Chapter 407. Motor Disorders of the Stomach, Small Bowel, and Colon

Propulsion of the luminal contents along the gastrointestinal tract requires coordinated contractions of the intestinal smooth muscle in response to input from the enteric neurons. The enteric nervous system is capable of independent function that is modulated by motor input from the brain. Gastrointestinal motor function develops between 26 to 36 weeks of gestation, but it is poorly developed before 30 weeks and not fully developed until 36 weeks gestation. Thus, it is not unusual for preterm infants to have poor gastric emptying and feeding intolerance.1 GI motility disorders result from weak or uncoordinated contractions due to abnormalities of the neuromuscular apparatus or abnormal sensory and motor input from the brain. These disorders range in severity from mild disorders, such as recurrent abdominal pain, to severe, such as chronic idiopathic pseudo-obstruction syndrome with intestinal failure.2

Motor disorders of the stomach can result from either too rapid or too slow gastric emptying. The stomach is a complex electromechanical chamber, and the rate of gastric emptying is influenced by the meal consistency, calorie concentration, and central neural and hormonal input mechanisms. The act of swallowing initiates gastric accommodation (receptive relaxation) such that the stomach fundus expands to receive the ingested food. This reflex is mediated by vagal pathways and can also be initiated by gastric distension, duodenal distension, or nutrient infusion into the small bowel. Pharmacologic inhibition of gastric accommodation induces early satiety and weight loss. A gradual increase in the proximal stomach muscle tone transfers the food into the distal stomach. Liquids are transferred rapidly from the proximal to the distal stomach and emptied into the duodenum by series of antral peristaltic contractions. In contrast, solids are emptied relatively slower. There is a significant lag phase in the delivery of solids from the stomach into the duodenum, as food particles first need to be ground into a thick chyme, consisting of particles 1 to 2 mm in diameter. The strong antral contractions that typically occur at a rate of 3 per minute help to grind and mix the food before it is emptied into the duodenum. Following passage of the food into the small intestine, rhythmic contractions of the small intestine mix the chyme, allowing maximum mucosal exposure of nutrients, and propels the food to the cecum. Fluid is absorbed as the undigested colonic contents pass distally to the cecum where segmenting waves allow fluid absorption. Following meals and upon awakening, high-amplitude propagating contractions occur that propel colonic contents into the rectum, initiating the need to defecate.

Clinical Features and Differential Diagnosis

Early satiety, postprandial fullness and discomfort, reduced calorie intake with weight loss, and halitosis are all symptoms of delayed gastric emptying.3 When gastric emptying is marked, food ingested several hours or sometimes days earlier may be vomited. Anatomic obstruction of the gastric outlet or proximal small bowel can present similarly to motor disorders. If these are excluded, then a variety of disorders may cause slow emptying, as listed in Table 407-1. Diabetic, postsurgical, and idiopathic causes are the 3 most common forms of gastroparesis. Gastric emptying is delayed in preterm infants4 due to immaturity of the enteric nervous system. In older children it can follow various infections (Epstein-Barr virus, cytomegalovirus),5 eosinophilic gastroenteropathy, or damage to vagal nerve or its branches during surgery.6

Delayed gastric emptying should be differentiated from gastrointestinal obstruction. Aerophagia can present with abdominal distension and dyspeptic symptoms, but normal gastric emptying.7 The child either voluntarily or unconsciously swallows excessive amounts of air with saliva or may swallow excessive air due to a swallowing disorder. Sometimes in aerophagia the abdominal and gastric distension gradually worsen during the day and improve overnight.

Diagnostic Evaluation

Abdominal X-ray examination often reveals a large dilated stomach, but both aerophagia and anatomic obstruction can present similarly. Upper GI contrast study is required to exclude a gastric outlet obstruction and if severely prolonged, suggests gastroparesis (eFig. 407.1). Diagnosis of gastroparesis is best determined using a radioisotope-labeled solid meal with scintigraphic imaging for at least 2 hours, and preferably 4 hours, postprandially. Most commonly, a 99mTc sulfur colloid-labeled egg sandwich with imaging at 0, 1, 2, and 4 hours is used in adults or adolescents. Radioisotope-labeled milk is used for infants.8 Scintigraphic gastric emptying studies in children are fraught with difficulties. Infants and uncooperative toddlers cannot lie motionless under the gamma camera for extended periods of time. Standard test meals cannot be given to infants with dietary protein allergies or to children who refuse to eat, and there are no normal values for healthy children. Due to the difficulties encountered in performing reliable scintigraphic emptying studies in infants and children, breath tests to assess gastric emptying using a carbon 13 octanoic acid-labeled test meal is being used as an alternative to scintigraphy.9 The major benefit of stable isotope emptying studies is the lack of exposure to radiation. Antroduodenal manometry enables a direct record of the gastric antrum contractions and evaluation of the gastric motor response to a meal and drugs, such as erythromycin. Ultrasound has also been used to evaluate gastric emptying in young infants, but it is not as reliable as other methods. Electrogastrography allows recording of gastric myoelectric activity using skin electrodes. In healthy subjects the dominant frequency is 3 cycles per minute. Gastric dysrhythmias have been associated with a variety of conditions that can present with gastric motor disorders.

Treatment

Treatment of delayed gastric emptying is challenging.10 The aims of treatment are to control symptoms and to maintain adequate nutrition and hydration. Administration of small meals consisting of liquids (which often empty better), low fat, and fiber, is often helpful. Diabetic patients must control blood glucose levels since symptom exacerbation is frequently associated with poor glycemic control. Treatment with the prokinetic metoclopramide may be helpful, but side effects of tardive dyskinesia may limit use. Domperidone (not readily available in the United States) is preferable to metoclopramide due to a lower risk of side effects. If this regimen is unsuccessful, then alternative prokinetic agents erythromycin or tegaserod may be considered. Antiemetic agent may be helpful to control nausea, with orally dissolving odansetron being particularly effective. Symptom modulators such as low-dose tricyclic antidepressants can be tried to reduce symptoms, but these do not improve gastric emptying. If all medical therapy fails, other therapeutic options include the injection of botulinum toxin into the pylorus, placement of a feeding jejunostomy, and/or placement of a gastric electrical stimulator.

In premature infants administration of either small, frequent feeds or slow nasogastric drip often allows adequate nutritional support until emptying improves with maturation. Breast milk empties faster than formula feeds.6 Nasojejunal tube feeding may be necessary if the infant is unable to tolerate gastric feeds. In infants, prokinetic agents are of limited value. Erythromycin, a motilin receptor agonist, accelerates gastric emptying and improves feeding intolerance but is associated with an increased risk of pyloric stenosis with erythromycin use in infancy. Metoclopramide and domperidone may increase emptying but have neurologic side effects.

Clinical Features and Differential Diagnosis

Rapid emptying of the meal (dumping syndrome) into the proximal small bowel produces fluid shifts and a surge in blood glucose. Symptoms of abdominal fullness, pain, and nausea are frequent. Insulin release in response to elevated blood glucose results in a rebound hypoglycemia, causing tachycardia, diaphoresis, lethargy, and sometimes syncope.

Accelerated gastric emptying can result from decreased gastric compliance caused by vagal denervation or altered pyloric function as a result of pyloroplasty, surgical bypass procedures, or gastric drainage procedures. Dumping syndrome has also been reported in up to 5% of children following fundoplication.11 Another common cause of intermittent dumping syndrome in children is accidental migration of a gastrostomy feeding tube through the pylorus so that when bolus feeding is administered, the symptoms of dumping syndrome are mimicked.

Diagnostic Evaluation

Clinical symptoms are usually sufficient for the diagnosis, but fluctuations in blood glucose concentration can be documented by a glucose-tolerance test. Gastric emptying scans will demonstrate accelerated emptying if measurements are obtained frequently following the meal.

Treatment

Small, frequent meals and substituting complex carbohydrates such as uncooked corn starch in the diet will help prevent fluctuations in blood glucose and associated symptoms.12 Nasogastric drip feeds may be required to slowly infuse nutrients into the stomach. Octreotide, a long-acting somatostatin analog, has also been used to slow the gastric emptying, but chronic use is impractical.

Chronic intestinal pseudo-obstruction syndrome refers to a heterogeneous group of disorders with a similar phenotypic presentation characterized by obstructive intestinal symptoms in the absence of an anatomical obstruction.13 Abnormalities of the enteric neurons or the enteric smooth muscle result in ineffective gastric and intestinal propulsive activity. Based on the strict definition, chronic intestinal pseudo-obstruction syndrome should only be diagnosed once a mechanical obstruction has been excluded. The exact incidence is not known, but it is estimated that 100 children with congenital pseudo-obstruction are born in the United States every year.

Pathophysiology and Genetics

Familial and nonfamilial forms, with autosomal recessive and dominant patterns of inheritance, have been reported. In a majority of children, chronic intestinal pseudo-obstruction syndrome is idiopathic or primary, and in a small percentage it is associated with a systemic disorder (Table 407-2).13 In utero exposure to toxins and viral infection has been linked to chronic intestinal pseudo-obstruction syndrome. Patients with mitochondrial neurogastrointestinal encephalopathy can present with chronic intestinal pseudo-obstruction syndrome14 prior to the onset of neurological symptoms. Immune-mediated damage to enteric neurons or smooth muscle is a rare cause of acquired chronic intestinal pseudo-obstruction syndrome.

Clinical Features and Differential Diagnosis

Almost half of the patients present in infancy, and 40% of them also have intestinal malrotation.13,15 If symptoms persist after surgery for malrotation, the child should be investigated for mechanical obstruction, and if absent, a diagnosis of chronic intestinal pseudo-obstruction syndrome is considered. Common symptoms include nausea, vomiting, abdominal distension, constipation, abdominal pain, and failure to thrive. Diarrhea due to small bowel bacterial overgrowth and bile acid malabsorption is also common. Apart from the GI tract, urinary tract and bladder involvement can result in megacystis and megaureter. In most children with congenital disease, the clinical course has an illness plateau with intermittent increases in acuity. Triggers for decompensation include viral or bacterial infections, central line sepsis, general anesthesia, psychological stress, and malnutrition.

Nonspecific radiographic signs include dilated stomach, small intestine, and colon with air-fluid levels (eFig. 407.2). Contrast studies are helpful in excluding an anatomic obstruction. Prolonged contrast stasis and bezoar formation is a known complication of such studies in patients with chronic intestinal pseudo-obstruction syndrome, so evacuation of barium must be planned or water-soluble contrast used.Manometric studies can help to evaluate the strength and coordination of contractions in the esophagus, gastric antrum, small intestine, and colon.16-18 Severe manometric abnormalities usually correlate with more severe clinical symptoms. In children with abnormalities of the enteric nervous system, the small bowel contractions are of normal amplitude but uncoordinated, and phase 3 of the migrating motor complex is absent (eFig. 407.3). Patients with abnormalities of the bowel muscle lining have coordinated contractions, but the amplitude of contractions is reduced. Colon manometry studies show absence of high-amplitude colon contractions or abnormal retrograde or simultaneous colon contractions. Recently, it has been recognized that inflammatory enteric neuronal damage can be reversed by using immunosuppressive agents if it is diagnosed early.19 Full-thickness intestinal biopsy is necessary for histologic evaluation.

Treatment

Providing adequate nutritional support to ensure normal growth and development of the child with chronic intestinal pseudo-obstruction syndrome (CIPS) guides all management decisions (Table 407-3). Almost a third of patients require parenteral nutritional support. Ninety percent of the deaths due to CIPS are related to complications of parenteral nutrition and include central line sepsis and parenteral nutrition–induced liver cirrhosis and decompensation.15,16,17 Therefore, optimal use of enteral nutrition and discontinuation of parenteral nutrition at the earliest opportunity is important. Children who are unable to feed orally or who do not tolerate bolus feeds may tolerate continuous nasogastric tube or gastrostomy feeding. Children who have gastroparesis can be fed directly into the proximal small bowel through a gastrojejunal tube or a jejunostomy.

Small bowel bacterial overgrowth is common in patients with CIPS.16 Symptoms include increased bowel distension and diarrhea. Steatorrhea and malabsorption of vitamin B12 may result from bacterial overgrowth. Judicious use of oral antibiotics is required for treatment to prevent emergence of antibiotic-resistant organisms. If frequent treatment is required, antibiotics should be cycled, and additional use of antifungal agents may be considered. Chronic pain is often the most distressing symptom of CIPS. Treatment options include bowel decompression, low-dose tricyclic antidepressants, and gabapentin. Narcotics disrupt intestinal motility, are not effective in controlling chronic pain, and should be avoided if possible. A gastrostomy tube can be used to evacuate the gastric contents and relieve nausea, vomiting, and pain related to stomach and proximal small bowel distension; however, loss of fluid and electrolytes can be excessive, so replacement fluids are often required. Stool softeners and stimulant laxatives are used to treat chronic constipation, and sometimes suppositories and enemas are necessary.

Management of acute obstructive episodes is often challenging, especially in children with previous surgeries. Unnecessary surgeries should be avoided as postoperative ileus is prolonged and adhesions develop, creating a diagnostic problem each time there is new obstructive episode. Children with colon dilatation due to chronic constipation are at risk of developing colon volvulus (eFig. 407.4). They usually present with obstipation and excruciating pain that is different from their typical pseudo-obstruction pain, nausea, and vomiting.

Children who have life-threatening complications of chronic intestinal pseudo-obstruction syndrome should be referred for consideration of possible intestinal transplantation (Chapter 131).20,21 The quality of life for children with chronic intestinal pseudo-obstruction and their parents is relatively poor compared to most other chronic diseases.22 An interdisciplinary team that can provide adequate support and care for the child and the family is crucial.

Hirschsprung disease is a neurocristopathy due to the aberrant migration, proliferation, or differentiation of vagal neural crest cells. The most common form of the disease (~ 80% of patients) is called short-segment Hirschsprung disease, where aganglionosis does not extend beyond the sigmoid colon. In the 20% of the patients, the aganglionic region extends more proximally, sometimes involving much of the small intestine.23

Epidemiology and Associated Disorders

Hirschsprung disease occurs in 1 in 5000 live births and is the most common cause of lower intestinal obstruction in neonates. Hirschsprung disease is a male-predominant disease, with male-to-female ratio of 4:1 in children with rectosigmoid disease. The recurrence risk for siblings of a child with short-segment Hirschsprung disease is 4%.18 As the length of aganglionic segment increases, the recurrence risk to siblings increases and is almost 20% with total colonic aganglionosis.18 The male predominance decreases with increasing length of bowel aganglionosis. Racial distribution is equal for white and African American infants. Hirschsprung disease is associated with a variety of genetic syndromes including Down syndrome (up to 10% of patients with Down syndrome), multiple endocrine neoplasia type 2A, Shah-Waardenburg syndrome, Santos syndrome, and Haddad syndrome (eTable 407.1).

Pathophysiology and Genetics

The migration and differentiation of the neural crest cells is under the control of variety of neuropathic factors secreted by mesenchymal cells.24 Expression of these molecules is controlled by a several genes or gene pathways, including the Hox and Sox homeobox genes, RET gene pathway, and endothelin type B receptor pathway.24 RET gene on chromosome 10q encodes a receptor tyrosine kinase expressed in cells of neural crest origin. It transduces extracellular signals that influence cell proliferation, migration, differentiation, and programmed cell death. Many of the mutations identified in RET in individuals with Hirschsprung disease are heterozygous loss-of-function mutations distributed throughout the gene. The penetrance of RET mutations is estimated to be approximately 50% to 70%. RET mutations are much more likely to be identified in familial cases of Hirschsprung disease (~ 50%) than in sporadic cases. Mutations in the RET ligands, GDNF and NTN, have been identified in a small minority of cases of Hirschsprung disease. EDNRB is a G protein–coupled receptor activated by 21 amino acid peptides known as endothelins. Patients with homozygous mutation of this gene often have pigmentation defects of skin and hair and sensorineural hearing loss, referred to as Shah-Waardenburg syndrome. Mutations in human SOX10 have also been identified in patients with Hirschsprung disease and Shah-Waardenburg syndrome.

The inheritance pattern varies depending upon the length of intestine involved. For short-segment disease (sigmoid only), the inheritance pattern is multifactorial (caused by an interaction of more than 1 gene and environmental factors; risk lower than 50%) or autosomal recessive (1 disease gene inherited from each parent; risk closer to 25%) with low penetrance. For longer segment disease, inheritance appears to be autosomal dominant with reduced penetrance and an inheritance risk closer to 50%.

Clinical Features and Differential Diagnosis

Children with Hirschsprung disease may present with delayed passage of meconium, abdominal distension, bilious vomiting, or enterocolitis.23 Ninety percent of full-term normal infants pass meconium within 24 hours and 99% within 48 hours after birth, but 94% of infants with Hirschsprung disease fail to pass meconium in 24 hours. Therefore, full-term infants who fail to pass meconium within 48 hours of birth should be investigated for Hirschsprung disease. Complete bowel obstruction can develop in the neonatal period or later. Enterocolitis most commonly occurs in the second to fourth week of life and is characterized by fever; abdominal distension; and explosive, foul-smelling, and sometimes bloody stools. About 5% of children present with chronic constipation, 3% with intestinal perforation during the neonatal period, 5% with rectal bleeding from an anal fissure, and 5% with hydroureter from urethral compression.

Diagnosis

The diagnosis of Hirschsprung disease can be made using rectal biopsy, barium enema, or anorectal manometry. However, the most accurate diagnostic test for Hirschsprung disease is a suction rectal biopsy.25 Because of the aganglionosis of the bowel, the extrinsic parasympathetic and sympathetic nerves are overexpressed and hypertrophied. These nerves can be seen in the lamina propria and muscularis mucosa. The contractile action of the neuropeptide Y is unopposed because of lack of vasoactive intestinal peptide and nitric oxide synthesizing enteric nerves. The aganglionic bowel and the anal sphincter are constantly contracted, causing physiologic bowel obstruction. The upstream colon becomes dilated and the muscular wall hypertrophies over time. In short-segment Hirschsprung disease, hypertrophied nerve trunks are present in the submucosa and the myenteric plexus. In total colonic Hirschsprung disease, the thickened nerve trunks are not always seen, therefore the tissue being biopsied should be sufficiently deep to include the submucosa to document absence of ganglion cells. If suction biopsy does not provide definitive results, a full-thickness surgical biopsy is required. Acetylcholinesterase staining can be useful to document hypertrophied nerve trunks.

A normal anorectal manometry can exclude Hirschsprung disease,25 but this test requires specialized expertise and equipment. Failure of the internal anal sphincter to relax during balloon distension of the rectum is suggestive of Hirschsprung disease (eFig. 407.5), but the diagnosis needs to be confirmed by a rectal biopsy (Fig. 407-1). In children with anal achalasia, the internal anal sphincter does not relax with balloon distension, and the rectal biopsy shows normal ganglion cells and no hypertrophied nerve trunks. Barium enema demonstrates a contracted distal aganglionic segment of bowel with a dilated proximal region.4 It is unreliable for diagnosis or exclusion of Hirschsprung disease (especially in cases of short-segment disease or in younger infants), but it can help the surgeon in planning the surgery by providing information regarding the length of the aganglionic bowel.

Treatment

Treatment of Hirschsprung disease is surgical. If enterocolitis occurs, fluid resuscitation, broad-spectrum antibiotics coverage, and warm saline rectal washouts to facilitate colonic decompression are required prior to surgery, which should be performed when the patient has improved. Surgical approaches all involve resection of the aganglionic bowel and anastomosis of the normal ganglionic bowel to the anal canal.23 These include the Swenson, Duhamel, Soave, and Boley procedures. Early bowel reconstruction is currently preferred, and most surgeons perform primary pull-through without preliminary diversion. The results of neonatal pull-through operations are comparable to multistage repair or pull-through performed in later infancy. Reconstruction surgery is now usually performed by laparoscopic-assisted approach26 with excellent cosmetic results and is associated with less postoperative pain and shorter hospital stay. A total transanal endorectal pull-through approach has also gained in popularity recently. Early reports suggest it is associated with less bleeding and pain, faster return to normal feeding, and a shorter hospital stay.

The common immediate postoperative complications include stricture or leakage at the anastomotic site. Following surgery, 60% to 70% of children have continuing problems with defecation.27-29 Persistent constipation following Hirschsprung disease surgery can result from fecal retention, neuropathy proximal to the aganglionic segment, and hypertensive anal sphincter. It can be difficult to distinguish among these conditions when they follow Hirschsprung disease surgery. Colon and anorectal manometry can clarify the diagnosis and help with the treatment planning. Almost 50% of the patients with successful surgery have difficulties with fecal incontinence that may last into adult life. Fecal incontinence results from the high-amplitude colon contractions propagating up to the neorectum rather than stopping at the distal sigmoid colon. Loperamide and amitriptyline often firm up the stools and reduce soiling episodes by reducing the frequency of colon contractions.

Neuromuscular disorders other than Hirschsprung disease present with chronic intractable constipation, usually without incontinence and poorly responsive to conventional laxative therapy. The bowel transit time can be slow, and colon manometry is abnormal.30 Histologic abnormalities do not correlate well with manometry. Hypoganglionosis, in which the number of myenteric neurons is reduced, can be congenital or acquired.31,32 Controversy has existed regarding the existence of a disorder known as intestinal neuronal dysplasia, a condition that must be differentiated from transmural intestinal ganglioneuromatosis, which occurs in association with multiple endocrine neoplasia type 2B. Intestinal neuronal dysplasia can be localized or disseminated. In type A, there is sympathetic aplasia, myenteric plexus hyperplasia, and colonic inflammation, and in type B the submucosal plexus is affected more and there is no sympathetic aplasia. The clinical course is variable, and frequently symptoms resolve with conservative therapy.33 Reduced substance P fibers have also been reported in children with slow transit constipation.34 If oral laxative therapy is ineffective, Malone appendicostomy or a cecostomy button for antegrade enemas can be used to manage symptoms. In carefully selected patients with isolated colon motility abnormalities documented by colon manometry, a partial or total colectomy can be curative.35

Anal achalasia usually presents with chronic intractable constipation from early infancy. Commonly, Hirschsprung disease was considered and excluded by the presence of ganglion cells on rectal biopsy. Anorectal manometry shows an anal sphincter that fails to relax with rectal balloon distension. The lack of anal sphincter relaxation causes partial physiologic anal outlet obstruction.36

Botulinum toxin injection into the anal sphincter can help lower the sphincter pressure and facilitate bowel movement.36 Botulinum toxin is a potent bacterial neurotoxin that acts on the neuromuscular junction to block the release of acetylcholine from presynaptic cholinergic nerves. It weakens the muscle in a focal and transient fashion. In almost half of the patients, symptoms may relapse after 4 to 6 weeks. Therefore, 2 to 3 injections at 6- to 8-week intervals may be necessary. If response to botulinum toxin injection is short or inadequate, internal anal sphincter myectomy can be considered.