Chicago Classification of Esophageal Motility Disorders: Lessons Learned.

PURPOSE OF REVIEW: High-resolution manometry (HRM) is increasingly performed worldwide, to study esophageal motility. The Chicago classification is subsequently applied to interpret the manometric findings and facilitate a diagnosis of esophageal motility disorders. This review will discuss new insights regarding the diagnosis and management using the Chicago classification. RECENT FINDINGS: Recent studies have demonstrated that high-resolution manometry is superior to conventional manometry, and has a higher sensitivity to diagnose achalasia. Furthermore, the subclassification of achalasia as used in the Chicago classification has prognostic value and can be used to direct treatment. Diagnosis of esophageal spasm has been improved by using the distal latency as diagnostic criterion. Recently, criteria for minor disorders of peristalsis have been sharpened, leading to a lower rate of patients with abnormal results, thereby increasing the relevance of a diagnosis. High-resolution manometry is now considered the gold standard for diagnosis of esophageal motility disorders. The Chicago classification provides a standardized approach for analysis and categorization of abnormalities that has led to a significant increase in our knowledge regarding the diagnosis and management of motility disorders. Further refinement of the classification will be required.

Inter-observer agreement for diagnostic classification of esophageal motility disorders defined in high-resolution manometry.

High-resolution esophageal manometry (HRM) is a recent development used in the evaluation of esophageal function. Our aim was to assess the inter-observer agreement for diagnosis of esophageal motility disorders using this technology. Practitioners registered on the HRM Working Group website were invited to review and classify (i) 147 individual water swallows and (ii) 40 diagnostic studies comprising 10 swallows using a drop-down menu that followed the Chicago Classification system. Data were presented using a standardized format with pressure contours without a summary of HRM metrics. The sequence of swallows was fixed for each user but randomized between users to avoid sequence bias. Participants were blinded to other entries. (i) Individual swallows were assessed by 18 practitioners (13 institutions). Consensus agreement (≤ 2/18 dissenters) was present for most cases of normal peristalsis and achalasia but not for cases of peristaltic dysmotility. (ii) Diagnostic studies were assessed by 36 practitioners (28 institutions). Overall inter-observer agreement was 'moderate' (kappa 0.51) being 'substantial' (kappa > 0.7) for achalasia type I/II and no lower than 'fair-moderate' (kappa >0.34) for any diagnosis. Overall agreement was somewhat higher among those that had performed >400 studies (n = 9; kappa 0.55) and 'substantial' among experts involved in development of the Chicago Classification system (n = 4; kappa 0.66). This prospective, randomized, and blinded study reports an acceptable level of inter-observer agreement for HRM diagnoses across the full spectrum of esophageal motility disorders for a large group of clinicians working in a range of medical institutions. Suboptimal agreement for diagnosis of peristaltic motility disorders highlights contribution of objective HRM metrics.

Inter- and intra-rater reproducibility of automated and integrated pressure-flow analysis of esophageal pressure-impedance recordings.

BACKGROUND: Automated impedance manometry pressure-flow analysis (AIM analysis) determines pressure measurements relative to bolus flow and has to date shown subtle variations in esophageal motility in relation to dysphagia. In this study, we assessed intra- and inter-rater reproducibility of AIM metrics derived using purpose designed software. METHODS: Fifty patients referred for evaluation of gastro-esophageal reflux symptoms (33 men, age 52 ± 1.9 years) underwent combined high-resolution impedance manometry and completed a dysphagia questionnaire. From 10 liquid and 10 viscous swallows, a subset of four swallows (two saline and two viscous) was systematically selected from each patient for manual and AIMplot analysis, which was performed twice by five observers (two experts, three non-experts). Intra- and inter-rater agreement were determined using intraclass correlation coefficients. KEY RESULTS: AIMplot-based analysis showed high intra-rater and inter-rater reproducibility for all metrics (mean ICCs of 0.95 and 0.94, respectively). Reproducibility of metrics derived for liquid and viscous did not differ (ICCs of 0.96 and 0.91 for liquid and viscous, respectively). In addition, metrics derived by experts had an equivalent level of reproducibility compared to non-experts (ICCs of 0.96 and 0.94, respectively). Variables that could be derived with commercial software (ManoView™) correlated highly with variables from AIMplot-based analysis, such as 4-s integrated relaxation pressure (r = 0.85) and the 20-mmHg isobaric contour defect (r = 0.92). CONCLUSIONS & INFERENCES: Esophageal AIM analysis is highly reproducible, independent of an observer's level of experience in esophageal motility. Therefore, AIM analysis produces data that are reliable for clinical and research purposes.

Electrical tissue impedance spectroscopy: a novel device to measure esophageal mucosal integrity changes during endoscopy.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) have impaired esophageal mucosal integrity. Measurement of the mucosal integrity is complex and time-consuming. Electrical tissue impedance spectroscopy (ETIS) is a device that measures impedance of tissue in vivo during endoscopy. In this study, we aimed to validate ETIS as a measure of esophageal mucosal integrity. METHODS: Electrical tissue impedance spectroscopy measurements were performed during upper endoscopy in 12 GERD patients and 11 healthy controls after cessation of proton pump inhibition. During endoscopy biopsies of the distal esophagus were obtained for transmission electron microscopy to determine dilation of intercellular spaces (DIS) and for Ussing chamber experiments to determine transepithelial permeability and transepithelial electrical resistance. KEY RESULTS: Extracellular impedance measured in vivo by ETIS was significantly lower in GERD patients compared to controls [mean (SD) 5621 (3299) Ω.m and 8834 (2542) Ω.m, respectively, P < 0.05]. We found a strong inverse relation between extracellular impedance determined by ETIS and DIS (r = -0.76, P < 0.05), and between extracellular resistance in vivo and transepithelial permeability of esophageal biopsies (r = -0.65, P < 0.01). CONCLUSIONS & INFERENCES: Electrical tissue impedance spectroscopy is a new tool that can be used to evaluate esophageal mucosal integrity changes during endoscopy.

Esophageal stasis on a timed barium esophagogram predicts recurrent symptoms in patients with long-standing achalasia.

OBJECTIVES: In achalasia, early recognition of the need for retreatment is of crucial importance to reduce morbidity and long-term complications such as esophageal decompensation. In clinical practice, symptoms and parameters of esophageal function including lower esophageal sphincter (LES) pressure and esophageal emptying are used to decide whether additional treatment is required. However, which of these tests performs best remains unclear. METHODS: A cohort of 41 patients with long-standing achalasia (median 17 years), underwent esophageal manometry, timed barium esophagogram and symptom evaluation. Patients were followed up for 10 years, and were regarded as a therapeutic failure if Eckardt score was >3 or when retreatment was needed. Predictors of therapeutic failure were evaluated. RESULTS: Of the 41 included patients, 7 patients had an elevated LES pressure (>10 mm Hg) and 26 had esophageal stasis >5 cm on timed barium esophagogram. During follow-up, 25 patients had recurrence of symptoms and were considered therapeutic failures. Of the 25 patients, 5 had an elevated LES pressure, whereas 22 had esophageal stasis on barium esophagogram. Hence, the sensitivity to predict the need of retreatment is higher for esophageal stasis (88%) compared with LES pressure (20%). A total of 16 patients (39%) were in long-term remission, of which 12 patients (75%) did not have stasis at their initial visit. CONCLUSIONS: In contrast to LES pressure, esophageal stasis is a good predictor of treatment failure in patients with long-standing achalasia. Based on these findings, we propose to use timed barium esophagogram rather than esophageal manometry as test to decide on retreatment.

The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers.

BACKGROUND: Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. AIM: To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. METHODS: Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH-impedance measurements were taken after each dose. RESULTS: A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose-dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. CONCLUSION: The mGluR5-mediated inhibition of TLESRs may be a useful approach for inhibiting gastro-oesophageal reflux.

Localization of mGluR5, GABAB, GABAA, and cannabinoid receptors on the vago-vagal reflex pathway responsible for transient lower esophageal sphincter relaxation in humans: an immunohistochemical study.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the predominant mechanisms underlying gastro-esophageal reflux. TLESRs are mediated by a vago-vagal reflex, which can be blocked by interaction with metabotropic Glutamate Receptor 5 (mGluR5), γ-aminobutyric acid type B (GABA(B)), γ-aminobutyric acid type A (GABA(A)), and cannabinoid (CB) receptors. However, the distribution of these receptors in the neural pathway underlying the triggering of TLESRs has not been evaluated in humans. METHODS: Using immunohistochemistry, we investigated the distribution of mGluR5, GABA(A), GABA(B), CB1, and CB2 receptors in the human nodose ganglion, the brain stem, and the myenteric plexus of the esophagus. KEY RESULTS: MGluR5, GABA(B), CB1, and CB2 receptors are abundantly expressed in neurons of the myenteric plexus of the LES, nodose ganglion cell bodies and nerve fibers, the dorsal motor nucleus, and nucleus of the solitary tract in the brain stem. GABA(A) receptors are expressed in the same regions except in the nodose ganglion and myenteric plexus of the LES. CONCLUSIONS & INFERENCES: Human mGluR5, GABA(A,B), and CB(1,2) receptors are abundantly expressed along the vago-vagal neural pathway and involved in the triggering of TLESRs. These findings are not only in line with the central side effects observed during treatment with reflux inhibitors such as GABA(B) receptor agonists and mGluR5 antagonists, but also suggest that peripherally acting compounds may be effective.

Effect of azithromycin on acid reflux, hiatus hernia and proximal acid pocket in the postprandial period.

BACKGROUND: The risk for acidic reflux is mainly determined by the position of the gastric acid pocket. It was hypothesised that compounds affecting proximal stomach tone might reduce gastro-oesophageal reflux by changing the acid pocket position. OBJECTIVE: To study the effect of azithromycin (Azi) on acid pocket position and acid exposure in patients with gastro-oesophageal reflux disease (GORD). METHODS: Nineteen patients with GORD were included, of whom seven had a large hiatal hernia (≥3 cm) (L-HH) and 12 had a small or no hiatal hernia (S-HH). Patients were randomised to Azi 250 mg/day or placebo during 3 days in a crossover manner. On each study day, reflux episodes were detected using concurrent high-resolution manometry and pH-impedance monitoring after a standardised meal. The acid pocket was visualised using scintigraphy, and its position was determined relative to the diaphragm. RESULTS: Azi reduced the number of acid reflux events (placebo 8.0±2.2 vs Azi 5.6±1.8, p<0.01) and postprandial acid exposure (placebo 10.5±3.8% vs Azi 5.9±2.5%, p<0.05) in all patients without affecting the total number of reflux episodes. Acid reflux occurred mainly when the acid pocket was located above, or at the level of, the diaphragm, rather than below the diaphragm. Treatment with Azi reduced hiatal hernia size and resulted in a more distal position of the acid pocket compared with placebo (below the diaphragm 39% vs 29%, p=0.03). Azi reduced the rate of acid reflux episodes in patients with S-HH (38% to 17%) to a greater extent than in patients with L-HH (69% to 62%, p=0.04). CONCLUSION: Azi reduces acid reflux episodes and oesophageal acid exposure. This effect was associated with a smaller hiatal hernia size and a more distal position of the acid pocket, further indicating the importance of the acid pocket in the pathogenesis of GORD. CLINICAL TRIAL REGISTRATION: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1970 NTR1970.

Postoperative problems 2011: fundoplication and obesity surgery.

Although the surgical treatment of both GERD and obesity is very successful, these procedures have a significant impact on the physiology and function of the proximal GI tract. With the increasing prevalence of both GERD and obesity, more and more patients present at the motility outpatient clinic with symptoms related to surgical interventions for these medical problems. In this review, we describe the main complications following antireflux surgery: dysphagia, gas bloat syndrome, recurrent (persistent) GERD symptoms, and dyspeptic symptoms. The most common motility-related complications of obesity surgery are dumping syndrome and esophageal dysmotility.

High-resolution esophageal pressure topography is superior to conventional sleeve manometry for the detection of transient lower esophageal sphincter relaxations associated with a reflux event.

BACKGROUND: Transient lower esophageal sphincter relaxations (TLESRs) are the main mechanism underlying gastro-esophageal reflux and are detected during manometric studies using well defined criteria. Recently, high-resolution esophageal pressure topography (HREPT) has been introduced and is now considered as the new standard to study esophageal and lower esophageal sphincter (LES) function. In this study we performed a head-to-head comparison between HREPT and conventional sleeve manometry for the detection of TLESRs. METHODS: A setup with two synchronized MMS-solar systems was used. A solid state HREPT catheter, a water-perfused sleeve catheter, and a multi intraluminal impedance pH (MII-pH) catheter were introduced in 10 healthy volunteers (M6F4, age 19-56). Subjects were studied 0.5 h before and 3 h after ingestion of a standardized meal. Tracings were blinded and analyzed by the three authors according to the TLESR criteria. KEY RESULTS: In the HREPT mode 156 TLESRs were scored, vs 143 during sleeve manometry (P = 0.10). Hundred and twenty-three TLESRs were scored by both techniques. Of all TLESRs (177), 138 were associated with reflux (78%). High-resolution esophageal pressure topography detected significantly more TLESRs associated with a reflux event (132 vs 119, P = 0.015) resulting in a sensitivity for detection of TLESRs with reflux of 96% compared to 86% respectively. Analysis of the discordant TLESRs associated with reflux showed that TLESRs were missed by sleeve manometry due to low basal LES pressure (N = 5), unstable pharyngeal signal (N = 4), and residual sleeve pressure >2 mmHg (N = 10). CONCLUSIONS & INFERENCES: The HREPT is superior to sleeve manometry for the detection of TLESRs associated with reflux. However, rigid HREPT criteria are awaited.

Pathophysiology and management of gastroesophageal reflux disease.

Gastroesophageal reflux is a physiological phenomenon but becomes pathological if troublesome symptoms and/or complications occur. Gastroesophageal reflux disease (GERD) has different phenotypes ranging from non-erosive reflux disease (NERD), through reflux esophagitis and Barrett's esophagus, and can present with either typical symptoms such as regurgitation and heartburn, or extra-esophageal symptoms such as cough and laryngitis. In the diagnosis of GERD endoscopy, empirical PPI test, and pH impedance testing all have their own position. Although proton pump inhibitors (PPIs) are very effective in the treatment of esophagitis, a significant proportion of patients have persistent symptoms even during high dosing of PPIs. Therefore, insight into the multifactorial pathophysiology of GERD is needed to develop new anti-reflux therapies. The predominant mechanism underlying reflux is the transient lower esophageal sphincter relaxation (TLESR). Hiatal hernia, impaired esophageal clearance and reduced lower esophageal sphincter pressure play a significant role in patients with moderate to severe reflux disease. Refluxate containing acid, pepsin and bile can cause epithelial injury when epithelial barrier of the esophagus fails to defend. In the majority of patients there is histopathological evidence of epithelial injury, even with NERD where there are more dilated intercellular spaces. The perception of heartburn can be enhanced due to visceral hypersensitivity, leading to more and more severe symptoms. Anti-reflux surgery is as effective as PPI therapy, but has higher morbidity and results decline in the long term. Therefore, new pharmacological, endoscopic and surgical interventions are being developed for these patients.