Diagnosis and Treatment of Chronic Intestinal Pseudo-Obstruction in Children: Report of Consensus Workshop

The diagnostic term, chronic intestinal pseudo-obstruction (CIP) is often used with poor regard to its meaning. The resultant inconsistency in the use of the term has hampered the clinical investigation and management of children with disorders of gastrointestinal motility (1). In addition, inappropriate application of a diagnosis of CIP based on exaggerated symptoms and overinterpretation of diagnostic tests has resulted in the perpetuation of and inadvertent physician collusion in Munchausen syndrome-by-proxy (2-4). Therefore, a Consensus Working Group was convened to address these problems, arrive at a clear definition for CIP, and suggest approaches for the diagnosis and treatment of this disorder. DEFINITION AND CLASSIFICATION OF PSEUDO-OBSTRUCTION Terminology, clinical presentation, causes, and diagnostic approaches to gastrointestinal pseudo-obstruction in adults was summarized in a 1990 working team report (5). The terms defined in the adult working team report are applicable to pediatric patients. The term pseudo-obstruction denotes signs and symptoms resembling a physical obstruction to luminal flow, but without a true mechanical obstruction. Pseudo-obstruction may occur in any and all regions of the gastrointestinal tract. Further, pseudo-obstruction may occur as an acute response, as in paralytic ileus, or as a chronic remitting or persistent disorder. Although the term was initially applied only to syndromes suggesting intestinal obstruction, this broader definition encompasses other region and specific segmental motor disorders of the gastrointestinal tract, including achalasia, gastroparesis, Hirschsprung disease, and slow-transit constipation. Diagnostic approaches to these segmental motor disorders are described in standard medical textbooks and are not addressed here. DEFINITION OF CIP CIP is a rare, severe, disabling disorder characterized by repetitive episodes or continuous symptoms and signs of bowel obstruction, including radiographic documentation of dilated bowel with airfluid levels, in the absence of a fixed, lumen-occluding lesion. If pseudo-obstruction is congenital and persists for the first 2 months of life, or if the disorder is acquired and persists for >6 months, it is considered chronic. The small intestine is always involved, and the esophagus, stomach, and colon may be affected as well. Use of the term does not imply that the cause of the disorder is unknown. CIP may occur in many of the irreversible disorders that are listed in Table 1. In a few congenital cases, the intestinal neuropathy is such that the stomach does not empty and the bowel does not dilate. In such cases, histopathological evidence (e.g., total aganglionosis) is sufficient for a diagnosis of CIP and the requirement for bowel dilation is omitted. The proposed definition for CIP is purposefully narrow in order to prevent use of the term to describe other disorders of gastrointestinal motility, such as acute reversible forms of pseudo-obstruction or irritable bowel syndrome. There is concern that an over-use of the term CIP has confused the classification of gastrointestinal motility disorders, resulting in the unnecessary use of aggressive therapies, including parenteral nutrition in children with less severe disorders. Disorders that resemble CIP, but that do not meet the criteria of the above definition, are listed in Table 2. These disorders are usually less resistant to therapy and do not necessarily portend a chronic, lifelong disease process. Although a definition requiring bowel dilation might delay the diagnosis of idiopathic CIP, such a delay should not necessarily adversely affect management. Children with CIP or other disorders of gastrointestinal sensory or motor function respond to a variety of therapeutic interventions depending on the region of bowel involved and the severity of disease. Treatment should not be withheld because the diagnostic criteria for CIP have not been manifested. However, an incorrect or premature assignment of the diagnosis of CIP may reinforce the sick role. The restricted definition of CIP is intended to prevent the overaggressive treatment of children with less severe gastrointestinal motility disorders and to encourage rigor in establishing explanations for symptoms. In addition, the definition can serve as a standard definition for future studies of the pathogenesis and treatment of CIP. Rather than using the term CIP, the term gastroparesis can be used to more accurately describe patients without dilated bowel but with disorders of gastric emptying. CLINICAL SPECTRUM OF CIP CIP may be classified either as primary or secondary. In primary CIP, the disease usually is limited to the hollow viscera, whereas in secondary forms, CIP is associated with an existing systemic disorder (Table 1). Some conditions classified as primary CIP are associated with extragastrointestinal manifestations involving the urinary tract or autonomic, peripheral, and central nervous systems. This classification scheme does not imply that the gastrointestinal tract is normal in the so-called “secondary” disorders nor does it aid in understanding the underlying disease mechanisms. Disorders associated with primary CIP are classified as either myopathy or neuropathy depending on histopathology. The term “idiopathic” is applied when the disorder does not fit a recognizable genetic syndrome, when there is no apparent secondary cause, and when affected tissues are unavailable or appear normal under histological examination. Further subclassification as congenital or acquired is based on the presence or absence of symptoms at birth. Congenital myopathies and neuropathies present with symptoms at birth or shortly after. In most cases of congenital CIP, disease severity is greatest at birth and tends to improve or plateau over the first months of life. In contrast, forms of noncongenital CIP present later in childhood or adulthood. Other noncongenital disorders may be acquired through infection or immune-mediated inflammation within the myenteric plexus. Acquired forms of CIP may worsen or improve over time. In most kindreds presenting with CIP, those affected develop symptoms requiring medical care after childhood that tend to worsen with time. Disorders causing secondary CIP are classified according to presumed underlying pathophysiology to facilitate an organized approach to evaluation. There may be considerable overlap in pathogenesis. For example, infiltrative diseases (such as amyloidosis) may damage both gastrointestinal smooth muscle and nerves. Symptoms include nausea, anorexia, dysphagia, regurgitation, vomiting, abdominal distension and pain, and constipation (6,7), depending on the regions of the gastrointestinal tract involved. Other symptoms may arise from secondary complications, such as diarrhea from bacterial overgrowth, or from involvement of other organ systems, such as the urinary tract. Symptoms may be intermittent or persistent. In some kindreds, asymptomatic individuals may have clear radiographic signs of bowel dilation prior to onset of symptoms, indicating a discordance between symptoms and clinical findings (8). DIAGNOSIS OF CIP An algorithm for the diagnosis of CIP is shown in Fig. 1. In a patient with symptoms of gastrointestinal obstruction, evaluation begins with supine and upright plain radiographs of the abdomen. Documentation of intermittent or persistent bowel obstruction with characteristic radiographic findings of air-fluid levels and bowel distention is required for the diagnosis of idiopathic CIP (9,10). In symptomatic patients without these radiographic findings, other diagnostic possibilities, including functional abdominal pain (11), gastroparesis, aerophagia (12), functional constipation, and nonulcer dyspepsia (13), should be considered (Table 2). An episode of radiographically documented obstruction calls for a complete blood cell count, measures of serum electrolyte concentrations (including calcium and magnesium), and drug screen. A careful history, particularly regarding possible familial pseudo-obstruction, should be obtained. Initial treatment includes nasogastric decompression and correction of abnormalities in fluid and electrolyte homeostasis. Drugs that slow gastrointestinal motility should be discontinued whenever possible. If bowel dilation persists despite correction of laboratory abnormalities and discontinuation of suspect drugs, then radiographic contrast studies should be performed. Enteroclysis may be necessary to rule out a partial mechanical obstruction (14,15). In chronic cases, and after excluding mechanical obstruction, secondary causes of pseudo-obstruction should be considered (Table 1). In immunodeficiency states, including those induced by medication following organ transplantation, symptoms of CIP should prompt an evaluation for myenteric plexus neuritis due to cytomegalovirus or Epstein-Barr virus. Screening blood tests for diabetesmellitus (hemoglobin A1C or postprandial blood glucose concentration), connective tissue and skeletal muscle disorders (antinuclear antibody panel, creatine phosphokinase, aldolase), and hypothyroidism (16) should be performed. Other tests to consider include serology for Chagas disease, urinary cate-cholamines to rule out pheochromocytoma (17,18), urinary porphyrins, and enteric neuronal autoantibodies (19). Hirschsprung's disease is diagnosed with a suction rectal biopsy. A full-thickness rectal biopsy may be indicated to exclude the neuronal intestinal dysplasias (20,21), particularly those associated with multiple endocrine neoplasia, type 3 (22-25). Antiendomysial antibody testing or small intestinal biopsy may be considered to rule out celiac disease (26,27). Further evaluation is not necessary after treatable causes of pseudo-obstruction have been ruled out. Antroduodenal manometry and full-thickness bowel biopsies may aid in clarifying pathophysiology and histology, respectively, but, in most cases, will not alter treatment (see below). If symptoms and signs of pseudo-obstruction persist for >2 months after birth or >6 months in a child presenting after birth, a firm diagnosis of idiopathic CIP is warranted. OTHER DIAGNOSTIC APPROACHES At this time, no single diagnostic test is specific enough to assume an accurate diagnosis of idiopathic CIP. The use of motility testing is discussed briefly bwlow. Motility is a term that encompasses measures of both wall movements and luminal transit through the gastrointestinal tract. Measurement of Transit Orally administered radio-opaque markers to measure transit through the colon may discriminate between slow-transit constipation and fecal with-holding in children (28,29). This method is not useful for the evaluation of small-bowel transit. Mouth-to-cecum transit can be measured by ingestion of substances that are degraded by bacteria in the colon to a product detectable in breath; the lactulose breath hydrogen test is an example of this approach (30). However, these methods are unreliable in pseudo-obstruction due to small bowel bacterial overgrowth and the wide variations in intestinal transit time in normal children (31). Labeling of meals with radioactive isotopes and imaging with a gamma camera provides reliable measures of esophageal transit (32) and gastric emptying in children (33,34). The use of scintigraphy also has been validated for the measurement of small bowel and colon transit in adults (32,35). However, normal values are not established for children. These techniques offer useful preliminary information. If solid meals exit the stomach normally, it is unlikely that there is a serious underlying gastric motility disorder. Antroduodenal Manometry Antroduodenal manometry is used extensively to assess the physiology that could explain symptoms of a motility disorder. Although there are only a few published studies in normal children, extensive data from healthy neonates (36), adults (37,38) and sick children (39) provide information sufficient to permit limited interpretation of data from children. Interpretation of antroduodenal motility studies in the context of the clinical history may provide information that can aid in management. Antroduodenal manometric studies usually are abnormal in children with CIP, with more obvious abnormalities being observed in severely affected patients (40-42). Subtle or infrequent discrete abnormalities in manometric patterns may be observed in some children with gastroesophageal reflux (13), nonulcer dyspepsia (13,43), and recurrent functional abdominal pain (11). Motor patterns are affected by sleep, pain, anxiety and anger, various drugs, and prior surgery. There are a variety of artifacts that may confound data analysis. Despite these reservations, antroduodenal manometry may be useful in guiding the management of patients with certain gastrointestinal motility disorders. In general, normal amplitude, uncoordinated contractions characterize neuropathies, and persistently low amplitude, coordinated contractions characterize myopathies. In children, presence of a normal migrating motor complex predicted successful enteral nutrition support (40,41). In adults, characteristic patterns of small bowel contraction, including postprandial cluster activity (44) and simultaneous broad-based contractions, may suggest mechanical obstruction (44,45). If these patterns are observed, more detailed radiographic evaluation with enteroclysis should be pursued. Antroduodenal manometry is also useful to distinguish between vomiting and rumination (46). Vomiting is an involuntary reflex with characteristic features that precede, accompany, and follow the event. Emesis with rumination is associated with brief increases in intraabdominal pressure evident as simultaneous short duration increases in pressure in all recording sites. The absence of antroduodenal manometric abnormalities also may be useful in certain clinical situations. Normal antroduodenal manometry usually indicates that a gastrointestinal motility disorder does not underlie a child's symptoms. Instead, behavioral disorders in the child or the family, including Munchausen's syndrome-by-proxy and somatiform pain disorder (47), should be considered (Table 2). Documentation of abnormal antroduodenal manometry prior to intestinal transplantation may prove helpful in predicting the need for a feeding jejunostomy in the transplant recipient. Antroduodenal manometry may be helpful to rule out a generalized motility disorder in patients with intractable constipation who are being considered for colectomy. Electrogastrography Surface electrogastrography measures the rhythm and amplitude of gastric electrical activity. In a clinical research setting, gastric antral dysrhythmias have been demonstrated, by this method, in some patients with CIP (48). This noninvasive technique requires further validation and development before it can be useful for the clinical assessment of CIP in infants and children. Histology Abnormalities of gastrointestinal nerve and muscle have been demonstrated in children and adults with CIP (49-52). Demonstration of histologic abnormalities is not required for diagnosis of idiopathic CIP; however, if tissue can be obtained safely when surgery is performed for another indication, such as ostomy placement, histologic studies are warranted (53). Staining with conventional metachromatic dyes may demonstrate degenerative changes in smooth muscle and excess collagen deposition within the muscularis propria. Immunochemical staining for specific smooth muscle proteins, such as α-actin, may reveal specific deficits (54). Tangential sections stained with silver stains, acetylcholinesterase stains, and immunochemical stains may demonstrate degeneration of neurons and axons, hypoganglionosis, proliferation of neurons or nerve fibers in the lamina propria, or glial cell proliferation. As the pathogenesis of the various causes of CIP is clarified, more detailed histologic study may be useful for determining prognosis and guiding treatment. TREATMENT OF CIP Optimal nutrition by enteral or parenteral routes is of utmost importance both for supporting normal growth and development, and for digestion. When gastroparesis prevents oral or intragastric tube feedings, a trial of postpyloric feedings is occasionally successful (55). Even when parenteral feedings are required, at least small volumes of enteral feeding are desirable to prevent cholestatic liver disease (56) and to maintain bowel mucosal integrity (57). Bacterial overgrowth, a frequent complication of pseudo-obstruction (58,59), often causes malabsorption (60) and may be associated with increased mucosal permeability to macromolecules (61) and bacterial translocation across the bowel (62,63). Intermittent treatment of bacterial overgrowth provides symptomatic relief and may decrease the risk of hepatobiliary injury (64) and sepsis. Cisapride may provide symptomatic improvement in some children with pseudo-obstruction (40,65). Erythromycin (66), metoclopramide (67,68), bethanechol (68), domperidone (69), and naloxone (70) have not been of proven benefit but may be useful in selected cases. Combined therapy with octreotide and erythromycin reduced nausea and abdominal pain in adult patients with idiopathic and scleroderma-associated intestinal pseudo-obstruction (71). Bowel decompression by nasogastric suction is useful during acute exacerbations in patients with cyclical symptoms. Patients with frequent exacerbations or chronic distension often benefit from placement of a venting enterostomy (72-75). Patients who have severe disability due to bowel dilation and who have sepsis may occasionally benefit from subtotal enterectomy and parenteral nutrition (74). Small intestine transplant may offer a potential for cure in children with life-threatening disease due to bowel dilation and recurrent sepsis, or with serious complications of parenteral nutrition, including liver failure or limited central venous access (76). Acknowledgment: The Consensus Workshop and subsequent manuscript preparation were supported through an Unrestricted Educational Grant provided by Janssen Pharmaceutica.FIG. 1: . Diagnostic algorithm for primary idiopathic CIP in infants and children who present with symptoms suggestive of a primary motility disorder. Antroduodenal manometry is not required for the diagnosis, but provides convincing confirmation of a physiological disturbance in some cases of CIP (see discussion). Similarly, full-thickness intestinal biopsy is not required for diagnosis, but may provide a clearer understanding of the etiology of CIP in an individual patient (see discussion).