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Keywords:

  • pseudo-obstruction;
  • gastrointestinal motility;
  • histopathology;
  • natural history

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Abstract  Chronic intestinal pseudo-obstruction (CIPO) is a rare pathological condition characterized by a marked derangement of gut propulsive motility mimicking mechanical obstruction, in the absence of any lesion occluding the gut lumen. This disease is often associated with a disabling and potentially life-threatening complications and is still too often unrecognized even in referral centres. As a result, patients receive neither appropriate care nor recognition of their severe health condition. Medical and surgical therapies are often unsatisfactory and long-term outcome turns out to be poor in the vast majority of cases. This article focuses on the main clinical features, the management and long-term outcome of patients affected by CIPO, with particular emphasis on those aspects which remain a matter of debate.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Chronic intestinal pseudo-obstruction (CIPO) is a rare disabling and potentially life-threatening disorder characterized by a severe impairment of gastrointestinal propulsion which results in a clinical picture resembling mechanical obstruction in the absence of any lesion occluding the gut.1–3 Between occlusive episodes, patients may be asymptomatic, but generally complain of severe digestive symptoms.2–3 CIPO is an important cause of chronic intestinal failure, since affected individuals are often unable to maintain normal body weight and/or normal oral nutrition. CIPO typically passes unrecognized for long periods of time before the correct diagnosis is established, so that adequate management is delayed and patients undergo repeated and potentially dangerous abdominal surgeries. The lack of appropriate medical recognition causes dangerous misunderstandings at all levels, from the family to health authorities, which contribute to the further deterioration of the extremely poor quality of life of the affected individuals. Abnormalities of smooth muscle cells, interstitial cells of Cajal (ICC), intrinsic (enteric) and extrinsic neural supplies, and the central nervous system are responsible for the severe abnormalities of digestive motor activities which in turn determine the disease.1,4–5 CIPO can be secondary to a variety of systemic, metabolic or organic diseases (Table 1). When no underlying cause is found using currently available diagnostic tests, CIPO is defined idiopathic (i.e. chronic idiopathic intestinal pseudo-obstruction, CIIPO).1 Whether and to which extent subtle, as yet unidentified, diseases contribute to CIIPO remains a matter for research. Most cases of CIIPO in adults are referred to as sporadic, but familial forms have also been described.1 Specifically, syndromic autosomal dominant, autosomal recessive and X-linked forms of CIIPO have been reported.1,4,5 An X-linked locus has been mapped to the Xq28 region.4,5 Genes involved in the pathogenesis of Hirschsprung's disease, namely GDNF (glial-cell line derived neurotrophic factor), GFRA1 (GDNF receptor-α1), EDN3 (endothelin 3), EDNRB (endothelin 3 receptor B), and SOX10, did not show any mutation in a family with autosomal dominant CIIPO.4–6 Until now, only a few genes have been identified as being responsible for syndromic CIIP. These include the thymidine phosphorylase gene (TP, also known as endothelial cell growth factor-1, ECGF1) on chromosome 22 (22p13), the DNA polymerase gamma gene (POLG), on chromosome 21 (21q17), and the transcription factor SOX10 on chromosome 22 (22p12).4

Table 1.   Main causes of secondary chronic idiopathic pseudo-obstruction and relative gut tissue that is predominantly involved
Affected control mechanism of GI functionUnderlying disease
Extrinsic autonomic nervous systemStroke, encephalitis, calcification of basal ganglia, orthostatic hypotension and diabetes
Enteric nervous systemParaneoplastic, viral infections, iatrogenic (anthraquinones), diabetes, Hirschsprung, Chagas and Von Recklinghausen
Enteric smooth muscle layerMyotonic dystrophy and progressive systemic sclerosis
Mixed enteric neuro-myopathyScleroderma, dermatomyositis, amyloidosis, Ehlers-Danlos, jejunal diverticulosis and radiation enteritis
UndeterminedHypothyroidism, hypoparathyroidism, phaeochromocytoma and iatrogenic (clonidine, phenothiazines, antidepressants, antiparkinsonians, antineoplastics, bronchodilators)

This article reviews the current knowledge on diagnosis, treatment and long-term outcome of CIPO with a specific focus on those issues which remain controversial and contribute to make the management of this condition unsatisfactory.

Diagnosis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Clinical features

The diagnosis of CIPO is based on the recognition of typical clinical manifestations, radiological signs of intestinal mechanical occlusion, and the exclusion of any organic obstruction of the gut lumen. Clinical manifestations and associated conditions are summarized in Table 2. The most impressive feature of CIPO is the self-limiting nature of sub-occlusive episodes, with symptom severity and gut distension fluctuating between acute episodes. However, in the most severe cases, disabling symptoms are constantly present and bowel loops remain chronically dilated, thus CIPO is virtually indistinguishable from mechanical obstruction exclusively on the basis of symptoms and signs. Furthermore, since most cases have undergone repeated abdominal surgery, patients inevitably have abdominal adhesions. Thus, the concomitant presence of functional and mechanical (secondary to adhesions) obstruction is impossible to rule out despite extensive investigation.

Table 2.   Clinical manifestations suggestive of chronic intestinal pseudo-obstruction
Main features
 Chronically recurrent episodes of abdominal pain, abdominal distension and inability to defecate, with or without vomiting
 Radiological evidence of distended bowel loops during acute episodes (air–fluid levels must be present when the patient is investigated in the upright position)
 History of repeated abdominal laparotomies/laparoscopies without substantial modification of abdominal symptoms
 Lack of evidence of mechanical occlusion of the gut after an appropriate diagnostic work-up
Adjunctive features
 Inability to maintain normal body weight, despite dietary manipulations
 Need for parenteral nutrition
 Distended, hypercontractile bowel loops which are visible through an abnormally thin abdominal wall (suggestive of long-lasting disease)
 Family history of similar digestive disorders
 Abnormal motor patterns at small bowel manometry
Associated conditions
 Esophageal motor disorders (dysphagia, non-cardiac chest pain, reflux disease)
 Gastroparesis (severe postprandial fullness, nausea, vomiting of food ingested much earlier or of large amounts of gastrointestinal digestive secretions, succession splash)
 Intestinal bacterial overgrowth (diarrhoea, malabsorption)
 Intractable constipation
 Urinary symptoms generally associated with evidence of urinary tract distension
 Evidence of organic, systemic, metabolic diseases which can be potential causes of secondary CIPO (see Table 1)
 Depression or other psychological disturbances (often secondary to the disabling digestive problem and the disappointing quality of healthcare received)

The clinical picture is generally dominated by abdominal pain and distension,2 although all digestive symptoms can be extremely severe in these patients. Symptoms and signs of malnutrition and malabsorption are also common and food ingestion often exacerbates digestive symptoms so that providing adequate nutritional support by an oral route frequently becomes impossible. Nausea, vomiting and weight loss predominate when the disease mainly affects the proximal portions of the GI tract. Diarrhoea is often secondary to small bowel bacterial overgrowth and can be corrected by antibiotics. Notably, patients may experience a deterioration of symptoms when the pathologically accelerated transit of a contaminated intestine is pharmacologically reverted into an intractable constipation.

Radiology

Radiology plays a pivotal role in the diagnosis of CIPO. Plain abdominal films are necessary to identify distended bowel loops with air–fluid levels, while contrast studies remain the gold standard for excluding the presence of organic lesions occluding the gut lumen. Since air–fluid levels may occasionally occur in non-dilated bowel loops proximal to organic lesions occluding the gut lumen, these findings are considered to be the radiological landmark of intestinal obstruction by some authors.7,8 However, air–fluid levels are visible only with the patient in an upright position and this may be difficult in some cases during acute episodes. Furthermore, old data challenge the utility of erect abdominal radiographs in the diagnosis of intestinal mechanical obstruction, since neither the diagnostic accuracy nor the capability of identifying the level of obstruction of supine plain films was found to be significantly improved by erect radiographs, as determined by four independent observers.9 Some authors propose the diagnosis of ‘mild forms of CIPO’ for those patients with severe digestive symptoms, but no radiological feature suggestive of mechanical obstruction of the gut. The diagnosis of CIPO is therefore based on the combination of abnormal GI manometric studies, transit measurement and histopathological assessment regardless of the presence of typical radiological findings.10 We prefer to adopt the strict, above-reported definition of CIPO for two reasons. First, preliminary studies suggest that patients with extremely severe digestive symptoms and the inability to maintain normal body weight on oral nutrition, but show no radiological evidence suggestive of intestinal occlusion not only have a significantly reduced probability of undergoing abdominal surgery, but also present less severe motility disorders.11 Second, lumping all severe digestive syndromes under the term of CIPO does not help to decrease the confusion existing among general practitioners and specialists alike when it comes to hypothesizing the existence of this condition which still too often ends up being confused in the big bag of functional digestive syndromes. In contrast, CIPO is characterized by unique clinical features and natural history (see below). Traditional contrast follow through studies in this field will likely be replaced by the entero-CT scan which allows simultaneous internal and external views of the gut wall, but data in patients with CIPO are still lacking and results still strongly depend on observer experience. Abdominal CT and MR scans are also important in investigating possible causes of gut compression, while MR angiography may non-invasively identify congenital or acquired vascular abnormalities. Finally, excretory urograms should be performed in patients with urinary symptoms, since diffuse neuro-myopathies may simultaneously involve both gastrointestinal and urinary tract.

Endoscopy

Upper gastrointestinal endoscopy is particularly important in ruling out false positive radiological diagnoses of mechanical occlusion in the duodenum and proximal small bowel, such as in many cases of the so-called ‘aorto-mesenteric compression syndrome’. This is frequently due to sustained uncoordinated contractions rather than true obstruction due to vascular abnormalities.12 Mucosal biopsies of the small bowel should be taken to rule out celiac disease. Colonoscopy has both a diagnostic and a therapeutic potential, since it can be used to try to decompress the large bowel, although the manoeuvre only rarely provides satisfactory results.13

Laboratory tests

Once the diagnosis is established, further tests should be performed to identify the presence of potentially curable diseases responsible for secondary forms.1 The monitoring of hydro-electrolyte balance and of circulating levels of essential elements is pivotal in patients on parenteral nutrition or, in general, with the inability to maintain a normal oral diet.

Manometry

A diagnosis of CIPO cannot be based on small bowel manometric recordings, due to the lack of specificity (see below). However, small bowel manometry plays a supportive role in defining the diagnosis, since it may provide indirect information regarding the underlying pathophysiological mechanism. In fact, powerful uncoordinated contractions are suggestive of an intact smooth muscle layer and abnormal intrinsic neurogenic control while low amplitude, normally coordinated contractions indicate the existence of a normally functioning enteric nervous system (ENS) associated with a diseased muscle layer. Nonetheless, low amplitude contractions may merely reflect the inability of the manometric technique to record non-occlusive contractions such as in the case of dilated bowel loops.2–5,14 Abnormal ‘neurogenic’ motor abnormalities include abnormal activity fronts, bursts of uncoordinated contractions, sustained uncoordinated contractions and the inability to respond to meal ingestion,3 but identical abnormalities can be recorded in a variety of clinical conditions which are not characterized by sub-occlusive episodes.11,12,15 Thus, a diagnosis of CIPO cannot be exclusively based on the identification of these manometric findings. Small bowel manometry also contributes to differentiating mechanical from functional obstruction, the former being characterized by postprandial, prolonged, high pressure, non-propagated contractions, although mixed patterns can be found in patients who underwent abdominal surgeries.15 The introduction of ambulatory manometry has not substantially modified the manometric criteria established by stationary manometry3 which are still used in the management of CIPO.15,16Table 3 summarizes the main manometric abnormalities described in the literature.2,3,14,17–24

Table 3.   Small bowel manometric findings in patients with a diagnosis of chronic intestinal pseudo-obstruction (CIPO) and/or of idiopathic CIPO (CIIPO)
Author and manometric techniquePatients who underwent small bowel manometry and inclusion criteriaAbnormal manometric patterns (number of patients presenting)
  1. *Radiological criteria of intestinal obstruction were not present in all patients or not reported in the text, as specified in the second column.

Stanghellini et al.3* Stationary42 CIIPO adults Clinical features; exclusion of mechanical obstruction and primary diseases Dilated bowel loops/air fluid levels only in 24 patientsBursts of incoordinated contractions (30) Phase III aberrant configuration or propagation (25) Sustained incoordinated contractions (15) Failure of meal to induce a fed pattern (8)
Hyman et al.17 Stationary13 CIPO children Clinical, pathologic and radiological criteria Dilated bowel loops in allAbsent migrating motor complexes, with phase 3-like activity at the start of meals (neuropathic variety) (5) Postprandial hypomotility (3) Very low amplitude or absent contractions (myopathic variety) (2) Other (3)
Hyman et al.18* Stationary51 CIPO children Clinical features and abnormal antroduodenal manometry Dilated bowel loops only in 24 patientsAbsence of phase III (≥4 h fasting recording) (27) Failure of meal to induce a fed pattern (7) Plus discrete MMCs abnormalities (7) Myopathy patterns [very low amplitude (<15 mmHg) coordinated contractions] (6) Postprandial duodenal hypomotility (4)
Boige et al.19* Stationary20 CIPO children Clinical features + histological neuropathy Radiology not an inclusion criteriaHypomotility (20) Absence of phase III (13)
Cucchiara et al.20 Stationary19 CIIPO children Clinical features; exclusion of mechanical obstruction and primary diseases Dilated bowel loops in allNeuropathic patterns (12; 7 confirmed by histology):  fasting and/or fed sustained incoordinated contractions  phase III aberrant propagation and/or configuration  failure of meal to induce a fed pattern  fasting/fed bursts of non-propagated contractions Myopathic patterns (4; 2 confirmed by histology):  severe fasting/fed infrequent low-amplitude contractions, sometimes with some degree of propagation Patterns suggestive of mechanical obstruction (3; all confirmed):  repetitive postfeeding clusters  simultaneous repeated giant contractions
Di Lorenzo et al.21* Stationary18 CIPO children Clinical features; unspecified radiological criteria (radiological exclusion of mechanical obstruction only)Absence of phase III (4 h fasting recording) (9) Stationary clusters (≡ bursts) (9) Abnormal feeding patterns (≡ activity fronts or [DOWNWARDS ARROW] duodenal motility index within 30 min after the meal) (4) Phase III aberrant propagation (3) Tonic contractions (2) Minute rhythm (≡ propagated clusters) (2)
Fell et al.14* Stationary14 CIIPO children Clinical features + intolerance to enteral feeding; contrast radiology to confirm diagnosis Dilated bowel loops in only 10 patientsAbsence of phase III (4 h fasting recording) (5) Low amplitude phase III (5) Poorly formed phase III (3) Phase III aberrant propagation (2) Decreased intestinal motility index in 4/5 with myopathic histology
Heneyke et al.22* Stationary30 CIPO children Clinical features Dilated bowel loops in only 10 patientsUnspecified neuropathic patterns (14) Unspecified myopathic patterns (13)
Mousa et al.23* Stationary85 congenital children CIPO Clinical features and contrast radiology for the exclusion of mechanical obstruction in all Unspecified radiological criteriaUnspecified neuropathic patterns (48) Unspecified myopathic patterns (32) Unspecified mixed patterns (5)
Knowles et al.24* Ambulatory manometry23 CIIPO adults Clinical features + proven abnormal small bowel motility and/or radiological criteria Dilated bowel loops in only nine patientsGeneralized hypomotility (3) Phase III aberrant configuration (17) Phase III abnormal propagation (17) Bursts of incoordinated contractions (14) Sustained incoordinated contractions (14) Discrete clustered contractions (12) Reduced phase III velocity (8) Reduced or absent phase III (7)
Stanghellini et al.2 Stationary59 CIIPO adults Clinical features and radiological criteria Dilated bowel with air fluid levels in allPhase III aberrant configuration or propagation (39) Bursts of incoordinated contractions (35) Clustered contractions (20) Hypomotility (12) Failure of meal to induce a fed pattern (6)

Oesophageal manometry generally adds very little to the diagnostic work-up of CIPO, but it plays an important diagnostic and prognostic role if the disease is secondary to scleroderma. Ano-rectal manometry is important to rule out Hirschsprung's disease, particularly in patients with intractable constipation and a marked distension of the large intestine.

Histopathology

Tissue analysis of the gastrointestinal neuromuscular wall obtained from patients with CIPO has long been a highly debated issue having both advantages and disadvantages. The former include the diagnostic potential unveiled by the identification of the intimate nature/cellular site(s) of the disorder underlying gut dysmotility, and implications relevant for the prognosis and management of patients with CIPO. The latter include various factors ranging from the common clinical experience that surgery per se may often worsen the underlying dysmotility (or induce adhesions which complicate the challenging clinical picture with a ‘mechanical’ component) to discouraging pathologic reports describing an apparently ‘normal’ neuromuscular layer of patients with remarkable dilatation of bowel loops associated with severe dysmotility. Moreover, important drawbacks to histopathology regard the limited experience on normal human tissues as well as the classification of gastrointestinal neuromuscular disorders which is based on partial understanding of altered enteric smooth muscle cells, ICC and neurons. This, in turn, largely contributes to an uncertain nosology/nosography. For example, previously adopted classifications of gut neuromuscular pathology, based on routine haematoxylin and eosin and Smith's silver histochemical technique (for review, see4,5), have lost their value over time because of the growing understanding of the ENS, ICC and muscular physiology/pathophysiology.4,5 Finally, the lack of solid and generally accepted guidelines on tissue processing, quantitative analysis (i.e. correct methods to count enteric neurons and ICC abnormalities) and adequate control tissue evaluation represent important problems experienced daily by pathologists reporting on biopsies of patients with CIPO.

Nonetheless, the recent introduction of laparoscopic surgery along with a significant refinement of several methodological approaches and better understanding of gut function marked a revival of interest for the pathological analysis of gut specimens. In this paragraph, we will briefly discuss some practical aspects of gut neuromuscular histopathology including 1) which patients having severe dysmotility should be eligible for a full-thickness biopsy; 2) which gut segment should be biopsied; 3) how to collect and process the material obtained during surgery; and 4) main possible results in CIPO. First of all, although there is a need to establish guidelines for gastrointestinal biopsy samples, current general agreement among gastroenterologists indicates that tissue samples should be sought in all patients with severe dysmotility of unknown aetiology who undergo surgery for any reason and especially in those cases refractory to therapy, with suspected mechanical obstruction (not previously ruled out by a preoperative diagnostic work-up), with poor postsurgical outcome, or in patients with a permanent catheter for enteral or parenteral nutrition.4 Secondly, unless in cases characterized by a selective involvement of gut segments, biopsies should be taken from any portion of the stomach, small bowel and colon since most CIPO are classically diffuse motility disorders.1,5 Thirdly, intestinal full-thickness specimens require appropriate tissue handling. This has been previously detailed elsewhere4 and discussing technical details goes beyond the aims of this review.

Full thickness biopsies are obtained only rarely despite repeated surgical procedures,2 thus providing an indirect confirmation that CIPO still remains unsuspected for long periods of time. Criteria and histopathologic patterns suggestive of enteric neuropathies and myopathies have recently been reviewed.4,5,25 A summary of the main histopathological findings reported up to now in CIPO patients has been reported in Table 4.2,14,20,22,24,26,27 Histopathologic evaluation of tissue specimens in patients with CIPO may provide the following results: 1) the presence of myopathic abnormalities with an apparently spared ENS; 2) the occurrence of an underlying neuropathy, i.e. changes of the ENS without involvement of the smooth muscle layer; 3) mixed forms of neuro-myopathies; and, finally, 4) cases characterized by a predominant depletion or abnormalities of the ICC network.4,5

Table 4.   Histopathologic findings in patients with chronic intestinal pseudoobstruction (CIPO)
Author and methodsNumber patients (number of patients with histology), radiological inclusion criteriaHistological findings (number of patients presenting)
  1. *Radiological criteria of intestinal obstruction were not present in all patients or not reported in the text, as specified in the second column or previously reported (see Table 3 for details).

Cucchiara et al.2019 CIPO children (9)Myopathy (2) Neuropathy (7)
Fell et al.14*14 CIIPO children (14)Myopathy (5) Neuropathy (4) Indeterminate (5)
Mann et al.2620 CIIPO adults (19)Myopathy (13) Neuropathy (3) Indeterminate (3)
Heneyke et al.22*44 CIPO children (38)Myopathy (22) Neuropathy (16)
Faure et al.27*105 CIPO children (99) Dilated bowel loops in 84 patientsMyopathy (17) Neuropathy (58) Indeterminate (24)
Emmanuel et al.3115 CIPO adults (15)Myopathy (7) Neuropathy (5) Indeterminate (3)
Knowles et al.24*115 CIIPO adults (115)Neuropathy: degenerative neuropathy (20), inflammatory plexitis (20), lymphocytic ganglionitis (13) myopathy: degenerative leiomyopathy (16), vacuolar myopathy (7), hollow visceral myopathy (4), inclusion body myopathy (4), inflammatory leiomyositis (1) decreased number of ICCs (2) α-actin deficiency (28)
Stanghellini et al.259 CIIPO adults (11)Neuropathy (11) ICC abnormalities (5)

Natural history

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Table 5 reports some aspects of the clinical outcome of CIPO in long-term studies.2,14,18,21–23,26,27 Unfortunately, strict inclusion criteria were rarely adopted and information in this respect remains insufficient. We have recently reported the natural history of CIPO, as detected in 59 adults who matched strict inclusion criteria for CIIPO and were followed up for as long as 13 years.2 The onset of the disease was generally characterized by the presence of non-specific, progressively more severe digestive symptoms which preceded the first sub-occlusive episode by 1–46 years. The disease onset coincided with an acute event in only one-fourth of the cases. The median time between the first sub-occlusive episode and recognition of the disease was 8 years (range 0–47). Once the diagnosis was established, the frequency of sub-occlusive episodes decreased in about two-thirds of the patients and surgical procedures also decreased. Nevertheless, in keeping with previous reports, the clinical course of CIPO turned out to be almost invariably severe.1,22,23,26,27 Digestive symptoms showed a tendency to become progressively more severe and abdominal pain became intractable or responsive only to opioids in 20% of the patients. The vast majority of patients presented important nutritional limitations and almost one-third required long-term home parenteral nutrition (HPN). These data are also in keeping with those of previous reports in which the percentage of patients requiring enteral or parenteral nutrition was >80% in children.23 In our series, four patients underwent small bowel transplantation with variable outcomes and five died from disease-related complications. Similar mortality rates of about 10% have recently been reported in adults.26 While mortality rates within the first year of age are particularly high in congenital CIPO2, a mortality rate ranging from 10% to 25%27,23 has been reported in children. A variety of clinical, histological and manometric parameters have been found to be predictive of a poor clinical outcome, as summarized in Table 6.2,14,18,21–23,27–31 Among these, myopathy and decreased contractile activity have been reported in different series. To our knowledge, the only prognostic factors indicative of a good clinical outcome are represented by clinical and manometric positive response to treatment with cisapride30 and octreotide,29 respectively.

Table 5.   Clinical outcome in patients with chronic intestinal pseudoobstruction (CIPO)
AuthorDesign months of follow-up (range)Number of pts (number of females)Outcome (number of pts)
  1. *Radiological criteria of intestinal obstruction were not present in all patients or not reported in the text, as specified in Table 3.

Hyman et al.18*Prospective 1251 CIPO children (26)Response to cisapride (24)
Di Lorenzo et al.21*Prospective 19 (6–48)18 CIPO children (7)Shift total parenteral nutrition (TPN) [RIGHTWARDS ARROW]jejunal feeding (12)
Fell et al.14*Prospective 12–12014 children (7)Nutrition: enteral nutrition (6), parenteral nutrition (8) Deaths (5): TPN-related complications (4), Surgery-related complications (1)
Mann et al.26Cross-sectional (unspecified)20 CIIPO adults (9)Nutrition: normal (8), enteral (2), parenteral (8) Opiate dependence (5) Deaths (2): Myocardial infarction from extensive caval thrombosis (1), Bronchopneumonia (1)
Heneyke et al.22*Prospective (unspecified)44 CIPO children (19)Nutrition: normal (4), enteral (16), parenteral (10) Deaths (14): TNP-related complications (9), Withholding/withdrawing therapy (3), Surgery related complications (2)
Faure et al.27*Retrospective Multicenter 85 (3–192)105 children (48); 89 FUNutrition:enteral (3), parenteral (39) Deaths (11): TPN-related complications (5), Septic shock of GI origin (4), Sudden unexplained death (2)
Mousa et al.23*Retrospective 2585 congenital CIPO children (47)Nutrition: enteral (22), parenteral (50) small bowel transplantation (8) deaths (22): TNP-related complications (17), post-transplantation complications (5)
Stanghellini et al.2Prospective 55 (12–156)59 CIIPO adults (49)[DOWNWARDS ARROW] frequency of subocclusions (41) Nutrition: Inability to maintain oral feeding (36), Parenteral (16) Intractable pain (12) Small bowel transplantation (3) Deaths (5): TNP-related complications (4), Post-transplantation complications (1)
Table 6.   Prognostic factors in patients with chronic intestinal pseudoobstruction (CIPO)
AuthorDesign patients, duration of follow-up (FU)Good outcomePoor outcome
  1. *Radiological criteria of intestinal obstruction were not present in all patients or not reported in the text, as specified in the second column or previously reported (see Table 3 for details).

Camilleri et al.28*RDBPC two dose CISA 37 neuropathic adults with gastroparesis or intestinal dysmotility or CIPO 12 weeksCriteria •Improvement of overall symptom score after cisapride Prognostic factor •Absence of vagal dysfunction (only at 6 weeks therapy) •Presence of general sympathetic dysfunctions (at 12 weeks therapy) 
Verne et al.29*Open label trial with erythromycin and octreotide14 CIPO adults with dilated bowel in 7 20–33 weeksCriteria •Symptomatic improvement Prognostic factors •>5 activity fronts/4 h after octreotide 50 mcg sc 
Cogliandro et al.30Prospectic 32 CIIPO adults 42 months (12–120 months)Criteria •[UPWARDS ARROW] BMI and [DOWNWARDS ARROW] frequency of subocclusive episodes Prognostic factors •Response to cisapride 30–90 mg day−1, ≥2 months 
Hyman et al.18*Prospectic 51 CIPO children 12 monthsCriteria •Diet status before cisapride Response to cisapride Prognostic factors •Presence of MMCs •Normal bowel diameter 
Di Lorenzo et al.21*Prospectic 18 CIPO children 19 months FU (6–48 months)Criteria •Shift TPN[RIGHTWARDS ARROW]jejunal feeding Prognostic factors •Presence of MMCs 
Fell et al.14*Prospectic 14 CIIPO children 12–120 months FU Criteria •Long-term TPN •Death Prognostic factors •Phase III motility index <10 kPa min−1
Heneyke et al.22*Prospectic 44 CIPO children Criteria •Death •TPN dependence Prognostic factors •Malrotation •Short small bowel •Urinary involment •Myopathy
Faure et al.27*Retrospective multicenter 105 CIPO children 85 months (3–192 months) Criteria •Dependence on artificial feeding Prognostic factors •Onset at birth •Acute onset •Megacystis •Surgery
Mousa et al.23*Retrospective 85 children congenital CIPO 25 mos FU Criteria •Death •Prognostic factors •Myopathy •TPN •Absence of MMCs
Emmanuel et al.31Retrospective 15 CIPO adults 41 months FU (13–64 months)Criteria •Improvement of symptoms during therapy with Erythromycin 1.5–2.0 g day−1 Prognostic factors •Gender (male) •Myopathy 
Stanghellini et al.2Prospective 59 CIIPO adults 55 months (12–156 months) Criteria •Unchanged or increased frequency of subocclusions •Inability to maintain normal oral nutrition •Need of parenteral nutrition •Chronic abdominal pain requiring opiates or untractable pain Prognostic factors •Bursts •Inadequate response to meals •Hypomotility

Therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Treatment of CIPO is disappointing. Secondary forms may respond to treatment of the underlying disease,32 provided that irreversible gut neuromuscular derangement has not yet taken place. Nutritional, pharmacological and surgical therapies, nevertheless, have somewhat improved the management of these patients in the last few decades. More importantly, identification and understanding of the disease has led to an increasing awareness among doctors, so that patients should now receive more appropriate recognition of the severity of their condition when compared with what had generally happened in the past, with obvious positive effects on their quality of life.

Nutritional support

The main problem of patients with involvement of the proximal portion of the alimentary canal is malnutrition, due to both malabsorption and inadequate food intake as a consequence of severe digestive symptoms. Small meals with liquid or homogenized foods are generally better tolerated and may help patients with sufficient residual digestive functions. Supplementation with multivitamins and salts is generally necessary. Hypercaloric liquid formulae are available on the market and can be helpful if tolerated. In the case of gastrointestinal motility derangements severe enough to prevent sufficient nutrient intake by oral feeding, enteral nutrition is an option which, however, is rarely feasible. Only patients whose motility disorder is mainly localized in the stomach and duodenum will benefit from this form of nutritional support which, similar to parenteral nutrition, requires slow infusion for many hours during the day, but presents fewer complications. In the most severe cases, HPN is necessary to satisfy nutritional requirements. The infusion velocity of nutrients should be progressively increased to the limit of the metabolic capacities of each individual, to allow them to be free from infusion for some time during the day. Patients on HPN should be allowed to taste some food, if tolerated, to decrease the major distress associated with the procedure. The main limitations of HPN include severe complications such as liver insufficiency, pancreatitis, glomerulonephritis and catheter-related complications (i.e. thrombosis and septicemia).33 Approximately, half of such complications were infectious and half required removal of the catheter. Adequate training of all those who are involved in the handling of the catheter is crucial for safe management of HPN. Metabolic complications can be prevented by thorough individualized preparation of the nutritive admixture.

Pharmacological therapy

The treatment of choice of secondary forms is aimed at the underlying pathological conditions. In all cases, small bowel bacterial overgrowth is an important cause of diarrhoea and malnutrition, and should be treated with antibiotic therapy. Although unabsorbable antibiotics (i.e. rifaximin) should represent the treatment of choice,34 courses of other antibiotics, such as metronidazole, ciprofloxacin and doxycycline, may be introduced to decrease resistance. Another fundamental target of pharmacological therapy is represented by the improvement of gastrointestinal motor functions and the control of visceral sensitivity. A variety of drugs including indomethacin, xylocaine, cholinergic and anticholinesterase drugs, noradrenaline, meperidine, metoclopramide, domperidone, cisapride, erythromycin, prostaglandins, somatostatin, serotonin, leuprolide and octreotide have been described as either effective or ineffective in isolated cases, but no firm conclusion can be drawn from these reports. Since CIPO is such a rare condition, only a few trials have been published so far (Table 7).18,20,21,31,35–39 The vast majority of these studies are uncontrolled. In two controlled trials, Camilleri and colleagues described a positive effects of cisapride in accelerating gastric emptying35 and improving symptoms.39 This latter effect was restricted to patients without vagal dysfunction and generalized sympathetic dysfunction. Notably both trials also included patients with gastroparesis and other unspecified motility disorders. Various associations of prokinetic drugs are often empirically tested2 in an attempt to increase their therapeutic effects while decreasing the risk of tachyphylaxis and side effects.

Table 7.   Therapy in patients with chronic intestinal pseudoobstruction (CIPO)
Author Patient Duration of study Treatment regimenDesignResponse
  1. *Radiological criteria of intestinal obstruction were not present in all patients or not reported in the text, as specified in the first column or previously reported (see Table 3 for details).

Camilleri et al.35* 26 adults (15 intestinal dysmotility or CIPO) 6 weeks therapy Cisapride 10 mg t.i.d./placeboParallel groupsNo significant differences of overall symptom response [UPWARDS ARROW] Gastric emptying of solids
Abell et al.37* 21 adults (12 CIPO) 12 months therapy Cisapride 10 mg t.i.d.Open trialNo significant differences of symptom response in CIPO [UPWARDS ARROW] Gastric emptying of solids in CIPO
Soudah et al.38 5 CIPO adults with scleroderma and bacterial overgrowth 3 weeks Octreotide 100 mcg scOpen trialReduced bacterial overgrowth Reduced symptom score for nausea, vomiting, bloating and abdominal pain
Hyman et al.18* 49 CIPO children 12 months Cisapride 0.1 mg kg−1 t.i.d.Open trialUnchanged symptom score (25 patients) Fair (improved symptom score) (17 patients) Excellent (TPN[RIGHTWARDS ARROW]tube feeding; tube feeding[RIGHTWARDS ARROW]oral feeding) (7 patients)
Camilleri et al.28* 37 neuropathic adults with gastroparesis or intestinal dysmotility or CIPO 12 weeks Cisapride 10 and 20 mg t.i.d./placeboParallel groupsNo significant effect of treatment on overall symptom score Significant reduction of overall symptom score at 6 weeks in patients without vagal dysfunction Significant reduction of overall symptom score at 12 weeks in patients with general sympathetic dysfunction
Verne et al.29* 14 CIPO adults 20–33 weeks Octreotide 50 mcg sc od+ Erythromycin 200 t.i.d. oralOpen trialLong-term improvement of nausea and abdominal pain (5 patients)
Camilleri et al.39* 37 neuropathic adults with gastroparesis or intestinal dysmotility or CIPO 12 months Cisapride 20 mg t.i.d.Open trialImprovement of overall symptom score No significant change in body weight Improvement of overall symptom score in the presence of general sympathetic dysfunctions and in the absence of vagal dysfunctions
Emmanuel et al.31 15 CIPO adults 41 months FU (13–64 months) Erythromycin 1.5–2.0 g day−1Open, retrospective analysis of responders to erythromycin (6 patients)Increased overall symptomatic score (6 patients) Improved vomiting (5 patients) Increased body weight (4 patients)

In very selected cases in which CIPO is related to an underlying inflammatory neuropathy (i.e. myenteric ganglionitis) established by tissue analysis or suspected by the identification of circulating anti-neuronal (e.g. anti-Hu) antibodies, a course with immunosuppressive treatment is recommended.4 The most common immunosuppressive agent used has been either methylprednisolone or prednisone, both administered at different doses depending on the series treated (usually very small numbers). Overall, the immunosuppressive treatment significantly improved the severe dysmotility syndrome, although these promising results should be taken with caution, since further trials on a consistent number of patients are awaited.

Surgical therapy

The elevated number of abdominal surgeries which characterizes the natural history of CIPO2 is sufficient per se to demonstrate the impotence of traditional surgical procedures in correcting the generally diffuse disorders of digestive motility typical of this disease. A few exceptions exist and must be taken into consideration. Gastrostomies and enterostomies can effectively decrease retching, vomiting and abdominal distension. Decompression of bowel loops can exert a positive effect on the transport capacities of the alimentary canal which, in turn, results in a decreased frequency of hospital admissions and other forms of abdominal surgery.10 Enterostomies can also be useful for infusion feeding (see above). In the rare cases having a localized involvement of the gastrointestinal tract, a surgical bypass of the affected bowel loop can be beneficial.10 However, although the disease may sometimes appear to be restricted to a specific tract of the alimentary canal, it generally turns out to be a progressively diffuse motor disorder, so that the benefit obtained by a surgical bypass or resection is likely temporary.

When all other therapeutic options have failed, transplantation should be considered. Both isolated intestinal and multivisceral transplantation are gaining acceptance as the standard treatment for patients with intestinal failure and insurmountable HPN complications. Small bowel or multiorgan transplant has very specific indications. Besides, locally invasive tumours of the abdomen, Italian guidelines for intestinal transplantation also include any form of chronic intestinal failure with a high risk of mortality, life-threatening complications of HPN, lack of venous access for HPN, disease-related poor quality of life despite optimal HPN.33 Despite the unique immunobiologic features of the small bowel, overall outcomes of the procedures continue to improve with the use of the immunosuppressive agent tacrolimus variably associated with a number of induction agents such as alemtuzumab, antithymocyte globulins and daclizumab. One year patient survival rates approaching 100% have recently been reported after isolated small bowel transplantation,40 but highly variable results have been reported for multiorgan transplant and long-term outcomes are awaited. The need for long-term HPN, re-laparotomies, organ rejection and, especially, bacterial infections are frequent complications. Relatively high percentages of post-transplant lymphoproliferative diseases in the long-term have also been reported. Small bowel transplant may be particularly challenging in CIPO patients when compared with other forms of intestinal failure for different reasons including: concomitant neuromuscular disorders of the urinary tract, chronic use of opioids and technical problems determined by previous multiple laparorotomies and/or the need of gastrectomy for gastroparesis.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

Chronic intestinal pseudo-obstruction is a rare, severe and still too often misdiagnosed pathological condition. Confusion in its definition has a negative impact on the clinical management of affected individuals. Diagnosis is difficult and often delayed due to the lack of a biological marker and the symptomatic overlap with severe forms of other digestive syndromes including intractable dyspepsia and inertia coli which are characterized by similar gut motor dysfunction, but different natural histories. Management of CIPO remains extremely challenging even in referral centres with a specific interest in the field and the majority of patients experience disabling and potentially life-threatening complications over time. A greater awareness of the clinical features of CIPO by doctors would help to recognize possible underlying causes of secondary forms and limit surgical procedures to a minimum. The collection of full-thickness biopsies for analysis of the gut neuromuscular layer at an early and potentially curable stage of the disease may provide new expectations for patients with CIPO.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References

This study was supported by the Italian Ministry of University, Research, Science and Technology (nos 2002068514_002 and 2003064378_003 to VS, RDeG, GB, and RC).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Diagnosis
  5. Natural history
  6. Therapy
  7. Conclusions
  8. Acknowledgments
  9. References
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