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Background and Purpose: Ineffective esophageal motility (IEM) is the most frequently diagnosed esophageal motility abnormality and characterized by diminished esophageal peristaltic vigor and frequent weak, absent, and/or fragmented peristalsis on high-resolution esophageal manometry. Despite its commonplace occurrence, this condition can often provoke uncertainty for both patients and clinicians. Although the diagnostic criteria used to define this condition has generally become more stringent over time, it is unclear whether the updated criteria result in a more precise clinical diagnosis. While IEM is often implicated with symptoms of dysphagia and gastroesophageal reflux disease, the strength of these associations remains unclear. In this review, we share a practical approach to IEM highlighting its definition and evolution over time, commonly associated clinical symptoms, and important management and treatment considerations. We also share the significance of this condition in patients undergoing evaluation for anti-reflux surgery and consideration for lung transplantation., (© 2024 John Wiley & Sons Ltd.)

Background: Esophagogastric junction outflow obstruction (EGJOO) is a heterogenous disorder in which the correct management strategy is unclear. We assessed whether functional lumen imaging probe (FLIP) topography data could select EGJOO, which would benefit from lower esophageal sphincter Botulinum toxin (Botox) injection., Methods: This was a single-center prospective study of adult patients meeting Chicago Classification (CC) v3.0 criteria for EGJOO. We assessed differences in pretreatment physiologic measurements on high-resolution manometry (HRM) and FLIP and other relevant clinical variables in predicting Botox response (>50% in BEDQ at 2 months)., Key Results: Sixty-nine patients were included (ages 33-90, 73.9% female). Of these, 42 (61%) were Botox responders. Majority of physiologic measures on HRM and FLIP and esophageal emptying were not different based on Botox response. However, a spastic-reactive (SR) FLIP contractile response (CR) pattern predicted a Botox response with OR 25.6 (CI 2.9-229.6) when compared to antegrade FLIP CR; and OR for impaired-disordered/absent CR was 22.5 (CI 2.5-206.7). Logistic regression model using backward elimination (p value = 0.0001, AUC 0.79) showed that a SRCR or IDCR/absent response and the upright IRP predicted Botox response. Response rates in tiered diagnostic groups were: (i) CCv3.0 EGJOO (60.9%), (ii) CCv4.0 EGJOO (73.1%), (iii) CCv4.0 + FLIP REO (80%), (iv) CCv4.0, FLIP REO, and abnormal FLIP CR (84.2%), and (v) CCv4.0, FLIP REO, and SR FLIP CR (90%)., Conclusions and Inferences: FLIP helps identify patients with EGJOO who are likely to response to LES Botox therapy. An abnormal FLIP contractile response pattern is the single-most important predictor of a Botox response., (© 2024 John Wiley & Sons Ltd.)

Background: Esophageal motility disorders can be diagnosed by either high-resolution manometry (HRM) or the functional lumen imaging probe (FLIP) but there is no systematic approach to synergize the measurements of these modalities or to improve the diagnostic metrics that have been developed to analyze them. This work aimed to devise a formal approach to bridge the gap between diagnoses inferred from HRM and FLIP measurements using deep learning and mechanics., Methods: The "mechanical health" of the esophagus was analyzed in 740 subjects including a spectrum of motility disorder patients and normal subjects. The mechanical health was quantified through a set of parameters including wall stiffness, active relaxation, and contraction pattern. These parameters were used by a variational autoencoder to generate a parameter space called virtual disease landscape (VDL). Finally, probabilities were assigned to each point (subject) on the VDL through linear discriminant analysis (LDA), which in turn was used to compare with FLIP and HRM diagnoses., Results: Subjects clustered into different regions of the VDL with their location relative to each other (and normal) defined by the type and severity of dysfunction. The two major categories that separated best on the VDL were subjects with normal esophagogastric junction (EGJ) opening and those with EGJ obstruction. Both HRM and FLIP diagnoses correlated well within these two groups., Conclusion: Mechanics-based parameters effectively estimated esophageal health using FLIP measurements to position subjects in a 3-D VDL that segregated subjects in good alignment with motility diagnoses gleaned from HRM and FLIP studies., (© 2024 The Author(s). Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disorder, and more than 80% of PD patients will develop oropharyngeal dysphagia. Despite its striated histology, proximity to airway, and potential negative impact of its dysfunction on bolus transport and airway safety, the contractile function of the striated esophagus in PD patients has not been systematically studied., Methods: Using our repository of clinical manometry and the Milwaukee ManoBank, we analyzed high-resolution manometry (HRM) studies of 20 PD patients, mean age 69.1 (range 38-87 years); 30 non-PD patients with dysphagia, mean age 64.0 (44-86 years); and 32 healthy volunteers, mean age 65.3 (39-86 years). Patients with abnormal findings based on Chicago Classification 4.0 were identified. Repeat analysis was performed in 20% of the manometric tracings by a different investigator with inter-rater concordance between 0.91 and 0.99., Key Results: The striated esophageal contractile integral in PD patients was significantly lower than that in non-PD dysphagic patients and healthy controls (p = 0.03 and <0.01, respectively). This significant difference persisted after excluding patients with concurrent Chicago Classification motility disorders (p = 0.02 and 0.01, respectively). In both analyses, the distal esophageal contractile integral did not show any significant difference between groups (p = 0.58 and 0.93, respectively)., Conclusions & Inferences: PD is associated with a significant decrease in striated esophagus contractility compared to non-PD and healthy controls. This finding may play a pathophysiologic role in development of dysphagia in this patient population., (© 2024 John Wiley & Sons Ltd.)

Background: Diabetes Mellitus (DM) is known to induce a wide range of harmful effects on several organs, notably leading to ineffective esophageal motility (IEM). However, the relationship between DM and IEM is not fully elucidated. We aimed to determine the relationship between DM and IEM and to evaluate the impact of DM's end organ complications on IEM severity., Methods: A multicenter cohort study of consecutive patients undergoing high-resolution esophageal manometry (HREM) was performed. We reviewed medical records of patients diagnosed with IEM using HREM, encompassing data on demographics, DM history, antidiabetic and other medications as well as comorbidities., Key Results: Two hundred and forty six subjects met the inclusion criteria. There was no significant difference in any of the HREM parameters between diabetics and nondiabetics. Out of 246 patients, 92 were diabetics. Diabetics with neuropathy presented a significantly lower distal contractile integral (DCI) value compared to those without neuropathy (248.2 ± 226.7 mmHg·cm·sec vs. 375.6 ± 232.4 mmHg·cm·sec; p = 0.02) Similarly, the DCI was lower in diabetics with retinopathy compared to those without retinopathy (199.9 ± 123.1 mmHg·cm·sec vs. 335.4 ± 251.7 mmHg·cm·sec; p = 0.041). Additionally, a significant difference was observed in DCI values among DM patients with ≥2 comorbidities compared to those without comorbidities (224.8 ± 161.0 mmHg·cm·sec vs. 394.2 ± 243.6 mmHg·cm·sec; p = 0.025). Around 12.6% of the variation in DCI could be explained by its linear relationship with hemoglobin A1c (HbA1c), with a regression coefficient (β) of -55.3., Conclusion & Inferences: DM is significantly associated with IEM in patients with neuropathy, retinopathy, or multiple comorbidities. These results are pivotal for tailoring patient-specific management approaches., (© 2024 John Wiley & Sons Ltd.)

Background: The objective measurement for esophageal bolus volume and bolus clearance could classify abnormal high-resolution manometry (HRM) beyond the current Chicago classification. We aimed to compare the novel four-dimensional impedance manometry (4D HRM) volume metrics with timed barium esophagram (TBE)., Methods: Adults with esophageal symptoms undergoing HRM and TBE were included. A custom-built program for 4D HRM analysis measured esophageal luminal cross-sectional area (CSA) from impedance and subsequently derived esophageal bolus volume and clearance. 4D HRM volume metrics included pre-swallow residual volume, maximal volume, retention volume, and clearance ratio defined as 1.0-retention volume divided by the maximal volume. An abnormal TBE was defined as a column height >5 cm at 1 min or 5 min., Key Results: A total of 95 patients (normal motility: 33%; ineffective esophageal motility: 12%; absent contractility: 10%; esophagogastric junction outflow obstruction: 30%; type I achalasia: 5%; type II achalasia: 12%) were categorized into normal TBE (58%), abnormal TBE at 1 min (17%), and abnormal TBE at 5 min (25%). The AUROC demonstrated that, among all 4D HRM volume metrics, the clearance ratio had the best performance in predicting abnormal TBE at 5 min (AUROC, 95% confidence interval: 0.89, 0.82-0.96), and exhibited a strong negative correlation with TBE at 5 min (r = -0.65; p < 0.001)., Conclusions & Inferences: Novel 4D HRM volume metrics provide objective measurement of esophageal bolus volume and bolus clearance. The clearance ratio has a strong correlation with TBE and could potentially serve as a substitute for TBE to measure esophageal retention., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Functional lumen imaging probe (FLIP) panometry evaluates esophageal motility, including the contractile response to distension, that is, secondary peristalsis. Impaired/disordered contractile response (IDCR) is an abnormal, but nonspecific contractile response that can represent either hypomotility or spastic motor disorders on high-resolution manometry (HRM). We hypothesized that FLIP pressure could be incorporated to clarify IDCR and aimed to determine its utility in a cohort of symptomatic esophageal motility patients., Methods: 173 adult patients that had IDCR on FLIP panometry and HRM with a conclusive Chicago Classification v4.0 (CCv4.0) diagnosis were included and analyzed as development (n = 118) and validation (n = 55) cohorts. FLIP pressure values were assessed for prediction of either hypomotility or spasm, defined on HRM/CCv4.0., Key Results: HRM/CCv4.0 diagnoses were normal motility in 48 patients (28%), "hypomotility" (ineffective esophageal motility, absent contractility, or Type I or II achalasia) in 89 (51%), and "spasm" (Type III achalasia, distal esophageal spasm, or hypercontractile esophagus) in 36 (21%). The pressure at esophagogastric junction-distensibility index (DI) (60 mL) was lower in hypomotility (median [interquartile range] 34 [28-42] mmHg) than in spasm (49 [40-62] mmHg; p < 0.001) and had an area under the receiver operating characteristic curve of 0.80 (95% CI 0.73-0.88) for hypomotility and 0.76 (0.69-0.83) for spasm. For "spasm" on HRM, a threshold FLIP pressure of >35 mmHg provided 90% sensitivity (47% specificity) while >55 mmHg provided 93% specificity (40% sensitivity)., Conclusion & Inferences: Pressure on FLIP panometry can help clarify the significance of IDCR, with low-pressure IDCR associated with hypomotility and high-pressure IDCR suggestive of spastic motor disorders., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: For many patients with lung disease the only proven intervention to improve survival and quality of life is lung transplantation (LTx). Esophageal dysmotility and gastroesophageal reflux (GER) are common in patients with respiratory disease, and often associate with worse prognosis following LTx. Which, if any patients, should be excluded from LTx based on esophageal concerns remains unclear. Our aim was to understand the effect of LTx on esophageal motility diagnosis and examine how this and the other physiological and mechanical factors relate to GER and clearance of boluses swallowed., Methods: We prospectively recruited 62 patients with restrictive (RLD) and obstructive (OLD) lung disease (aged 33-75 years; 42 men) who underwent high resolution impedance manometry and 24-h pH-impedance before and after LTx., Key Results: RLD patients with normal motility were more likely to remain normal (p = 0.02), or if having abnormal motility to change to normal (p = 0.07) post-LTx than OLD patients. Esophageal length (EL) was greater in OLD than RLD patients' pre-LTx (p < 0.001), reducing only in OLD patients' post-LTx (p = 0.02). Reduced EL post-LTx associated with greater contractile reserve (r = 0.735; p = 0.01) and increased likelihood of motility normalization (p = 0.10). Clearance of reflux improved (p = 0.01) and associated with increased mean nocturnal baseline impedance (p < 0.001) in RLD but not OLD. Peristaltic breaks and thoraco-abdominal pressure gradient impact both esophageal clearance of reflux and boluses swallowed (p < 0.05)., Conclusions and Inferences: RLD patients are more likely to show improvement in esophageal motility than OLD patients post-LTx. However, the effect on GER is more difficult to predict and requires other GI, anatomical and pulmonary factors to be taken into consideration., (© 2024 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background and Aims: This study aimed to systematically evaluate a classification scheme of secondary peristalsis using functional luminal imaging probe (FLIP) panometry through comparison with primary peristalsis on high-resolution manometry (HRM)., Methods: 706 adult patients that completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers ("controls") were included. Secondary peristalsis, that is, contractile responses (CRs), was classified on FLIP panometry by the presence and pattern of contractility as normal (NCR), borderline (BCR), impaired/disordered (IDCR), absent (ACR), or spastic-reactive (SRCR). Primary peristalsis on HRM was assessed according to the Chicago Classification., Results: All 35 of the controls had antegrade contractions on FLIP panometry with either NCR (89%) or BCR (11%). The average percentages of normal swallows on HRM varied across contractile response patterns from 84% in NCR, 68% in BCR, 39% in IDCR, to 11% in ACR, as did the percentage of failed swallows on HRM: 4% in NCR, 12% in BCR, 36% in IDCR, and 79% in ACR. SRCR on FLIP panometry was observed in 18/57 (32%) patients with type III achalasia, 4/15 (27%) with distal esophageal spasm, and 7/15 (47%) with hypercontractile esophagus on HRM., Conclusions: The FLIP panometry contractile response patterns reflect a pathophysiologic transition from normal to abnormal esophageal peristaltic function with shared features with primary peristaltic function/dysfunction on HRM. Thus, these patterns of the contractile response to distension can facilitate the evaluation of esophageal motility using FLIP panometry., (© 2021 John Wiley & Sons Ltd.)

Introduction: High amplitude peristaltic esophageal contractions, that is, nutcracker esophagus, were originally described in association with "angina-like pain" of esophageal origin. However, significant number of nutcracker patients also suffer from dysphagia. High-resolution esophageal manometry (HRM) assesses only the contraction phase of peristalsis. The degree of esophageal distension during peristalsis is a surrogate of relaxation and can be measured from the intraluminal esophageal impedance measurements., Aims: Determine the amplitude of distension and temporal relationship between distension and contraction during swallow-induced peristalsis in nutcracker patients., Methods: HRM impedance (HRMZ) studies were performed and analyzed in 24 nutcracker and 30 normal subjects in the Trendelenburg position. A custom-built software calculated the numerical data of the amplitudes of distension and contraction, the area under the curve (AUC) of distension and contraction, and the temporal relationship between distension and contraction., Results: In normal subjects, the distension peaks similar to contraction traverse sequentially the esophagus. The amplitude of contraction is greater in the nutcracker esophagus but the amplitude of distension and area under the curve of distension are smaller in patients compared to controls. Distension peaks are aligned closely with contraction in normal subjects, but in patients, the bolus travels faster to the distal esophagus, resulting in a smaller time interval between the onset of swallow and distension peak. Receiver operative characteristics (ROC) curve reveals high sensitivity and specificity of the above parameters in patients., Conclusion: Abnormalities in the distension phase of peristalsis are a possible mechanism of dysphagia in patients with nutcracker esophagus., (© 2021 John Wiley & Sons Ltd.)

Esophageal hypomotility disorders manifest with abnormal esophageal body contraction vigor, breaks in peristaltic integrity, or failure of peristalsis in the context of normal lower esophageal sphincter relaxation on esophageal high-resolution manometry (HRM). The Chicago Classification version 4.0 recognizes two hypomotility disorders, ineffective esophageal motility (IEM) and absent contractility, while fragmented peristalsis has been incorporated into the IEM definition. Updated criteria for ineffective swallows consist of weak esophageal body contraction vigor measured using distal contractile integral (DCI, 100-450 mmHg·cm·s), transition zone defects >5 cm measured using a 20 mmHg isobaric contour, or failure of peristalsis (DCI < 100 mmHg·cm·s). More than 70% ineffective swallows and/or ≥50% failed swallows are required for a conclusive diagnosis of IEM. When the diagnosis is inconclusive (50%-70% ineffective swallows), supplementary evidence from multiple rapid swallows (absence of contraction reserve), barium radiography (abnormal bolus clearance), or HRM with impedance (abnormal bolus clearance) could support a diagnosis of IEM. Absent contractility requires 100% failed peristalsis, consistent with previous versions of the classification. Consideration needs to be given for the possibility of achalasia in absent contractility with dysphagia despite normal IRP, and alternate complementary tests (including timed upright barium esophagram and functional lumen imaging probe) are recommended to confirm or refute the presence of achalasia. Future research to quantify esophageal bolus retention on stationary HRM with impedance and to understand contraction vigor thresholds that predict bolus clearance will provide further refinement to diagnostic criteria for esophageal hypomotility disorders in future iterations of the Chicago Classification., (© 2021 John Wiley & Sons Ltd.)

Background: Esophageal hypercontractility (EHC) is considered a major esophageal motor disorder of unclear etiology. Different mechanisms have been proposed, including an imbalance in inhibitory and excitatory esophageal innervation. We hypothesized that patients with EHC suffer from cholinergic hyperactivity., Aim: To interrogate the excitatory and inhibitory neurotransmission in EHC by assessing the esophageal motor response to atropine (ATR) and cholecystokinin (CCK), respectively, in EHC patients., Method: We retrospectively reviewed patients who underwent high-resolution manometry (HRM) with pharmacologic challenge in a tertiary referral center between 2007 and 2017. We identified 49 EHC patients who were categorized based on frequency of hypercontractile peristaltic sequence into "frequent" and "infrequent" and motility diagnosis groups. Deglutitive pressure metrics and esophageal motor responses to ATR (12 mcg/kg iv) and CCK (40 ng/kg iv) were analyzed across groups., Results: Atropine abolished hypercontractility across all groups studied, converting nearly half of patients to a motor pattern of ineffective esophageal motility. Abnormal CCK responses primarily occurred in the patient groups with concomitant outflow obstruction., Conclusions: Hypercontractility is cholinergically mediated in all esophageal motor disorders. Most patients with isolated EHC appear to have excessive cholinergic drive, rather than loss of inhibitory innervation, and might be candidates for treatment with anticholinergic agents., (© 2020 John Wiley & Sons Ltd.)

Background: Several patients in gastroenterology practice present with esophageal symptoms, and in case of normal endoscopy with biopsies, high-resolution manometry (HRM) is often the next step. Our aim was to develop a European consensus on the clinical application of esophageal HRM, to offer the clinician guidance in selecting patients for HRM and using its results to optimize clinical outcome., Methods: A Delphi consensus was initiated with 38 multidisciplinary experts from 16 European countries who conducted a literature summary and voting process on 71 statements. Quality of evidence was evaluated using grading of recommendations assessment, development, and evaluation (GRADE) criteria. Consensus (defined as >80% agreement) was reached for 33 statements., Results: The process generated guidance on when to consider esophageal HRM, how to perform it, and how to generate the report. The Delphi process also identified several areas of uncertainty, such as the choice of catheters, the duration of fasting and the position in which HRM is performed, but recommended to perform at least 10 5-ml swallows in supine position for each study. Postprandial combined HRM impedance is considered useful for diagnosing rumination. There is a large lack of consensus on treatment implications of HRM findings, which is probably the single area requiring future targeted research., Conclusions and Inferences: A multinational and multidisciplinary group of European experts summarized the current state of consensus on technical aspects, indications, performance, analysis, diagnosis, and therapeutic implications of esophageal HRM., (© 2020 John Wiley & Sons Ltd.)

Introduction: Patients with esophageal symptoms often remain with an uncertain diagnosis after high-resolution manometry., Aim: To determine the added value of concomitant pressure and symptom analysis in response to a rapid drink challenge (RDC)., Methods: In consecutive patients referred for esophageal manometry, a RDC consisting in free drinking of 200 ml of water as quick as possible was performed after the standard single water swallows manometry. Both pressure patterns and usual symptoms induced by the RDC were analyzed., Results: A total of 1319 patients were included, (64.7% women, mean age 58.2 years, range 11-90). There were significant differences in pressure responses between patients with obstructive disorders, major hypercontractile disorders, esophageal hypomotility disorders and normal motility. The RDC provoked usual symptoms in 388 (29.4%) patients, associated with hyperpressive and obstructive patterns in 14.0% and 16.6%, respectively. Reproduction of dysphagia and regurgitation (not pain) was significantly associated with abnormal pressure responses during the RDC (p < 0.001 and p = 0.002, respectively). The RDC elicited both abnormal pressure patterns and symptoms in 6.2%, 1.6%, and 20.8% of patients with normal motility, ineffective esophageal motility, and esophago-gastric junction outflow obstruction, respectively., Conclusion: Concomitant evaluation of symptoms and pressure responses to a RDC may increase the specificity of esophageal motor testing in patients with inconclusive diagnosis or normal esophageal motility., (© 2020 John Wiley & Sons Ltd.)

The Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). A key feature of CCv.4.0 is the more rigorous and expansive protocol that incorporates single wet swallows acquired in different positions (supine, upright) and provocative testing, including multiple rapid swallows and rapid drink challenge. Additionally, solid bolus swallows, solid test meal, and/or pharmacologic provocation can be used to identify clinically relevant motility disorders and other conditions (eg, rumination) that occur during and after meals. The acquisition and analysis for performing these tests and the evidence supporting their inclusion in the Chicago Classification protocol is detailed in this technical review. Provocative tests are designed to increase the diagnostic sensitivity and specificity of HRM studies for disorders of esophageal motility. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification, decrease the proportion of HRM studies that deliver inconclusive diagnoses and increase the number of patients with a clinically relevant diagnosis that can direct effective therapy. Another aim in establishing a standard manometry protocol for motility laboratories around the world is to facilitate procedural consistency, improve diagnostic reliability, and promote collaborative research., (© 2021 John Wiley & Sons Ltd.)

Background/aim: The aim was to investigate whether there is a difference in secondary peristalsis on high-resolution manometry (HRM) among gastroesophageal reflux disease (GERD) patients with and without ineffective esophageal motility (IEM), and healthy individuals., Methods: Twenty-eight GERD patients and seventeen healthy controls were included. Secondary peristalsis was stimulated by a rapid injection of 20 ml air in mid-esophagus. We compared HRM metrics and the response and effective rate of triggering secondary peristalsis between patients with and without IEM and healthy controls., Results: Sixteen patients had IEM, and the remaining 12 had normal manometry. By triggering of secondary peristalsis, patients without IEM and healthy controls had significantly higher distal contractile integral (DCI) values than IEM patients (p = 0.006). A successful secondary peristalsis was triggered more frequently in healthy controls than in GERD patients with normal peristalsis or IEM (56.9% vs. 20.2% vs. 9.1%, all p < 0.001). The effective rate which determined as DCI > 450 mm Hg.cm.s was higher in healthy controls compared to patients with normal peristalsis (36.5% vs. 19.4%, p < 0.001) and IEM (36.5% vs. 6.3%, p < 0.001). Patients with IEM had lower successful triggering response (9.1% vs. 20.2%) and effective secondary peristalsis (6.3% vs. 19.4%) compared with patients without IEM (p < 0.001)., Conclusions: Our work has demonstrated that GERD patients, in particular those with IEM, have significant defects in the triggering of secondary peristalsis on HRM. HRM helps characterize esophageal secondary peristalsis which exhibits differently in patients with and without IEM., (© 2020 John Wiley & Sons Ltd.)

Background: Esophagogastric junction outflow obstruction (EGJOO) as defined by Chicago Classification of esophageal motility disorders (CCv3.0) encompasses a broad range of diagnoses, thus posing clinical challenges. Our aims were to evaluate multiple rapid swallow (MRS) and rapid drink challenge (RDC) during high-resolution manometry (HRM) to aid identifying clinically relevant EGJOO., Methods: Patients with a HRM diagnosis of EGJOO based on CCv3.0 that also completed MRS and RDC during HRM and barium esophagram were retrospectively identified. Radiographic EGJOO (RAD-EGJOO) was defined by either liquid barium retention or delayed passage of a barium tablet on barium esophagram. Thirty healthy asymptomatic controls that completed HRM were also included. MRS involved drinking 2 mL for 5 successive swallows. RDC involved rapid drinking of 200 mL liquid. Integrated relaxation pressure (IRP) and presence of panesophageal pressurization (PEP) during MRS and RDC were assessed., Key Results: One hundred one patients, mean (SD) age 56 (16) years, were included; 32% had RAD-EGJOO, 68% did not. RAD-EGJOO patients more frequently had elevated (>12 mmHg) upright IRP (100%), MRS-IRP (56%), RDC-IRP (53%), and PEP during RDC (66%) than both controls [17%; 0%; 7%; 3%] and patients without RAD-EGJOO [83%; 35%; 39%; 41%] Having IRP >12 mmHg during both MRS and RDC was twice as likely to be associated with RAD-EGJOO (19%) than those without RAD-EGJOO (9%) among patients with upright IRP >12 mmHg., Conclusions and Inferences: Adjunctive HRM maneuvers MRS and RDC appear to help identify clinically significant EGJOO. While future outcome studies are needed, comprehensive multimodal evaluation helps clarify relevance of EGJOO on HRM., (© 2020 John Wiley & Sons Ltd.)

Background: Motor abnormalities of pharyngeal contraction or upper esophageal sphincter (UES) relaxation can lead to swallowing problems., Methods: We reviewed high-resolution esophageal manometry of children ≤18 years and classified into two groups based on the results of videofluoroscopic study of swallow (VFSS), as normal or abnormal. The UES metrics (integrated relaxation pressure [IRP], resting pressure [URP], and nadir pressure [UNP]), as well as peak pharyngeal pressure (velopharyngeal and meso-hypopharyngeal), were analyzed., Results: UES metrics: There were 142 and 19 subjects in the normal and abnormal groups, respectively. In the normal group, the median UES-IRP at 0.2, 0.4, 0.6, 0.8 seconds, URP, and UNP were 1.0, 4.0, 11.0, 18.0, 53.5, and -1.0 mm Hg while in the abnormal group were 10.0, 13.0, 21.0, 25.5, 47.0, and 8.0 mm Hg. The UES-IRP at 0.2, 0.4, 0.6 seconds, and UNP was significantly higher in the abnormal group. Pharyngeal metrics: We included 58 subjects in normal and 10 subjects in the abnormal group. The median of peak velopharyngeal and meso-hypopharyngeal pressures were lower in the abnormal group; 188.50 vs 210.50, P = .185 and 110.00 vs 144.75 mm Hg, P = .065., Conclusions and Inferences: The UES-IRP was lower than adults, URP was higher than preterm but less than adults, and UNP was lower than neonates but similar to adults. The pharyngeal pressures were higher than those reported for neonates and adults. Our data indicate that motor dynamics of swallowing may change from neonates to adulthood and reflect a maturational process. The subjects with abnormal VFSS had significantly higher UES-IRP and UNP compared to normal VFSS., (© 2020 John Wiley & Sons Ltd.)

Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high-resolution manometry (HRM). Fifty-two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two-years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ., (© 2020 John Wiley & Sons Ltd.)

Hypercontractile esophagus (HE), also known as jackhammer esophagus, is an esophageal motility disorder. Nowadays, high-resolution manometry (HRM) is used to diagnose the disorder. According to the latest iteration of the Chicago classification, HE is present when at least 2 out 10 liquid swallow-induced peristaltic waves have an abnormally high Distal Contractile Integral. In the era of conventional manometry, a similar condition, referred to as nutcracker esophagus, was diagnosed when the peristaltic contractions had an abnormally high mean amplitude. Although the HRM diagnosis of HE is relatively straight-forward, effective management of the disorder is challenging as the correlation with symptoms is variable and treatment effects are dubious. In this mini-review, we discuss the most troublesome uncertainties that still surround HE, in the light of new data on etiology and epidemiology published in this issue of Neurogastroenterology and Motility., (© 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

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., (© 2020 John Wiley & Sons Ltd.)

The pathophysiology of jackhammer esophagus is complex and remains unclear. Radiofrequency catheter ablation is indicated for highly symptomatic and drug-refractory atrial fibrillation. This technique can induce esophageal and nerve lesions, due to thermal injury. In this report, we describe a case of hypercontractile esophagus diagnosed by HRM (high-resolution manometry). Esophageal symptoms and HRM normalized immediately after RFCA, and we discuss the pathophysiology of hypercontractile esophagus., (© 2020 John Wiley & Sons Ltd.)

Background: Esophagogastric junction outflow obstruction (EGJOO) detected by manometry in the supine position is prevalent in patients with morbid obesity, but not all EGJOOs are clinically significant. We investigated whether including upright swallows during high-resolution manometry (HRM) could help identify non-clinically significant EGJOO in patients with morbid obesity., Methods: We performed a retrospective study of consecutive morbidly obese patients diagnosed with EGJOO by HRM from July 2012 through July 2018. The HRM protocol included 10 supine and five upright 5-mL water swallows. Endoscopy, esophagram, and computed tomography were performed to identify whether the patients should be diagnosed as having clinically significant EGJOO., Key Results: A total of 230 patients with morbid obesity underwent HRM in the supine position during the study period. Fifty (21.7%) patients were diagnosed with EGJOO, among which 32 completed HRM both in the supine and upright positions. Only 8/32 patients were diagnosed with EGJOO in an upright position. Fewer artifacts were displayed in esophageal pressure topography in the upright position. None of the 32 patients could be diagnosed as clinically significant EGJOO based on all the examinations. Median esophageal gastric junction pressure, integrated relaxation pressure, and distal contractile integral were higher, and median distal latency was longer in the supine position compared with the upright position (all P < .05)., Conclusions and Inferences: Esophagus manometry in the upright position could reduce EGJOO overdiagnosis in patients with morbid obesity. Prolongation of the HRM study with some swallows in the upright position could be recommended in obese patients., (© 2020 John Wiley & Sons Ltd.)

Background: Jackhammer esophagus (JE) is a newly described esophageal motility disorder. However, there are limited data on JE and this entity remains misunderstood., Methods: We performed a systematic review of clinical series on JE through MEDLINE, EMBASE, and Web of Science. Data from included studies were then extracted, and random-effects meta-analyses were performed., Results: Thirty-eight studies met inclusion criteria. The pooled prevalence of JE was 1.97% [95% CI: 1.39%-2.78%] among patients referred for high-resolution manometry (HRM). The mean age at diagnosis was 60.8 years [95% CI: 57.1-64.4] and 65% [95% CI: 58%-72%] of patients were female. JE was significantly more prevalent in postlung transplant patients and morbidly obese patients undergoing HRM (23.99% [95% CI: 9.00%-38.97%] and 5.18% [95% CI: 1.76%-14.3%] respectively). Dysphagia was the most common presentation of JE (64% [95% CI: 52%-77%]) followed by gastroesophageal reflux disease (46% [95% CI: 26%-67%]). The pooled mean distal contractile integral (DCI) of all standard HRM swallows was 9249 mm Hg·s·cm [95% CI: 7834-10 663], and the pooled mean integrated relaxation pressure (IRP) was 13.9 mm Hg [95% CI: 8.2-19.7]. Overall, 73.6% [95% CI: 64.0%-83.1%] of JE patients who underwent treatment achieved clinical symptom improvement (79% [95% CI: 74%-85%] for endoscopic treatment and 63% [95% CI: 47%-79%] for medical treatment). The pooled clinical success rate of peroral endoscopic myotomy (POEM) specifically was 82% [95% CI: 75%-90%]., Conclusions: JE is a new motility disorder most commonly presenting with dysphagia. High clinical suspicion is important because the diagnosis can only be made through HRM., (© 2020 John Wiley & Sons Ltd.)

High-resolution manometry revolutionized the assessment of esophageal motility disorders and upgraded the classification through the Chicago Classification. A known disadvantage of standard HRM, however, is the inability to record esophageal motility function for an extended time interval; therefore, it represents only a more snapshot view of esophageal motor function. In contrast, ambulatory esophageal manometry measures esophageal motility over a prolonged period and detects motor activity during the entire circadian cycle. Furthermore, ambulatory manometry has the ability to measure temporal correlations between symptoms and motor events. This article aimed to review the clinical implications of ambulatory esophageal manometry for various symptoms, covering literature on the manometry catheter, interpretation of findings, and relevance in clinical practice specific to the evaluation of non-cardiac chest pain, chronic cough, and rumination syndrome., (© 2020 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background: Proximal esophageal striated muscle contractility may be abnormal in patients with esophageal symptoms, but is not assessed in the Chicago Classification (CC) v3.0. We aimed to (a) determine the prevalence of abnormal proximal esophageal contractility in patients with esophageal symptoms; (b) compare proximal esophageal contractility in patients with different esophageal motility disorders; (c) assess the association of abnormal proximal esophageal contractility with esophageal symptoms., Methods: Patients undergoing high-resolution esophageal manometry (HREM) from 7/2019 to 11/2019 and healthy volunteers (HVs) were studied. Measurements of the proximal esophageal segment included the vigor of contractility of the proximal esophagus (proximal contractile integral/PCI). Patients rated gastrointestinal symptoms' severity., Key Results: HREM was performed on 221 patients (63.8% females, mean age 57.1 ± 1.1 years) and 19 HVs. Mean PCI in HVs was 299.5 ± 30.6 (95% CI 32.3-566.7 mm Hg . s . cm). Of all patients, 61 (27.6%) had abnormal PCI. HVs and patients with different esophageal motility disorders had significantly different PCI (P < .01). Type 1 achalasia patients had weaker PCI than patients with absent contractility (P = .02). Patients with abnormal PCI had more severe dysphagia (P = .02), nausea (P = .03), vomiting (P = .03), and lower bolus clearance (P < .01) than patients with normal PCI., Conclusions and Inferences: Abnormal PCI was found in a fourth of patients with esophageal symptoms. PCI may be useful to distinguish some esophageal motility disorders. Patients with abnormal PCI had a higher severity of some upper gastrointestinal symptoms than patients with normal PCI. Assessing the proximal esophageal segment on HREM may be useful in characterizing patients with esophageal symptoms., (© 2020 John Wiley & Sons Ltd.)

Background: The definition and relevance of ineffective esophageal motility (IEM) remains debated. Our aim was to determine motility patterns and symptoms associated with IEM defined as impaired bolus clearance., Methods: To define altered bolus clearance, normal range of swallows with complete bolus transit (CBT) on high-resolution impedance manometry (HRIM) was determined in 44 asymptomatic controls. The results were then applied to a cohort of 81 patients with esophageal symptoms to determine the motility patterns which best predicted altered bolus clearance. Subsequently, in a cohort of 281 consecutive patients the identified motility patterns were compared with patients' customary symptoms., Key Results: In asymptomatic controls, the normal range of swallows with CBT was 50%-100%. In patients, altered bolus transit (<50% CBT) was only associated with 30% or more failed contractions (P < .001). Neither weak peristalsis nor absence of contraction reserve (CR) was associated with altered bolus clearance. The patterns which best predicted altered bolus clearance were failed contractions ≥30% (specificity 88.2% and sensitivity of 84.6%), and ≥70% ineffective (failed + weak) contractions (sensitivity 84.6% and specificity 80.9%). No motility pattern was correlated to symptom scores., Conclusions and Inferences: Based on bolus clearance assessed by HRIM, ≥30% failed contractions and ≥70% ineffective contractions have the best sensitivity and specificity to predict altered bolus clearance. Weak contractions and absence of CR are not relevant with respect to bolus clearance., (© 2020 John Wiley & Sons Ltd.)

Background: Absent esophageal contractility (AC) is distinguished from type 1 achalasia (ACH1) during high-resolution manometry (HRM) on the basis of normal or elevated deglutitive integrated relaxation pressure (IRP) values. However, IRP measurements are subject to pressure recording error. We hypothesized that distinctive responses to pharmacologic provocation using amyl nitrite (AN) and cholecystokinin (CCK) could reliably distinguish AC patients from those with ACH1., Aim: To compare esophageal response with AN and CCK in a well-defined cohort of ACH1 and AC patients., Method: All available clinical, radiographic, endoscopic, and manometric information in 34 patients with aperistalsis was reviewed to determine the final diagnosis of ACH1 and AC. The differences in response to provocative challenges with the rapid drink challenge (RDC) test and administration of AN and CCK were compared between these two groups., Results: Eighteen patients were diagnosed with ACH1 and sixteen with AC. While IRP values were significantly higher in ACH1, the standard criterion value misclassified four AC patients as having ACH1 and five ACH1 patients as having AC. IRP values on the RDC did not accurately segregate AC from ACH1, but we were able to identify AN and CCK esophageal motor response criteria that allowed correct classification of ACH1 and AC patients., Conclusions: Nearly a quarter of AC and ACH1 patients may be misdiagnosed based on manometric IRP criteria alone. Differences in the esophageal motor responses to AN and CCK have the potential to facilitate the correct diagnosis in these challenging patients., (© 2020 John Wiley & Sons Ltd.)

Background: The functional lumen imaging probe (FLIP) system is an FDA-approved tool for dynamic evaluation of the esophagogastric junction (EGJ). Even though commercially available since 2009, FLIP utilization remains low, partly due to lack of consensus in methodology and interpretation. Therefore, we aimed to analyze the influence of concurrent endoscopy on FLIP measurements., Methods: In this single-center study, we reviewed data from 93 patients undergoing FLIP for symptomatic esophageal motility disorders between 2016 and 2018. During sedated endoscopy, we measured luminal values (distensibility, cross-sectional area (CSA), and balloon pressure) at the EGJ and distal esophagus using 30, 40, and 50 mL distension volumes, with and without concurrent endoscope presence. All recorded values were compared at the various distension volumes between the two measurements using a Wilcoxon rank sum test., Key Results: There was a significant difference in distensibility and CSA with index distension volume (40 mL) at the EGJ comparing the two measurements: Lower median distensibility was 2.1 mm 2  mm Hg -1 in the group with concurrent inserted endoscope, respectively, 3.4 mm 2  mm Hg -1 without endoscope (P < .001), and median CSA was 86.0 resp. 110.0 mm 2 (P < .001). No significant difference could be found in the measurements of the distal esophagus., Conclusions & Inferences: Our results show a significant difference in FLIP measurements with and without endoscope presence. This underlines the importance of establishing a consensus of a standardized FLIP protocol to define normal luminal values and guiding future FLIP diagnostic studies., (© 2020 John Wiley & Sons Ltd.)

Background: The contractile activity of Jackhammer esophagus(JE) is heterogeneous and abnormalities in the balance of pre- and post-peak contractile activity has been reported. We observed that the progression of the peak contraction is disordered in JE patients, which reflect underlying abnormalities in the inhibitory and excitatory influence in esophageal contraction. In order to better define this abnormality, we developed novel time metrics to define trajectory of the pressure wave peak and assessed it in healthy controls and JE patients., Methods: 38 patients with JE (ages 43-70, 19 females) and 71 asymptomatic controls (ages 19-48; 33 females) were retrospectively evaluated. High resolution manometry was performed in all subjects with 10 supine liquid swallows. The first 5 intact supine swallows and supine swallow with the greatest DCI were analyzed using ManoView™ software and customized MATLAB program. The time distance, negative time distance sum and chaotic ratio were calculated. JE patients were subcategorized by the Brief Esophageal Dysphagia Questionnaire (BEDQ) with cut-off of 6., Key Results: Jackhammer patients had longer time distance, longer negative time distance, and higher chaotic ratio than controls( p < 0.001). The distribution of the number of negative time distances differed between JE patients with BEDQ>6 and BEDQ≤6., Conclusions & Inferences: The trajectory of the pressure wave peak propagation commonly occurred in an unordered fashion in JE, but rarely in controls. Additionally, differences in pressure propagation trajectory was associated with higher symptom scores thus trajectory of the pressure wave peak may be an important marker of abnormal esophageal motor function., (© 2019 John Wiley & Sons Ltd.)

Background: Esophagogastric junction outflow obstruction (EGJOO) is a manometric diagnosis based on the Chicago Classification defined by inadequate relaxation of the gastroesophageal junction (GEJ) with swallowing, but with sufficient peristalsis such that the criteria for achalasia are not met. Possible causes include anatomical and functional etiologies. Further investigations, including computed tomography (CT) of the chest and endoscopic ultrasound (EUS), to help elucidate the etiology of EGJOO have been suggested, but the utility of this approach has not been proven., Methods: All new diagnoses of EGJOO made in the calendar years 2015-2016 were included. A review was performed for each patient to assess clinical outcomes, diagnostic, and therapeutic interventions after the EGJOO diagnosis., Key Results: 107 EGJOO patients were included. Their primary complaints were dysphagia (68%), chest pain (12%), reflux (8%), pre-operative assessment (6%), regurgitation (3%), and cough (3%). The mean IRP was 21.8 mm Hg. After a mean follow-up period of 463 days, the etiology of EGJOO remained undetermined in 67% of patients. 48% of patients were investigated with cross-sectional imaging (and 10% with EUS to rule out external compression or malignancy as a cause of EGJOO; none of these tests provided any further useful information). In only two cases did the EGJOO progress to achalasia., Conclusions & Inferences: EGJOO is a manometric diagnosis with unclear clinical significance and outcome. CT and EUS of the GEJ were unhelpful at determining the cause of this entity. In this series, very few appear to progress to achalasia, none were due to malignancy, and many resolved spontaneously., (© 2019 John Wiley & Sons Ltd.)

Background: The pathophysiological mechanism(s) of gastroesophageal reflux disease (GERD)-related chronic cough (CC) is unclear. We aimed to determine the mechanism of reflux-induced cough by synchronous monitoring of reflux episodes, esophageal motility, and cough., Methods: Patients with GERD were prospectively enrolled and classified into GERD with CC (GERD-CC) and without CC (GERD) groups. Twenty-four-hour ambulatory pH-impedance-pressure monitoring was performed; the reflux patterns, esophageal motility during prolonged exposure to acid and characteristics of reflux episodes that induced coughing paroxysms were analyzed., Key Results: Thirty-one patients with GERD-CC and 47 with GERD were enrolled; all of whose monitoring results fulfilled the criteria for diagnosis of GERD. Patients with GERD-CC had higher reflux symptom scores, longer exposure to acid, higher DeMeester scores, and more frequent reflux episodes, proximal extent reflux detected by impedance, and higher percentage of strongly acidic reflux than patients in the GERD group (all P < .05). Of 63 reflux-cough episodes identified in the GERD-CC group, 74.6% of distal reflux and 67.0% of proximal reflux episodes were acidic. More patients had low pan-esophageal pressure in primary peristalsis (48.5% vs 11.8%, P = .000) and synchronous contraction in secondary peristalsis during prolonged exposure to acid in the GERD-CC than in the GERD group (63.9% vs 9.1%, P = .000)., Conclusions & Inferences: Proximal acidic reflux and distal reflux-reflex are jointly associated with reflux-induced cough in patients with GERD. Low pan-esophageal pressure in primary peristalsis and synchronous contraction in secondary peristalsis may play important roles in GERD-associated chronic cough., (© 2019 The Authors. Neurogastroenterology & Motility published by John Wiley & Sons Ltd.)

Background/aim: Esophageal acid sensitivity plays a role in symptomatic manifestation of gastroesophageal reflux disease (GERD). Esophageal hypomotility is common in patients with GERD. We aimed to determine whether esophageal acid sensitivity may differ between patients with and without esophageal hypomotility., Methods: We prospectively enrolled 41 consecutive patients (10 females, mean age 53 years, range 32-79) with typical reflux symptoms and 10 healthy subjects (5 females, mean age 45 years, range 28-56) for esophageal acid sensitivity and motility tests. Demographics, body mass index (BMI), and reflux symptoms using a validated questionnaire (GERDQ) were recorded. All subjects underwent infusion of 0.1 N hydrochloric acid in the esophagus at a rate of 10 mL/min for 10 minutes. The parameters for esophageal acid infusion included lag time, intensity rating, and acid sensitivity score., Results: Esophageal motility diagnosis included 24 patients with normal motility and 17 patients with ineffective esophageal motility (IEM). Lag time was similar between the patient groups. No differences between patients with normal motility and IEM were found for any of other acid infusion parameters. There was a positive correlation between lag time and BMI (r = .33, P = .04). GERDQ was negatively correlated to lag time (r = -.73, P < .001)., Conclusions: Esophageal acid sensitivity was similar in GERD patients with and without hypomotility. Decreased acid sensitivity in individuals with increasing body mass index may play a pathological role in symptomatic modulation of patients with GERD., (© 2019 John Wiley & Sons Ltd.)

Background: Ineffective esophageal motility (IEM) is a heterogenous minor motility disorder diagnosed when ≥50% ineffective peristaltic sequences (distal contractile integral <450 mm Hg cm s) coexist with normal lower esophageal sphincter relaxation (integrated relaxation pressure < upper limit of normal) on esophageal high-resolution manometry (HRM). Ineffective esophageal motility is not consistently related to disease states or symptoms and may be seen in asymptomatic healthy individuals., Purpose: A 1-day symposium of esophageal experts reviewed existing literature on IEM, and this review represents the conclusions from the symposium. Severe IEM (>70% ineffective sequences) is associated with higher esophageal reflux burden, particularly while supine, but milder variants do not progress over time or consistently impact quality of life. Ineffective esophageal motility can be further characterized using provocative maneuvers during HRM, especially multiple rapid swallows, where augmentation of smooth muscle contraction defines contraction reserve. The presence of contraction reserve may predict better prognosis, lesser reflux burden and confidence in a standard fundoplication for surgical management of reflux. Other provocative maneuvers (solid swallows, standardized test meal, rapid drink challenge) are useful to characterize bolus transit in IEM. No effective pharmacotherapy exists, and current managements target symptoms and concurrent reflux. Novel testing modalities (baseline and mucosal impedance, functional lumen imaging probe) show promise in elucidating pathophysiology and stratifying IEM phenotypes. Specific prokinetic agents targeting esophageal smooth muscle need to be developed for precision management., (© 2019 John Wiley & Sons Ltd.)

Background: The Chicago Classification of esophageal motility includes a group of patients who show evidence of esophagogastric junction outflow obstruction (EGJOO) as demonstrated by elevated integrated relaxation pressure (IRP) and preserved peristalsis. Our aim is to classify EGJOO patients based on response to amyl nitrite (AN) during high-resolution manometry., Methods: Patients were considered to have true EGJOO if elevated IRP during supine swallow persisted in the upright position and was associated with high intrabolus pressure. The EGJ response to AN was compared between patients with achalasia type 2 (A2) and normal esophageal motility. Based on the relaxation gain (deglutitive IRP-AN IRP) value that best discriminated these two groups (10 mm Hg), patients with true EGJOO were categorized as being in either the AN-responsive (AN-R) or AN-unresponsive (AN-U) subgroups., Key Results: In the group of 49 patients with true EGJOO, the AN response classified 27 patients (IRP = 25 ± 10 mm Hg) with AN-R and 22 patients (IRP = 20 ± 5 mm Hg) with AN-U (P = 0.2). In AN-R, AN produced a relaxation gain and rebound after-contraction response at the EGJ comparable to A2 patients. AN-U patients had an elevated IRP after AN and a relaxation gain similar to normal esophageal motility patients. AN-U patients were obese and had higher prevalence of sleep apnea (P < 0.05)., Conclusions: Among patients with true EGJOO, only half have pharmacologic evidence of impaired LES relaxation. Pharmacologic interrogation of the EGJ is thus necessary to identify the subgroup of EGJOO patients who could be expected to benefit from LES ablative therapies., (© 2019 John Wiley & Sons Ltd.)

Background: Upper esophageal sphincter (UES) metrics on high-resolution manometry (HRM), particularly nadir UES residual pressure (UES-RP), are abnormal in achalasia and may help characterize the underlying mechanism or predict management outcome in esophagogastric junction outflow obstruction (EGJOO)., Methods: A database of consecutive patients undergoing esophageal HRM from 2008 to 2013 yielded 134 patients (59.8 ± 1.4 years, 68% F) with EGJOO. Final clinical diagnoses and treatment response were extracted from chart review. Esophageal body, UES, and lower esophageal sphincter (LES) metrics were compared between EGJOO and asymptomatic healthy controls (n = 16, 27.7 ± 0.7 years, 56% F). Logistic regression evaluated differences between HRM metrics amongst etiologies of EGJOO grouped into motor versus mechanical disorders., Key Results: Distal contractile integral, distal latency, and nadir UES-RP were significantly different between EGJOO subgroups (P ≤ 0.01 for each comparison), but only nadir UES-RP remained independently predictive of subgroups (adjusted odds ratio 1.15, 95% confidence intervals 1.05-1.27, P < 0.01). Nadir UES-RP was highest in achalasia variants, and lowest in mechanical EGJOO and controls (P < 0.001). Of 19 patients who underwent LES myotomy, durable benefit was reported by 68.4% over mean 3.6 years of follow-up. Significantly higher nadir UES-RP was noted with symptom relief (3.4 vs -0.7 mm Hg with symptom recurrence, 95% confidence intervals of difference = 1.35-6.83). A threshold UES-RP of ≥2.0 mm Hg yielded a sensitivity of 84.6% and specificity of 83.3% in predicting symptom resolution following myotomy., Conclusions and Inferences: Nadir UES-RP offers clues to differentiation of subtypes within EGJOO and may predict symptom outcome from myotomy., (© 2019 John Wiley & Sons Ltd.)

Background and Aim: Acute esophageal acid infusion promotes distension-induced secondary peristalsis. The gamma-aminobutyric acid receptor type B (GABA-B) receptors activation inhibits secondary peristalsis. This study aimed to test the hypothesis whether acid excitation of secondary peristalsis can be influenced by baclofen., Methods: Secondary peristalsis was performed with intra-esophageal slow and rapid air injections in 13 healthy subjects. Direct esophageal infusion of 0.1 N HCl following pretreatment with placebo or baclofen was randomly performed at least 1 week apart. Symptom intensity, distension thresholds, and peristaltic parameters were determined and compared between each study protocol., Results: The intensity of heartburn symptom in response to esophageal acid infusion was significantly greater with baclofen than the placebo (P = 0.002). The threshold volume of secondary peristalsis during slow air injections in response to acid infusion was significantly greater with baclofen than the placebo (P = 0.001). Baclofen significantly increased the threshold volume of secondary peristalsis during rapid air injections in response to acid infusion (P = 0.001). The frequency of secondary peristalsis in response to acid infusion was significantly decreased by baclofen as compared with the placebo (P = 0.001). Baclofen significantly decreased peristaltic amplitudes in response to acid infusion during rapid air injections (P = 0.007)., Conclusions: Gamma-aminobutyric acid receptor type B agonist baclofen inhibits acid excitation of secondary peristalsis in human esophagus, which is probably mediated by both muscular and mucosal mechanoreceptors. This work supports the evidence of potential involvement of GABA-B receptors in negative modulation of acid excitation of esophageal perception as well as secondary peristalsis., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: High-resolution impedance manometry (HRIM) allows evaluation of esophageal bolus retention, flow, and pressurization. We explored novel HRIM measures and assessed their temporal relationship to dysphagia symptoms for boluses of different volume and consistency in non-obstructive dysphagia (NOD) patients., Methods: Thirty-three NOD patients (n = 19 minor or no disorder of peristalsis ("Normal") and n = 14 esophagogastric junction outflow obstruction ("EGJOO")) were evaluated with HRIM. Patients were administered 5 and 10 mL liquid, semisolid, and 2 and 4 cm solid boluses and indicated bolus perception during individual swallows using a 5-point Likert scale. HRIM was analyzed to assess Chicago Classification and pressure flow metrics, esophageal impedance integral (EII) ratio, and bolus flow time (BFT)., Key Results: Overall, bolus perception increased with increasing bolus consistency (P < 0.001), but did not differ significantly between EGJOO and Normal patients. EGJOO patients had higher IRP4, higher levels of bolus residual (ie, EII ratio and IR), and restricted esophageal emptying. The results for linking semisolid bolus perception to semisolid-derived measures revealed more biomechanically plausible and consistent patterns when compared to those derived for liquid boluses. In Normal patients, perception of boluses of heavier viscosity was related to higher bolus flow resistance during transport, whilst in EGJOO, perception was related to restriction of esophageal emptying., Conclusion & Inferences: These novel pressure-impedance measures may aid in the evaluation of NOD patients by revealing abnormal motor patterns, which may explain symptom generation. Future studies are needed to evaluate which of these measures are worthy of calculation and to establish protocol settings that allow for their meaningful interpretation., (© 2018 John Wiley & Sons Ltd.)

Objective: This study assessed whether high-resolution manometry (HRM) with a test meal can detect clinically relevant, abnormal motility already in very early systemic sclerosis (SSc) and whether this finding is associated with subsequent disease progression., Methods: This prospective, longitudinal cohort study recruited 68 consecutive SSc patients (group #1: 32 established disease (ACR, American College of Rheumatology /EULAR, The European League against Rheumatism 2013 and ACR 1980 criteria fulfilled); group #2: 24 early disease (only ACR/EULAR 2013 fulfilled); group #3: 12 very early disease (clinical expert diagnosis of SSc) and 72 healthy controls. HRM evaluated esophageal motility for water swallows and a solid test meal., Results: Systemic sclerosis patients had less frequent effective esophageal contractions during the test meal compared to healthy controls even in very early disease (0.15, 1.0, 2.1 per minute for groups #1, #2, and #3, vs 2.5 per minute in health; P < 0.001, P < 0.001, and P < 0.0085, respectively). Ineffective motility at HRM was associated with a higher modified Rodnan skin score at baseline. Moreover, at mean 18 (10-31) months of follow-up, the presence of ineffective motility at baseline was associated with progression of skin disease (P = 0.01). Cox proportional hazard regression analysis identified hypotensive peristalsis in the test meal (<15% effective solid swallows) and low distal contractile integral (DCI; <400 mm Hg·cm·s) as predictors for skin aggravation, but not for new organ involvement., Conclusion: Ineffective motility during a test meal is present already in patients with very early SSc. Findings on HRM studies are associated with disease severity at baseline, and low percentage of effective swallows in test meal and low mean DCI are both predictors of skin progression during follow-up., (© 2018 John Wiley & Sons Ltd.)

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., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Proximal reflux and incomplete transit of boluses swallowed are risk factors for obstructive chronic lung allograft dysfunction (o-CLAD) post-lung transplantation (LTx). Likewise, so is esophagogastric junction outflow obstruction (EGJOO), but not hypo-contractility, when diagnosed using Chicago Classification (CC) v3.0. Given, peristaltic breaks as defined using CCv2.0 can prolong esophageal clearance, both swallowed and refluxed, but which are deemed within normality using CCv3.0, our aim was to determine whether hypo-contractility as diagnosed using CCv2.0, influences the association with reflux, along with its clearance, and that of boluses swallowed, and thus its association to allograft failure., Methods: Esophageal motility abnormalities were classified using CC v3.0 and v2.0 in 50 patients post-LTx (26 female, 55 years (20-73 years))., Results: Reclassification from CCv3.0 to v2.0 resulted in 7 patients with normal motility being reclassified to hypo-contractility (n = 6) or hyper-contractility (n = 1); 2 patients with hypo-contractility to normal motility; and 3 patients with EGJOO without hyper-contractility to EGJOO with hyper-contractility. The main consequence of reclassification was that the sub-group exhibiting hypo-contractility became more likely to have abnormal numbers of reflux events (P = .025) and incomplete bolus transit (P = .002) than those with normal motility using CCv2.0; associations not seen using CCv3.0. Irrespective of CC used only patients with EGJOO appeared more likely to develop o-CLAD than those with normal motility (P < .05)., Conclusions: Irrespective of CC used, o-CLAD appears linked to EGJOO. CCv2.0 however, accentuates the increased reflux and incomplete bolus transit associated with hypo-contractility post-LTx, suggesting that these motor abnormalities, though considered minor, may be of importance after lung transplant., (© 2018 John Wiley & Sons Ltd.)

Background: Esophago-gastric junction (EGJ) outflow obstruction is of unclear significance. Rapid drink challenge (RDC) test is easy to perform during esophageal high resolution manometry. We aimed to assess the yield of RDC test in patients with EGJ outflow obstruction., Methods: Manometry studies of patients with EGJ outflow obstruction according to the Chicago Classification v3.0 were retrospectively reviewed. Pan-esophageal pressurization (PEP), esophageal shortening, and pressure gradient across the EGJ were analyzed during RDC test (200-mL free drinking in sitting position) and compared according to the causes of EGJ outflow obstruction determined by charts review., Key Results: Seventy-five patients (29 males, mean age 62 years) were included. Causes of EGJ outflow obstruction were previous esophago-gastric surgery (40%), incomplete form of achalasia (7%), mediastinal neoplasia (7%), other associated conditions (21%), and undetermined (25%). Rapid drink challenge test was successfully performed in 70 patients and associated with PEP and shortening in 41% and 13%, respectively. The causes of EGJ outflow obstruction were similarly distributed in patients with and without PEP during RDC test. Esophageal shortening tended to be more likely in patients with definitive findings of obstruction (achalasia, previous surgery, neoplasia) than in the others. Dysphagia was more severe in patients with PEP and/or shortening during RDC test compared to those without., Conclusions & Inferences: Pan-esophageal pressurization and esophageal shortening were associated with symptoms severity but did not predict the cause of this disorder. Further prospective studies are necessary to determine if RDC test could help to select patients who might benefit from treatment., (© 2018 John Wiley & Sons Ltd.)

Background: High-resolution esophageal manometry (HREM) has become a leading tool in the assessment of esophageal motor disorders, replacing conventional manometry. However, there is limited data about the contribution of HREM as compared with conventional manometry to the assessment of esophageal motor disorders in patients with non-cardiac chest pain (NCCP). The aim of the study was to compare the distribution of esophageal motor disorders in patients with NCCP using HREM as compared with conventional manometry and to determine if HREM improved diagnosis of these disorders., Methods: In this study, we included 300 consecutive patients with NCCP who underwent either HREM or conventional manometry over a period of 10 years. A total of 150 patients had conventional manometry and the other 150 patients HREM. The Chicago 3.0 classification and the Castell and Spechler classification were used to determine the esophageal motor disorder of NCCP patients undergoing HREM and conventional manometry, respectively., Key Results: In both HREM and the conventional manometry groups, normal esophageal motility was the most frequent finding (47% and 36%; respectively, P = .054). Hypotensive lower esophageal sphincter was the most common motility disorder identified by conventional manometry (27.3%), while ineffective esophageal motility was the most common esophageal motor disorder identified by HREM (25.3%)., Conclusions & Inferences: There is a discrepancy in the type of esophageal motor disorders identified by HREM as compared with conventional manometry in NCCP patients. Hypotensive motility disorders are the most commonly diagnosed by both manometric techniques., (© 2017 John Wiley & Sons Ltd.)

Background: Esophageal pressure topography (EPT) diagnosis of ineffective esophageal motility (IEM) can be non-specific with unclear clinical significance., Aims: To determine whether peristaltic vigor or lower esophageal sphincter (LES) integrity is associated with poor clearance and acid reflux in IEM., Methods: Bolus clearance on high-resolution impedance manometry (HRIM) and available reflux studies in patients with IEM were retrospectively reviewed. Bolus clearance was assessed using both line tracing and colored contour methods on HRIM. EPT parameters, bolus clearance, and acid reflux variables were explored., Key Results: Eighty-eight patients with IEM were included. Bolus clearance occurred in 71% of all swallows, and 55.7% of patients had complete bolus transit (CBT, bolus clearance in ≥80% of swallows). Bolus clearance was impaired in swallows with distal contractile integral (DCI) <100 mmHg•cm•s compared to DCI 100-450 (0.43 vs 0.79, P < .0001). A cutoff at DCI 100 mmHg•cm•s was associated with clearance with an accuracy of 76% compared to 49% at DCI 450 (P = .0001 for both). A median DCI <100 was associated with a higher Eckardt score (9 vs 3, P = .03), and on reflux testing available in 47 patients, with abnormal acid exposure time (P = .002). Peristaltic reserve (PR) defined as (DCI of multiple rapid swallow/median DCI of wet swallows), integrated relaxation pressure, and resting lower esophageal sphincter pressure were not associated with clearance or acid exposure., Conclusions & Inferences: Failed peristalsis, as defined by DCI <100 mmHg•cm•s, is associated with impaired bolus clearance and more severe dysphagia in IEM, and likely abnormal acid exposure., (© 2018 John Wiley & Sons Ltd.)

Background: We hypothesized that symptoms in Jackhammer esophagus (JH) are associated with an imbalance between the prepeak and postpeak phases of contraction. Thus, we developed a method to distinguish the contractile integral components of prepeak and postpeak phase contractile activity to determine the contribution of each phase and their association with dysphagia., Methods: Patients diagnosed with JH were enrolled and compared to controls. The first five intact swallows during manometry were analyzed. A single swallow was divided into a prepeak and postpeak phase. The contractile integral of each phase and its corresponding time-controlled integral were computed. All metrics were compared between controls and JH patients subcategorized by the impaction dysphagia question (IDQ) score with cut-off of 6., Key Results: Thirty eight JH patients and 71 controls were included. Twelve JH patients had IDQ ≤ 6 and 26 with IDQ > 6. JH patients had higher contractile integral in both phases, and a higher ratio between postpeak to prepeak contractile integral independent of duration. Similarly, JH patients with an IDQ > 6 had higher contractile metrics than those with IDQ ≤ 6. There was a correlation between the IDQ score and the ratio within the postpeak to prepeak contractile integral (r = .375)., Conclusions: Abnormalities in contractile integral of the postpeak phase are more significant in JH with higher dysphagia scores Although the total postpeak contractile integral was higher in symptomatic patients, this was associated with longer duration of postpeak activity suggesting that dysphagia patients with JH have a defect in the postpeak phase of peristalsis., (© 2017 John Wiley & Sons Ltd.)

Background: Dysphagia and non-cardiac chest pain are common symptoms associated with a novel hypercontractile disorder, namely Jackhammer esophagus (JE). The aim of this study was to explore these symptoms in patients with JE and to elucidate associations with disease defining metrics, crucial for subsequent therapies., Methods: All consecutive patients, who were referred between January 2014 and December 2016 and fulfilled the criteria for JE were included in this study. Exclusion criteria were opioid intake, previous gastrointestinal surgery, mechanical esophageal obstruction and diseases explaining their symptoms., Key Results: Of 2205 examined subjects, thirty patients (females: n = 17, 56.7%) with a median age of 58 (51.6-64.9) years were finally enrolled. Dysphagia was noted in 53.3% (n = 16), whereas non-cardiac chest pain was specified within 40% (n = 12) with symptom duration of up to 10 years. Perception of dysphagia (P = .03) and presence of both symptoms (P = .008) increased to the end of the study period. Dysphagia was significantly associated with distal contractile integral (DCI) scores of all (P = .023), hypercontractile (P = .011) and maximum DCI swallows (P = .008). Symptoms duration influenced hypercontractile DCI scores (P = .015, r = .438) and significantly correlated with the intensity of perceived dysphagia (P = .01, r = .585). Presence of non-cardiac chest pain was not associated with any of these metrics., Conclusions & Interferences: The DCI mediates dysphagia in patients with JE. Duration of symptoms affected hypercontractile DCI scores and aggravated perception of dysphagia indicating a progressive character of disease., (© 2017 John Wiley & Sons Ltd.)

Background: Multiple rapid swallows (MRS) is a provocative test for assessment of contraction reserve, however reproducibility on repetitive MRS is incompletely understood. Our aim was to determine the optimal number of MRS sequences for consistent assessment of contraction reserve., Methods: One hundred and fifty-nine consecutive patients (79 IEM and 80 normal motility) who underwent high-resolution manometers were enrolled. Ten single swallows (SS) and 10 MRS were performed. Gold standard for evaluation of the contraction reserve was the ratio between the mean DCI of 10 MRS and the mean DCI of 10 SS (MRS/SS DCI ratio). Rates of false negatives and false positives were calculated for increasing numbers of MRS sequences, using either mean DCI or the MRS with the highest DCI., Key Results: According to the gold standard, 50 IEM and 50 normal motility patients had contraction reserve. With progressively increasing numbers of MRS sequences, contraction reserve was detected using mean MRS DCI within three and four MRS sequences in IEM and normal motility respectively, whereas two and three MRS sequences were needed using the MRS sequence with the highest DCI. False positives were much higher with highest DCI method compared with mean DCI, (22% vs 9% respectively in IEM; 24% vs 9% in normal motility) when three MRS sequences were considered., Conclusions & Inferences: At least three MRS are needed to reliably assess contraction reserve. The mean DCI of the three MRS sequences is the best variable to utilize as evidence of contraction reserve., (© 2017 John Wiley & Sons Ltd.)

High resolution manometry (HRM) is the gold standard to diagnose esophageal motility disorders but has some limitations. The inclusion of provocative tests might enhance the diagnostic yield of HRM. These tests are easy to perform and to add to the regular manometry protocol. Multiple rapid swallows (MRS; 5 2-mL swallows) is useful to assess the contractile reserve and deglutitive inhibition. The optimal number of MRS to perform might be 3 as suggested by Mauro et al. in this issue of Neurogastroenterology & Motility. The absence of contractile reserve might be associated with gastro-esophageal reflux disease and with an increased risk of post fundoplication dysphagia. Single viscous and solid swallows might enhance the detection of esophageal motility disorders but are not significantly associated with symptom occurrence. Test meal has the advantage to represent a real-life scenario and is promising to depict significant motility findings responsible for esophageal symptoms. Post-prandial recording might also be of interest to diagnose rumination and belching disorders. The best indication of rapid drink challenge test (free drinking of 200 mL) is currently the diagnosis of esophago-gastric junction obstruction. Finally, abdominal compression might be an option to evaluate response of esophageal peristalsis in a context of outflow resistance as proposed by Brink et al. in this issue. These provocative maneuvers appear to provide a complementary role in the evaluation of esophageal motility but require prospective studies to determine the validity of the findings and whether they will lead to changes in clinical practice., (© 2018 John Wiley & Sons Ltd.)