Dysphagia associated with esophageal wall thickening in patients with nonspecific high-resolution manometry findings: Understanding motility beyond the Chicago classification version 4.0.

BACKGROUND: Previous studies have demonstrated that 50% of patients with normal high-resolution manometry (HRM) findings or ineffective esophageal motility (IEM) may have abnormal functional luminal imaging probe (FLIP) results. However, the specific HRM findings associated with abnormal FLIP results are unknown. Herein, we investigated the relationship between nonspecific manometry findings and abnormal FLIP results. METHODS: We retrospectively analyzed 684 patients who underwent HRM at a tertiary care center in Seoul, Korea, based on the Chicago Classification version 4.0 protocol. KEY RESULTS: Among the 684 patients, 398 had normal HRM findings or IEM. Of these 398 patients, eight showed esophageal wall thickening on endoscopic ultrasonography or computed tomography; however, no abnormalities were seen during esophagogastroduodenoscopy. Among these eight patients, seven showed repetitive simultaneous contractions (RSCs) in at least one of the two positions: 61% (±29%) in 10 swallows in the supine position and 51% (±30%) in five swallows in the upright position. Four patients who underwent FLIP had a significantly decreased esophagogastric junction distensibility index (1.0 ± 0.5 m m 2 mmHg - 1 at 60 mL). Two of these patients underwent per-oral endoscopic myotomy (POEM) due to a lack of response to medication. Esophageal muscle biopsy revealed hypertrophic muscle with marginal eosinophil infiltration. CONCLUSIONS & INFERENCES: A subset of patients (2%) with normal HRM findings or IEM and RSCs experienced dysphagia associated with poor distensibility of the thickened esophageal wall. FLIP assessment or combined HRM and impedance protocols may help better define these patients who may respond well to POEM.

Eosinophils Infiltration in Esophageal Muscularis Propria Induces Achalasia-like Esophageal Motility Disorder in Mice.

Eosinophil infiltration in esophageal muscularis propria is common in achalasia (AC). This study aims to evaluate the effect of eosinophil infiltration in muscularis propria of the esophagus on esophageal motility in mice. A mouse model with eosinophil infiltration in the esophageal muscle layer was established by long term Ovalbumin (OVA) exposure. The histopathology features of esophageal muscularis propria as well as parameters of esophageal motility, such as lower esophageal sphincter pressure (LESP) and esophageal emptying, were compared between model and control group. In addition, the histopathology and motility of esophagus at each time point in the model group were compared. The esophageal motor function severely deteriorated in the model group, mimicking the abnormal esophageal motility of AC, with more eosinophils and fewer SOX-10-IR cells in esophageal muscularis propria in the model group, compared with control. With the prolongation of OVA treatment, esophageal motility disorder was aggravated, accompanied by increased eosinophils in the the muscle layer of esophagus and decreased SOX-10-IR cells in the model group. In addition, the eosinophil count was negatively correlated with SOX-10-IR cells. Long-term exposure to OVA assisted by alum may induce eosinophil infiltration in esophageal muscularis propria, reduced SOX-10-IR cells and abnormal esophageal motility, which simulates the functional and histopathological features of some AC patients. This suggests that eosinophil infiltration in esophageal muscularis propria may play a role in the pathogenesis of a subgroup of AC.

Use of the Functional Lumen Imaging Probe in Clinical Esophagology.

The functional lumen imaging probe (FLIP) measures luminal dimensions using impedance planimetry, performed most often during sedated upper endoscopy. Mechanical properties of the esophageal wall and opening dynamics of the esophagogastric junction (EGJ) can be objectively evaluated in esophageal motor disorders, eosinophilic esophagitis, esophageal strictures, during esophageal surgery and in postsurgical symptomatic states. Distensibility index, the ratio of EGJ cross sectional area to intraballoon pressure, is the most useful FLIP metric. Secondary peristalsis from balloon distension can be displayed topographically as repetitive anterograde or retrograde contractile activity in the esophageal body, similar to high-resolution manometry. Real-time interpretation and postprocessing of FLIP metadata can complement the identification of esophageal outflow obstruction and achalasia, especially when findings are inconclusive from alternate esophageal tests in symptomatic patients. FLIP can complement the diagnosis of achalasia when manometry and barium studies are inconclusive or negative in patients with typical symptoms. FLIP can direct adequacy of disruption of the EGJ in achalasia when used during and immediately after myotomy and pneumatic dilation. Lumen diameter measured using FLIP in eosinophilic esophagitis and in complex strictures can potentially guide management. An abbreviated modification of the Grading of Recommendations Assessment, Development, and Evaluation was used to determine the quality of available evidence and recommendations regarding FLIP utilization. FLIP metrics that are diagnostic or suggestive of an abnormal motor pattern and metrics that define normal esophageal physiology were developed by consensus and are described in this review.

Inflammatory conditions of the esophagus: an update.

A variety of inflammatory disorders involve the esophagus. This commentary discusses the pathology of some forms of esophagitis, with an emphasis on recent developments. The initial section focuses on some common forms of nonreflux esophagitis, including lymphocytic esophagitis and eosinophilic esophagitis. Recent studies suggest that lymphocytic esophagitis may be associated with esophageal motility disorders and gastroesophageal reflux disease. Immunophenotypic features of intraepithelial lymphocytes may be helpful in distinguishing these conditions. Updates on the criteria and the limitations of histologic approach to the diagnosis of eosinophilic esophagitis are presented and new diagnostic adjuncts are discussed. In the remaining section, novel entities, such as IgG4-related esophagitis, are discussed. IgG4-related esophagitis has been recognized as a cause of esophageal lymphoplasmacytic inflammation. Increased understanding of esophageal inflammation remains an important goal that likely will lead to new approaches in the therapy of inflammatory esophageal diseases.

Jackhammer esophagus: Clinical presentation, manometric diagnosis, and therapeutic results-Results from a multicenter French cohort.

BACKGROUND/AIMS: Jackhammer esophagus (JE) is a hypercontractile esophageal motor disorder defined by at least two swallows with a distal contractile integral (DCI) >8000 mm Hg.s.cm during high-resolution manometry (HRM). The relationship between symptoms and hypercontractility and the response to therapies have been poorly evaluated. The aim of this study was to determine the clinical presentation, manometric diagnosis, and therapeutic results in a large cohort of JE patients. METHODS: Patients with JE diagnosed among the HRM tests performed in nine academic French centers from 01/01/2010 to 08/31/2016 were included. Patient charts were reviewed to collect clinical and therapeutic data. RESULTS: Among the 16 264 HRM tests performed during this period, 227 patients (60.8 ± 13.8 years, 151 male) had JE (1.7%). Dysphagia was the most frequent symptom (74.6%), followed by regurgitation (37.1%) and chest pain (36.6%); 4.7% of the patients were asymptomatic. The diagnostic workup was heterogeneous, and only a minority of patients had esophageal biopsies. None of the individual symptoms were significantly associated with any of the manometric parameters defined, except for dysphagia, which was significantly associated with the mean of all DCIs >8000 mm Hg.s.cm (P = .04). Additionally, the number of symptoms was not associated with any manometric parameter. Medical treatment and endoscopic treatments had poor efficacy and a high relapse rate. CONCLUSION: Jackhammer esophagus is a rare motility disorder. Diagnostic workup is heterogeneous and should be standardized. Symptoms are poorly associated with manometric parameters. The medical treatments and endoscopic therapies currently used are inefficient.

Durability of Esophageal Motor Disorders Identified on High-Resolution Esophageal Manometry: A Case Series.

BACKGROUND/AIM: Diagnosis of esophageal motor disorders using high-resolution esophageal manometry (HREM) may result in medical, endoscopic or surgical intervention. However, prior to any intervention, durability of the HREM findings should be established. The aim of this case series was to assess 25 patients who had undergone HREM twice, at least 6 months apart, and to determine the durability of the initial manometric diagnosis. METHODS AND PATIENTS: This is a case series of 25 patients who underwent HREM at least twice, 6 months apart, at a large safety net hospital. All patients were evaluated in between the tests for any clinical intervention. Demographics, patients' indication for HREM and clinical presentation were documented as well. RESULTS: Of the 25 patients, HREM results improved in 32%, worsened in 20% and were unchanged in 48%. Some interventions were employed between the first and second HREM diagnosis. Those associated with an improved diagnosis included doubling the proton pump inhibitor (PPI) dose, re-starting a PPI, adding a histamine 2 blocker (H2 blocker) and use of empiric dilation. CONCLUSIONS: In this case series, about half of the patients undergoing two esophageal manometries, at least 6 months apart, demonstrated lack of durability of their initially diagnosed esophageal motor disorder.

Reduced Esophageal Contractility Is Associated with Dysplasia Progression in Barrett's Esophagus: A Multicenter Cohort Study.

BACKGROUND: The incidence of Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) continues to rise, and risk stratification of patients with BE is needed. Impaired esophageal motility is associated with gastroesophageal reflux disease; however, whether esophageal dysmotility is a risk factor for dysplasia progression in BE is incompletely understood. This study aimed to characterize esophageal motility patterns in patients with BE and identify physiologic factors associated with dysplasia progression in BE. METHODS: This multicenter retrospective study assessed data from adult patients with histologically confirmed BE who underwent high-resolution esophageal manometry from 1/2014 to 1/2018 at four tertiary care centers. Longitudinal data were collected when available among patients with non-dysplastic BE (NDBE) and separated as: no dysplastic progression or positive dysplastic progression. Multivariable logistic regression assessed for independent predictors of dysplasia progression. RESULTS: Among 193 patients, histology at index endoscopy identified 152 (79%) NDBE, 23 (12%) low-grade dysplasia, 14 (7%) high-grade dysplasia, and 4 (2%) EAC. Ninety-eight (51%) had abnormal esophageal motor function on manometry. Longitudinal data were available for 84 of 152 patients with initial NDBE. Twelve (14%) exhibited dysplastic progression to low-grade (6) or high-grade (6) dysplasia. Mean esophageal distal contractile integral was lower for patients that progressed [455 mmHg s cm (SD 515)] compared with patients who did not progress [987 mmHg s cm (SD 953); aOR 1.21 (95% CI 1.01, 1.44)]. CONCLUSION: In this retrospective study of 193 BE patients, the majority exhibited abnormal esophageal motor function. Reduced esophageal contractility was independently associated with dysplastic progression in BE. Characterizing esophageal physiology in BE may help to risk stratify patients.

Peroral endoscopic myotomy alone is effective for esophageal motility disorders and esophageal epiphrenic diverticulum: a retrospective single-center study.

BACKGROUND: Esophageal epiphrenic diverticulum (ED) is associated with esophageal motility disorder (EMD). If a diverticulum associated with EMD is enlarging with worsening symptoms, surgical intervention, including laparoscopic epiphrenic diverticulectomy with myotomy and fundoplication, is indicated. However, some studies suggest that myotomy alone, with less adverse events, is sufficient to improve symptoms. Additionally, peroral endoscopic myotomy (POEM) is considered effective and safe for EMD. Since theoretically, POEM is endoscopic Heller myotomy, POEM without diverticulectomy is considered a less invasive, promising treatment option for EMD and ED. We aimed to determine the efficacy and safety of POEM alone for ED with EMD. METHODS: This single-center study was retrospective. A total of 298 patients underwent POEM in Kobe University Hospital from April 2015 to October 2018. Of them, 14 patients had ED. Procedure-related outcomes and treatment outcomes 3 months post POEM were evaluated in these patients. RESULTS: The median maximum ED diameter was 29 (range 9-90) mm; and the median POEM procedure time, 77.5 (range 41-123) min. Pneumoperitoneum, which required needle decompression, occurred in one patient, but no fatal adverse events occurred. The median Eckardt score significantly decreased from 5 [range 2-11] pre POEM to 0 [range 0-2] post POEM (P < 0.0001). The median integrated relaxation pressure significantly decreased from 22.5 [13.9-34.3] mmHg pre POEM to 10.2 [0.7-23.9] mmHg post POEM (P < 0.0001). Of 14 patients, only one patient complained of gastroesophageal reflux disease symptoms, which could be controlled with a potassium-competitive acid blocker. CONCLUSIONS: POEM alone seemed effective and safe for patients with EMD and ED.

Esophageal motility classification can be established at the time of endoscopy: a study evaluating real-time functional luminal imaging probe panometry.

BACKGROUND AND AIMS: A novel device that provides real-time depiction of functional luminal image probe (FLIP) panometry (ie, esophagogastric junction [EGJ] distensibility and distension-induced contractility) was evaluated. We aimed to compare real-time FLIP panometry interpretation at the time of sedated endoscopy with high-resolution manometry (HRM) in evaluating esophageal motility. METHODS: Forty consecutive patients (aged 24-81 years; 60% women) referred for endoscopy with a plan for future HRM from 2 centers were prospectively evaluated with real-time FLIP panometry during sedated upper endoscopy. The EGJ distensibility index and contractility profile were applied to derive a FLIP panometry classification at the time of endoscopy and again (post-hoc) using a customized program. HRM was classified according to the Chicago classification. RESULTS: Real-time FLIP panometry motility classification was abnormal in 29 patients (73%), 19 (66%) of whom had a subsequent major motility disorder on HRM. All 9 patients with an HRM diagnosis of achalasia had abnormal real-time FLIP panometry classifications. Eleven patients (33%) had normal motility on real-time FLIP panometry and 8 (73%) had a subsequent HRM without a major motility disorder. There was excellent agreement (κ = .939) between real-time and post-hoc FLIP panometry interpretation of abnormal motility. CONCLUSIONS: This prospective, multicentered study demonstrated that real-time FLIP panometry could detect abnormal esophageal motility, including achalasia, at the endoscopic encounter. Additionally, normal motility on FLIP panometry was predictive of a benign HRM. Thus, real-time FLIP panometry incorporated with endoscopy appears to provide a suitable and well-tolerated point-of-care esophageal motility assessment.

Esophagogastric junction outflow obstruction: Where are we now in diagnosis and management?

Esophagogastric junction outflow obstruction (EGJOO) is a major motility disorder based on the Chicago Classification of esophageal motility disorders. This entity involves a heterogenous group of underlying etiologies. The diagnosis is reached by performing high-resolution manometry. This reveals evidence of obstruction at the esophagogastric junction, manifested by an elevated integrated relaxation pressure (IRP) above a cutoff value (IRP threshold varies by the manometric technology and catheter used), with preserved peristalsis. Further tests like endoscopy, timed barium esophagram, and cross-sectional imaging can help further elucidate the underlying etiology and rule out mechanical causes. Treatment is tailored to the underlying cause. Similar to achalasia, treatment targeting lower esophageal sphincter disruption like pneumatic dilation, peroral endoscopic myotomy, and botulinum injection are used in patients with functional EGJOO and persistent symptoms.

¿El reflujo gastroesofágico y la aspiración de contenido gástrico están implicados en la etiopatogenia y la progresión de la fibrosis pulmonar idiopática? / Does gastroesophageal reflux and gastric content aspiration have some role in the pathogenesis and progression of Idiopathic Pulmonary Fibrosis?

Resumen El reflujo gastroesofágico (RGE) y la aspiración oculta de contenido digestivo están probablemente implicados en la etiopatogenia y progresión de la fibrosis pulmonar idiopática (FPI). Los mecanismos patogénicos involucrados son la disminución de la distensibilidad pulmonar y el consiguiente aumento de la presión negativa intratorácica durante la inspiración, así como la disminución de los mecanismos de control de la motilidad esofágica o del tono del esfínter esofágico inferior. La prevalencia de RGE y anomalías de la motilidad esofágica están aumentadas en los pacientes con FPI comparado con la población general. Entre los pacientes con FPI, el 67-76% demostraron exposición anormal al contenido ácido en el esófago. Sin embargo, no hubo relación entre la gravedad del RGE y la gravedad de la FPI. Los estudios que han examinado el tratamiento antirreflujo en esta población han sido escasos. Incluso, algunos datos sugieren que el tratamiento antiácido puede ser perjudicial en algunos pacientes con esta condición. Después de analizar toda la evidencia relevante encontrada hasta la fecha, concluimos que no se puede establecer una relación causal entre el RGE, la aspiración del contenido gástrico y la patogénesis de la FPI. Además, existe escasa evidencia clínica que haya examinado el tratamiento antirreflujo en pacientes con fibrosis pulmonar idiopática.

ABSTRACT Gastroesophageal reflux (GERD) and hidden aspiration of gastric contents are probably involved in the pathogenesis and progression of idiopathic pulmonary fibrosis (IPF). The pathological mechanisms involved are decreased pulmonary distensibility and consequent increase of intrathoracic negative pressure during inspiration, as well as decreased control mechanisms of esophageal motility or lower esophageal sphincter. The prevalence of GERD and oesophageal dysmotility was higher in patients with IPF as compared with general population. Among patients with IPF, 67-76% demonstrated abnormal oesophageal acid exposure. However, no relationship was demonstrated between severity of GERD and severity of IPF. Data are scant on outcomes of antireflux treatment in patients with IPF. Actually, some data suggests that antacid treatment may be deleterious in some IPF patients. After analyzing all the relevant evidence found to date, a causal relationship between GERD, gastric content aspiration and IPF pathogenesis cannot be established. There is scant evidence examining antireflux treatment in idiopathic pulmonary fibrosis patients.

Muscle layer thickness affects the peroral endoscopic myotomy procedure complexity.

Esophageal motility disorders can cause severe dysphagia, regurgitation, and/or noncardiac chest pain due to a lack of coordinated esophageal motility function. However, the clinical significance of esophageal muscle layer thickness remains unclear. The aims of this study are to elucidate the clinical significance of esophageal muscle layer thickness in patients with esophageal motility disorders who undergo peroral endoscopic myotomy (POEM), and to identify predictors of a longer POEM procedure time. Seventy-four consecutive patients with esophageal motility disorders who underwent POEM procedures at Kobe University Hospital from April 2015 to December 2016 were prospectively recruited into this study. First, we investigated the associations between the thickness of the esophageal muscular layer and clinical parameters. There were no significant differences, except in the POEM procedure time, between the patients with esophageal muscle layer thickness values of ≥1.5 mm (group A) and <1.5 mm (group B). However, the relative frequency of a longer POEM procedure time (≥78 min) was significantly higher in group A than in group B (66.7% vs. 19.5, P < 0.0001). Next, independent clinical factors that were related to longer POEM procedures were investigated. Multivariate logistic regression analysis with stepwise selection demonstrated that a thick esophageal muscle layer and the length of myotomy were an independent predictor of a longer POEM procedure (odds ratio: 13.9 and 12.0, respectively). Our results indicate that preoperative endoscopic ultrasonography evaluations can help to predict the technical complexity of POEM procedures.

Mucosally Expressed Cytokines are Associated with the Esophageal Motility Function.

BACKGROUND AND AIM: Although basic research has shown that certain cytokines affect gastrointestinal motility, the clinical evidence is lacking. The objective of this study was to explore the association between mucosally expressed cytokines and the esophageal motility function in humans. METHODS: We enrolled a total of 57 patients with suspected esophageal motility disorders (EMDs) who underwent high-resolution manometry. RESULTS: The diagnoses of the patients were as follows: normal esophageal motility (n = 25), ineffective esophageal motility (n = 5), esophagogastric junction outflow obstruction (EGJOO; n = 10), distal esophageal spasm (n = 5), achalasia (n = 10), absent contractility (n = 1), and jackhammer esophagus (n = 1). The expression of tumor necrosis factor (TNF)-α in the esophagogastric junction (EGJ) was significantly higher in EGJOO (14.6, 14.0-15.8, n = 10) than in normal esophageal motility (13.3, 12.8-14.1, n = 25); however, there was no difference in the expression of TNF-α between achalasia (13.4, 13.0-14.1, n = 10) and normal esophageal motility (13.3, 12.8-14.1, n = 25). EGJOO was discriminated from achalasia/normal by a linear discriminant analysis (AUC = 0.917). A multivariable regression analysis revealed that interleukin (IL)-13 and IL-23A were predictive of the distal contractile integral, whereas TNF-α and IL-6 were predictive of the basal EGJ pressure. CONCLUSIONS: The esophageal motility was associated with mucosally expressed cytokines in humans; these cytokines could be useful targets for the diagnosis and treatment of EMDs.

Evaluation of symptomatic esophagogastric junction outflow obstruction.

BACKGROUND AND AIM: Esophagogastric junction outflow obstruction (EGJOO) may be due to anatomical abnormalities, but it is unclear how to evaluate them after high-resolution manometry. We aimed to determine (i) clinical and high-resolution manometry parameters differentiating anatomical EGJOO from functional EGJOO, (ii) investigations chosen and yield for anatomical EGJOO, and (iii) clinical outcomes of functional EGJOO. METHODS: Medical records of consecutive patients with symptomatic EGJOO from February 2012 to December 2015 were reviewed. EGJOO was defined as anatomical if investigations identified a macroscopic or microscopic pathology accounting for EGJOO. RESULTS: Forty of 292 (13.7%) had EGJOO, of which 6/40 (15%) had anatomical EGJOO (two PPI-responsive esophageal eosinophilia, two infiltrating cancers, and two external compressions). Anatomical EGJOO was more likely to present with dysphagia (100% vs 29.4%, P = 0.001) and less likely with regurgitation (0% vs 41.2%, P = 0.05). Anatomical EGJOO had higher frequencies of premature contraction (50% vs 5.9%, P = 0.003) and lower mean values of distal latency (5.6 +/- 1.3 vs 6.7 +/- 1.2, P = 0.004). Computed tomography scans revealed 50% (3/6) of etiologies of anatomical EGJOO. Approximately, 73.5% (25/34) of patients with functional EGJOO had spontaneous resolution of their symptoms. One underwent pneumatic dilatation with symptom resolution while remaining eight with persistent symptoms were attributed to gastroesophageal reflux disease. CONCLUSION: Anatomical causes are present in 15% of EGJOO. Evaluation is warranted especially in patients presenting with dysphagia. Esophageal biopsies, barium swallows, computed tomography scans, and endoscopic ultrasound are complementary in EGJOO evaluation. In patients with non-obstructive symptoms and no anatomical etiologies, monitoring for spontaneous resolution is an option.

Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology.

High-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) have contributed significantly to the field of esophageal motility disorders in recent years. The development of HRM has categorized various esophageal motility disorders with a focus on a diverse range of manometric anomalies. Additionally, the Chicago classification criteria is widely used for manometric diagnosis. Moreover, POEM was introduced as a minimally invasive radical therapy for achalasia and shows promise for other spastic esophageal motility disorders as well. POEM has also enabled a transluminal endoscopic approach for determining the histology of the esophageal muscle layer, which is expected to assist in elucidating the etiology of disorders associated with esophageal motility. The purpose of this review is to update the diagnosis, pathology, and treatment of esophageal motility disorders, with a focus on the recent advances in this field.

Primary Esophageal Motility Disorders: Beyond Achalasia.

The best-defined primary esophageal motor disorder is achalasia. However, symptoms such as dysphagia, regurgitation and chest pain can be caused by other esophageal motility disorders. The Chicago classification introduced new manometric parameters and better defined esophageal motility disorders. Motility disorders beyond achalasia with the current classification are: esophagogastric junction outflow obstruction, major disorders of peristalsis (distal esophageal spasm, hypercontractile esophagus, absent contractility) and minor disorders of peristalsis (ineffective esophageal motility, fragmented peristalsis). The aim of this study was to review the current diagnosis and management of esophageal motility disorders other than achalasia.

Ineffective esophageal motility: clinical, manometric, and outcome characteristics in patients with and without abnormal esophageal acid exposure.

The etiology and clinical impact of ineffective esophageal motility (IEM) remain poorly understood. Unless gastroesophageal acid reflux (GERD) is identified, symptomatic patients with IEM are challenging to treat. We sought to determine whether any clinical or functional characteristics could distinguish those patients with IEM and either normal or abnormal esophageal acid exposure.In this retrospective cohort study, we identified 46 consecutive patients presenting with heartburn, and other GER symptoms who underwent clinical, endoscopic, and functional evaluation that included high-resolution manometry (HRM) and ambulatory pH monitoring. IEM was defined using the Chicago Classification criteria (v.3) as ≥50% ineffective swallows (DCI ≤ 450 mmHg.s.cm). Esophageal acid exposure by ambulatory pH monitoring was considered abnormal when total time with esophageal pH < 4 exceeded 4.2%.Of the 46 IEM patients identified, 19 (mean age: 42 years, 37% female), had normal esophageal acid exposure and 27 patients, mean age 54 years, 33% female, evidence of pathologic acid reflux. There was a 12 years age difference between the groups, with those with normal acid exposure being significantly younger (P < 0.01); the mean body mass index (BMI) was 22.6 ± 0.6 in the normal group and 25.4 ± 0.7 in the abnormal group (P < 0.001); otherwise the groups were endoscopically and histologically similar. Symptoms were not discriminatory and heartburn and regurgitation were the most prevalent in both groups. HRM did not discriminate symptomatic patients with IEM and either normal or abnormal esophageal acid exposure. Proton pump inhibition (PPI) therapy was significantly more effective (74% vs. 10%) in patients with pathologic acid reflux (P < 0.001). As pH exposure becomes abnormal in the context of IEM, there is dominance for supine reflux.IEM appears to be an early, primary event, eventually associated with pathologic acid exposure, particularly supine. Higher BMI is also associated with abnormal esophageal acid exposure in such patients. GER symptoms are not discriminatory in patients with IEM with and without underlying pathologic acid reflux. Clinical response to PPI in such patients depends on the presence of esophageal pathologic acid exposure. Those with IEM and normal acid exposure remain symptomatic and mostly resistant to therapy.