The impact of transcutaneous electrical acustimulation (TEA) on rectal distension-induced pain in patients with irritable bowel syndrome (IBS)-A study to determine the optimal TEA delivery modalities and effects on rectal sensation and autonomic function.

BACKGROUND: Treatment options for abdominal pain in IBS are inadequate. TEA was reported effective treatment of disorders of gut-brain interaction but its mechanism of action and optimal delivery method for treating pain in IBS are unknown. This study aims to determine the most effective TEA parameter and location to treat abdominal pain in patients with IBS-Constipation and delineate the effect of TEA on rectal sensation and autonomic function. METHODS: Nineteen IBS-C patients underwent TEA at acupoints ST36 (leg), PC6 (wrist), or sham-acupoint. Each patient was studied in five randomized sessions on separate days: (1) TEA/ST36-100 Hz; (2) TEA/ST36-25 Hz; (3) TEA/PC6-100 Hz; (4) TEA/PC6-25 Hz; (5) TEA/Sham-25 Hz. In each session, barostat-guided rectal distention (RD) was performed before and after TEA. Patients graded the RD-induced pain and recorded three rectal sensation thresholds. A heart rate variability (HRV) signal was derived from the electrocardiogram for autonomic function assessment. KEY RESULTS: Studied patients were predominantly female, young, and Caucasian. Compared with baseline, patients treated with TEA/ST36-100 Hz had significantly decreased pain scores at RD pressure-points 20-50 mmHg (p < 0.04). The average pain reduction was 40%. Post-treatment scores did not change significantly with other TEA modalities except with sham-TEA (lesser degree compared to ST36-100 Hz, p = 0.04). TEA/ST36-100, but not other modalities, increased the rectal sensation threshold (first sensation: p = 0.007; urge to defecate: p < 0.026). TEA/ST36-100 Hz was the only treatment that significantly decreased sympathetic activity and increased parasympathetic activity with and without RD (p < 0.04). CONCLUSIONS & INFERENCES: TEA at ST36-100 Hz is superior stimulation point/parameter, compared to TEA at PC-6/sham-TEA, to reduce rectal distension-induced pain in IBS-C patients. This therapeutic effect appears to be mediated through rectal hypersensitivity reduction and autonomic function modulation.

Percutaneous electrical nerve field stimulation for adolescents with irritable bowel syndrome: Cost-benefit and cost-minimization analysis.

Abdominal pain drives significant cost for adolescents with irritable bowel syndrome (IBS). We performed an economic analysis to estimate cost-savings for patients' families and healthcare insurance, and health outcomes, based on abdominal pain improvement with percutaneous electrical nerve field stimulation (PENFS) with IB-Stim® (Neuraxis). We constructed a Markov model with a 1-year time horizon comparing outcomes and costs with PENFS versus usual care without PENFS. Clinical outcomes were derived from a sham-controlled double-blind trial of PENFS for adolescents with IBS. Costs/work-productivity impact for parents were derived from appropriate observational cohorts. PENFS was associated with 18 added healthy days over 1 year of follow-up, increased annual parental wages of $5,802 due to fewer missed work days to care for the child, and $4744 in cost-savings to insurance. Percutaneous electrical field nerve stimulation for adolescents with IBS appears to yield significant cost-savings to patients' families and insurance.

Best Parameters of Heart Rate Variability for Assessing Autonomic Responses to Brief Rectal Distention in Patients with Irritable Bowel Syndrome.

Heart rate variability (HRV) has been used to measure autonomic nervous system (ANS) activity noninvasively. The purpose of this study was to identify the most suitable HRV parameters for ANS activity in response to brief rectal distension (RD) in patients with Irritable Bowel Syndrome (IBS). IBS patients participated in a five-session study. During each visit, an ECG was recorded for 15 min for baseline values and during rectal distension. For rectal distension, a balloon was inflated in the rectum and the pressure was increased in steps of 5 mmHg for 30 s; each distension was followed by a 30 s rest period when the balloon was fully deflated (0 mmHg) until either the maximum tolerance of each patient was reached or up to 60 mmHg. The time-domain, frequency-domain and nonlinear HRV parameters were calculated to assess the ANS activity. The values of each HRV parameter were compared between baseline and RD for each of the five visits as well as for all five visits combined. The sensitivity and robustness/reproducibility of each HRV parameter were also assessed. The parameters included the Sympathetic Index (SI); Root Mean Square of Successive Differences (RMSSD); High-Frequency Power (HF); Low-Frequency Power (LF); Normalized HF Power (HFn); Normalized LF Power (LFn); LF/HF; Respiratory Sinus Arrhythmia (RSA); the Poincare Plot's SD1, SD2 and their ratio; and the pNN50, SDSD, SDNN and SDNN Index. Data from 17 patients were analyzed and compared between baseline and FD and among five sessions. The SI was found to be the most sensitive and robust HRV parameter in detecting the ANS response to RD. Out of nine parasympathetic parameters, only the SDNN and SDNN Index were sensitive enough to detect the parasympathetic modulation to RD during the first visit. The frequency-domain parameters did not show any change in response to RD. It was also observed that the repetitive RD in IBS patients resulted in a decreased autonomic response due to habituation because the amount of change in the HRV parameters was the highest during the first visit but diminished during subsequent visits. In conclusion, the SI and SDNN/SDNN Index are most sensitive at assessing the autonomic response to rectal distention. The autonomic response to rectal distention diminishes in repetitive sessions, demonstrating the necessity of randomization for repetitive tests.

Regional changes in intestinal permeability in cirrhosis are associated with mucosal bacteria.

BACKGROUND: Several complications of cirrhosis are theorized to result from the translocation of bacteria or their products across the intestinal epithelium. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with cirrhosis. APPROACH AND RESULTS: We collected 247 duodenum, ileum, and colon biopsies from 58 consecutive patients with cirrhosis and 33 controls during clinically indicated endoscopies. Patients with cirrhosis were similarly aged to controls (60 vs. 58 y) and had a median Model for End-stage Liver Disease of 8 (interquartile range 7, 10). Biopsies underwent 16S rRNA-encoding gene amplicon sequencing to determine mucosal bacteria composition and transepithelial electrical resistance (TEER) to determine epithelial permeability. In the entire cohort, there were regional differences in TEER with the lowest TEER (ie, more permeable) in the ileum; duodenum TEER was 43% higher and colon TEER 20% higher than ileum TEER (ANOVA p = 0.0004). When comparing patients with cirrhosis and controls, both TEER (26% lower in cirrhosis, p = 0.006) and alpha diversity differed in the duodenum (27% lower in cirrhosis, p = 0.01) but not ileum or colon. A beta-binomial model found that 26 bacteria were significantly associated with TEER. Bifidobacteriaceae Bifidobacterium in duodenal mucosa was protective of epithelial permeability and future hospitalization for hepatic decompensation. CONCLUSIONS: Duodenal epithelial permeability was higher, and mucosal bacteria alpha diversity was lower in cirrhosis compared to controls, while no such differences were seen in the ileum or colon. Specific bacteria were associated with epithelial permeability and future hepatic decompensation.

Diagnostic Methods for Evaluation of Gastric Motility-A Mini Review.

Gastric motility abnormalities are common in patients with disorders of gut-brain interaction, such as functional dyspepsia and gastroparesis. Accurate assessment of the gastric motility in these common disorders can help understand the underlying pathophysiology and guide effective treatment. A variety of clinically applicable diagnostic methods have been developed to objectively evaluate the presence of gastric dysmotility, including tests of gastric accommodation, antroduodenal motility, gastric emptying, and gastric myoelectrical activity. The aim of this mini review is to summarize the advances in clinically available diagnostic methods for evaluation of gastric motility and describe the advantages and disadvantages of each test.

Can a Defecation Posture Modifying Device Correct an Abnormal Balloon Expulsion Test in Chronically Constipated Patients?

Evacuation disorders are common among chronically constipated (CC) patients who fail to respond to laxatives and are typically diagnosed by anorectal manometry (ARM) and/or balloon expulsion testing (BET).1,2 Recently, there has been emerging interest in the use of defecation posture-modifying devices (DPMDs) to improve constipation symptoms, presumably by replicating the physiologic benefits of squatting on stool evacuation, such as straightening of the anorectal angle and relaxing the pelvic floor. However, the ability of DPMDs to normalize anorectal function in adult patients with CC has not been studied.

Age- and Gender-Based Differences in Anorectal Function, Gastrointestinal Symptoms, and Constipation-Specific Quality of Life in Patients with Chronic Constipation.

BACKGROUND: The effect of age and gender differences on anorectal function, symptoms severity, and quality of life (QoL) in patients with chronic constipation (CC) is not well studied. This study examines the impact of age and gender on anorectal function testing (AFT) characteristics, symptoms burden, and QoL in patients with CC. METHODS: This is a retrospective analysis of prospectively collected data from 2550 adults with CC who completed AFT. Collected data include demographics, sphincter response to simulated defecation during anorectal manometry (ARM), balloon expulsion testing (BET), and validated surveys assessing constipation symptoms and QoL. DD was defined as both the inability to relax the anal sphincter during simulated defecation and an abnormal BET. RESULTS: 2550 subjects were included in the analysis (mean age = 48.6 years). Most patients were female (81.6%) and Caucasian (82%). 73% were < 60 years old (mean = 41) vs. 27% ≥ 60 years old (mean = 69). The prevalence of impaired anal sphincter relaxation on ARM, abnormal BET, and DD in patients with CC was 48%, 42.1%, and 22.9%, respectively. Patients who were older and male were significantly more frequently diagnosed with DD and more frequently had impaired anal sphincter relaxation on ARM, compared to patients who were younger and female (p < 0.05). Conversely, CC patients who were younger and female reported greater constipation symptoms severity and more impaired QoL (p ≤ 0.004). CONCLUSION: Among patients with CC referred for anorectal function testing, men and those older than 60 are more likely to have dyssynergic defecation, but women and patients younger than 60 experience worse constipation symptoms and QoL.

A Randomized Pilot Study to Compare the Effectiveness of a Low FODMAP Diet vs Psyllium in Patients With Fecal Incontinence and Loose Stools.

INTRODUCTION: The aim of the study was to compare the effectiveness of a low fermentable oligosaccharide, disaccharide, monosaccharide, and polyol diet (LFD) vs psyllium on the frequency and severity of fecal incontinence (FI) episodes in patients with loose stools. METHODS: This was a single-center, randomized pilot trial of adult patients with FI (Rome III) with at least 1 weekly FI episode associated with loose stool. Eligible patients were randomized to 4 weeks of either a dietitian-led LFD or 6 g/d psyllium treatment. RESULTS: Forty-three subjects were randomized from October 2014 to May 2019. Thirty-seven patients completed the study (19 LFD and 18 psyllium). There was no statistically significant difference in the proportion of treatment responders (>50% reduction in FI episodes compared with baseline) for treatment weeks 1-4 (LFD 38.9%, psyllium 50%, P = .33). Compared with baseline, mean fecal incontinence severity index score significantly improved with LFD (39.4 vs 32.6, P = .02) but not with psyllium (35.4 vs 32.1, P = .29). Compared with baseline values, the LFD group reported improvements in fecal incontinence quality of life coping/behavior, depression/self-perception, and embarrassment subscales. The psyllium group reported improvement in incontinence quality of life coping/behavior. DISCUSSION: In this pilot study, there was no difference in the proportion of patients who reported a 50% reduction of FI episodes with the LFD or psyllium. Subjects in the psyllium group reported a greater reduction in overall FI episodes, whereas the LFD group reported consistent improvements in FI severity and quality of life. Further work to understand these apparently discrepant results are warranted but the LFD and psyllium seem to provide viable treatment options for patients with FI and loose stools.

Evidence of Duodenal Epithelial Barrier Impairment and Increased Pyroptosis in Patients With Functional Dyspepsia on Confocal Laser Endomicroscopy and "Ex Vivo" Mucosa Analysis.

INTRODUCTION: Duodenal epithelial barrier impairment and immune activation may play a role in the pathogenesis of functional dyspepsia (FD). This study was aimed to evaluate the duodenal epithelium of patients with FD and healthy individuals for detectable microscopic structural abnormalities. METHODS: This is a prospective study using esophagogastroduodenoscopy enhanced with duodenal confocal laser endomicroscopy (CLE) and mucosal biopsies in patients with FD (n = 16) and healthy controls (n = 18). Blinded CLE images analysis evaluated the density of epithelial gaps (cell extrusion zones), a validated endoscopic measure of the intestinal barrier status. Analyses of the biopsied duodenal mucosa included standard histology, quantification of mucosal immune cells/cytokines, and immunohistochemistry for inflammatory epithelial cell death called pyroptosis. Transepithelial electrical resistance (TEER) was measured using Ussing chambers. Epithelial cell-to-cell adhesion proteins expression was assessed by real-time polymerase chain reaction. RESULTS: Patients with FD had significantly higher epithelial gap density on CLE in the distal duodenum than that of controls (P = 0.002). These mucosal abnormalities corresponded to significant changes in the duodenal biopsy samples of patients with FD, compared with controls, including impaired mucosal integrity by TEER (P = 0.009) and increased number of epithelial cells undergoing pyroptosis (P = 0.04). Reduced TEER inversely correlated with the severity of certain dyspeptic symptoms. Furthermore, patients with FD demonstrated altered duodenal expression of claudin-1 and interleukin-6. No differences in standard histology were found between the groups. DISCUSSION: This is the first report of duodenal CLE abnormalities in patients with FD, corroborated by biopsy findings of epithelial barrier impairment and increased cell death, implicating that duodenal barrier disruption is a pathogenesis factor in FD and introducing CLE a potential diagnostic biomarker in FD.

Is Dyssynergic Defecation an Unrecognized Cause of Chronic Constipation in Patients Using Opioids?

OBJECTIVES: The impact of opioids on anorectal function is poorly understood but potentially relevant to the pathogenesis of opioid-induced constipation (OIC). To evaluate anorectal function testing (AFT) characteristics, symptom burden, and quality of life in chronically constipated patients prescribed an opioid (OIC) in comparison with constipated patients who are not on an opioid (NOIC). METHODS: Retrospective analysis of prospectively collected data on 3,452 (OIC = 588 and NOIC = 2,864) chronically constipated patients (Rome 3) who completed AFT. AFT variables included anal sphincter pressure and response during simulated defecation, balloon expulsion test (BET), and rectal sensation. Dyssynergic defecation (DD) was defined as an inability to relax the anal sphincter during simulated defecation and an abnormal BET. Patients completed Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. RESULTS: The mean age of the study cohort was 49 years. Most patients were women (82%) and whites (83%). Patients with OIC were older than NOIC patients (50.7 vs 48.3, P = 0.001). OIC patients were significantly more likely to have DD (28.6% vs 21.4%, P < 0.001), an abnormal simulated defecation response on anorectal manometry (59% vs 43.8%, P < 0.001), and an abnormal BET (48% vs 42.5%, P = 0.02) than NOIC patients. OIC patients reported more severe constipation symptoms (P < 0.02) and worse quality of life (P < 0.05) than NOIC patients. DISCUSSION: Chronically constipated patients who use opioids are more likely to have DD and more severe constipation symptoms than NOIC.

A Statistically Significant Association Between Esophageal Granular Cell Tumors and Eosinophilic Esophagitis: A 16-year Analysis at Two Large Hospitals of 167,434 EGDs.

BACKGROUND: Esophageal granular cell tumor (eGCT) is a rare, usually benign, neoplasm of neuroectodermic origin. Eosinophilic esophagitis (EoE) is a relatively uncommon, immune-mediated, chronic disease. Both diseases commonly present with dysphagia. One case has been reported of simultaneous occurrence of both diseases. AIMS: To determine the association between diseases. METHODS: The present study was an IRB-approved, retrospective review of esophagogastroduodenoscopies (EGDs) with esophageal biopsies from two large hospitals, 1999-2014. RESULTS: Among 29,235 EGDs with esophageal biopsies for 16 years (167,434 total EGDs), 16 patients had pathologically diagnosed eGCT, and 1225 patients had pathologically diagnosed EoE. Five (31%) of 16 patients with eGCT had concomitant EoE (p = 0.001, OR 10.43, 95% ORCI 3.16-32.44, Fisher's exact test). Patients with simultaneous eGCT and EoE were young (mean age = 33.6 ± 12.9 years). Three were female. Dysphagia was presenting symptom in 4 (80%) of patients. Three had asthma. All five patients had > 20 eosinophils/hpf in esophageal biopsy specimens. Three patients had endoscopic esophageal abnormalities suggesting EoE. Four patients were treated with a PPI (before and after diagnosis of EoE), and 2 patients underwent six-food-elimination diet with partial symptomatic improvement. The eGCTs averaged 13.4 ± 4.2 mm in maximal diameter and were located in upper-2, middle-2, and lower esophagus-2 (1 patient had 2 eGCTs). eGCTs were endoscopically resected-3 patients, and monitored-2 patients. Surveillance endoscopies revealed no recurrence or growth of eGCTs after resection (mean follow-up = 4.6 years). CONCLUSIONS: This novel report of 5 patients with simultaneous EoE and eGCT adds to one, previously published case and suggests these two diseases are associated, and have a common pathophysiologic link, despite apparently different pathogenesis. Large, prospective, endoscopic and pathologic studies are warranted to further investigate this association.

Distinctive aspects of peptic ulcer disease, Dieulafoy's lesion, and Mallory-Weiss syndrome in patients with advanced alcoholic liver disease or cirrhosis.

AIM: To systematically review the data on distinctive aspects of peptic ulcer disease (PUD), Dieulafoy's lesion (DL), and Mallory-Weiss syndrome (MWS) in patients with advanced alcoholic liver disease (aALD), including alcoholic hepatitis or alcoholic cirrhosis. METHODS: Computerized literature search performed via PubMed using the following medical subject heading terms and keywords: "alcoholic liver disease", "alcoholic hepatitis"," alcoholic cirrhosis", "cirrhosis", "liver disease", "upper gastrointestinal bleeding", "non-variceal upper gastrointestinal bleeding", "PUD", ''DL'', ''Mallory-Weiss tear", and "MWS''. RESULTS: While the majority of acute gastrointestinal (GI) bleeding with aALD is related to portal hypertension, about 30%-40% of acute GI bleeding in patients with aALD is unrelated to portal hypertension. Such bleeding constitutes an important complication of aALD because of its frequency, severity, and associated mortality. Patients with cirrhosis have a markedly increased risk of PUD, which further increases with the progression of cirrhosis. Patients with cirrhosis or aALD and peptic ulcer bleeding (PUB) have worse clinical outcomes than other patients with PUB, including uncontrolled bleeding, rebleeding, and mortality. Alcohol consumption, nonsteroidal anti-inflammatory drug use, and portal hypertension may have a pathogenic role in the development of PUD in patients with aALD. Limited data suggest that Helicobacter pylori does not play a significant role in the pathogenesis of PUD in most cirrhotic patients. The frequency of bleeding from DL appears to be increased in patients with aALD. DL may be associated with an especially high mortality in these patients. MWS is strongly associated with heavy alcohol consumption from binge drinking or chronic alcoholism, and is associated with aALD. Patients with aALD have more severe MWS bleeding and are more likely to rebleed when compared to non-cirrhotics. Pre-endoscopic management of acute GI bleeding in patients with aALD unrelated to portal hypertension is similar to the management of aALD patients with GI bleeding from portal hypertension, because clinical distinction before endoscopy is difficult. Most patients require intensive care unit admission and attention to avoid over-transfusion, to correct electrolyte abnormalities and coagulopathies, and to administer antibiotic prophylaxis. Alcoholics should receive thiamine and be closely monitored for symptoms of alcohol withdrawal. Prompt endoscopy, after initial resuscitation, is essential to diagnose and appropriately treat these patients. Generally, the same endoscopic hemostatic techniques are used in patients bleeding from PUD, DL, or MWS in patients with aALD as in the general population. CONCLUSION: Nonvariceal upper GI bleeding in patients with aALD has clinically important differences from that in the general population without aALD, including: more frequent and more severe bleeding from PUD, DL, or MWS.

Gastrointestinal bleeding from Dieulafoy's lesion: Clinical presentation, endoscopic findings, and endoscopic therapy.

Although relatively uncommon, Dieulafoy's lesion is an important cause of acute gastrointestinal bleeding due to the frequent difficulty in its diagnosis; its tendency to cause severe, life-threatening, recurrent gastrointestinal bleeding; and its amenability to life-saving endoscopic therapy. Unlike normal vessels of the gastrointestinal tract which become progressively smaller in caliber peripherally, Dieulafoy's lesions maintain a large caliber despite their peripheral, submucosal, location within gastrointestinal wall. Dieulafoy's lesions typically present with severe, active, gastrointestinal bleeding, without prior symptoms; often cause hemodynamic instability and often require transfusion of multiple units of packed erythrocytes. About 75% of lesions are located in the stomach, with a marked proclivity of lesions within 6 cm of the gastroesophageal junction along the gastric lesser curve, but lesions can also occur in the duodenum and esophagus. Lesions in the jejunoileum or colorectum have been increasingly reported. Endoscopy is the first diagnostic test, but has only a 70% diagnostic yield because the lesions are frequently small and inconspicuous. Lesions typically appear at endoscopy as pigmented protuberances from exposed vessel stumps, with minimal surrounding erosion and no ulceration (visible vessel sans ulcer). Endoscopic therapy, including clips, sclerotherapy, argon plasma coagulation, thermocoagulation, or electrocoagulation, is the recommended initial therapy, with primary hemostasis achieved in nearly 90% of cases. Dual endoscopic therapy of epinephrine injection followed by ablative or mechanical therapy appears to be effective. Although banding is reportedly highly successful, it entails a small risk of gastrointestinal perforation from banding deep mural tissue. Therapeutic alternatives after failed endoscopic therapy include repeat endoscopic therapy, angiography, or surgical wedge resection. The mortality has declined from about 30% during the 1970's to 9%-13% currently with the advent of aggressive endoscopic therapy.

Short and medium-term therapeutic effects of pneumatic dilatation for achalasia: a 15-year tertiary centre experience.

BACKGROUND: Pneumatic dilatation (PD) is a commonly used endoscopic technique to weaken the lower oesophageal sphincter in patients with achalasia. It is considered as the most effective non-surgical therapeutic option for achalasia, but further data on the overall effectiveness and rate of complications is needed. AIMS: To determine the short- and medium-term therapeutic effectiveness of PD for achalasia and estimate the cumulative probability of remaining in remission over one year after a single treatment. The study also aimed to identify clinical predictors of therapeutic outcome achieved by PD and assess for PD-related complications. METHODS: A total of 26 patients with achalasia who were treated with PD between 1997 and 2011 at a tertiary care centre were followed for up to 1 year. Data related to demographics, clinical symptoms and PD-related complications were collected. Short (1 and 3 months) and medium (1 year) term therapeutic effectiveness of PD was assessed with the use of the Eckhart scoring system for evaluation of clinical symptoms. The probability of staying in remission one year after a single PD was determined by using a Kaplan-Meier estimator. In order to prevent major complications, limited maximal pressure of no more than 11 PSI was used during PD. RESULTS: Twenty-six patients with symptomatic achalasia (mean age 47.1±18.5 years, 82% males) underwent 44 PD procedures (mean 1.7/patient). Thirteen patients (50%) had a single PD, 10 patients (38%) had two dilatations, and 3 patients (12%) had three or more dilatations over one year. Nineteen out of the 26 patients (73%) were in remission at one and three months each, following the initial PD. Seventeen out of the 26 patients (65%) remained in remission after one year. A total of 5 patients (19%) were referred for surgery over 1 year due to lack of success of the endoscopic treatment. The mean Eckhart symptom scores, at 1 month (3.2±1.2), 3 months (3.5±1.3) and 1 year (1.8±0.6) after the initial PD, were significantly lower when compared to the mean initial Eckhart symptom score (9.7±4.4, P<0.05). Using a symptom score above 3 as a cutoff value for treatment failure, the probability of remaining in remission (relapse-free) after a single dilatation was 35% at one year. Patient gender appeared as an important treatment outcome predictor. Namely, 4 of the 5 patients (80%) with PD treatment failure were males. There were no major complications from the 44 PDs. One patient (3.8%) developed significant heartburn. The majority of PDs (33/44, 75%) were followed with minor, subclinical oesophageal mucosal bleeding from the dilation site as seen on post-dilation oesophagoscopy. CONCLUSION: Pneumatic dilatation is an effective short and medium term treatment option for the majority of patients with achalasia without significant related complications. Further studies are warranted to assess the possible role of limited maximal pressure use of no more than 11 PSI during PD in preventing oesophageal perforations.