Joel H. Blumin

Clinical Practice Guideline: Improving Voice Outcomes after Thyroid Surgery

Objective 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. Purpose 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. Results 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.

Receptor-Mediated Uptake of Pepsin by Laryngeal Epithelial Cells

Objectives: Previous data suggest a mechanistic link between exposure to pepsin and cellular changes that lead to laryngopharyngeal disorders. Initial confocal microscopy analysis of pepsin uptake by cultured hypopharyngeal epithelial cells revealed that pepsin may be taken up by a specific process. The objective of this study was to use electron microscopy to confirm the initial confocal findings and to determine whether uptake of pepsin by laryngeal epithelial cells is receptor-mediated. Methods: Cultured human hypopharyngeal FaDu cells and human laryngeal biopsy specimens, taken from the posterior larynx of “control” patients without symptoms or findings of laryngopharyngeal reflux, were exposed to purified human pepsin 3b with or without transferrin (a marker for receptor-mediated endocytosis) in vitro. Uptake of pepsin was documented by electron microscopy. Results: Pepsin co-localized with transferrin in intracellular vesicles; this finding confirms that pepsin is taken up by laryngeal epithelial cells by receptor-mediated endocytosis. Conclusions: This is a novel finding that further defines the role and mechanism of pepsin-mediated injury in laryngopharyngeal reflux. The objective of ongoing research is to identify the receptor and investigate potential antagonists as a new therapeutic option for patients with reflux-attributed disease — In particular, those patients who have persistent symptoms despite acid suppression therapy.

Pepsin in nonacidic refluxate can damage hypopharyngeal epithelial cells.

Objectives: Studies using combined multichannel intraluminal impedance with pH monitoring reveal a role for nonacidic reflux in laryngopharyngeal symptoms and injury. We have discovered that pepsin is taken up by laryngeal epithelial cells by receptor-mediated endocytosis. This finding reveals a novel mechanism by which pepsin could cause cell damage, potentially even in nonacidic refluxate. The objective of this study was to determine whether pepsin, at pH 7.4 and thus in nonacidic refluxate, causes cell damage. Methods: Cultured hypopharyngeal epithelial (FaDu) cells were exposed to human pepsin (0.1 mg/mL) at pH 7.4 for either 1 hour or 12 hours at 37°C and analyzed by electron microscopy, cytotoxicity assay, and SuperArray. Results: We report mitochondrial and Golgi complex damage in cells exposed to pepsin at neutral pH, observed by electron microscopy. We also report cell toxicity of pepsin at pH 7.4, measured by a cytotoxicity assay. Furthermore, using SuperArray, we found that pepsin at pH 7.4 significantly alters the expression levels of multiple genes implicated in stress and toxicity. Conclusions: These findings are perhaps the first to explain why many patients have symptoms and injury associated with nonacidic reflux, and could have important implications for the development of new therapies for reflux, such as pepsin receptor antagonists and/or irreversible inhibitors of peptic activity.

Evidence of extraesophageal reflux in idiopathic subglottic stenosis

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.

Mucin Gene Expression in Human Laryngeal Epithelia: Effect of Laryngopharyngeal Reflux

Objectives: We sought to document the mucin gene profile in normal human laryngeal epithelium and compare it with that in patients with reflux-attributed laryngeal injury or disease. We also investigated the effect of low pH with or without pepsin on mucin messenger RNA levels in vitro. Methods: Laryngeal biopsy specimens were obtained from 3 patients with clinically diagnosed laryngopharyngeal reflux and from 2 control subjects who had no signs or symptoms of reflux. Signs and symptoms were assessed by the Reflux Finding Score and the Reflux Symptom Index, respectively. Reverse transcription–polymerase chain reaction (RT-PCR) was performed to establish the mucin gene profile. Human hypopharyngeal epithelial cells were exposed to pH 7, 5, 4, and 2 with and without pepsin (0.1 mg/mL) for 20 minutes at 37°C, and expression of selected mucins was analyzed via real-time RT-PCR. Results: Mucin 1–5, 7, 9, 13, 15, 16, and 18–20 transcripts were detected in normal laryngeal epithelium, whereas mucin 6, 8, and 17 transcripts were not. Mucins 2, 3, and 5 were expressed at reduced levels in patients with reflux-attributed laryngeal injury or disease. These mucin genes were up-regulated after exposure to low pH in vitro (p < 0.005). Pepsin inhibited this up-regulation (p < 0.001). Conclusions: Reflux laryngitis is associated with down-regulation of mucin gene expression.

Laryngeal Findings in Advanced Parkinson's Disease

Parkinsons disease is a major source of neurologic morbidity. A majority of patients with Parkinsons disease complain of problems with voice, speech, and swallowing. Treatments for these problems center on the improvement of vocal fold adduction through either speech therapy or vocal fold augmentation. No prior study has looked at laryngeal improvement after neurologic surgery, specifically deep brain stimulation, performed to treat Parkinsons disease. The goal of this study was to establish a baseline of laryngeal findings in patients who are considering deep brain stimulation. Fifteen patients underwent physical examination with videostroboscopy and fiberoptic endoscopic evaluation of swallowing before deep brain stimulation. In addition, they were asked to self-report voice handicap. Eighty-seven percent of patients demonstrated significant vocal fold bowing. All patients had some degree of pharyngeal residue of solids noted on evaluation of swallowing. All but one patient had a significant self-reported voice handicap. These findings are reviewed and established as a baseline for further study.

Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells.

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.

Long-term follow-up results of selective laryngeal adductor denervation-reinnervation surgery for adductor spasmodic dysphonia.

Selective laryngeal adductor denervation‐reinnervation surgery for the treatment of adductor spasmodic dysphonia was reported in 1999 in 21 patients with encouraging results. Here, we report long‐term results of this procedure. Surgical outcome was evaluated using patient surveys and perceptual voice assessment. Measured outcomes included Voice Handicap Index (VHI)‐10 scores, patient questionnaire, and perceptual evaluation for voice breaks and breathiness. Patient survey was obtained from 83 patients, and perceptual voice evaluation was performed in voice samples from 46 patients. Average follow‐up interval was 49 months. Mean VHI‐10 scores improved from a mean of 35.6 to 12.7. Eighty‐three percent showed significantly improved VHI‐10 scores, representing improved physical, social, and emotional well‐being. There was a high degree of patient satisfaction, with 91% agreeing that their voice is more fluent after the surgery. Perceptual evaluation of postoperative voice samples revealed voice breaks in 26% (15% mild, 4% moderate, 7% severe) and breathiness in 30% (11% mild, 13% moderate, 6% severe). A majority of patients had stable, long‐lasting resolution of spasmodic voice breaks.

Rationale for Targeting Pepsin in the Treatment of Reflux Disease

Objectives: We undertook to 1) obtain unequivocal evidence to confirm or rebut our initial observations that pepsin is taken up by hypopharyngeal epithelial cells by receptor-mediated endocytosis, 2) investigate whether uptake of pepsin at pH 7, in nonacidic refluxate, is of pathological significance, and 3) test our hypothesis that inactive but stable pepsin (<pH 8) taken up by hypopharyngeal epithelial cells causes damage by becoming reactivated inside the cell. Methods: Human posterior cricoid biopsy specimens and cultured hypopharyngeal FaDu epithelial cells were used to perform competitive binding studies and to investigate colocalization of pepsin with clathrin, Rab-9, and TRG-46. FaDu cells were exposed to pepsin (both irreversibly and reversibly inactivated) in the presence and absence of wortmannin and dimethyl amiloride and analyzed by electron microscopy, MTT cytotoxicity assay, and Stress and Toxicity SuperArray. Results: Pepsin is unequivocally taken up by hypopharyngeal epithelial cells by receptor-mediated endocytosis. Uptake of pepsin at pH 7, in nonacidic refluxate, causes mitochondrial damage and changes the expression of several genes implicated in stress and toxicity. Irreversible, but not reversible, inhibition of peptic activity prevents these changes. Conclusions: Pepsin, at pH 7, in nonacidic refluxate, causes damage by becoming reactivated inside the cell. Irreversible inhibitors of peptic activity hold promise as a new therapy for reflux.

Pediatric Voice-Related Quality of Life: Findings in Healthy Children and in Common Laryngeal Disorders

Objectives: Although several instruments have been validated to assess voice quality, the incidence and degree of impairment in normal, healthy children has not been widely reported. It is hypothesized that healthy children outside a medical setting do not demonstrate impairment as measured by the Pediatric Voice-Related Quality of Life (PVRQOL) instrument; in contrast, patients with vocal fold paralysis (VFP), vocal nodules (VNs), and paradoxical vocal fold dysfunction (PVFD) have significant impairment as compared to control populations. Methods: The PVRQOL was measured prospectively in children with VFP, VNs, and PVFD. The findings were compared to findings in 100 children surveyed at the 2006 Wisconsin State Fair. Results: Of the 100 surveys of healthy children and their parents, 95 were completed correctly; their mean (±SD) PVRQOL score was 96.8 ± 5.85. The VFP patients (n = 11; mean PVRQOL score, 70.5 ± 28.6) reported significant impairment (p < .0001, unpaired t-test). This was also true of patients with VNs (n = 13; PVRQOL score, 84.8 ± 9.4; p < .0001) and PVFD (n = 25; PVRQOL score, 86.7 ± 14.3; p < .0001); statistically significant differences were also noted for the Social-Emotional and Physical-Functional domains for each of the 3 disease states compared to the group of healthy children (p < .001). Conclusions: The PVRQOL scores of healthy children reveal essentially no self-reported vocal impairment. In contrast, common disorders such as VNs, VFP, and PVFD demonstrate statistically significant impairment in age-matched children for total PVRQOL, as well as for the Social-Emotional and Physical-Functional domains. This is the first report of normative PVRQOL data in children.