Geriatric patients with esophageal motility disorders benefit more from minimally invasive peroral endoscopic myotomy: a multicenter study in Japan

Summary Geriatric patients with existing studies on the safety and efficacy of peroral endoscopic myotomy (POEM) for achalasia involve small sample sizes and single institutions. However, multi-center, large-scale data analyses are lacking. The study aimed to clarify the characteristics of geriatric patients with esophageal motility disorders (EMDs) and determine the procedure-related outcomes and clinical course following POEM. This cohort study included 2,735 patients with EMDs who were treated at seven Japanese facilities between 2010 and 2019. The patients’ characteristics and post-POEM clinical courses were compared between the geriatric (age ≥ 75 years; n = 321) and non-geriatric (age < 75 years; n = 2,414) groups. Compared with the non-geriatric group, the geriatric group had higher American Society of Anesthesiologists physical status scores; more recurrent cases; lower incidence of chest pain; and higher incidence of type III achalasia, distal esophageal spasm, and Jackhammer esophagus. Furthermore, the incidence of sigmoid esophagus was higher, although esophageal dilation was not severe in this group. POEM was safe and effective for geriatric patients with treatment-naïve and recurrent EMDs. Furthermore, compared with the non-geriatric group, the geriatric group had lower post-POEM Eckardt scores, fewer complaints of refractory chest pain, and a lower incidence rate of post-POEM reflux esophagitis. Geriatric patients are characterized by worse clinical conditions, more spastic disorders, and greater disease progression of EMDs, which are also the indications for minimally invasive POEM. POEM is more beneficial in geriatric patients as it has lowering symptom scores and incidence rates of reflux esophagitis.

Engaging biological oscillators through second messenger pathways permits emergence of a robust gastric slow-wave during peristalsis

Peristalsis, the coordinated contraction—relaxation of the muscles of the stomach is important for normal gastric motility and is impaired in motility disorders. Coordinated electrical depolarizations that originate and propagate within a network of interconnected layers of interstitial cells of Cajal (ICC) and smooth muscle (SM) cells of the stomach wall as a slow-wave, underly peristalsis. Normally, the gastric slow-wave oscillates with a single period and uniform rostrocaudal lag, exhibiting network entrainment. Understanding of the integrative role of neurotransmission and intercellular coupling in the propagation of an entrained gastric slow-wave, important for understanding motility disorders, however, remains incomplete. Using a computational framework constituted of a novel gastric motility network (GMN) model we address the hypothesis that engaging biological oscillators (i.e., ICCs) by constitutive gap junction coupling mechanisms and enteric neural innervation activated signals can confer a robust entrained gastric slow-wave. We demonstrate that while a decreasing enteric neural innervation gradient that modulates the intracellular IP3 concentration in the ICCs can guide the aboral slow-wave propagation essential for peristalsis, engaging ICCs by recruiting the exchange of second messengers (inositol trisphosphate (IP3) and Ca2+) ensures a robust entrained longitudinal slow-wave, even in the presence of biological variability in electrical coupling strengths. Our GMN with the distinct intercellular coupling in conjunction with the intracellular feedback pathways and a rostrocaudal enteric neural innervation gradient allows gastric slow waves to oscillate with a moderate range of frequencies and to propagate with a broad range of velocities, thus preventing decoupling observed in motility disorders. Overall, the findings provide a mechanistic explanation for the emergence of decoupled slow waves associated with motility impairments of the stomach, offer directions for future experiments and theoretical work, and can potentially aid in the design of new interventional pharmacological and neuromodulation device treatments for addressing gastric motility disorders.

Esophageal Motility Disorders: Are We Missing in Our Busy Endoscopy Practice?

Esophageal motility disorders (EMDs) form a significant part of a busy endoscopist's practice. Endoscopy plays an all-encompassing role in the diagnosis and management of EMDs including achalasia cardia. The focus on in-vogue third-space endoscopic procedures such as per-oral endoscopic myotomy often digresses the important role of endoscopy. Endoscopic evaluation forms the part of standard first-line evaluation of any dysphagia and serves to rule out a secondary cause such as an esophagogastric junction malignancy and eosinophilic esophagitis. Moreover, endoscopic evaluation may itself provide corroborative evidence that may contribute to the diagnosis of the motility disorder. Achalasia cardia may present with a wide spectrum of endoscopic findings from being entirely normal and the well-known and pathognomonic dilated sigmoid-shaped esophagus with food residue, to lesser-known ornate signs. The evidence on the role of endosonography in EMDs is conflicting and largely restricted to evaluation of pseudoachalasia. High-resolution manometry (HRM) remains the gold standard in the diagnosis of EMDs. Endoscopists must also keep abreast of the latest iteration of the Chicago classification version 4.0, which differs significantly from its predecessor in being more stringent in making diagnosis of esophagogastric junction outflow obstruction and disorders of peristalsis since these manometric findings may be seen in normal individuals and may be mimicked by opioid use and gastroesophageal reflux. The latest rendition also includes the use of provocative maneuvers and testing in both supine and sitting posture. Despite being the gold standard, there are certain lacunae in the use and interpretation of the Chicago classification of which the users should be well aware. Emerging technologies such as functional lumen imaging probe and planimetry, and timed barium esophagogram fill the lacuna in diagnosis of these motility disorders, which at times is beyond the resolution of HRM.

Evaluating the impact of an enhanced triage process on the performance and diagnostic yield of oesophageal physiology studies post COVID-19

ObjectivesThe COVID-19 pandemic significantly impacted on the provision of oesophageal physiology investigations. During the recovery phase, triaging tools were empirically recommended by national bodies for prioritisation of referrals amidst rising waiting lists and reduced capacity. We evaluated the performance of an enhanced triage process (ETP) consisting of telephone triage combined with the hierarchical ‘traffic light system’ recommended in the UK for prioritising oesophageal physiology referrals.DesignIn a cross-sectional study of patients referred for oesophageal physiology studies at a tertiary centre, data were compared between patients who underwent oesophageal physiology studies 6 months prior to the COVID-19 pandemic and those who were investigated within 6 months after service resumption with implementation of the ETP.Outcome measuresAdjusted time from referral to investigation; non-attendance rates; the detection of Chicago Classification (CC) oesophageal motility disorders on oesophageal manometry and severity of acid reflux on 24 hours pH/impedance monitoring.ResultsFollowing service resumption, the ETP reduced non-attendance rates from 9.1% to 2.8% (p=0.021). Use of the ‘traffic light system’ identified a higher proportion of patients with CC oesophageal motility disorders in the ‘amber’ and ‘red’ triage categories, compared with the ‘green’ category (p=0.011). ETP also reduced the time to test for those who were subsequently found to have a major CC oesophageal motility diagnosis compared with those with minor CC disorders and normal motility (p=0.004). The ETP did not affect the yield or timing of acid reflux studies.ConclusionETPs can effectively prioritise patients with oesophageal motility disorders and may therefore have a role beyond the current pandemic.

Positive allosteric modulation of endogenous delta opioid receptor signaling in the enteric nervous system is a potential treatment for gut motility disorders

Background and Purpose: Allosteric modulators (AMs) are molecules that can fine-tune signaling by G protein-coupled receptors (GPCRs). Although they are a promising therapeutic approach for treating a range of disorders, allosteric modulation of GPCRs in the context of the enteric nervous system (ENS) and digestive dysfunction remains largely unexplored. This study examined allosteric modulation of the delta opioid receptor (DOR) in the ENS and assessed the suitability of DOR AMs for the treatment of irritable bowel syndrome (IBS) symptoms using mouse models. Experimental Approach: The effects of the positive allosteric modulator (PAM) of DOR, BMS-986187, on neurogenic contractions of the mouse colon and on DOR internalization in enteric neurons were quantified. The ability of BMS-986187 to influence colonic motility was assessed both in vitro and in vivo. Key Results: BMS-986187 displayed DOR selective PAM-agonist activity and orthosteric agonist probe-dependence in the mouse colon. BMS-986187 augmented the inhibitory effects of DOR agonists on neurogenic contractions and enhanced reflex-evoked DOR internalization in myenteric neurons. BMS-986187 significantly increased DOR endocytosis in myenteric neurons in response to the weakly internalizing agonist ARM390. BMS-986187 reduced the generation of complex motor patterns in the isolated intact colon. BMS-986187 reduced fecal output and diarrhea onset in the novel environment stress and castor oil models of IBS symptoms, respectively. Conclusion and Implications: DOR PAMs enhance DOR-mediated signaling in the ENS and have potential benefit for the treatment of dysmotility. This study provides proof of concept to support the use of GPCR AMs for treatment of gastrointestinal motility disorders.