Satish S Rao - University of Iowa Carver College of Medicine
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Satish S Rao
University of Iowa Carver College of Medicine
Publications Authored By Satish S Rao
Although immunohistochemical staining is reportedly useful for identifying the mesenchymopathic type, its role in diagnosing enteric visceral myopathy and neuropathy has been fraught with difficulties. We present two cases of chronic intestinal pseudo-obstruction that are clinically and histopathologically suggestive of type III visceral enteric myopathy, aiming to expound upon the diagnostic and pathogenic features. We found that the outer-longitudinal layer of the muscularis propria was more severely affected as compared with the inner circular layer. To investigate the value of this finding, we performed immunostains in the one case in which a paraffin block was available. We found increased peripherin and calretinin immunopositive nerve fibers in the outer layer as compared with inner, but without any significant increase in S-100 positivity or alteration in neuronal morphology of myenteric plexus, a novel finding. This differential staining pattern was completely different from Hirschsprung disease, in which we found rare to absent peripherin and calretinin staining. It is unclear if this increase in the outer layer in visceral myopathy reflects a reactive change or dysfunctional axons. In addition, the history of volvulus in one patient and transmural inflammatory changes in the second raise concerns about the higher propensity of clinical complications secondary to the attenuated outer muscular layer. This study suggests that enteric visceral myopathy has histologic and staining characteristics different from Hirschsprung disease, a finding of diagnostic significance in the differential diagnosis of bowel obstruction. Moreover, these features may have pathogenic value and need further confirmation.
Anorectal physiology tests and balloon expulsion test are essential for a diagnosis. Newer techniques such as high-resolution manometry and magnetic resonance defecography can provide mechanistic insights. Recently, randomized controlled trials have shown that biofeedback therapy is more effective than laxatives and other modalities, both in the short term and long term, without side effects. Also, symptom improvements correlated with changes in underlying pathophysiology. Biofeedback therapy has been recommended as the first-line of treatment for dyssynergic defecation. Here, we provide an overview of the burden of illness and pathophysiology of dyssynergic defecation, and how to diagnose and treat this condition with biofeedback therapy.
Slow-transit constipation is characterized by prolonged colonic transit in the absence of pelvic floor dysfunction. This subtype of constipation can be identified using either the radio-opaque marker test or wireless motility capsule test, and is best treated with laxatives such as polyethylene glycol or newer agents such as linaclotide or lubiprostone. If unsuccessful, subspecialist referral should be considered. Dyssynergic defecation results from impaired coordination of rectoanal and pelvic floor muscles, and causes difficulty with defecation. The condition can be identified using anorectal manometry and balloon expulsion tests and is best managed with biofeedback therapy. Opioid-induced constipation is an emerging entity, and several drugs including naloxegol, methylnaltrexone and lubiprostone are approved for its treatment. In this Review, we provide an overview of the burden and pathophysiology of chronic constipation, as well as a detailed discussion of the available diagnostic tools and treatment options.
The lack of a systematic approach toward the diagnosis and treatment of ECP has led to significant disability and increased health care costs for this condition. Identifying the underlying cause(s) or mechanism(s) for chest pain is key for its successful management. Common etiologies include gastroesophageal reflux disease, esophageal hypersensitivity, dysmotility, and psychological conditions, including panic disorder and anxiety. However, the pathophysiology of this condition is not yet fully understood. Randomized controlled trials have shown that proton pump inhibitor therapy (either omeprazole, lansoprazole, or rabeprazole) can be effective. Evidence for the use of antidepressants and the adenosine receptor antagonist theophylline is fair. Psychological treatments, notably cognitive behavioral therapy, may be useful in select patients. Surgery is not recommended. There remains a large unmet need for identifying the phenotype and prevalence of pathophysiologic mechanisms of ECP as well as for well-designed multicenter clinical trials of current and novel therapies.
The bearing down maneuver was assessed in a subset of 18 subjects. We compared data analyzed by an expert with findings from automated software analysis. Measurements made in a subset of 16 subjects, 2 weeks apart, were compared to determine reproducibility.
Resting, squeezing, and sustained squeezing pressures were significantly higher in men than in women (P < .05); other parameters were similar. Desire and urgency to defecate were similar between men and women, but the maximal tolerable volume was significantly lower in women (P < .05). Older women (>50 years) had significantly lower resting (P < .01) and sustained squeeze pressures (P < .04). Dyssynergic patterns of defecation were observed in 12 of 18 subjects (67%) who attempted to defecate without the 60-mL rectal balloon distention and in 6 of 18 subjects (33%) with the 60-mL rectal balloon distention. Test-retest values correlated (r = 0.81), as did analyses made by an expert vs software analyses of data (r = 0.99).
On the basis of HDAM-3D measurements in healthy adults, anal sphincter pressures are higher in men than in women, but sensory and other parameters are similar; older subjects have weaker sphincters. Many people were found to have dyssynergic patterns of defecation, which could be related to the probe or other technical issues, so this technique may not be suitable for assessing defecation patterns. Measurements made by HDAM-3D are reproducible, and data can be accurately analyzed by its software.
Two recent studies showed that 26 % (24/94) and 25.3 % (38/150) of a series of patients with unexplained GI symptoms had SIFO. The most common symptoms observed in these patients were belching, bloating, indigestion, nausea, diarrhea, and gas. The underlying mechanism(s) that predisposes to SIFO is unclear but small intestinal dysmotility and use of proton pump inhibitors has been implicated. However, further studies are needed; both to confirm these observations and to examine the clinical relevance of fungal overgrowth, both in healthy subjects and in patients with otherwise unexplained GI symptoms. Importantly, whether eradication or its treatment leads to resolution of symptoms remains unclear; at present, a 2-3-week course of antifungal therapy is recommended and may be effective in improving symptoms, but evidence for eradication is lacking.
Electrical stimulation of the anal mucosa is ineffective, but continuous electrical pulsing of sacral nerves produces a ≥50% reduction in FI frequency in a median 73% of patients. Tibial nerve electrical stimulation with needle electrodes is promising but remains unproven. Sphincteroplasty produces short-term clinical improvement in a median 67%, but 5-year outcomes are poor. Injecting an inert bulking agent around the anal canal led to ≥50% reductions of FI in up to 53% of patients. Colostomy is used as a last resort because of adverse effects on quality of life. Several new devices are under investigation but not yet approved. FI researchers identify the following priorities for future research: (1) trials comparing the effectiveness, safety, and cost of current therapies; (2) studies addressing barriers to consulting for care; and (3) translational research on regenerative medicine. Unmet patient needs include FI in special populations (e.g., neurological disorders and nursing home residents) and improvements in behavioral treatments.
Rough estimates suggest that FI is associated with a substantial economic burden, particularly in patients who require surgical therapy. Bowel disturbances, particularly diarrhea, the symptom of rectal urgency, and burden of chronic illness are the strongest independent risk factors for FI in the community. Smoking, obesity, and inappropriate cholecystectomy are emerging, potentially modifiable risk factors. Other risk factors for FI include advanced age, female gender, disease burden (comorbidity count, diabetes), anal sphincter trauma (obstetrical injury, prior surgery), and decreased physical activity. Neurological disorders, inflammatory bowel disease, and pelvic floor anatomical disturbances (rectal prolapse) are also associated with FI. The pathophysiological mechanisms responsible for FI include diarrhea, anal and pelvic floor weakness, reduced rectal compliance, and reduced or increased rectal sensation; many patients have multifaceted anorectal dysfunctions. The type (urge, passive or combined), etiology (anorectal disturbance, bowel symptoms, or both), and severity of FI provide the basis for classifying FI; these domains can be integrated to comprehensively characterize the symptom. Several validated scales for classifying symptom severity and its impact on the quality of life are available. Symptom severity scales should incorporate the frequency, volume, consistency, and nature (urge or passive) of stool leakage. Despite the basic understanding of FI, there are still major knowledge gaps in disease epidemiology and pathogenesis, necessitating future clinical research in FI.
The search was extended to unpublished trials on ClinicalTrials.gov and relevant publications cited in included articles. Conservative approaches, including dietary modifications, medications, muscle-strengthening exercises, and biofeedback, have been shown to provide short-term benefits. Transcutaneous electrical stimulation was considered ineffective in a randomized clinical trial. Unlike initial studies, sacral nerve stimulation has shown reasonable short-term effectiveness and some complications. Dynamic graciloplasty and artificial sphincter and bowel devices lack randomized controlled trials and have shown inconsistent results and high rates of explantation. Of injectable bulking agents, dextranomer microspheres in non-animal stabilized hyaluronic acid (NASHA Dx) has shown significant improvement in incontinence scores and frequency of incontinence episodes, with generally mild adverse effects. For the treatment of FI, conservative measures and biofeedback therapy are modestly effective. When conservative therapies are ineffective, invasive procedures, including sacral nerve stimulation, may be considered, but they are associated with complications and lack randomized, controlled trials. Bulking agents may be an appropriate alternative therapy to consider before more aggressive therapies in patients who fail conservative therapies.
Recently, colonic manometry with sensory/tone/compliance assessment with a barostat study has been shown to be useful. Technical challenges aside, adequate preparation, and appropriate equipment and knowledge of co-lonic physiology are keys for a successful procedure. The test itself appears to be safe with little complications. Currently, colon-ic manometry is usually performed with a 6-8 solid state or water-perfused sensor probe, although high-resolution fiber-optic colonic manometry with better spatiotemporal resolutions may become available in the near future. For a test that has evolved over 3 decades, normal physiology and abnormal findings for common phenotypes of chronic constipation, especially slow transit constipation, have been well characterized only recently largely through the advent of prolonged 24-hour ambulatory colonic manometry studies. Even though the test has been largely restricted to specialized laboratories at the moment, emerg-ing new technologies and indications may facilitate its wider use in the near future.(J Neurogastroenterol Motil 2014;20:547-552).
Clinical trials demonstrate the efficacy of linaclotide, and a platform to better understand the symptomatology of IBS-C. Based on recent clinical evidence, linaclotide should be considered for patients with IBS-C because it improves abdominal pain and bowel symptoms. In phase III trials, linaclotide met the US Food and Drug Administration responder endpoint with a number needed to treat (NNT) of 5.1-7.9, and European Medicines Agency coprimary endpoints at 12 weeks with a NNT of 4.39-7.69, and at 26 weeks with a NNT of 4.93-5.68. It is safe and effective, with diarrhea reported as the most common adverse effect, which leads to discontinuation of the medication in approximately 5% of patients.
However, treatment remains a challenge. Here we examined the efficacy and safety of various commonly used modalities for treatment of esophageal (noncardiac) chest pain (ECP) and provided evidence-based recommendations.
We reviewed the English language literature for drug trials evaluating treatment of ECP in PubMed, Cochrane, and MEDLINE databases from 1968-2012. Standard forms were used to abstract data regarding study design, duration, outcome measures and adverse events, and study quality.
Thirty-five studies comprising various treatments were included and grouped under 5 broad categories. Patient inclusion criteria were extremely variable, and studies were generally small with methodological concerns. There was good evidence to support the use of omeprazole and fair evidence for lansoprazole, rabeprazole, theophylline, sertraline, trazodone, venlafaxine, imipramine, and cognitive behavioral therapy. There was poor evidence for nifedipine, diltiazem, paroxetine, biofeedback therapy, ranitidine, nitrates, botulinum toxin, esophageal myotomy, and hypnotherapy.
Ideally, treatment of ECP should be aimed at correcting the underlying mechanism(s) and relieving symptoms. Proton pump inhibitors, antidepressants, theophylline, and cognitive behavioral therapy appear to be useful for the treatment of ECP. However, there is urgent and unmet need for effective treatments and for rigorous, randomized controlled trials.
The study took place in 2 tertiary care centers.
Subjects included adults with fecal incontinence and healthy subjects.
Translumbar and transsacral magnetic stimulations were performed bilaterally by applying a magnetic coil to the lumbar and sacral regions in 50 subjects with fecal incontinence (1 or more episodes per week) and 20 healthy subjects. Both motor-evoked potentials and pudendal nerve terminal motor latency were assessed in 30 subjects with fecal incontinence. Stimulation-induced, motor-evoked potentials were recorded simultaneously from the rectum and anus with 2 pairs of bipolar ring electrodes.
Latency and amplitude of motor-evoked potentials after lumbosacral magnetic stimulation and agreement with pudendal nerve terminal motor latency were measured.
When compared with control subjects, 1 or more lumbo-anal, lumbo-rectal, sacro-anal, or sacro-rectal motor-evoked potentials were significantly prolonged (p < 0.01) and were abnormal in 44 (88%) of 50 subjects with fecal incontinence. Positive agreement between abnormal motor-evoked potentials and pudendal nerve terminal motor latency was 63%, whereas negative agreement was 13%. Motor-evoked potentials were abnormal in more (p < 0.05) subjects with fecal incontinence than pudendal nerve terminal motor latency, in 26 (87%) of 30 versus 19 (63%) of 30, and in 24% of subjects with normal pudendal nerve terminal motor latency. There were no adverse events.
Anal EMG was not performed.
Translumbar and transsacral magnetic stimulation-induced, motor-evoked potentials provide objective evidence for rectal or anal neuropathy in subjects with fecal incontinence and could be useful. The test was superior to pudendal nerve terminal motor latency and appears to be safe and well tolerated.
In two phase 3 trials, patients who met modified Rome II criteria for IBS-C were randomly assigned to groups given oral, once-daily linaclotide (290 μg) or placebo for 12 weeks. During the baseline (2 weeks prior to treatment) and treatment periods, patients rated abdominal pain, discomfort, bloating, fullness, and cramping daily (from 0 = none to 10 = very severe). Linaclotide's effects on abdominal symptoms, global measures, and IBS-related QOL were assessed in subpopulations of patients who rated specific individual abdominal symptoms as severe (≥ 7.0) at baseline.
In the intent-to-treat population (1602 patients; 797 receiving placebo and 805 receiving linaclotide), baseline prevalence values for severe abdominal symptoms were 44% for bloating, 44% for fullness, 32% for discomfort, 23% for pain, and 22% for cramping, with considerable overlap among symptoms. In patients with severe symptoms, linaclotide reduced all abdominal symptoms; mean changes from baseline severity scores ranged from -2.7 to -3.4 for linaclotide vs -1.4 to -1.9 for placebo (P < .0001). Linaclotide improved global measures (P < .0001) and IBS-QOL scores (P < .01) compared with placebo. Diarrhea was the most common adverse event of linaclotide in patients with severe abdominal symptoms (18.8%-21.0%).
Of 5 severe abdominal symptoms assessed, bloating and fullness were most prevalent in patients with IBS-C. Linaclotide significantly improved all abdominal symptoms, global measures, and IBS-QOL in subpopulations of IBS-C patients with severe abdominal symptoms. Clinicaltrials.gov
Clinical manifestations of IBS such as pain, altered gut motility, and psychological dysfunction may each be explained, in part, through the changes in the BGA, but there is conflicting information, and its precise role is not fully understood. A better understanding of the BGA may shed more knowledge regarding the pathophysiology of IBS that in turn may lead to the discovery of novel therapies for this common disorder.
The capsule has 3 sensors for measurement of pH, pressure and temperature, and collec-tively the information provided by these sensors is used to measure gastric emptying time, small bowel transit time, colonic transit time and whole gut transit time. Current approved indications for the test include the evaluation of gastric emptying in gastroparesis, colonic transit in constipation and evaluation of generalised dysmotility. Rare capsule retention and malfunc-tion are known limitations and some patients may experience difficulty with swallowing the capsule. The use of WMC has been validated for the assessment of gastrointestinal transit. The normal range for transit time includes the following: gastric empty-ing (2-5 hours), small bowel transit (2-6 hours), colonic transit (10-59 hours) and whole gut transit (10-73 hours). Besides avoiding the use of multiple endoscopic, radiologic and functional gastrointestinal tests, WMC can provide new diagnoses, leads to a change in management decision and help to direct further focused work-ups in patients with suspected disordered motility. In conclusion, WMC represents a significant advance in the assessment of segmental and whole gut transit and mo-tility, and could prove to be an indispensable diagnostic tool for gastrointestinal physicians worldwide.
supine) on LES function, and (b) to determine the diagnostic yield of HREPT and endoscopy for detection of hiatal hernia.
A total of 50 subjects underwent both HREPT and endoscopy. The manometric/topographic changes of LES were examined in both supine and standing positions. Endoscopy assessed presence and length of hiatal hernia. Diagnostic agreement was compared between HREPT and endoscopy.
The resting LES pressure was higher (P=0.0001), its mean length was longer (P=0.0003), and length of high-pressure zone was longer (P=0.0001) in the standing position compared with the supine position. HREPT detected twice as many subjects with hiatal hernia in standing (P=0.0001) compared with supine position or endoscopy with significant new diagnostic information (79%). Endoscopy detection rate (34%) was similar to supine manometry with good diagnostic agreement (77%) between HREPT and endoscopy. Hiatal hernia length was longer (P=0.0001) with HREPT in standing position compared with endoscopy.
Body position significantly affects in the LES function and its measurements. HREPT when performed on standing position offers the best yield for detection of hiatal hernia and is superior to endoscopy or supine manometry.
A clear understanding and working knowledge of the functional anatomy and pathophysiology will enable appropriate diagnosis and treatment of these disorders.
Newer diagnostic tools (eg, high-resolution manometry and magnetic resonance defecography) provide a refined understanding of anorectal dysfunctions and identify phenotypes in defecatory disorders and fecal incontinence. Conservative approaches, including biofeedback therapy, are the mainstay for managing these disorders; new minimally invasive approaches may benefit a subset of patients with fecal incontinence, but more controlled studies are needed. This mini-review highlights advances, current concepts, and controversies in the area.
Here, we have examined the most up-to-date research on these food-related intolerances, discussed controversies, and have provided some guidelines for the dietary management of these conditions. Breath testing for carbohydrate intolerance appears to be standardized and essential for the diagnosis and management of these conditions, especially in the Western population. While current research shows that the FODMAP diet may be effective in treating some patients with irritable bowel syndrome, additional research is needed to identify more foods items that are high in FODMAPs, and to assess the long-term efficacy and safety of dietary interventions.
Unlike the traditional manometry that utilized 3 or 6 unidirectional sensors, the closely spaced circumferential arrangement facilitates superior spatiotemporal mapping of pressures at rest and during various dynamic maneuvers. HDAM can provide knowledge of the three muscles that govern the anal continence namely, the puborectalis, and the internal and external anal sphincters, and can show how they mediate the rectoanal inhibitory reflex and sensorimotor responses and the spatiotemporal orientation of these muscles. Also, anal sphincter defects can be mapped and readily detected using 3-D technology. Similarly, HRAM has facilitated confirmation and development of phenotypes of dyssynergic defecation. Recently, normative data have also been reported with HRAM and HDAM, together with the influence of age, gender, and test instructions. The greater yield of anatomical and functional information may supersede the limitations of costs, fragility, and shorter life-span associated with these new techniques. Thus, HDAM and HRAM are not just new gadgets but constitute a significant and novel diagnostic advance. However, more prospective studies are needed to better define anorectal disorders with these techniques and to confirm their superiority.
Randomized clinical trials have established that biofeedback therapy is effective in treating DD. Because DD may coexist with conditions such as solitary rectal ulcer syndrome (SRUS) and rectocele, before considering surgery, biofeedback therapy should be tried and an accurate assessment of the entire pelvis and its function should be performed. Several surgical approaches have been advocated for the treatment of pelvic floor disorders including open, laparoscopic, and transabdominal approach, stapled transanal rectal resection, and robotic colon and rectal resections. However, there is lack of well-controlled randomized studies and the efficacy of these surgical procedures remains to be established.
Common side effects of lubiprostone include nausea, diarrhea, abdominal pain and bloating, and the rare side effect dyspnea. Likely mechanisms for these side effects may be related to lubiprostone's primary action on small bowel secretion and the associated intestinal distension, as well as smooth muscle contraction.
This article reviews the pharmacokinetic and safety profile of lubiprostone, with particular relevance to the two FDA-approved dosages.
Lubiprostone acts topically in the gut lumen and is almost completely metabolized in the gut lumen. Lubiprostone's M3 metabolite can be detected in low concentrations in the serum and may be responsible for some of its side effects. However, the exact mechanisms by which the side effects are produced are currently unknown.
Patients with symptoms of dysmotility and normal endoscopic/radiologic evaluations were assessed with WMC test and conventional motility tests (CMT). Diagnostic utility of WMC was assessed retrospectively by examining device agreement and new information compared with CMT.
On the basis of predominant symptom(s), 86 patients were classified into 2 subgroups: lower GI (LGI=50) and upper GI (UGI=36). Clinical suspicion was confirmed in 52% and 66% of patients, respectively, and there was good device agreement between WMC and CMT in 76% and 81% in the LGI and UGI groups, respectively. There was new diagnostic information with the WMC test in 53% of the LGI (P=0.006) and 47% of the UGI group (P=0.001). WMC detected generalized motility disorder in 44 (51%) patients and influenced management in 30% of LGI and 50% of UGI subjects.
WMC confirmed clinical suspicion, provided new diagnostic information, influenced clinical management, and detected many patients with generalized motility disorder. It had good device agreement with conventional tests.
In these studies, 1260 patients (females 76.1 and 72.1%, respectively) who had IBS without constipation were randomized to receive either rifaximin 550 mg or placebo, three-times daily for 2 weeks. Subsequently, daily symptoms were assessed and patients were followed up for 10 weeks. The primary outcome measure - adequate relief of global IBS symptoms during the first 4 weeks after treatment - was met in significantly more patients who received rifaximin than placebo (p < 0.001). In addition, more patients in the rifaximin group than in the placebo group (p < 0.001) reported an adequate relief of bloating, and an improvement in abdominal pain and stool consistency - secondary outcome measures. The incidence of adverse events with rifaximin was similar to placebo, and the drug was well tolerated. In summary, a 2-week course of rifaximin provided significant relief of IBS symptoms, as well as bloating and abdominal pain.
Lubiprostone (Amitiza) has been approved by the US Food and Drug Administration (FDA) for the treatment of chronic-idiopathic constipation . It is an oral bicyclic fatty acid that selectively activates type 2 chloride channels in the apical membrane of the intestinal epithelial cells, hence stimulating chloride secretion, along with passive secretion of sodium and water, inducing peristalsis and laxation, without stimulating gastrointestinal smooth muscle. Several trials have shown it to be effective in the treatment of chronic idiopathic constipation, and recently also IBS-C. It has little systemic absorption and almost free of any serious adverse effects, however, occasionally can cause nausea. Based on the available evidence, it is reasonable to conclude that lubiprostone should be added to the short list of evidence-based pharmacotherapies for chronic constipation and IBS-C. Given the overlap between chronic constipation and IBS-C, clinicians can consider two strategies when deciding on the initial dose of lubiprostone. Based on current product labeling, it is recommended that 8 μg bid be started in patients with IBS-C whereas 24 μg bid be used in those with chronic constipation. Thus far, lubiprostone offers a novel approach to our therapeutic armamentarium, however, there is a need for more drugs with different mechanisms of action, in order to treat constipation that is often multifunctional.
Translumbar and transsacral magnetic stimulations, anorectal manometry, and pudendal nerve terminal motor latency (PNTML) were performed in 39 subjects with SCI and anorectal problems and in 14 healthy controls, and data were compared. MEPs were recorded with an anorectal probe containing bipolar ring electrodes.
The MEPs were significantly prolonged (P<0.05) bilaterally, and at lumbar and sacral levels, as well as at rectal and anal sites in SCI subjects compared with controls. A total of 95% of SCI subjects had abnormal MEPs and 53% had abnormal PNTML. All subjects with abnormal PNTML also demonstrated abnormal MEP, but 16/17 subjects with normal PNTML had abnormal MEP. Overall, SCI patients had weaker anal sphincters (P<0.05), higher prevalence of dyssynergia (85%), and altered rectal sensation (82%).
Translumbar and transsacral MEPs revealed significant and hitherto undetected lumbosacral neuropathy in 90% of SCI subjects. Test was safe and provided neuropathophysiological information that could explain bowel dysfunction in SCI subjects.
Anorectal 3-D pressure topography was performed in 10 healthy subjects during graded rectal balloon distention using a novel high-definition manometry system consisting of a probe with 256 pressure sensors arranged circumferentially. The anal pressure changes before, during, and after the onset of SMR were measured at every millimeter along the length of anal canal and in 3-D by dividing the anal canal into 4 × 2.1-mm grids. Pressures were assessed in the longitudinal and anterior-posterior axis. Anal ultrasound was performed to assess puborectalis morphology. 3-D topography demonstrated that rectal distention produced an SMR coinciding with desire to defecate and predominantly induced by contraction of puborectalis. Anal ultrasound showed that the puborectalis was located at mean distance of 3.5 cm from anal verge, which corresponded with peak pressure difference between the anterior and posterior vectors observed at 3.4 cm with 3-D topography (r = 0.77). The highest absolute and percentage increases in pressure during SMR were seen in the superior-posterior portion of anal canal, reaffirming the role of puborectalis. The SMR anal pressure profile showed a peak pressure at 1.6 cm from anal verge in the anterior and posterior vectors and distinct increase in pressure only posteriorly at 3.2 cm corresponding to puborectalis. We concluded that SMR is primarily induced by the activation and contraction of the puborectalis muscle in response to a sensation of a desire to defecate.
Several innovative manometric, neurophysiologic, and radiologic techniques have been discovered, which have improved the accuracy of identifying the neuromuscular mechanisms of chronic constipation. These include use of digital rectal examination, Bristol stool scale, colonic scintigraphy, wireless motility capsule for assessment of colonic and whole gut transit, high resolution anorectal manometry, and colonic manometry. These tests provide a better definition of the underlying mechanism(s), which in turn can lead to improved management of this condition. In this review, we summarize the recent advances in diagnostic testing with a particular emphasis on when and why to test, and discuss the utility of diagnostic tests for chronic constipation.
Several randomised controlled trails have demonstrated that biofeedback therapy using neuromuscular training and visual and verbal feedback is not only efficacious but superior to other modalities such as laxative or sham training. Also the symptom improvement is due a change in the underlying pathophysiology. Development of user friendly approaches to biofeedback therapy and use of home biofeedback programs will significantly enhance the adoption of this treatment by gastroenterologists and colorectal surgeons in the future. Improved reimbursement for this proven and relatively inexpensive treatment will carry a significant impact on the problem.
Successful management of these patients depends on identifying and treating underlying cause(s), such as infection, dietary factors, medication, or immobility-induced incontinence, constipation, or fecal impaction. For a hospitalized patient, a digital rectal examination should be performed to rule out fecal impaction and overflow incontinence. If there is no impaction but a weak anal sphincter, stool softeners or laxatives should be discontinued, as they cause diarrhea/fecal incontinence. In a patient with diarrhea/incontinence and suspected infection, management includes checking stool for Clostridium difficile toxin, E0157, ova and parasites, and culture. If the patient is on enteral nutrition, osmotic diarrhea-induced incontinence should be considered. Nursing care includes use of absorbent pads, special undergarments, anal hygiene, and skin care. Medications such as loperamide or diphenoxylate/atropine are useful for diarrhea with incontinence. Laxatives (eg, polyethylene glycol, lactulose), secretagogues (eg, lubiprostone), enemas, suppositories, and timed toileting assistance may be effective for constipation. Despite appropriate management, older hospitalized patients may remain incontinent because of dementia, immobility, or comorbid issues. Treatment should be tailored to the underlying mechanism(s) and needs of each patient.
Also, significant new knowledge has emerged over the past decade that includes the development of newer diagnostic tools such as high-resolution manometry and magnetic resonance defecography as well as a better delineation of the clinical and pathophysiologic subtypes of constipation and incontinence. This article provides an up-to-date review on the role of diagnostic tests in the evaluation of fecal incontinence and constipation with dyssynergic defecation.
Consecutive patients with chronic constipation (Rome III criteria, n = 209) underwent DREs, anorectal manometry analyses, balloon expulsion tests, and colonic transit studies. In the DRE, dyssynergia was identified by 2 or more of the following features: impaired perineal descent, paradoxic anal contraction, or impaired push effort; diagnostic yields were compared with physiological test results.
Of the patients included in the study, 187 (87%) had dyssynergic defecation, based on standard criteria; 134 (73%) of these were identified to have features of dyssynergia, based on DREs. The sensitivity and specificity of DRE for identifying dyssynergia in patients with chronic constipation were 75% and 87%, respectively; the positive predictive value was 97%. DRE was able to identify normal resting and normal squeeze pressure in 86% and 82% of dyssynergic patients, respectively.
DRE appears to be a reliable tool for identifying dyssynergia in patients with chronic constipation and detecting normal, but not abnormal, sphincter tone. DREs could facilitate the selection of appropriate patients for further physiologic testing and treatment.
Thirty healthy volunteers underwent 24-hour ambulatory colonic manometry with colonoscopic-assisted probe placement, and fluoroscopic confirmation of the location of most proximal sensor at hepatic flexure. Participants were randomized to 2 groups; in 14 participants (m/f=8/6), the probe was anchored to the colonic mucosa using mucosal clips and in 16 participants, (m/f=9/7), the probe was left unattached in the colon. Magnitude of transducer displacement was assessed by fluoroscopic localization. The difference between the number of transducers in each segment at the beginning (x) and at the end (y) of each study was summed up and divided by 2, to calculate the "displacement score" and this was taken as the main outcome measure.
In participants without clipping, the mean (s.d.) displacement score was 1.6 (0.9), implying displacement of transducers by 1.6 colonic segments relative to their initial location. In contrast, there was no displacement of transducers in those who received clipping. Clipping caused no adverse events.
Endoscopic mucosal clipping is safe and effective for prevention of probe displacement, and ensures more accurate temporospatial resolution of data for prolonged colonic manometry recording.
Colonic manometry with sensation and tone assessment (barostat) and anorectal manometry with rectal sensation and compliance assessment and balloon expulsion test can provide a comprehensive evaluation of colonic and anorectal sensorimotor function and facilitate a diagnosis of slow transit constipation, dyssynergic defecation or irritable bowel syndrome, or an overlap of these disorders. This review provides a critical appraisal of the role of manometric techniques toward augmenting our understanding of colonic and anorectal physiology, both in health and constipation and discussing their clinical utility in the diagnosis and management of chronic constipation.
This article focuses on the pharmacology of traditional and newer agents for the treatment of constipation.
One hundred twelve NH residents.
Intervention subjects were offered toileting assistance, exercise, and choice of food and fluid snacks every 2 hours for 8 hours per day over 3 months.
Frequency of UI and FI and rate of appropriate toileting as determined by direct checks from research staff. Anorectal assessments were completed on a subset of 29 residents.
The intervention significantly increased physical activity, frequency of toileting, and food and fluid intake. UI improved (P=.049), as did frequency of bowel movements (P<.001) and percentage of bowel movements (P<.001) in the toilet. The frequency of FI did not change. Eighty-nine percent of subjects who underwent anorectal testing showed a dyssynergic voiding pattern, which could explain the lack of efficacy of this intervention program alone on FI.
This multicomponent intervention significantly changed multiple risk factors associated with FI and increased bowel movements without decreasing FI. The dyssynergic voiding pattern and rectal hyposensitivity suggest that future interventions may have to be supplemented with bulking agents (fiber), biofeedback therapy, or both to improve bowel function.
Likewise, blood tests and colonoscopy may identify organic causes such as colon cancer. Physiological tests such as colonic transit study with radio-opaque markers or wireless motility capsule, anorectal manometry, and balloon expulsion tests can identify disorders of colonic and anorectal function. However, in the elderly, there is usually more than one mechanism, requiring an individualized but multifactorial treatment approach. The management of constipation continues to evolve. Although osmotic laxatives such as polyethylene glycol remain mainstay, several new agents that target different mechanisms appear promising such as chloride-channel activator (lubiprostone), guanylate cyclase agonist (linaclotide), 5HT(4) agonist (prucalopride), and peripherally acting mu-opioid receptor antagonists (alvimopan and methylnaltrexone) for opioid-induced constipation. Biofeedback therapy is efficacious for treating dyssynergic defecation and fecal impaction with soiling. However, data on efficacy and safety of drugs in elderly are limited and urgently needed.
Thresholds for first sensation, desire, and urgency to defecate were assessed. The lowest balloon volume that evoked rectoanal inhibitory reflex, rectoanal contractile reflex, and sensorimotor response and manometric characteristics and rectal compliance were examined.
Reflex responses were present in all subjects. The balloon volumes were higher in subjects with rectal hyposensitivity for inducing rectoanal inhibitory reflex (P = .008) and contractile reflex (P = .001) compared with controls. All controls showed a sensorimotor response, but in 13 hyposensitive subjects (43%) the onset of sensorimotor response was associated with absent sensation and in 17 (57%), with a transient rectal sensation. Thresholds for eliciting sensorimotor response were similar between patients and controls, but the amplitude, duration, and magnitude of response were higher (P < .05) in patients. Rectal compliance was similar between controls and hyposensitive subjects with transient sensation but higher (P = .001) in subjects with absent sensation.
Constipated subjects with rectal hyposensitivity demonstrate higher thresholds for inducing rectoanal reflexes and abnormal characteristics of sensorimotor response. These findings suggest either disruption of afferent gut-brain pathways or rectal wall dysfunction. These altered features may play a role in the pathogenesis of bowel dysfunction in rectal hyposensitivity.
Whether methanogenic flora alters colonic transit or stool characteristics and its relationship to constipation is unclear. The aim of this study was to examine the prevalence and association of methanogenic flora in patients with slow transit (ST) constipation and normal transit (NT) constipation and non-constipated controls.
Ninety-six consecutive subjects with chronic constipation (CC) (Rome III) were evaluated with radio-opaque marker (ROM) transit studies and were classified as ST (>20% ROM retention) or NT. All constipated subjects and 106 non-constipated controls underwent breath tests to assess methane production. Baseline CH4 of >or=3 p.p.m. was used to define presence of methanogenic flora. Stool frequency and consistency were assessed using a prospective stool diary. Correlation analyses were performed.
Forty-eight subjects had ST and 48 had NT. Prevalence of methanogenic flora was higher (P<0.05) in ST (75%) compared to NT (44%) or controls (28%). ST patients had higher methane production compared to NT and controls (P<0.05). NT patients also produced more methane compared to controls (P<0.05). There was moderate(P<0.05) correlation among baseline, peak, and area under the curve (AUC) of methane response with colonic transit but not with stool characteristics.
Presence of methanogenic flora is associated with CC. Methane production after carbohydrate challenge and its prevalence were higher in ST than NT, although stool characteristics were similar in both groups. Methane production correlated with colonic transit, suggesting an association with stool transport but not with stool characteristics.
All subjects were seen at 3-month intervals and received reinforcement. Primary outcome measure (intention-to-treat analysis) was a change in the number of complete spontaneous bowel movements (CSBMs) per week. Secondary outcome measures included bowel symptoms, changes in dyssynergia, and anorectal function.
Of 44 eligible patients with dyssynergic defecation, 26 agreed to participate in the long-term study. All 13 subjects who received biofeedback, and 7 of 13 who received standard therapy, completed 1 year; 6 failed standard therapy. The number of CSBMs per week increased significantly (P<0.001) in the biofeedback group but not in the standard group. Dyssynergia pattern normalized (P<0.001), balloon expulsion time improved (P=0.0009), defecation index increased (P<0.001), and colonic transit time normalized (P=0.01) only in the biofeedback group.
Biofeedback therapy provided sustained improvement of bowel symptoms and anorectal function in constipated subjects with dyssynergic defecation, whereas standard therapy was largely ineffective.
Stool form and frequency were correlated with transit times using Spearman's rank correlation. Accuracy of stool form in predicting delayed transit was assessed by receiver operating characteristic analysis.
In the constipated adults (42 females, 4 males), moderate correlations were found between stool form and whole-gut transit measured by WMC (r=-0.61, P<0.0001) or ROM (-0.45, P=0.0016), as well as colonic transit measured by WMC (-0.62, P<0.0001). A Bristol stool form value <3 predicted delayed whole-gut transit with a sensitivity of 85% and specificity of 82% and delayed colonic transit with a sensitivity of 82% and specificity of 83%. No correlation between stool form and measured transit was found in healthy adults, regardless of gender. No correlation was found between stool frequency and measured transit in constipated or healthy adults. The correlation between stool frequency and measured transit remained poor in constipated adults with <3 bowel movements per week.
Stool form predicts delayed vs. normal transit in adults. However, only a moderate correlation exists between stool form and measured whole-gut or colonic transit time in constipated adults. In contrast, stool frequency is a poor surrogate for transit, even in those with reduced stool frequency.
The effects of 12 mg oral tegaserod were compared with 125 mg intravenous erythromycin by quantifying pressure wave activity and assessing motor patterns.
Motor activity increased (p<0.05) in antrum, duodenum and jejunum with both drugs when compared to baseline period. The motor response with tegaserod was higher (p<0.05) in jejunum and occurred during the second or third hours, whereas with erythromycin, it was higher (p<0.05) in antrum and occurred within 30 minutes. After tegaserod, a 'fed-response' like pattern was seen whereas after erythromycin, large amplitude (>100 mmHg) antral contractions at 3 cycles per minute were seen. Following tegaserod and erythromycin, phase III MMCs occurred in 12 (55%) and 8 (36%) patients respectively (p>0.05).
Both drugs increase upper gut motility and induce MMC's, but exert a differential response. Tegaserod produces a more sustained prokinetic effect in the duodenum/jejunum, whereas erythromycin predominantly increases antral motor activity.
Use of absorbent pads and special undergarments is useful. Anorectal physiologic testing of nursing home residents has revealed an association between constipation, stool retention, and fecal incontinence. Impaired sphincter function (risk factor for fecal incontinence), decreased rectal sensation, and sphincter dyssynergia (risk factor for constipation and impaction) are found in a high proportion of incontinent nursing home residents. Biofeedback and sacral nerve stimulation may be useful in refractory patients and should be considered before colostomy in community-dwelling adults. Despite appropriate management, nursing home residents may remain incontinent because of dementia and health or restraint related immobility.
Management consists of education and counseling regarding bowel function, diet, laxatives, and behavioral therapies. Recently, several randomized, clinical trials have shown that biofeedback therapy is effective in dyssynergic defecation. Dyssynergia may also coexist in structural disorders such as solitary rectal ulcer syndrome or rectocele. Hence, before proceeding with surgery, neuromuscular training or biofeedback should be considered. Several surgical approaches, including stapled transanal rectal resection, have been advocated, but well-controlled randomized studies are lacking and their efficacy is unproven.
Subjects wore a data receiver and kept daily stool diaries for 5 days. SmartPill recordings assessed CTT, whole-gut transit time (WGTT), small-bowel transit time, and gastric emptying time. Abdominal radiographs on days 2 and 5 assessed ROM transit. Sensitivity/specificity and receiver operating characteristics (ROCs) of each technique and utility were compared.
Gastric emptying time, CTT, and WGTT were slower (P < .01) in constipated subjects than controls. CTT was slower in women than men (P = .02). Day 2 and day 5 ROM transits were slower (P < .001) in constipated subjects. Correlation of the SmartPill CTT with ROMs expelled on day 2/day 5 was r = 0.74/r = 0.69 in constipation, and r = 0.70/r = 0.40 in controls, respectively. The diagnostic accuracy of the SmartPill CTT to predict constipation from ROC was 0.73, with a specificity of 0.95. These were comparable with those of day 5 ROM (ROC, 0.71; specificity, 0.95).
The SmartPill is a novel ambulatory technique of assessing regional (gastric, small bowel, colonic) and WGTT without radiation. It reveals hitherto unrecognized gender differences and upper-gut dysfunction in constipation. It correlates well with ROM and offers a standardized method of discriminating normal from slow colonic transit.
Today, an evidence-based approach can be used to treat patients with chronic constipation. The availability of specific drugs for the treatment of chronic constipation, such as tegaserod and lubiprostone, has enhanced the therapeutic armamentarium for managing these patients. Randomized controlled trials have also established the efficacy of biofeedback therapy in the treatment of dyssynergic defecation.
However, treatments for constipation vary in terms of their efficacy and safety. Furthermore, surveys of physicians and patients have revealed a strong desire for improved therapeutic options. Lubiprostone is a synthetic bicyclic fatty acid that is gut selective and stimulates type 2 chloride channels, resulting in increased chloride, sodium and water secretion into the lumen. The increased fluid secretion causes luminal distension, secondary peristalsis and laxation. Randomized Phase III trials have shown that lubiprostone is efficacious in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. The US FDA has approved lubiprostone at a dose of 24 microg twice daily for the treatment of chronic idiopathic constipation in adults, and at a dose of 8 microg twice daily for irritable bowel syndrome with constipation in adult women. Nausea, diarrhea and headaches are the most commonly reported side effects. In long-term studies, lubiprostone appears to be safe.
Development of user friendly approaches to biofeedback therapy and use of home biofeedback programs will significantly enhance the adoption of this treatment by gastroenterologists and colorectal surgeons.
These tests are mostly performed on patients referred to tertiary care centers, either following negative evaluations or when there is lack of response to conventional therapy. Judicious use of these tests can reveal significant and new understanding of the underlying mechanism(s) that could pave the way for better management of these disorders. In addition, these techniques are complementary to other modalities of investigation, such as pelvic floor imaging. The most commonly performed neurophysiological tests, along with their indications and clinical utility are discussed. Several novel techniques are evolving that may reveal new information on brain-gut interactions.
Patients with IBS (Rome II) and positive fructose breath test received instructions regarding fructose-restricted diet. One year later, their symptoms, compliance with, and effects of dietary modification on lifestyle were assessed using a structured interview.
Eighty patients (m/f=26/54) fulfilled Rome II criteria. Of 80 patients, 31 (38%) had positive breath test. Of 31 patients, 26 (84%) participated in follow-up (mean=13 mo) evaluation. Of 26 patients, 14 (53%) were compliant with diet; mean compliance=71%. In this group, pain, belching, bloating, fullness, indigestion, and diarrhea improved (P<0.02). Of 26 patients, 12 (46%) were noncompliant, and their symptoms were unchanged, except belching. The mean impact on lifestyle, compliant versus noncompliant groups was 2.93 versus 2.57 (P>0.05).
About one-third of patients with suspected IBS had fructose intolerance. When compliant, symptoms improved on fructose-restricted diet despite moderate impact on lifestyle; noncompliance was associated with persistent symptoms. Fructose intolerance is another jigsaw piece of the IBS puzzle that may respond to dietary modification.
Stool frequency, stool consistency (Bristol scale), number of incontinent episodes, satisfaction with bowel function (VAS), and anorectal physiology were assessed at 3 months and at 1 year after treatment. Data were compared with a matched group of 21 incontinent subjects (19 female, mean age 64 years) who received biofeedback alone (group B).
At 3 months and at 1 year, group A patients showed decreased stool frequency (p < 0.01), stool consistency (p = 0.001), and number of incontinent episodes (p < 0.04). In contrast, stool frequency (p = 0.8) and stool consistency (0.23) were not different from baseline in group B subjects. In both groups, there was improvement in the satisfaction with bowel function (p < 0.05), anal sphincter pressures (p < 0.05) and ability to retain saline infusion (p < 0.05). Mean dose of cholestyramine used was 3.6 g; 13 subjects (62%) required dose titration, and 7 (33%) subjects reported minor side effects.
Cholestyramine is safe and useful adjunct for the treatment of diarrhea and fecal incontinence. Most patients require small doses, and dose titration is important. The improvement in stool characteristics favors a drug effect, over and above the benefits of biofeedback therapy.
Constipation was defined using the Rome II criteria (presence of at least two of the following symptoms for at least one quarter of defecations: straining, lumpy or hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, manual maneuvers to facilitate defecation, and fewer than three defecations per week). Generalized linear logistic models explored factors associated with constipation during pregnancy.
One hundred three women were enrolled with mean (+/-standard deviation) age of 28 (+/-5) years; 54% were nulliparous and 92% white. Constipation prevalence rates were 24% (95% confidence interval [CI] 16-33%), 26% (95% CI 17-38%), 16% (95% CI 8-26%), and 24% (95% CI 13-36%) in the first, second, and third trimesters and 3 months postpartum, respectively. Additionally, irritable bowel syndrome (by Rome II criteria) prevalence rates were 19% (95% CI 12-28%), 13% (95% CI 6-23%), 13% (95% CI 6-23%) and 5% (95% CI 1-13%) in the first, second, and third trimesters and 3 months postpartum, respectively. In multivariable longitudinal analysis, iron supplements (OR 3.5, 95% CI 1.04-12.10) and past constipation treatment (OR 3.58, 95% CI 1.50-8.57) were associated with constipation during pregnancy.
Constipation measured using the Rome II criteria affects up to one fourth of women throughout pregnancy and at 3 months postpartum.
Stepwise graded rectal balloon distensions were performed in 23 healthy subjects by placing a six-sensor probe in the anorectum. Manometric changes, rectoanal reflexes, and sensory thresholds were assessed. Studies were repeated in six subjects.
All subjects showed rectoanal inhibitory and contractile reflexes, but rectal perception was associated with an anal contractile response (sensorimotor response). In 4 subjects (17 percent) the sensorimotor response first occurred synchronously with a sensation of fullness (Group 1) and in 19 (83 percent) with a desire to defecate (Group 2). Mean balloon volume for inducing the sensorimotor response in Groups 1 and 2 were 80 +/- 14 ml and 96 +/- 26 ml (P > 0.05). The onset, amplitude, duration, and area under curve of the response were similar in both groups. At higher volumes of balloon distention, all subjects (n = 23) reported a desire and an urge to defecate. The sensorimotor response associated with an urge to defecate had higher amplitude (P = 0.01) and higher area under curve (P = 0.001) compared with that associated with a desire to defecate. Repeat studies showed good reproducibility (intraclass correlation coefficient = 0.9; P < 0.05).
A desire to defecate is associated with a unique, consistent, and reproducible anal contractile response: the sensorimotor response. This response could play an integral role in regulating anorectal sensation and function.
Symptom scores for hostility and paranoid ideation were higher (P<.001) in patients with dyssynergic defecation than in patients with STC and control subjects. Scores for other psychological domains were higher (P<.0001) in patients with dyssynergic defecation and those with STC than in control subjects. Most QOL subscores were impaired (P<.05) in patients with dyssynergic defecation and some were impaired in patients with STC as compared with control subjects, but the two patient groups did not differ on these. The QOL subscores were strongly correlated (r(c) approximately .9) with the psychological subscores in patients with dyssynergic defecation and those with STC, although more QOL subscores among patients with dyssynergic defecation and more psychological subscores among patients with STC primarily contributed to the canonical correlations. A set of six commonly reported constipation symptoms showed significant correlations with QOL and psychological subscores, more so among patients with STC than among patients with dyssynergic defecation.
Patients with dyssynergic defecation had greater psychological distress and impaired health-related QOL as compared with patients with STC and control subjects. Both patient groups were also more affected as compared with the control group. There was a strong correlation between psychological dysfunction and impaired QOL, and both also correlated with constipation symptoms.
Today, an evidence-based approach can be used to treat patients with chronic constipation. The availability of specific drugs for the treatment of chronic constipation, such as tegaserod and lubiprostone, has enhanced the therapeutic armamentarium for managing these patients. Randomized controlled trials have also established the efficacy of biofeedback therapy in the treatment of dyssynergic defecation.
In a double-blind study, 20 healthy subjects received 10% solutions of 15, 25, and 50 g of fructose and 33% solution of 50-g fructose on 4 separate days at weekly intervals. Breath samples were assessed for hydrogen (H2) and methane (CH4) during a period of 5 hours, and symptoms were recorded.
No subject tested positive with 15 g. Two (10%) tested positive with 25 g fructose but were asymptomatic. Sixteen (80%) tested positive with 50 g (10% solution), and 11 (55%) had symptoms. Breath H2 was elevated in 13 (65%), CH4 in 1 (5%), and both in 2 (10%). Twelve (60%) tested positive with 50 g (33% solution), and 9 (45%) experienced symptoms. The area under the curve for H2 and CH4 was higher (P < .01) with 50 g compared with lower doses. There were no gender differences.
Healthy subjects have the capacity to absorb up to 25 g fructose, whereas many exhibit malabsorption and intolerance with 50 g fructose. Hence, we recommend 25 g as the dose for testing subjects with suspected fructose malabsorption. Breath samples measured for H2 and CH4 concentration at 30-minute intervals and for 3 hours will detect most subjects with fructose malabsorption.
The use of innovative manometric, neurophysiological and radiological techniques have shed new light on the underlying pathophysiology. Also, it has been recognised that psychological dysfunction play an important role. However, there is a lack of consensus regarding what is abnormal, regarding the overlap between phenotypes and regarding optimal diagnostic approaches or tests. There has been little advance in drug therapy for these conditions. Although several treatments have been tried and appear promising, controlled trials are either lacking or have provided insignificant evidence. There is a need for improved medical, behavioural and surgical treatments for these conditions.
Three subgroups of FI are recognized: a) passive incontinence: the involuntary discharge of stool or gas without awareness; b) urge incontinence: the discharge of fecal matter in spite of active attempts to retain bowel contents, and c) fecal seepage: the involuntary leakage of small volumes of stool after normal evacuation. Disruption of the normal structure or function of the anorectal unit leads to FI and is often due to multiple mechanisms. A detailed history and examination including digital rectal examination facilitates diagnosis. Anorectal physiological tests provide useful information regarding functional abnormalities and anal endosonography regarding sphincter defects. These tests provide insights regarding pathophysiology and can guide further management. Behavioral therapy is successful in most patients and should be offered first. Surgical treatment should be considered in cases who fail medical treatment or with sphincter defects. Several experimental approaches, including bulking of the anal sphincter, sacral nerve stimulation and the delivery of radiofrequency energy to the anal canal are under investigation.
Treatment involves several medical, behavioral, and surgical approaches. Recently, randomized controlled trials have shown that biofeedback therapy is an effective treatment for dyssynergic defecation. Stapled transanal rectal resection appears to be a promising technique for treating defecation disorders associated with rectocele, excessive perineal descent, and mucosal intussusception, but controlled trials are lacking.
In a double-blind study, sensory and biomechanical properties of the esophagus were assessed using impedance planimetry in 16 patients with esophageal hypersensitivity, after intravenous theophylline or placebo. In a second, randomized 4-wk crossover study, oral theophylline and placebo were administered to 24 patients with esophageal hypersensitivity. Frequency, intensity, and duration of chest pain episodes were evaluated.
After IV theophylline, chest pain thresholds (P=0.027) and esophageal cross-sectional area (P=0.03) increased and the esophageal wall became more distensible (P=0.04) compared with placebo. After oral theophylline, the number of painful days (P=0.03) and chest pain episodes (P=0.025), pain duration (P=0.002), and its severity (P=0.031) decreased. Overall symptoms improved in 58% on theophylline and 6% on placebo (P<0.02). There was no order effect.
Theophylline relaxed the esophageal wall, decreased hypersensitivity, and improved chest pain. Theophylline is effective in the treatment of functional chest pain.
We conducted a double-blind, randomized, placebo-controlled study of 22 volunteers. On the first postoperative day, patients began receiving intravenous erythromycin (125 mg) or placebo every 8 hours (maximum of 21 doses). The patients' ability to tolerate a general diet and return of bowel function was monitored.
A general diet was tolerated at a median of 9 days postoperatively for the EM arm and 8 for the placebo arm (P = 0.60). The first bowel sounds were detected at an average of 2 postoperative days for the EM arm and 3 for the placebo arm (P = 0.88). First flatus was present an average of 5 days postoperatively for both study arms (P = 0.35). The first bowel movement was present an average of 6 days postoperatively for the EM arm and 5 for the placebo arm (P = 0.98).
No significant difference was found between EM and placebo with regard to the onset of bowel sounds, passage of flatus, passage of the first bowel movement, and the time to tolerate a general diet. These data indicate that erythromycin is not useful in improving postoperative bowel function.
At baseline and after treatment (3 months), physiologic changes were assessed by anorectal manometry, balloon expulsion, and colonic transit study and symptomatic changes and stool characteristics by visual analog scale and prospective stool diary. Primary outcome measures (intention-to-treat analysis) included presence of dyssynergia, balloon expulsion time, number of complete spontaneous bowel movements, and global bowel satisfaction.
Subjects in the biofeedback group were more likely to correct dyssynergia (P < .0001), improve defecation index (P < .0001), and decrease balloon expulsion time (P = .02) than other groups. Colonic transit improved after biofeedback or standard (P = .01) but not after sham. In the biofeedback group, the number of complete spontaneous bowel movements increased (P < .02) and was higher (P < .05) than in other groups, and use of digital maneuvers decreased (P = .03). Global bowel satisfaction was higher (P = .04) in the biofeedback than sham group.
Biofeedback improves constipation and physiologic characteristics of bowel function in patients with dyssynergia. This effect is mediated by modifying physiologic behavior and colorectal function. Biofeedback is the preferred treatment for constipated patients with dyssynergia.
Subsequently, a modified Rome II functional bowel disorder questionnaire was mailed to these subjects. Prevalence of irritable bowel syndrome (IBS) and other functional disorder were determined using the Rome II criteria. In addition, we assessed the prevalence of chest pain in 81 patients with functional constipation.
There were 69 responders (54 women); 2 were excluded. Fifty-five patients (82%) fulfilled criteria for other functional disorders besides chest pain. Although there was an overlap, IBS (27%) and abdominal bloating (22%) were most common; dyspepsia (7%), dysphagia (7%), nonspecific bowel disorder (7%), constipation (4%), abdominal pain (3%), and diarrhea (1%) were less common. Among responders, 52 (78%) had esophageal hypersensitivity and 15 (22%) had normosensitivity, with similar prevalence of functional disorders. Thirty-two (39%) of the subjects with functional constipation reported chest pain occasionally, and 5 (6%) frequently.
Approximately 80% of patients with functional chest pain exhibit features of other functional disorders including IBS suggesting an overlap. This association is independent of esophageal hypersensitivity. Recognition of this overlap may facilitate better management of these patients.
All patients underwent standard laparoscopic NF. Eight GERD patients with persistent symptoms after surgery underwent repeat evaluations at least 12 months after surgery.
At baseline, GERD patients had lower thresholds for first perception (P < .001), discomfort (P < .001), and pain (P < .001) compared with controls. The esophagus was more reactive (P = .001) and less distensible (P = .04) in patients than controls. After NF, in patients with persistent symptoms, the sensory thresholds were unchanged (P > .05) but esophageal wall reactivity decreased (P = .001), and distensibility improved (P = .025).
NF improves esophageal biomechanical dysfunction but not the underlying hypersensitivity. Visceral hypersensitivity of the esophagus may explain persistent symptoms after NF.
Subjects also expelled a water-filled (50 cc) balloon or silicone-stool (FECOM) either lying or sitting and rated their stooling sensation.
When attempting to defecate in the lying position, a dyssynergic pattern was seen in 36% of subjects with empty rectum and 24% with distended rectum. When sitting, 20% showed dyssynergia with empty rectum and 8% with distended rectum. More subjects (p < 0.05) showed dyssynergia in lying position. When lying, 60% could not expel balloon and 44% FECOM. When sitting, fewer (p < 0.05) failed to expel balloon (16%) or FECOM (4%). FECOM expulsion time was quicker (p < 0.02). Stool-like sensation was more commonly (p < 0.005) evoked by FECOM than balloon.
In the lying position, one-third showed dyssynergia and one-half could not expel artificial stool. Whereas when sitting with distended rectum, most showed normal defecation pattern and ability to expel stool. Thus, body position, sensation of stooling and stool characteristics may each influence defecation. Defecation is best evaluated in the sitting position with artificial stool.
In this review, we summarize and highlight recent advances in the utility of diagnostic testing of chronic constipation.
These treatments include biofeedback therapy, tegaserod, and lubiprostone for chronic constipation.
Eleven patients (8f) with refractory SRUS underwent symptom assessments, anorectal manometry, defecography, balloon expulsion test, and sigmoidoscopy. Physiological tests were also performed in 15 (11f) healthy controls. Subsequently, SRUS patients underwent biofeedback treatment. Symptoms and manometry were reassessed.
Nine (82%) patients exhibited dyssynergia ( p < 0.001). Rectal sensory thresholds were decreased (p < 0.04). After biofeedback, straining effort and stool frequency decreased ( p < 0.05), and bowel satisfaction score (VAS) improved ( p < 0.001). Digital maneuvers were discontinued by all five patients and bleeding stopped in 56%. The defecation index increased ( p < 0.05), dyssynergia normalized, and balloon expulsion time decreased ( p < 0.05). There was complete healing in 4 (36%), > or =50% healing in 2 (18%), and <50% healing in 4 (36%) patients.
SRUS associated with excessive straining, digital disimpaction, rectal hypersensitivity, dyssynergic defecation, and prolonged evacuation. BT may improve symptoms and anorectal function and facilitate healing.
Study was repeated in six volunteers after intravenous atropine was given.
Fundic distention induced large amplitude antral contractions in all subjects. The area under the curve was higher (P<0.05) during fundic distention. First sensation was reported at 12+/-4 mmHg, moderate sensation at 18+/-4 mmHg and discomfort at 21+/-4 mmHg. Discomfort was associated with a decrease in antral motility. After atropine was given, the area under the curve of pressure waves and fundic tone decreased (P<0.05). Sensory thresholds were not affected.
Fundic balloon distention induces an antral motor response, the fundo-antral reflex, which in part may be mediated by cholinergic mechanisms.
We searched the English literature using MEDLINE and PUBMED databases from 1966 to 2004 for studies in adults published as full manuscripts whose methodological quality was above a minimum score.
No studies assessed the routine use of blood tests or abdominal x-ray. One retrospective endoscopic study showed that cancer and polyp detection rate was comparable to historical controls. Two studies of barium enema were unhelpful in diagnosis of constipation. Physiological studies showed differences in study population, methodology, and interpretation, and there was no gold standard. Ten colonic transit studies showed prevalence of 38-80% in support of slow transit constipation. Nine anorectal manometry studies showed prevalence of 20-75% for detecting dyssynergia. Nine studies of balloon expulsion showed impaired expulsion of 23-67%. Among 10 defecography studies, abnormalities were reported in 25-90% and dyssynergia in 13-37%.
Evidence to support the use of blood tests, radiography, or endoscopy in the routine work up of patients with constipation without alarm features is lacking. Colonic transit, anorectal manometry, and balloon expulsion tests reveal physiologic abnormalities in many selected patients with constipation, but no single test adequately defines pathophysiology. Large, well-designed, prospective studies are required to examine the utility of these tests.
We searched the English literature for drug trials evaluating treatment of constipation by using MEDLINE and PUBMED databases from 1966 to 2003. Only studies that were randomized, conducted on adult subjects, and published as full manuscripts were included. Studies were assigned a quality score based on published methodology. Standard forms were used to abstract data regarding study design, duration, outcome measures, and adverse events. By using the cumulative evidence of published data for each agent, recommendations were made regarding their use following the United States Preventive Services Task Force guidelines.
Good evidence (Grade A) was found to support the use of polyethylene glycol (PEG) and tegaserod. Moderate evidence (Grade B) was found to support the use of psyllium, and lactulose. There was a paucity of quality data regarding many commonly used agents including milk of magnesia, senna, bisacodyl, and stool softeners.
There is good evidence to support the use of PEG, tegaserod, lactulose, and psyllium. Surprisingly, there is a paucity of trials for many commonly used agents. These aspects should be considered when designing trials comparing new agents with traditional therapies because their use may not be well validated.
Whether visceral hypersensitivity is a central or peripheral perturbation of the gut-brain axis remains debatable. Response to empirical therapy with high-dose proton pump inhibitors, upper endoscopy, or prolonged recording of esophageal pH may identify gastroesophageal reflux disease as a source of chest pain. Esophageal balloon distension study can serve as a useful test for identifying hypersensitivity. Newer techniques, including functional magnetic resonance imaging, magnetoencephalogram, and cortical evoked potentials, are being investigated. High doses of proton pump inhibitors and low doses of tricyclic antidepressants or trazadone remain the mainstay of therapy, although several new approaches including theophylline have been shown to be beneficial.
Quantitative and qualitative manometric analysis was performed in 8-h epochs. Patients were followed up for 1 yr.
Constipated patients showed fewer pressure waves and lower area under the curve (p < 0.05) than controls during daytime, but not at night. Colonic motility induced by waking or meal was decreased (p < 0.05) in patients. High-amplitude propagating contractions (HAPCs) occurred in 43% of patients compared to 100% of controls and with lower incidence (1.7 vs 10.1, p < 0.001) and propagation velocity (p < 0.04). Manometric features suggestive of colonic neuropathy were seen in 10, myopathy in 5, and normal profiles in 4 patients. Seven patients with colonic neuropathy underwent colectomy with improvement. The rest were managed conservatively with 50% improvement at 1 yr.
Patients with slow-transit constipation exhibited either normal or decreased pressure activity with manometric features suggestive of colonic neuropathy or myopathy as evidenced by absent HAPC or attenuated colonic responses to meals and waking. In refractory patients, colonic manometry may be useful in characterizing the underlying pathophysiology and in guiding therapy.
Predisposing factors for fecal seepage were back injury (7), obstetric injury (6), hemorrhoidectomy (3), pelvic radiotherapy (1), and unknown (8). In the seepage group, the resting and squeeze sphincter pressures were lower (p < 0.02) than healthy controls, but higher (p < 0.002) than incontinent group. During straining, the intrarectal pressure and defecation index were lower (p < 0.05) in the seepage group compared to controls; 72% showed dyssynergia and balloon expulsion time was prolonged (p < 0.01). Threshold for first rectal sensation was impaired (p < 0.002) in the seepage group compared to controls and incontinent group. The seepage group retained more (p < 0.001) saline than the incontinent group but pudendal nerve latency time was impaired (p < 0.05) in both patient groups compared to controls.
Anal sphincter function and rectal reservoir capacity were relatively well preserved but most patients with seepage demonstrated dyssynergia with impaired rectal sensation and impaired balloon expulsion. Thus, incomplete evacuation of stool may play a significant role in the pathogenesis of seepage.
7% had no urge to defecate. Abdominal bloating was reported by 74%. More women than men reported infrequent bowel movements and need to strain excessively (P < 0.05). Forty eight percent of patients, more women (P < 0.05) than men used digital maneuvers to evacuate. Hard stools was reported by 60% of women and 41% of men. Sexual abuse was reported by 22%; 21% were women (P = 0.02). Physical abuse was reported by 32%. Bowel problem adversely affected family life in 33%, sexual life in 56%, work life in 69% and social life in 76% of patients. Most patients with dyssynergia reported an excessive need to strain, feeling of incomplete evacuation and abdominal bloating and one half used digital maneuvers. It significantly affected quality of life, particularly in women.
Disruption or weakness of the EAS can cause urge-related or diarrhea-associated fecal incontinence. Damage to the endovascular cushions may produce a poor anal "seal" and an impaired anorectal sampling reflex. The ability of the rectum to perceive the presence of stool leads to the rectoanal contractile reflex response, an essential mechanism for maintaining continence. Pudendal neuropathy can diminish rectal sensation and lead to excessive accumulation of stool, causing fecal impaction, mega-rectum, and fecal overflow. The puborectalis muscle plays an integral role in maintaining the anorectal angle. Its nerve supply is independent of the sphincter, and its precise role in maintaining continence needs to be defined. Obstetric trauma, the most common cause of anal sphincter disruption, may involve the EAS, the IAS, and the pudendal nerves, singly or in combination. It remains unclear why most women who sustain obstetric injury in their 20s or 30s typically do not present with fecal incontinence until their 50s. There is a strong need for prospective, long-term studies of sphincter function in nulliparous and multiparous women.
This information, in concert, provides clues to the pathophysiology of fecal incontinence and may help to guide medical, surgical, or biofeedback therapy. These tests have also been used to assess the effectiveness of the therapeutic modalities. No data are available on the cost-effectiveness of diagnostic testing in fecal incontinence. Newer techniques, including electrophysiologic testing and morphologic imaging of the anorectum, are being pursued.
Graded balloon distentions were performed at the striated muscle and the smooth muscle segments of the esophagus in a random order using impedance planimetry. Impedance planimetry facilitated simultaneous assessments of the biomechanical properties and sensory perception.
We found that both at the striated and smooth muscle segments, the cross-sectional area, circumferential wall tension-strain relationship and the sensory thresholds were similar between men and women. In contrast, at both of these segments, the cross-sectional area was larger (p < 0.05), the circumferential wall tension-strain association had shifted significantly (p < 0.05) to the left (i.e., the wall was stiffer), and the median thresholds for discomfort and pain were higher (p < 0.05) in older subjects. The biomechanical properties and thresholds for sensory perception also varied between the two esophageal segments.
Aging was associated with a larger lumen and a stiffer but less sensitive esophageal wall. Thus, aging but not gender may influence esophageal function.
recombinant methionyl-human NT-3 enhanced transit throughout the GI tract and increased stool frequency in normal and constipated subjects. Our aim was to assess 1) the dose-related effects of NT-3 on bowel function, colon transit, and symptoms of chronic constipation, and 2) its safety.
This was a double-blind, randomized, placebo-controlled phase II study. A total of 107 patients with a diagnosis of functional constipation (Rome II criteria) were randomized to receive 4 wk of double blind, s.c. injections of either placebo, 3 mg, or 9 mg NT-3 once per week (qW) or three times per week (TTW); or 9 mg NT-3 TTW for 1 wk, then qW. The primary endpoint was the change in number of spontaneous, complete bowel movements per week. Colon transit was assessed before and at end of treatment.
Compared with placebo, patients who received 9 mg NT-3 TTW showed significant increases in frequency of spontaneous, complete bowel movements and total bowel movements, as well as dose-related softening of stool and improved ease of passage. The number of days per week without a bowel movement also decreased, colon transit improved, as did constipation-related symptoms. Weekly dosing was ineffective. Transient injection-site reactions, seen in one third of patients receiving NT-3 TTW, were the most frequent adverse event.
NT-3, administered TTW, increased stool frequency, enhanced colon transit, and improved symptoms of chronic constipation. NT-3 seems to be a novel, safe, and effective agent for the treatment of functional constipation.
Patients received 50 g fructose in 150 ml water (33% solution). Breath samples were collected for hydrogen and methane. In a second study, breath test was performed after giving either 10%, 20%, or 33% fructose solution. Data were analyzed retrospectively.
A total of 183 patients (50 male, 133 female) had breath tests, of whom 134 (73%) were positive. Among these, 119 (89%) had elevated H(2), and 15 (11%) had elevated CH(4) or both gases. Questionnaires showed that flatus (83%), pain (80%), bloating (78%), belching (70%), and altered bowel habit (65%) were the most common symptoms. Breath test reproduced symptoms in 101 patients (75%). In the second study, 14/36 (39%) tested positive with a 10% solution, 23/33 (70%) with a 20% solution, and 16/20 (80%) with a 33% solution (10% versus 20% or 33%, p < 0.01).
Fructose intolerance may cause unexplained GI symptoms. The higher yield of positive tests in our initial study may be due to referral bias or testing conditions; lower test dose produced a lower yield. Nonetheless, recognition and treatment of fructose intolerance may help many patients.
The Rome criteria for functional constipation together with modifications proposed here for dyssynergic defecation may serve as useful guidelines for making a diagnosis. Recent advances in technology, together with a better understanding of the underlying mechanisms, have led to real progress in the diagnosis of this condition. Management options are limited, however, and evidence to support these treatments is only modest. The treatment is primarily medical; surgical options should be reserved for refractory disease and after careful diagnostic work-up. Although laxatives remain the mainstay of therapy, prokinetics that are colon-selective are optimal for treating patients with slow-transit constipation, but they are not yet available for clinical use. Recent controlled trials, however, are promising. Biofeedback therapy is the preferred treatment for patients with dyssynergia, but is not widely available. In the near future, user-friendly biofeedback programs including home therapy may facilitate wider use of these methods for patients with dyssynergic defecation.
Patients found to have a hypersensitive esophagus received intravenous theophylline and balloon distension was repeated. If the hypersensitivity improved, oral theophylline was prescribed for three months as an open label trial. Balloon distension reproduced typical chest pain in 16 (76%) patients at thresholds suggestive of hypersensitivity. After theophylline infusion, pain thresholds increased in 12 (75%) patients. Median threshold pressures for discomfort and pain improved (P < 0.01). Cross-sectional area increased (P < 0.05) and the tension/strain association shifted to the right (P < 0.01). Seven of eight patients reported sustained improvement in pain after oral theophylline. Theophylline may ameliorate chest pain in patients with hypersensitive esophagus, possibly by altering adenosine-mediated nociception.