Integrative Effects and Vagal Mechanisms of Transcutaneous Electrical Acustimulation on Gastroesophageal Motility in Patients With Gastroesophageal Reflux Disease.

INTRODUCTION: Impaired esophageal and gastric motilities are known to contribute to symptoms of gastroesophageal reflux disease (GERD). However, there is a lack of GERD therapy, targeting both gastric and esophageal functions. This study was designed to investigate the effects of transcutaneous electrical acustimulation (TEA) on symptoms of GERD and gastroesophageal functions and possible mechanisms in patients with GERD. METHODS: Thirty patients with GERD with ineffective esophageal motility were equally divided and randomized into a 4-week sham-TEA or 4-week TEA treatment. The GERD questionnaire (GerdQ), GERD health-related quality-of-life questionnaire, high-resolution esophageal manometry, a nutrient drink test, the electrogastrogram, and ECG were performed to assess the severity of reflux symptoms, low esophageal sphincter (LES) pressure, distal contractile integral (DCI), gastric accommodation, gastric slow waves (GSW), and autonomic functions, respectively. RESULTS: Compared with sham-TEA, the 4-week TEA treatment significantly decreased the GerdQ score (P = 0.011) and GERD health-related quality of life (P = 0.028) and improved nutrient drink-induced fullness (P < 0.001) and belching (P < 0.001) in patients with GERD. Although only acute TEA significantly enhanced LES pressure (P < 0.05), both acute and chronic TEA remarkedly increased DCI (P < 0.05) and reduced the incidence of ineffective esophageal contractions during wet swallows (P = 0.02). In addition, chronic TEA significantly increased gastric accommodation and the percentage of postprandial normal GSW compared with sham-TEA and baseline. Concurrently, TEA-enhanced vagal activity (P = 0.02) and the vagal activity positively correlated with LES pressure (r = 0.528; P = 0.003) and DCI (r = 0.522; P = 0.003). DISCUSSION: The TEA treatment performed in this study improves reflux-related symptoms, increases DCI, reduces the incidence of ineffective esophageal contractions during wet swallows, and improves gastric accommodation and slow waves. The improvement in GERD symptoms might be attributed to the integrative effects of TEA on these gastroesophageal functions mediated via the vagal mechanism.

Pressure and length of the lower esophageal sphincter as predictive indicators of therapeutic efficacy of baclofen for refractory gastroesophageal reflux-induced chronic cough.

BACKGROUND: Therapeutic efficacy of baclofen is suboptimal in the treatment of refractory gastroesophageal reflux-induced chronic cough (GERC). The purpose of the study is to identify its therapeutic predictors in a prospective clinical study. METHODS: 138 patients with suspected refractory GERC were treated with baclofen. Before the therapy, all the patients underwent esophageal manometry and multichannel intraluminal impedance-pH monitoring to establish the diagnosis. After the efficacy of baclofen was evaluated, a stepwise logistic regression analysis was performed to identify the therapeutic predictors of baclofen and to establish a regression prediction model. RESULTS: The overall response rate of baclofen treatment was 52.2% (72/138). The lower esophageal sphincter pressure (LESP) (odds ratio (OR) = 0.592, P = 0.000) and lower esophageal sphincter length (LESL) (OR = 0.144, P = 0.008) were independent predictors of baclofen efficacy. The optimal cut-off point to predict baclofen efficacy for LESP was 11.00 mmHg, with a sensitivity of 83.7% and specificity of 79.1% while that for LESL was 2.35 cm, with a sensitivity of 81.6% and specificity of 72.1%. The highest predictive specificity (90.7%) was achieved when both LESP and LESL were jointly used. CONCLUSIONS: LESP and LESL may be used to screen the patients with refractory GERC suitable for baclofen therapy and help improve the therapeutic precision. CLINICAL TRIAL REGISTRATION: ChiCTR- ONC-13003123.

Physiological and pathological roles of the accommodation response in lower esophageal sphincter relaxation during wet swallows.

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1-11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, - 0.6-6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5-44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18-28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.

Optimal cutoff value of integrated relaxation pressure on the esophagogastric junction to detect outflow obstruction using starlet high-resolution manometry system.

BACKGROUND: Achalasia and esophagogastric junction outflow obstruction (EGJOO) are idiopathic esophageal motility disorders characterized by impaired deglutitive relaxation of the lower esophageal sphincter (LES). High-resolution manometry (HRM) provides integrated relaxation pressure (IRP) which represents adequacy of LES relaxation. The Starlet HRM system is widely used in Japan; however, IRP values in achalasia/EGJOO patients assessed with the Starlet system have not been well studied. We propose the optimal cutoff of IRP for detecting achalasia/EGJOO using the Starlet system. METHODS: Patients undergone HRM test using the Starlet system at our institution between July 2018 and September 2020 were included. Of these, we included patients with either achalasia or EGJOO and those who had normal esophageal motility without hiatal hernia. Abnormally impaired LES relaxation (i.e., achalasia and EGJOO) was diagnosed if prolonged esophageal emptying was evident based on timed barium esophagogram (TBE). RESULTS: A total of 111 patients met study criteria. Of these, 48 patients were diagnosed with achalasia (n = 45 [type I, n = 20; type II, n = 22; type III, n = 3]) or EGJOO (n = 3). In the 48 patients who had a prolonged esophageal clearance based on TBE, IRP values distributed along a wide-range of minimal 14.1 to a maximal of 72.2 mmHg. The optimal cutoff value of IRP was 24.7 mmHg with sensitivity of 89.6% and specificity of 84.1% (AUC 0.94). CONCLUSION: The optimal cutoff value of IRP to distinguish achalasia/EGJOO was ≥ 25 mmHg using the Starlet HRM system in our cohort. This indicates that the current proposed cutoff of 26 mmHg appears to be relevant.

The mechanisms associated with reflux episodes in ambulant subjects with gastro-esophageal reflux disease.

BACKGROUND: The mechanisms associated with gastro-esophageal reflux (GER) episodes were studied using combined High-resolution Impedance Manometry (HRIM) and pH monitoring in ambulant subjects with different patterns of GERD. METHODS: Sixteen subjects with mild-moderate esophagitis (Los Angeles (LA) grade A&B) (group A) and 11 subjects with severe esophagitis (LA grade C&D) or Barrett's esophagus (BE) were studied before and after a meal, resting, while walking, and during standardized exercise, using a HRIM and a pH probe. KEY RESULTS: Post-prandial acid GER episodes were more common in group B (median 10 range (3-18) vs A (6.5 (0-18), p = 0.048). Postprandial acid clearance time was much longer in group B (median 0.71( 0.07-2.66 min) vs A (0.17 (0.04-2.44 min), p = 0.02). Transient lower esophageal sphincter relaxation (TLESR) was the most frequent mechanism associated with GER episodes in both groups. Post-prandial TLESRs with GER were more common in group B (median 17 (9-24) vs A 13.5 (7-34), p = 0.014), particularly during exercise (B 8 (6-9) vs A 6 (5-6.8), p = 0.007). Post-prandially TLESR with acid reflux increased during exercise in both groups (A rest median 2.4 (0-6.4) per hour vs exercise 4.7 (0-17.3), p = 0.005 and B 4 (0.8-9.6) vs 5.3 (2.7-13.3) per hour, p = 0.045). CONCLUSIONS AND INFERENCES: TLESR was the most common mechanism associated with reflux episodes in all subjects. Acid reflux episodes were more common in subjects with severe esophagitis or BE and esophageal acid clearance was much slower. Post-prandial exercise increased TLESR with acid reflux and GERD patients should be encouraged to avoid exercise immediately after a meal.

Effects of Diaphragmatic Breathing on the Pathophysiology and Treatment of Upright Gastroesophageal Reflux: A Randomized Controlled Trial.

INTRODUCTION: Uncontrolled results suggest that diaphragmatic breathing (DB) is effective in gastroesophageal reflux disease (GERD) but the mechanism of action and rigor of proof is lacking. This study aimed to determine the effects of DB on reflux, lower esophageal sphincter (LES), and gastric pressures in patients with upright GERD and controls. METHODS: Adult patients with pH proven upright GERD were studied. During a high-resolution impedance manometry, study patients received a standardized pH neutral refluxogenic meal followed by LES challenge maneuvers (Valsalva and abdominal hollowing) while randomized to DB or sham. After that, patients underwent 48 hours of pH-impedance monitoring, with 50% randomization to postprandial DB during the second day. RESULTS: On examining 23 patients and 10 controls, postprandial gastric pressure was found to be significantly higher in patients compared with that in controls (12 vs 7 mm Hg, P = 0.018). Valsalva maneuver produced reflux in 65.2% of patients compared with 44.4% of controls (P = 0.035). LES increased during the inspiratory portion of DB (42.2 vs 23.1 mm Hg, P < 0.001) in patients and healthy persons. Postprandial DB reduced the number of postprandial reflux events in patients (0.36 vs 2.60, P < 0.001) and healthy subjects (0.00 vs 1.75, P < 0.001) compared with observation. During 48-hour ambulatory study, DB reduced the reflux episodes on day 2 compared with observation on day 1 in both the patient and control groups (P = 0.049). In patients, comparing DB with sham, total acid exposure on day 2 was not different (10.2 ± 7.9 vs 9.4 ± 6.2, P = 0.804). In patients randomized to DB, esophageal acid exposure in a 2-hour window after the standardized meal on day 1 vs day 2 reduced from 11.8% ±6.4 to 5.2% ± 5.1, P = 0.015. DISCUSSION: In patients with upright GERD, DB reduces the number of postprandial reflux events pressure by increasing the difference between LES and gastric pressure. These data further encourage studying DB as therapy for GERD.

The not-so-rare absent RAIR: Internal anal sphincter achalasia in a review of 1072 children with constipation undergoing high-resolution anorectal manometry.

BACKGROUND: Our objective is to describe the prevalence of patients with internal anal sphincter achalasia (IASA) without Hirschsprung disease (HD) among children undergoing anorectal manometry (ARM) and their clinical characteristics. METHODS: We performed a retrospective review of high-resolution ARM studies performed at our institution and identified patients with an absent rectoanal inhibitory reflex (RAIR). Clinical presentation, medical history, treatment outcomes, and results of ARM and other diagnostic tests were collected. We compared data between IASA patients, HD patients, and a matched control group of patients with functional constipation (FC). KEY RESULTS: We reviewed 1,072 ARMs and identified 109 patients with an absent RAIR, of whom 28 were diagnosed with IASA. Compared to patients with FC, patients with IASA had an earlier onset of symptoms and were more likely to have abnormal contrast enema studies. Compared to patients with HD, patients with IASA were more likely to have had a normal timing of meconium passage, a later onset of symptoms, and were diagnosed at an older age. At the latest follow-up, the majority of patients diagnosed with IASA (54%) were only using oral laxatives. Over half of patients with IASA had been treated with anal sphincter botulinum toxin injection, and 55% reported a positive response. CONCLUSIONS AND INFERENCES: Patients diagnosed with IASA may represent a more severe patient population compared to patients with FC, but have a later onset of symptoms compared to patients with HD. They may require different treatments for their constipation and deserve further study.

The gastro-sphincteric pressure gradient: A new parameter to diagnose a rumination episode.

BACKGROUND: Rumination is defined as the repetitive, effortless regurgitation of recently ingested food into the mouth. These episodes are preceded by a rise in intragastric pressure (IGP) and mainly occur postprandially. IGP peaks >30 mmHg have been proposed as a cutoff to differentiate rumination from reflux events. In clinical practice, we observed that this cutoff, which does not consider esophagogastric junction (EGJ) resistance, is not always reached. METHODS: We studied 27 patients with rumination syndrome [age: 43.6, 59% female] and 28 gastro-esophageal reflux disease patients [age: 45.9, 54% female]. For each rumination episode, reflux event, transient lower esophageal sphincter relaxation (TLESR), or straining without regurgitation, the following parameters were registered: maximal IGP, IGP, and EGJ pressure preceding the respective episodes. We also quantified the gastro-sphincteric pressure gradient (GSPG) prior to the respective episodes. KEY RESULTS: Five reflux episodes were characterized by a maximal IGP >30 mmHg. In 28% of the rumination episodes, the IGP peak did not exceed 30 mmHg. Median GSPG was positive for rumination episodes and significantly higher compared with TLESRs, reflux episodes, and straining without regurgitation (7 [3-13] vs. 0 [-1-0] vs. 0 [-1-0] vs. -9 [-13--2]; p < 0.0001). CONCLUSIONS & INTERFERENCES: Applying the proposed cutoff of 30 mmHg, 28% of the rumination episodes were missed. We found that the GSPG differentiates between rumination (positive GSPG), TLESRs and reflux events (GSPG around 0), and straining without regurgitation (negative GSPG). We propose a GSPG value ≥2 mmHg to distinguish rumination from reflux episodes, TLESRs, and straining without regurgitation.

Magnetic sphincter augmentation device placement for treatment of gastroesophageal reflux.

Gastroesophageal reflux disease typically is treated with lifestyle modifications and proton pump inhibitors (PPIs). Surgery is effective in treating the symptoms associated with gastroesophageal reflux, but common procedures involve invasive techniques that can leave the patient unable to belch or vomit. Research has raised concerns regarding the long-term use of PPIs, leaving few treatment options for patients with refractory reflux symptoms. The magnetic sphincter augmentation device demonstrates similar efficacy to existing antireflux procedures, avoids complex surgery techniques, and preserves normal physiologic functions at the lower esophageal sphincter. This device is a safe and effective alternative to more invasive procedures for patients whose GERD does not respond to medical management.

Achalasia: physiology and diagnosis.

Achalasia is a rare motility disorder with incomplete relaxation of the lower esophageal sphincter and ineffective contractions of the esophageal body. It has been hypothesized that achalasia does not result from only one pathway but rather involves a combination of infectious, autoimmune, and familial etiological components. On the basis of other observations, a novel hypothesis suggests that a muscular form of eosinophilic esophagitis is involved in the pathophysiology of achalasia in some patients. This appears to progressively diminish the myenteric plexus at stage III, gradually destroy it at stage II, and finally eliminate it at stage I, the most advanced and final stage of achalasia. Although high-resolution manometry has identified these three different types of achalasia, another subset of patients with a normal-appearing sphincter relaxation has been proposed. Provocative maneuvers, such as the rapid drinking challenge, have recently been demonstrated to improve diagnosis in certain borderline patients, but have to be studied in more detail. However, whether the different types of achalasia will have a long-term impact on tailored therapies is still a matter of debate. Additionally, novel aspects of the standard timed barium swallow appear to be an important adjunct of diagnosis, as it has been shown to have a diagnostic as well as a predictive value.

Endoscopic treatments for GERD.

Gastroesophageal reflux disease (GERD) is a condition with increasing prevalence and morbidity in the United States and worldwide. Despite advances in medical and surgical therapy over the last 30 years, gaps remain in the therapeutic profile of options. Flexible upper endoscopy offers the promise of filling in these gaps in a potentially minimally invasive approach. In this concise review, we focus on the plethora of endoluminal therapies available for the treatment of GERD. Therapies discussed include injectable agents, electrical stimulation of the lower esophageal sphincter, antireflux mucosectomy, radiofrequency ablation, and endoscopic suturing devices designed to create a fundoplication. As new endoscopic treatments become available, we come closer to the promise of the incisionless treatment of GERD. The known data surrounding the indications, benefits, and risks of these historical, current, and emerging approaches are reviewed in detail.

The hypercontractile esophagus: Still a tough nut to crack.

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.

Clinical and Manometric Characteristics of Patients with Achalasia: One Disease with Three Presentations or Three Diseases with One Presentation?

BACKGROUND AND AIMS: The three manometric patterns of achalasia are considered by some authors as different stages in the evolution of the same disorder. The aims of our study were to characterize patients with achalasia, in order to find key differences supporting the idea of progression from one type to the other, and to assess the clinical evolution in time. METHODS: From 280 high resolution esophageal manometry recordings we selected unique patients with achalasia. A standardized questionnaire used prior to each manometry recorded their symptoms. Manometric parameters (resting lower esophageal sphincter (LES) pressure, 4s-integrated relaxation pressure (IRP), length of the esophagus, etc.) were recorded. Patients were contacted to establish the clinical evolution. RESULTS: We identified 108 new achalasia cases (mean age 48.2±16.2 years, 52.8% type I, 42.6% type II), 52 (48.1%) women. Dysphagia (98.1%), cough (64.8%), belching (60.2%) and reflux symptoms (53.7%) were frequently reported. Patients with type I achalasia reported more often that dysphagia worsened, compared to type II patients (χ2=7.3, p =0.007). Age, duration of dysphagia, body mass index (p=0.067) and esophageal length were similar in type I and type II achalasia. Resting LES pressure (64.7±22.6 mmHg vs. 54.3±21.6 mmHg, p=0.019) and 4s-IRP (45.3±17.6 mmHg vs. 38.4±15.5 mmHg, p=0.036) were higher in type II compared to type I achalasia. Overweight patients had a lower LES resting pressure and 4s-IRP compared to lean subjects. After a mean follow-up of 36.8±13.4 months, 49 (45.3%) patients responded to our follow-up, and 77.5% had an Eckardt score ≤ 3. CONCLUSIONS: Type I achalasia was the most common in our group. Type I patients had lower BMI but similar duration of dysphagia and mean age compared to type II. Type III is seldom and present in older patients. These findings suggest low probability of progression from type III and II to type I achalasia. Patients with type II achalasia had higher resting LES pressure and 4s-IRP than type I achalasia patients.

Rethinking gastroesophageal reflux disorder.

Gastroesophageal reflux disease (GERD) is a common clinical condition for which our understanding has evolved over the past decades. It is now considered a cluster of phenotypes with numerous anatomical and physiological abnormalities contributing to its pathophysiology. As such, it is important to first understand the underlying mechanism of the disease process for each patient before embarking on therapeutic interventions. The aim of our paper is to highlight the mechanisms contributing to GERD and review investigations and interpretation of these results. Finally, the paper reviews the available treatment modalities for this condition, ranging from medical intervention, endoscopic options through to surgery and its various techniques.

ACG Clinical Guidelines: Diagnosis and Management of Achalasia.

Achalasia is an esophageal motility disorder characterized by aberrant peristalsis and insufficient relaxation of the lower esophageal sphincter. Patients most commonly present with dysphagia to solids and liquids, regurgitation, and occasional chest pain with or without weight loss. High-resolution manometry has identified 3 subtypes of achalasia distinguished by pressurization and contraction patterns. Endoscopic findings of retained saliva with puckering of the gastroesophageal junction or esophagram findings of a dilated esophagus with bird beaking are important diagnostic clues. In this American College of Gastroenterology guideline, we used the Grading of Recommendations Assessment, Development and Evaluation process to provide clinical guidance on how best to diagnose and treat patients with achalasia.

Achalasia: what to do in the face of failures of Heller myotomy.

Achalasia is a primary motility disorder of the esophagus, and while there are several treatment options, there is no consensus regarding them. When therapeutic intervention for achalasia fails, a careful evaluation of the cause of the persistent or recurrent symptoms using upper endoscopy, esophageal manometry, and contrast radiologic studies is required to understand the cause of therapy failure and guide plans for subsequent treatment. Options for reintervention are the same as for primary intervention and include pneumatic dilation, botulinum toxin injection, peroral endoscopic myotomy, or redo esophageal myotomy. When reintervention fails or if the esophagus is not amenable to intervention and the disease is considered end-stage, esophagectomy is the last option to manage recurrent achalasia.

Quantifying Factors Essential to the Integrity of the Esophagogastric Junction During Antireflux Procedures.

OBJECTIVE: To quantify the contribution of key steps in antireflux surgery on compliance of the EGJ. BACKGROUND: The lower esophageal sphincter and crural diaphragm constitute the intrinsic and extrinsic sphincters of the EGJ, respectively. Interventions to treat reflux attempt to restore the integrity of the EGJ. However, there are limited data on the relative contribution of critical steps during antireflux procedures to the functional integrity of the EGJ. METHODS: Primary antireflux surgery was performed on 100 consecutive patients with pathologic reflux. Intraoperative EGJ measurements including distensibility index (DI), cross-sectional area (CSA), and HPZ length were collected using EndoFLIP. Data was acquired pre-repair, post-diaphragmatic re-approximation with sub-diaphragmatic EGJ relocation, and post-sphincter augmentation. RESULTS: Patients underwent Nissen (45%), Toupet (44%), or LINX (11%). After diaphragmatic re-approximation, DI decreased by a median 0.77 mm2/mm Hg [95%-confidence interval (CI): -0.99, -0.58; P < 0.0001], CSA decreased 16.0 mm2 (95%-CI: -20.0, -8.0; P < 0.0001), whereas HPZ length increased 0.5 cm (95%-CI: 0.5, 1.0; P < 0.0001). After sphincter augmentation, DI decreased 0.14 mm2/mm Hg (95%-CI: -0.30, -0.04; P = 0.0005) and CSA decreased 5.0 mm2 (95%-CI: -10.0, 1.0; P = 0.0.0015), whereas HPZ length increased 0.5 cm (95%-CI: 0.50, 0.54; P < 0.0001). Diaphragmatic re-approximation had a higher percent contribution to distensibility (79% vs 21%), CSA (82% vs 18%), and HPZ (60% vs 40%) than sphincter augmentation. CONCLUSION: Dynamic intraoperative monitoring demonstrates that diaphragmatic re-approximation and sub-diaphragmatic relocation has a greater effect on EGJ compliance than sphincter augmentation. As such, antireflux procedures should address both for optimal improvement of EGJ physiology.

Understanding the relationship between esophageal motor disorders and reflux disease.

INTRODUCTION: The management of gastro-esophageal reflux disease (GERD) patients is often complex as the clinical presentation is heterogeneous and the mechanisms underlying symptoms are multifactorial. In the past decades, investigations conducted with conventional manometry and, above all, the more accurate high resolution manometry (HRM), helped us in exploring the field of esophageal motility and in understanding the link between motor features and GERD pathogenesis. AREAS COVERED: Several studies carried out with conventional manometry and HRM have confirmed a relevant role of esophageal motor function in GERD pathogenesis. In particular, HRM studies have shown a direct correlation between impaired esophageal body motility, disruption of the esophagogastric junction and reflux burden. These findings impact the clinical and therapeutical management of GERD patients. Moreover, HRM findings might be helpful in evaluating patients with proton pump inhibitor (PPI) resistance and inconclusive evidences of GERD. EXPERT OPINION: The relationship between esophageal motility and GERD pathogenesis needs to be further evaluated by multicenter outcome studies involving a large number of GERD patients and healthy controls. However, other more promising areas could be progressed.