Disrupted Neural Pathways

Parasympathetic (vagal) neural input stimulates intestinal motor activity, whereas sympathetic (splanchnic) input is inhibitory. Sympathetic activity is the predominant inhibitory influence on intestinal motility and provides the efferent limb of multiple reflex pathways. Sympathetic stimulation is a key factor in the development of postoperative ileus. Local stimuli trigger an inhibitory reflex that results in intestinal dilatation, for which the somatic and splanchnic nerves provide both the afferent and efferent pathways.²⁴ Local stimuli include incising the abdominal wall and handling of the intestine; blocking sympathetic stimuli during surgery does not fully prevent such inhibition of intestinal motility.

NANC neurotransmitters also play a role in postoperative ileus. Nitric oxide (NO) may be the predominant NANC neurotransmitter that mediates the inhibitory influence of ENS neurons on smooth muscle. Other NANC neurotransmitters, including vasoactive intestinal peptide (VIP) and neuropeptide Y act through inhibitory pathways similar to the NO pathway to relax intestinal smooth muscle; substance P and adenosine triphosphate (ATP) act through excitatory motor pathways to influence postoperative ileus.^25,26 NO inhibitors, and VIP and substance P antagonists decrease postoperative ileus in animal studies, but the potential usefulness of these agents in humans is unclear.^18,25

Release of Neurohumoral Stress Mediators

Surgical stress and circulating inflammatory mediators activate pathways that trigger release of hypothalamic corticotrophin-releasing factor (CRF).²⁷ CRF modulates feeding behavior under stressful conditions—explaining why anorexia is a common reaction to stress—and is considered essential in orchestrating the stress response.²⁸ Experimental studies have shown that administration of CRF or CRF-related peptides delays gastric emptying and inhibits gastric motility^29,30 similar to postoperative gastric ileus, whereas administration of the CRF₁ antagonist, CP-154,526, blocks surgery-induced delay in gastric emptying.¹⁹

Abdominal surgery also stimulates capsaicin-sensitive afferent fibers, activating the inhibitory efferent pathways that disrupt coordinated intestinal motility.³¹ These fibers have been shown to play a crucial role in acute gastroprotection. Release of neurotransmitters such as calcitonin gene-related peptide (CGRP) and the related increase in mucosal blood flow have been identified as key factors in the protective effect of the stimulation of these fibers by capsaicin.³² Capsaicin-sensitive afferent nerves can influence ulcer healing by mediating the hyperemic response through the release of CGRP and facilitating acid disposal in the mucosa.³² Studies are ongoing to determine mechanisms of CRF activity and other stress mediators in the inhibition of gastrointestinal motility.

Intestinal Inflammation

Handling the intestine during surgery results in a marked inflammatory reaction,^33–35 leading to induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the release of mast cells, monocytes, and neutrophils within the muscularis propria, but not the mucosa. Bowel handling also leads to secretion of numerous proinflammatory cytokines including interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1 and up-regulates intercellular adhesion molecule (ICAM)-1.³⁶ Thus, extensive manipulation of the intestine or exposure of the peritoneum to irritants (e.g., pus or blood) increases the probability of developing postoperative ileus. The effect on intestinal transit appears to be proportional to the magnitude of the inflammatory response.³⁷

In addition to autonomic signaling pathways, extrinsic noradrenergic nerves contribute to the regulation of various digestive functions, including intestinal propulsion, mucosal secretions, and bowel sensation, through activation of α₂-adrenoceptors. In the presence of intestinal inflammation, enteric α₂-adrenoceptors are up-regulated, giving enhanced inhibitory control of cholinergic and noradrenergic transmission.^38,39 Located on neurons and inflammatory cells, α₂-adrenoreceptors may be important in the pathogenesis of postoperative ileus, because their location provides a link between the inflammation induced by intestinal handling and activation of neuronal pathways.⁴⁰

Perioperative Fluid Excesses

Intravenous fluid overload during or after surgery delays recovery of gastrointestinal function⁴¹ and is associated with poor survival and complications.⁴² In patients undergoing colon resection, use of perioperative and postoperative restricted fluid regimens has resulted in reduced hospital stays, faster return of gastrointestinal function, and fewer postoperative complications including reduced nausea and vomiting compared with higher-volume strategies.⁴³

Pharmacologic Mechanisms

Standard

Bowel rest neither shortens the time to first bowel movement nor decreases the time to oral intake. Large meals can induce nausea and bloating, but small meals can stimulate gastrointestinal motility and reduce the duration of postoperative ileus.^56,57 Nasogastric tube decompression, once considered standard of care, is not recommended in routine abdominal operations because it does not hasten recovery from ileus.^58,59 In fact, routine use of nasogastric decompression has been associated with a higher postoperative complication rate of atelectasis and aspiration pneumonia and prolonged hospitalization. Early mobilization after surgery is recommended to reduce complications of atelectasis, pneumonia, and deep venous thrombosis; however, there is little evidence that ambulation hastens resolution of ileus.⁶⁰

Preventive

Chewing Gum

Several studies show gum chewing in the postoperative period significantly reduces the time to first flatus and the time to first passage of feces compared with standard treatment alone,^78,79 although the length of hospital stay is only marginally reduced. Chewing gum does not increase complications or readmissions and is a low-risk, inexpensive, first-line approach to resolving ileus after colorectal surgery.⁸⁰

Early Oral Intake

Several randomized, controlled trials support early postoperative feeding (within 24 hours) in patients undergoing gastrointestinal surgery.⁸¹ Although early postoperative feeding can increase vomiting, mortality is reduced with a trend toward reduction of risk of postsurgical complications and shorter hospitalization. Early oral nutrition attenuates catabolism and reduces intestinal permeability that can lessen infectious complications.^82,83 Despite ongoing controversy, studies suggest early postoperative feeding may be of benefit.

Symptoms and Signs

The most characteristic feature of acute colonic pseudo-obstruction is abdominal distention, which can develop gradually over three to seven days or more acutely within 24 hours. About 60% of patients experience nausea and vomiting. Abdominal pain (80%) tends to be mild and constant, with occasional slight rebound tenderness and painless distention.¹⁰³ Low-grade fever may be present. Disturbances of electrolyte levels occur, notably hypokalemia, hypocalcemia, hyponatremia, and hypomagnesemia. New abdominal pain or tenderness, increasing fever, and increasing white blood cell count are features of ischemia or perforation. About 90% of patients have abnormal bowel sounds, which vary from absent to hyperactive. In many cases, the abnormal bowel sounds are high-pitched and suggest mechanical obstruction.²

Radiology

The most distinctive feature of acute colonic pseudo-obstruction on a plain abdominal film is dilatation of the colon that preferentially affects the right side of the colon. The maximal diameter of the cecum typically ranges from nine to 25 cm, often with a cutoff sign at the hepatic or splenic flexure (Fig. 120-3). The left colon, including the rectosigmoid, and the small bowel also may be dilated. Air-fluid levels can be seen in the small intestine but usually do not occur in the colon. Haustral folds often are visualized despite severe distention.

Figure 120-3. Acute colonic pseudo-obstruction. Left, Upright plain film of the abdomen revealing diffuse, but predominantly right, colonic distention, with a cecal diameter of 13 cm, that developed after placement of a right hip prosthesis for a fractured femur. Right, Colonic distention resolved shortly after administration of intravenous neostigmine.

(From Bharucha AE, Camilleri M. Common large intestinal disorders. In: Hazzard WR, Blass JP, Halter JB, et al, editors. Principles of Geriatric Medicine and Gerontology. New York: McGraw-Hill; 2003. p 652.)

Air throughout all colonic segments helps differentiate this condition from mechanical obstruction. Free air is usually a radiologic sign of intestinal perforation, although when free air occurs with pneumatosis intestinalis, it might not be associated with perforation. A water-soluble contrast enema or CT scan can exclude mechanical obstruction if gas and distention are present throughout all colonic segments, including the rectum and sigmoid colon.

Differential Diagnosis

The differential diagnosis includes mechanical obstruction, toxic megacolon, and ischemic colitis. Frequent clinical evaluation including white blood count and plain abdominal radiography are vital to identifying bowel perforation.

Medical Decompression

Adrenergic blockers and the acetylcholinesterase inhibitor neostigmine have been tested in open-label studies. Only neostigmine has been tested in a randomized, controlled trials and has an effective initial treatment response rate of 60% to 90%.^109,110

Abdominal cramping with the passage of gas and decompression of the colon occurs promptly after administration of neostigmine, but such volume decompression has not been shown to reduce the risk of perforation and mortality in these patients. Nonetheless, if there are no contraindications to its use, neostigmine is a safe choice in patients whose cecal diameter is greater than nine centimeters for 72 hours. Contraindications include bradycardia, hypotension, active bronchospasm, serum creatinine concentration greater than 3 mg/dL, mechanical obstruction of the gastrointestinal or genitourinary tract, and peritonitis. Adverse events described after intravenous administration of 2.0 to 2.5 mg of neostigmine include abdominal cramps (17%), excessive salivation (13%), sweating (4%), nausea or vomiting (4%), and transient bradycardia (6%); a starting dose of 1 mg rather than 2 mg reduces the likelihood of bradycardia. A second dose of neostigmine should be considered if there is partial or no response to the first trial or if ileus recurs after an initial response.

5-HT₄ receptor agonists, motilin receptor agonists, and muscarinic receptor agonists have been the subject of anecdotal reports, but none have been formally tested in the setting of acute colonic pseudo-obstruction.¹⁰⁸ Metoclopramide has shown very small or insignificant benefit in the treatment of postoperative ileus.⁹² The peripherally acting µ-opioid receptor antagonist alvimopan significantly shortens the duration of postoperative ileus, but neither metoclopramide nor alvimopan has been sufficiently tested as treatment for acute colonic pseudo-obstruction.^89–92

Endoscopic Decompression

Randomized, controlled trials of endoscopic decompression are lacking. Colonoscopic decompression can be achieved technically in 80% of patients with acute colonic pseudo-obstruction, albeit with a high risk of cecal perforation.¹¹⁰ The complication rate ranges from about 1% to 5%,⁵ with a 3% perforation rate.¹⁰⁴ Colonic decompression has not been shown to improve the outcome of these patients. It has a high recurrence rate and colonoscopy of unprepared bowel can distend the colon further and result in perforation.³ Placement of a decompression tube into either the right or transverse colon has a similar technical success rate.¹⁰⁴ Endoscopic decompression should be considered in patients with a high risk of cecal perforation when conservative and pharmacologic maneuvers have failed.

Percutaneous Cecostomy

In view of the high rate of recurrence of colonic dilatation after endoscopic decompression, alternative techniques to decompress the colon have been proposed to avoid surgery. Percutaneous cecostomy has been reported to be successful in several case reports and one small case series, but it is associated with significant morbidity. Percutaneous cecostomy can be performed endoscopically, radiographically, or surgically.^111,112

Surgical Decompression

Surgical decompression, which includes cecostomy, colostomy, or resection, is associated with a 6% morbidity and a 30% mortality overall.³ It is used for patients with more-severe disease who have failed to respond to conservative or other measures. In cases of ischemia or perforation, segmental or subtotal colectomy is indicated.¹¹¹

Enteric Neuropathies

Inflammatory neuropathies that cause chronic pseudo-obstruction may be primary or secondary to a variety of infectious, paraneoplastic, and neurologic disorders. Inflammatory neuropathies are characterized by an intense inflammatory infiltrate of CD4 and CD8 lymphocytes that are CD3 positive and confined to the myenteric plexus.^115,116 The juxtaposition of lymphocytes that are CD3 positive with myenteric neurons is the foundation by which immunologic interactions affect ganglion cell structure and survival.^114,117 In the gastrointestinal tract, inflammation and immune activity have been shown to significantly influence the morphology and function of the enteric nerves.

Many patients with intestinal dysfunction secondary to paraneoplastic visceral neuropathy exhibit circulating antineuronal autoantibodies, such as anti-Hu antineuronal antibodies; autoantibodies reinforce a probable role of the immune system in neuronal dysfunction.¹¹² Experimentally, these autoantibodies can elicit neuronal hyperexcitability¹¹⁸ and modify the ascending reflex pathway of peristalsis.¹¹³ When incubated with a primary culture of myenteric neurons, anti-Hu neuronal antibodies have been shown to trigger activity of caspase-3 and apaf-1 together with apoptosis,¹¹⁹ which implies that anti-Hu antibodies contribute in a direct way to the lymphocytic infiltrate in ENS dysfunction and degeneration observed in patients with inflammatory neuropathy. Indication of viral infection, such as herpes virus DNA, has been isolated deep in the myenteric plexus of some patients with severe neuropathic intestinal dysmotility, lending evidence to viral infectious agents as a cause of inflammatory ganglionitis.¹²⁰ Eosinophilic ganglionitis has been recognized in some pediatric patients with pseudo-obstruction,¹²¹ although in these cases, eosinophilic ganglionitis did not appear to cause neuronal deterioration or loss.¹¹³ Also, mast cell ganglionitis has been described in patients with severe intestinal dysfunction¹²² and is associated with a reduced nitric oxide synthase expression, suggesting impaired inhibitory innervation of the ENS.

Noninflammatory (degenerative) neuropathies may be familial or sporadic and the result of dysfunctional mitochondria, altered calcium signaling, and accumulation of free radicals that leads to eventual degeneration and loss of neurons.¹²³ Sporadic cases can be primary or secondary to a wide range of conditions including radiation, diabetes mellitus, amyloidosis, myxedema, and drug toxicity.¹¹³ Two predominant pathologic patterns have emerged in visceral neuropathy from degenerative sporadic causes. One pattern shows a reduction in the number of intramural cells that occur in relation to swollen processes and nerve cell bodies, an increase in glial cells, and fragmentation and loss of axons; in the second pattern, in the absence of dendritic swelling or glial proliferation there is a loss of the normal staining that occurs in subsets of enteric neurons.^113,114,124 Severe forms of idiopathic intestinal intrinsic neuropathy have been associated with a decreased expression of the protein encoded by Bcl-2, a gene related to one of the intracellular pathways leading to apoptosis.^125–127

Enteric Mesenchymopathies

The ICC are derived from mesenchymal cells that express c-kit. ICC are important for pacing electrical slow-wave activity and for gastrointestinal motor contractions^128,129 (see Chapters 97 and 98). Spindle-shaped ICC are distributed within the muscularis (ICC-IM), and network-forming ICC are closely associated with the myenteric plexus (ICC-MY) of the ENS. The division of morphologically distinct classes of ICC within different layers of the GI musculature suggests that different ICC can perform discrete physiologic roles in intestinal motility.¹³⁰

ICC are closely apposed to nerve terminals and electrically coupled via gap junctions to neighboring smooth muscle cells. Studies indicate they play a fundamental role in the reception and transduction of both inhibitory and excitatory enteric motor neurotransmission.¹³¹ Confocal electron microscopy shows abnormalities of ICC in patients with chronic intestinal pseudo-obstruction that include irregular cell surface markings,¹³² damaged intracellular organelles and cytoskeleton, and decreased ICC density.^113,133 As a result, it has been proposed that ICC involved in pacemaker activity and neurotransmission to smooth muscle can contribute to the enteric motility abnormalities detectable in patients with chronic pseudo-obstruction.

Enteric Myopathies

Smooth muscle fibrosis and vacuolization are histologic abnormalities that have been observed in the circular and longitudinal muscle layers of some patients with primary visceral myopathies.^124,134 In a large series of well-characterized patients with chronic pseudo-obstruction, a deficiency of one isoform of the cytoskeletal smooth muscle protein actin, α-actin, was described in approximately 25% of patients with the myopathic phenotype.¹³⁵ The authors proposed that a selective decrease or absence of α-actin staining in the circular muscle of the small bowel wall could be a biologic marker of chronic intestinal pseudo-obstruction,¹³⁵ although controlled studies have not yet been done.

Sporadic Nonfamilial Visceral Neuropathy

Also known as chronic idiopathic intestinal pseudo-obstruction (CIIPO), sporadic, nonfamilial visceral neuropathy can result from injury to the myenteric plexus from various causes including drug toxicity, ischemia, radiation, or viral infections such as cytomegalovirus, Epstein-Barr virus, and herpes simplex virus.¹³⁶ CIIPO is the most common diagnosis given to cases of intestinal pseudo-obstruction, followed by various secondary causes that are covered later. Delayed gastric emptying and intestinal dysmotility have been observed in patients after viral gastroenteritis, which is associated with permanent damage to the myenteric plexus in some patients. Kamm and colleagues have documented such a syndrome in association with herpes viral elements in the myenteric plexus of patients with pseudo-obstruction.¹²⁰

Patients with CIIPO often have disturbed motility of the entire gastrointestinal tract. The intestine may be dilated. Histologic examination of the myenteric plexus may reveal a reduction in the number or an abnormal morphology of neurons, which may be enlarged with thick, irregular clubbed processes. Hypertrophy of one or both muscle layers of the muscularis propria has been described. Intestinal phasic pressure studies are abnormal, but routine histology findings often were normal in patients whose tissue was available for analysis.¹³⁷

Familial Intestinal Pseudo-obstruction

Primary familial cases of intestinal pseudo-obstruction result from abnormalities of smooth muscle cells of the muscularis propria (familial visceral myopathies) or abnormalities of the enteric neuronal structures (familial visceral enteropathies). These are rare genetic disorders with autosomal dominant, autosomal recessive, or X-linked transmission.¹¹⁵ Abnormal genes and loci have been recognized in various syndromic forms of CIIPO, including the DNA polymerase gamma gene (POLG) on chromosome 21 (21q17), the transcription factor SOX10 on chromosome 22 (22p12), and a locus on chromosome 8.^{113,115,116,130} X-linked recessive forms of CIIPO have been mapped to Xq28I, and a large cytoskeletal protein filamin A has been identified as vital for proper enteric neuron development.¹³⁶ Some familial disorders have been well characterized based on the pattern of inheritance and predominant abnormalities.

Familial Visceral Myopathies

FVMs are uncommon genetic disorders causing chronic pseudo-obstruction and are characterized by degeneration and fibrosis of gastrointestinal smooth muscle; one type also involves urinary smooth muscle. There are at least two phenotypes.

Type I is autosomal dominant and usually is diagnosed after the first decade of life, with esophageal dilatation, megaduodenum, megacystis, and mydriasis. Patients respond favorably to regional resection or bypass of affected tissue segments, and the prognosis generally is good.

Type II, called MNGIE (mitochondrial DNA neurogastrointestinal encephalopathy) is the best-characterized myopathic phenotype, although the pathogenetic mechanisms causing its intestinal dysmotility remain unclear. It is an autosomal recessive mitochondrial encephalopathy that can lead to chronic pseudo-obstruction because of dysfunction of the mitochondrial respiratory chain.¹³⁸ MNGIE is characterized by exacerbations with severe symptoms on a background of chronic intestinal pseudo-obstruction with mildly dilated small intestine and dilated stomach, lactic acidosis, ptosis, ophthalmic paralysis, peripheral neuropathy, alterations in the white matter on magnetic resonance imaging (MRI) of the brain, skeletal muscle ragged red fibers (Fig. 120-5), and specific mitochondrial changes at the ultrastructural level.^138,139 Patients manifest skeletal muscle pain and cramps and lactic acidosis with elevated circulating muscle enzyme levels, including creatine phosphokinase (CPK), alanine transferase (ALT), and aldolase. Small intestinal diverticulosis complicated by inflammation and perforation is the cause of death in a majority of these patients in early adulthood.¹³⁸

Figure 120-5. Histologic section of a biopsy specimen taken from skeletal muscle showing ragged red fibers (center) containing subsarcolemmal accumulations of mitochondria. Most fibers are morphologically normal.

(Used with permission from Mueller LA, Camilleri M, Emslie-Smith AM. Mitochondrial neurogastrointestinal encephalopathy: manometric and diagnostic features. Gastroenterology 1999; 116:959-963.)

MNGIE syndrome results from mutations in the thymidine phosphorylase gene, which leads to markedly reduced thymidine phosphorylase activity that, in turn, results in accumulation of thymidine (dThd) and deoxyuridine (dUrd) in blood and tissues.¹⁴⁰ High levels of dThd and dUrd lead to nucleoside pool imbalances that cause abnormalities in DNA including depletion, point mutations, and multiple deletions.^140,141 A link has been established between DNA depletion and myopathic changes involving the external layer of the muscularis propria.¹³⁸ Screening tests for MNGIE include measurements of serum lactic acid, circulating muscle enzymes, and thymidine phosphorylase in circulating leukocytes.¹⁴²

Familial Visceral Neuropathies

FVNs are rare genetic diseases characterized by degeneration of the neural structures of the myenteric plexus. There are at least two distinct phenotypes of FVN.¹⁴³ Type I is autosomal dominant, results in segmental dilatation of varying lengths of the small intestine, megacolon, and gastroparesis and has its onset of gastrointestinal symptoms at any age; more than 75% of patients with FVN type I have gastrointestinal symptoms. Histology demonstrates degeneration of argyrophilic neurons and reduced numbers of nerve fibers. Type II FVN is autosomal recessive and its findings include hypertrophic pyloric stenosis, malrotation of the small intestine, and short and dilated small intestine; CNS malformation and patent ductus arteriosis are seen in some cases. Onset of symptoms is in infancy, and histologically there is a deficiency of argyrophilic neurons and increased numbers of neuroblasts. There is no effective treatment (medical or surgical) for type II FVN, and prognosis is poor.

Several syndromic congenital neuropathies exist that can be classified broadly¹⁴⁴ as:

Disorders of colonization by migrating neural crest-derived neurons (e.g., Hirschsprung’s disease) related to abnormalities in the RET gene (the gene for tyrosine kinase) and GDNF (glial derived neurotrophic factor), or the disorder of ET-3 (endothelin-3) and its receptor, ETB (endothelin B receptor);

Disorders of differentiation of enteric nerves (e.g., intestinal ganglioneuromatosis) related to a specific germline point mutation in RET at codon 918 of exon 16 (M918T) or codon 883 (A883F) in multiple endocrine neoplasia (MEN) 2B syndrome;

Disorders of the survival or maintenance of enteric nerves (e.g., hypoganglionosis and possibly congenital achalasia) related to one of several derangements of ligands (e.g., 5-HT or neurotrophin-3) and their receptors (e.g., 5-HT_2B and tyrosine kinase C) or transcription factors (e.g., SOX₁₀).

Disturbances in these mechanisms result in syndromic dysmotilities such as Hirschsprung’s disease, Waardenburg-Shah syndrome, MEN type 2A or B, and idiopathic hypertrophic pyloric stenosis.

Hirschsprung’s disease, perhaps the most common congenital neuropathy, occurs in one in 5000 live births (see Chapter 96). It is often associated with chromosomal abnormalities, the most frequent being trisomy 21 (Down syndrome) and affecting 2% to 10% of patients. Mutations in gene-encoding receptors or ligands, such as GDNF-Ret or ET-3-ETB, can occur. Mutations in the receptors are much more commonly encountered than mutations in the ligands. Different mechanisms can cause the terminal colon to become aganglionic: A deficiency of GDNF-Ret that is less severe and does not cause the entire bowel to become aganglionic; a deficiency of ET-3-ETB in which neural crest-derived cells differentiate prematurely and precursors cease dividing prematurely, leaving the last segment uncolonized; and other syndromes that result from mutations of transcription factors.

Waardenburg syndrome (WS) is an autosomal dominant familial disorder that affects body pigments and has a sensorineural hearing loss.¹⁴⁵ It occurs with an incidence of 1/50,000 live births and accounts for 2% to 5% of congenital hearing loss. There are at least four types of the syndrome, and four genes have been identified in this condition: PAX3, MITF, EDNRB, and EDN3. The combination of Hirschsprung’s disease with WS defines the WS4 type.¹⁴⁶ Patients with a Sox10 mutation and WS4 can present with ataxia, central and peripheral demyelinating neuropathies, and megacolon.¹⁴⁷

Multiple endocrine neoplasia type 2B syndrome (MEN 2B) is a severe congenital familial neuropathic condition transmitted as an autosomal dominant trait and characterized by medullary carcinoma and tumor development in the neuroendocrine system (see Chapter 122). Presenting symptoms can include severe constipation or megacolon, diarrhea (when associated with enterocolitis), or obstruction, typically occurring shortly after birth.¹⁴⁴ External stigmata of MEN 2B include a characteristic facies with “blubbery” lips due to mucosal neuromas that involve the lips, tongue, face, and eyelids (Fig. 120-6)¹⁴⁸; marfanoid habitus; medullated corneal nerve fibers; and medullary thyroid carcinoma. Biopsies characteristically show findings of transmural ganglioneuromatosis with massive proliferation of neural tissue, including neurons, supporting cells; nerve fibers appear as thickened nerve trunks among mature nerve cells.

Figure 120-6. Typical mucocutaneous feature of multiple endocrine neoplasia type IIB. Clinical photograph shows multiple ganglioneuromas of the tongue, lips (arrows), and face.

(Used with permission from Tan FLS, Tan YM, Lim DTH. The significance of cystic adrenal lesions in multiple endocrine neoplasia IIB syndrome. Singapore Med J 2004; 45[10]:495.)

Childhood Visceral Myopathies

CVMs have been recognized as two distinctive forms of disease that differ from FVM in their mode of inheritance and clinical presentations (Table 120-10). Degeneration and fibrosis of gastrointestinal and urinary smooth muscle can be detected in both types of CVM and result in obstructive symptoms, bowel dilatation, and hydroureteronephrosis or megacystis, the latter resulting from degeneration of bladder muscle.¹⁴⁹

Table 120-10 Classification of Childhood Visceral Myopathies

GI, gastrointestinal; Rx, treatment.

* Megacystis-microcolon-intestinal hypoperistalsis.

Camilleri M. Acute and chronic pseudo-obstruction. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and liver disease: pathophysiology, Diagnosis, Management. 8th ed. Philadelphia: Saunders Elsevier; 2006. pp 2679-2702.

Systemic Sclerosis (Scleroderma)

Systemic sclerosis (SSc) is a generalized disorder of the microvasculature and connective tissue that results in increased deposition of collagen and other matrix elements, leading to thickening and fibrosis of the skin, with involvement of synovia and fibrosis of intestinal organs. The highest incidence of SSc occurs between 45 and 55 years of age. The gastrointestinal tract is the second most common target organ after the skin and the esophagus is the most commonly affected gastrointestinal organ, followed by the small intestine.¹⁵⁰ Small bowel dysmotility leads to bacterial overgrowth resulting in steatorrhea, malabsorption, and weight loss.

There are two forms of SSc, diffuse cutaneous and limited cutaneous. Gastrointestinal symptoms are associated with diffuse cutaneous SSc and occur along with other manifestations of systemic involvement, including interstitial lung disease, kidney failure associated with malignant hypertension crisis, and myocardial disease.

Intestinal and gastric involvement can be identified radiologically in up to 40% of patients. Contrast studies can reveal dilatation of the duodenum and jejunum, along with fixed, narrow, tightly packed valvulae conniventes, despite bowel dilatation, producing an accordion appearance (Fig. 120-7) or a “hide-bound” appearance.¹⁵¹ Wide-necked diverticula are seen more often in the colon than in the small intestine.

Figure 120-7. Select view from an upper gastrointestinal series in a patient with systemic sclerosis showing a markedly dilated duodenum and proximal jejunum, with an increased number of small bowel folds crowded together (despite luminal distention), producing a “hide-bound” appearance. Also note multiple outpouchings (arrows) due to asymmetrical fibrosis with sacculation of the opposite bowel wall.

(Used with permission from Levine MS, Rubesin SE, Laufer I. Pattern approach for diseases of mesenteric small bowel on barium studies. Radiology 2008; 249:451.)

Disturbances of small bowel motility^152,153 result in delayed gastric or small bowel transit¹⁵⁴ and include absence or hypomotility of the interdigestive MMC, low-amplitude clusters of propagated and nonpropagated contractions, a prolonged MMC cycle, diminished activity of phase III,¹⁵³ and antral hypomotility (characterized by low-amplitude contractions, typically less than 40 mm Hg). Intestinal involvement usually causes fasting and postprandial contractile amplitude to fall below 10 mm Hg.¹⁵⁵ Gastric emptying may be delayed by resistance to flow in the hypomotile small intestine, even if the stomach itself is unaffected. SSc patients without gastrointestinal involvement demonstrate normal small bowel manometry¹⁵⁵ and normal intestinal transit time.

Dermatomyositis and Polymyositis

The gastrointestinal tract is involved in half of the cases of dermatomyositis and polymyositis. Dysphagia is often the presenting symptom, associated with weakness and atrophy of skeletal muscles of the esophagus. Megaduodenum and delayed intestinal transit are prominent features of chronic pseudo-obstruction. Histopathology demonstrates atrophy and fibrosis of intestinal smooth muscle, most consistent with a visceral myopathy.¹⁵⁵

Systemic Lupus Erythematosus

Abdominal pain is the most common gastrointestinal complaint, which occurs in up to 20% of patients. Autopsy studies reveal a 65% prevalence of peritoneal inflammation, although documented cases of serositis as a cause of abdominal pain are rare. Smooth muscle dysfunction related to ischemia can lead to dilatation of the small intestine. Diarrhea occurs in 10% of lupus patients. Chronic intestinal pseudo-obstruction can occur as the presenting symptom and is potentially reversible with early treatment.¹⁵⁶

Lupus enteritis is the term used to describe the bowel changes in this disease that result from vasculitis of small blood vessels. Ischemia leads to intestinal mucosal ulceration, edema, and hemorrhage. The diagnosis often can be made radiologically, and small bowel changes include dilatation, thick folds, and thumbprinting related to subepithelial edema and hemorrhage. Unusual intestinal manifestations can cause diagnostic difficulties. Lupus can simulate Crohn’s ileitis or can cause a severe protein-losing enteropathy in association with vasculitis and basement membrane thickening that can be diagnosed on full-thickness jejunal biopsy.

Diabetes Mellitus

Patients with diabetes mellitus often have diarrhea, which may be due to bacterial overgrowth, pancreatic exocrine insufficiency, bile salt malabsorption, impaired absorption or secretion, loss of adrenergic sympathetic innervation, or disturbed motility. In patients presenting with symptoms of gastroparesis, the small intestine also may be affected, and such involvement can be documented by prolonged transit,¹⁵⁴ by manometry,¹⁵⁷ or sometimes by evidence of a dilated intestine.

Motility studies of the small intestine in patients with diabetes have varied significantly. Normal MMCs are found in many patients with documented gastroparesis, but absence of intestinal phase III has been demonstrated in some. Other abnormalities include MMCs that originate in the distal duodenum or jejunum and uncoordinated bursts of nonpropagated contractions (Fig. 120-8).¹⁵⁸ The clinical relevance of these abnormal findings is uncertain. Demyelination of the proximal vagus nerve and sympathetic nerves supplying the bowel occurs in patients with long-standing diabetes. The intrinsic nervous system of the intestine does not appear to be affected because no morphologic abnormalities of the myenteric or submucosal plexuses have been observed; however, animal models and a single case report of a patient requiring transplantation of the pancreas and kidneys was associated with degeneration of the ICC.¹⁵⁷ Although thickening of the small bowel muscle layers and eosinophilic hyaline bodies in smooth muscle cells have been observed,¹⁵⁹ most authorities believe that myopathy is not a cause of gastrointestinal dysmotility in diabetic patients.

Figure 120-8. Gastroduodenal motility tracings in a healthy control subject and in a patient with diabetes mellitus. These postprandial tracings show normal amplitude and irregular contractility in the healthy control and a paucity of antral contractions, tonic contractions at the pylorus (third tracing), and development of a fasting-like migrating motor complex pattern in the small intestine in a patient with diabetes mellitus.

(Adapted from Camilleri M. Acute and chronic pseudo-obstruction. In: Feldman M, Friedman LS, Brandt LJ, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease: pathophysiology, Diagnosis, Management. 8th ed. Philadelphia: Saunders Elsevier; 2006. p 2687.)

Parkinson’s Disease

Patients with Parkinson’s disease often have symptoms of gastrointestinal dysfunction. Proximal dysphagia, bloating, constipation, and difficulty with evacuation of stool occur commonly.¹⁶⁰ Dilatation of the small bowel may be seen radiologically.¹⁶¹ Small intestinal dysmotility does occur, but its frequency is not known, and the contribution of these abnormalities to symptoms is not clear. Compared with controls, manometric studies in patients with Parkinson’s disease reveal infrequent or absent MMCs, hypomotility in the fed state, and an increased incidence of retrograde and tonic contractions.¹⁶²

The pathogenesis of small intestinal dysmotility in Parkinson’s disease has not been determined. Lewy bodies are neurons containing cytoplasmic hyaline inclusions that originally were identified in the brain of parkinsonian patients. They have not yet been reported in the small intestine but have been found in the myenteric plexus of the esophagus and colon.¹⁶³ Dopaminergic neurons are reported to be deficient in colons from patients with Parkinson’s disease and constipation.¹⁶⁴

Spinal Cord Injury

Spinal cord injury usually produces only mild and probably insignificant dysmotility in the small intestine. The only documented changes in manometric studies performed in a group of patients with spinal cord injury were a greater number of phase III contractions that began in the duodenum rather than in the antrum in patients with high spinal cord lesions.¹⁶⁵ Patients with injury to the lower spinal cord demonstrated no abnormalities, a finding consistent with the preservation of innervation to the intestine from the vagus and third thoracic sympathetic levels. One report described a woman with cervical spinal stenosis and paraplegia who displayed normal MMCs but a two-fold to three-fold prolonged interval between MMCs.

Immediately after spinal cord injury, a state of spinal shock develops in which there is complete loss of all sensory, motor, and reflex function below the level of injury. Paralytic ileus with abdominal distention follows and usually resolves in a few days. In the long term, however, postprandial abdominal distention and discomfort occur in more than 40% of patients with spinal cord injuries; these symptoms are likely due to the more significant problem of constipation. Many stable patients with spinal cord injury exhibit increased amounts of gas in the small and large intestine on routine abdominal plain films.

Colonic dysmotility is well recognized and is responsible for the common problems of constipation and difficulty of evacuation in patients with spinal cord injury.¹⁶⁶ Spinal cord injury decreases colonic motility; though the postprandial colonic response is present, it is suboptimal and confined to the descending colon.¹⁶⁷ In these patients, rectal compliance and resting anal sphincter pressures are lower than normal values, and ramp rectal inflation demonstrates patterns of sphincter activity similar to those recorded in the patients’ cystometrograms. There is no definite relationship of bowel function to the findings on anorectal manometry in patients with spinal cord injury.

Rehabilitation goals include continence of stool, simple voluntary independent defecation, and prevention of gastrointestinal complications. Individualized person-centered bowel care includes diet, laxatives, enemas, suppositories, and scheduling of bowel care to initiate defecation and accomplish fecal evacuation. Digital-rectal stimulation is a technique used during bowel care of patients with spinal cord injury to open the anal sphincter and facilitate reflex peristalsis.¹⁶⁸

Neurofibromatosis (von Recklinghausen’s Disease)

Gastrointestinal involvement in neurofibromatosis is estimated to occur in 11% to 25% of patients.¹⁶⁹ Small bowel dysmotility and intestinal pseudo-obstruction due to neurofibromatosis, however, are rare. Involvement of the intestine occurs in three principal forms: hyperplasia of the submucosal and myenteric nerve plexuses and mucosal ganglioneuromatosis, which can lead to disordered intestinal motility and chronic pseudo-obstruction; GIST tumors that show varying degrees of neural or smooth muscle differentiation and typically manifest with bleeding; and a glandular, somatostatin-rich carcinoid of the periampullary region of the duodenum, which also has been associated with pheochromocytoma.¹⁷⁰

Paraneoplastic Visceral Neuropathies

Paraneoplastic neurologic syndrome is a remote effect of cancer that results in (visceral) neuropathy. It is not caused by the tumor or metastases, and it is not caused by infection, ischemia, or metabolic disruptions.¹⁷¹ Paraneoplastic neurologic syndrome is caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system, designated as onconeural antigens. Paraneoplastic neurologic syndrome is rare, occurring in less than 0.01% of patients with cancer¹⁷²; the Lambert-Eaton myasthenic syndrome is more common, occurring in nearly 1% of patients with small-cell lung cancer.¹⁷³ Less than 50% of patients have detectable antibodies and up to 10% have an atypical antibody that is not well characterized.¹⁷¹ Paraneoplastic neurologic syndrome is considered to be mediated by the immune system, so suppression of the immune response represents another potential treatment approach.¹⁷¹ Associated neoplasms include small cell lung cancer (SCLC), thymoma, gynecologic and breast tumors, Hodgkin’s lymphoma, multiple myeloma, and colon cancer.

The most commonly associated tumor is SCLC, and the most common antibodies are Hu-Ab or CV2-Ab.¹⁷¹ Experimental evidence suggests that anti-Hu antibodies can exert a direct pathogenic role or can contribute, in association with the lymphocytic infiltrate, to ENS dysfunction in patients with chronic intestinal pseudo-obstruction related to an inflammatory neuropathy.¹¹³ Some patients with subacute parasympathetic and sympathetic autonomic failure and prominent gastrointestinal dysfunction also have antibodies directed against the neuronal autonomic ganglion type of acetylcholine receptors (nAchR antibodies). In these cases, the main associated tumors are thymoma and SCLC.

Patients with paraneoplastic neurologic syndrome can experience weight loss, persistent bloating, and abdominal distention from damage to the neurons of the enteric plexuses.¹⁷¹ Some patients present with dysphagia, nausea, and vomiting due to esophageal dysmotility or gastroparesis, or, more commonly, they present with symptoms of severe constipation. Radiologic studies can show dilatation of the small bowel, colon, or stomach.¹⁷¹ Esophageal manometry can reveal spasm or achalasia.

These inflammatory neuropathies are characterized by a dense inflammatory infiltrate with CD3-positive CD4 and CD8 lymphocytes that almost invariably are confined to the myenteric plexus.^115,116,130

Myotonic Dystrophy

Myotonic muscular dystrophy is a slowly progressive disease characterized by myotonia, or difficulty in muscle relaxation. Diarrhea and abdominal cramping occur in up to one third of affected persons, malabsorption and steatorrhea have been reported in a few cases, and constipation is frequent and can alternate with diarrhea. The small intestine can demonstrate abnormal but nonspecific radiologic changes, including dilatation, diminished motility, and delayed transit.¹⁷⁴

Dysmotility of the small intestine can play a significant role in the production of intestinal symptoms. Manometric findings included low-amplitude contractions in fasting and fed states, retrograde propagation of phase III waves, interruption of phase III, and increased incidence of tonic contractions.¹⁷⁵ Spontaneous pneumoperitoneum, megacolon, and low-amplitude small intestinal contractions have been documented.

Histologically, smooth muscle cells in the small intestine show changes similar to those found in dystrophic skeletal muscle: They are swollen, partially destroyed, decreased in size, and replaced by fat. Using silver stain, degenerative changes of the myenteric plexus of the colon were found in a patient with megacolon,¹⁷⁶ indicating that intestinal dysmotility may be caused by smooth muscle as well as enteric nerve dysfunction. In most patients, the predominant cause of dysmotility appears to be smooth muscle damage.

Duchenne’s Muscular Dystrophy

Duchenne’s muscular dystrophy is the most common of the inherited muscular dystrophies. A sex-linked disease, it affects one in 3500 boys; without respiratory support, death can occur before age 25 years. It is caused by mutations in the gene for dystrophin, a protein that helps stabilizes muscle cell membrane.¹⁷⁷ In some cases, the mutations lead to an aberrant messenger RNA and result in a highly truncated dystrophin or no protein at all. Without functional dystrophin, muscle cell membranes leak, followed by muscle fiber necrosis and regeneration, and progressive replacement of muscle by fibrosis and fat. The muscles steadily waste away, and paralysis eventually occurs.^177,178

In a milder form with onset in the teens or early adulthood (Becker’s muscular dystrophy) the muscle cells produce dystrophin that is not normal but retains enough activity for normal function. As with Duchenne’s, muscle weakness begins in the hips and pelvic girdle. The rate of degeneration is variable in Becker’s muscular dystrophy with many patients living to old age.

Gastrointestinal symptoms usually are related to esophageal and gastric dysmotility, which are more severely affected than is the small intestine. Dysphagia is the predominant gastrointestinal symptom (36% in one series), followed by vomiting, diarrhea, and constipation.¹⁷⁹ Gastric emptying delay and acute gastrointestinal dilatation characterize the clinical course.¹⁸⁰ Orocecal transit time can be normal in asymptomatic subjects, although severe bowel dysmotility can occur.

Amyloidosis

Amyloidosis is a mixed group of disorders characterized by extracellular deposits of abnormal protein fibrils with a β-sheet fibrillar structure. The abnormal structure can be identified by x-ray diffraction studies and visualized with electron microscopy, but clinically, amyloid is identified by viewing the intestine with polarized light after staining it with Congo red.¹⁸¹

In patients with amyloidosis, diarrhea and constipation often are present for years and are followed or accompanied by a myriad of disparate problems including gastrointestinal bleeding, steatorrhea, protein loss, perforation, obstruction, intussusception, ischemia, pneumatosis, and pseudo-obstruction.¹⁸² A variety of mechanisms might explain the diarrhea: delayed motility and small bowel bacterial overgrowth,¹⁸³ bile salt diarrhea,¹⁸⁴ a sprue-like condition with amyloid deposition in the tips in the villi,¹⁸⁵ and rapid orocecal transit.¹⁸⁶

The severity of gastrointestinal dysmotility is correlated to the quantity and distribution of deposited amyloid. Amyloid is slowly deposited between muscle fibers, causing pressure atrophy of adjacent fibers so that eventually, the whole muscle layer is replaced by amyloid.¹⁸² Neuromuscular infiltration initially affects the intrinsic nervous system and results in a neuropathic process¹⁸⁷ characterized by contractions that have normal amplitude but are uncoordinated.^182,188 At a later stage, tissue wall infiltration results in a myopathic process with low-amplitude contractions that typically are associated with prolonged transit as in other systemic disorders, such as scleroderma. The vasculature often is involved, with amyloid deposition in the subintima or adventitia, and often involving the submucosa. When the vessel wall thickens, the lumen narrows and eventually obstructs, resulting in ischemia, infarction, and perforation.¹⁸⁹ Mucosal architecture remains normal until massive deposits of amyloid destroy the mucosal structures.

There are several forms of amyloidosis: primary (AL), secondary (AA), hemodialysis-related (Aβ₂MG), hereditary (ATTR), senile, and localized. AL is most common and has the most significant gastrointestinal involvement. AL amyloid reflects a generalized deposition of excess light chains associated with plasma cell dyscrasia, and 15% of patients with AL have multiple myeloma.¹⁹⁰ Amyloid protein is deposited in the small intestine in all forms of amyloidosis.¹⁹¹

Secondary (AA) amyloidosis with acute-phase reactant serum amyloid A protein (A) is associated with infectious, inflammatory, or, rarely, neoplastic disorders.^182,192 The incidence of amyloidosis in patients with rheumatoid arthritis ranges from 7% to 21%, the highest prevalence derived from an autopsy study.¹⁸² Other disorders associated with AA are Crohn’s disease, ankylosing spondylitis, Reiter’s syndrome, psoriasis, progressive systemic sclerosis, primary biliary cirrhosis, and systemic lupus erythematosus.

Inherited forms of amyloidogenic proteins are rare. The most common of this type is with variant transthyretin (TTR), which is produced by the liver,^182,183 and the resulting amyloidosis (ATTR) is called familial amyloidotic polyneuropathy. Besides familial amyloidotic polyneuropathy, there are hereditary non-neuropathic systemic amyloidoses associated with mutations in genes for apolipoprotein AI, lysozyme, and fibrinogen α-chain.

Senile amyloidosis is found in 10% to 36% of patients older than 80 years and mainly involves the heart, but it also can be seen throughout the gastrointestinal tract. Amyloid has been observed in the subserosal veins of the large and small intestine in 41% to 44% of elderly patients.¹⁹³

Chagas’ Disease

In nearly one third of patients, the late phase of infection with Trypanosoma cruzi leads to destruction of the submucosal and myenteric plexuses along the length of the gastrointestinal tract resulting in dilatation (see Chapter 109). Megacolon and megaesophagus are the most common presentations, although megaduodenum and megajejunum also can occur. Swallowing difficulties may be the first symptom of digestive disturbances and can lead to malnutrition. Some patients are entirely asymptomatic despite significant destruction of neurons. The early phase of gastric emptying of liquids is accelerated in patients who have Chagas’ disease and megaduodenum, suggesting that increased duodenal receptivity has a significant effect on the gastroduodenal transfer of liquids.¹⁹⁴

Thyroid Disease

The earliest manifestation of a thyroid disorder might be gastrointestinal dysfunction. Hypothyroid patients often complain of constipation, and their gastric emptying time may be significantly delayed.¹⁹⁵ Intestinal dysmotility (associated with change in the frequency of the slow wave oscillations of smooth muscle electrical potential) results from the altered thyroid state and has been considered to be the cause of symptoms. In hypothyroidism, small intestinal transit is significantly slowed.¹⁹⁶ Many hypothyroid patients develop constipation, which may be the result of colonic dysmotility. In one patient, manometry revealed decreased amplitude of small intestinal contractions and an overall decreased motility index.¹⁹⁷ With severe hypothyroidism (myxedema), paralytic ileus and intestinal pseudo-obstruction can occur. These abnormalities return to normal after the thyroid disorder is corrected.

Hypoparathyroidism

Cases of pseudo-obstruction and malabsorption have been observed in patients with hypoparathyroidism, although the mechanism is not known. Calcium is essential for smooth muscle contraction, and hypocalcemia can impair intestinal contractile activity. Symptoms improve with administration of calcium.

Medications

Many drugs profoundly affect gastrointestinal motility.¹⁹⁸ Although the colon is considered the principal target organ for drug-induced dysmotility, the small intestine often is similarly affected. Tricyclic antidepressants are noted for causing ileus. Phenothiazines and some antiparkinsonian drugs decrease colonic and small intestinal motility and can cause constipation, colonic pseudo-obstruction, and adynamic ileus. The anticholinergic agents atropine and scopolamine and related belladonna alkaloids decrease intestinal tone along with the amplitude and frequency of peristaltic contractions.

Opiate analgesics act on µ-opiate receptors throughout the intestinal tract to suppress motility; this effect is most pronounced in the colon. Loperamide, a predominantly peripheral opioid antagonist, causes chronic pseudo-obstruction by this antikinetic mechanism.¹⁹⁸ Morphine enhances the amplitude of nonpropulsive small intestinal contractions and markedly decreases propulsive contractions. The duodenum and jejunum are more prone to these effects than is the ileum, and the overall effect is a delay in transit through the small intestine.

Calcium channel antagonists, particularly verapamil, by their direct stimulation of smooth muscle relaxation, cause constipation in up to 20% of patients and can also cause chronic pseudo-obstruction.¹⁹⁹ Small intestinal transit time in subjects taking verapamil was unchanged from pretreatment values, although transit through the colon was slowed and this effect likely accounts for the constipation seen with this drug.

Celiac Disease

Intestinal pseudo-obstruction has been documented in association with celiac disease,²⁰⁰ but the mechanism is unclear. Dilated loops of small intestine with delayed transport of barium can be observed radiologically. In one patient who underwent exploratory laparotomy with full-thickness jejunal biopsy, the nerves and muscle cells appeared normal on both light and electron microscopy.²⁰⁰

Jejunal Diverticulosis

Diverticula can occur anywhere in the small intestine, but diverticulosis is most common in the jejunum. Like their counterparts in the colon, diverticula represent herniations through the mesenteric side of the bowel and usually are acquired. Jejunal diverticulosis is associated with many diseases, including scleroderma, celiac disease, MNGIE cytopathy, and Cronkhite-Canada syndrome.²⁰¹ Patients can present with symptoms of small intestinal bacterial overgrowth, including diarrhea, steatorrhea, weight loss, and megaloblastic anemia. Local complications of diverticula also can occur, such as diverticulitis, bleeding, and perforation.

Acute and Chronic Irradiation

Ionizing radiation results in damage to all structures of the small intestine, including the mucosa, blood vessels, connective tissue, enteric nerves, and smooth muscle (see Chapter 39). Radiation damage to the intestine can be separated into acute and chronic injury.

Acute radiation injury is associated with symptoms of nausea, vomiting, abdominal pain, and diarrhea, which subside soon after exposure is discontinued. Small intestinal dysmotility can play a significant role in acute radiation enteropathy. Changes in small bowel absorption are considered the main cause of diarrhea. Delayed intestinal fasting and fed motility patterns can persist up to four weeks following the last exposure.^202,203 One study has shown accelerated small intestinal transit in a group of patients undergoing abdominopelvic irradiation compared with their pretreatment values.²⁰⁴ More than 75% of the patients exhibited diarrhea during treatment.

Chronic radiation injury can cause gastrointestinal complications decades after the initial exposure. The neuropathic and myopathic injury results in intestinal dysmotility that leads to bacterial overgrowth, diarrhea, and malabsorption. Contrast studies often show dilated, thickened loops of bowel with air-fluid levels. Atrophy and fibrosis of smooth muscle fibers is a characteristic histologic finding, and proliferation of submucosal neurons of the myenteric plexus with extension into the circular muscle coat has been observed.²⁰⁵

Diffuse Lymphoid Infiltration

Diffuse lymphoid infiltration is a rare cause of pseudo-obstruction characterized by a diffuse infiltration of small lymphocytes mixed with mature polyclonal plasma cells that reflects a pseudolymphoma rather than a true neoplasm.¹⁷⁹ It affects all the layers of the intestinal wall²⁰⁶ and is associated with extensive damage to the submucosal and myenteric nerve plexus.¹⁷⁹

Idiopathic Myenteric Ganglionitis

Ganglionitis refers to an inflammatory neuropathy characterized by a dense lymphoplasmacytic infiltrate of the myenteric plexus^134,205 and a marked reduction in the number of ganglia. Other cases have shown an eosinophil-predominant infiltrate, and neurons in the myenteric ganglia expressed the potent eosinophil chemoattractant IL-5.^121,179 Ganglionitis is typically associated with paraneoplastic, infectious, or neurologic disorders, although some cases remain idiopathic. The diagnosis of enteric ganglionitis is supported by detecting circulating antineuronal antibodies against certain targets, such as Hu and Yo proteins, neurotransmitter receptors, and ion channels.¹³⁴ A brief course of glucocorticoids or other immunosuppressive agent has been shown to be beneficial in some cases, thus reinforcing the value of establishing a correct diagnosis in the early stages of the disease process.^134,207

Anorexia Nervosa and Bulimia

Delayed gastric emptying of solids and prolonged orocecal transit are well-established abnormalities in patients with anorexia or bulimia.²⁰⁸ Electrolyte abnormalities, such as hypokalemia, may be responsible in some cases and be related to nutritional deficiencies or concomitant diuretic abuse. Typically, the motility disorder is less significant than the underlying psychological and nutritional manifestations of the disease.

Malnutrition

Malnutrition occurs in patients with severe dysmotility of the small intestine as a result of insufficient food intake, vomiting, bacterial overgrowth, diarrhea, and malabsorption. Anemia can occur due to deficiencies of iron, folate, and vitamin B₁₂. Serum cholesterol, calcium, and albumin levels may be low, especially in patients with malabsorption secondary to bacterial overgrowth. In severe cases, especially in patients with intestinal dysfunction due to myopathy, long-term parenteral nutrition may be necessary to provide sufficient nutrients.

Total Parenteral Nutrition–Related Disorders

Patients with disabling gastrointestinal symptoms and irreversible intestinal failure often require total parenteral nutrition (TPN) (see Chapter 5). These patients are at risk for developing complications such as catheter-related sepsis, venous thrombosis, loss of venous access, and liver failure. Long-term TPN may be complicated by progressive cholestatic liver disease that can become irreversible The onset of hepatic dysfunction in a patient who has intestinal failure and is on chronic TPN is an indication for transplantation of intestine, in isolation or combined with a liver graft.²¹⁰

Small Intestinal Bacterial Overgrowth

Common in chronic pseudo-obstruction, small bowel bacterial overgrowth syndrome is a condition associated with the proliferation of colon-type bacteria within the small intestine (see Chapter 102). The syndrome is characterized by steatorrhea, flatulence, abdominal discomfort, and bloating, with symptoms of macrocytic anemia, malabsorption of nutrients and vitamins, and weight loss; some patients have no symptoms.²¹¹ Direct quantitative cultures of jejunal contents is the diagnostic gold standard,²¹² although in the clinical setting noninvasive hydrogen breath tests are much more commonly used.²¹¹

Pneumatosis Cystoides Intestinalis

Pneumatosis cystoides intestinalis is a rare condition characterized by multiple gas-filled cysts in the submucosa or subserosa of the colon and, less often, the small intestine.²¹³ The mechanism is thought to involve increased gas production by intestinal bacteria, thereby altering the partial pressure of nitrogen in the intestinal wall.²¹⁴ Pneumatosis cystoides intestinalis is more common in patients with chronic obstructive pulmonary disease, but it occurs in cases of systemic sclerosis and has been described in patients with polymyositis, diabetes, duodenal and gastric ulceration, regional enteritis, and gastrointestinal malignancy. Intestinal peristaltic hypofunction associated with chronic pseudo-obstruction leads to raised intraluminal pressure, allowing the gas-producing bacteria to invade the intestinal mucosa through breaks in the mucosal integrity, forming pneumocysts. This condition can be diagnosed radiologically and endoscopically (Fig. 120-9). Subserous pneumocysts, in particular, are liable to rupture, releasing free gas into the peritoneal cavity (pneumoperitoneum), making it important to distinguish this condition from bowel perforation. Pneumoperitoneum from rupture of pneumatosis cysts does not per se mandate operation, and is not complicated by peritonitis.

Figure 120-9. Pneumatosis cystoides intestinalis. A, Endoscopic view showing multiple cystic lesions with an overlying normal mucosal layer in the right colon. B, CT colonography image of the same patient in A showing multiple air-containing polypoid lesions in the ascending colon.

(From Kim BN, Jeong JY, Sohn KD, et al. Pneumatosis cystoides coli of the ascending colon: Colonoscopic and CT colonoscopic features. Endoscopy 2007; 39:E73-4.)

Radiologic Studies

Plain abdominal films are very useful in patients who complain of abdominal distention and bloating because they might show gaseous distention of the areas affected by severe dysmotility; dilatation is greater in cases of pseudo-obstruction related to myopathy than when the cause is neuropathic dysmotility. Enteroclysis can be useful for detecting lesions in the small intestine and ruling out mechanical obstruction. Entero-CT scanning allows simultaneous internal and external views of the intestinal wall. Abdominal CT and MR scans are important in investigating possible causes of bowel compression, and MR angiography can noninvasively identify congenital or acquired vascular abnormalities. Excretory urograms should be performed in patients with urinary symptoms.¹¹³

Radiopaque polyethylene markers that move with the colonic contents are robust measures of intestinal transit and are used to evaluate whole-gut transit. Segmental colonic transit can be measured with daily abdominal plain films after a single dose of radiopaque markers. Metcalf and colleagues²¹⁸ simplified the method so that only one film with high kV technique is necessary and radiation exposure is minimized. By this method, radiopaque markers are taken in fixed numbers (24 per day), at the same time (arbitrarily, 9:00 a.m.) each day for three days. On the fourth day, again at the same time, plain film is taken. The method works on the assumption that a 24-hour sampling interval approximates continuous observation. Rapid transit can cause all the markers to be lost in the feces before filming on the fourth day; conversely, in slow transit, all 72 markers may be present on the single plain film; a film on day seven then gives more information.

Laboratory Tests

A complete blood count can reveal anemia and macrocytosis as a result of malnutrition and bacterial overgrowth (see Chapters 101 and 102). Blood chemistries also reflect malnutrition and malabsorption. Diabetic patients have hyperglycemia, and hypoparathyroid patients can have hypocalcemia. Patients with connective tissue disease can have a positive antinuclear antibody or SCL-70. Patients with thyroid disease have changes in serum T₃, T₄, and TSH levels. Muscular dystrophy or mitochondrial cytopathy patients can have elevated creatine phosphokinase (CPK) and isoenzymes. Hemagglutination and complement fixation for Chagas’ disease may be positive in patients with a history of living in Central or South America.

Antineuronal nuclear antibody (ANNA), SCLC, and anti-Hu and anti-CV₂ antibodies should be sought in patients with an acute presentation of symptoms to exclude a paraneoplastic cause of pseudo-obstruction. Blood lactate, pyruvate (signs of acidosis), CPK, ALT (muscle damage), and leukocyte thymidine phosphorylase are screening tests for mitochondrial cytopathy.

Endoscopy

The main indication for upper gastrointestinal endoscopy is to obtain aspirates from the small intestine in patients with clinically suspected bacterial overgrowth and to exclude mechanical occlusion of the gastroduodenal and gastrojejunal regions. Mucosal biopsies of the small intestine should be taken to rule out celiac disease. Colonoscopy can be used to decompress the colon (see earlier).

Surgery

Full-thickness biopsies should be obtained from dilated and nondilated areas of the intestinal tract in all patients with suspected chronic pseudo-obstruction who undergo surgery for unexplained occlusive episodes; biopsy should be considered in patients with acute symptoms. Biopsies should be processed by traditional staining and by specialized immunohistochemistry techniques in dedicated laboratories with a specific interest in this area.¹²⁵

Manometry

Small intestine manometry lacks the specificity to diagnose the underlying disease but can provide information about the pathophysiologic process (see below).

Secondary Causes

A few types of secondary small intestine dysmotility, such as hypothyroidism, celiac disease, hyperglycemia associated with diabetes, and drug-induced dysmotility, can be treated with thyroid replacement, a gluten-free diet, improving glycemic control, and discontinuing the offending drugs, respectively. There are no specific treatments for most of the secondary causes of small intestine dysmotility.

Pain

Long-term narcotic use should be discouraged because patients can become addicted to narcotics, and narcotics can further disturb gastrointestinal motility. Tramadol, gabapentin, and pregabalin sometimes are prescribed for such pain, but these too can retard intestinal transit. Unfortunately, there are conflicting data on transit effects of these medications in otherwise healthy people and virtually no such data in patients with intestinal pseudo-obstruction.^219–221

Constipation

Constipation is common in patients who also have colon involvement. It is important to make certain that these patients have a good bowel movement at least once every few days, because constipation tends to increase symptoms of intestinal dysmotility. Milk of magnesia can be effective in doses of 30 to 60 mL per day (or two tablets three times daily). Enemas may be useful if the patients have had no bowel movement for three days. Bulk-forming laxatives should be avoided in patients with severe small intestine dysmotility, because they often exacerbate gastrointestinal symptoms.

Acute Subocclusive Episodes

Acute episodes are treated similarly to acute mechanical obstruction. Fluid, electrolyte, and caloric support should be given intravenously. Nasogastric decompression may be beneficial for nausea and vomiting; rectal tubes often are ineffective, but placement of a colonoscopic decompression tube or cecostomy can be attempted for acute refractory dilation (see earlier). Pharmacotherapy using prokinetic agents can be used to reduce duration of the acute episode (see earlier). Prolonged subocclusive episodes necessitate appropriate nutritional support and intravenous or poorly absorbable antibiotics to prevent bacterial overgrowth.

Nutrition Management

In patients with gastrointestinal dysmotility, abdominal pain, bloating, nausea, and vomiting often are related to eating. Symptoms usually can be minimized by manipulating the amount, constituents, and frequency of meals. Patients need sufficient calories without overloading the inefficient bowel: a useful general rule is 25 cal/kg of the patient’s ideal body weight per day taken in small, equal-size feedings four to six times daily. Multivitamins and salt supplementation generally is recommended. Because a liquid meal empties faster from the stomach and probably progresses more readily through the small intestine than a solid meal does, the liquid meal or perhaps an emulsified solid meal may be better tolerated than a solid meal. Supplemental formulas contain the daily vitamin and nutrient requirements, and many are lactose free. There is no advantage to using elemental formulas. Hypercaloric solutions are available, although generally formulas that have a lower caloric content (1 kcal/mL) are better tolerated than those with greater caloric density. Parenteral nutrition may be required to meet caloric and nutritional needs, but oral intake should continue as tolerated. TPN-related complications including catheter-related sepsis or thrombosis, liver insufficiency, pancreatitis, and glomerulonephritis¹¹³ significantly increase the morbidity associated with chronic intestinal pseudo-obstruction.

Pharmacotherapy

The aim of treatment is to reduce digestive symptoms and lower the risk of complications. Disordered motility of the small intestine leads to bacterial overgrowth and malnutrition. Poorly absorbed antibiotics, such as rifaximin, are the preferred treatment for bacterial overgrowth. Cycled treatments using metronidazole, ciprofloxacin, and doxycycline can limit resistance. Antiemetics and antispasmodic agents should be tried, although their benefit may be short-lived. Improving intestinal motor function is another means of reducing symptoms. Two controlled trials showed cisapride can improve symptoms and enhance emptying in patients with chronic intestinal dysmotility.^222–224 The positive effect of cisapride is not as apparent in patients with vagal dysfunction, such as in diabetes and following vagotomy.²²⁴

Other prokinetic agents, including erythromycin, metoclopramide, domperidone, neostigmine, and bethanechol, have been used to treat chronic pseudo-obstruction, but results are anecdotal and high quality studies are lacking. Domperidone is not FDA approved and is unavailable in the United States. In a small, short-term study, the somatostatin analog octreotide stimulated intestinal motility, possibly reduced bacterial overgrowth, and improved abdominal symptoms in patients with scleroderma.¹⁵² Other open-labeled studies confirmed the long-term effectiveness of octreotide with erythromycin in the treatment of chronic pseudo-obstruction, but some data show that octreotide retards gastric²²⁵ and small bowel transit in health, and many use the drug (50 µg dose) to induce MMC-like contractions at least two hours after the last meal of the day to sweep residue out of the small intestine toward the colon and prevent bacterial overgrowth.²²⁶ Oral pyridostigmine (60 mg/5 mL, to 2 teaspoons one to three times daily with gradual titration as needed 10-15 minutes before meals) may be effective in reducing symptoms of bloating and constipation, but clinical trials with this agent are needed.

Treatment of inflammatory neuropathies is centered on the use of immunosuppressive therapies. The diagnosis should be suspected because of the presence of circulating antibodies and proved through specialized tissue analysis, if available.¹²⁴ When a diagnosis of an enteric ganglionitis or inflammatory neuropathy has been established, glucocorticoids, such as prednisolone (60-100 mg/day), methylprednisolone (up to 600 mg/day), or beclomethasone (200 µg three times daily), alone or in combination with other immunosuppressive treatments, such as azathioprine or cyclophosphamide, have been associated with significant clinical improvement.¹³⁴

Surgical Therapy

In carefully selected patients, such as those with megaduodenum of the small intestine, resection or bypass of dysfunctional segments can have a good prognosis.²²⁷ Venting gastrostomy and enterostomy may be used to reduce abdominal distention and vomiting, which can have a positive effect on conveying intestinal contents through the gastrointestinal tract.¹¹³ Because chronic intestinal pseudo-obstruction tends to be a progressive disorder, surgery might provide only temporary benefit. Unnecessary surgery should be avoided because it can create adhesions and future additional difficulties.

Small intestine and multiorgan transplantation are gaining recognition as standard treatment for patients with irreversible intestinal failure in whom TPN fails or those who have high morbidity and poor disease-related quality of life despite optimal parenteral nutrition.²²⁸ Isolated intestinal transplant is technically less complex than transplantation of combined or multiorgan grafts, and it is preferred in cases of liver disease associated with intestinal failure because the liver failure often reverses if transplantation is successful.²²⁹

Immunosuppressive management, such as tacrolimus, represents a landmark in the treatment of patients undergoing transplantation for intestinal failure. Advances in immunosuppressive protocols, including induction therapy with monoclonal antibodies (daclizumab, alemtuzumab, or thymoglobulin), has lowered immunosuppressive requirements and reduced the risk of renal failure and sepsis. Advances in surgical techniques and graft monitoring via graft ileoendoscopy and intestinal biopsy have led to improved graft and patient survival rates.²²⁹ In one series of isolated intestinal transplants in adult patients, the survival rates were similar to those for other solid organ transplantations.²²⁹ Three year patient survival rates of 70% for isolated intestinal transplantations and 41% for multivisceral transplantations are reported, with mortality rates of 32.5% from sepsis (63%) or rejection.²²⁹