Capsules for the Diagnosis and Treatment of Gastrointestinal Motility Disorders- A Game Changer.

PURPOSE OF REVIEW: Over the last few decades, there have been remarkable strides in endoscopy and radiological imaging that have advanced gastroenterology. However, the management of neurogastroenterological disorders has lagged behind, in part handicapped by the use of catheter-based manometry that is both non-physiological and uncomfortable. The advent of capsule technology has been a game changer for both diagnostic and therapeutic applications. RECENT FINDINGS: Here, we discuss several capsule devices that are available or under investigation. There are three technologies that are FDA approved. Wireless motility capsule measures pH and pressure and provides clinically impactful information regarding gastric, small intestine and colonic transit, without radiation that has been demonstrated to guide management of gastroparesis, dyspepsia and constipation. Wireless ambulatory pH monitoring capsule is currently the gold standard for assessing gastroesophageal acid reflux. In the therapeutics arena, an orally ingested vibrating capsule has been recently FDA approved for the treatment of chronic constipation, supported by a robust phase 3 clinical trial which showed significant improvement in constipation symptoms and quality of life. There are several capsules currently under investigation. Smart capsule bacterial detection system and Capscan® are capsules that can sample fluid in the small or large bowel and provide microbiome analysis for detection of small intestinal bacterial (SIBO) or fungal overgrowth (SIFO). Another investigational gas sensing capsule analyzing hydrogen, CO2, volatile fatty acids and capsule orientation, can measure regional gut transit time and luminal gas concentrations and assess gastroparesis, constipation or SIBO. Therapeutically, other vibrating capsules are in development. Innovations in capsule technology are poised to transform our ability to investigate gut function physiologically, and non-invasively deliver targeted treatment(s), thereby providing both accurate diagnostic information and luminally-directed, safe therapy.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Accuracy of patient-reported bowel symptoms for fecal incontinence: Historical recall versus prospective evaluation.

INTRODUCTION: Fecal incontinence (FI) is characterized by both irregular and unpredictable bowel symptoms. An accurate history of symptoms is important for diagnosis and guiding management. Whether a patient's history of bowel symptoms is reliable or if there is recall bias is unknown. AIM: To evaluate the accuracy of FI symptoms based on patient's recall compared with a prospective stool diary. METHODS: FI (Rome IV) patients completed a bowel questionnaire that included leakage episodes and stool consistency. Subsequently they completed a one-week FI stool diary. Agreement and correlation between historical recall and stool diary were compared. RESULTS: One hundred patients participated. On average they reported 12 bowel movements (BMs) and five FI episodes per week. Fifty-two percent had completed under-graduation, 33% high school and 15% postgraduation. Using recall, 23% of patients accurately reported the number of FI episodes, whereas 41% underestimated and 36% overestimated its prevalence compared to the FI diary. Similarly, the concordance for the number of BMs was 30%, urgency was 54%, amount of stool leakage was 16%, and stool consistency was 12.5%. The concordance for nocturnal FI events, use of pads and lack of stool awareness were 63%, 75%, and 66.6% respectively. CONCLUSION: There is poor concordance for key bowel symptoms including the number of FI episodes as reported by FI patients, suggesting significant recall bias. Thus, historical recall of chronic FI symptoms may be less accurate. A prospective stool diary could provide more accurate information for the evaluation of FI patients.

Evaluation of bidirectional gut-brain axis and anorectal function in Parkinson's disease with constipation.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative movement disorder with prodromal and highly prevalent gastrointestinal (GI) symptoms, especially constipation. Although PD models suggest gut-brain axis dysfunction, the mechanistic underpinnings and their correlation with GI symptoms are poorly understood. AIM: To examine the bidirectional gut-brain axis function in PD and correlate it with constipation severity, PD duration, and severity. METHODS: Rectal sensory thresholds and afferent cortical evoked potentials (CEP) were assessed using a 4-ring EMG electrode probe. Efferent anal and rectal motor evoked potentials (MEPs) were obtained following transcranial and lumbosacral magnetic stimulation. Bowel symptoms were assessed by prospective stool diary. The CEP and MEP latencies, rectal sensory thresholds, and anorectal sensorimotor data were compared between PD subjects and age-adjusted healthy subjects. KEY RESULTS: Twenty-five PD subjects with constipation (F/M = 6/19) and 20 healthy subjects (F/M = 14/6) were enrolled. The first and pain sensation thresholds were higher in PD subjects than healthy subjects (p < 0.002) but lost significance after adjustment for age. Age-adjusted rectal CEP and right-sided cortico-anal MEP latencies were prolonged in PD subjects compared to healthy subjects (p < 0.04). Also, half (4 of 8) age-adjusted spino-anal and rectal MEP latencies in PD subjects were significantly longer. In multivariate linear analysis, first rectal sensation and right-sided MEP latencies showed moderate correlation with constipation severity. CONCLUSIONS & INFERENCES: Parkinson's disease is associated with significant bidirectional gut-brain axis dysfunction as evidenced by prolonged afferent and efferent neuronal signaling. Constipation severity in PD is correlated to abnormal rectal sensation and lateralized disturbance of efferent brain-gut signaling.

Pathoetiology of Levator Ani Syndrome and Its Treatment With Translumbosacral Neuromodulation Therapy.

INTRODUCTION: The pathoetiology and treatment of levator ani syndrome (LAS) remain unclear. METHODS: We evaluated pathophysiology using translumbosacral motor-evoked potentials and anorectal manometry in patients with LAS and compared with healthy controls. A cohort underwent translumbosacral neuromodulation therapy (TNT). RESULTS: Lumbar and sacral motor-evoked potential latencies were prolonged in 32 patients with LAS compared with 31 controls ( P < 0.013), with higher prevalence of anal neuropathy ( P = 0.026). TNT improved anorectal pain ( P = 0.003) and neuropathy ( P < 0.02) in 13 patients with LAS. DISCUSSION: Patients with LAS demonstrate significant lumbosacral neuropathy that may cause anorectal pain. TNT improved anorectal pain and neuropathy, providing a novel therapeutic option.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Influence of Demographic Factors on Clinical Outcomes in Adults With Chronic Idiopathic Constipation Treated With Plecanatide.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common condition that affects some patient groups more often. Demographic/clinical characteristics can differ in presentation and therapeutic response. The impact of these characteristics on plecanatide efficacy/safety was examined. METHODS: Data from 2 identically designed, randomized, phase 3 trials of adults with CIC receiving 3 mg of plecanatide, 6 mg of plecanatide, or placebo for 12 weeks were analyzed. Subgroups were baseline age, body mass index (BMI), race/ethnicity, and sex/gender. Endpoints included durable overall complete spontaneous bowel movement (CSBM) responder rate, weekly CSBMs and spontaneous bowel movements (SBMs), and adverse events. RESULTS: Overall (N = 2,639; 3 mg of plecanatide [n = 877]; 6 mg of plecanatide [n = 877]; and placebo [n = 885]), CSBM responder rates were significantly greater with 3 mg of plecanatide and 6 mg of plecanatide vs placebo in subgroups with those younger than 65 years ( P < 0.001), females ( P < 0.001), White individuals ( P < 0.001), and BMI <25 kg/m 2 ( P ≤ 0.004) and 25-30 kg/m 2 ( P < 0.001); as well, for 3 mg: 65 years or older ( P = 0.03), non-White individuals ( P < 0.001), and BMI ≥30 kg/m 2 ( P = 0.02). Improvement from baseline in weekly CSBM and SBM frequency occurred in all subgroups for both plecanatide doses vs placebo ( P ≤ 0.02) at week 12, except those aged 65 years or older for 6 mg of plecanatide. The most common adverse event was diarrhea (3 mg [4.9%]; 6 mg [5.4%]; and placebo [1.3%]). DISCUSSION: Pooled data from identically designed CIC trials strengthened the ability to identify meaningful subgroup comparisons regarding plecanatide efficacy and safety.

Rifaximin Treatment for Individual and Multiple Symptoms of Irritable Bowel Syndrome With Diarrhea: An Analysis Using New End Points.

PURPOSE: Rifaximin is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults. The current aim was to evaluate rifaximin efficacy on individual and composite IBS-D symptoms using definitions not previously examined. METHODS: Phase III post hoc analyses of two randomized, double-blind, placebo-controlled trials and the open-label phase of a randomized, double-blind, placebo-controlled trial were conducted. Adults with IBS-D received a 2-week course of rifaximin 550 mg TID. Individual and composite responses for abdominal pain (mean weekly improvements from baseline of ≥30%, ≥40%, or ≥50%), bloating (mean weekly improvements from baseline of ≥1 or ≥2 points; or ≥30%, ≥40%, or ≥50%), stool consistency (mean weekly average stool consistency score <3 or <4), and urgency (improvement from baseline of ≥30% or ≥40% in percentage of days with urgency) for ≥2 of the first 4 weeks after treatment, and weekly for 12 weeks, were assessed. FINDINGS: Overall, 1258 patients from the double-blind trials (rifaximin [n = 624]; placebo [n = 634]) and 2438 from an open-label trial were analyzed. The percentage of bloating or urgency responders was significantly greater with double-blind rifaximin versus placebo (P ≤ 0.03). A significantly greater percentage of the double-blind group were composite abdominal pain and bloating responders versus placebo for all thresholds analyzed (P < 0.05). A significantly greater percentage of the double-blind group were tri-symptom composite end point responders (abdominal pain, bloating, and fecal urgency) versus placebo (P = 0.001). A significantly greater percentage of patients achieved response (≥30% composite tri-symptom threshold) with double-blind rifaximin versus placebo as early as 1 week posttreatment, with significance maintained through ≥5 weeks after treatment. Open-label results were consistent with those of the double-blind study. IMPLICATIONS: Rifaximin significantly improved multiple, concurrent IBS-D symptoms, using clinically relevant definitions of treatment response. Using a novel tri-symptom composite end point (ie, abdominal pain, bloating, fecal urgency), adults with IBS-D treated with a 2-week course of rifaximin were significantly more likely to be composite end point responders than those receiving placebo (≥30% or ≥40% threshold) for the three symptoms. Thus, rifaximin not only met current standard thresholds used for adjudication of responders in clinical trials but also achieved higher thresholds for many of these symptoms, suggesting potential for even more robust clinical improvements. CLINICALTRIALS: gov identifiers: NCT00731679, NCT00724126, and NCT01543178.

Randomized Placebo-Controlled Phase 3 Trial of Vibrating Capsule for Chronic Constipation.

BACKGROUND & AIMS: Despite therapeutic advances, effective treatments for chronic constipation remain an unmet need. The vibrating capsule is a nonpharmacologic, orally ingested, programmable capsule that vibrates intraluminally to induce bowel movements. We aimed to determine the efficacy and safety of the vibrating capsule in patients with chronic constipation. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial of patients with chronic constipation, who were randomized to receive either a vibrating or placebo capsule, once daily, 5 days a week for 8 weeks. The primary efficacy end points were an increase of 1 or more complete spontaneous bowel movements per week (CSBM1 responder) or 2 or more CSBMs per week (CSBM2) from baseline during at least 6 of the 8 weeks. Safety analyses were performed. RESULTS: Among 904 patients screened, 312 were enrolled. A greater percentage of patients receiving the vibrating capsule achieved both primary efficacy end points compared with placebo (39.3% vs 22.1%, P = .001 for CSBM1; 22.7% vs 11.4% P = .008 for CSBM2). Significantly greater improvements were seen with the vibrating capsule for the secondary end points of straining, stool consistency, and quality-of-life measures compared with placebo. Adverse events were mild, gastrointestinal in nature, and similar between groups, except that a mild vibrating sensation was reported by 11% of patients in the vibrating capsule group, but none withdrew from the trial. CONCLUSIONS: In patients with chronic constipation, the vibrating capsule was superior to placebo in improving bowel symptoms and quality of life. The vibrating capsule was safe and well tolerated. (Clinical trials.gov, Number: NCT03879239).

Sucrose intolerance in adults with common functional gastrointestinal symptoms.

Sucrose intolerance is a form of carbohydrate malabsorption caused by sucrase-isomaltase deficiency that is more common than recognized. Its symptoms include postprandial cramping, bloating, gas, and diarrhea, which are difficult to distinguish from irritable bowel syndrome. The gold standard test for diagnosing sucrase deficiency is a sucrase enzyme assay of duodenal biopsies obtained by endoscopy. Hydrogen-methane or 13C-sucrose breath tests are noninvasive methods to screen for sucrose malabsorption. This chart review included 258 consecutive adults (47 men and 211 women) with chronic unexplained gastrointestinal symptoms and suspected sucrose intolerance who were screened with a hydrogen-methane or 13C-sucrose breath test. The incidence of sucrose malabsorption with two different hydrogen-methane breath tests was 34.4% (21/61) (Commonwealth Diagnostics International, Inc., Salem, MA) and 40% (20/50) (Aerodiagnostics, Concord, MA). The incidence of sucrose malabsorption with the 13C-sucrose breath test was 26.5% (39/147). In a subgroup of patients with positive breath tests and clinical follow-up, counseling regarding diet and/or enzyme replacement led to symptomatic improvement in 26/43 (60%). In conclusion, sucrose malabsorption may present with irritable bowel syndrome symptoms in a proportion of adult patients, and breath tests may be useful in identifying sucrose malabsorption and differentiating it from other gastrointestinal disorders.

Evidence-based treatment recommendations for OTC management of chronic constipation.

ABSTRACT: Chronic constipation is a common gastrointestinal condition, and most individuals self-treat with multiple over-the-counter (OTC) laxatives prior to consulting a health care provider. This brief report is a synopsis of an updated systematic review the authors conducted of published data on the efficacy and safety of OTC treatments to provide evidence-based recommendations. After applying the selection criteria, 41 randomized controlled clinical trials of ≥ 4-week duration were identified and analyzed. Standardized definitions of constipation were applied across these studies; however, definitions for stool frequency and consistency varied. Overall, the short- and long-term efficacy of polyethylene glycol-based preparations and senna were supported by good (grade A) evidence suggesting their use as first-line laxatives. Modest evidence (grade B) supported the use of other agents including the stimulants bisacodyl and sodium picosulfate, fiber, fruit-based laxatives, and magnesium oxide. Additional evidence from rigorously designed studies is needed to support the use of other options for chronic constipation. The OTC products studied were generally well tolerated with common adverse effects being abdominal pain, cramping, bloating, diarrhea, and nausea.

Recognizing and Defining Occasional Constipation: Expert Consensus Recommendations.

Constipation is a common problem, affects 15% of the population, and is often self-diagnosed and self-managed. Over the past 3 decades, there have been significant advances in our understanding and management of chronic constipation, with the emerging recognition that occasional constipation (OC) is another subtype that falls outside current classifications. The purpose of this review was to describe the process of developing and proposing a new definition for OC based on expert consensus and taking into consideration the multifactorial nature of the problem such as alterations in bowel habit that include stool frequency and difficulty with stool passage, perception of the sufferer, duration of symptoms, and potential responsiveness to treatment. Leading gastroenterologists from 5 countries met virtually on multiple occasions through an online digital platform to discuss the problem of OC and recommended a practical, user-friendly definition: "OC can be defined as intermittent or occasional symptomatic alteration(s) in bowel habit. This includes a bothersome reduction in the frequency of bowel movements and/or difficulty with passage of stools but without alarming features. Bowel symptoms may last for a few days or a few weeks, and episodes may require modification of lifestyle, dietary habits and/or use of over-the-counter laxatives or bulking agents to restore a satisfactory bowel habit." Prospective studies are required to validate this definition and determine OC prevalence in the community. This review highlights current knowledge gaps and could provide impetus for future research to facilitate an improved understanding of OC and development of evidence-based management guidelines.

Bacterial overgrowth and lactose intolerance: how to best assess.

PURPOSE OF REVIEW: To provide an up-to-date review on the clinical assessment of two important gastrointestinal problems with overlapping symptomatology but diverse cause and testing methods. Small intestinal bacterial overgrowth (SIBO) is characterized by the presence of excess bacteria in the small intestine associated with bloating, distention, gas, and diarrhea. Lactose intolerance is caused by lactase enzyme deficiency in the small bowel mucosa leading to lactose malabsorption and symptoms of bloating, gas, and diarrhea. RECENT FINDINGS: SIBO is assessed by hydrogen/methane breath test using glucose as a substrate and/or small bowel aspirate and culture but these tests have shortcomings. Consequently, several new diagnostic techniques, including novel capsule technologies and other approaches are being evaluated. Lactose intolerance can be assessed by hydrogen/methane breath test using lactose as a substrate, or small bowel mucosal lactase assay, genetic testing and lactose tolerance test, although the efficacy and practicality of these diagnostic modalities are not equal. SUMMARY: In clinical practice, gas, bloating, distention, pain, and diarrhea are common gastrointestinal symptoms that often remain unexplained when routine gastrointestinal endoscopy, imaging, and stool tests are negative. These patients should be evaluated for SIBO and/or food intolerances including lactose intolerance.

Organizing and Developing a GI Motility Lab in Community Practice: Challenges and Rewards.

PURPOSE OF REVIEW: Neurogastroenterology and motility is a rapidly evolving subspecialty that encompasses over 33% of gastroenterological disorders, and up to 50% of referrals to gastroenterology practice. It includes common problems such as dysphagia, gastroesophageal reflux disease, irritable bowel syndrome, chronic constipation, gastroparesis, functional dyspepsia, gas/bloating, small intestinal bacterial overgrowth, food intolerance and fecal incontinence Standard diagnostic tests such as endoscopy or imaging are normal in these conditions. To define the underlying mechanism(s)/etiology of these disorders, diagnostic motility tests are often required. These are best performed by well-trained personnel in a dedicated motility laboratory. Our purpose is to provide an up-to-date overview on how to organize and develop a motility laboratory based on our collective experiences in setting up such facilities in academia and community practice. RECENT FINDINGS: A lack of knowledge, training and facilities for providing diagnostic motility tests has led to suboptimal patient care. A motility laboratory is the hub for diagnostic and therapeutic motility procedures. Common procedures include esophageal function tests such as esophageal manometry and pH monitoring, anorectal function tests suchlike anorectal manometry, neurophysiology and balloon expulsion, dysbiosis and food intolerance tests such as hydrogen/methane breath tests, and gastrointestinal transit assessment. These tests provide an accurate diagnosis and guide clinical management including use of medications, biofeedback therapy, neuromodulation, behavioral therapies, evidence-based dietary interventions and endoscopic or surgical procedures. Further, there have been recent developments in billing and coding of motility procedures and training requirements that are not well known. This review provides a stepwise approach on how to set-up a motility laboratory in the community or academic practice and includes the rationale, infrastructure, staffing needs, commonly performed motility tests and their clinical utility, billing and coding strategies, training needs and economic considerations for setting up this service.

Dyssynergic Defecation and Other Evacuation Disorders.

Constipated patients are frequently referred to gastroenterologists for symptoms refractory to lifestyle modifications and laxatives. Dyssynergic defecation, the dyscoordination of rectoanal, abdominal, and pelvic floor muscles to facilitate defecation, is a major cause of refractory primary constipation. Understanding of the diagnosis, evaluation, and management of dyssynergic defecation and other evacuation disorders will allow providers to effectively manage these patients. This review focuses on the definition, pathophysiology, evaluation, and treatment of dyssynergic defecation and other evacuation disorders. Emerging treatments for these disorders include home biofeedback therapy for dyssynergic defecation and translumbosacral neuromodulation therapy for levator ani syndrome.

Review of the indications, methods, and clinical utility of anorectal manometry and the rectal balloon expulsion test.

BACKGROUND: Anorectal manometry (ARM) comprehensively assesses anorectal sensorimotor functions. PURPOSE: This review examines the indications, techniques, interpretation, strengths, and weaknesses of high-resolution ARM (HR-ARM), 3-dimensional high-resolution anorectal manometry (3D-HR-ARM), and portable ARM, and other assessments (i.e., rectal sensation and rectal balloon expulsion test) that are performed alongside manometry. It is based on a literature search of articles related to ARM in adults. HR-ARM and 3D-HR-ARM are useful for diagnosing defecatory disorders (DD), to identify anorectal sensorimotor dysfunction and guide management in patients with fecal incontinence (FI), constipation, megacolon, and megarectum; and to screen for anorectal structural (e.g., rectal intussusception) abnormalities. The rectal balloon expulsion test is a useful, low-cost, radiation-free, outpatient assessment tool for impaired evacuation that is performed and interpreted in conjunction with ARM. The anorectal function tests should be interpreted with reference to age- and sex-matched normal values, clinical features, and results of other tests. A larger database of technique-specific normal values and newer paradigms of analyzing anorectal pressure profiles will increase the precision and diagnostic utility of HR-ARM for identifying abnormal mechanisms of defecation and continence.