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Summary: Background: Mechanisms underlying perception of dysphagia and chest pain have not been completely elucidated, although oesophageal mucosal afferent nerves might play an important role. Aims: To evaluate the relationship between oesophageal mucosal afferent nerves and the severity of dysphagia and chest pain in oesophageal motility disorders. Methods: We prospectively recruited patients with oesophageal motility disorders having dysphagia and/or chest pain from whom oesophageal biopsies were obtained. High‐resolution manometry classified patients into disorders of oesophagogastric junction (OGJ) outflow and disorders of peristalsis. Symptom severity was assessed using validated questionnaires including Brief Oesophageal Dysphagia Questionnaire (BEDQ). Immunohistochemistry was performed on oesophageal biopsies to evaluate the location of calcitonin gene‐related peptide (CGRP)‐immunoreactive mucosal afferent nerves. Findings were compared to existing data from 10 asymptomatic healthy volunteers. Results: Of 79 patients, 61 patients had disorders of OGJ outflow and 18 had disorders of peristalsis. CGRP‐immunoreactive mucosal nerves were more superficially located in the mucosa of patients with oesophageal motility disorders compared to healthy volunteers. Within disorders of OGJ outflow, the location of CGRP‐immunoreactive nerves negatively correlated with BEDQ score both in the proximal (ρ = −0.567, p < 0.001) and distal oesophagus (ρ = −0.396, p = 0.003). In the proximal oesophagus, strong chest pain was associated with more superficially located mucosal nerves than weak chest pain (p = 0.04). Multivariate analysis showed superficial nerves in the proximal oesophagus was independently associated with severe dysphagia in disorders of OGJ outflow (p = 0.008). Conclusions: Superficial location of mucosal nerves in the proximal oesophagus might contribute to symptoms, especially severe dysphagia, in disorders of OGJ outflow. [ABSTRACT FROM AUTHOR]

Pediatric gastrointestinal motility disorders represent some of the most challenging clinical conditions with largely undefined pathogenetic pathways and therefore limited therapeutic options. Herein, we provide an overview of the recent advances in treatment options for these disorders and their clinical impact. PubMed and Medline databases were searched for relevant articles related to the treatment of achalasia, esophageal atresia, gastroparesis, PIPO and constipation published between 2017 and 2022. In this article, we review and summarize recent advances in management of gastrointestinal motility disorders in children with a particular focus on emerging therapies as well as novel diagnostic modalities that help guide their application or develop new, more targeted treatments. Gastrointestinal motility disorders represent one of the most challenging conundrums in pediatric age and despite significant advances in investigative tools, the palette of treatment options remain limited. Overall, while pharmacological options have failed to bring a curative solution, recent advances in minimal invasive therapeutic and diagnostic techniques have emerged as potential keys to symptom and quality of life improvement, such as ENDOFLIP, POEM, cine-MRI, fecal microbiota transplantation. [ABSTRACT FROM AUTHOR]

Background: Pediatric intestinal pseudo‐obstruction (PIPO) encompasses a variety of rare, heterogeneous, and disabling disorders that severely affect gastrointestinal motility and are associated with high morbidity and mortality. PIPO management is complex and focuses on maintaining an optimal nutritional status, improving gut function, relieving symptoms, and treating complications. Nutritional issues prevail, and PIPO patients often experience severe undernutrition and faltering growth. Thus, nutritional management plays a pivotal role for achieving the most favorable clinical outcomes. The calorie and nutrient intake of each patient needs to be tailored to age, extent and severity of gut involvement and nutritional needs to support an optimal nutritional status. After defining the extent and severity of gut dysmotility, an experienced team should perform a careful nutritional assessment. An oral diet should always be encouraged and might include bite and dissolve solids, liquid diet or simple oral stimulation. If oral caloric intake is inadequate, liquid gastric feeds should provide the subsequent step. In the presence of severe gastric dysmotility, continuous post‐pyloric feeding represents a viable option. In the most severe cases, parenteral nutrition (PN) is required to meet appropriate nutritional requirements. Purpose: Pediatric data on this topic are scarce and mainly extrapolated from adult studies. In this review, we discuss current evidence and knowledge regarding nutritional options, implications of the use of different feed types, including a blended diet, and the use of PN. Moreover, based on our experience and the evidence from the literature, we propose a flow chart to guide the nutritional management of PIPO patients. [ABSTRACT FROM AUTHOR]

Background: Excessive belching is frequently reported in adult patients with gastro‐oesophageal reflux disease (GORD) and dyspepsia. Although postprandial gastric belching (GB) is considered a physiological mechanism for gastric venting, supra‐gastric belching (SGB) is considered a distinct behavioural disorder. We aimed to define the prevalence of different types of belching and its association with reflux disease in paediatric patients. Methods: We retrospectively analysed reflux monitoring studies from 287 patients (median age: 7.0 years; interquartile range 3.0–11.3 years) with a suspicion of GORD. Based on oesophageal acid exposure time (AET) patients were divided in 3 groups: (a) physiological AET, (b) borderline AET and (c) pathological AET. MII‐pH studies were manually edited and reflux disease parameters were measured together with quantification of GB and SGB. Key Results: Two hundred one children (70.0%) had physiological AET (median: 0.8; interquartile range 0.3–1.6), 52 (18.1%) had borderline AET (median: 4.2; interquartile range 3.4–5.3) and 34 (11.9%) had pathologic AET (median: 10.7; interquartile range 9.1–14.2). Gastric belching was observed in all studies. Gastric belching related reflux was more frequently observed in patients with borderline and pathological AET (p < 0.001). This was more common in older children. SGB were observed in only 7 (2.4%) children (age range: 8–17years) in our population and all patients had Physiological AET. Only 3 (1%) patients had pathological number of SGB (>13/24 h). Conclusions and Inferences: Gastric belching related reflux is observed in children with increased AET. SGB is very rare in the paediatric population. [ABSTRACT FROM AUTHOR]

Background/Aims Mean nocturnal baseline impedance (MNBI) during multichannel intraluminal impedance pH-monitoring (MII-pH) reflects the status of esophageal mucosal integrity. MNBI is suggested as an adjunctive method to distinguish patients with true gastroesophageal reflux disease (GERD) from functional heartburn (FH) and might predict outcomes for anti-reflux treatment. However, current methodology for calculation of MNBI is time-consuming and subject to operator-dependent selection bias. We aim to simplify and provide a more objective method to calculate MNBI. Methods We retrospectively analyzed 100 MII-pH tracings from 20 patients with erosive reflux disease, 20 with non-erosive reflux disease (NERD), 20 with reflux hypersensitivity, 20 with functional heartburn (FH), and 20 healthy asymptomatic volunteers. We compared the current "conventional" MNBI analysis with our "simple" MNBI analysis measured by selecting the whole supine period using the impedance average calculation function in the MII-pH software. Results Absolute values were very similar and there was a strong correlation between conventional and simple MNBI values in the most distal channel in all groups (r = 0.8, P < 0.001) including patients with increased supine acid reflux. Distal esophageal simple MNBI negatively correlated with acid exposure time (r = -0.695, P < 0.001). Patients with erosive reflux disease and NERD had lower simple MNBI values in the most distal channel compared to other groups (P < 0.001). With a cutoff value of 1785 ohms, simple MNBI can discriminate patients with GERD from those with reflux hypersensitivity and FH (sensitivity 80.0% and specificity 89.7%). Conclusion Simple MNBI analysis provides very similar values and has an excellent correlation with conventional MNBI analysis. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Esophageal mucosa innervation in adults with nonerosive reflux disease (NERD) is more superficial compared with healthy volunteers. We delineated the esophageal mucosal innervation in pediatric NERD and controls. METHODS: Distal and proximal pediatric esophageal biopsies were immunohistochemically stained with calcitonin gene-related peptide and transient receptor potential cation channel subfamily V member 1. RESULTS: Mucosal innervation was assessed in 18 controls (9M:9F, median age: 9 years) and 11 NERD patients (6M:5F, median age: 5 years). Calcitonin gene-related peptide positive nerve fibers were lying deep in the mucosa in both groups, P > 0.05 and did not coexpress transient receptor potential cation channel subfamily V member 1. DISCUSSION: The pediatric esophageal mucosa in NERD displays deep lying nerve fibers, in contrast to adults. [ABSTRACT FROM AUTHOR]

Background & Aims Little is known about the causes of heartburn in patients with gastro-esophageal reflux disease. Visible epithelial damage is seldom associated with symptom severity, evidenced by the significant symptom burden in patients with nonerosive reflux disease (NERD) compared with patients with erosive reflux disease (ERD) or Barrett’s esophagus (BE). We studied the distribution of mucosal nerve fibers in patients with NERD, ERD, and BE, and compared the results with those of healthy subjects. Methods We performed a prospective study of 13 patients with NERD, 11 patients with ERD, and 16 patients with BE undergoing endoscopic evaluation in the United Kingdom or Greece. Biopsies were obtained from the proximal and distal esophageal mucosa of patients with NERD, from the distal esophageal mucosa of patients with ERD, and the distal-most squamous epithelium of patients with BE. These were examined for the presence and location of nerve fibers that reacted with a labeled antibody against calcitonin gene-related peptide (CGRP), a marker of nociceptive sensory nerves. The results were compared with those from 10 healthy volunteers (controls). Results The distribution of CGRP-positive nerves did not differ significantly between the distal esophageal mucosa of controls (median, 25.5 cell layers to surface; interquartile range [IQR], 21.4–28.8) vs patients with ERD (median, 23 cell layers to surface; IQR, 16–27.5), or patients with BE (median, 21.5 cell layers to surface; IQR, 16.1–27.5). However, CGRP-positive nerves were significantly more superficial in mucosa from patients with NERD—both distal (median, 9.5 cell layers to surface; IQR, 1.5–13.3; P < .0001 vs ERD, BE, and controls) and proximal (median, 5.0 cell layers to surface; IQR, 2.5–9.3 vs median 10.4 cell layers to surface; IQR, 8.0–16.9; P = .0098 vs controls). Conclusions Proximal and distal esophageal mucosa of patients with NERD have more superficial afferent nerves compared with controls or patients with ERD or BE. Acid hypersensitivity in patients with NERD might be partially explained by the increased proximity of their afferent nerves to the esophageal lumen, and therefore greater exposure to noxious substances in refluxate. [ABSTRACT FROM AUTHOR]

Gastrointestinal dysmotility is a common problem in a subgroup of children with intestinal failure (IF), including short bowel syndrome (SBS) and pediatric intestinal pseudo-obstruction (PIPO). It contributes significantly to the increased morbidity and decreased quality of life in this patient population. Impaired gastrointestinal (GI) motility in IF arises from either loss of GI function due to the primary disorder (e.g., neuropathic or myopathic disorder in the PIPO syndrome) and/or a critical reduction in gut mass. Abnormalities of the anatomy, enteric hormone secretion and neural supply in IF can result in rapid transit, ineffective antegrade peristalsis, delayed gastric emptying or gastroesophageal reflux. Understanding the underlying pathophysiologic mechanism(s) of the enteric dysmotility in IF helps us to plan an appropriate diagnostic workup and apply individually tailored nutritional and pharmacological management, which might ultimately lead to an overall improvement in the quality of life and increase in enteral tolerance. In this review, we have focused on the pathogenesis of GI dysmotility in children with IF, as well as the management and treatment options. [ABSTRACT FROM AUTHOR]

Background: Discontinuation of long‐term proton pump inhibitors (PPIs) on patients with reflux symptoms can be challenging, as symptoms often exacerbate after stopping. The mechanism remains unknown. Our aim was to evaluate the impact of stopping long‐term PPIs on patients with heartburn, and its association with esophageal acid exposure. Methods: Patients with heartburn on long‐term PPIs underwent symptom questionnaire, high‐resolution manometry, and 24h ambulatory impedance‐pH studies, following a 7‐day PPIs discontinuation. We investigated the association between exacerbation of symptoms and findings on ambulatory reflux studies. Key Results: We studied 37 patients. After stopping PPIs, 27 patients (73%) had exacerbation of heartburn. Esophageal acid exposure time% (AET) in patients with exacerbation of heartburn was not significantly higher than in patients without (3.5% [1.3‐9.7] vs 2.5% [1.3‐8.7], NS). Fourteen of 27 patients with exacerbation had physiological AET (<4%) as compared with 6 of 10 patients with physiological AET (NS). All questioned symptoms (heartburn, regurgitation, epigastric discomfort/pain, bloating/belch) worsened after stopping PPIs (NS). Conclusions & Inferences: Exacerbation of heartburn after discontinuation of PPIs does not appear to be due to increased esophageal acid exposure. [ABSTRACT FROM AUTHOR]

Background: Mucosal innervation in non‐erosive reflux disease (NERD; pathological esophageal acid exposure, normal macroscopic mucosa) is clearly distinct from that of healthy volunteers (HV) and from patients with esophagitis or Barrett's esophagus: The nerves in NERD are situated much closer to the luminal surface of the mucosa. Patients with functional heartburn (FH) have a similar symptom profile to patients with NERD and indistinguishable macroscopic appearances. However, they have physiological acid exposure and no reflux‐symptom association. The aim of our study was to delineate the position of esophageal mucosal nerve fibers in patients with FH and compare it with that in NERD and HV. Methods: Distal esophageal biopsies from patients with FH were immunohistochemically stained for CGRP. CGRP‐positive nerve fibers were identified, and their position relative to the lumen was determined. These results were compared to our previously published cohort of HV and NERD. Results: Eleven patients were included in the FH group with a mean age of 46 years (range 33‐69); 7F:4M. Nine patients had visible nerve fibers. The location of the afferent nerve fibers in the distal esophageal mucosa (median of 22, range 10.4‐28) was similar to the HV group (median 25.5) and significantly deeper than the superficial nerves seen in NERD (median 9.5). Conclusions: The mucosal innervation pattern in FH is more alike that of healthy individuals than that of NERD, with afferent nerves lying deep in the mucosa, away from the luminal surface. This supports the theory that heartburn in FH has a distinct nociceptive pathophysiology. [ABSTRACT FROM AUTHOR]

Background/aims: Mean nocturnal baseline impedance (MNBI) during multichannel intraluminal impedance pH-monitoring (MII-pH) reflects the status of esophageal mucosal integrity. MNBI is suggested as an adjunctive method to distinguish patients with true gastroesophageal reflux disease (GERD) from functional heartburn (FH) and might predict outcomes for anti-reflux treatment. However, current methodology for calculation of MNBI is time-consuming and subject to operator-dependent selection bias. We aim to simplify and provide a more objective method to calculate MNBI., Methods: We retrospectively analyzed 100 MII-pH tracings from 20 patients with erosive reflux disease, 20 with non-erosive reflux disease (NERD), 20 with reflux hypersensitivity, 20 with functional heartburn (FH), and 20 healthy asymptomatic volunteers. We compared the current "conventional" MNBI analysis with our "simple" MNBI analysis measured by selecting the whole supine period using the impedance average calculation function in the MII-pH software., Results: Absolute values were very similar and there was a strong correlation between conventional and simple MNBI values in the most distal channel in all groups ( r ≥ 0.8, P < 0.001) including patients with increased supine acid reflux. Distal esophageal simple MNBI negatively correlated with acid exposure time ( r = -0.695, P < 0.001). Patients with erosive reflux disease and NERD had lower simple MNBI values in the most distal channel compared to other groups ( P < 0.001). With a cutoff value of 1785 ohms, simple MNBI can discriminate patients with GERD from those with reflux hypersensitivity and FH (sensitivity 80.0% and specificity 89.7%)., Conclusion: Simple MNBI analysis provides very similar values and has an excellent correlation with conventional MNBI analysis.

Objectives: Up to 20% of patients with refractory gastroesophageal reflux disease (GERD) might have postprandial rumination. The aim of this study was to distinguish persistent GERD-related postprandial regurgitation from rumination in patients with refractory GERD undergoing ambulatory multichannel intraluminal impedance-pH (MII-pH) monitoring., Methods: We first characterized 24-hour and postprandial MII-pH patterns in 28 consecutive patients with confirmed rumination syndrome (positive clinical and high-resolution manometry/impedance). We compared such MII-pH patterns with those from 30 patients with typical GERD symptoms (10 nonerosive reflux disease, 10 hyperactive esophagus, and 10 functional heartburn) and 27 healthy controls. Using ROC curves, we selected the best MII-pH parameters to prepare an MII-pH rumination score. We prospectively tested the performance of the new MII-pH rumination score in 26 consecutive patients with refractory GERD (predominant regurgitation)., Results: Compared with GERD controls, patients with rumination were more often females, younger, and had significantly more postprandial early nonacid reflux episodes with high proximal extent. Postprandial reflux in ruminators had a distinct nadir pH profile over time (from nonacid to acid). Despite increased reflux events, baseline impedance in ruminators was similar to that in healthy subjects. Ruminators marked postprandial symptoms earlier and much more often than patients with GERD. An MII-pH-based rumination score (using postprandial nonacid reflux/hour and Symptom Index) diagnosed rumination in 46% of patients with refractory GERD and persistent regurgitation (sensitivity 91.7% and specificity 78.6%)., Discussion: Postprandial rumination is very common in refractory GERD with persistent regurgitation. A simple MII-pH score detects rumination in these patients with high sensitivity and specificity.

Detailed investigations and objective measurements in patients with symptoms of gastro-oesophageal reflux should be performed with the intent of making the correct diagnosis, thus enabling choice of appropriate therapy. Establishing the most effective therapy is particularly important in adults who do not respond to standard treatment and in children. The use of PPIs for suspected GERD has increased substantially over the past decade, providing great relief in patients with acid-related symptoms, but also leading to adverse effects and a considerable economic burden. Adults with functional heartburn do not benefit from PPIs, while prolonged PPI use in patients with extraoesophageal symptoms remains a controversial area. Moreover, PPIs are not indicated in infants with GERD unless symptoms are proven to be acid-related. With regard to antireflux surgery, patients must be carefully selected to avoid the need for ongoing PPI treatment postoperatively. Correct diagnosis and phenotyping of patients with symptoms attributed to gastro-oesophageal reflux through detailed investigations is therefore imperative, leading to improved patient outcomes and rationalized use of available treatment options. In this Review, we outline currently available diagnostic tests and discuss approaches to limit any unnecessary medical or surgical interventions.