Chronic constipation in adults: Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation.

BACKGROUND: Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2-day meeting held in London, entitled "Current perspectives in chronic constipation: a scientific and clinical symposium." In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting. PURPOSE: This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular "hot topics" and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.

Manometric demonstration of duodenal/jejunal motor function consistent with the duodenal brake mechanism.

BACKGROUND: High-resolution manometric studies below the stomach are rare due to technical limitations of traditional manometry catheters. Consequently, specific motor patterns and their impact on gastric and small bowel function are not well understood. High-resolution manometry was used to record fed-state motor patterns in the antro-jejunal segment and relate these to fasting motor function. METHODS: Antro-jejunal pressures were monitored in 15 healthy females using fiber-optic manometry (72 sensors at 1 cm intervals) before and after a high-nutrient drink. KEY RESULTS: Postprandial motility showed a previously unreported transition point 18.8 cm (range 13-28 cm) beyond the antro-pyloric junction. Distal to the transition, a zone of non-propagating, repetitive pressure events (11.5 ± 0.5 cpm) were dominant in the fed state. We have named this activity, the duodeno-jejunal complex (DJC). Continuous DJC activity predominated, but nine subjects also exhibited intermittent clusters of DJC activity, 7.4 ± 4.9/h, lasting 1.4 ± 0.55 minutes, and 3.8 ± 1.2 minutes apart. DJC activity was less prevalent during fasting (3.6 ± 3.3/h; P = .04). 78% of fed and fasting state propagating antro-duodenal pressure events terminated proximally or at the transition point and were closely associated with DJC clusters. CONCLUSIONS AND INFERENCES: High-resolution duodeno-jejunal manometry revealed a previously unrecognized transition point and associated motor pattern extending into the jejunum, consistent with the duodenal brake previously identified fluoroscopically. Timing suggests DJC activity is driven by chyme stimulating duodenal mucosal chemosensors. These findings indicate that the duodenum and proximal jejunum consists of two major functional motor regions.

The international anorectal physiology working group (IAPWG) recommendations: Standardized testing protocol and the London classification for disorders of anorectal function.

BACKGROUND: This manuscript summarizes consensus reached by the International Anorectal Physiology Working Group (IAPWG) for the performance, terminology used, and interpretation of anorectal function testing including anorectal manometry (focused on high-resolution manometry), the rectal sensory test, and the balloon expulsion test. Based on these measurements, a classification system for disorders of anorectal function is proposed. METHODS: Twenty-nine working group members (clinicians/academics in the field of gastroenterology, coloproctology, and gastrointestinal physiology) were invited to six face-to-face and three remote meetings to derive consensus between 2014 and 2018. KEY RECOMMENDATIONS: The IAPWG protocol for the performance of anorectal function testing recommends a standardized sequence of maneuvers to test rectoanal reflexes, anal tone and contractility, rectoanal coordination, and rectal sensation. Major findings not seen in healthy controls defined by the classification are as follows: rectoanal areflexia, anal hypotension and hypocontractility, rectal hyposensitivity, and hypersensitivity. Minor and inconclusive findings that can be present in health and require additional information prior to diagnosis include anal hypertension and dyssynergia. CONCLUSIONS AND INFERENCES: This framework introduces the IAPWG protocol and the London classification for disorders of anorectal function based on objective physiological measurement. The use of a common language to describe results of diagnostic tests, standard operating procedures, and a consensus classification system is designed to bring much-needed standardization to these techniques.

Neural motor complexes propagate continuously along the full length of mouse small intestine and colon.

Cyclical propagating waves of muscle contraction have been recorded in isolated small intestine or colon, referred to here as motor complexes (MCs). Small intestinal and colonic MCs are neurogenic, occur at similar frequencies, and propagate orally or aborally. Whether they can be coordinated between the different gut regions is unclear. Motor behavior of whole length mouse intestines, from duodenum to terminal rectum, was recorded by intraluminal multisensor catheter. Small intestinal MCs were recorded in 27/30 preparations, and colonic MCs were recorded in all preparations (n = 30) with similar frequencies (0.54 ± 0.03 and 0.58 ± 0.02 counts/min, respectively). MCs propagated across the ileo-colonic junction in 10/30 preparations, forming "full intestine" MCs. The cholinesterase inhibitor physostigmine increased the probability of a full intestine MC but had no significant effect on frequency, speed, or direction. Nitric oxide synthesis blockade by Nω-nitro-l-arginine, after physostigmine, increased MC frequency in small intestine only. Hyoscine-resistant MCs were recorded in the colon but not small intestine (n = 5). All MCs were abolished by hexamethonium (n = 18) or tetrodotoxin (n = 2). The enteric neural mechanism required for motor complexes is present along the full length of both the small and large intestine. In some cases, colonic MCs can be initiated in the distal colon and propagate through the ileo-colonic junction, all the way to duodenum. In conclusion, the ileo-colonic junction provides functional neural continuity for propagating motor activity that originates in the small or large intestine.NEW & NOTEWORTHY Intraluminal manometric recordings revealed motor complexes can propagate antegradely or retrogradely across the ileo-colonic junction, spanning the entire small and large intestines. The fundamental enteric neural mechanism(s) underlying cyclic motor complexes exists throughout the length of the small and large intestine.

High-resolution anatomic correlation of cyclic motor patterns in the human colon: Evidence of a rectosigmoid brake.

Colonic cyclic motor patterns (CMPs) have been hypothesized to act as a brake to limit rectal filling. However, the spatiotemporal profile of CMPs, including anatomic origins and distributions, remains unclear. This study characterized colonic CMPs using high-resolution (HR) manometry (72 sensors, 1-cm resolution) and their relationship with proximal antegrade propagating events. Nine healthy volunteers were recruited. Recordings were performed over 4 h, with a 700-kcal meal given after 2 h. Propagating events were visually identified and analyzed by pattern, origin, amplitude, extent of propagation, velocity, and duration. Manometric data were normalized using anatomic landmarks identified on abdominal radiographs. These were mapped over a three-dimensional anatomic model. CMPs comprised a majority of detected propagating events. Most occurred postprandially and were retrograde propagating events (84.9 ± 26.0 retrograde vs. 14.3 ± 11.8 antegrade events/2 h, P = 0.004). The dominant sites of initiation for retrograde CMPs were in the rectosigmoid region, with patterns proximally propagating by a mean distance of 12.4 ± 0.3 cm. There were significant differences in the characteristics of CMPs depending on the direction of travel and site of initiation. Association analysis showed that proximal antegrade propagating events occurred independently of CMPs. This study accurately characterized CMPs with anatomic correlation. CMPs were unlikely to be triggered by proximal antegrade propagating events in our study context. However, the distal origin and prominence of retrograde CMPs could still act as a mechanism to limit rectal filling and support the theory of a "rectosigmoid brake."NEW & NOTEWORTHY Retrograde cyclic motor patterns (CMPs) are the dominant motor patterns in a healthy prepared human colon. The major sites of initiation are in the rectosigmoid region, with retrograde propagation, supporting the idea of a "rectosigmoid brake." A significant increase in the number of CMPs is seen after a meal. In our study context, the majority of CMPs occurred independent of proximal propagating events, suggesting that CMPs are primarily controlled by external innervation.

Predicting the activation states of the muscles governing upper esophageal sphincter relaxation and opening.

The swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation and deactivation of neural inputs to these muscles, including the intrinsic cricopharyngeus (CP) and extrinsic submental (SM) muscles, results in their mechanical activation or deactivation, which changes the diameter of the lumen, alters the intraluminal pressure, and ultimately reduces or promotes flow of content. By measuring the changes in diameter, using intraluminal impedance, and the concurrent changes in intraluminal pressure, it is possible to determine when the muscles are passively or actively relaxing or contracting. From these "mechanical states" of the muscle, the neural inputs driving the specific motor behaviors of the UES can be inferred. In this study we compared predictions of UES mechanical states directly with the activity measured by electromyography (EMG). In eight subjects, pharyngeal pressure and impedance were recorded in parallel with CP- and SM-EMG activity. UES pressure and impedance swallow profiles correlated with the CP-EMG and SM-EMG recordings, respectively. Eight UES muscle states were determined by using the gradient of pressure and impedance with respect to time. Guided by the level and gradient change of EMG activity, mechanical states successfully predicted the activity of the CP muscle and SM muscle independently. Mechanical state predictions revealed patterns consistent with the known neural inputs activating the different muscles during swallowing. Derivation of "activation state" maps may allow better physiological and pathophysiological interpretations of UES function.

Upper esophageal sphincter mechanical states analysis: a novel methodology to describe UES relaxation and opening.

The swallowing muscles that influence upper esophageal sphincter (UES) opening are centrally controlled and modulated by sensory information. Activation of neural inputs to these muscles, the intrinsic cricopharyngeus muscle and extrinsic suprahyoid muscles, results in their contraction or relaxation, which changes the diameter of the lumen, alters the intraluminal pressure and ultimately inhibits or promotes flow of content. This relationship that exists between the changes in diameter and concurrent changes in intraluminal pressure has been used previously to calculate the "mechanical states" of the muscle; that is when the muscles are passively or actively, relaxing or contracting. Diseases that alter the neural pathways to these muscles can result in weakening the muscle contractility and/or decreasing the muscle compliance, all of which can cause dysphagia. Detecting these changes in the mechanical state of the muscle is difficult and as the current interpretation of UES motility is based largely upon pressure measurement (manometry), subtle changes in the muscle function during swallow can be missed. We hypothesized that quantification of mechanical states of the UES and the pressure-diameter properties that define them, would allow objective characterization of the mechanisms that govern the timing and extent of UES opening during swallowing. To achieve this we initially analyzed swallows captured by simultaneous videofluoroscopy and UES pressure with impedance recording. From these data we demonstrated that intraluminal impedance measurements could be used to determine changes in the internal diameter of the lumen when compared to videofluoroscopy. Then using a database of pressure-impedance studies, recorded from young and aged healthy controls and patients with motor neuron disease, we calculated the UES mechanical states in relation to a standardized swallowed bolus volume, normal aging and dysphagia pathology. Our results indicated that eight different mechanical states were almost always seen during healthy swallowing and some of these calculated changes in muscle function were consistent with the known neurally dependent phasic discharge patterns of cricopharyngeus muscle activity during swallowing. Clearly defined changes in the mechanical states were observed in motor neuron disease when compared to age matched healthy controls. Our data indicate that mechanical state predictions were simple to apply and revealed patterns consistent with the known neural inputs activating the different muscles during swallowing.

Factor analysis identifies subgroups of constipation.

AIM: To determine whether distinct symptom groupings exist in a constipated population and whether such grouping might correlate with quantifiable pathophysiological measures of colonic dysfunction. METHODS: One hundred and ninety-one patients presenting to a Gastroenterology clinic with constipation and 32 constipated patients responding to a newspaper advertisement completed a 53-item, wide-ranging self-report questionnaire. One hundred of these patients had colonic transit measured scintigraphically. Factor analysis determined whether constipation-related symptoms grouped into distinct aspects of symptomatology. Cluster analysis was used to determine whether individual patients naturally group into distinct subtypes. RESULTS: Cluster analysis yielded a 4 cluster solution with the presence or absence of pain and laxative unresponsiveness providing the main descriptors. Amongst all clusters there was a considerable proportion of patients with demonstrable delayed colon transit, irritable bowel syndrome positive criteria and regular stool frequency. The majority of patients with these characteristics also reported regular laxative use. CONCLUSION: Factor analysis identified four constipation subgroups, based on severity and laxative unresponsiveness, in a constipated population. However, clear stratification into clinically identifiable groups remains imprecise.

Colonic dysmotility in constipation.

Constipation is a common and distressing condition with major morbidity, health care burden, and impact on quality of life. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in the most severe cases of chronic constipation and physiological testing plays a role in identifying the colonic dysmotility and the subsequent patient management. Measurement of colonic motor patterns and transit has enhanced our knowledge of normal and abnormal colonic motor physiology. The scope of this review encompasses the latest findings that improve our understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation.

Paediatric and adult colonic manometry: a tool to help unravel the pathophysiology of constipation.

Colonic motility subserves large bowel functions, including absorption, storage, propulsion and defaecation. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in chronic constipation, a heterogeneous condition which is extremely prevalent in the general population, and has huge socioeconomic impact and individual suffering. Physiological testing plays a crucial role in patient management, as it is now accepted that symptom-based assessment, although important, is unsatisfactory as the sole means of directing therapy. Colonic manometry provides a direct method for studying motor activities of the large bowel, and this review provides a contemporary understanding of how this technique has enhanced our knowledge of normal colonic motor physiology, as well as helping to elucidate pathophysiological mechanisms underlying constipation. Methodological approaches, including available catheter types, placement technique and recording protocols, are covered, along with a detailed description of recorded colonic motor activities. This review also critically examines the role of colonic manometry in current clinical practice, and how manometric assessment may aid diagnosis, classification and guide therapeutic intervention in the constipated individual. Most importantly, this review considers both adult and paediatric patients. Limitations of the procedure and a look to the future are also addressed.

Anal manometry: a comparison of techniques.

PURPOSE: Methods of anal manometry vary between centers, resulting in potential difficulties in interpretation of results. This study compared several accepted manometric techniques in healthy control subjects and in patients with fecal incontinence. METHODS: Eleven patients with fecal incontinence (M:F = 3:8; mean age = 67 years) and ten healthy control subjects (M:F = 3:7; mean age = 64 years) underwent anal manometry using five different methods: 1) water-perfused side hole; 2) water-perfused end hole; 3) microtransducer; 4) microballoon; 5) portable Peritron. Using a station pull-through technique, anal pressures (resting, squeeze, and cough pressures) were recorded at 1-cm intervals from rectum to anal verge, as well as radial pressures in four quadrants for Methods 1 and 2. RESULTS: Water perfusion side hole recorded slightly higher maximal resting pressures; however, there were no significant differences between any of the methods. In healthy control subjects, distal maximal squeeze pressures were significantly higher (P < 0.05) than proximally as measured by microtransducer. There were slight (nonsignificant) variations in radial pressures with water perfusion and microtransducer. Peritron values for maximum resting pressure and maximum squeeze pressure were lower than those recorded by water perfusion side hole by a factor of 0.8. CONCLUSIONS: There is no significant variation in anal pressure recordings using standard manometry techniques. Variations in radial pressures are slight and not significant in clinical studies. Results obtained with portable nonperfusion systems must be interpreted appropriately.

Assessment of intraluminal impedance for the detection of pharyngeal bolus flow during swallowing in healthy adults.

Intraluminal impedance, a nonradiological method for assessing bolus flow within the gut, may be suitable for investigating pharyngeal disorders. This study evaluated an impedance technique for the detection of pharyngeal bolus flow during swallowing. Patterns of pharyngoesophageal pressure and impedance were simultaneously recorded with videofluoroscopy in 10 healthy volunteers during swallowing of liquid, semisolid, and solid boluses. The timing of bolus head and tail passage recorded by fluoroscopy was correlated with the timing of impedance drop and recovery at each recording site. Bolus swallowing produced a drop in impedance from baseline followed by a recovery to at least 50% of baseline. The timing of the pharyngeal and esophageal impedance drop correlated with the timing of the arrival of the bolus head. In the pharynx, the timing of impedance recovery was delayed relative to the timing of clearance of the bolus tail. In contrast, in the upper esophageal sphincter (UES) and proximal esophagus, the timing of impedance recovery correlated well with the timing of clearance of the bolus tail. Impedance-based estimates of pharyngoesophageal bolus clearance time correlated with true pharyngoesophageal bolus clearance time. Patterns of intraluminal impedance recorded in the pharynx during bolus swallowing are therefore more complex than those in the esophagus. During swallowing, mucosal contact between the tongue base and posterior pharyngeal wall prolongs the duration of pharyngeal impedance drop, leading to overestimation of bolus tail timing. Therefore, we conclude that intraluminal impedance measurement does not accurately reflect the bolus transit in the pharynx but does accurately reflect bolus transit across the UES and below.

Colonic manometry via appendicostomy shows reduced frequency, amplitude, and length of propagating sequences in children with slow-transit constipation.

BACKGROUND/PURPOSE: We wish to define colonic motor function in children with slow-transit constipation (STC) using manometry catheters introduced through appendiceal stomas, previously sited for controlling fecal retention by colonic irrigation. METHODS: We undertook 24-hour pancolonic manometry of 6 children (5 boys; mean, 11.5 years; SD, 3.0) using a multilumen silastic catheter. RESULTS: were compared to nasocolonic motility studies obtained in healthy young adults. RESULTS: Antegrade propagating sequences (APSs) originated less frequently in the cecum compared to controls. There were fewer APS (mean +/- SEM: STC, 13 +/- 6 per 24 hours; controls, 52 +/- 6 per 24 hours; P < .01) and high-amplitude propagating contractions (HAPCs: STC, 5 +/- 2 per 24 hours; controls, 9.9 +/- 1.4 per 24 hours; P < .05). The amplitude of APS and HAPC was less in STC (APS, 39 +/- 9 mm Hg; controls, 54 +/- 3 per 24 hours; P < .05) (HAPC: STC, 94 +/- 10 mm Hg; control, 117 +/- 3 mm Hg; P < .01), whereas the amplitude of retrograde propagating sequences was greater in STC (43 +/- 6 mm Hg; control, 27 +/- 1 mm Hg; P < .01). The distances propagated by HAPC were significantly less in STC (36 +/- 4.5 vs 47 +/- 2.3 cm, controls; P < .05), and there was no evidence of a region-specific difference in propagation velocity of APS. Neither meal ingestion nor waking significantly increased colonic motor activity in patients with STC. CONCLUSIONS: Despite the small numbers available to be studied, we found that children with STC in whom an appendicostomy had been placed show significant abnormalities in pancolonic motor function.

Abnormal predefecatory colonic motor patterns define constipation in obstructed defecation.

BACKGROUND & AIMS: The pathophysiology of constipation in the syndrome of obstructed defecation is unknown. Using 24-hour pancolonic manometric recordings of the unprepared colon to record basal pressures and spontaneous defecation episodes, we tested the hypothesis that the frequency, timing, or spatial distribution of propagating colonic pressure waves is abnormal in patients with obstructed defecation. METHODS: In 11 patients with obstructed defecation and 16 healthy controls, pressures were recorded using a nasocolonic catheter that was positioned such that 16 recording sites spanned the unprepared colon at 7.5-cm intervals. RESULTS: The overall frequency of propagating sequences (PS) in the colon did not differ between patients and controls. When compared with controls, patients had a significant increase in the frequency of retrograde and antegrade PS (P < 0.05) in the left colon and a significant reduction in the amplitude of propagating pressure waves throughout the entire colon (P < 0.03). Defecation occurred in 6 of 11 patients and 9 of 16 controls. In the 15 minutes before defecation, controls showed a highly significant increase in frequency (P = 0.001) and amplitude (P = 0.01) of PS. In contrast, patients did not demonstrate this or the typical spatiotemporal organization of PS normally observed before expulsion of stool. CONCLUSIONS: Patients with obstructed defecation lack the normal predefecatory augmentation in frequency and amplitude of propagating pressure waves and lack the normal stereotypic spatiotemporal patterning of colonic pressure waves that would normally culminate in effective expulsion of stool.