Upper Esophageal Sphincter

The UES is functionally defined as the area of the distal pharynx and proximal esophagus that maintains a closed pharyngoesophageal segment and opens for specific physiologic demands (e.g., swallowing, belching). Anatomically, the UES is made up of the cricopharyngeus, the thyropharyngeus, and the proximal cervical esophagus.^41,42,44 Unlike other muscular sphincters, the UES is not a complete muscular circle but rather a C-shaped sling that attaches to the cricoid cartilage. The pharyngeal plexus innervates the UES and receives contributions from the vagus nerve (superior and recurrent laryngeal nerves), the glossopharyngeal nerve, and the sympathetic nerves from the superior cervical ganglion.⁴⁴ The motor neurons that control the cricopharyngeus are found in the brainstem in the nucleus ambiguus, and stimulation of the nucleus tractus solitarius (the afferent nucleus of the vagus) results in contraction of the cricopharyngeus.⁴⁴ In canine studies, vagal nerve stimulation produced UES relaxation, and sectioning of both vagus nerves produced severe dysphagia.¹⁴ Sensory information from the UES is transmitted via the glossopharyngeal nerve and the sympathetic nerves.⁴⁴

The UES maintains a closed pharyngoesophageal segment via tonic contraction of the cricopharyngeus.^41,44 During swallowing, UES relaxation occurs, and the cricoid cartilage is pulled upward and anteriorly by the laryngeal musculature, thereby resulting in a stretching of the cricopharyngeus, thus allowing for bolus passage.⁴¹ The UES tonic pressure is increased in response to laryngeal stimulation (laryngo-UES contractile reflex).^7,42 UES pressure is increased with acidification of the distal esophagus.^14,42,44 UES pressure increases with slow balloon distention of the distal esophagus.⁴⁴ General anesthetics, sleep state, cigarette smoking, and peppermint consumption are associated with decreased UES pressure.^14,42,44 Koufman¹⁴ reported that smoking and peppermint consumption produced a 50% reduction in UES resting pressure in healthy volunteers within minutes.

The UES is the final gatekeeper in the antireflux barrier, and UES dysfunction may be associated with head and neck manifestations of EER. Deveney and collegues⁴⁵ showed an increased incidence of UES hypotonia in patients with pulmonary problems associated with GERD. In patients with inflammatory lesions of the larynx, they found UES pressures that were somewhat lower than normal.⁴⁵ Ulualp and Toohill⁴² did not see significant differences between resting UES pressures in patients with posterior laryngitis and normal controls.

Lower Esophageal Sphincter

The LES is the most critical antireflux defense mechanism.^1,46 It is located at the gastroesophageal junction, and it is not as anatomically distinct as the UES. Contraction of the LES results in circular closure that prevents the egress of gastric contents. Relaxation of the LES occurs during swallowing, belching, and vomiting. The LES is anatomically surrounded by the diaphragmatic crura, which mechanically augment the sphincter mechanism and are believed to contribute to 25% of LES competence.¹⁴ Manometric measurements at the LES reflect the combined contributions of the esophageal LES and the diaphragmatic crura. The intrinsic resting pressure of the LES varies with the phase of the respiratory cycle as a result of differential diaphragmatic contraction.⁴⁶ During episodes of straining, LES pressure is increased as a result of greater diaphragmatic activity, yielding a stronger diaphragmatic squeeze of the LES.^41,46 Hormonal control of LES activity is complex. Gastrin, pitressin, angiotensin II, and motilin increase contractile tone, whereas secretin, cholecystokinin, glucagon, and vasoactive intestinal peptide reduce LES pressure.^14,46

To prevent GER, the LES must maintain a resting pressure that is higher than the gastric pressure. GER occurs when there is a reversal of this gastric-to-LES pressure gradient.^41,46 Retrograde flow occurs with relaxation of the LES, with chronic hypotonia of the LES, or with increases in gastric pressure that overcome the LES resting pressure. Transient relaxation of the LES occurs in normal healthy adults and children.⁴⁶ Research has shown that transient relaxation of the LES is the most critical mechanism in the production of GER.^21,94 Dent⁴⁶ demonstrated that 63% to 74% of GER episodes were associated with transient LES relaxation. Chronic hypotonia of the LES is thought to be associated with GER episodes in a smaller percentage of patients, but perhaps with more severe esophagitis.⁴⁶ Lower LES’s resting pressures are seen in patients with CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome, scleroderma, and isolated Raynaud’s phenomenon. Although chronic hypotonia of the LES results in more severe reflux, it is an uncommon mechanism for GERD.^46,47 Large hiatal hernias may result in disruption of the relationship of the LES to the diaphragmatic crura, which may in turn impair the ability of the LES to act as an antireflux barrier by removing the additional pressure generated by the squeeze of the diaphragm.^14,46 Although hiatal hernias may play a role in GERD in some patients, not all patients with hiatal hernias have GERD.¹ Box 65-1 lists agents that affect the LES pressure.^1,14

When gastric pressure exceeds LES pressure, reflux can occur. “Stress reflux” is seen with increased intra-abdominal pressure during bending over, heavy lifting, straining, and coughing.¹⁴ Excessive gastric distention resulting in higher gastric pressure can occur postprandially after a large meal and with severe gastroparesis. Impaired gastric emptying is more common in patients with GERD.⁴⁷ Pregnancy, in which abdominal pressure is increased, is a risk factor for GERD.

Esophageal Acid Clearance

Because some GER is normal, mechanisms exist to clear and neutralize gastric contents when they pass into the esophagus. Esophageal peristaltic waves—along with the effect of gravity—act to mechanically clear the esophagus. Weakened or ineffective peristalsis allows for refluxed materials to have longer contact time with esophageal tissues.^47a Knight and colleagues⁴⁷ studied 100 subjects with EER and noted that 52% had ineffective esophageal motility. Primary esophageal peristalsis in patients with GERD and posterior laryngitis has been shown to be similar to that in normal controls.⁴² In patients with GERD, secondary esophageal peristalsis was noted to be decreased in comparison with that in normal controls.⁴² Increased numbers of GER episodes seen in patients with GERD, when supine, can be partially explained by the loss of gravitational effects. Acidic refluxate left in the esophagus can be neutralized by gastric glandular secretions and buffering agents in saliva.¹⁴ Xerostomia, which can be caused by Sjögren’s disease, certain medications, and previous radiotherapy, may abolish this important antireflux barrier.¹⁴ The low pH of gastric material is damaging to epithelium, but alkaline pH pancreatic and bile juices, when present, can also injure tissues.^1,14

Epithelial Resistance Factors

When the antireflux barriers fail, the severity of tissue damage is determined by epithelial resistance factors. There are pre-epithelial, epithelial, and intracellular protective mechanisms. The epithelium is preceded by a mucus layer and an aqueous layer with high bicarbonate content.^14,42 Mucus resists penetration by large molecules such as pepsin, but it does not prevent the ingress of acid. The aqueous layer is alkaline, and it buffers acid material. At the cellular level, the cell membrane and the intracellular junctions resist acid and pepsin.¹⁴ Different tissues have variable epithelial resistance, with esophageal epithelium being more resistant than respiratory epithelium.^{11,14,42,43,45} Even slight amounts of GER in the hypopharynx or larynx may cause significant injury, whereas reflux to the same degree in the distal esophagus would be easily resisted.^{11,14,42,43,45} Hanson and Jiang³¹ postulate that the posterior glottis is especially susceptible to the effect of EER. They theorize that the cilia beat material to the posterior glottis, thereby resulting in longer contact with refluxate and, therefore, more injury to this epithelium.

Mechanisms of Symptoms due to Extraesophageal Reflux

Head and neck disorders associated with EER are postulated to occur via the following mechanisms: direct mucosal damage and direct effect on mucociliary clearance from exposure to gastric contents; GER-related distal esophageal damage that results in vagally mediated, referred symptomatology; and laryngeal reflexes mediated by the stimulation of distal esophageal afferents.^11,34,43 Gaynor^32a studied the effects of direct exposure of gastric contents on rabbit and canine larynges. In the rabbit, direct exposure at a pH of 4.0 resulted in an inflammatory response that involved the submucosa and muscle, and the extent of damage worsened with longer durations of exposure. When a pH of 1.4 was used, “severe mucosal ulceration, submucosal and deeper hemorrhage with marked inflammatory response as well as necrosis were noted.”⁴³ In canines, an effect on mucociliary flow was noted to begin at a pH of 5.0, and no mucociliary flow was observed at pH of 2.0. Ciliary activity persists after the cessation of mucociliary flow. Alteration of pH has a direct effect on mucociliary transport and may lead to increased viscosity of the mucus blanket.⁴³ A reduction in mucociliary transport may decrease resistance to infection and has been theorized to contribute to the pathogenesis of subglottic stenosis.⁴³

Pepsin, which is found in gastric contents, is maximally active at pH 4.5, and its enzymatic activity produces tissue damage.¹⁴ Koufman¹⁴ demonstrated the importance of pepsin in the production of epithelial damage in canine larynges. He created subglottic mucosal injuries in dogs and then compared healing and injury in control, acid-only, and acid- and pepsin-exposed conditions. The acid-only group had inflammatory lesions that healed in twice the time it took for the control group lesions. None of the acid- and pepsin-treated larynges showed healing, and they were noted to develop ulceration and granulation.¹⁴

Gaynor,^32a monitoring patients receiving intensive care who were intubated for prolonged periods, found lower pharyngeal pH readings ranging from 2.4 to 7.0. Forty percent of the patients were noted to have reflux episodes with pH less than 4.0. In patients treated with antacids or histamine H₂ blockers, pH readings ranged from 4.7 to 8.9. The works of Koufman,¹⁴ Gaynor,^32a and Maronian^47b support the use of anti-acid therapy in cases of potential subglottic trauma (e.g., intubation), because it may help prevent irreversible mucosal damage.

Direct stimulation of sensory receptors in the larynx by aspirated or refluxed material can result in reflexive vocal fold adduction or laryngospasm.^34,36,48 This laryngeal chemoreflex is associated with bradycardia, central apnea, and hypotension.⁹ Partial or complete laryngospasm and cough can also be triggered by GER to the distal esophagus via a vagally mediated reflex.^1,7,27,34 Laryngospasm associated with distal esophageal GER can be associated with bronchospasm, increased secretions, tachycardia, and hypertension.⁹ These reflexes have implications for respiratory manifestations of EER and in the mechanisms involved with sudden infant death syndrome and recurrent laryngospasm.^34,36,43,48

History

A good case history is very critical to both diagnosis and treatment in patients with EER. The clinician must identify not only symptoms but also behavioral and medical risk factors. It is also critical to patient compliance with treatment that the patient be actively involved in the identification of the risk factors that he or she can modify. Common symptoms described in association with EER are listed in Box 65-2.^1,5,11,12,22–²⁴,³¹,⁴⁹–⁵⁶

In a retrospective review of 216 patients with cervical symptoms that were believed to be associated with EER, Rival and associates¹¹ found that the most common complaint was cervical dysphagia (33%), followed by globus (19%), sore throat (17%), and chronic throat clearing (14%). The researchers found that 66% of the patients complained of classic symptoms of GERD, such as acid regurgitation and heartburn.¹¹ Fraser and coworkers⁵² prospectively reviewed patients with symptoms believed to be associated with EER in whom pH probe study results were positive and found cough and hoarseness as the most common symptoms; 77% of their patients also complained of classic symptoms of GERD. Other investigators report lower rates of symptomatic GERD in patients with EER, with estimates of 20%,⁵ 43%,¹⁴ and 55%.⁵⁴ In a survey of American Broncho-Esophagological Association members, respondents believed that the most common symptoms related to EER were throat clearing, persistent cough, heartburn/dyspepsia, globus sensation, and voice quality change.¹² The importance and relevance of these findings are supported by the work of Reavis and associates,⁵⁷ who showed that laryngopharyngeal manifestations of acid reflux, specifically cough and hoarsenesss, better predict the presence of adenocarcinoma of the esophagus than “classic” GERD symptoms such as heartburn and regurgitation.

Belafsky and colleagues^49,50,58 developed the Reflux Symptom Index (RSI), a self-administered survey of nine questions used to assess patients with EER (Box 65-3). They demonstrated that the instrument is reliable and that it provides reproducible and valid findings. Normative data gathered by these researchers support that an RSI of more than 10 is associated with a high likelihood of positive results of a dual-channel pH probe study.⁵⁹ They prospectively evaluated 40 patients with EER documented by dual pH probe studies and 2 months of medical management. The RSI was noted to show improvement before changes were seen in physical findings. The mean RSI at initiation of the study was 19.3, which improved to a mean of 13.9 after 2 months.⁴⁹

Physical Examination and Laryngeal Endoscopy

The physical examination can yield several clues to EER. Observations of the quality of the voice, frequent throat clearing, cough or stridor, muscle tension in extralaryngeal musculature, and general body habitus are important to the evaluation. The larynx can be evaluated with indirect laryngoscopy along with rigid and/or flexible laryngoscopy. Videoendoscopy and stroboscopy are very useful, especially for documenting treatment effects and for visualizing subtle signs associated with acid reflux.

The majority of laryngeal findings seen in patients with chronic laryngitis associated with EER are edematous changes, as opposed to erythematous changes, seen in the posterior larynx. Posterior laryngitis manifests as edema, loss of clear epithelial markings, and increased vascularity of the posterior commissure and arytenoids.^5,13,60 Chronic irritation can result in a thickening of the posterior laryngeal mucosa with hyperkeratosis, which is also called pachydermia laryngeus.^5,13 Hanson and colleagues¹³ describe this posterior mucosal thickening with increased granularity and rough cobblestone appearance as “granular mucositis.” Increased mucus formation and thickness, along with mucus stranding and pooling, may result from chronic irritation and alterations of mucociliary flow.^5,43 Laryngeal ulceration, granuloma formation, scarring, and stenosis may indicate more severe EER.^13,30–32 Cherry and Margulies first identified extraesophageal reflux of gastric acid as being associated with contact ulcers.⁴³

Although it has been traditionally thought that erythema of the posterior larynx is the key sign of EER,^13,31 it is really the edema consequent to acid reflux–induced trauma to the larynx that is the clinical hallmark of EER.^59,61–63 Habermann and colleagues,⁶⁰ reviewing the endoscopic findings in 29 patients with chronic dysphonia and chronic laryngitis, showed that edema of the posterior glottic mucosa was the most common finding. The researchers noted significant improvement in these changes with therapy. Alterations of the true vocal fold mucosa and false vocal folds were also noted to improve with treatment. Shaw and Searl⁶⁴ assessed 96 patients who had symptoms suggestive of EER and noted that posterior glottic edema and nodularity were the most “severe and frequent” findings. Only 47% of patients were found to have ulceration, and 3 patients were found to have granulomas. Branski and coworkers⁶² performed a prospective, randomized, blinded study to assess the reliability of the laryngoscopic evaluation of patients with EER. They found that both intrarater reliability and inter-rater reliability were poor; raters demonstrated a poor agreement on the severity of endoscopic findings for LPR. The investigators concluded that using laryngoscopic findings alone for the diagnosis of EER was highly subjective.

Pseudosulcus has been described as a common endoscopic finding in EER.^50,59,65 The term pseudosulcus refers to the edematous changes that take place along the undersurface of the vocal fold from the anterior to the posterior commissure.^50,50,65 By contrast, true sulcus vocalis involves the free edge of the fold and terminates at the vocal process. Belafsky and colleagues,⁵⁹ evaluating pseudosulcus in 30 patients with EER (i.e., with positive pH probe results) and 30 control patients, found pseudosulcus in 70% of patients with EER and in 30% of controls. Patients with pseudosulcus were 2.3 times more likely to have pH probe–documented EER. The sensitivity and specificity of pseudosulcus were estimated to be 70% and 77%, respectively.⁵⁹ Hickson and colleagues⁶⁵ prospectively assessed, with dual-channel pH probe studies, 20 patients in whom endoscopic evaluation had confirmed pseudosulcus; EER was identified with positive pH probe results in 18 of the 20 patients. These researchers estimated that the positive predictive value of pseudosulcus for EER was 90%.⁶⁵

Belafsky and coworkers⁵⁹ have developed an endoscopic grading scale for EER. The Reflux Finding Score (RFS) consists of eight findings, seven of which are related to edematous changes in the endolarynx and only one to redness of the endolarynx, that are graded as to severity to a score from 0 to 26 (Table 65-1). The researchers report that an RFS of more than 7 is associated with a high likelihood that dual pH probe results will be positive.⁵⁹ The RFS was tested in 40 control subjects and 40 patients with clinical history positive for EER and pH probe studies. This review showed excellent interobserver and intraobserver reliability for the RFS. The mean RFS for control subjects was 5.2, whereas the mean RFS at entry for the EER group was 11.5, and an individual with an RFS of more than 7 was noted to have EER with 95% certainty.⁵⁸

Table 65-1 The Reflux Finding Score

Beaver and colleagues⁶¹ conducted a prospective study of the videostroboscopic images of 49 patients diagnosed with laryngopharyngeal reflux disease on the basis of two or more symptoms (i.e., throat clearing, hoarseness, cough, globus, or excessive mucus) along with physical findings of chronic laryngitis. Subjects were evaluated before and after 6 weeks of high-dose proton pump inhibitor (PPI) therapy. Ten control patients without any symptoms of EER were included. Three otolaryngologists evaluated the photographs in a blinded manner and in random order and gave each a score using the Laryngopharyngeal Reflux Disease Index (Box 65-4). The mean index value for patients was significantly higher than that of controls (9.50 vs. 2.92, respectively), and posttreatment mean scores were significantly lower than pretreatment scores (7.35 vs. 9.50, respectively). The most useful items on the scoring system were as follows: supraglottic edema and erythema, glottic edema and erythema, and subglottic edema and erythema. Items 7 through 12 were not believed to be as useful, and very few patients had positive scores on these items. The key factor in the endoscopic assessment of acid reflux–induced changes in the laryngopharynx is that edema, not erythema, is the clinical hallmark of EER.

Voice Analysis

Hanson and colleagues⁶⁶ reviewed voice quality and measures of jitter, shimmer, and signal-to-noise ratios in 16 patients undergoing treatment for chronic posterior laryngitis. Perceptual analysis did not show correlation with acoustic measures, and it did not show significant change with treatment. The investigators did demonstrate that measures of jitter, shimmer, and signal-to-noise ratio improve significantly with antisecretory and antireflux treatment of chronic posterior laryngitis. Shaw and Searl⁶⁴ noted significant improvement in measurements of jitter, shimmer, habitual frequency, and frequency range with antireflux treatment in their series of patients with a pretreatment complaint of hoarseness. Hamdan and coworkers⁵³ did not find any change in acoustic parameters in patients undergoing medical treatment of EER.

Esophagram

Barium esophagram is a convenient, inexpensive, and noninvasive diagnostic test. It is a useful method to diagnose structural and functional abnormalities of the esophagus, including hiatal hernia, erosive esophagitis, strictures, Barrett’s esophagus, esophageal rings, extrinsic compression, motility disorders, diverticula, possible malignancy, cricopharyngeal spasm, aspiration, and esophageal shortening.^5,9,14,67,68

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