Interstitial cells of Cajal and human colon motility in health and disease.

Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.

A novel mechanism for acute colonic pseudo-obstruction revealed by high-resolution manometry: A case report.

BACKGROUND: Acute colonic pseudo-obstruction (ACPO) is a severe form of colonic dysmotility and is associated with considerable morbidity. The pathophysiology of ACPO is considered to be multifactorial but has not been clarified. Although colonic motility is commonly assumed to be hypoactive, there is little direct pathophysiological evidence to support this claim. METHODS: A 56-year-old woman who developed ACPO following spinal surgery underwent 24 h of continuous high-resolution colonic manometry (1 cm resolution over 36 cm) following endoscopic decompression. Manometry data were analyzed and correlated with a three-dimensional colonic model developed from computed tomography (CT) imaging. RESULTS: The distal colon was found to be profoundly hyperactive, showing near-continuous non-propagating motor activity. Dominant frequencies at 2-6 and 8-12 cycles per minute were observed. The activity was often dissociated and out-of-phase across adjacent regions. The mean amplitude of motor activity was higher than that reported from pre- and post-prandial healthy controls. Correlation with CT imaging suggested that these disordered hyperactive motility sequences might act as a functional pseudo-obstruction in the distal colon resulting in secondary proximal dilatation. CONCLUSIONS: This is the first detailed description of motility patterns in ACPO and suggests a novel underlying disease mechanism, warranting further investigation and identification of potential therapeutic targets.

Inducible Deletion of YAP and TAZ in Adult Mouse Smooth Muscle Causes Rapid and Lethal Colonic Pseudo-Obstruction.

BACKGROUND & AIMS: YAP (Yap1) and TAZ (Wwtr1) are transcriptional co-activators and downstream effectors of the Hippo pathway, which play crucial roles in organ size control and cancer pathogenesis. Genetic deletion of YAP/TAZ has shown their critical importance for embryonic development of the heart, vasculature, and gastrointestinal mesenchyme. The aim of this study was to determine the functional role of YAP/TAZ in adult smooth muscle cells in vivo. METHODS: Because YAP and TAZ are mutually redundant, we used YAP/TAZ double-floxed mice crossed with mice that express tamoxifen-inducible CreERT2 recombinase driven by the smooth muscle-specific myosin heavy chain promoter. RESULTS: Double-knockout of YAP/TAZ in adult smooth muscle causes lethality within 2 weeks, mainly owing to colonic pseudo-obstruction, characterized by severe distension and fecal impaction. RNA sequencing in colon and urinary bladder showed that smooth muscle markers and muscarinic receptors were down-regulated in the YAP/TAZ knockout. The same transcripts also correlated with YAP/TAZ in the human colon. Myograph experiments showed reduced contractility to depolarization by potassium chloride and a nearly abolished muscarinic contraction and spontaneous activity in colon rings of YAP/TAZ knockout. CONCLUSIONS: YAP and TAZ in smooth muscle are guardians of colonic contractility and control expression of contractile proteins and muscarinic receptors. The knockout model has features of human chronic intestinal pseudo-obstruction and may be useful for studying this disease.

Safety and Efficacy of Intermittent Bolus and Continuous Infusion Neostigmine for Acute Colonic Pseudo-Obstruction.

PURPOSE: To compare clinical response of intermittent bolus versus continuous infusion neostigmine for acute colonic pseudo-obstruction (ACPO). Acute colonic pseudo-obstruction occurs due to reduced colonic parasympathetic activity. Neostigmine is an acetylcholinesterase inhibitor that increases frequency of smooth muscle contraction by increasing acetylcholine at autonomic nervous system synapses. Although these administration modalities have been studied separately, they have never been compared. METHODS: This retrospective study compared bolus versus continuous infusion neostigmine for ACPO. The primary outcome was initial clinical response, defined as bowel movement (BM) within 4 hours of bolus dose or 24 hours of initiation of continuous infusion. Secondary outcomes included time to BM, bowel diameter reduction at 24 hours, incidence of bradycardia, additional neostigmine requirements, and need for colonic decompression or surgical intervention. RESULTS: Seventy-five patients were included (bolus n = 37; infusion n = 38). Median total 24-hour neostigmine dose was 2.0 mg (interquartile range [IQR]: 2.0-2.6) with bolus and 9.6 mg (IQR: 6.3-9.6) with continuous infusion. Initial clinical response was similar (infusion 81.6% vs bolus 62.2%, P = .06), but continuous infusion was associated with greater bowel diameter reduction (73.7% vs 40.5%, P = .004). Bolus administration had shorter time to BM (1.4 vs 3.5 hours, P = .0478) and increased need for colonic decompression (67.6% vs 39.5%, P = .0148). Bolus dosing was associated with less bradycardia (13.5% vs 39.5%, P = 0.011), with no difference in atropine usage (10.8% vs 5.3%, P = .43). CONCLUSION: Initial clinical response was similar between groups; however, continuous infusion neostigmine was associated with greater bowel diameter reduction at 24 hours. Bolus administration resulted in less bradycardia; however, given the lack of difference in atropine use, clinical significance is unknown. This study is the first to compare bolus versus continuous infusion neostigmine for ACPO. Further studies are needed to confirm findings.

Idiopathic Dilatation of the Colon in a Nursing Home Resident, with a Suspected Acute Colonic Pseudo-Obstruction (Ogilvie Syndrome).

Ogilvie syndrome (acute colonic pseudo-obstruction) represents a clinical condition with symptoms of colonic obstruction without a distinct mechanical factor. The damage to the neural ganglia in the intestinal wall is the most likely etiology. A 62-year man was admitted to the Emergency Department due to acute dyspnea and vomiting. The patient had not defecated for 10 days prior to admission. An angio-CT revealed dilated colon, especially its left part, up to 85 mm with gas inside its lumen. During laparotomy, extremely dilated colon was confirmed with signs of the intestinal wall necrosis. A left sided hemicolectomy was performed. Despite the intensive treatment in the intensive care unit (ICU), the patient died on 3rd day after the surgery. In this case, the acute pseudo-obstruction of the large intestine was recognised late. This is due to overcrowding in this type of institution, overworked staff, and their inability to give individual attention to each patient.

Acute colonic pseudo-obstruction: A systematic review of aetiology and mechanisms.

AIM: To critically review the literature addressing the definition, epidemiology, aetiology and pathophysiology of acute colonic pseudo-obstruction (ACPO). METHODS: A systematic search was performed to identify articles investigating the aetiology and pathophysiology of ACPO. A narrative synthesis of the evidence was undertaken. RESULTS: No consistent approach to the definition or reporting of ACPO has been developed, which has led to overlapping investigation with other conditions. A vast array of risk factors has been identified, supporting a multifactorial aetiology. The pathophysiological mechanisms remain unclear, but are likely related to altered autonomic regulation of colonic motility, in the setting of other predisposing factors. CONCLUSION: Future research should aim to establish a clear and consistent definition of ACPO, and elucidate the pathophysiological mechanisms leading to altered colonic function. An improved understanding of the aetiology of ACPO may facilitate the development of targeted strategies for its prevention and treatment.

[Drug related colonic perforation: Case report]. / Perforación colónica secundaria a polifarmacia: reporte de caso.

BACKGROUND: Acute pseudo-obstruction of the colon is a disorder characterised by an increase in intra-luminal pressure that leads to ischaemia and necrosis of the intestinal wall. The mechanism that produces the lesion is unknown, although it has been associated with: trauma, anaesthesia, or drugs that alter the autonomic nervous system. The pathophysiology of medication induced colon toxicity can progress to a perforated colon and potentially death. OBJECTIVE: Present a case of a colonic pseudo-obstruction in a patient with polypharmacy as the only risk factor and to review the medical literature related to the treatment of this pathology. CLINICAL CASE: The case is presented of a 67 year old woman with colonic pseudo-obstruction who presented with diffuse abdominal pain and distension. The pain progressed and reached an intensity of 8/10, and was accompanied by fever and tachycardia. There was evidence of free intraperitoneal air in the radiological studies. The only risk factor was the use of multiple drugs. The colonic pseudo-obstruction progressed to intestinal perforation, requiring surgical treatment, which resolved the problem successfully. CONCLUSION: It is important to consider drug interaction in patients with multiple diseases, as it may develop complications that can be avoided if detected on time.

Acute colonic pseudo-obstruction in pregnancy.

BACKGROUND: Acute colonic pseudo-obstruction is an uncommon but potentially morbid complication of pregnancy. The aim of the study was to review a single institution's experience with acute colonic pseudo-obstruction in post-partum patients and develop an algorithm for management based on a literature review. METHODS: This is a retrospective study where patients were identified over a 2-year period (1 December 2012 to 31 November 2014) by checking all deliveries in Christchurch Women's Hospital against diagnosis codes for bowel obstruction and ileus. Clinical records and radiology were then reviewed to identify those with acute colonic pseudo-obstruction and the management of these patients was reviewed. RESULTS: Over the study period, seven patients were identified from 10,240 deliveries. Two patients required laparotomy and the rest resolved without surgical intervention. One patient was treated with neostigmine and three with erythromycin. One patient had an unsuccessful attempt at endoscopic decompression, however, symptoms resolved without further intervention following this. A management algorithm was developed based on the literature review. CONCLUSIONS: Acute colonic pseudo-obstruction occurs in post-partum patients more frequently than suspected (one in 1500 deliveries). The management needs to be active with early correction of electrolyte abnormalities, avoidance of narcotic pain relief and early mobilization. Timely administration of neostigmine or endoscopic decompression can reduce the incidence of colonic ischaemia and perforation and the need for surgical intervention.

Acute and chronic pseudo-obstruction: a current update.

Acute colonic pseudo-obstruction (ACPO) and chronic intestinal pseudo-obstruction (CIPO) are distinct clinical entities in which patients present similarly with symptoms of a mechanical obstruction without an occlusive lesion. Unfortunately, they also share the issues related to a delay in diagnosis, including inappropriate management and poor outcomes. Advancements have been made in our understanding of the aetiologies of both conditions. Several predisposing factors linked to critical illness have been implicated in ACPO. CIPO is a functional motility disorder, historically misdiagnosed, with unnecessary surgery being performed in many patients with dire consequences. This review discusses the pathophysiology, clinical and diagnostic features, and treatment of each. For ACPO, a safer pharmacological approach to treatment is presented in a modified up-to-date algorithm. The importance of CIPO as a differential diagnosis when seeing patients with recurrent admissions for abdominal pain and distention is also discussed, as well as specific indications for surgery. While surgery is often a last resort, the role of the surgeon in the management of both ACPO and CIPO cannot be undervalued. By characterizing each condition in a common review, the knowledge gleaned aims to optimize outcomes for these frequently complex patients.

A case of delayed oxaliplatin-induced pseudo-obstruction: an atypical presentation of oxaliplatin neurotoxicity.

Chemotherapy-induced neurotoxicity is a serious complication of cancer treatment. Oxaliplatin, a third-generation platinum drug, has become one of the first-line therapies used in the treatment of metastatic colorectal cancer. Peripheral neuropathy is a common complication of platinum-based chemotherapy. Most commonly a sensory neuropathy occurs with cold-triggered symptoms in the acute phase and numbness and painful paresthesias as a late presentation. Autonomic neurotoxicity and late presentation, months after cessation of the therapy, has rarely been described. We report a patient who clinically presented with a pseudo-obstruction months after treatment with oxaliplatin for metastatic colorectal cancer. Intestinal adhesions and relapsing malignancy were carefully excluded. By exclusion the pseudo-obstruction was attributed to a toxic oxaliplatin-induced autonomic neuropathy which slowly improved during months of follow-up.

Chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIP) is a rare and serious disorder of the gastrointestinal (GI) tract characterized as a motility disorder with the primary defect of impaired peristalsis; symptoms are consistent with a bowel obstruction, although mechanical obstruction cannot be identified. CIP is classified as a neuropathy, myopathy, or mesenchymopathy; it is a neuropathic process in the majority of patients. The natural history of CIP is generally that of a progressive disorder, although occasional patients with secondary CIP note significant symptomatic improvement when the underlying disorder is identified and treated. Symptoms vary from patient to patient depending on the location of the luminal GI tract involved and the degree of involvement; however, the small intestine is nearly always involved. Common symptoms include dysphagia, gastroesophageal reflux, abdominal pain, nausea, vomiting, bloating, abdominal distension, constipation or diarrhea, and involuntary weight loss. Unfortunately, these symptoms are nonspecific, which can contribute to misdiagnosis or a delay in diagnosis and treatment. Since many of the symptoms and signs suggest a mechanical bowel obstruction, diagnostic tests typically focus on uncovering a mechanical obstruction, although routine tests do not identify an obstructive process. Nutrition supplementation is required for many patients with CIP due to symptoms of dysphagia, nausea, vomiting, and weight loss. This review discusses the epidemiology, etiology, pathogenesis, diagnosis, and treatment of patients with CIP, with an emphasis on nutrition assessment and treatment options for patients with nutrition compromise.

Electroacupuncture reduces duration of postoperative ileus after laparoscopic surgery for colorectal cancer.

BACKGROUND & AIMS: We investigated the efficacy of electroacupuncture in reducing the duration of postoperative ileus and hospital stay after laparoscopic surgery for colorectal cancer. METHODS: We performed a prospective study of 165 patients undergoing elective laparoscopic surgery for colonic and upper rectal cancer, enrolled from October 2008 to October 2010. Patients were assigned randomly to groups that received electroacupuncture (n = 55) or sham acupuncture (n = 55), once daily from postoperative days 1-4, or no acupuncture (n = 55). The acupoints Zusanli, Sanyinjiao, Hegu, and Zhigou were used. The primary outcome was time to defecation. Secondary outcomes included postoperative analgesic requirement, time to ambulation, and length of hospital stay. RESULTS: Patients who received electroacupuncture had a shorter time to defecation than patients who received no acupuncture (85.9 ± 36.1 vs 122.1 ± 53.5 h; P < .001) and length of hospital stay (6.5 ± 2.2 vs 8.5 ± 4.8 days; P = .007). Patients who received electroacupuncture also had a shorter time to defecation than patients who received sham acupuncture (85.9 ± 36.1 vs 107.5 ± 46.2 h; P = .007). Electroacupuncture was more effective than no or sham acupuncture in reducing postoperative analgesic requirement and time to ambulation. In multiple linear regression analysis, an absence of complications and electroacupuncture were associated with a shorter duration of postoperative ileus and hospital stay after the surgery. CONCLUSIONS: In a clinical trial, electroacupuncture reduced the duration of postoperative ileus, time to ambulation, and postoperative analgesic requirement, compared with no or sham acupuncture, after laparoscopic surgery for colorectal cancer. ClinicalTrials.gov number, NCT00464425.

The RNA-binding protein RBPMS2 regulates development of gastrointestinal smooth muscle.

BACKGROUND & AIMS: Gastrointestinal development requires regulated differentiation of visceral smooth muscle cells (SMCs) and their contractile activities; alterations in these processes might lead to gastrointestinal neuromuscular disorders. Gastrointestinal SMC development and remodeling involves post-transcriptional modification of messenger RNA. We investigated the function of the RNA-binding protein for multiple splicing 2 (RBPMS2) during normal development of visceral smooth muscle in chicken and expression of its transcript in human pathophysiological conditions. METHODS: We used avian replication-competent retroviral misexpression approaches to analyze the function of RBPMS2 in vivo and in primary cultures of chicken SMCs. We analyzed levels of RBPMS2 transcripts in colon samples from pediatric patients with Hirschsprung's disease and patients with chronic pseudo obstruction syndrome (CIPO) with megacystis. RESULTS: RBPMS2 was expressed strongly during the early stage of visceral SMC development and quickly down-regulated in differentiated and mature SMCs. Misexpression of RBPMS2 in differentiated visceral SMCs induced their dedifferentiation and reduced their contractility by up-regulating expression of Noggin, which reduced activity of bone morphogenetic protein. Visceral smooth muscles from pediatric patients with CIPO expressed high levels of RBPMS2 transcripts, compared with smooth muscle from patients without this disorder. CONCLUSIONS: Expression of RBPMS2 is present in visceral SMC precursors. Sustained expression of RBPMS2 inhibits the expression of markers of SMC differentiation by inhibiting bone morphogenetic protein activity, and stimulates SMC proliferation. RBPMS2 transcripts are up-regulated in patients with CIPO; alterations in RBPMS2 function might be involved in digestive motility disorders, particularly those characterized by the presence of muscular lesions (visceral myopathies).

Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction--a double-blind, placebo-controlled, cross-over, multiple n = 1 study.

BACKGROUND: Chronic intestinal pseudo-obstruction is a disabling condition for which there are no established drug therapies. The condition is caused by a diverse range of intestinal myopathies and neuropathies. AIM: To assess the therapeutic efficacy of prucalopride, a selective high-affinity 5-HT(4) receptor agonist, we employed a multiple n = 1 study design. Each patient acted as his/her own control, each day counting as one treatment episode, allowing comparison of 168 days on each of active drug and placebo. METHODS: Double-blind, randomised, placebo-controlled, cross-over trial of four 12-week treatment periods, with 2-4 mg prucalopride or placebo daily. In each of the first and second 6 months there was a prucalopride and a placebo treatment. Patients with proven chronic intestinal pseudo-obstruction, including dilated gut, were included. Evaluation was by patient diary and global evaluation. RESULTS: Seven patients participated (mean 42 years, five female, median symptom duration 11 years). Three discontinued, two due to study length, and one on prucalopride due to unrelated malnutrition and bronchopneumonia. Four patients (three visceral myopathy and one visceral neuropathy) completed the study; prucalopride significantly improved pain in three of four patients, nausea in two, vomiting in one, bloating in four and analgesic intake. Bowel function was not changed substantially. CONCLUSIONS: n = 1 studies in rare conditions allow drug efficacy assessment. Prucalopride relieves symptoms in selected patients with chronic pseudo-obstruction.

Methylnaltrexone for treatment of acute colonic pseudo-obstruction.

Acute colonic pseudo-obstruction (ACPO) or Ogilvie syndrome is an idiopathic syndrome of dilation of the colon without mechanical obstruction that develops in hospitalized patients usually in the setting of significant medical and surgical conditions. Standard care therapy includes colonoscopic decompression or neostigmine. The latter is not Food and Drug Administration-approved for this indication but has been the recent intervention of choice. A patient with ACPO failed 2 injections of neostigmine. A clinical trial of subcutaneous methylnaltrexone was administered because she was on opioid therapy. There was a brisk response to methylnaltrexone, a µ-opioid-receptor antagonist which does not cross the blood-brain barrier. This is the first case report in the literature and in the pharmaceutical company's data bank that illustrates a potential role for methylnaltrexone in ACPO. Prospective, larger studies to determine the role of methylnaltrexone in ACPO are warranted.

Conus medullaris syndrome and acute colonic pseudoobstruction in a child with acute lymphoblastic leukemia.

A 5(3/12)-year-old boy with Philadelphia chromosome (+) pre-B acute lymphoblastic leukemia (ALL) without extramedullary involvement did not achieve remission after induction therapy. His family stopped therapy, but he was readmitted eight months later due to pyoderma, pneumonia and active leukemia with leukocytosis. During cytoreductive and antibiotic therapy, he developed progressive abdominal distension, pain, globe vesicale, tachypnea, and respiratory alkalosis. Bowel sounds could not be auscultated. Dilation, mainly in the large intestine, was detected radiologically. His neurological examination revealed absence of superficial reflexes and hypoesthesia along with normal motor strength and deep tendon reflexes in the lower extremities, consistent with conus medullaris syndrome, which was thought to give rise to acute colonic pseudo-obstruction.

Acute colonic pseudo-obstruction in vascular patients (Ogilvie syndrome).

Two patients with acute colonic pseudo-obstruction are presented. Acute colonic pseudo-obstruction, first described by Ogilvie in 1948, is characterised by signs of colonic obstruction, but without mechanical obstruction to the intestinal flow. The current hypothesis states that it is caused by an imbalance between sacral parasympathetic excitatory nerves and sympathetic inhibitory nerves, thus inducing functional obstruction. It mostly develops in hospitalised patients with a variety of medical and surgical conditions. Two such patients with extensive co-morbidities, developed progressive colon dilatation with signs of acute peritonitis, and were operated on urgently. In both patients, right hemicolectomy and postoperative medical treatment resulted in complete recovery.

Acute colonic pseudoobstruction in a child with sickle cell disease treated with neostigmine.

Sickle cell disease is a disorder that produces significant morbidity and mortality. Vaso-occlusive pain crises are the most common presenting symptom associated with sickle cell patients. A rare, yet important to recognize, complication of sickle cell disease is acute colonic pseudoobstruction, also known as Ogilvie's syndrome. These patients may present with symptoms that are difficult to distinguish from other etiologies of abdominal pain, but a thorough diagnostic workup can provide important clues. Furthermore, there is no agreement on optimal treatment of pseudoobstruction. We report the first pediatric case of acute pseudoobstruction secondary to sickle cell disease that was treated successfully with neostigmine. Early recognition of this phenomenon is important as it alters patient management, can be treated medically, and may avoid unnecessary surgical intervention.

Unusual type of colonic neuromuscular disorder with extensive vacuolization.

Various pathological abnormalities of smooth muscle and innervation result in clinical syndromes with disordered motility of the small intestine and colon. Although these abnormalities have been extensively reported clinically, their pathologic changes and pathophysiologic mechanisms have not been well elucidated. We report a case of visceral neuropathy with secondary muscle changes in a 7-yr-old ventilator dependent, mentally retarded child who presented with a history of chronic constipation and symptoms of intestinal obstruction. The muscle layer of the colectomy specimen showed extensive infiltration of vacuolated cells that were positive for S-100 and synaptophysin but negative for glial fibrillary acidic protein (GFAP) and neural filament protein (NFP). Calretinin positivity was preserved in submucosal ganglion cells but was absent in vacuolated nerve branches. Masson's trichrome stain showed evidence of fibrosis, indicative of muscle damage. There was a reduced number of intestinal cells of Cajal in the muscularis propria, as indicated by CD117 (c-kit) immunostaining. This disorder is most likely a sporadic visceral neuropathy, secondarily affecting muscular function, that causes colonic pseudo-obstruction.