Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement.

Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenclature and variable approaches to assessment and management. A task force of the European Respiratory Society (ERS) and European Laryngological Society (ELS) was thus set up to address this, and to identify research priorities.A literature search identified relevant articles published until June 2016, using all identifiable terms for ILO, although including only articles using laryngoscopy. In total, 172 out of 252 articles met the inclusion criteria, summarised in sections on diagnostic approach, aetiology, comorbidities, epidemiology and treatment. The consensus taxonomy published by ERS, ELS and the American College of Chest Physicians (ACCP) in 2015 is used throughout this statement.We highlight the high prevalence of ILO and the clinical impact for those affected. Despite recent advances, most aspects of this condition unfortunately remain incompletely understood, precluding firm guidance. Specifically, validated diagnostic and treatment algorithms are yet to be established, and no randomised control studies were identified in this search; hence we also make recommendations for future research.

ERS/ELS/ACCP 2013 international consensus conference nomenclature on inducible laryngeal obstructions.

Individuals reporting episodes of breathing problems caused by re-occurring variable airflow obstructions in the larynx have been described in an increasing number of publications, with more than 40 different terms being used without consensus on definitions. This lack of an international consensus on nomenclature is a serious obstacle for the development of the area, as knowledge from different centres cannot be matched, pooled or readily utilised by others. Thus, an international Task Force has been created, led by the European Respiratory Society/European Laryngological Society/American College of Chest Physicians. This review describes the methods used to reach an international consensus on the subject and the resulting nomenclature, the 2013 international consensus conference nomenclature.

Voice and respiratory outcomes after permanent transoral surgery of bilateral vocal fold paralysis.

OBJECTIVES/HYPOTHESIS: Bilateral vocal fold paralysis (BVFP) is a rare but life-threatening condition mostly caused by iatrogenic damage to the peripheral recurrent laryngeal nerve. Endoscopic enlargement techniques have been the standard treatment for decades. However, prospective studies using internationally accepted phoniatric and respiratory evaluation guidelines are rare. STUDY DESIGN: Prospective observational multicenter study. METHODS: Twelve clinical centers screened 61 patients, of whom 36 were eligible according to the study protocol. Subjects were assessed with specific phoniatric and respiratory tests preoperatively and at 1 and 6 months postoperatively. RESULTS: Important respiratory parameters improved significantly 6 months postoperatively (peak expiratory and expiratory flow), confirming that a glottal enlargement effectively reduced the obstruction. Objective parameters dealing with voice quality worsened significantly (maximum phonation time, voice range profile, hoarseness), whereas subjective voice assessment (VHI-12) did not change significantly. CONCLUSION: Endoscopic glottal enlargement is an effective method for relieving symptoms of dyspnea due to BVFP. Postoperatively, voice quality objectively worsened; however, this was not perceived by the patients themselves. Laryngostroboscopic findings did not correlate strongly with voice and respiratory outcomes. LEVEL OF EVIDENCE: 2b.

Establishing principles of macromolecular crowding for in vitro fibrosis research of the vocal fold lamina propria.

OBJECTIVES/HYPOTHESIS: Vocal fold fibrosis represents a major disease burden. Screening of antifibrotic compounds could be facilitated by an in vitro fibrogenesis system. Limitations of existing models might be overcome by implication of the excluded volume effect. STUDY DESIGN: In-vitro study. METHODS: Vocal fold fibroblasts obtained from rats' lamina propria were cultured in four different settings: in standard medium, under "crowded" conditions by adding inert macromolecules, under external administration of transforming growth factor (TGF)ß-1, and under a combination of both. After 5 days, supernatant and cell layer were collected and analyzed by enzyme-linked immunosorbent assay. Immunofluorescence was additionally performed. RESULTS: Collagen-alpha1(I) deposition increased significantly under crowded conditions and after administration of TGFß-1. Amounts of collagen in the cell layer were significantly higher under crowding conditions with TGFß-1 compared to administration of TGFß-1 alone. CONCLUSION: Crowding enhanced collagen deposition, resulting in more favorable conditions for studying fibrogenesis. This can be the first step toward developing a robust in vitro model for testing antifibrotic compounds. LEVEL OF EVIDENCE: NA.

Vocal fold fibroblast response to growth factor treatment is age dependent: results from an in vitro study.

INTRODUCTION: Vocal fold (VF) fibroblasts (VFFs) are the central target in developing new strategies for treatment of VF injury and scarring. Nevertheless, only little is known about the basic biological characteristics of these cells. The aim of this study was to explore the impact of age of VFFs on the response to external growth factor stimulation. STUDY DESIGN: In vitro cell study using a rat model. METHODS: VFFs were extracted from young and aged rat VF 3 months after establishing unilateral injury. Resulting scar fibroblasts (SFs) and normal fibroblasts (NFs) were subsequently cultured separately with or without the addition of hepatocyte growth factor (HGF). After 24 and 72 hours, the production of hyaluronic acid (HA) was examined in the supernatant culture media using enzyme-linked immunosorbent assay. RESULTS: Only cultured SF and NF from young animals could be stimulated significantly in the production of HA by HGF. Within these, average percentage increase was higher in NF compared with SF. CONCLUSION: The response of VFFs in cell culture to growth factors stimulation is highly depending on the age of the animals. This is another step in a nearer characterization of scar VFF and could furthermore be an important point when estimating the success of an intervention. Age-depending effects must be considered as an important factor in developing possible therapeutic agents for VF scarring.

Age effects on extracellular matrix production of vocal fold scar fibroblasts in rats.

Vocal fold (VF) fibroblasts are the central subject of interest in fibrogenesis and wound healing after VF injury. Scar fibroblasts (SF) exhibit an aberrant production of several extracellular matrix (ECM) components which lead either to VF fibrosis or scarless wound healing. This study aimed to investigate the role of age at the time of injury on ECM production of SF. This is designed as an animal study. VF injury was established unilaterally in eight male Sprague-Dawley rats [3 months of age (n = 4), 11 months of age (n = 4)], while the other side was left intact. Three months after injury the larynges were excised and fibroblasts were extracted from VF [normal fibroblasts (NF)­scar fibroblasts (SF)] and cultured in vitro. After first passage, VF fibroblasts were plated in 24-well plates and levels of hyaluronic acid (HA) and collagen type I were determined enzymatically from supernatant after 24 and 72 h. Cultured SF from younger animals produced significantly higher levels of HA compared to NF fibroblasts from the same animals. HA concentrations of the older animals did not differ significantly between the NF and SF cultures, but the range in SF cultures was large. In contrast to previous studies, we found that even 3 months after VF injury cultured SF from young animals expressed higher levels of HA in comparison to SF from older animals. No difference in collagen levels were observed between the younger and older animals. Age of animals is an essential factor during VF healing and has to be considered for study design.

Subjective and objective vocal parameters in women with polycystic ovary syndrome.

INTRODUCTION: Despite the relatively high prevalence of the polycystic ovary syndrome (PCOS) affecting up to 15% of all women of reproductive age, only little is known about vocal changes related to this endocrinologic disorder that is characterized by biochemical or clinical hyperandrogenism, impaired cycles, and/or polycystic ovaries. The aim of our study was to describe objective and subjective vocal changes in women with a diagnosed PCOS compared with a control group. MATERIALS AND METHODS: Our study group comprised 34 women-24 cases with confirmed PCOS and 10 controls in whom PCOS was excluded. A complete endocrinologic laboratory status was obtained by all participants; study procedures included a videolaryngostroboscopy, voice recording, and completion of the German version of the Voice Handicap Index. RESULTS: A trend toward lower mean fundamental frequency was detectable, but this failed statistical significance. No differences were found in the objective and subjective voice parameters. CONCLUSION: Elevated serum levels of androgens, as found in women with PCOS, were shown not to have an impact on the subjective and objective voice parameters.

Laryngeal electromyography: a proposal for guidelines of the European Laryngological Society.

Although recognized as a valuable diagnostic tool for more than 60 years, many laryngologists do not routinely use laryngeal electromyography (LEMG). This may be due to a persisting lack of agreement on methodology, interpretation, validity, and clinical application of LEMG. To achieve consensus in these fields, a laryngeal electromyography working group of European neurolaryngologic experts was formed in order to (1) evaluate guidelines for LEMG performance and (2) identify issues requiring further clarification. To obtain an overview of existing knowledge and research, English-language literature about LEMG was identified using Medline. Additionally, cited works not detected in the initial search were screened. Evidence-based recommendations for the performance and interpretation of LEMG and also for electrostimulation for functional evaluation were considered, as well as published reports based on expert opinion and single-institution retrospective case series. To assess the data obtained by this literature evaluation, the working group met five times and performed LEMG together on more than 20 patients. Subsequently, the results were presented and discussed at the 8th Congress of the European Laryngological Society in Vienna, Austria, September 1-4, 2010, and consensus was achieved in the following areas: (1) minimum requirements for the technical equipment required to perform and record LEMG; (2) best practical implementation of LEMG; (3) criteria for interpreting LEMG. Based on this consensus, prospective trials are planned to improve the quality of evidence guiding the proceedings of practitioners.

Prevertebral tendinitis: how to avoid unnecessary surgical interventions.

OBJECTIVES/HYPOTHESIS: Prevertebral tendinitis is an inflammatory process that affects the cervicothoracic prevertebral muscles. Because of its clinical presentation and imaging features in computed tomography scans, prevertebral tendinitis can easily be mistaken for deep cervical abscess formation. Totally different therapy regimens require clinical and diagnostic pathways for sufficient differentiation between those two pathologic entities. STUDY DESIGN: Case series with comparison. METHODS: In 10 patients with prevertebral tendinitis, we evaluated the symptoms, laboratory reports, and radiological imaging findings. We compared these data to 65 patients with a deep cervical abscess formation. The basic radiologic imaging procedure was contrast-enhanced computed tomography. For detection of prevertebral tendinitis, we performed magnetic resonance imaging with diffusion-weighted images and calculated the apparent diffusion coefficient map. RESULTS: Patients with prevertebral tendinitis complained of severe neck pain, globus sensation, and neck stiffness. Diffusion-weighted images showed a typical benign prevertebral effusion. Computed tomography scans showed amorphous calcifications in the tendon of the prevertebral muscles. The C-reactive protein values were slightly increased in patients with prevertebral tendinitis, and white blood cell count remained normal. In comparison to patients with deep cervical abscess formation, the C-reactive protein and white blood cell count was significantly lower (P < .05) in the prevertebral tendinitis cases. CONCLUSIONS: Prevertebral tendinitis should be considered when patients suffer from neck pain, neck stiffness, and globus sensations despite low signs of inflammation in the laboratory report. To confirm the diagnosis, the best imaging feature is magnetic resonance imaging with diffusion-weighted images and apparent diffusion coefficient map.

Laryngeal electromyography: electrode guidance based on 3-dimensional magnetic resonance tomography images of the larynx.

OBJECTIVES/HYPOTHESIS: Laryngeal electromyography (LEMG) is an important tool for the assessment of laryngeal nerve and muscle functioning. The purpose of the study was to determine electrode insertion angle and insertion depth for the various laryngeal muscles. METHODS: Twenty-three cadaver larynges were examined with magnetic resonance tomography (MRT) and Materialize Interactive Medical Image Control System (Leuven, Belgium) 3-dimensional (3D) imaging software. Geometrical analysis was used to calculate the electrode insertion angles. RESULTS: All laryngeal muscles could be identified and 3D visualized on MRT scans. Although the insertion angles were the same in male and female larynges, the insertion depth was significantly larger in male than in female larynges (P<0.05). Of particular clinical importance is the fact that the electrode has to be directed lateral and upward for the thyroarytenoid muscle but lateral and downward for the lateral cricoarytenoid muscle (insertion point=midline lower border of the thyroid). CONCLUSIONS: This is the first study that analyzes electrode insertion angles and insertion depths for each laryngeal muscle using 3D imaging. We hope that the information gained from this study will help clinicians performing LEMG to localize the individual laryngeal muscles.

Interactive ontology debugging: Two query strategies for efficient fault localization.

Effective debugging of ontologies is an important prerequisite for their broad application, especially in areas that rely on everyday users to create and maintain knowledge bases, such as the Semantic Web. In such systems ontologies capture formalized vocabularies of terms shared by its users. However in many cases users have different local views of the domain, i.e. of the context in which a given term is used. Inappropriate usage of terms together with natural complications when formulating and understanding logical descriptions may result in faulty ontologies. Recent ontology debugging approaches use diagnosis methods to identify causes of the faults. In most debugging scenarios these methods return many alternative diagnoses, thus placing the burden of fault localization on the user. This paper demonstrates how the target diagnosis can be identified by performing a sequence of observations, that is, by querying an oracle about entailments of the target ontology. To identify the best query we propose two query selection strategies: a simple "split-in-half" strategy and an entropy-based strategy. The latter allows knowledge about typical user errors to be exploited to minimize the number of queries. Our evaluation showed that the entropy-based method significantly reduces the number of required queries compared to the "split-in-half" approach. We experimented with different probability distributions of user errors and different qualities of the a priori probabilities. Our measurements demonstrated the superiority of entropy-based query selection even in cases where all fault probabilities are equal, i.e. where no information about typical user errors is available.

DNA repair gene ERCC2 polymorphisms and risk of squamous cell carcinoma of the head and neck.

INTRODUCTION: Genetic aberrations of DNA repair enzymes are known to be common events and to be associated with different cancer entities. Aim of the following study was to analyze the genetic association of single nucleotide polymorphisms (SNP) of the DNA repair genes with the risk of squamous cell carcinoma of the head and neck (HNSCC). MATERIALS AND METHODS: Genetic variants ERCC2 Lys751Gln (rs13181), ERCC2 Asp312Asn (rs1799793), XRCC1 Arg194Trp (rs1799782); XRCC1 Gln399Arg (rs25487), XRCC1 Arg280His (rs25489) and XRCC3 Thr241Met (rs861539) were analyzed in a primary study group comprising 169 patients with histologically confirmed HNSCC and 463 healthy control subjects. Polymorphisms associated with HNSCC were furthermore analyzed in an independent replication study including 125 HNSCC. RESULTS: Only the ERCC2 751 Gln/Gln genotype was associated with HNSCC in the primary study (p=0.033) and in the replication study (p=0.023), resulting in an overall odds ratio of 0.54 (95% confidence interval 0.35-0.92; p=0.006). CONCLUSION: Carriers of the homozygous ERCC2 751 Gln/Gln genotype may be at lower risk for HNSCC.

Vitamin D status is associated with disease-free survival and overall survival time in patients with squamous cell carcinoma of the upper aerodigestive tract.

UNLABELLED: Considerable clinical and experimental data suggest that vitamin D plays a role in pathogenesis and progression of cancer; nevertheless clinical data for head and neck squamous cell carcinoma (HNSCC) are not available. The aim of our study was to associate tumor and clinical characteristics with status of vitamin D [25-hydroxyvitamin D (25(OH)D)]. 88 patients with newly diagnosed squamous cell carcinoma of the head and neck were included in the study. A blood draw was taken at the time of diagnosis. The observation period lasted from 2006 until 2010. RESULTS: When compared to a cohort from an epidemiological study, serum levels of 25(OH)D were significantly reduced in patients with HNSCC. We furthermore found disease-free survival, as well as overall survival times to be significantly associated with 25(OH)D levels. In conclusion, results from our study suggest an influence of vitamin D status on cancer incidence, as well as on mortality of HNSCC.

Subjective breathing impairment in unilateral vocal fold paralysis.

INTRODUCTION: Dysphonia is considered a major symptom of unilateral vocal fold paralysis (UVFP). Besides this, many patients complain of further symptoms such as dysphagia and dyspnea, which might not be expected to such an extent. The aim of this survey was to elucidate these symptoms in a cohort of patients with UVFP. SUBJECTS AND METHODS: Sixty-three patients (22 men, 41 women) suffering from UVFP were interviewed. Therefore we developed a questionnaire dealing with each of the three symptom categories: voice production, swallowing and breathing. RESULTS: All of the surveyed patients reported voice impairment, almost 60% complained of swallowing problems after the onset of paralysis. Seventy-five percent reported a subjectively impaired breathing sensation, not just phonatory dyspnea but during everyday physical activity as well. DISCUSSION: Our study revealed a certain discrepancy between objectively assessed laryngoscopic findings and subjective symptoms. A majority of patients suffered from an impairment in each of the three laryngeal functions (dysphonia, dysphagia and dyspnea). The latter two differ from the classic approach to this condition but must be considered as well in clinical diagnostics and therapy.

First report of intralaminar tumorlike lipomatous lesions of the thyroid cartilage.

INTRODUCTION: We present two cases of tumorlike lipomatous lesions in the thyroid cartilage. Both presented as circumscribed tumors by ultrasonography and were identified accidentally. METHODS: Two tumorlike lesions were identified in two different patients. Additionally, computed tomography and magnetic resonance imaging scans of the laryngeal skeleton were performed. Surgery was performed in one patient, and the lesion was excised. Histopathology revealed fatty tissue with several foci of hematopoietic cells. CONCLUSION: This is the first report of intralaminar tumorlike lipomatous lesions in the thyroid cartilage. These should be included in the differential diagnoses of primary cartilaginous lesions of the laryngeal skeleton.

Biomechanics of the cricoarytenoid joint: three-dimensional imaging and vector analysis.

OBJECTIVES/HYPOTHESIS: Laryngeal framework surgery requires a good understanding of the biomechanics of the cricoarytenoid (CA) joint, the precise function of which is still only poorly understood. The aim of the study was (1) to show that, by superimposing two or more three-dimensional (3D) images, we can visualize the exact position of the arytenoid cartilages within the larynx at different phases of their movement; and (2) to demonstrate that it is possible to analyze the arytenoid cartilage movements mathematically with the help of vector analysis. STUDY DESIGN: In vitro cadaver study. METHODS: Twenty fresh and intact cadaver larynges were scanned by high-resolution computerized tomography with the arytenoid cartilages in "respiratory" position and in "phonatory" position. The two positions were superimposed and rendered in 3D with MIMICS (Materialise Interactive Medical Image Control System, Leuven, Belgium). The spatial trajectory of the arytenoid cartilage movements was calculated with vector analysis. RESULTS: The movement from the "respiratory" to the "phonatory" position has three components: (1) an inward rocking action around the longitudinal CA joint; (2) a forward sliding movement along the longitudinal axis of the CA joint; and (3) an inward rotation around a virtual axis that runs perpendicular to the CA joint axis. CONCLUSIONS: Superimposing 3D images of the larynx with the help of the software package MIMICS allows us to visualize and to analyze mathematically the trajectory of the arytenoid cartilage. The arytenoid cartilages rock inward, slide forward, and rotate inward when they move from the "respiratory" to the "phonatory" position.

The role of the cricothyroid joint anatomy in cricothyroid approximation surgery.

OBJECTIVES/HYPOTHESIS: Cricothyroid approximation (CTA) surgery aims at raising the voice pitch in male-to-female transsexuals. However, 30% of the patients are not satisfied with the result. The purpose of our study was to examine the cricothyroid joint (CTJ) biomechanics and to analyze if (and how) the CTJ anatomy influences the movement of the cricoid and, consequently, the elongation of the vocal fold and the voice pitch after CTA. METHODS: Twenty-four cadaver larynges were examined with high-resolution computerized tomography and MIMICS three-dimensional imaging software (Materialise Interactive Medical Image Control System, Leuven, Belgium). After superimposing the two scans taken in "neutral" and in "CTA" positions, vector geometrical analysis was used to determine the effective rotation axis of the CTJ and to calculate the elongation of the vocal folds after CTA. RESULTS: Our results showed that the cricoid rotates around an axis, the position of which depends on the anatomical structure of the CTJ. Based on the location of this effective rotation axis, we could distinguish three groups. In group I (N=13), the rotation axis was located in the lower third; in group II (N=5), it was located in the middle third; and in group III (N=6), it was located in the upper third of the cricoid. The elongations of the vocal fold were 12%, 8%, and 3%, in groups I, II, and III, respectively. CONCLUSIONS: The anatomical structure of the CTJ influences directly (1) the position of the effective rotation axis and (2) the elongation of the vocal folds.

Developing a 3D model of the laryngeal cartilages using HRCT data and MIMICS's segmentation software.

Discussions relating to the biomechanics of the larynx are still generally controversial. The purpose of this study is to develop a 3D model of the larynx based on high-resolution computer tomography (HRCT) data identifying and visualizing anatomical landmarks and structures of the larynx. We examined four fresh cadaver larynges with HRCT. The DICOM (Digital Imaging and Communication in Medicine) data were post-processed with the software package MIMICS for three-dimensional visualization. All relevant structures of the laryngeal cartilages could be identified on HRCT and visualized in a 3D model. We conclude that 1) HRCT provides excellent data for three-dimensional visualization of the laryngeal anatomy, and 2) the combined technology of HRCT and MIMICS is useful to study the biomechanics on 3D images and for preoperative planning of laryngeal framework surgery.