Distinct Clinical Physiologic Phenotypes of Patients With Laryngeal Symptoms Referred for Reflux Evaluation.

BACKGROUND & AIMS: Heterogeneous presentations and disease mechanisms among patients with laryngeal symptoms account for misdiagnosis of laryngopharyngeal reflux (LPR), variations in testing, and suboptimal outcomes. We aimed to derive phenotypes of patients with laryngeal symptoms based on clinical and physiologic data and to compare characteristics across phenotypes. METHODS: A total of 302 adult patients with chronic laryngeal symptoms were prospectively enrolled at 3 centers between January 2018 to October 2020 (age 57.2 ± 15.2 years; 30% male; body mass index 27.2 ± 6.0 kg/m2). Discriminant analysis of principal components (DAPC) was applied to 12 clinical and 11 physiologic variables collected in stable condition to derive phenotypic groups. RESULTS: DAPC identified 5 groups, with significant differences across symptoms, hiatal hernia size, and number of reflux events (P < .01). Group A had the greatest hiatal hernia size (3.1 ± 1.0 cm; P < .001) and reflux events (37.5 ± 51; P < .001), with frequent cough, laryngeal symptoms, heartburn, and regurgitation. Group B had the highest body mass index (28.2 ± 4.6 kg/m2; P < .001) and salivary pepsin (150 ± 157 ng/mL; P = .03), with frequent cough, laryngeal symptoms, globus, heartburn, and regurgitation. Group C frequently reported laryngeal symptoms (93%; P < .001), and had fewest esophageal symptoms (9.6%; P < .001) and reflux events (10.7 ± 11.0; P < .001). Group D commonly reported cough (88%; P < .001) and heartburn. Group E (18%) was oldest (62.9 ± 14.3 years; P < .001) and distinguished by highest integrated relaxation pressure. CONCLUSIONS: DAPC identified distinct clinicophysiologic phenotypes of patients with laryngeal symptoms referred for reflux evaluation: group A, LPR and gastroesophageal reflux disease (GERD) with hiatal hernia; group B, mild LPR/GERD; group C, no LPR/No GERD; group D, reflex cough; and group E, mixed/possible obstructive esophagogastric junction. Phenotypic differences may inform targeted clinical trials design and improve outcomes.

Upper Esophageal Sphincter Compression Device as an Adjunct to Proton Pump Inhibition for Laryngopharyngeal Reflux.

BACKGROUND: The Reflux Band, an external upper esophageal sphincter (UES) compression device, reduces esophago-pharyngeal reflux events. This study aimed to assess device efficacy as an adjunct to proton pump inhibitor (PPI) therapy in patients with laryngopharyngeal reflux (LPR). METHODS: This two-phase prospective clinical trial enrolled adults with at least 8 weeks of laryngeal symptoms (sore throat, throat clearing, dysphonia) not using PPI therapy at two tertiary care centers over 26 months. Participants used double dose PPI for 4 weeks in Phase 1 and the external UES compression device nightly along with PPI for 4 weeks in Phase 2. Questionnaire scores and salivary pepsin concentration were measured throughout the study. The primary endpoint of symptom response was defined as reflux symptom index (RSI) score ≤ 13 and/or > 50% reduction in RSI. RESULTS: Thirty-one participants completed the study: 52% male, mean age 47.9 years (SD 14.0), and mean body mass index (BMI) 26.2 kg/m2 (5.1). Primary endpoint was met in 11 (35%) participants after Phase 1 (PPI alone) and 17 (55%) after Phase 2 (Device + PPI). Compared to baseline, mean RSI score (24.1 (10.9)) decreased at end of Phase 1 (PPI alone) (21.9 (9.7); p = 0.06) and significantly decreased at end of Phase 2 (Device + PPI) (15.5 (10.3); p < 0.01). Compared to non-responders, responders to Device + PPI had a significantly lower BMI (p = 0.02) and higher salivary pepsin concentration (p = 0.01). CONCLUSION: This clinical trial highlights the potential efficacy of the external UES compression device (Reflux Band) as an adjunct to PPI for patients with LPR (ClinicalTrials.Gov NCT03619811).

Sentinel lymph node biopsy in cutaneous melanoma of the head and neck using the indocyanine green SPY Elite system.

PURPOSE: Lymph node status is the single most important prognostic factor for patients with early-stage cutaneous melanoma. Sentinel lymph node biopsy (SLNB) has become the standard of care for intermediate depth melanomas. Modern SLNB implementation includes technetium-99 lymphoscintigraphy combined with local administration of a vital blue dye. However, sentinel lymph nodes may fail to localize in some cases and false-negative rates range from 0 to 34%. Here we demonstrate the feasibility of a new sentinel lymph node biopsy technique using indocyanine green (ICG) and the SPY Elite near-infrared imaging system. MATERIALS AND METHODS: Cases of primary cutaneous melanoma of the head and neck without locoregional metastasis, underwent SLNB at a single quaternary care institution between May 2016 and June 2017. Intraoperatively, 0.25 mL of ICG was injected intradermal in 4 quadrants around the primary lesion. 10-15 minute circulation time was permitted. SPY Elite identified the sentinel lymph node within the nodal basin marked by lymphoscintigraphy. Target first echelon lymph nodes were confirmed with a gamma probe and ICG fluorescence. RESULTS: 14 patients were included with T1a to T4b cutaneous melanomas. Success rates for sentinel lymph node identification using lymphoscintigraphy and the SPY Elite system were both 86%. Zero false negatives occurred. Median length of follow-up was 323 days. CONCLUSIONS: In this pilot study, Indocyanine green near-infrared fluorescence demonstrates a safe, and facile method of sentinel lymph node biopsy for cutaneous melanoma of the head and neck compared with lymphoscintigraphy and vital blue dyes.

Israel rake retractor modification to improve exposure during oropharyngeal surgery on patients with larger body habitus.

PURPOSE: Elective oropharyngeal surgery including tonsillectomy and uvulopalatopharyngoplasty performed for obstructive sleep apnea is increasingly performed on patients of larger body habitus. The use of the Crowe-Davis retractor in such patients may be complicated by a large barrel-chest making it difficult to anchor the retractor to the Mayo stand for suspension limiting oropharyngeal exposure. Here, we present a simple modification using the Israel Retractor to facilitate suspension of the Crowe-Davis mouth gag. METHODS: Operational instructions were followed for Israel retractor modification in oropharyngeal surgery. RESULTS: The Crowe-Davis retractor is able to anchor to the Israel retractor, whose prongs articulate on the Mayo Stand for suspension. This extension allows suspension of patients with larger body habitus in oropharyngeal surgery. CONCLUSIONS: Use of the Israel retractor as an extension of the Crowe-Davis retractor handle provides an easy, quick, safe, and reliable method for placing patients of larger body habitus into suspension.

Hypopharyngeal venous malformation presenting with foreign body sensation and dysphagia.

OBJECTIVE: Review the importance of imaging selection and clinicoanatomic correlation for a vascular malformations presenting with unique symptomatology. METHODS: Case study and literature review. RESULTS: A 64-year-old female presented with globus and dysphagia ongoing for 40 years. Esophagogastroduodenoscopy discovered a hypopharyngeal mass. A CT scan showed a soft tissue mass with shotty calcifications. Flexible laryngoscopy revealed a bluish compressible mass. MRI showed T2 hyperintensity with heterogeneous enhancement resulting in the diagnosis of a low-flow vascular malformation. CONCLUSIONS: All globus is not equal. Attention to symptoms, anatomy, and imaging selection is crucial for the diagnosis and treatment of vascular malformations uniquely presenting with dysphagia.

A Tracheostomy Support Device to Reduce Tracheostomy-Related Pressure Injury.

BACKGROUND: Tracheostomies provide many advantages for the care of patients who are critically ill but may also result in complications, including tracheostomy-related pressure injuries. Research efforts into the prevention of these pressure injuries has resulted in specialized clinical care teams and pathways. These solutions are expensive and labor intensive, and fail to target the root cause of these injuries; namely, pressure at the device-skin interface. Here we measure that pressure directly and introduce a medical device, the tracheostomy support system, to reduce it. METHODS: This was a cross-sectional study of 21 subjects in the ICU, each with a tracheostomy tube connected to a ventilator. A force-sensing resistor was used to measure baseline pressures at the device-skin interface along the inferior flange. This pressure was then measured again with the use of the tracheostomy support system in the inactive and active states. Resultant pressures and demographics were compared. RESULTS: Fifteen male and 6 female subjects, with an average age of 47 ± 14 (mean ± SD) years, were included in this study. Average pressures at the tracheostomy-skin interface at baseline in these 21 ICU subjects were 273 ± 115 (mean ± SD) mm Hg. Average pressures were reduced by 59% (median 62%, maximum 98%) with the active tracheostomy support system to 115 ± 83 mm Hg (P < .001). All the subjects tolerated the tracheostomy support system without issue. CONCLUSIONS: Despite best clinical practice, pressure at the tracheostomy-skin interface can remain quite high. Here we provide measures of this pressure directly and show that a tracheostomy support system can be effective at minimizing that pressure.

Validation of a 3D-Printed Silicone-Based Laryngeal Model for Resident Education.

OBJECTIVE: We sought to validate a laryngeal simulation model and subsequently demonstrate its efficacy in improving surgical technique. STUDY DESIGN: Pre-post interventional study. SETTING: Otolaryngology Program at a Tertiary Care Center. METHODS: A low-cost, high-fidelity laryngeal model was created using a 3-dimensional-printed cast and multilayered silicone to mimic vocal fold lesions. Participants (attendings and trainees) were first given a series of tasks including mucosal vocal fold lesion resection and microflap excision of a submucosal lesion. Trainees were then provided with an instructional video from a laryngologist and asked to repeat the same tasks on the model. Performance data was then assessed using validated surveys and blinded expert reviewers. RESULTS: Eighteen participants completed the simulation. All subjects agreed that the "simulation experience was useful" and 93% agreed "the simulator helped improve my ability to do microsurgical tasks." In the postinstruction self-evaluation, trainees reported a significant decrease in mental demand (95% confidence interval [CI]: 0.37-0.91; P = .038) and significant increase in subjective performance (95% CI: 1.51-51.89; P = .016) compared to the preinstruction self-evaluation. On the postinstruction attempt, there was a significant improvement in all domains of the adapted objective structured assessment of technical skills as measured by 3 blinded, expert reviewers. DISCUSSION: This study demonstrates the usefulness of a silicone larynx model and the value of instructional video in developing laryngeal microsurgical skills. Participants positively reviewed the laryngeal model and trainees saw both a subjective and objective improvement indicating tangible operative benefits from the use of this laryngeal simulation.

Immunomodulatory extracellular matrix hydrogel induces tissue regeneration in a model of partial glossectomy.

While oropharyngeal cancer treatment regimens, including surgical resection, irradiation, and chemotherapy, are effective at removing tumors, they lead to muscle atrophy, denervation, and fibrosis, contributing to the pathogenesis of oropharyngeal dysphagia - difficulty swallowing. Current standard of care of rehabilitative tongue strengthening and swallowing exercises is ineffective. Here, we evaluate an alternative approach utilizing an acellular and injectable biomaterial to preserve muscle content and reduce fibrosis of the tongue after injury. Skeletal muscle extracellular matrix (SKM) hydrogel is fabricated from decellularized porcine skeletal muscle tissue. A partial glossectomy injury in the rat is used to induce tongue fibrosis, and SKM hydrogels along with saline controls are injected into the site of scarring two weeks after injury. Tissues are harvested at 3 and 7 days post-injection for gene expression and immunohistochemical analyses, and at 4 weeks post-injection to evaluate histomorphological properties. SKM hydrogel reduces scar formation and improves muscle regeneration at the site of injury compared to saline. SKM additionally modulates the immune response towards an anti-inflammatory phenotype. This study demonstrates the immunomodulatory and tissue-regenerative capacity of an acellular and minimally invasive ECM hydrogel in a rodent model of tongue injury.

Voice Outcomes From Direct Vocal Fold Testosterone Injections, a Case Report.

Here we provide the first demonstration of targeted vocal fold testosterone injection to achieve voice masculinization in 2 transgender male patients. Successful voice outcome was achieved in 2-3 weeks, without side effects, and continues to be durable. Laryngoscope, 133:1211-1213, 2023.

Leave No Stone Unturned: A Case of an Actinomyces Rhinolith Presenting With Chronic Cough and Throat Pain.

Actinomycosis infection in the nasal cavity, especially an actinomyces rhinolith, is extremely rare. It should be considered in cases where a heterogenous calcified mass is found within the nasal cavity on endoscopy and radiographically. Treatment includes surgical debridement and a prolonged course of antibiotics, unique from the more typically encountered fungus ball. This case highlights the broad differential for chronic cough and throat pain and the importance of considering sinonasal contributions to throat symptoms.

Beyond CPAP: modifying upper airway output for the treatment of OSA.

Obstructive Sleep Apnea (OSA) is exceedingly common but often under-treated. Continuous positive airway pressure (CPAP) has long been considered the gold standard of OSA therapy. Limitations to CPAP therapy include adherence and availability. The 2021 global CPAP shortage highlighted the need to tailor patient treatments beyond CPAP alone. Common CPAP alternative approaches include positional therapy, mandibular advancement devices, and upper airway surgery. Upper airway training consists of a variety of therapies, including exercise regimens, external neuromuscular electrical stimulation, and woodwind instruments. More invasive approaches include hypoglossal nerve stimulation devices. This review will focus on the approaches for modifying upper airway muscle behavior as a therapeutic modality in OSA.

Endotracheal tube forces exerted on the larynx and a novel support device to reduce it.

Objective: Endotracheal tubes (ETTs) are commonly associated with laryngeal injury that may be short lasting and temporary or more severe and life altering. Injury is believed to result from forces that these ETTs exert on the larynx. Here we quantify the forces of ETTs of various sizes on the laryngotracheal complex to gain a more quantitative understanding of these potential damaging forces. Here we also perform preclinical testing of a novel support device to offload these forces. Methods: Endotracheal intubation was performed on a fresh human cadaver using various ETT sizes. A strain-sensitive graphene nanosheet sensor and a commercially available force sensing resistor were secured behind the larynx, anterior to the prevertebral fascia. The forces exerted on the larynx were measured for each of the commonly used ETTs. A novel support device, ETT clip (Endo Clip), was attached to the ETTs and changes in these forces were observed. Results: Forces exerted on the laryngotracheal complex by various ETTs were observed to increase with increasing tube size. This pressure can be significantly reduced with a novel ETT clip. Conclusion: Here we demonstrate the first quantitative measurement of forces that ETTs exert on the larynx. We demonstrate a novel device that can easily clip onto an ETT reducing pressure on the laryngotracheal complex. This preclinical test paves the way for a human clinical trial. Level of evidence: 5.

Noninvasive brain stimulation in traumatic brain injury.

OBJECTIVE: To review novel techniques of noninvasive brain stimulation (NBS), which may have value in assessment and treatment of traumatic brain injury (TBI). METHODS: Review of the following techniques: transcranial magnetic stimulation, transcranial direct current stimulation, low-level laser therapy, and transcranial Doppler sonography. Furthermore, we provide a brief overview of TMS studies to date. MAIN FINDINGS: We describe the rationale for the use of these techniques in TBI, discuss their possible mechanisms of action, and raise a number of considerations relevant to translation of these methods to clinical use. Depending on the stimulation parameters, NBS may enable suppression of the acute glutamatergic hyperexcitability following TBI and/or counter the excessive GABAergic effects in the subacute stage. In the chronic stage, brain stimulation coupled to rehabilitation may enhance behavioral recovery, learning of new skills, and cortical plasticity. Correlative animal models and comprehensive safety trials seem critical to establish the use of these modalities in TBI. CONCLUSIONS: Different forms of NBS techniques harbor the promise of diagnostic and therapeutic utility, particularly to guide processes of cortical reorganization and enable functional restoration in TBI. Future lines of safety research and well-designed clinical trials in TBI are warranted to determine the capability of NBS to promote recovery and minimize disability.

Translational neuromodulation: approximating human transcranial magnetic stimulation protocols in rats.

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a well-established clinical protocol with numerous potential therapeutic and diagnostic applications. Yet, much work remains in the elucidation of TMS mechanisms, optimization of protocols, and in development of novel therapeutic applications. As with many technologies, the key to these issues lies in the proper experimentation and translation of TMS methods to animal models, among which rat models have proven popular. A significant increase in the number of rat TMS publications has necessitated analysis of their relevance to human work. We therefore review the essential principles for the approximation of human TMS protocols in rats as well as specific methods that addressed these issues in published studies. MATERIALS AND METHODS: We performed an English language literature search combined with our own experience and data. We address issues that we see as important in the translation of human TMS methods to rat models and provide a summary of key accomplishments in these areas. RESULTS: An extensive literature review illustrated the growth of rodent TMS studies in recent years. Current advances in the translation of single, paired-pulse, and repetitive stimulation paradigms to rodent models are presented. The importance of TMS in the generation of data for preclinical trials is also highlighted. CONCLUSIONS: Rat TMS has several limitations when considering parallels between animal and human stimulation. However, it has proven to be a useful tool in the field of translational brain stimulation and will likely continue to aid in the design and implementation of stimulation protocols for therapeutic and diagnostic applications.

The Feasibility of Outpatient Type I Thyroplasty with Laryngeal Reinnervation.

Type I thyroplasty has increasingly been performed on an outpatient basis. Laryngeal reinnervation is recognized for its long-term and functional benefits but is typically performed inpatient under general anesthesia. Herein we report the first published outpatient type I thyroplasty with laryngeal reinnervation performed under monitored anesthesia care (MAC). Three adults underwent type I thyroplasty with ansa cervicalis to recurrent laryngeal nerve (RLN) reinnervation. A 23-year-old female with a history of generalized idiopathic epilepsy s/p vagal nerve stimulator implantation presented with persistent dysphonia. She developed longstanding left vocal fold paralysis. She underwent left type I thyroplasty with silastic implant and ansa cervicalis to RLN neurorrhaphy under MAC-local anesthesia. The patient was discharged home on the day of surgery. Two additional patients underwent the same procedure, including a 58-year-old male with postsurgical dysphonia who was admitted for overnight observation due to a small amount of incisional crepitus and a 23-year-old female with postsurgical vocal cord paralysis who was admitted overnight due to multiple comorbidities. Both were discharged on post-operative day one without issue and demonstrated improvement in voice at follow up. Outpatient type I thyroplasty with laryngeal reinnervation under MAC is feasible with proper patient selection.

Patient-worn endoscopy mask to protect against viral transmission.

OBJECTIVES: To design and evaluate patient-worn personal protective equipment (PPE) that allows providers to perform endoscopy while protecting against droplet and airborne disease transmission. STUDY DESIGN: Single subject study. METHODS: Mask efficacy was evaluated using a cough simulator that sprays dye visible under ultra-violet light. User-testing was performed on an airway trainer mannequin where each subject performed the endoscopy with and without the mask in random orders. Their time to completion and number of attempts before successful completion were recorded, and each subject was asked to fill out a NASA Task Load Index (TLX) form with respect to their experience. RESULTS: The mask has a filtration efficiency of 97.31% and eliminated any expelled particles with the cough simulator. Without the mask, a simulated cough is visualized as it progresses away from the cough origin. Subjects who performed trans-nasal endoscopy spent 27.8 ± 8.0 s to visualize the vocal cords for the no mask condition and 28.7 ± 13.6 s for the mask condition (mean ± SD, p > .05). There was no statistically significant difference found in the mental demand, physical demand, temporal demand, performance, effort, and frustration of endoscopy under the no mask and mask conditions (all p > .05). CONCLUSION: The designed PPE provides an effective barrier for viral droplet and airborne transmission while allowing the ability to perform endoscopy with ease. LEVEL OF EVIDENCE: 3 Laryngoscope, 2021.

Measures of cortical inhibition by paired-pulse transcranial magnetic stimulation in anesthetized rats.

Paired-pulse transcranial magnetic stimulation (ppTMS) is a noninvasive method to measure cortical inhibition in vivo. Long interpulse interval (50-500 ms) ppTMS (LI-ppTMS) provokes intracortical inhibitory circuits and can reveal pathologically impaired cortical inhibition in disorders such as epilepsy. Adaptation of ppTMS protocols to rodent disease models is highly desirable to facilitate basic and translational research. We previously adapted single-pulse TMS (spTMS) methods to rats, but ppTMS has yet to be applied. Specifically, whether ppTMS elicits an inhibitory response in rodents is unknown. ppTMS in rats also requires anesthesia, a setting under which the preservation of these measures is undetermined. We therefore tested, in anesthetized rats, whether anesthetic choice affects spTMS-motor-evoked potentials (MEPs), LI-ppTMS in rats, as in humans, elicits intracortical inhibition of the MEP, and rat LI-ppTMS inhibition is acutely impaired in a seizure model. Rats were anesthetized with pentobarbital (PB) or ketamine-atropine-xylazine (KAX) and stimulated unilaterally over the motor cortex while recording bilateral brachioradialis MEPs. LI-ppTMS was applied analogous to human long interval intracortical inhibition (LICI) protocols, and acute changes in inhibition were evaluated following injection of the convulsant pentylenetetrazole (PTZ). We find that spTMS-evoked MEPs were reliably present under either anesthetic, and that LI-ppTMS elicits inhibition of the conditioned MEP in rats, similar to human LICI, by as much as 58 ± 12 and 71 ± 11% under PB and KAX anesthesia, respectively. LI-ppTMS inhibition was reduced to as much as 53% of saline controls following PTZ injection, while spTMS-derived measures of corticospinal excitability were unchanged. Our data show that regional inhibition, similar to human LICI, is present in rats, can be elicited under PB or KAX anesthesia, and is reduced following convulsant administration. These results suggest a potential for LI-ppTMS as a biomarker of impaired cortical inhibition in murine disease models.

Characterizing brain cortical plasticity and network dynamics across the age-span in health and disease with TMS-EEG and TMS-fMRI.

Brain plasticity can be conceptualized as nature's invention to overcome limitations of the genome and adapt to a rapidly changing environment. As such, plasticity is an intrinsic property of the brain across the lifespan. However, mechanisms of plasticity may vary with age. The combination of transcranial magnetic stimulation (TMS) with electroencephalography (EEG) or functional magnetic resonance imaging (fMRI) enables clinicians and researchers to directly study local and network cortical plasticity, in humans in vivo, and characterize their changes across the age-span. Parallel, translational studies in animals can provide mechanistic insights. Here, we argue that, for each individual, the efficiency of neuronal plasticity declines throughout the age-span and may do so more or less prominently depending on variable 'starting-points' and different 'slopes of change' defined by genetic, biological, and environmental factors. Furthermore, aberrant, excessive, insufficient, or mistimed plasticity may represent the proximal pathogenic cause of neurodevelopmental and neurodegenerative disorders such as autism spectrum disorders or Alzheimer's disease.

Breathy Dysphonia, Not Just a Pain in the Neck.

We describe a rare occurrence of unilateral vocal fold paralysis associated with a cervical osteophyte abutting the course of the recurrent laryngeal nerve. Trans-nasal laryngoscopy is vital in diagnosing vocal fold paralysis, but often does not provide insight into etiology. This case highlights the importance of radiographic imaging in newly diagnosed vocal fold paralysis, and underscores the principle that a diagnosis is not idiopathic until all sources have been ruled out.

Exuberant Intratracheal Granuloma.

BACKGROUND: Upper airway granulomas are commonly encountered benign masses and are a result of pronounced tissue reactivity to localized respiratory mucosal trauma. The mechanism of injury to respiratory epithelium is most commonly iatrogenic and associated with intubation or indwelling tracheostomy. Case Report. A 40-year-old obese female with a history of multiple intubations, poorly controlled diabetes mellitus type II, and history of tracheal stenosis presented with sudden onset respiratory distress requiring intubation at an outside hospital. Direct laryngoscopy revealed a rapidly forming transglottic tissue mass, measuring 5.0 × 2.2 × 0.8 cm. The following case represents an unusual exception to our experience with granulomas given its rapidity of onset and migration of tissue around the endotracheal tube. Discussion. Laryngeal erythema and granulation formation are expected postintubation findings in most patients; however, the large size of granuloma tissue and rapid onset of symptoms in this case make it remarkable. Our patient had multiple risk factors for postintubation stenosis: female sex, poorly controlled diabetes, hypertension, obesity, and multiple prior intubations for periods lasting longer than forty-eight hours. CONCLUSION: Our case highlights a rare laryngeal finding of a large granulation tissue mass causing sudden onset airway obstruction.