Defining lower esophageal sphincter physiomechanical states among esophageal motility disorders using functional lumen imaging probe panometry.

BACKGROUND: Functional lumen imaging probe (FLIP) panometry assesses esophageal motility in response to controlled volumetric distension. This study aimed to describe the physiomechanical states of the lower esophageal sphincter (LES) in response to serial filling/emptying regimes for esophageal motility disorders. METHODS: Fourty-five patients with absent contractile response on FLIP and diagnoses of normal motility (n = 6), ineffective esophageal motility (IEM; n = 8), scleroderma (SSc; n = 10), or nonspastic achalasia (n = 21) were included, as were 20 patient controls with normal motility on FLIP and manometry. LES diameter and pressure were measured after stepwise FLIP filling at 60 mL, 70 mL, and emptying to 60 mL with relative changes used to define physiomechanical states. KEY RESULTS: Passive dilatation after FLIP filling occurred in 63/65 (97%) patients among all diagnoses. After FLIP emptying, passive shortening occurred in 12/14 (86%) normal motility/IEM, 10/10 (100%) SSc, 9/21(43%) achalasia, and 16/20 (80%) controls, with auxotonic relaxation seen in 2/14 (14%) normal motility/IEM, 12/21 (57%) achalasia, and 4/20 (20%) controls. After achalasia treatment (LES myotomy), 21/21 (100%) achalasia had passive shortening after FLIP emptying. CONCLUSIONS & INFERENCES: Physiomechanical states of the LES can be determined via response to FLIP filling and emptying regimes. While passive shortening was the general response to FLIP emptying, auxotonic relaxation was observed in achalasia, which was disrupted by LES myotomy. Further investigation is warranted into the clinical impact on diagnosis and treatment of esophageal motility disorders.

Esophageal epithelial Ikkß deletion promotes eosinophilic esophagitis in experimental allergy mouse model.

Background: Eosinophilic esophagitis (EoE) is a chronic T helper type 2 (Th2)-associated inflammatory disorder triggered by food allergens, resulting in esophageal dysfunction through edema, fibrosis, and tissue remodeling. The role of epithelial remodeling in EoE pathogenesis is critical but not fully understood. Objective: To investigate the role of epithelial IKKß/NFκB signaling in EoE pathogenesis using a mouse model with conditional Ikk ß knockout in esophageal epithelial cells ( Ikk ß EEC-KO ). Methods: EoE was induced in Ikkß EEC-KO mice through skin sensitization with MC903/Ovalbumin (OVA) followed by intraesophageal OVA challenge. Histological and transcriptional analyses were performed to assess EoE features. Single-cell RNA sequencing (scRNA-seq) was used to profile esophageal mucosal cell populations and gene expression changes. Results: Ikkß EEC-KO /EoE mice exhibited hallmark EoE features, including eosinophil infiltration, intraepithelial eosinophils, microabscesses, basal cell hyperplasia, and lamina propria remodeling. RNA-seq revealed significant alterations in IKKß/NFκB signaling pathways, with decreased expression of RELA and increased expression of IKKß negative regulators. scRNA- seq analyses identified disrupted epithelial differentiation and barrier integrity, alongside increased type 2 immune responses and peptidase activity. Conclusion: Our study demonstrates that loss of epithelial IKKß signaling exacerbates EoE pathogenesis, highlighting the critical role of this pathway in maintaining epithelial homeostasis and preventing allergic inflammation. The Ikkß EEC-KO /EoE mouse model closely mirrors human EoE, providing a valuable tool for investigating disease mechanisms and therapeutic targets. This model can facilitate the development of strategies to prevent chronic inflammation and tissue remodeling in EoE. Key Messages: Critical Role of Epithelial IKKß/NFκB Signaling: Loss of this signaling exacerbates EoE, causing eosinophil infiltration, basal cell hyperplasia, and tissue remodeling, highlighting its importance in esophageal health.Molecular Insights and Therapeutic Targets: scRNA-seq identified disrupted epithelial differentiation, barrier integrity, and enhanced type 2 immune responses, suggesting potential therapeutic targets for EoE. Relevance of the Ikkß EEC-KO /EoE Mouse Model: This model replicates human EoE features, making it a valuable tool for studying EoE mechanisms and testing treatments, which can drive the development of effective therapies. Capsule Summary: This study reveals the crucial role of epithelial IKKß/NFκB signaling in EoE, providing insights into disease mechanisms and potential therapeutic targets, highly relevant for advancing clinical management of EoE.

Effects of Cholecystokinin on Esophageal Motor Response to Distension in Asymptomatic Volunteers.

Background/Aims: Cholecystokinin (CCK) administration has been shown to reduce lower esophageal sphincter (LES) pressure in normal subjects in manometric studies. Functional luminal imaging probe (FLIP) panometry offers a method to assess esophageal motility in response to sustained distension though mechanisms related to this response remain unexplored. The aim of this study is to evaluate the effect of CCK-8 on the esophageal response to distension in asymptomatic volunteers using FLIP. Methods: Esophageal response to distension was studied in 7 asymptomatic volunteers (mean age ± SD [27 ± 2]; 86% female) before and after CCK-8 administration in a crossover study design. During sedated endoscopy, FLIP was performed twice with CCK-8 administered via intravenous push in one of 2 protocols: during filling (n = 4) or during emptying (n = 3). Esophagogastric junction distensibility index (EGJ-DI) at 60 mL fill volume and esophageal body contractile response patterns were analyzed. Results: During the baseline FLIP study, all subjects had a contractile response with repetitive antegrade contractions both before and after CCK-8 administration. However, a sustained LES contraction or a sustained occluding contraction with esophageal shortening was observed in all subjects in the filling protocol, but in none during the emptying protocol. EGJ-DI was similar before and after CCK-8 during both filling (4.7 ± 1.9 mm2/mmHg vs 4.3 ± 1.8 mm2/mmHg) and emptying protocol (7.5 ± 1.4 mm2/mmHg vs 6.9 ± 0.6 mm2/mmHg). Conclusion: While EGJ-DI appeared unaffected by CCK-8 administration in asymptomatic volunteers, CCK induced spastic-reactive contractions of the LES during distention suggesting that exogenous CCK interferes with normal LES relaxation during secondary peristalsis.

Enhancing Chicago Classification diagnoses with functional lumen imaging probe-mechanics (FLIP-MECH).

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.

Age Affects Esophageal Secondary Peristalsis More Than Primary as Assessed by FLIP Panometry and High-resolution Manometry.

Age-related changes in esophageal function involve increased rates of dysmotility with advancing age (sometimes described as presbyesophagus).1-4 Specifically, advanced age has been associated with increased lower esophageal sphincter (LES) pressure and decreased peristaltic vigor.1-4 However, the mechanisms underlying these changes, including the relative relationship of primary peristalsis and secondary peristalsis over the lifespan, remain incompletely understood. Current approaches assess primary peristalsis using high-resolution manometry (HRM), with esophageal motility disorders defined using the Chicago Classification version 4.0 (CCv4.0), and secondary peristalsis using functional lumen imaging probe (FLIP) panometry.5,6 Although HRM and FLIP panometry motility diagnoses are often analogous, they can sometimes differ. For example, abnormal secondary peristalsis can occur when primary peristalsis is normal, which has been associated with reflux and non-obstructive dysphagia.7,8 This study aimed to examine the effect of age on primary peristalsis and secondary peristalsis.

Discriminating "impaired" from "disordered" contractile response on FLIP panometry by utilizing pressure measurement.

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.

Four-dimensional impedance manometry volume metrics for predicting abnormal bolus retention.

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.

An endoscopic scoring system for achalasia: the CARS score.

BACKGROUND AND AIMS: The diagnosis of achalasia is associated with an average delay of 2 years. Endoscopic features may prompt an earlier diagnosis. We aimed to develop and test a novel endoscopic score, CARS, for the prediction of achalasia. METHODS: Part 1: Twenty endoscopic videos were taken from patients undergoing endoscopy for dysphagia or reflux. A survey with videos and endoscopic criteria options was distributed to 6 esophagologists and 6 general gastroenterologists. Inter-rater reliability (IRR) was measured and logistic regression was used to evaluate predictive performance. Three rounds of review were conducted to select the final score of 4 components. Part 2: A retrospective review was conducted for consecutive patients who had comprehensive esophageal testing. Each patient had a CARS endoscopic score calculated based on findings reported at endoscopy. RESULTS: From a video review and analysis of score components, IRR ranged from 0.23 to 0.57 for score components. The final CARS score was selected based on the following 4 components: Contents, Anatomy, Resistance, and Stasis. In a mixed-effects model, the mean score across raters was higher for achalasia compared with nonachalasia subjects (4.44 vs 0.87; P < .01). In part 2 of the study, achalasia patients had a higher mean CARS score compared with those with no or ineffective motility disorder (mean 4.1 vs 1.3; P < .01). CONCLUSIONS: We developed a CARS score based on reliability performance in a video-based survey and tested the score in a clinical setting. The CARS score performed well in predicting achalasia.

Neurological disorders leading to mechanical dysfunction of the esophagus: an emergent behavior of a neuromechanical dynamical system.

An understanding how neurological disorders lead to mechanical dysfunction of the esophagus requires knowledge of the neural circuit of the enteric nervous system. Historically, this has been elusive. Here, we present an empirically guided neural circuit for the esophagus. It has a chain of unidirectionally coupled relaxation oscillators, receiving excitatory signals from stretch receptors along the esophagus. The resulting neuromechanical model reveals complex patterns and behaviors that emerge from interacting components in the system. A wide variety of clinically observed normal and abnormal esophageal responses to distension are successfully predicted. Specifically, repetitive antegrade contractions (RACs) are conclusively shown to emerge from the coupled neuromechanical dynamics in response to sustained volumetric distension. Normal RACs are shown to have a robust balance between excitatory and inhibitory neuronal populations, and the mechanical input through stretch receptors. When this balance is affected, contraction patterns akin to motility disorders are observed. For example, clinically observed repetitive retrograde contractions emerge due to a hyper stretch sensitive wall. Such neuromechanical insights could be crucial to eventually develop targeted pharmacological interventions.

Effect of esophageal body recoil on clinical outcomes in non-spastic achalasia.

BACKGROUND: Despite the established efficacy of achalasia treatments on symptomatic outcomes, there are limited data evaluating the treatment effect on esophageal dilatation. This study aimed to assess the effect achalasia treatment on esophageal dilatation and the effect of esophageal width reduction ("recoil") on clinical outcomes. METHODS: Patients with type I or type II achalasia that completed high-resolution manometry (HRM), functional lumen imaging probe (FLIP), and timed barium esophagram (TBE) pre and post treatment were included. Esophageal width was measured using TBE. Focused subgroup analysis was performed on patients with normal posttreatment EGJ opening on FLIP. Good clinical outcomes were defined as barium column height of <5 cm at 5 min and Eckardt Score ≤3. KEY RESULTS: Sixty-nine patients (41% type I and 59% type II) were included. Esophageal width decreased from pre to post treatment mean (SD) 4.2 (1.3) cm-2.8 (1.2) cm; p < 0.01. In the normal post treatment EGJ opening subgroup, esophageal width was less in patients with good TBE outcome compared to poor outcome mean (SD) 2.2 (0.7) cm versus 3.2 (1.4) cm (p < 0.01), but did not differ in good versus poor symptomatic outcome groups. Esophageal width recoil >25% posttreatment was associated with a greater rate of good TBE outcome (71% vs. 50%, p = 0.04) and good symptomatic outcome (88% vs. 50%; p = 0.04). CONCLUSIONS AND INFERENCES: Esophageal recoil was associated with good achalasia treatment outcome in patients without posttreatment EGJ obstruction. This suggests that mechanical properties of the esophageal wall, likely associated with tissue remodeling, play a role in clinical outcomes following achalasia treatment.

Validated Clinical Score to Predict Gastroesophageal Reflux in Patients With Chronic Laryngeal Symptoms: COuGH RefluX.

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict the likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms. METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms who underwent objective testing (upper gastrointestinal endoscopy and/or ambulatory reflux monitoring) between March 2018 and May 2023. The training phase identified a model with optimal receiver operating characteristic curves, and ß coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model. RESULTS: A total of 856 adults, 304 in the training cohort and 552 in the validation cohort, were included. In the training phase, the optimal predictive model (area under the curve, 0.68; 95% CI, 0.62-0.74), was the Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX (COuGH RefluX) score, with a lower threshold of 2.5 and an upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an area under the curve of 0.67 (95% CI, 0.62-0.71), with 79% sensitivity and 81% specificity for proven GERD. CONCLUSIONS: The externally validated COuGH RefluX score is a clinically practical model to predict the likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.

High Diagnostic Yield of Abnormal Endoscopic Findings in the Evaluation of Laryngopharyngeal Reflux.

Esophagogastroduodenoscopy (EGD) is recommended in patients with typical gastroesophageal reflux disease (GERD) symptoms (heartburn, regurgitation, chest pain) in the setting of proton pump inhibitor (PPI) nonresponse. EGD evaluates for erosive disease, assesses antireflux barrier integrity, excludes non-GERD conditions, and, in the absence of erosive findings, is followed by reflux testing.1,2 The diagnostic utility of EGD is less clear in the evaluation for laryngopharyngeal reflux (LPR), and the current reference standard is ambulatory reflux monitoring.1,3,4 This study of patients referred for evaluation of chronic laryngeal symptoms had the following aims: (1) to characterize endoscopic findings, (2) to discern whether findings differed between patients with or without concomitant esophageal reflux symptoms, and (3) to measure the association between endoscopic findings and objective GERD on ambulatory reflux monitoring.

Secondary peristalsis and esophagogastric junction distensibility in symptomatic post-fundoplication patients.

BACKGROUND: The impact of esophageal dysmotility among patients with post-fundoplication esophageal symptoms is not fully understood. This study aimed to investigate secondary peristalsis and esophagogastric junction (EGJ) opening biomechanics using functional lumen imaging probe (FLIP) panometry in symptomatic post-fundoplication patients. METHODS: Eighty-seven adult patients post-fundoplication who completed FLIP for symptomatic esophageal evaluation were included. Secondary peristaltic contractile response (CR) patterns and EGJ opening metrics (EGJ distensibility index (EGJ-DI) and maximum EGJ diameter) were evaluated on FLIP panometry and analyzed against high-resolution manometry (HRM), patient-reported outcomes, and fundoplication condition seen on esophagram and/or endoscopy. KEY RESULTS: FLIP CR patterns included 14 (16%) normal CR, 30 (34%) borderline CR, 28 (32%) impaired/disordered CR, 13 (15%) absent CR, and 2 (2%) spastic reactive CR. Compared with normal and borderline CRs (i.e., CR patterns with distinct, antegrade peristalsis), patients with impaired/disordered and absent CRs demonstrated significantly greater time since fundoplication (2.4 (0.6-6.8) vs. 8.9 (2.6-14.5) years; p = 0.002), greater esophageal body width on esophagram (n = 50; 2.3 (2.0-2.8) vs. 2.9 (2.4-3.6) cm; p = 0.013), and lower EGJ-DI (4.3 (2.7-5.4) vs. 2.6 (1.7-3.7) mm2/mmHg; p = 0.001). Intact fundoplications had significantly higher rates of normal CRs compared to anatomically abnormal (i.e., tight, disrupted, slipped, herniated) fundoplications (9 (28%) vs. 5 (9%); p = 0.032), but there were no differences in EGJ-DI or EGJ maximum diameter. CONCLUSIONS & INFERENCES: Symptomatic post-fundoplication patients were characterized by frequent abnormal secondary peristalsis after fundoplication, potentially worsening with time after fundoplication or related to EGJ outflow resistance.

The Severity of Reduced Esophageal Distensibility Parallels Eosinophilic Esophagitis Disease Duration.

BACKGROUND & AIMS: Chronic inflammation of eosinophilic esophagitis (EoE) results in progressive, fibrostenotic remodeling of the esophageal wall. This study aimed to demonstrate objective changes in esophageal distensibility relative to duration of EoE disease using a functional lumen imaging probe (FLIP). METHODS: Adult patients with EoE who completed a 16-cm FLIP protocol during endoscopy were evaluated in a cross-sectional study. FLIP analysis focused on distensibility plateau (DP) of the esophageal body. The time from onset of symptoms to time of endoscopy with FLIP was assessed, as was time from symptom onset to EoE diagnosis (ie, diagnostic delay). RESULTS: A total of 171 patients (mean age 38 ± 12 years; 31% female) were included; the median symptom duration was 8 (interquartile range, 3-15) years and diagnostic delay was 4 (interquartile range, 1-12) years. At the time of endoscopy with FLIP, there were 54 patients (39%) in histologic remission (<15 eosinophils per high-power field [eos/hpf]). Symptom duration and diagnostic delay were negatively correlated with DP (rho = -0.326 and -0.309; P values < .001). Abnormal esophageal distensibility (DP ≤17 mm) was more prevalent with increased duration of symptoms (P < .004): 23% at <5 years to 64% at ≥25 years. When stratifying the cohort based on mucosal eosinophil density, patients with ≥15 eos/hpf had significantly lower DP with greater symptom duration (P = .004), while there was not a significant difference among patients with <15 eos/hpf (P = .060). CONCLUSIONS: Esophageal distensibility objectively measured with FLIP was reduced in EoE patients with greater symptom duration and diagnostic delay. This supports that EoE is a progressive, fibrostenotic disease and that FLIP may be a useful tool to monitor disease progression in EoE.

Diagnostic Yield of Ambulatory Reflux Monitoring Systems for Evaluation of Chronic Laryngeal Symptoms.

INTRODUCTION: Among patients with chronic laryngeal symptoms, ambulatory reflux monitoring off acid suppression is recommended to evaluate for laryngopharyngeal reflux (LPR). However, reflux monitoring systems are diverse in configuration and monitoring capabilities, which present a challenge in creating a diagnostic reference standard in these patients. This study aimed to compare diagnostic yield and performance between reflux monitoring systems in patients with chronic laryngeal symptoms. METHODS: This multicenter, international study of adult patients referred for evaluation of LPR over a 5-year period (March 2018-May 2023) assessed and compared diagnostic yield of pathologic gastroesophageal reflux (GER+) on ambulatory reflux monitoring off acid suppression. RESULTS: Of 813 patients, 296 (36%) underwent prolonged wireless pH, 532 (65%) underwent 24-hour pH-impedance monitoring, and 15 (2%) underwent both tests. Overall diagnostic yield for GER+ was 36% and greater for prolonged wireless pH compared with that for 24-hour pH-impedance monitoring (50% vs 27%; P < 0.01). Among 15 patients who underwent both prolonged wireless pH and 24-h pH-impedance monitoring, concordance between systems for GER+ was 40%. The most common source of discordance was strong evidence of GER+ across multiple days on prolonged wireless pH compared with no evidence of GER+ on pH-impedance. DISCUSSION: In this multicenter international study of patients with chronic laryngeal symptoms referred for LPR evaluation, diagnostic yield of ambulatory reflux monitoring off acid suppression was 36% and rose to 50% when using wireless pH monitoring. In patients referred for chronic laryngeal symptoms, 24-hour pH-impedance monitoring may risk a low negative predictive value in patients with unproven GER+ disease.

Composite score of physiomechanical esophageal function using functional lumen imaging probe panometry in eosinophilic esophagitis.

BACKGROUND AND AIMS: The evaluation provided by functional lumen imaging probe (FLIP) panometry includes esophageal distensibility/compliance (mechanics) of the esophageal body and esophagogastric junction (EGJ) and esophageal motility (secondary peristalsis). We developed a composite score using these parameters to characterize physiomechanical function in patients with eosinophilic esophagitis (EoE). METHODS: Two hundred fifteen adult patients with EoE who completed FLIP panometry during sedated endoscopy with esophageal biopsy sampling were included. FLIP metrics of esophageal body Compliance, Contractile response, Distensibility plateau, and maximum EGJ Diameter (C2D2) were scored as 0 for normal versus 1 or 2 for increasing degree of abnormality. Scores were summed to calculate the composite C2D2 score. RESULTS: The C2D2 score had a significant positive correlation with mucosal eosinophil count (ρ = .241) and total Endoscopic EoE Reference Score (ρ = .467). Among 46 patients off treatment at the baseline evaluation, future proton pump inhibitor (PPI) responders (ie, achieved mucosal eosinophil count <15 per high-powered field after PPI treatment) had lower C2D2 scores than PPI nonresponders (median, 2 [interquartile range, 1-3] vs 4 [interquartile range, 2-6], respectively; P = .003). A regression model (that controlled for age, sex, and baseline eosinophil count) showed a C2D2 score ≤3 had an odds ratio of 14.5 (95% confidence interval, 2.6-85) to predict future PPI response. However, total Endoscopic EoE Reference Scores (P = .142) and baseline eosinophil count (P = .480) did not differ between PPI responders and PPI nonresponders. CONCLUSIONS: This composite score of FLIP panometry metrics, the C2D2 score, may facilitate characterizing physiomechanical function in EoE and serve as an objective outcome measure.

Presence of esophageal contractility after achalasia treatment is associated with improved esophageal emptying.

BACKGROUND AND AIMS: Some achalasia patients exhibit esophageal contractile activity on follow-up after treatment, yet its importance remains unclear. We aimed to identify factors associated with presence of contractility after treatment and to assess its impact on timed barium esophagram (TBE) and clinical outcomes. METHODS: Patients with type I or II achalasia on baseline high-resolution manometry (HRM) who completed HRM, TBE, and functional lumen imaging probe (FLIP) after treatment were retrospectively identified. Contractility was defined on post-treatment HRM as presence of at least 1 supine swallow with DCI ≥100 mmHg s cm. KEY RESULTS: One hundred twenty-two patients were included (mean age 48 ± 17 years, 50% female). At follow-up evaluation after treatment (54% peroral endoscopic myotomy, 24% pneumatic dilation, 22% laparoscopic Heller myotomy), 61 (50%) patients had contractility on HRM. Patients with contractility (compared to those without) more frequently had type II achalasia (84% vs 57%, p = 0.001) and a post-treatment normal EGJ opening classification on FLIP (69% vs 49%; p < 0.001). In the subgroup of patients with post-treatment integrated relaxation pressure <15 mmHg and normal EGJ opening on FLIP (n = 53), those with contractility had a lower median column height on TBE at 1 min (4 vs 7 cm, p = 0.002) and 5 min (0 vs 5 cm, p = 0.001). In patients with "abnormal" EGJ metrics, patients with contractility showed lower symptom scores (median Eckardt score 2 vs 3, p = 0.03). CONCLUSIONS & INFERENCES: Occurring more frequently in type II achalasia, and if adequate EGJ opening is achieved after treatment, esophageal contractility may contribute to improved esophageal emptying and improved symptoms in non-spastic achalasia. Preservation of esophageal body muscle could improve outcomes in these patients.

A Mechanics-Based Perspective on the Function of Human Sphincters During Functional Luminal Imaging Probe Manometry.

Functional luminal imaging probe (FLIP) is used to measure cross-sectional area (CSA) and pressure at sphincters. It consists of a catheter surrounded by a fluid filled cylindrical bag, closed on both ends. Plotting the pressure-CSA hysteresis of a sphincter during a contraction cycle, which is available through FLIP testing, offers information on its functionality, and can provide diagnostic insights. However, limited work has been done to explain the mechanics of these pressure-CSA loops. This work presents a consolidated picture of pressure-CSA loops of different sphincters. Clinical data reveal that although sphincters have a similar purpose (controlling the flow of liquids and solids by opening and closing), two different pressure-CSA loop patterns emerge: negative slope loop (NSL) and positive slope loop (PSL). We show that the loop type is the result of an interplay between (or lack thereof) two mechanical modes: (i) neurogenic mediated relaxation of the sphincter muscle or pulling applied by external forces, and (ii) muscle contraction proximal to the sphincter which causes mechanical distention. We conclude that sphincters which only function through mechanism (i) exhibition NSL whereas sphincters which open as a result of both (i) and (ii) display a PSL. This work provides a fundamental mechanical understanding of human sphincters. This can be used to identify normal and abnormal phenotypes for the different sphincters and help in creating physiomarkers based on work calculation.

Assessing mechanical function of peristalsis with functional lumen imaging probe panometry: Contraction power and displaced volume.

BACKGROUND AND AIMS: The distal contractile integral (DCI) quantifies the contractile vigor of primary peristalsis on high-resolution manometry (HRM), whereas no such metric exists for secondary peristalsis on functional lumen imaging probe (FLIP) panometry. This study aimed to evaluate novel FLIP metrics of contraction power and displaced volume in asymptomatic controls and a patient cohort. METHODS: Thirty-five asymptomatic controls and adult patients (with normal esophagogastric junction outflow/opening and without spasm) who completed HRM and FLIP panometry were included. The patient group also completed timed barium esophagram (TBE). Contraction power (estimate of esophageal work over time) and displaced volume (estimate of contraction-associated fluid flow) were computed from FLIP. HRM was analyzed per Chicago Classification v4.0. KEY RESULTS: In controls, median (5th-95th percentile) contraction power was 27 mW (10-44) and displaced volume was 43 mL (17-66). 95 patients were included: 72% with normal motility on HRM, 17% with ineffective esophageal motility (IEM), and 12% with absent contractility. Among patients, DCI was significantly correlated with both contraction power (rho = 0.499) and displaced volume (rho = 0.342); p values < 0.001. Both contraction power and displaced volume were greater in patients with normal motility versus IEM or absent contractility, complete versus incomplete bolus transit, and normal versus abnormal retention on TBE; p values < 0.02. CONCLUSIONS: FLIP panometry metrics of contraction power and displaced volume appeared to effectively quantify peristaltic vigor. These novel metrics may enhance evaluation of esophageal motility with FLIP panometry and provide a reliable surrogate to DCI on HRM.

Relaxation of the lower esophageal sphincter in response to reduced volume distension during FLIP Panometry.

BACKGROUND: The esophageal response to stepwise distension during the functional lumen imaging probe (FLIP) Panometry study often parallels high-resolution manometry (HRM) motility diagnoses. This study aimed to describe the changes in FLIP metrics during FLIP emptying, that is, reduced volume distension. METHODS: Adult patients who completed FLIP and HRM for esophageal motility evaluation were included. Esophagogastric junction (EGJ) opening parameters were assessed during stepwise FLIP filling to volumes of 60 mL ("filling 60 mL"), then 70 mL, and then back to 60 mL ("emptying 60 mL"). HRM studies were analyzed per Chicago classification version 4.0 (CCv4.0). KEY RESULTS: Among 265 patients included, HRM/CCv4.0 diagnoses included achalasia in 80 patients (30%), normal motility in 70 (26%), and ineffective esophageal motility (IEM) in 43 (16%). EGJ-distensibility index (DI) and EGJ diameter were greater during emptying 60 mL than filling 60 mL in achalasia, normal motility, and IEM (p values <0.002). If applying the emptying 60 mL EGJ-DI (vs. filling 60 mL EGJ-DI), EGJ opening classification changed from reduced EGJ opening to borderline EGJ opening in 31% of achalasia patients and in 2% of patients with normal motility or IEM. EGJ opening classification was unchanged in 69% achalasia and 96% of normal motility/IEM. CONCLUSIONS AND INFERENCES: This study suggests that isotonic or auxotonic relaxation of the lower esophageal sphincter occurs with reduced volume distension in patients with achalasia and normal motility. The study also supports the importance of utilizing a standardized FLIP motility study protocol (i.e., controlled, stepwise filling to 50 mL, 60 mL, then 70 mL) to provide reliable and generalizable FLIP metrics to facilitate diagnosis of esophageal motility disorders.