Publications by authors named "Samuel P Gubbels"

44 Publications

Hydroxyapatite cement cranioplasty for reconstruction of translabyrinthine approach: aesthetic results, long-term satisfaction, quality of life, and complications.

Acta Neurochir (Wien) 2021 Oct 13. Epub 2021 Oct 13.

Departments of Neurosurgery and Otolaryngology, University of Colorado School of Medicine, 1635 Aurora Ct, 4th floor, Aurora, CO, 80045, USA.

Background: Translabyrinthine approaches (TLAs) for resection of skull base neoplasms are complex with variable reconstruction techniques. Fat grafts in conjunction with hydroxyapatite bone cement techniques have seldom been described in terms of possible superiority to other skull base reconstruction techniques. We sought to determine the impact of this skull base reconstruction technique on clinical outcomes and patient's satisfaction.

Method: We performed a retrospective analysis of all patients who underwent translabyrinthine approaches for resection of CPA lesions over a 5-year period. Both post-op objective and subjective markers of reconstruction, as well as postoperative complications, were collected and analyzed.

Results: Sixty-nine patients were included, 34 underwent reconstruction with hydroxyapatite and fat (rHAC) and 35 with fat alone (rF). rHAC was associated with fewer cranial wound superficial infection/dehiscence (0% vs 14.3%; p = 0.029) and shorter length of stay (mean ± standard deviation) (6.9 ± 7.4 vs 4.4 ± 3.7 days, p = 0.008). Postoperative subjective characterization of rHAC demonstrated improved satisfaction scores (1.38 ± 0.5 vs 1.83 ± 1; p = 0.049) and fewer reports of post-operative irregularities (11.5% vs 37.5%; p = 0.017).

Conclusion: The use of hydroxyapatite for cranial reconstruction after translabyrinthine approaches has improved patient satisfaction and decreased cranial defects in our small series. Postoperative complications are consistent with other described methods, but with shorter hospital stay, decreased risk of superficial wound dehiscence/infection, and a perceived superiority in preventing percutaneous post-op CSF leaks.
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http://dx.doi.org/10.1007/s00701-021-05024-6DOI Listing
October 2021

Selective ablation of cochlear hair cells promotes engraftment of human embryonic stem cell-derived progenitors in the mouse organ of Corti.

Stem Cell Res Ther 2021 06 19;12(1):352. Epub 2021 Jun 19.

Department of Otolaryngology, University of Colorado Denver, Academic Office One, Suite 3001, 12631 E 17th Avenue, MS B205, Aurora, CO, 80045, USA.

Background: Hearing loss affects 25% of the population at ages 60-69 years. Loss of the hair cells of the inner ear commonly underlies deafness and once lost this cell type cannot spontaneously regenerate in higher vertebrates. As a result, there is a need for the development of regenerative strategies to replace hair cells once lost. Stem cell-based therapies are one such strategy and offer promise for cell replacement in a variety of tissues. A number of investigators have previously demonstrated successful implantation, and certain level of regeneration of hair and supporting cells in both avian and mammalian models using rodent pluripotent stem cells. However, the ability of human stem cells to engraft and generate differentiated cell types in the inner ear is not well understood.

Methods: We differentiate human pluripotent stem cells to the pre-placodal stage in vitro then transplant them into the mouse cochlea after selective and complete lesioning of the endogenous population of hair cells.

Results: We demonstrate that hair cell ablation prior to transplantation leads to increased engraftment in the auditory sensory epithelium, the organ of Corti, as well as differentiation of transplanted cells into hair and supporting cell immunophenotypes.

Conclusion: We have demonstrated the feasibility of human stem cell engraftment into an ablated mouse organ of Corti.
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http://dx.doi.org/10.1186/s13287-021-02403-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8214253PMC
June 2021

Reversible Canalith Jam of the Horizontal Semicircular Canal Mimicking Cupulolithiasis.

Ann Otol Rhinol Laryngol 2021 Nov 3;130(11):1213-1219. Epub 2021 Apr 3.

Department of Otolaryngology, The University of Colorado School of Medicine, Aurora, CO, USA.

Objective: To describe a case of benign paroxysmal positional vertigo (BPPV) resulting in reversible horizontal semicircular canalith jam successfully treated with horizontal canal occlusion. A brief literature review of similar cases was performed.

Methods: Case report and literature review.

Results: A 68-year-old female presented with apogeotropic positional nystagmus, attributed to reversible horizontal canalith jam mimicking cupulolithiasis that was refractory to tailored repositioning maneuvers across months. She was unable to work due to the severity of her symptoms. She underwent surgical occlusion of the affected canal with immediate resolution of her symptoms. A literature review revealed similar cases of canalith jam mimicking cupulolithiasis.

Conclusions: Reversible canalith jam, in which particles moving with horizontal head position alternate between obstructing the semicircular canal and resting on the cupula, can mimic signs of cupulolithiasis. This variant of BPPV can be effectively managed with surgical canal occlusion should symptoms fail to resolve after tailored repositioning maneuvers.
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http://dx.doi.org/10.1177/00034894211007245DOI Listing
November 2021

Sex difference in the efferent inner hair cell synapses of the aging murine cochlea.

Hear Res 2021 05 21;404:108215. Epub 2021 Feb 21.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

Efferent innervation of the inner hair cells changes over time. At an early age in mice, inner hair cells receive efferent feedback, which helps fine-tune tonotopic maps in the brainstem. In adulthood, inner hair cell efferent innervation wanes but increases again in older animals. It is not clear, however, whether age-related inner hair cell efferents increase along the entire range of the cochlear frequencies, or if this increase is restricted to a particular frequency-region, and whether this phenomenon occurs in both sexes. Age-related hearing loss, presbycusis, affects men and women differently. In mice, this difference is also strain specific. In aging black six mice, the auditory brainstem response thresholds increase in females earlier than in males. Here, we study age-related increase of the inner hair cell efferent innervation throughout the cochlea before hearing onset, in one month old and in ten months old and older male and female black six mice. We collected confocal images of immunostained inner hair cell efferents and quantified the labeled terminals in the entire cochlea using a machine learning algorithm. The overall number of the inner hair cell efferents in both sexes did not change significantly between age-groups. The distribution of the inner hair cell efferent innervation did not differ across frequencies in the cochlea. However, in females, inner hair cells received on average up to four times more efferent innervation than in males per each of the frequency regions tested. Sex differences were also found in the oldest age-group tested (≥ 10 months) where on average inner hair cells received six times more efferents in females than in males of matching age. Our findings emphasize the importance of including both sexes in sensorineural hearing loss research.
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http://dx.doi.org/10.1016/j.heares.2021.108215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143057PMC
May 2021

Multi-omic studies on missense PLG variants in families with otitis media.

Sci Rep 2020 09 14;10(1):15035. Epub 2020 Sep 14.

Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.
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http://dx.doi.org/10.1038/s41598-020-70498-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490366PMC
September 2020

The Changing Paradigm of Head and Neck Paragangliomas: What Every Otolaryngologist Needs to Know.

Ann Otol Rhinol Laryngol 2020 Nov 2;129(11):1135-1143. Epub 2020 Jun 2.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Recommendations regarding head and neck paragangliomas (HNPGL) have undergone a fundamental reorientation in the last decade as a result of increased understanding of the genetic and pathophysiologic basis of these disorders.

Objective: We aim to provide an overview of HNPGL and recent discoveries regarding their molecular genetics, along with updated recommendations on workup, treatment, and surveillance, and their implications for otolaryngologists treating patients with these disorders.

Results: susceptibility gene mutations, encoding subunits of the enzyme succinate dehydrogenase (SDH), give rise to the Hereditary Pheochromocytoma/Paraganglioma Syndromes. , and mutations each result in unique phenotypes with distinct penetrance and risk for variable tumor development as well as metastasis. Genetic and biochemical testing is recommended for every patient with HNPGL. Multifocal disease should be managed in multi-disciplinary fashion. Patients with mutations require frequent biochemical screening and whole-body imaging, as well as lifelong follow-up with an expert in hereditary pheochromocytoma and paraganglioma syndromes.

Conclusion: Otolaryngologists are likely to encounter patients with HNPGL. Keeping abreast of the latest recommendations, especially regarding genetic testing, workup for additional tumors, multi-disciplinary approach to care, and need for lifelong surveillance, will help otolaryngologists appropriately care for these patients.
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http://dx.doi.org/10.1177/0003489420931540DOI Listing
November 2020

Practical aspects of inner ear gene delivery for research and clinical applications.

Hear Res 2020 09 6;394:107934. Epub 2020 Mar 6.

Kresge Hearing Research Institute, Department of Otolaryngology, Head and Neck Surgery, Michigan Medicine, Ann Arbor, MI, USA. Electronic address:

The application of gene therapy is widely expanding in research and continuously improving in preparation for clinical applications. The inner ear is an attractive target for gene therapy for treating environmental and genetic diseases in both the auditory and vestibular systems. With the lack of spontaneous cochlear hair cell replacement, hair cell regeneration in adult mammals is among the most important goals of gene therapy. In addition, correcting gene defects can open up a new era for treating inner ear diseases. The relative isolation and small size of the inner ear dictate local administration routes and carefully calculated small volumes of reagents. In the current review, we will cover effective timing, injection routes and types of vectors for successful gene delivery to specific target cells within the inner ear. Differences between research purposes and clinical applications are also discussed.
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http://dx.doi.org/10.1016/j.heares.2020.107934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415623PMC
September 2020

Time-based Assessment of Hearing Preservation Rates After Microsurgical Resection of Vestibular Schwannomas: A Systematic Review.

Otol Neurotol 2020 06;41(5):679-685

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

Objective: To determine short- and intermediate-term hearing preservation rates after microsurgical resection of vestibular schwannoma (VS).

Data Sources: Systematic review of the Ovid, Cochrane, EMBASE, and Web of Science databases.

Study Selection: This study was restricted to full-text English-language articles detailing VS resection via the middle cranial fossa or retrosigmoid approaches. Documentation of pre- and posttreatment hearing outcomes with American Academy of Otolaryngology-Head and Neck Surgery, Gardner-Robertson, or word recognition score scales, as well as time to follow-up were required. Duplicate data sets, studies with >10% of patients with neurofibromatosis two, previous or nonsurgical VS treatment, case reports with
Data Extraction: Two authors independently performed full-text reviews to determine study eligibility. Discrepancies were settled by consensus. "Class A/B, I/II" hearing was defined as AAO-HNS Class A or B, Gardner-Robertson Class 1 or 2, or PTA ≤ 50 dB with word recognition score ≥ 50% on audiogram.

Data Synthesis: Pooled estimates of preserved Class A/B, I/II hearing at last postoperative follow-up.

Conclusions: Of 1323 reports, 14 were utilized in analyses yielding data from 2,977 patients. Mean follow-up was 52.5 months (SD = 19.9). Class A/B, 1/2 hearing was preserved at last follow-up in 57% of patients. Meta-regression revealed that resection through the middle cranial fossa was associated with preservation of serviceable hearing. Moreover, when preserved in the immediate postoperative period, it seems to be stable over time.
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http://dx.doi.org/10.1097/MAO.0000000000002598DOI Listing
June 2020

Identification of Novel Genes and Biological Pathways That Overlap in Infectious and Nonallergic Diseases of the Upper and Lower Airways Using Network Analyses.

Front Genet 2019 17;10:1352. Epub 2020 Jan 17.

Department of Otolaryngology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

Previous genetic studies on susceptibility to otitis media and airway infections have focused on immune pathways acting within the local mucosal epithelium, and outside of allergic rhinitis and asthma, limited studies exist on the overlaps at the gene, pathway or network level between the upper and lower airways. In this report, we compared [1] pathways identified from network analysis using genes derived from published genome-wide family-based and association studies for otitis media, sinusitis, and lung phenotypes, to [2] pathways identified using differentially expressed genes from RNA-sequence data from lower airway, sinus, and middle ear tissues, in particular cholesteatoma tissue compared to middle ear mucosa. For otitis media, a large number of genes ( = 1,806) were identified as differentially expressed between cholesteatoma and middle ear mucosa, which in turn led to the identification of 68 pathways that are enriched in cholesteatoma. Two differentially expressed genes and overlap in middle ear, sinus, and lower airway samples and are potentially novel genes for otitis media susceptibility. In addition, 56 genes were differentially expressed in both tissues from the middle ear and either sinus or lower airways. Pathways that are common in upper and lower airway diseases, whether from published DNA studies or from our RNA-sequencing analyses, include chromatin organization/remodeling, endocytosis, immune system process, protein folding, and viral process. Taken together, our findings from genetic susceptibility and differential tissue expression studies support the hypothesis that the unified airway theory wherein the upper and lower respiratory tracts act as an integrated unit also applies to infectious and nonallergic airway epithelial disease. Our results may be used as reference for identification of genes or pathways that are relevant to upper and lower airways, whether common across sites, or unique to each disease.
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http://dx.doi.org/10.3389/fgene.2019.01352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979043PMC
January 2020

Risks of Intracochlear Pressures From Laser Stapedotomy.

Otol Neurotol 2020 03;41(3):308-317

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

Hypothesis: Surgical manipulations during laser stapedotomy can produce intracochlear pressure changes comparable to pressures created by high-intensity acoustic stimuli.

Background: New-onset sensorineural hearing loss is a known risk of stapes surgery and may result from pressure changes from laser use or other surgical manipulations. Here, we test the hypothesis that high sound pressure levels are generated in the cochlea during laser stapedotomy.

Methods: Human cadaveric heads underwent mastoidectomy. Fiber-optic sensors were placed in scala tympani and vestibuli to measure intracochlear pressures during key steps in stapedotomy surgery, including cutting stapedius tendon, lasering of stapedial crurae, crural downfracture, and lasering of the footplate.

Results: Key steps in laser stapedotomy produced high-intensity pressures in the cochlea. Pressure transients were comparable to intracochlear pressures measured in response to high intensity impulsive acoustic stimuli.

Conclusion: Our results demonstrate that surgical manipulations during laser stapedotomy can create significant pressure changes within the cochlea, suggesting laser application should be minimized and alternatives to mechanical downfracture should be investigated. Results from this investigation suggest that intracochlear pressure transients from stapedotomy may be of sufficient magnitude to cause damage to the sensory epithelium and affirm the importance of limiting surgical traumatic exposures.
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http://dx.doi.org/10.1097/MAO.0000000000002499DOI Listing
March 2020

First MRI With New Cochlear Implant With Rotatable Internal Magnet System and Proposal for Standardization of Reporting Magnet-Related Artifact Size.

Otol Neurotol 2019 08;40(7):883-891

Department of Otolaryngology.

Objective: To report on the first known magnetic resonance imaging (MRI) with a new cochlear implant (CI) with rotatable internal magnet system, to review the literature on MRI in cochlear implantees, and to advocate for standardization of reporting magnet-related artifact size.

Study Design: Case report and review of literature.

Setting: Tertiary care hospital.

Results: A patient with congenital rubella and bilateral profound hearing loss was incidentally found to have a petroclival meningioma. After resection and radiosurgery, she underwent cochlear implantation with the Advanced Bionics HiRes Ultra 3D device (Advanced Bionics LLC, Valencia, CA) with rotatable internal magnet system, due to need for imaging surveillance of residual meningioma. During 1.5 T MRI brain scan without a head wrap, she experienced no adverse events. The images obtained were adequate for visualization of residual tumor. Implant recipients with non-rotatable magnets who undergo MRI, with or without recommended head wrap, may suffer various complications. All images in patients with retained internal magnets are subject to magnet-related artifact, but reports regarding its size are variable and lack detail on how measurements are made.

Conclusions: MRI in patients with a new CI device with rotatable magnet system may be performed without discomfort or device dislodgement at 1.5 T, even without a head wrap, though external magnet replacement may require multiple attempts due to internal magnet realignment. Despite significant artifact, the structure of interest may still be visualized for accurate diagnosis. Measuring magnet-related artifact size should be standardized by reporting artifact in radii at the image level of maximal signal loss.
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http://dx.doi.org/10.1097/MAO.0000000000002269DOI Listing
August 2019

A2ML1 and otitis media: novel variants, differential expression, and relevant pathways.

Hum Mutat 2019 08 21;40(8):1156-1171. Epub 2019 May 21.

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.
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http://dx.doi.org/10.1002/humu.23769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711784PMC
August 2019

FUT2 Variants Confer Susceptibility to Familial Otitis Media.

Am J Hum Genet 2018 11 25;103(5):679-690. Epub 2018 Oct 25.

Division of Infectious Diseases, Department of Medicine, CUSOM, Aurora, CO 80045, USA.

Non-secretor status due to homozygosity for the common FUT2 variant c.461G>A (p.Trp154) is associated with either risk for autoimmune diseases or protection against viral diarrhea and HIV. We determined the role of FUT2 in otitis media susceptibility by obtaining DNA samples from 609 multi-ethnic families and simplex case subjects with otitis media. Exome and Sanger sequencing, linkage analysis, and Fisher exact and transmission disequilibrium tests (TDT) were performed. The common FUT2 c.604C>T (p.Arg202) variant co-segregates with otitis media in a Filipino pedigree (LOD = 4.0). Additionally, a rare variant, c.412C>T (p.Arg138Cys), is associated with recurrent/chronic otitis media in European-American children (p = 1.2 × 10) and US trios (TDT p = 0.01). The c.461G>A (p.Trp154) variant was also over-transmitted in US trios (TDT p = 0.01) and was associated with shifts in middle ear microbiota composition (PERMANOVA p < 10) and increased biodiversity. When all missense and nonsense variants identified in multi-ethnic US trios with CADD > 20 were combined, FUT2 variants were over-transmitted in trios (TDT p = 0.001). Fut2 is transiently upregulated in mouse middle ear after inoculation with non-typeable Haemophilus influenzae. Four FUT2 variants-namely p.Ala104Val, p.Arg138Cys, p.Trp154, and p.Arg202-reduced A antigen in mutant-transfected COS-7 cells, while the nonsense variants also reduced FUT2 protein levels. Common and rare FUT2 variants confer susceptibility to otitis media, likely by modifying the middle ear microbiome through regulation of A antigen levels in epithelial cells. Our families demonstrate marked intra-familial genetic heterogeneity, suggesting that multiple combinations of common and rare variants plus environmental factors influence the individual otitis media phenotype as a complex trait.
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http://dx.doi.org/10.1016/j.ajhg.2018.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6217759PMC
November 2018

Is hearing preserved following radiotherapy for vestibular schwannoma?

Laryngoscope 2019 04 3;129(4):775-776. Epub 2018 Oct 3.

Department of Otolaryngology , University of Colorado School of Medicine, Aurora, Colorado, U.S.A.

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http://dx.doi.org/10.1002/lary.27421DOI Listing
April 2019

Primary Middle Ear Mucosal Melanoma: Case Report and Comprehensive Literature Review of 21 Cases of Primary Middle Ear and Eustachian Tube Melanoma.

Ann Otol Rhinol Laryngol 2018 Nov 13;127(11):856-863. Epub 2018 Aug 13.

1 Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado, USA.

Objective: To present a case of primary middle ear mucosal melanoma and perform a comprehensive literature review of middle ear and eustachian tube mucosal melanoma.

Patient: A 61-year-old female presented with no prior history of melanoma and 3 months of aural fullness. A middle ear mass demonstrated primary mucosal melanoma. The mass extended from mesotympanum into hypotympanum, epitympanum, protympanum, eustachian tube, and mastoid antrum. Additionally, a nonenhancing expansile lesion of the petrous apex was noted on magnetic resonance imaging.

Intervention: Subtotal temporal bone resection with transotic approach to the petrous abnormality was performed. Postoperative adjuvant radiation and immunotherapy were given.

Results: Five months postoperatively, the patient developed an isolated cutaneous metastatic focus treated with wide local excision and has had no further evidence of recurrence to date. Upon comprehensive literature review, patients with primary middle ear melanomas (n = 10) present with otorrhea (50%), aural fullness (40%), and hearing loss (30%) most commonly, while hearing loss (81.8%) and aural fullness (54.5%) were the most common presenting symptoms for eustachian tube melanomas (n = 11). Patients were treated with combinations of surgery, radiation, and/or chemotherapy. Middle ear melanoma demonstrated particularly poor outcomes, with 70% mortality, 20% local recurrence, and 50% distant metastasis, whereas eustachian tube origin demonstrated 9.1%, 18.2%, and 36.4%, respectively.

Conclusions: Middle ear and eustachian tube mucosal melanomas are exceedingly rare, with middle ear melanomas demonstrating a worse prognosis. Multimodality therapy is commonly used; however, outcomes are poor, with high mortality among affected patients.
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http://dx.doi.org/10.1177/0003489418793154DOI Listing
November 2018

Challenges in Cell-Based Therapies for the Treatment of Hearing Loss.

Trends Neurosci 2018 11 19;41(11):823-837. Epub 2018 Jul 19.

Department of Otolaryngology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. Electronic address:

Hearing loss in mammals is an irreversible process caused by degeneration of the hair cells of the inner ear. Current therapies for hearing loss include hearing aids and cochlear implants that provide substantial benefits to most patients, but also have several shortcomings. There is great interest in the development of regenerative therapies to treat deafness in the future. Cell-based therapies, based either on adult, multipotent stem, or other types of pluripotent cells, offer promise for generating differentiated cell types to replace lost or damaged hair cells of the inner ear. In this review, we focus on the methods proposed and avenues for research that seem the most promising for stem cell-based auditory sensory cell regeneration, from work collected over the past 15 years.
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http://dx.doi.org/10.1016/j.tins.2018.06.008DOI Listing
November 2018

Sudden Bilateral Hearing Loss, Tinnitus, and Vertigo as Presenting Symptoms of Chronic Myeloid Leukemia.

Ann Otol Rhinol Laryngol 2018 Oct 21;127(10):731-734. Epub 2018 Jul 21.

2 UCHealth Hearing and Balance Clinic, University of Colorado Hospital, Aurora, Colorado, USA.

Objectives: The objective was to describe a unique case of sudden bilateral hearing loss, tinnitus, and vertigo presenting as the first symptoms of chronic myeloid leukemia (CML).

Methods: A patient case is discussed along with a review of associated literature.

Results: A patient presented with sudden onset hearing loss, tinnitus, and vertigo, and was diagnosed with CML with an initial white blood cell (WBC) count of 555 000 per microliter. The proposed etiology of otologic symptoms is hyperleukocytosis. Serial audiograms showed minimal improvement in hearing despite reduction of WBC.

Conclusion: In cases of bilateral, sudden onset sensorineural hearing loss, evaluation for systemic causes of otologic symptoms, including CML, should be considered.
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http://dx.doi.org/10.1177/0003489418787831DOI Listing
October 2018

Systematic Review of Hearing Preservation After Radiotherapy for Vestibular Schwannoma.

Otol Neurotol 2018 03;39(3):273-283

Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado.

Objective: To determine the long-term hearing preservation rate for spontaneous vestibular schwannoma treated by primary radiotherapy.

Data Sources: The MEDLINE/PubMed, Web of Science, Cochrane Reviews, and EMBASE databases were searched using a comprehensive Boolean keyword search developed in conjunction with a scientific librarian. English language papers published from 2000 to 2016 were evaluated.

Study Selection: Inclusion criteria: full articles, pretreatment and posttreatment audiograms or audiogram based scoring system, vestibular schwannoma only tumor type, reported time to follow-up, published after 1999, use of either Gamma Knife or linear accelerator radiotherapy.

Exclusion Criteria: case report or series with fewer than five cases, inadequate audiometric data, inadequate time to follow-up, neurofibromatosis type 2 exceeding 10% of study population, previous treatment exceeding 10% of study population, repeat datasets, use of proton beam therapy, and non-English language.

Data Extraction: Two reviewers independently analyzed papers for inclusion. Class A/B, 1/2 hearing was defined as either pure tone average less than or equal to 50 db with speech discrimination score more than or equal to 50%, American Academy of Otolaryngology-Head & Neck Surgery (AAO-HNS) Hearing Class A or B, or Gardner-Robertson Grade I or II. Aggregate data were used when individual data were not specified.

Data Synthesis: Means were compared with student t test.

Conclusions: Forty seven articles containing a total of 2,195 patients with preserved Class A/B, 1/2 hearing were identified for analysis. The aggregate crude hearing preservation rate was 58% at an average reporting time of 46.6 months after radiotherapy treatment. Analysis of time-based reporting shows a clear trend of decreased hearing preservation extending to 10-year follow-up. This data encourages a future long-term controlled trial.
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http://dx.doi.org/10.1097/MAO.0000000000001672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807198PMC
March 2018

Drill-induced Cochlear Injury During Otologic Surgery: Intracochlear Pressure Evidence of Acoustic Trauma.

Otol Neurotol 2017 08;38(7):938-947

*Department of Otolaryngology, University of Colorado School of Medicine, Aurora, Colorado †Auditory Protection and Performance Division, U.S. Army Aeromedical Research Lab, Fort Rucker, Alabama ‡Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, Colorado.

Hypothesis: Drilling on the incus produces intracochlear pressure changes comparable to pressures created by high-intensity acoustic stimuli.

Background: New-onset sensorineural hearing loss (SNHL) following mastoid surgery can occur secondary to inadvertent drilling on the ossicular chain. To investigate this, we test the hypothesis that high sound pressure levels are generated when a high-speed drill contacts the incus.

Methods: Human cadaveric heads underwent mastoidectomy, and fiber-optic sensors were placed in scala tympani and vestibuli to measure intracochlear pressures (PIC). Stapes velocities (Vstap) were measured using single-axis laser Doppler vibrometry. PIC and Vstap were measured while drilling on the incus. Four-millimeter diamond and cutting burrs were used at drill speeds of 20k, 50k, and 80k Hz.

Results: No differences in peak equivalent ear canal noise exposures (134-165 dB SPL) were seen between drill speeds or burr types. Root-mean-square PIC amplitude calculated in third-octave bandwidths around 0.5, 1, 2, 4, and 8 kHz revealed equivalent ear canal (EAC) pressures up to 110 to 112 dB SPL. A statistically significant trend toward increasing noise exposure with decreasing drill speed was seen. No significant differences were noted between burr types. Calculations of equivalent EAC pressure from Vstap were significantly higher at 101 to 116 dB SPL.

Conclusion: Our results suggest that incidental drilling on the ossicular chain can generate PIC comparable to high-intensity acoustic stimulation. Drill speed, but not burr type, significantly affected the magnitude of PIC. Inadvertent drilling on the ossicular chain produces intense cochlear stimulation that could cause SNHL.
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http://dx.doi.org/10.1097/MAO.0000000000001474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535777PMC
August 2017

Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update).

Otolaryngol Head Neck Surg 2017 03;156(3_suppl):S1-S47

16 American Academy of Otolaryngology-Head and Neck Surgery Foundation, Alexandria, Virginia, USA.

Objective This update of a 2008 guideline from the American Academy of Otolaryngology-Head and Neck Surgery Foundation provides evidence-based recommendations to benign paroxysmal positional vertigo (BPPV), defined as a disorder of the inner ear characterized by repeated episodes of positional vertigo. Changes from the prior guideline include a consumer advocate added to the update group; new evidence from 2 clinical practice guidelines, 20 systematic reviews, and 27 randomized controlled trials; enhanced emphasis on patient education and shared decision making; a new algorithm to clarify action statement relationships; and new and expanded recommendations for the diagnosis and management of BPPV. Purpose The primary purposes of this guideline are to improve the quality of care and outcomes for BPPV by improving the accurate and efficient diagnosis of BPPV, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary testing such as radiographic imaging, and increasing the use of appropriate therapeutic repositioning maneuvers. The guideline is intended for all clinicians who are likely to diagnose and manage patients with BPPV, and it applies to any setting in which BPPV would be identified, monitored, or managed. The target patient for the guideline is aged ≥18 years with a suspected or potential diagnosis of BPPV. The primary outcome considered in this guideline is the resolution of the symptoms associated with BPPV. Secondary outcomes considered include an increased rate of accurate diagnoses of BPPV, a more efficient return to regular activities and work, decreased use of inappropriate medications and unnecessary diagnostic tests, reduction in recurrence of BPPV, and reduction in adverse events associated with undiagnosed or untreated BPPV. Other outcomes considered include minimizing costs in the diagnosis and treatment of BPPV, minimizing potentially unnecessary return physician visits, and maximizing the health-related quality of life of individuals afflicted with BPPV. Action Statements The update group made strong recommendations that clinicians should (1) diagnose posterior semicircular canal BPPV when vertigo associated with torsional, upbeating nystagmus is provoked by the Dix-Hallpike maneuver, performed by bringing the patient from an upright to supine position with the head turned 45° to one side and neck extended 20° with the affected ear down, and (2) treat, or refer to a clinician who can treat, patients with posterior canal BPPV with a canalith repositioning procedure. The update group made a strong recommendation against postprocedural postural restrictions after canalith repositioning procedure for posterior canal BPPV. The update group made recommendations that the clinician should (1) perform, or refer to a clinician who can perform, a supine roll test to assess for lateral semicircular canal BPPV if the patient has a history compatible with BPPV and the Dix-Hallpike test exhibits horizontal or no nystagmus; (2) differentiate, or refer to a clinician who can differentiate, BPPV from other causes of imbalance, dizziness, and vertigo; (3) assess patients with BPPV for factors that modify management, including impaired mobility or balance, central nervous system disorders, a lack of home support, and/or increased risk for falling; (4) reassess patients within 1 month after an initial period of observation or treatment to document resolution or persistence of symptoms; (5) evaluate, or refer to a clinician who can evaluate, patients with persistent symptoms for unresolved BPPV and/or underlying peripheral vestibular or central nervous system disorders; and (6) educate patients regarding the impact of BPPV on their safety, the potential for disease recurrence, and the importance of follow-up. The update group made recommendations against (1) radiographic imaging for a patient who meets diagnostic criteria for BPPV in the absence of additional signs and/or symptoms inconsistent with BPPV that warrant imaging, (2) vestibular testing for a patient who meets diagnostic criteria for BPPV in the absence of additional vestibular signs and/or symptoms inconsistent with BPPV that warrant testing, and (3) routinely treating BPPV with vestibular suppressant medications such as antihistamines and/or benzodiazepines. The guideline update group provided the options that clinicians may offer (1) observation with follow-up as initial management for patients with BPPV and (2) vestibular rehabilitation, either self-administered or with a clinician, in the treatment of BPPV.
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March 2017

Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update) Executive Summary.

Otolaryngol Head Neck Surg 2017 03;156(3):403-416

16 American Academy of Otolaryngology-Head and Neck Surgery Foundation, Alexandria, Virginia, USA.

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the "Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update)." To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed emphasize diagnostic accuracy and efficiency, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary testing, and increasing the appropriate therapeutic repositioning maneuvers. An updated guideline is needed due to new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group.
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http://dx.doi.org/10.1177/0194599816689660DOI Listing
March 2017

Can routine office-based audiometry predict cochlear implant evaluation results?

Laryngoscope 2017 01 31;127(1):216-222. Epub 2016 Oct 31.

University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, U.S.A.

Objectives/hypothesis: Determining cochlear implant candidacy requires a specific sentence-level testing paradigm in best-aided conditions. Our objective was to determine if findings on routine audiometry could predict the results of a formal cochlear implant candidacy evaluation. We hypothesize that findings on routine audiometry will accurately predict cochlear implant evaluation results in the majority of candidates.

Study Design: Retrospective, observational, diagnostic study.

Methods: The charts of all adult patients who were evaluated for implant candidacy at a tertiary care center from June 2008 through June 2013 were included. Routine, unaided audiologic measures (pure-tone hearing thresholds and recorded monosyllabic word recognition testing) were then correlated with best-aided sentence-level discrimination testing (using either the Hearing in Noise Test or AzBio sentences test).

Results: The degree of hearing loss at 250 to 4,000 Hz and monosyllabic word recognition scores significantly correlated with sentence-level word discrimination test results. Extrapolating from this association, we found that 86% of patients with monosyllabic word recognition scores at or below 32% (or 44% for patients with private insurance) would meet candidacy requirements for cochlear implantation.

Conclusions: Routine audiometric findings can be used to identify patients who are likely to meet cochlear implant candidacy upon formal testing. For example, patients with pure-tone thresholds (250, 500, 1,000 Hz) of ≥75 dB and/or a monosyllabic word recognition test score of ≤40% have a high likelihood of meeting candidacy criteria. Utilization of these predictive patterns during routine audiometric evaluation may assist hearing health professionals in deciding when to refer patients for a formal cochlear implant evaluation.

Level Of Evidence: 4 Laryngoscope, 127:216-222, 2017.
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January 2017

Bone-anchored hearing aid and skin graft removal with subsequent cochlear implantation.

Laryngoscope 2016 11 10;126(11):2601-2604. Epub 2016 Feb 10.

Division of Otolaryngology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

We describe a novel technique of scalp flap rearrangement for cochlear implant (CI) candidates who have previously undergone ipsilateral bone-anchored hearing aid (BAHA) placement. One patient with single-sided deafness (SSD) underwent removal of a BAHA with subsequent scalp rearrangement for coverage of the implant site. After adequate healing of the scalp rotational flap, he underwent uncomplicated cochlear implantation without soft tissue complications. With increasing utilization of CIs in SSD, there will be more patients undergoing cochlear implantation who have previously had a BAHA. We present a novel method for accomplishing this goal while minimizing the risk of soft tissue complications. Laryngoscope, 126:2601-2604, 2016.
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http://dx.doi.org/10.1002/lary.25875DOI Listing
November 2016

Evaluation of Nestin Expression in the Developing and Adult Mouse Inner Ear.

Stem Cells Dev 2016 10 7;25(19):1419-32. Epub 2016 Sep 7.

2 Waisman Center, University of Wisconsin-Madison , Madison, Wisconsin.

Adult stem cells are undifferentiated cells with the capacity to proliferate and form mature tissue-specific cell types. Nestin is an intermediate filament protein used to identify cells with stem cell characteristics. Its expression has been observed in a population of cells in developing and adult cochleae. In vitro studies using rodent cochlear tissue have documented the potential of nestin-expressing cells to proliferate and form hair and supporting cells. In this study, nestin coupled to green fluorescent protein (GFP) transgenic mice were used to provide a more complete characterization of the spatial and temporal expression of nestin in the inner ear, from organogenesis to adulthood. During development, nestin is expressed in the spiral ganglion cell region and in multiple cell types in the organ of Corti, including nascent hair and supporting cells. In adulthood, its expression is reduced but persists in the spiral ganglion, in a cell population medial to and below the inner hair cells, and in Deiters' cells in the cochlear apex. Moreover, nestin-expressing cells can proliferate in restricted regions of the inner ear during development shown by coexpression with Ki67 and MCM2 and by 5-ethynyl-2'-deoxyuridine incorporation. Results suggest that nestin may label progenitor cells during inner ear development and may not be a stem cell marker in the mature organ of Corti; however, nestin-positive cells in the spiral ganglion exhibit some stem cell characteristics. Future studies are necessary to determine if these cells possess any latent stem cell-like qualities that may be targeted as a regenerative approach to treat neuronal forms of hearing loss.
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http://dx.doi.org/10.1089/scd.2016.0176DOI Listing
October 2016

Characterization of a unique cell population marked by transgene expression in the adult cochlea of nestin-CreER(T2)/tdTomato-reporter mice.

J Comp Neurol 2015 Jul 10;523(10):1474-87. Epub 2015 Mar 10.

Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, 53705.

Hair cells in the adult mammalian cochlea cannot spontaneously regenerate after damage, resulting in the permanency of hearing loss. Stem cells have been found to be present in the cochlea of young rodents; however, there has been little evidence for their existence into adulthood. We used nestin-CreER(T2)/tdTomato-reporter mice to trace the lineage of putative nestin-expressing cells and their progeny in the cochleae of adult mice. Nestin, an intermediate filament found in neural progenitor cells during early development and adulthood, is regarded as a multipotent and neural stem cell marker. Other investigators have reported its presence in postnatal and young adult rodents; however, there are discrepancies among these reports. Using lineage tracing, we documented a robust population of tdTomato-expressing cells and evaluated these cells at a series of adult time points. Upon activation of the nestin promoter, tdTomato was observed just below and medial to the inner hair cell layer. All cells colocalized with the stem cell and cochlear-supporting-cell marker Sox2 as well as the supporting cell and Schwann cell marker Sox10; however, they did not colocalize with the Schwann cell marker Krox20, spiral ganglion marker NF200, nor glial fibrillary acidic acid (GFAP)-expressing supporting cell marker. The cellular identity of this unique population of tdTomato-expressing cells in the adult cochlea of nestin-CreER(T2)/tdTomato mice remains unclear; however, these cells may represent a type of supporting cell on the neural aspect of the inner hair cell layer.
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http://dx.doi.org/10.1002/cne.23747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439321PMC
July 2015

Investigating long-term effects of cochlear implantation in single-sided deafness: a best practice model for longitudinal assessment of spatial hearing abilities and tinnitus handicap.

Otol Neurotol 2014 Oct;35(9):1525-32

*Division of Otolaryngology, Department of Surgery; †Waisman Center; and ‡Department of Communication Sciences and Disorders, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

Objectives: To evaluate methods for measuring long-term benefits of cochlear implantation in a patient with single-sided deafness (SSD) with respect to spatial hearing and to document improved quality of life because of reduced tinnitus.

Patient: A single adult male with profound right-sided sensorineural hearing loss and normal hearing in the left ear who underwent right-sided cochlear implantation.

Methods: The subject was evaluated at 6, 9, 12, and 18 months after implantation on speech intelligibility with specific target-masker configurations, sound localization accuracy, audiologic performance, and tinnitus handicap. Testing conditions involved the acoustic (NH) ear only, the cochlear implant (CI) ear (acoustic ear plugged), and the bilateral condition (CI+NH). Measures of spatial hearing included speech intelligibility improvement because of spatial release from masking (SRM) and sound localization. In addition, traditional measures known as "head shadow," "binaural squelch," and "binaural summation" were evaluated.

Results: The best indicator for improved speech intelligibility was SRM, in which both ears are activated, but the relative locations of target and masker(s) are manipulated. Measures that compare performance with a single ear to performance using bilateral auditory input indicated evidence of the ability to integrate inputs across the ears, possibly reflecting early binaural processing, with 12 months of bilateral input. Sound localization accuracy improved with addition of the implant, and a large improvement with respect to tinnitus handicap was observed.

Conclusion: Cochlear implantation resulted in improved sound localization accuracy when compared with performance using only the NH ear, and reduced tinnitus handicap was observed with use of the implant. The use of SRM addresses some of the current limitations of traditional measures of spatial and binaural hearing, as spatial cues related to target and maskers are manipulated, rather than the ear(s) tested. Sound testing methods and calculations described here are therefore recommended for assessing performance of a larger sample size of individuals with SSD who receive a CI.
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http://dx.doi.org/10.1097/MAO.0000000000000437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334463PMC
October 2014

In response to "is nasopharyngoscopy necessary in adult-onset otitis media with effusion?".

Laryngoscope 2014 Nov 30;124(11):E446. Epub 2014 Jan 30.

Department of Surgery, Otolaryngology Division, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

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http://dx.doi.org/10.1002/lary.24568DOI Listing
November 2014

Radiographic features of superior semicircular canal dehiscence in the setting of chronic ear disease.

Otol Neurotol 2014 Jan;35(1):91-6

*Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, †Department of Radiology, Section of Neuroradiology, ‡Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, Section of Otology and Neurotology, University of Wisconsin Hospital and Clinics; and §Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

Objective: To determine if radiologic chronic otitis media (COM), both with and without cholesteatoma, is associated with superior semicircular canal dehiscence (SSCD).

Study Design: Retrospective review of consecutive high-resolution computed tomography (HRCT) scans of the temporal bone.

Setting: Tertiary care medical center.

Patients: Two hundred consecutive patients undergoing HRCT of the temporal bone beginning January 1, 2012.

Intervention: Imaging was evaluated by 3 reviewers (2 neuroradiologists and 1 neurotologist). All scans were assessed for the presence of SSCD, cholesteatoma, chronic otomastoiditis, tegmen dehiscence, and for abnormalities of the cochlea, vestibule, facial nerve, and temporal bone vasculature.

Main Outcome Measure: Ears with COM associated with chronic otomastoiditis or cholesteatoma were compared with those without COM with respect to the presence of SSCD or other temporal bone abnormalities. Statistical analysis was performed to assess for differences between the groups studied.

Results: One-hundred ninety-four patients (388 ears) were included. Cholesteatoma was identified in 48 ears (12.4%) and chronic otomastoiditis in 62 ears (16%). Ten ears with cholesteatoma had ipsilateral SSCD, and 8 ears with chronic otomastoiditis had ipsilateral SSCD. In 340 ears without either cholesteatoma or chronic otomastoiditis, SSCD was found in 18 (5.3%). SSCD was found to occur significantly more often in patients with ipsilateral radiologic cholesteatoma. No cases of SSCD were associated with cochlear, facial nerve, or vascular abnormalities.

Conclusion: Our findings suggest that COM with cholesteatoma is associated with the presence of SSCD, although the nature of this association is unclear.
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http://dx.doi.org/10.1097/MAO.0b013e3182a03522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3947802PMC
January 2014

Repair of posterior semicircular canal dehiscence from a high jugular bulb.

Ann Otol Rhinol Laryngol 2013 Apr;122(4):269-72

Department of Surgery, Division of Otolaryngology-Head and Neck Surgery, University of Wisconsin School of Medicine and Public Health, 600 Highland Ave, Clinical Science Center-K4, Madison, WI 53792-3284, USA.

Objectives: We describe the clinical evaluation and operative management of posterior semicircular canal dehiscence caused by a high jugular bulb.

Methods: We performed a retrospective case report.

Results: The patient had clinical and audiometric findings consistent with semicircular canal dehiscence and imaging findings that demonstrated erosion of the posterior semicircular canal by a high jugular bulb. Resurfacing of the eroded canal provided resolution of the vestibular symptoms without damage to the inner ear.

Conclusions: Dehiscence of the posterior semicircular canal can cause clinical and audiometric findings similar to those of superior semicircular canal dehiscence syndrome. Resurfacing of the area of dehiscence can successfully relieve the vestibular symptoms. In the case of dehiscence of the posterior canal from a high jugular bulb, resurfacing may offer advantages over canal plugging for definitive management.
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http://dx.doi.org/10.1177/000348941312200409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972486PMC
April 2013

Is nasopharyngoscopy necessary in adult-onset otitis media with effusion?

Laryngoscope 2013 Sep 12;123(9):2081-2. Epub 2013 Feb 12.

School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, U.S.A.

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http://dx.doi.org/10.1002/lary.23967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3745820PMC
September 2013
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