Globus Sensation and Hyperdynamic Upper Esophageal Sphincter: Another Piece in the Puzzle?

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Kwiatek MA, Mirza F, Kahrilas PJ, et al. (Division of Gastroenterology, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois). Hyperdynamic upper esophageal sphincter pressure: a manometric observation in patients reporting globus sensation. Am J Gastroenterol 2009;104:289–298.

Globus is defined as a persistent or intermittent nonpainful sensation of a lump, retained food bolus, or foreign body in the throat. It usually occurs between meals and improves with eating. Globus sensation has a high prevalence in the general population, predominantly affecting middle-aged patients, with a predominance of women seeking medical attention. The strict Rome III definition of functional globus stipulated further the absence of dysphagia, odynophagia, histopathology-based esophageal motility disorders, or typical gastroesophageal reflux (Gastroenterology 2006;130:1459–1465). A psychosomatic impact has been postulated, and the globus sensation could be modified by stress and changes of emotional status (Arch Intern Med 1998;158:1365–1373). In addition, abnormalities in the upper esophageal sphincter (UES), esophageal motility and esophageal reflux, and acid exposure have been documented and linked to the etiology of globus sensation.

The study by Kwiatek et al aimed to quantify manometric characteristics of the UES in 131 patients with globus sensation (31 males and 100 females) selected from a pool of 990 consecutive patients referred to a tertiary center. These patients were compared with 46 patients with gastroesophageal reflux disease (GERD) without globus sensation (28 males and 18 females) from the same collective and to 68 healthy controls (35 males and 33 females). Globus patients were divided into a group with normal (64; 49%) and abnormal (67; 51%) swallow-induced relaxation and distal esophageal function. When evaluated with a standardized questionnaire, only 24 out of the 131 patients (18.1%) had isolated globus sensation, whereas in most patients the globus sensation was associated with dysphagia and/or heartburn. Thus, according to clinical presentation and manometry only 13 of the 131 fulfilled the Rome III criteria. This accounts only for 10% of the patients with globus sensation and for only 1% of the total patient population. Patients with globus sensation were older (49 versus 54 years) when compared with healthy controls (22 years) and controls with GERD (42 years) and showed a higher percentage of female patients.

High-resolution manometry (HRM) was performed in the supine position with a special transnasal manometric probe with 36 circumferential pressure transducers in 1 cm intervals. The catheter was positioned to record from pharynx to the proximal stomach (Gastroenterology 2008;135:756–769). The UES, detectable as a high-pressure zone, was analyzed with a special software model (eSleeve), which allowed to analyzed the highest pressure in the UES, irrespective of movement artifacts and the pressure during inspiration and expiration, was determined. This technology overcomes several drawbacks of perfused or Dent-sleeve manometry, such as special and temporal resolution, movement artifacts, and fidelity.

The basal pressure of the UES in healthy controls, GERD patients, and patients with globus sensation was not significantly different, supporting previous findings that the basal pressure is unaltered in globus patients. As described earlier (Gastroenterology 1987;92:466–471), the pressure in the UES showed a characteristic increase with inspiration, which was present in 87% of the patients and both control groups. However, in patients with globus sensation, respiratory fluctuations of the UES pressure were significantly enhanced 3-fold. Normal controls and GERD patients showed only a respiratory increase of UES pressure of 10.6 and 13 .0 mmHg, respectively, whereas globus patients with or without dysmotility showed a respiratory augmentation of 37.3 and 38.5 mmHg, respectively. Of the controls, 95% showed a respiratory augmentation <27 mmHg. Based on this striking differences, the authors defined a “hyperdynamic augmentation” of the UES pressure when a pressure increase of >27 mmHg occurred. This “hyperdynamic augmentation” of the UES was present in >60% of the globus patients and <15% of the controls. This “hyperdynamic augmentation” was independent of the presence or absence of distal esophageal motility disturbances, levels of the UES basal pressure, respiratory variation of the esophagogastric junction or distal esophageal motility, or deglutive UES relaxation. Additionally, there was no correlation of the respiratory augmentation with age.

Interestingly, in 13% of the globus patients, GERD patients or healthy controls showed an inverse pattern of the respiratory modulation of the UES, a pressure increase with expiration was observed. It is not clearly stated whether these patients also showed differences in the respiratory augmentation.

Only 13 of the 131 patients fulfilled the strict Rome III criteria for functional globus. Interestingly, this subgroup of patients with functional globus showed no significant increase of the respiratory augmentation (16 mmHg).

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Comment 

Despite several methodologic limitations (retrospective design, gender and age differences between globus and control groups), the study is interesting and novel in several aspects. It also raises several new questions. It describes a thus far unknown, respiration-linked hyperdynamic status of the UES in patients with globus sensation, irrespective of the presence or absence of dysphagia and reflux symptoms.

The UES is a complex structure composed of striated muscle and the pressure is not myogenic, but caused by a tonic central nervous input mainly from the motor nuclei of the vagal nerves (Arch Intern Med 1976;136:524–531). Several reflex pathways modulating the UES have been described, which link the UES with esophageal and pharyngeal motility, but also with esophageal fluid and acid exposure (Gastroenterology 1977;72:1292–1298; Gastroenterology 1978;75:268–274). Additionally, changes of the UES pressure in response to stress have been reported (Dig Dis Sci 1989;34:672–676). Based on these mechanisms, several reports linked abnormalities of the UES, esophageal motility, or gastroesophageal reflux to the pathogenesis of globus sensation in patients. These include increased pressure in the UES (Dig Dis Sci 1998;43:1513–1517), increased pharyngeal contractions, and swallow-induced contractions of the UES (Arch Otolaryngol Head Neck Surg 1989;115:1086–1090), increased acidic reflux (Laryngoscope 1997;107:1373–1377), increased acid exposure, especially of the proximal esophagus (Gastroenterology 1991;100:305–310), changes or abnormalities of the esophageal motility (Gastroenterology 1991;101:1512–1521), or association with psychological abnormalities (Arch Intern Med 1998;158:1365–1373). However, other studies failed to demonstrate such associations (Clin Otolaryngol Allied Sci 1987;12:271–275; Dig Dis Sci 1998;43:1513–1517; Am J Gastroenterol 1994;89:503–508; Dig Dis Sci 1989;34:672–676). Furthermore, findings such as an association between radiological laryngeal penetration during deglutition (World J Gastroenterol 2002;8:952–955) or the presence and ablation of a gastric inlet patch (Endoscopy 2006;38:566–570) were recently linked with the etiology of globus sensation. However, none of these findings fully explains development and pathogenesis of globus sensations in all patients. The diversity and the differences in the experimental findings published are intriguing. Whether these differences are due to different inclusion criteria, study populations, or differences in methodology is unclear. Since the introduction of multichannel intraluminal impedance recording and high-resolution manometry, several technical shortcomings have been solved and most of the recent data used these advanced techniques (Ann Otol Rhinol Laryngol 2006;115:563). The study by Kwiatek et al supports previous findings that basal pressure of the UES does not distinguish between patients with globus sensation and control patients. On the other hand, they describe a hyperdynamic response of the UES with an augmented respiratory increase of the UES pressure. The respiratory augmentation was observed irrespective of the presence or absence of symptoms (dysphagia, heartburn) or esophageal motility changes (normal abnormal distal esophageal motility). However, the relatively small group of patients that would fulfill the Rome III criteria showed no significant respiratory augmentation. The Rome III classification for functional globus excludes all patients with either erosive or nonerosive gastroesophageal reflux, manometric abnormalities of the esophagus or the upper sphincter, or symptoms of reflux and/or dysphagia (Gastroenterology 2006;130:1459–1465). As documented in the present study, this functional globus is present only in a small minority of patients with globus sensation (∼10%) or patients referred for esophageal evaluation (1%). Thus, the Rome III definition describes only a small but distinct subset of patients in the clinical setting with negative functional findings. Unfortunately, negative findings in this group were not analyzed further, and the respiratory augmentation was not stated when patients with functional globus were excluded. Thus, it remains speculative whether respiratory augmentation could identify patients with globus sensation associated with esophageal symptoms or disorders.

There are conflicting data on the association of globus with gastroesophageal reflux (Laryngoscope 1997;107:1373–1377; Clin Otolaryngol Allied Sci 1987;12:271–275; Dig Dis Sci 1998;43:1513–1517; Am J Gastroenterol 1994;89:503–508). The paper by Kwiatek et al does not provide any detailed information on the respiratory augmentation in patients with or without reflux symptoms, or in patients with or without increased acid exposure or reflux esophagitis. Thus, the association of globus sensation and hyperdynamic UES response to erosive or nonerosive reflux disease remains unclear. This would be of interest for one of several intriguing questions arising. What is the mechanism of the hyperdynamic UES response? Both respiration and UES pressure are centrally regulated, suggesting an involvement of a vagally mediated pathway. How is this hyperdynamic response generated, mediated, and linked with respiratory activity? Is there a hypersensitivity or a hyperreactive state similar to the increased swallow-induced contractions described (Arch Otolaryngol Head Neck Surg 1989;115:1086–1090)? Is there a link with hypersensitive esophagus or other functional disorders? What is the physiologic function of the respiratory augmentation? In a subset of patients and controls UES augmentation occurred during expiration; what functional consequences does this have and why did it occur in such a fixed proportion?

Based on different results of previous studies and the data of the study by Kwiatek et al, one might speculate that different subsets of patients with globus sensation must exist. It remains to be shown whether the respiratory augmentation can be used in prospective studies to identify and eventually subdivide patients with globus sensation. Thus, this study is a piece of the puzzle; it also broadened our picture of globus sensation.