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

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1 Diseases of the Esophagus (2017) 30, 1 8 DOI: /dote/dox012 Original Article Ineffective esophageal motility: clinical, manometric, and outcome characteristics in patients with and without abnormal esophageal acid exposure K. P. Shetler, 1 S. Bikhtii, 1 G. Triadafilopoulos 2 1 Department of Gastroenterology, Palo Alto Medical Foundation, Mountain View, California, USA and 2 Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA SUMMARY. 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. KEY WORDS:: esophageal motility, esophageal ph monitoring, gastroesophageal reflux disease, high-resolution esophageal manometry. ABBREVIATIONS: DCI: distal contractile integral; EGJ: esophagogastric junction; EPT: esophageal pressure topography; GERD: gastroesophageal reflux disease; HRM: high-resolution manometry; IEM: ineffective esophageal motility; IRP: integrated residual pressure; LESP: lower esophageal sphincter pressure; PPI: proton pump inhibitors INTRODUCTION Address correspondence to: George Triadafilopoulos, MD, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, 300 Pasteur Drive, M-211, Stanford, CA 94306, USA. vagt@stanford.edu Grant Support: None. Disclosures: None. Specific author contributions: Planning and/or conducting the study: Sergii Bikhtii, Katerina P. Shetler, George Triadafilopoulos; Collecting and/or interpreting data: Sergii Bikhtii, Katerina Ineffective esophageal motility (IEM) is characterized by both failed peristalsis and frequent swallows with breaks in the middle/distal peristaltic wave and it may result in symptoms reflecting poor esophageal P. Shetler, George Triadafilopoulos; Drafting the manuscript and revision: Katerina P. Shetler, George Triadafilopoulos. C The Authors Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please journals.permissions@oup.com 1

2 2 Diseases of the Esophagus emptying. As such, IEM may play a role in gastroesophageal reflux disease (GERD) and nonobstructive dysphagia. 1 The definition of IEM has evolved after the introduction of high-resolution manometry (HRM), esophageal pressure topography (EPT), and the Chicago Classification of esophageal motility, that in its second version defined IEM as weak peristalsis, small (2 5 cm) and large (over 5 cm) peristaltic defects, or frequent (>30%) failed peristalsis. 2 More recently however, the updated third version of the Chicago Classification eliminated small and large breaks from the list of criteria and defined ineffective swallows by a DCI < 450 mmhg.s.cm with 50% ineffective swallows constituting IEM, thus eliminating the distinction between failed swallows and weak swallows. 3 IEM, as well as fragmented peristalsis, is considered as minor disorders of peristalsis and their clinical significance remains debatable. Regardless, the pathophysiology of IEM is unclear. The condition may result from an intermittent defect in triggering distal esophageal peristalsis with or without weakness of the muscle contraction, possibly due to release of inflammatory mediators, such as interleukin-6 and platelet activating factor, that are known to reduce acetylcholine release from excitatory myenteric neurons. 4 Abnormalities in peristalsis may lead to abnormal esophageal clearance and dysphagia. 1,5 Failed peristalsis and weak peristalsis with large defects are uniformly associated with incomplete bolus transit (IBT) (sensitivity 71%, specificity 100%). In contrast, weak peristalsis with small defects (in the range of 2 5 cm) is variably associated with IBT (16% of instances) (sensitivity 100%, specificity 84%). 6 8 Clinically, patients with IEM represent a heterogeneous group, with an array of intermittent symptoms, such as dysphagia, heartburn and regurgitation, chest fullness or pain and frequent need for throat clearing, variable degrees of esophageal ineffective peristaltic severity and frequently, but not universally, by pathologic esophageal acid exposure times. The esophageal clearance also depends on the type: liquid versus viscous material used under physiological conditions and during HRM. For example, up to 1/3 (32.9%) of patients may have normal bolus transit for both liquid and viscous swallows, and almost 1 / 4 of the patients with IEM and abnormal bolus transit for liquid shows normal bolus clearance with viscous material. 9 IEM, attributed to acid-related effects on esophageal muscle contractility, is found in 21% 38% of patients with GERD and is thought to be associated with more severe esophageal acid exposure and symptoms. 10,11 Intriguingly however, IEM can be observed in patients without any evidence of GERD; in such cases, its pathogenesis is almost unknown and its treatment challenging. 12,13 Despite the prevalence and putative clinical impact of IEM, a systematic analysis of cohorts of patients with IEM has not been undertaken. In this retrospective cohort analysis, we sought to determine any clinical, functional and outcome characteristics that would distinguish IEM patients who either exhibit normal or abnormal esophageal acid exposure. PATIENTS AND METHODS Patients This retrospective cohort study was approved by the Institutional Research Board of El Camino Hospital and was conducted at the Neurogastroenterology and Motility Center of Silicon Valley Gastroenterology, in Mountain View, CA. The study was considered exempt from the need for individual informed consent from participating patients. Inclusion criteria We included consecutive patients with IEM, defined using HRM, who were all evaluated because of dysphagia, heartburn, acid regurgitation, chest pain, and/or belching. A detailed review of patient s medical, endoscopic, manometric, ph, and histological records was then performed to ensure proper inclusion in the study (see study flow in Fig. 1). Upon presentation, all patients in the cohort were symptomatic with esophageal complaints that were recorded upon questioning and formal questionnaire-based assessment. Exclusion criteria Patients <18 years old, those with known obstructive esophageal disease by endoscopy (i.e. cancer, stricture), systemic illnesses, scleroderma, esophagogastric junction (EGJ) outflow obstruction (mean integrated relaxation pressure 15 mmhg), achalasia, absent peristalsis (100% of swallows with failed peristalsis), diffuse esophageal spasm, hypercontractile esophagus, rapid contraction with normal latency, or hypertensive peristalsis, as defined by the Chicago classification (v3) and those who had previously undergone esophageal surgery (i.e. antireflux surgery or myotomy) or endoscopic intervention (i.e. transoral fundoplication) were excluded. Patients with atypical (ENT or respiratory) symptoms only and those with oropharyngeal dysphagia without associated esophageal symptoms were also excluded. Upon presentation, none of the patients were receiving medication affecting esophageal motility. Of note, the study, albeit community based, was on a referral population to a motility unit with emphasis on esophageal disease.

3 Ineffective esophageal motility and acid reflux 3 Fig. 1 Study flow diagram. Of the 223 patients with GER symptoms evaluated using HRM and ph monitoring 177 were excluded since they did not fulfill criteria for IEM or because of other exclusion criteria (see Methods). Questionnaires In order to qualify for inclusion into the study, patients had to be symptomatic on a simple and previously validated questionnaire. In this questionnaire, the symptoms were graded with scores for dysphagia, heartburn, regurgitation, lower chest pain, and belching (0 = no symptom, 1 = mild symptom, 2 = moderate symptom, and 3 = severe symptom, occurring at various frequencies [once a week = 0, 2 to 6 times a week = 1,7to15timesaweek= 2, and more than 15 times a week = 3]). 14 Patients were deemed symptomatically completely controlled using proton pump inhibitors (PPI) if upon followup, their questionnaire values were zero. In contrast, patients with questionnaire scores above zero were considered as exhibiting incomplete response to PPI therapy. Since available therapies for IEM are sparse, all study patients were given a twice-daily PPI trial, given the potential of these drugs to reduce gastric volume and thereby volume reflux. 15 Patients were then reassessed 2 months later for PPI responsiveness. Many of these patients underwent additional pharmacologic (i.e. H2 blockade, prokinetics), endoscopic (i.e. Stretta), or surgical therapies (i.e. antireflux surgery) for symptom control (data not shown). Endoscopy and biopsies Upper endoscopy with random proximal and distal esophageal biopsies as well as targeted biopsies of esophageal lesions was performed as part of the structural assessment of the cohort. Patients were classified in various disease categories as follows: Normal: Endoscopy-negative; Erosive esophagitis: endoscopy-positive for any LA classification grades; Barrett s esophagus (BE): Endoscopically visible and histologically proven intestinal metaplasia. Sliding hiatal hernia was defined endoscopically and also confirmed by HRM and graded in cm length. Esophagitis and BE were also independently assessed histologically using standard criteria Ambulatory ph monitoring Esophageal ambulatory ph monitoring was performed off PPI therapy using a dual-sensor impedance/ph catheter connected to a portable digital data recorder that stored data for up to 24 hours or a wireless 48-hour Bravo ph system (Medtronic, Sunnyvale, CA). The positioning of the ph catheter was established based on the ph difference between the distal (gastric) and proximal (esophageal) sensors and previous lower esophageal sphincter (LES) identification by HRM or directly, upon demarcation of the EGJ during endoscopy. The catheter s distal sensor recorded ph 10 cm below the gastroesophageal junction and its proximal sensor recorded 5 cm above the LES; the Bravo ph capsule was placed 6 cm proximal to the EGJ. Patients were instructed to carry out normal daily activities without dietary restrictions during the study. No instructions

4 4 Diseases of the Esophagus Table 1 Demographics, endoscopic, and histologic findings in IEM patients with and without abnormal esophageal acid exposure Normal ph N = 19 Abnormal ph N = 27 P-value Mean age ± SEM (range) 42 ± 3 (22 68) 54 ± 2 (29 72) 0.01 Female gender 7 (37%) 9 (33%) NS BMI ± SEM (range) 22.3 ± 0.6 (17 27) 25.4 ± 0.7 (19 34) Endoscopy Normal (%) NS Erosive esophagitis (%) 1 3 NS Barrett s esophagus (%) 0 3 NS Hiatal hernia (%) 2 6 NS Histology Normal (%) NS Esophagitis (%) 4 6 NS Barrett s esophagus 0 3 NS Ambulatory ph %phtime<4.0 (±SEM) 1.15 ± ± 9 < DeMeester score (±SEM) 5.7 ± ± 35 < BMI, body mass index; IEM, ineffective esophageal motility; SEM, scanning electron microscope. were given in regards to consumption of food or drink between dinner and bedtime. The ph data were analyzed using the standard software. The ph test was considered abnormal when total esophageal ph < 4 was over 4.2% of the time or the DeMeester score was over In the patients who underwent wireless ph monitoring, the data from the day with the worse ph profile was used. Patients were divided into two groups, those with normal and those with abnormal esophageal acid exposure. Total ph times <4.0 as well as upright and supine times were recorded as percentages. High-resolution manometry A solid-state HRM catheter with 4.2 mm outer diameter with 36 circumferential sensors located at 1 cm intervals was used for the study (Medtronic, Sunnyvale, CA). Manometric studies were performed with patients in supine position after at least a 6-hour fast. The HRM catheter was placed transnasally and positioned to record from the hypopharynx to the stomach. The manometric protocol included baseline recording and ten 5 ml water/saline swallows. The high-resolution EPT of each swallow was analyzed for integrity of the 20 mmhg isobaric contours. The length of the break within 20 mmhg isobaric contour (IBC) was measured using the smart mouse tool in ManoView Software (Medtronic, Sunnyvale, CA). Esophageal peristalsis was defined as intact if no break longer than 5 cm was observed within the IBC. The final diagnosis was made according to the Chicago Classification v.3, where ineffective swallows were characterized by a DCI 450 mmhg.s.cm and IEM was defined as 50% ineffective swallows. Fragmented peristalsis was also recorded, defined as 50% swallows with large (>5 cm) defects in the 20 mmhg isobaric contour and a DCI 450 mmhg.s.cm. 3 Individual swallows were excluded from analysis in case of double or multiple swallows that could lead to deglutitive inhibition of peristalsis. Statistics Statistical analysis was performed using a commercial statistical software (Minitab Express). The two-tailed t-test was used to compare continuous variables. For all statistical analyses, the level of significance was set at p < Results are depicted as tables, bar graphs, and box plots, as needed. RESULTS Figure 1 depicts the study flow. Out of 223 patients presenting with various GER symptoms and studied by both HRM and ambulatory ph monitoring, 177 were excluded since they did not fulfill the Chicago classification (v.3) criteria for IEM (n = 160), or if they did, they had previous esophagogastric surgery (n = 6), eosinophilic esophagitis (n = 4), scleroderma, 5 or EGJ outflow obstruction (n = 2). Therefore, our study cohort consisted of 46 symptomatic patients with IEM who had undergone ambulatory ph monitoring off acid suppressive therapy: 20 patients had ambulatory 24-hour ph/impedance monitoring and 26 patients had Bravo ph monitoring. The overall prevalence of IEM was 63/223, or 28%. Nineteen patients, mean age 42 years, 37% female, had normal esophageal acid exposure and 27 patients, mean age 54 years, 33% female, had evidence of pathologic acid reflux (Table 1). There was a 12 years age difference between the groups, with those with normal acid exposure being significantly younger (P < 0.01) and without gender differences. 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). The

5 Ineffective esophageal motility and acid reflux 5 Fig. 2 GER symptom scores in patients IEM and normal or abnormal esophageal acid exposure. Although heartburn and regurgitation were the most prominent symptoms, there were no differences between the two groups for any GER symptoms assessed. Table 2 HRM parameters in patients with IEM with and without abnormal esophageal acid exposure HRM parameters Normal ph N = 19 Abnormal ph N = 27 P-value Mean LESP ± SEM (range) 21.7 ± 3.0 ( mmhg) 21.8 ± 2.1 ( mmhg) NS Mean residual LESP (range) 8.5 ± 0.7 ( mmhg) 9.4 ± 0.5 ( mmhg) NS Hiatal hernia (manometric) 12%, mean length: 1.5 cm 22%, mean length: 2.5 cm NS Mean DCI ± SEM (range) 284 ± 38 (10 446) 306 ± 28 ( ) NS % Fragmented peristalsis (mean ± SEM) 48 ± 5 43± 5 NS DCI, distal contractile integral; HRM, high-resolution manometry; IEM, ineffective esophageal motility; LESP, lower esophageal sphincter; SEM, scanning electron microscope. ph profiles of the two groups were de facto significantly different (P < 0.001); otherwise the groups were endoscopically and histologically similar (Table 1). In terms of symptom prevalence, dysphagia was noted in 37% and 48% (p = 0.45) in the normal and abnormal ph groups respectively; similarly, heartburn was seen in 79% and 81% (p = 0.8), regurgitation in 79 and 81% (p = 0.8), chest pain in 53% and 48% (p = 0.77), and belching in 32% and 66% (p = 0.11) (data not shown). Figure 2 highlights the symptom scores in the two groups: Heartburn and regurgitation were significantly more severe, but all symptoms were not discriminatory and collectively a clinical distinction based on symptoms could not be made between the two groups. Specifically for the two groups, dysphagia scores were 0.57 and 0.88 (95%CI: 0.9, 0.2, p = 0.29), heartburn scores were 1.52 and 1.48 (95%CI: 0.6, 0.6, p = 0.88), regurgitation 1.84 and 1.33 (95%CI: 0.16, 1.18, p = 0.13), chest pain 1.10 and 0.88 (95%CI: 0.47, 0.9, p = 0.52) and belching 0.57 and 0.66 (95%CI: 0.6, 0.5, p = 0.77). There were no statistically significant differences in the HRM parameters between the two groups Fig. 3 Percent complete response to PPI therapy in patients with IEM with and without abnormal esophageal acid exposure. (Table 2). Figure 3 outlines the clinical outcomes with PPI therapy in the two groups. The majority (74%) of patients with abnormal acid exposure responded well to acid suppressive therapy with PPI in contrast to only 10% of patients with IEM and normal ph studies (95%CI: 0.8, 0.38, P < ). Patients

6 6 Diseases of the Esophagus Fig. 4 Total, upright, and supine esophageal ph profiles in patients with IEM with (bottom) and without (top) abnormal esophageal acid exposure times. The box plots reveal that the two groups not only differ by definition in terms of total esophageal reflux (P < ), but also in terms of the magnitude of supine acid exposure as compared to upright (P < 0.004). with normal acid reflux remain resistant to endoscopic and any additional therapy (data not shown). Analysis of the upright and supine profiles of the two groups revealed that in the group of normal acid exposure the upright and supine percentages were 1.67 and 0.45 (95%CI: 0.41, 2.02, P < 0.004), while this was not the case in the group of abnormal acid exposure where the upright and supine percentages were 13.0 and 15.6 (95%CI: 10.2, 5.1, p = 0.5) (Fig. 4). These data suggest that, as ph exposure becomes abnormal in the context of IEM, there is dominance for supine reflux. DISCUSSION The aim of this study is to identify any clinical or functional characteristics that could distinguish those patients with IEM and either normal or abnormal esophageal acid exposure. We found that heartburn and regurgitation and not dysphagia are the most prevalent symptoms in patients with IEM irrespective of underlying pathologic reflux but that the clinical response to PPI therapy in such patients depends on the presence of such reflux. These results have several key clinical implications: First, since HRM cannot discriminate symptomatic patients with IEM and either normal or abnormal esophageal acid exposure, ambulatory esophageal ph monitoring is essential to recognize GERD and guide selection and duration of therapy. Second, IEM appears to be a primary event, potentially leading to GERD in certain patients and not a sequel to pathologic acid exposure. Third, a substantial number of patients with GER symptoms but without abnormal esophageal acid exposure suffer from IEM that is resistant to PPI therapy and require other interventions, such as the use of prokinetics. Similar to our study, IEM has been found to be a frequent motility disorder in patients with GERD with or without Barrett s esophagus with prevalence up to 49.4% 20 and it is the most likely cause of the dysphagia seen in this group of patients. 21 Kahrilas et al. showed that bolus retention resulted from weakened peristaltic contractile wave at that level in patients with peptic esophagitis. 22 Ghosh et al. analyzed 17 concurrent HRM and imaging studies in healthy subjects and nine studies in esophagitis patients and determined that the length of the manometrically defined transition zone in the esophagitis patients was approximately 2.5 cm wider as compared to controls (7.4 cm [ cm] vs. 4.9 cm [ cm]), occupied a greater proportion of esophageal length (33% vs. 19%) and led to abnormal bolus clearance. 23 In our cohort, IEM and fragmented peristalsis were similar and independent of the underlying presence of esophageal pathologic acid exposure, suggesting that the process leading to these minor disorders of peristalsis might be a primary event. Indeed, the fact that the patients with normal ph exposure were 12 years younger than those with pathologic GERD implies that the motor abnormalities occur first, followed by those of ph. Although the group of patients with IEM and abnormal esophageal exposure were statistically more likely to be obese, there is no biological plausibility to attribute IEM to obesity, but there is no doubt that higher BMI would contribute to acid reflux. Transition zone defects can lead to the bolus retention, dysphagia, and associated GERD. Finding a consistent defect associated with poor bolus transit or proximal escape may be associated with dysphagia, pill esophagitis, and a sensation of proximal pressure and regurgitation. Abnormal esophageal peristalsis may be seen in GERD and systemic disorders, such as diabetes mellitus and scleroderma, typically as a result of nerve dysfunction and subsequent smooth muscle fibrosis, 24 but this was not studied in our series since all the patients in the cohort had no systemic illnesses. Delayed or abnormal activation of the excitatory cholinergic neurons in the smooth muscle esophagus may be contributing to those defects. Such motor abnormality may play a permissive role for gastroesophageal reflux due to lack of esophageal clearance

7 Ineffective esophageal motility and acid reflux 7 or the motor abnormality itself may be the result of chronic esophageal exposure to injurious gastroduodenal refluxate, as, we believe, our data suggest. In a similar fashion to our study, in the one of Leite et al., patients with IEM demonstrated significant increase in recumbent median percentage of time of ph < 4 (4.5%) and median distal esophageal acid clearance (4.2 min/episode), similar to that seen in patients with systemic sclerosis (5.4%, 4.2 min/episode). 25 There are no good therapeutic options for restoring esophageal peristalsis in patients with IEM. Multiple agents have been tried in order to improve of bolus transit, but they are not widely used due to their nonavailability, side effects, or unproven efficacy. 12 In some cases, antireflux surgery may not only improve reflux symptoms but also reduce dysphagia. 10 The 5-HT4 agonists, such as cisapride and tegaserod, may improve bolus transport by enhancing esophageal contractility at the transition zone level, but neither of these agents is available for clinical use today Administration of psychotropic drugs may be also used to treat visceral hypersensitivity present in many patients with IEM, 29 but this was not examine in our study. Empiric PPI therapy is a reasonable approach, as the motor abnormality may either play a permissive role for gastroesophageal reflux due to lack of appropriate clearance, or the motor abnormality itself may be the result of chronic esophageal exposure. 30 In our study, we were able to assess the responsiveness to PPI because all our patients, irrespective of their ph profiles, were treated empirically, aiming either to control esophageal acid exposure, volume reflux, or both. Complete PPI response was seen in 74% of patients with abnormal ph profiles, consistent with other studies. 31 In contrast, patients with IEM and normal acid exposure remained symptomatic and mostly resistant to therapy. A number of studies have suggested that injecting botulinum toxin into the LES of patients with esophageal motility disorders not only improved dysphagia and regurgitation, but also decreased chest pain, albeit temporarily. Miller et al. treated 29 patients with esophageal motility abnormalities (including IEM) with injection of 100 IU of botulinum toxin into the LES. There was 79% reduction in the mean chest pain score from 3.7 to 0.78 (P < ) and a reduction in the mean heartburn score (56%) from 1.5 ± 0.39 to 0.7 ± 0.22 (P < 0.06). 32 Some of our patients with IEM, normal ph profiles and dysphagia, proceeded with botulinum toxin injection to the LES with good results. The role of empiric dilation or botulinum toxin injection to the LES is controversial, but may be an option with continuous dysphagia despite PPI therapy. Given its retrospective cohort design, there are some notable limitations to our study. First, this is a selected patient cohort with significant esophageal symptoms who underwent HRM and ph monitoring and were found to have IEM. To what degree the 26% prevalence of IEM and its clinical, manometric, and outcome features would be applicable to the general population with GER symptoms who are not referred or studied at a gastroenterology unit is unclear. One would also argue that the small number of patients studied is inadequate to draw strong conclusions. However, the definition of IEM has become stricter with the Chicago v.3 that eliminates small and large breaks on HRM as its criteria, thereby making such patients harder to find. 3 Second, although efforts were made to ensure effectiveness of therapy using our standard questionnaires, their validity has not been proven in patients with IEM. Nevertheless, this was not an interventional trial and detailed quantification may not be as critical. Third, other the empiric twice-daily PPI therapy, patients in the study did not have standardized medical, endoscopic or other therapies, or longer-term follow-up. Such follow up would be important if one were to further substantiate the notion that IEM is a primary event that may evolve into IEM with pathologic acid exposure. Further, since not all of our patients underwent impedance testing, our data are limited only to ph and HRM correlates. Nevertheless, we were able to examine a sizeable cohort of symptomatic, community-based IEM patients with and without GERD, with good generalizability. Larger scale and longitudinal multicenter trials will be needed to further phenotypically characterize IEM with its clinical implications and response to therapy. In conclusion, heartburn and regurgitation not dysphagia are most prevalent in patients with IEM, irrespective of underlying pathologic reflux. HRM does not discriminate symptomatic patients with IEM and either normal or abnormal esophageal acid exposure. 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