A Targeted Approach for Congenital Cytomegalovirus Screening Within Newborn Hearing Screening.

BACKGROUND AND OBJECTIVE: Congenital cytomegalovirus (cCMV) infection remains a leading cause of childhood hearing loss. Currently universal CMV screening at birth does not exist in the United States. An alternative approach could be testing infants who do not pass their newborn hearing screening (NHS) for cCMV. This study was undertaken to evaluate whether a targeted approach will identify infants with CMV-related sensorineural hearing loss (SNHL). METHODS: Infants born at 7 US medical centers received NHS and were also screened for cCMV while in the newborn nursery. Infants who tested positive for CMV received further diagnostic audiologic evaluations to identify or confirm hearing loss. RESULTS: Between 2007 and 2012, 99 945 newborns were screened for both hearing impairment and cCMV. Overall, 7.0% of CMV-positive infants did not pass NHS compared with 0.9% of CMV-negative infants (P < .0001). Among the cCMV infants who failed NHS, diagnostic testing confirmed that 65% had SNHL. In addition, 3.6% of CMV-infected infants who passed their NHS had SNHL confirmed by further evaluation during early infancy. NHS in this cohort identified 57% of all CMV-related SNHL that occurred in the neonatal period. CONCLUSIONS: A targeted CMV approach that tests newborns who fail their NHS identified the majority of infants with CMV-related SNHL at birth. However, 43% of the infants with CMV-related SNHL in the neonatal period and cCMV infants who are at risk for late onset SNHL were not identified by NHS.

The utility of early developmental assessments on understanding later nonverbal IQ in children who are deaf or hard of hearing.

OBJECTIVE: In children who are deaf or hard of hearing (DHH), it is helpful to have meaningful early measures of development in order to provide effective interventions and offer benchmarks that help recognize varied developmental trajectories. The main objective of this study was to compare results of an early developmental assessment prior to 3 years of age to later nonverbal IQ assessed between 3 and 6 years of age in children who are DHH. METHODS: This study included children 3-6 years of age with bilateral permanent hearing who were enrolled in a prospective cohort study on developmental outcomes. As part of the study, children received the Leiter International Performance Scale-Revised, which provided a nonverbal Brief IQ, as well as standardized language assessment and behavioral checklists. Children were included in this analysis if they had received an early developmental assessment with the Gesell Developmental Schedules-Revised as part of a clinical visit with a developmental pediatrician. Correlation coefficients and multiple regression analysis were used to associate the scores on the Gesell (using a developmental quotient) with scores on the Leiter-R Brief IQ. RESULTS: Forty-five participants who enrolled in the observational study had available evaluation results from the Gesell and complete Brief IQ results from the Leiter-R. The adaptive domain of the Gesell had good correlation (r = 0.61, p < 0.0001) with the Brief IQ on the Leiter-R. Children who had stable developmental or intelligence classifications based on scores (<70, 70 to <85, 85 to <100, ≥100) over time were older (>24 months) at the early Gesell assessment. Degree of hearing loss or maternal education did not appear to confound the relationship between the Gesell and the Leiter-R. CONCLUSIONS: The adaptive domain of the Gesell Developmental Schedules - Revised administered in early childhood (under 3 years of age) has good correlation with the nonverbal Brief IQ on the Leiter International Performance Scale-R. Because children who are DHH have a higher likelihood of having a developmental disability compared to the general population, early developmental assessments are often important. Although early developmental assessments have their limitations, our results indicate that they are fairly robust indicators of later development. Such early indicators can be extremely useful in the clinical and educational management of children who are DHH.

Combination therapies using an intratympanic polymer gel delivery system in the guinea pig animal model: A safety study.

OBJECTIVES: High dose antivirals have been shown to cause hearing loss when applied via the intratympanic route. The aim of this study was to determine if a combination therapy using dexamethasone (DXA) with either Cidofovir (CDV) or Ganciclovir (GCV), in solution or in PLGA-PEG-PLGA (PPP) hydrogel, is innocuous to the inner ear. METHODS: Cytomegalovirus (CMV)-free guinea pigs were separated into four principal study groups and treated via intratympanic injection (IT) of CDV/DXA solution, CDV/DXA Hydrogel, GCV/DXA solution and GCV/DXA hydrogel. Hearing thresholds were evaluated with pretreatment ABR and post injection weekly ABRs for a total follow up of 28 days. Temporal bone tissue was harvested and stained with Hematoxylin and Eosin for histologic analysis. RESULTS: ABR analysis revealed that GCV/DXA in solution and in hydrogel led to a mild hearing loss at days 7-21 but returned to baseline by day 28 When administered via PPP hydrogel, CDV/DXA demonstrated mild persistent hearing loss at 32kHz at 28 days. An inflammatory response was identified in the cochlear specimen of the CDV/DXA/PPP hydrogel group, in concert with mild hearing loss, at days 21 and 28. CONCLUSION: Results of this study support the safe intratympanic use of higher concentrations of antivirals when combined with DXA, both in solution and when applied via PPP hydrogel.

Chd7 cooperates with Sox10 and regulates the onset of CNS myelination and remyelination.

Mutations in CHD7, encoding ATP-dependent chromodomain helicase DNA-binding protein 7, in CHARGE syndrome lead to multiple congenital anomalies, including craniofacial malformations, neurological dysfunction and growth delay. Mechanisms underlying the CNS phenotypes remain poorly understood. We found that Chd7 is a direct transcriptional target of oligodendrogenesis-promoting factors Olig2 and Smarca4/Brg1 and is required for proper onset of CNS myelination and remyelination. Genome-occupancy analyses in mice, coupled with transcriptome profiling, revealed that Chd7 interacted with Sox10 and targeted the enhancers of key myelinogenic genes. These analyses identified previously unknown Chd7 targets, including bone formation regulators Osterix (also known as Sp7) and Creb3l2, which are also critical for oligodendrocyte maturation. Thus, Chd7 coordinates with Sox10 to regulate the initiation of myelinogenesis and acts as a molecular nexus of regulatory networks that account for the development of a seemingly diverse array of lineages, including oligodendrocytes and osteoblasts, pointing to previously uncharacterized Chd7 functions in white matter pathogenesis in CHARGE syndrome.

Radioprotective Effect of Aminothiol PrC-210 on Irradiated Inner Ear of Guinea Pig.

Radiotherapy of individuals suffering with head & neck or brain tumors subserve the risk of sensorineural hearing loss. Here, we evaluated the protective effect of Aminothiol PrC-210 (3-(methyl-amino)-2-((methylamino)methyl)propane-1-thiol) on the irradiated inner ear of guinea pigs. An intra-peritoneal or intra-tympanic dose of PrC-210 was administered prior to receiving a dose of gamma radiation (3000 cGy) to each ear. Auditory Brainstem Responses (ABRs) were recorded one week and two weeks after the radiation and compared with the sham animal group. ABR thresholds of guinea pigs that received an intra-peritoneal dose of PrC-210 were significantly better compared to the non-treated, control animals at one week post-radiation. Morphologic analysis of the inner ear revealed significant inflammation and degeneration of the spiral ganglion in the irradiated animals not treated with PrC-210. In contrast, when treated with PrC-210 the radiation effect and injury to the spiral ganglion was significantly alleviated. PrC-210 had no apparent cytotoxic effect in vivo and did not affect the morphology or count of cochlear hair cells. These findings suggest that aminothiol PrC-210 attenuated radiation-induced cochlea damage for at least one week and protected hearing.

Radiographic Evaluation of Children with Hearing Loss.

Computed tomography (CT) and MRI have become an integral part of the evaluation of children with hearing loss. Abnormalities on CT or MRI are found in 20% to 50% of children with sensorineural hearing loss and correlate with the degree of hearing loss. CT and MRI have distinct advantages and disadvantages in imaging the middle and inner ear. The timing of radiographic imaging is an important consideration. This article reviews radiographic abnormalities associated with sensorineural, mixed, and conductive hearing losses in children and offers guidance about the proper utilization of imaging studies.

A semi-supervised Support Vector Machine model for predicting the language outcomes following cochlear implantation based on pre-implant brain fMRI imaging.

INTRODUCTION: We developed a machine learning model to predict whether or not a cochlear implant (CI) candidate will develop effective language skills within 2 years after the CI surgery by using the pre-implant brain fMRI data from the candidate. METHODS: The language performance was measured 2 years after the CI surgery by the Clinical Evaluation of Language Fundamentals-Preschool, Second Edition (CELF-P2). Based on the CELF-P2 scores, the CI recipients were designated as either effective or ineffective CI users. For feature extraction from the fMRI data, we constructed contrast maps using the general linear model, and then utilized the Bag-of-Words (BoW) approach that we previously published to convert the contrast maps into feature vectors. We trained both supervised models and semi-supervised models to classify CI users as effective or ineffective. RESULTS: Compared with the conventional feature extraction approach, which used each single voxel as a feature, our BoW approach gave rise to much better performance for the classification of effective versus ineffective CI users. The semi-supervised model with the feature set extracted by the BoW approach from the contrast of speech versus silence achieved a leave-one-out cross-validation AUC as high as 0.97. Recursive feature elimination unexpectedly revealed that two features were sufficient to provide highly accurate classification of effective versus ineffective CI users based on our current dataset. CONCLUSION: We have validated the hypothesis that pre-implant cortical activation patterns revealed by fMRI during infancy correlate with language performance 2 years after cochlear implantation. The two brain regions highlighted by our classifier are potential biomarkers for the prediction of CI outcomes. Our study also demonstrated the superiority of the semi-supervised model over the supervised model. It is always worthwhile to try a semi-supervised model when unlabeled data are available.

Cochlear implantation in patients with Meniere's disease.

OBJECTIVES: Few studies have addressed the benefits of cochlear implantation for the small group of patients with bilateral, end-stage Meniere's disease, or unilateral disease with contralateral hearing loss from another cause. Our retrospective study evaluates the effectiveness and post-operative performance in these Meniere's disease patients and discusses these findings relative to other post-lingually deafened adults. METHODS: Among 456 adults who received cochlear implants, we identified eight (1.7%) patients with Meniere's disease who met clinical indications for implantation and a control group of seven non-Meniere's patients of comparable age and deafness. Data gathered included demographics, auditory and vestibular symptoms pre-implantation, and clinical course after implantation, including audiometric scores (consonant-nucleus-consonant (CNC), hearing-in-noise testing (HINT), and AzBio score) and audiologic evaluations. RESULTS: Comparing the Meniere's and non-Meniere's patients, pre- to post-implant scores averaged 15 and 16%-57 and 76% for CNC; and 4.5 and 40.5%-78 and 81% for AzBio and/or HINT tests, respectively; scores between groups did not statistically differ. Of note, five of eight patients had 0% word recognition scores pre-operatively. Fluctuations in CI performance were seen in five patients with Meniere's disease but not for those without the disease. CONCLUSIONS: Audiologic testing found a strong likelihood that CIs did benefit our subset of Meniere's patients with severe to profound sensorineural hearing loss. Fluctuations in hearing sensitivity (perhaps owing to physical changes relative to the implant array with the spiral ganglion neurons during an acute attack or changes in spiral ganglion neurons because of the hydropic state) can often be resolved by subsequent reprogramming.

Assessment of PLGA-PEG-PLGA copolymer hydrogel for sustained drug delivery in the ear.

Temperature sensitive copolymer systems were previously studied using modified diffusion cells in vitro for intratympanic injection, and the PLGA-PEG-PLGA copolymer systems were found to provide sustained drug delivery for several days. The objectives of the present study were to assess the safety of PLGA-PEG-PLGA copolymers in intratympanic injection in guinea pigs in vivo and to determine the effects of additives glycerol and poloxamer in PLGA-PEGPLGA upon drug release in the diffusion cells in vitro for sustained inner ear drug delivery. In the experiments, the safety of PLGA-PEG-PLGA copolymers to inner ear was evaluated using auditory brainstem response (ABR). The effects of the additives upon drug release from PLGA-PEG-PLGA hydrogel were investigated in the modified Franz diffusion cells in vitro with cidofovir as the model drug. The phase transition temperatures of the PLGA-PEG-PLGA copolymers in the presence of the additives were also determined. In the ABR safety study, the PLGA-PEG-PLGA copolymer alone did not affect hearing when delivered at 0.05-mL dose but caused hearing loss after 0.1-mL injection. In the drug release study, the incorporation of the bioadhesive additive, poloxamer, in the PLGA-PEG-PLGA formulations was found to decrease the rate of drug release whereas the increase in the concentration of the humectant additive, glycerol, provided the opposite effect. In summary, the PLGA-PEG-PLGA copolymer did not show toxicity to the inner ear at the 0.05-mL dose and could provide sustained release that could be controlled by using the additives for inner ear applications.