Objectives/Hypothesis:
Idiopathic subglottic stenosis (iSGS) is a disease predominantly of females that, by definition, has no known etiology. Collagen–vascular disease, localized trauma, ...extraesophageal reflux (EER), and hormonal alterations have all been postulated as potential etiologies of iSGS. It is hypothesized that iSGS is a reflux mediated disease and that evidence of EER exists in affected patients.
Study Design:
Case–control study.
Methods:
Patients with iSGS were identified prospectively over a 2.5‐year period (2007–2010). During their endoscopic management, biopsies of the subglottic scar and postcricoid area were evaluated for the presence of pepsin, an indicator of exposure to gastric refluxate. Control patients had similar biopsies while undergoing operative management for disease unrelated to reflux. Charts of both patients and controls were reviewed for clinical history of reflux, pH‐metry, and laboratory testing for collagen–vascular disease.
Results:
Twenty‐two patients with iSGS were treated. All patients were female. No patient had serology positive for collagen–vascular disease. Thirteen (59%) patients with iSGS had pepsin present in their larynx or trachea. Control patients did not have detectable pepsin in their tissue (P = .041). Dual probe 24‐hour pH studies were performed in 10 (45%) patients. These studies were positive for EER in seven patients but this did not statistically correlate to the presence of pepsin in their tissue (P = 1.0).
Conclusions:
iSGS is a disease almost exclusively of women. EER is implicated in the development of iSGS. Pepsin is detectable in the subglottic scar and larynges of patients with iSGS. Standard pH‐metry may be inadequate in predicting degree of EER in patients with iSGS.
Thyroidectomy may be performed for clinical indications that include malignancy, benign nodules or cysts, suspicious findings on fine needle aspiration biopsy, dysphagia from cervical esophageal ...compression, or dyspnea from airway compression. About 1 in 10 patients experience temporary laryngeal nerve injury after surgery, with longer lasting voice problems in up to 1 in 25. Reduced quality of life after thyroid surgery is multifactorial and may include the need for lifelong medication, thyroid suppression, radioactive scanning/treatment, temporary and permanent hypoparathyroidism, temporary or permanent dysphonia postoperatively, and dysphagia. This clinical practice guideline provides evidence-based recommendations for management of the patient's voice when undergoing thyroid surgery during the preoperative, intraoperative, and postoperative period.
The purpose of this guideline is to optimize voice outcomes for adult patients aged 18 years or older after thyroid surgery. The target audience is any clinician involved in managing such patients, which includes but may not be limited to otolaryngologists, general surgeons, endocrinologists, internists, speech-language pathologists, family physicians and other primary care providers, anesthesiologists, nurses, and others who manage patients with thyroid/voice issues. The guideline applies to any setting in which clinicians may interact with patients before, during, or after thyroid surgery. Children under age 18 years are specifically excluded from the target population; however, the panel understands that many of the findings may be applicable to this population. Also excluded are patients undergoing concurrent laryngectomy. Although this guideline is limited to thyroidectomy, some of the recommendations may extrapolate to parathyroidectomy as well.
The guideline development group made a strong recommendation that the surgeon should identify the recurrent laryngeal nerve(s) during thyroid surgery. The group made recommendations that the clinician or surgeon should (1) document assessment of the patient's voice once a decision has been made to proceed with thyroid surgery; (2) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, if the patient's voice is impaired and a decision has been made to proceed with thyroid surgery; (3) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, once a decision has been made to proceed with thyroid surgery if the patient's voice is normal and the patient has (a) thyroid cancer with suspected extrathyroidal extension, or (b) prior neck surgery that increases the risk of laryngeal nerve injury (carotid endarterectomy, anterior approach to the cervical spine, cervical esophagectomy, and prior thyroid or parathyroid surgery), or (c) both; (4) educate the patient about the potential impact of thyroid surgery on voice once a decision has been made to proceed with thyroid surgery; (5) inform the anesthesiologist of the results of abnormal preoperative laryngeal assessment in patients who have had laryngoscopy prior to thyroid surgery; (6) take steps to preserve the external branch of the surperior laryngeal nerve(s) when performing thyroid surgery; (7) document whether there has been a change in voice between 2 weeks and 2 months following thyroid surgery; (8) examine vocal fold mobility or refer the patient for examination of vocal fold mobility in patients with a change in voice following thyroid surgery; (9) refer a patient to an otolaryngologist when abnormal vocal fold mobility is identified after thyroid surgery; (10) counsel patients with voice change or abnormal vocal fold mobility after thyroid surgery on options for voice rehabilitation. The group made an option that the surgeon or his or her designee may monitor laryngeal electromyography during thyroid surgery. The group made no recommendation regarding the impact of a single intraoperative dose of intravenous corticosteroid on voice outcomes in patients undergoing thyroid surgery.
Objectives/Hypothesis
The natural clinical progression of aspiration to eventual pulmonary compromise is not well understood. We hypothesized that dietary modification recommendations, ...Penetration‐Aspiration Scale (PAS) score, and dysphagia etiology would be associated with changes in time to first pulmonary event and overall survival for patients with documented aspiration on radiologic testing. This study identified a cohort of patients with detectable unsensed penetration or aspiration on videofluoroscopic swallowing study (VFSS), and followed this cohort over time for development of pulmonary events and death. We then evaluated the association of aspiration severity and dietary modification recommendations on incidence of these endpoints.
Study Design
Retrospective chart review.
Methods
A total of 2,616 VFSS exam reports were reviewed from our institution performed between January 1, 2009 and December 31, 2010. Aspiration or unsensed penetration (PAS of 5 or greater) was detected in 564 (21.5%) of these patients, who were then included in the study cohort. Medical records were reviewed retrospectively for development of pulmonary events (pneumonia, pneumonitis, or other life‐threatening pulmonary illness) and all‐cause mortality for up to 54 months after initial VFSS. Univariate Kaplan‐Meier analysis and multivariate Cox regression were performed for time to first pulmonary event and survival predicted by recommended diet, PAS score, and dysphagia etiology.
Results
Dysphagia etiology was highly associated with increased development of pulmonary events for some patients, especially those with generalized nonspecific dysphagia due to deconditioning or frailty (hazard ratio HZ vs. stroke 2.95, 95% confidence interval CI: 1.53‐5.69, P = .001) and esophageal dysphagia (HZ: 2.66, 95% CI: 1.17‐6.02, P = .019). Dysphagia etiology was also associated with increased mortality for patients with generalized nonspecific dysphagia due to deconditioning or frailty (HZ: 3.32, 95% CI: 2.0‐5.52, P < .001), postsurgical patients (HZ: 1.73, 95% CI: 1.05‐2.86, P = .032), and chronic neurologic disease (HZ: 1.87, 95% CI: 1.12‐3.13, P = .017). Dietary modification recommendations at the time of VFSS (prohibition of oral intake or modification of food consistency) had no significant impact on time to first pulmonary event (P = .37) or survival (P = .17), whereas PAS score was associated with decreased time to first pulmonary event on univariate but not multivariate analysis (HZ for 1‐point increase: 1.6, 95% CI: 0.99‐1.36, P = .067). Kaplan‐Meier estimate of overall 3‐year mortality for this patient cohort was 39%.
Conclusions
Etiology of dysphagia is associated with a higher mortality rate and development of pulmonary events in patients with unsensed penetration or aspiration on VFSS, especially for those patients with generalized deconditioning and frailty or esophageal dysphagia. Severity of aspiration as defined by PAS was not associated with altered overall survival. Recommendations for dietary modification to a nothing by mouth status or modified food consistency had no statistically significant association with development of pulmonary events or survival in patients with detectable unsensed penetration or aspiration on VFSS compared to full‐diet recommendation.
Level of Evidence
4. Laryngoscope, 127:S1–S10, 2017
Objective
To evaluate the efficacy of distal esophageal mean nocturnal baseline impedance (MNBI), a general marker of esophageal mucosal barrier integrity, in predicting laryngopharyngeal reflux ...(LPR) and symptomatic response to acid reflux therapy.
Methods
This retrospective study analyzed 173 patients who presented with symptoms of laryngopharyngeal reflux and underwent 24‐h multichannel intraluminal impedance‐pH (MII‐pH) testing. Mean nocturnal baseline impedance values were calculated and assessed for their association and ability to predict LPR symptoms, MII‐pH results, treatment response, and other markers of LPR.
Results
Notably, 153 of the 173 patients were tested off acid suppression medication and included in statistical analysis. Based on the MII‐pH probe data, 108 (71%) patients had LPR, 8 (5%) had gastroesophageal reflux disease (GERD), and 37 (24%) were without pathologic reflux. Distal esophageal MNBI of LPR patients was significantly lower in LPR patients than patients with negative studies (1332 ± 94.8 vs. 2158 ± 173.5, p = 0.001). Among 118 patients who trialed antireflux therapy, a distal esophageal MNBI cutoff value of <1580 Ω was an independent predictor of treatment response (OR = 4.148 1.877–9.189). This value better predicted improvement with antireflux therapy for LPR than other objective MII‐pH probe data, which were not independent predictors of treatment response.
Conclusion
Distal esophageal MNBI values may have value in the diagnosis of LPR and potentially predict medication responsiveness in LPR patients.
Level of Evidence
3 Laryngoscope, 134:4071–4077, 2024
Mean nocturnal baseline impedance (MNBI) is a value calculated on multichannel intraluminal impedance‐pH studies and provides a functional measure of the esophageal epithelial barrier. MNBI has been shown to help with the diagnosis, characterization, and management of patients with gastroesophageal reflux disease. We analyzed its utility in patients with laryngopharyngeal reflux (LPR) symptoms and found it to be predictive of LPR and responsiveness to antireflux treatment.
Objectives
Mean nocturnal baseline impedance (MNBI) is a measure of the esophageal epithelial barrier function calculated via high‐resolution impedance manometry and can be used as a diagnostic tool ...and treatment response predictor for gastroesophageal reflux disease (GERD). However, its utility for laryngopharyngeal reflux (LPR) has been minimally studied. We aimed to investigate the relationship of MNBI between patients with suspected LPR, healthy controls, and their 24‐h multichannel intraluminal impedance‐pH (MII‐pH) study results.
Methods
Retrospective patient series analysis was performed of patients with suspected LPR and healthy controls who underwent 24‐h MII‐pH monitoring. MNBI values were calculated from impedance channels at the level of the hypopharynx, proximal esophagus, and distal esophagus. We compared these MNBI values between the subject groups with secondary analysis on MII‐pH results, reflux symptom index, reflux findings score, DeMeester score, and salivary pepsin levels.
Results
Twenty‐three patients with suspected LPR and 14 healthy controls were enrolled. Decreased distal esophageal MNBI was found to be significantly decreased in patients with suspected LPR compared with healthy controls (p < 0.01) and in subjects with positive MII‐pH studies compared to negative MII‐pH studies (p < 0.01). There were no significant correlations of MNBI at the hypopharynx or proximal esophagus.
Conclusion
Distal esophageal MNBI has significant correlations with many phenotypic and biological markers of LPR. These findings indicate that MNBI has the potential to be applied to LPR, similar to its emerging use as a diagnostic tool and treatment response predictor for GERD.
Level of Evidence
3 Laryngoscope, 133:1927–1932, 2023
Mean nocturnal baseline impedance (MNBI) is a functional measure of the esophageal epithelial barrier that can be easily calculated from intraluminal impedance studies. MNBI has been shown to be beneficial in the evaluation of gastroesophageal reflux disease, but there is limited data on its use for laryngopharyngeal reflux (LPR). Our study found a significant correlation between LPR symptoms and a decreased MNBI at the distal esophageal, which signifies diminished integrity of the mucosa.
Minimal data exist to define the use of contemporary dual pH with multichannel intraluminal impedance (MII) probes integrating both pharyngeal acid and impedance sensors to evaluate laryngopharyngeal ...reflux (LPR) symptoms in a laryngology clinic population. This study was performed to review a series of patients tested with dual pH-MII for suspected LPR symptoms and to analyze pH-MII data findings for this patient cohort.
Case series with planned data collection.
Tertiary laryngology clinic.
Patients with symptoms suggestive of possible LPR (dysphonia, chronic cough, globus sensation, subglottic stenosis,) were evaluated with a dual pH-MII system, as well as previously validated reflux finding score (RFS) and reflux symptom index (RSI) instruments.
A total of 109 patients were evaluated with dual pH-MII studies between 2010 and 2015, with 51 (47%) studies interpreted as "positive" for evidence of significant LPR, 43 (39%) as "negative," and 15 (14%) as "equivocal." Dual pH-MII data analysis showed that positive studies had an average of 2.84 pharyngeal acid exposures below pH 4 (vs 0.28 for negative) and 46 episodes of proximal reflux exposure (either acid or nonacid) by impedance detection (vs 30.6 for negative). RSI scores were significantly different between positive and negative studies, while RFS scores were not.
Dual pH-MII analysis is a useful supplementary tool to provide objective evidence of pharyngeal reflux exposure in patients with suspected LPR. RSI scores appear to correlate with objective evidence of acid exposure in the pharynx, while RFS scores do not.
Objectives
Idiopathic subglottic stenosis (iSGS) is commonly characterized by laryngeal fibrosis thought to arise by epithelia‐mesenchymal transition (EMT) induced by chronic inflammation. Pepsin is ...a potent inducer of inflammation in the airways during chronic laryngopharyngeal reflux and has been observed in the subglottic mucosa of patients with iSGS, absent in normal mucosa. The aim of this study was to examine the effect of pepsin on mechanisms of EMT in laryngeal cells with implications for iSGS.
Study Design
In vitro translational research study.
Methods
Human laryngeal epithelial cell cultures were exposed to 0.1 mg/mL or 1.0 mg/mL pepsin at pH7 for 24 and 48 hours, or media pH5 ± 0.1 mg/mL pepsin for 10 minutes and harvested after 24 and 48 hours. EMT marker expression was measured by qPCR and enzyme‐linked immunosorbent assays. Wound‐healing scratch assay was performed on immortalized human vocal fold fibroblasts pretreated with media pH5 ± 0.1 mg/mL pepsin (10 minutes) or continuously treated with media pH7 ± 0.1 to 1 mg/mL pepsin for 24 hours.
Results
Pepsin yielded no effect on MMP1, MMP9, FN1, COL1A1, HAS2, or CDH1 gene expression or matrix metalloproteinase‐9 or fibronectin protein expression, either alone or in the presence of weak acid. Pepsin and/or acid produced no effect on fibroblast migration.
Conclusion
Whereas pepsin has been shown to be present in the subglottic mucosa of patients with iSGS, this in vitro acute exposure investigation does not provide evidence of a direct causal role for development of fibrosis in subglottic epithelial cell cultures.
Levels of Evidence
NA. Laryngoscope, 130:154–158, 2020
Objective
Laryngopharyngeal reflux (LPR) is a common affliction that contributes to laryngeal inflammation, symptoms that impact quality of life, and life‐threatening illnesses such as cancer. ...Effective treatment strategies for LPR are lacking. Pepsin is a proinflammatory and carcinogenic element of refluxate. Investigation of molecular pathways involved in pepsin‐mediated damage may lead to identification of novel biomarkers and therapeutic targets for LPR. In this study, RNA sequencing was used to examine changes in human laryngeal epithelial cells following brief pepsin insult. Cells were immortalized to generate a model to aid future study of laryngeal injury and therapeutics.
Study Design
In vitro translational.
Methods
Laryngeal epithelial cells were cultured from a patient without signs or symptoms of LPR or laryngeal cancer. Cells were treated with 0.1 mg/ml pepsin for 1 hour or normal growth media (control) prior to RNA sequencing. Cells were immortalized via HPV E6/7 and characterized by microscopy, immunohistochemistry, G‐banding, and soft agar assay.
Results
Three hundred ninety‐seven genes exhibited differences in expression with pepsin treatment (P < .05). Pathway analysis revealed association with cancer and related signaling processes including dysregulation of cancer‐associated molecules, Metastasis‐Associated Lung Adenocarcinoma Transcript 1 and KRT82, and the long‐noncoding RNA, lipoprotein receptor‐related protein 1 (LRP1)–AS, which regulates the putative pepsin receptor LRP1.
Conclusions
A single, brief exposure to pepsin activated cancer‐associated signaling pathways in laryngeal cells in vitro, revealing novel mechanisms by which chronic reflux may contribute to carcinogenesis. The cell line developed herein represents a novel tool in which to investigate pepsin‐dysregulated pathways identified by RNA sequencing and disparities of tumor proneness of laryngeal subsites.
Level of Evidence
N/A Laryngoscope, 131:121–129, 2021
Objective/Hypothesis:
Laryngopharyngeal reflux (LPR) is thought to be a significant risk factor for laryngeal squamous cell carcinoma (SCC), but causality has never been proven. It is accepted that ...chronic reflux into the esophagus can induce metaplastic changes in esophageal mucosa with subsequent increased risk of esophageal adenocarcinoma, but no similar associations have been established for LPR and laryngopharyngeal SCC. The objective of this study was to test the hypothesis that reflux of pepsin into the laryngopharynx can promote carcinogenesis.
Study Design:
Translational research study.
Methods:
Normal human laryngeal primary epithelial cell cultures and hypopharyngeal FaDu SCC cells were exposed to human pepsin and analyzed by Human Cancer PathwayFinder and miRNA Superarrays, flow cytometry, and Western blot to determine the effect of pepsin on carcinogenesis. Laryngeal biopsy specimens taken from cancer patients and normal control subjects were analyzed for the presence of pepsin by Western blot.
Results:
Microarray analysis demonstrated that pepsin significantly altered the expression of 27 genes implicated in carcinogenesis and also affected the expression of 22 microRNAs known to be altered in human head and neck cancers. Pepsin increased proliferation in both FaDu SCC cells and cultured normal laryngeal epithelial primary cells by increasing S phase distribution on flow cytometry analysis in a time‐ and dose‐dependent manner. Furthermore, pepsin was detected in 60% (3/5) human laryngeal cancer biopsies, absent in all (0/5) normal control specimens.
Conclusions:
These data support a role for refluxed pepsin in the promotion of epithelial proliferation and carcinogenesis of the larynx and pharynx. Laryngoscope, 2012
A roadblock for research on adductor spasmodic dysphonia (ADSD), abductor SD (ABSD), voice tremor (VT), and muscular tension dysphonia (MTD) is the lack of criteria for selecting patients with these ...disorders.
To determine the agreement among experts not using standard guidelines to classify patients with ABSD, ADSD, VT, and MTD, and develop expert consensus attributes for classifying patients for research.
From 2011 to 2016, a multicenter observational study examined agreement among blinded experts when classifying patients with ADSD, ABSD, VT or MTD (first study). Subsequently, a 4-stage Delphi method study used reiterative stages of review by an expert panel and 46 community experts to develop consensus on attributes to be used for classifying patients with the 4 disorders (second study). The study used a convenience sample of 178 patients clinically diagnosed with ADSD, ABSD, VT MTD, vocal fold paresis/paralysis, psychogenic voice disorders, or hypophonia secondary to Parkinson disease. Participants were aged 18 years or older, without laryngeal structural disease or surgery for ADSD and underwent speech and nasolaryngoscopy video recordings following a standard protocol.
Speech and nasolaryngoscopy video recordings following a standard protocol.
Specialists at 4 sites classified 178 patients into 11 categories. Four international experts independently classified 75 patients using the same categories without guidelines after viewing speech and nasolaryngoscopy video recordings. Each member from the 4 sites also classified 50 patients from other sites after viewing video clips of voice/laryngeal tasks. Interrater κ less than 0.40 indicated poor classification agreement among rater pairs and across recruiting sites. Consequently, a Delphi panel of 13 experts identified and ranked speech and laryngeal movement attributes for classifying ADSD, ABSD, VT, and MTD, which were reviewed by 46 community specialists. Based on the median attribute rankings, a final attribute list was created for each disorder.
When classifying patients without guidelines, raters differed in their classification distributions (likelihood ratio, χ2 = 107.66), had poor interrater agreement, and poor agreement with site categories. For 11 categories, the highest agreement was 34%, with no κ values greater than 0.26. In external rater pairs, the highest κ was 0.23 and the highest agreement was 38.5%. Using 6 categories, the highest percent agreement was 73.3% and the highest κ was 0.40. The Delphi method yielded 18 attributes for classifying disorders from speech and nasolaryngoscopic examinations.
Specialists without guidelines had poor agreement when classifying patients for research, leading to a Delphi-based development of the Spasmodic Dysphonia Attributes Inventory for classifying patients with ADSD, ABSD, VT, and MTD for research.
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