Randomized double blind trial of amitriptyline versus placebo in treatment of chronic laryngopharyngeal neuropathy.

OBJECTIVE: A neuropathic etiology has been suggested for patients with chronic laryngopharyngitis symptoms without visible structural pathology. Prior studies have shown that treatment with neuro-modulating medications is beneficial, but it is unknown if this was due to placebo effect. Our objective was to compare the efficacy of amitriptyline versus placebo in treating chronic laryngopharyngeal neuropathy. STUDY DESIGN: Prospective, randomized placebo-controlled trial. METHODS: Patients were randomized to receive placebo or amitriptyline for 8weeks. Primary outcome was change in modified Reflux Symptom Index (mRSI) score. Secondary outcomes were change in Voice Handicap Index-10 (VHI) scores, rates of adverse effects, and overall symptom severity. RESULTS: Eighteen patients completed the study. The average difference in mRSI and VHI-10 scores after treatment were not significantly different between study arms. However, more subjects taking amitriptyline felt their symptoms had subjectively improved (6 out of 9, 67%), while the remainder noted no change. In the placebo group, only 4 out of 9 subjects (44%) felt their symptoms were better and 2 felt worse. Subjects took an average of 25mg of amitriptyline or placebo daily by the end of the 8-week treatment period. No serious adverse effects were noted. CONCLUSION: Although there was a trend toward greater subjective improvement in overall symptoms with amitriptyline, interpretation is limited due to the small sample size. Larger randomized controlled trials to determine the efficacy of neuro-modulating agents in the treatment of chronic laryngopharyngeal neuropathy, as well as better metrics to characterize this disorder, are warranted.

[Upper airway stimulation in obstructive sleep apnea]. / Stellungnahme der Taskforce "Neurostimulation bei Schlafapnoe" zur Stimulation der oberen Atemwege.

The stimulation of the upper airway represents an effective treatment option in case of CPAP failure in patients with moderate to severe obstructive sleep apnea. The stimulation with respiratory sensing (Inspire Medical Systems) has shown a high level of evidence in larger cohorts and longer follow-up studies. Whether the results of the stimulation without respiratory sensing (ImThera Medical) can be compared with the therapy with sensing, remains open up to now. Additional data are awaited after the planned phase III study THN#2. To optimize both procedure and to provide long term results, more studies are needed. The workgroup "sleep medicine" of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery supports theses activities with the help of the newly founded task force "Neurostimulation in Sleep Apnea".

Intrinsic neuroendocrine cells in the outer wall of the human pyriform recess.

The extrinsic neural supply of the hypopharynx is well established. However, little is known about the intrinsic neurons and neuroendocrine cells (NECs) of the human hypopharynx that are under the influence of the extrinsic nerves. We aimed to identify and characterize such cell populations within the outer wall of the pyriform recess. We applied antibodies for neuron-specific enolase (NSE), calretinin (CR) and neurofilaments (NF) to autopsy samples from four donor cadavers. Within the lamina propria and the muscle layer of the pyriform recess outer wall, usually in perivascular areas, we found NSE-, CR- and NF-positive cells, mostly apolar, that were considered on a histological and immunohistochemical basis to be NECs. Although these cells have not, to our knowledge, been described previously in this anatomical location, their presence within the hypopharynx wall may explain the appearance of rare forms of local primary neuroendocrine carcinomas.

Hypopharyngeal pharyngoplasty in the treatment of severe aspiration following skull base tumor removal: experience in pediatric patients.

OBJECTIVE: To report the surgical treatment of severe swallowing disorders associated with skull base surgery resulting in unilateral pharyngolaryngeal paralysis in pediatric patients. DESIGN: Retrospective case review. SETTING: Tertiary referral center for pediatric otolaryngology. PATIENTS: Five infants undergoing swallowing rehabilitation surgery for severe dysphagia and aspiration resulting from skull base or brainstem surgery. INTERVENTION: A hypopharyngeal pharyngoplasty, consisting of the partial resection of the inferior constrictor and cricopharyngeal muscles, was performed for the treatment of severe swallowing disorders. A thyroplasty was also performed if clinically significant glottic incompetence was present. MAIN OUTCOME MEASURES: Functional outcomes after surgery were evaluated with a videoendoscopic swallowing study and videofluoroscopy. Postoperative clinical evaluation included respiratory, swallowing, and nutritional outcomes. RESULTS: A hypopharyngeal pharyngoplasty was performed following a mean period of 6 weeks (range, 1-10 weeks) after skull base surgery. In 3 patients a thyroplasty and a temporary tracheotomy were performed. Oral feeding was reintroduced after a mean period of 6 days (range, 4-20 days). Complete oral feeding autonomy was obtained after 13 days (range, 7-25 days). Postoperative swallowing assessment revealed the disappearance of pharyngeal stasis and aspiration in all patients. Three infants died because of tumor recurrence. Neither dysphagia or bronchopulmonary infections were observed after a mean follow-up period of 33 months (range, 6-61 months). CONCLUSIONS: Pharyngolaryngeal paralysis represents a severe consequence of skull base and brainstem surgery. This condition leads to high morbidity, particularly in the pediatric population. The hypopharyngeal pharyngoplasty, with a possible thyroplasty, may be considered to treat patients with severe pharyngolaryngeal paralysis after skull base or brainstem surgery.

[Electric stimulation in dysphagia therapy--a review]. / Elektrische Stimulation in der Dysphagietherapie - Eine Ubersicht.

In the last years an increased interest in the electrical stimulation has consisted in the treatment of dysphagia. In the article we introduce the anatomical and physiological premises for the method. In a critical analysis the present state of art is represented, the clinical results are checked and the chances for the future are examined.

Perineural invasion of the major and minor nerves in laryngeal and hypopharyngeal cancer.

OBJECTIVE: To investigate the perineural invasion in patients with squamous cell carcinoma of the larynx and hypopharynx. STUDY DESIGN: A prospective study of patients with laryngeal and hypopharyngeal squamous cell carcinoma who underwent total or partial laryngectomy. METHODS: Patients with squamous cell carcinoma of the larynx and pyriform sinus who underwent laryngectomy between 2002 and 2006 in the ENT Clinic of Cluj-Napoca were investigated for histopathological identification of perineural invasion. RESULTS: The present study included 256 patients. Perineural invasion was present in 86 cases out of the 256. Perineural invasion was detected in the major nerves of only one case out of 219 patients who had undergone total laryngectomy. The difference between the mean disease-free survival of patients with or without perineural invasion of the minor nerves was statistically significant (Mann-Whitney U test, P = 0.000102). The local recurrence rates in the cases with or without perineural invasion were significantly different (log-rank test, P = 0.00001). CONCLUSION: Major nerves do not constitute a way of spreading in the squamous cell carcinoma of the larynx and hypopharynx, whereas minor nerves remain a potential one.

Cough, expiration and aspiration reflexes following kainic acid lesions to the pontine respiratory group in anesthetized cats.

The importance of neurons in the pontine respiratory group for the generation of cough, expiration, and aspiration reflexes was studied on non-decerebrate spontaneously breathing cats under pentobarbitone anesthesia. The dysfunction of neurons in the pontine respiratory group produced by bilateral microinjection of kainic acid (neurotoxin) regularly abolished the cough reflexes evoked by mechanical stimulation of both the tracheobronchial and the laryngopharyngeal mucous membranes and the expiration reflex mechanically induced from the glottis. The aspiration reflex elicited by similar stimulation of the nasopharyngeal region persisted in 73% of tests, however, with a reduced intensity compared to the pre-lesion conditions. The pontine respiratory group seems to be an important source of the facilitatory inputs to the brainstem circuitries that mediate cough, expiration, and aspiration reflexes. Our results indicate the significant role of pons in the multilevel organization of brainstem networks in central integration of the aforementioned reflexes.

Targeted sensory restoration to the upper aerodigestive tract with physiologic implications.

BACKGROUND: Sensory restoration through sensate flaps placed into critical areas of the upper aerodigestive tract is an attractive reconstructive goal to achieve optimal post-therapy function. The question that has remained unanswered is whether sensory recovery takes place through the newly established neural pathway or through ingrowth of sensory nerves from the periphery of the defect. METHODS: Three patients with squamous cell cancer underwent resection and primary reconstruction of the laryngopharynx with a sensate radial forearm flap. The flaps were designed with a smaller, proximal paddle to serve as a monitor. Reneurotization of the flaps was carried out to the superior laryngeal nerve. RESULTS: All three patients were followed for a minimum of 12 months. Each of these patients reported the development of a cough that resulted from stimulation of the external monitor. This phenomenon was easily duplicated by light stimulation of the monitor, which not only produced the cough but was consistently perceived by the patient as arising from inside their throat. CONCLUSIONS: This series conclusively demonstrates that sensory feedback can be restored in a targeted fashion through neural anastomoses and that a physiologic response that helps in airway protection can be produced through the use of sensate flaps with a strategically selected recipient nerve.

Age-related remodeling of the hypopharyngeal constrictor muscle and its subneural apparatuses: a scanning electron microscopical study in rats.

Age-related remodeling of the hypopharyngeal constrictor muscle was studied by comparing the morphological features of the subneural apparatus (SNA) of the thyropharyngeal (TP) and cricopha ryngeal (CP) muscles in young and old rats. Scanning electron microscopy revealed that the TP and CP muscles had both gutter- and depression-type SNAs, although different proportions of the two types of apparatus were found in each muscle. In young-adult rats, the gutter-type SNA was predominant in the TP muscle, whereas in the CP muscle the depression type was predominant. By contrast, in old rats, the depression-type SNA was predominant in the TP muscle, while no such transformation of the dominant SNA was noted in the CP muscle. In addition, the number of type IIb and type I muscle fibers was lower and greater, respectively, in older animals compared with those of younger animals. Furthermore, there were more type IIc fibers in the TP muscle of old rats, but no difference in the CP muscle between young and old animals. These findings suggest that the transformation of SNAs and the muscle fibers of the hypopharyngeal constrictor muscle takes place during aging and that their remodeling processes differ in the TP and CP muscles.

Sensory nerve supply of the human oro- and laryngopharynx: a preliminary study.

To date, the details of human sensory innervation to the pharynx and upper airway have not been demonstrated. In this study, a single human oro- and laryngopharynx obtained from autopsy was processed with a whole-mount nerve staining technique, Sihler's stain, to determine its entire sensory nerve supply. The Sihler's stain rendered all mucosa and soft tissue translucent while counterstaining nerves. The stained specimen was then dissected and the nerves were traced from their origins to the terminal branches. It was found that the sensory innervation of the human pharynx is organized into discrete primary branches that innervate specific areas, although these areas are often connected by small neural anastomoses. The density of innervation varied, with some areas receiving almost no identifiable nerve supply (e.g., posterior wall of the hypopharynx) and certain areas contained much higher density of sensory nerves: the posterior tonsillar pillars; the laryngeal surface of the epiglottis; and the postcricoid and arytenoid regions. The posterior tonsillar pillar was innervated by a dense plexus formed by the pharyngeal branches of the IX and X nerves. The epiglottis was densely innervated by the internal superior laryngeal nerve (ISLN) and IX nerve. Finally, the arytenoid and postcricoid regions were innervated by the ISLN. The postcricoid region had higher density of innervation than the arytenoid area. The use of the Sihler's stain allowed the entire sensory nerve supply of the pharyngeal areas in a human to be demonstrated for the first time. The areas of dense sensory innervation are the same areas that are known to be the most sensitive for triggering reflex swallowing or glottic protection. The data would be useful for further understanding swallowing reflex and guiding sensory reinnervation of the pharynx to treat neurogenic dysphagia and aspiration disorders.

Role of sensation in swallowing function.

OBJECTIVES: Sensation in the oral cavity and laryngopharynx has long been believed to be crucial for normal swallowing. One illustration of this belief has been intense interest in reconstruction after cancer resection using sensate tissue transfer as a means of improving swallowing function. A contrarian view is that mucosal sensation, by itself, is, in fact, relatively unimportant to swallowing function. STUDY DESIGN: A prospective study was designed to test the hypothesis that normal swallow function can occur with anesthesia of the upper aerodigestive tract mucosa. METHODS: Baseline (sensate) swallowing function of 13 healthy adults was assessed via video endoscopic swallow studies (VESS). Each subject was then topically anesthetized with lidocaine applied to the oral cavity, oropharynx, hypopharynx, and larynx. Swallowing was then reassessed via VESS and compared to the baseline examination to look for differences in function. RESULTS: There was little difference in swallowing ability between sensate and anesthetized states, even though all the subjects felt that their swallowing had been profoundly disrupted after lidocaine was applied. The main difference was a small increase in the time from food administration to swallowing. A few experienced trace aspiration, which was instantly eliminated on subsequent swallows with simple coaching. CONCLUSION: Normal swallowing can occur spontaneously or with simple coaching even with complete anesthesia of the upper aerodigestive tract mucosa. Current beliefs about the value of sensate free flaps and the importance of sensation in swallowing in general may need refinement.

Recurrent and superior laryngeal nerves: a new look with implications for the esophageal surgeon.

BACKGROUND: Injury to the recurrent laryngeal nerve (RLN) is an unwelcome and not infrequent complication of operations on or near the upper thoracic or cervical esophagus. Because anatomic information useful to the surgeon is difficult to come by, the aim of this study was to reinvestigate and display the RLNs and superior laryngeal nerves in humans. METHODS: Postmortem en bloc specimens were studied: 23 by macroscopic dissection and 11 by large field serial histology. The nerves and their branches and supply areas were photographed at each step of dissection from the lateral (the surgeon's approach) and from the posterior aspect. RESULTS: The RLNs were 2- to 3-mm thick compact slack cords, sinuously passing upward within the lateral peritracheal, and less frequent periesophageal, loose connective tissue, the left RLN being closer to the tracheoesophageal groove than the right. Both RLNs gave off 8 to 14 branches, equally distributed to the esophagus and trachea. These were 2.5- to 1-cm long when stretched. The primarily identical pattern became unpredictable underneath the thyroid gland, an area that covered approximately 3 cm of the proximal esophagus. The RLN, still fairly robust (>1 mm) dipped, being firmly attached, into the larynx laterocaudad to the cricopharyngeus muscle. As the RLN and superior laryngeal nerves supply the same laryngeal muscles and mucosa, this twofold innervation may compensate for some sequelae of RLN injury. CONCLUSIONS: Displaying the RLNs, an important step in a variety of neck operations, dissection of the RLNs branches close to the esophagus and intestinocervical anastomosis as low as possible, will certainly reduce RLN injury.

Laryngeal evoked brainstem responses in humans: a preliminary study.

Laryngeal evoked brainstem responses (LBRs) were recorded in normal human subjects in an attempt to develop a central laryngeal function test and enhance our understanding of neurolaryngologic disorders. The results showed that the human LBR consists of five positive peaks and five negative peaks reproducible within 10 ms after a vibratory stimulation to the superior laryngeal nerve (SLN). The waveform reproducibility was verified by blocking the SLN and topically anesthetizing the hypopharyngeal cavity. The morphology and latency of peak 5 were similar to results obtained in animal LBR experiments. It was concluded that a vibratory stimulation to the SLN was a noninvasive method to elicit far-field potentials from the central laryngeal pathway. These findings encourage further effort to establish normative data and explore clinical correlations.

Sensory discrimination in the larynx and hypopharynx.

The traditional approach to evaluating swallowing disorders has focused on upper aerodigestive tract motor function. The evaluation of the sensory apparatus in the larynx and pharynx as part of the workup of dysphagia has heretofore not been addressed. The purpose of this work is to discuss a new, noninvasive method to measure sensory discrimination in the supraglottic larynx and hypopharynx. An air pulse, of precise duration and pressure, was delivered through a flexible fiberoptic telescope to the submucosally situated superior laryngeal nerve along the anterior wall of the pyriform sinus. Three hundred sixty trials were conducted in 30 healthy adults. The average sensory discrimination was 2.24 +/- 0.28 mm Hg. Brief air-pulse stimulation is a safe, reliable means of determining supraglottic and hypopharyngeal sensory discrimination thresholds.

Restoration of laryngopharyngeal sensation by neural anastomosis.

OBJECTIVE: To demonstrate that sensory nerve transposition may be used to reestablish sensation of the laryngopharynx after central nervous system injury and vagal deficit. DESIGN: Prospective preliminary report of 2 patients following brain-stem stroke with aspiration pneumonia confirmed on chest radiography, severe dysphagia and inability to tolerate oral alimentation, and modified barium swallow that demonstrated cricopharyngeal spasm and impaired laryngeal elevation. Both patients also had severe, bilateral laryngopharyngeal sensory deficits as determined by delivery of air pulse stimuli to the mucosa innervated by the superior laryngeal nerve via a fiberoptic telescope. Each patient underwent surgery as part of management of dysphagia after failure of aggressive nonsurgical treatment. INTERVENTION: During a cricopharyngeal myotomy and laryngeal suspension, a unilateral microneurorrhaphy between the greater auricular nerve and the superior laryngeal nerve was performed. OUTCOME MEASURES: Ability to tolerate oral diet without development of aspiration pneumonia and postoperative laryngopharyngeal sensory capacity. RESULTS: By 12 months after surgery, both patients had ipsilateral restoration of laryngopharyngeal sensation, with no further episodes of aspiration pneumonia. CONCLUSIONS: In select cases of severe dysphagia after central nervous system injury, sensory nerve transposition may be a useful adjunct to the surgical rehabilitation of the patient with dysphagia.

Electrical stimulation of upper airway musculature.

Investigators have postulated that pharyngeal collapse during sleep in patients with obstructive sleep apnea (OSA) may be alleviated by stimulating the genioglossus. The effect of electrical stimulation (ES) of the genioglossus on pharyngeal patency was examined in an isolated feline upper airway preparation and in apneic humans during sleep. We found that stimulation of the genioglossus (n = 8) and of the hypoglossal nerve (n = 1) increased maximum airflow through the isolated feline upper airway in humans during sleep. Additional findings in the isolated feline upper airway suggest that such increases in airflow were due to decreases in pharyngeal collapsibility. The evidence suggests that improvements in airflow dynamics with electrical stimulation are due to selective recruitment of the genioglossus, rather than due to nonspecific activation of the pharyngeal musculature or arousal from sleep. The implications of these results for future therapy with ES are discussed.

Supraglottic and pharyngeal sensory abnormalities in stroke patients with dysphagia.

Dysphagia and aspiration are two devastating sequelae of stroke, accounting for nearly 40,000 deaths from aspiration pneumonia each year in the United States. While motor deficits in the larynx and pharynx are thought responsible for dysphagia and aspiration in stroke patients, no prior study has evaluated whether these patients also have sensory deficits. The aim of this study was to evaluate the sensory capacity of the laryngopharynx (LP) in supratentorial or brain stem stroke patients who presented with dysphagia. Fifteen stroke patients (mean age, 66.7 +/- 13.8 [SD] years) were prospectively evaluated by means of our previously described method whereby air pulse stimuli were delivered via a flexible fiberoptic telescope to the mucosa innervated by the superior laryngeal nerve. There were 15 age-matched controls. No LP sensory deficits were found in any of the age-matched controls. In all stroke patients studied, either unilateral (n = 9) or bilateral (n = 6) sensory deficits were identified. Deficits were defined as either a moderate impairment in sensory discrimination thresholds (3.5 to 6.0 mm Hg) or a severe sensory impairment (> 6.0 mm Hg). These sensory discrimination thresholds were significantly greater than in age-matched controls (7.05 +/- 0.17 mm Hg for the supratentorial group and 6.05 +/- 1.22 mm Hg for the infratentorial group versus 2.61 +/- 0.69 mm Hg for the controls). Among patients with unilateral deficits, sensory thresholds were moderately to severely elevated in all 9 cases on the affected side compared with the unaffected side (p < .01, Fisher's exact test). Moreover, the sensory thresholds of the unaffected side were not significantly different from those of age-matched controls (2.51 +/- 0.25 mm Hg versus 2.61 +/- 0.69 mm Hg, respectively). All 6 patients with bilateral deficits had severe impairments. The results of an outcome assessment in 13 of 15 patients revealed that 2 out of 5 patients with moderate LP sensory impairment and 5 out of 8 with severe impairment developed aspiration. Our results show for the first time that stroke patients with dysphagia have significant sensory deficits in the LP and that these impairments are likely to contribute to the development of aspiration.

[Autonomic and peptidergic innervation of the human larynx]. / Die autonome und peptiderge Innervation des menschlichen Kehlkopfes.

Autonomic and peptidergic innervation of the human larynx (vocal cords, ventricular folds, epiglottis, subglottic region and recurrent nerves) was studied by application of single and double immunocytochemistry and radioimmunoassay. In all tissues investigated, immunoreactivities for a variety of regulatory peptides were detected and included vasoactive intestinal polypeptide (VIP), peptide histidine methionine (PHM), helospectin, neuropeptide Y (NPY), C-flanking peptide of NPY (C-PON), calcitonin gene-related peptide (CGRP), substance P and neurokinin A. In the recurrent nerves, only a few peptide-immunoreactive nerve fibers were found. The laryngeal region of the epiglottis and the subglottic region showed characteristic corpuscular nerves containing substance P and CGRP running underneath and within the epithelium.

[Neurological complications following tonsillectomy]. / Neurologische Komplikationen nach Tonsillektomie.

Iatrogenic neurological complications of tonsillectomy have been extremely rarely described. We report on 5 patients who developed glossopharyngeal paresis, impairment of taste on the base of the tongue, or hypoglossal paresis following tonsillectomy, and discuss the possible etiology of these isolated lesions of the cranial nerves.

[Clinical aspects of anatomy of the nervous apparatus of the pharyngoesophageal junction]. / Klinicheskie aspekty anatomii nervnogo apparata glotochno-pishchevodnogo perekhoda.

By examining extraorgan innervation of the pharyngeal-esophageal junction of adult cadavers, it was found that the risk of injury of the superior laryngeal nerve and its branches was very high during larynx resection and extirpation, lateral pharyngotomy, thyroid gland resection according to the method of A.V. Martynov, and Crile's operation. Esophageal branches of the recurrent laryngeal nerve or the inferior laryngeal nerve can be damaged during larynx extirpation or strumectomy according to the method of O. V. Nikolaev. The nervous apparatus of the pharyngeal-esophageal junction consists of nerve bundles located in the adventitia, muscular layer, and submucous base.