Henry P. Parkman MD1
Professor of Medicine
1Temple University School of Medicine, Director, GI Motility Laboratory, Temple University Hospital
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Gastrointestinal motility disorders are characterized by acute, recurrent, or chronic symptoms with objective evidence of slow or rapid GI transit or motility in the absence of mucosal disease or obstruction. Some of these disorders include achalasia, diffuse esophageal spasm, gastroesophageal reflux disease (GERD) [see 4:I Esophageal Disorders], gastroparesis, chronic intestinal pseudo-obstruction (CIP), colonic inertia, and fecal incontinence. Many of these GI motility disorders, especially gastroparesis and fecal incontinence, are being increasingly recognized.
Functional GI disorders are characterized primarily by symptoms suggesting impaired motor or sensory functions in the absence of mucosal or structural abnormality or of known biochemical or metabolic disorders. In the United States, functional GI disorders are estimated to affect 25 million persons. Some of these disorders include functional heartburn, functional dyspepsia, and irritable bowel syndrome (IBS). IBS is the most common of the disorders; it results in abdominal pain and altered bowel movements and is present in 10% to 15% of the population.1
Normal Gastrointestinal Motility
The important motor events related to normal gastric emptying include (1) postprandial receptive relaxation of the gastric fundus, which allows accommodation of food without significantly increasing gastric pressure; (2) rhythmic antral contractions for trituration of large food particles and breakdown into appropriate size; (3) pyloric relaxation, which allows food to enter the duodenum; (4) coordination of antropyloroduodenal motor events; and (5) neural/hormonal inhibitory feedback from nutrients in the small bowel.
Solid and liquid foods empty from the stomach at different rates. Liquids empty from the stomach at an exponential rate; solids are initially retained selectively within the stomach until particles have been triturated to a size smaller than 2 mm, at which point they can be emptied at a linear rate from the stomach.
Normal gastric emptying is regulated by the influences of the central nervous system predominantly through vagal efferent pathways and the enteric nervous system acting on gastric smooth muscle. When a meal is ingested, the proximal portion of the stomach (i.e., the fundus) relaxes to accommodate the food. This response, called gastric accommodation, is mediated by the vagus nerves and involves the activation of intrinsic nitrergic inhibitory nerves in the wall of the stomach. Subsequent fundic and antral smooth muscle contractions result primarily from cholinergically mediated contractions; these contractions result from alterations of the electrical potential of the cell membrane from ions flowing through channels of the cell membrane. The enteric nervous system consists of intrinsic neurons of the GI tract and is organized in ganglionated plexi (primarily the submucosal and myenteric plexi). The enteric nervous system is organized in intricate excitatory and inhibitory circuits. These circuits play essential roles in controlling peristalsis and the migrating motor complex. Among the enteric plexi are interstitial cells of Cajal, which serve as gastric pacemakers. The afferent enteric nerves are also important in mediating sensation from the stomach.
Small Intestinal Motility
The small intestine transports solids and liquids at approximately the same rate. Because there is a separation of the two phases in the stomach, liquids may arrive in the colon before the head of the solid phase of the meal. Ileal emptying of chyme is characterized by bolus transfers.
GI motility is characterized by distinct patterns of contractile activity in the fasting and postprandial periods. This is particularly evident in the stomach and small intestine. The fasting period is characterized by a cyclic motor phenomenon called the migrating motor complex. In healthy people, it occurs approximately once every 90 minutes and comprises a period of quiescence (phase I), a period of intermittent pressure activity (phase II), and an activity front, during which the stomach and small intestine contract at their highest frequency (phase III). During phase III of the migrating motor complex, the frequency of contractions reaches three a minute in the stomach and 11 or 12 a minute in the proximal small intestine. The interdigestive activity front migrates a variable distance down the small intestine; there is a gradient in the frequency of contractions during phase III, from 11 or 12 a minute in the duodenum to as low as five a minute in the ileum. The distal small intestine also demonstrates another characteristic motor pattern—a propagated prolonged contraction, or power contraction—that serves to empty residue from the ileum to the colon in bolus transfers.
In the postprandial period, the fasting cyclic activity of the stomach and small intestine is replaced by irregular, fairly frequent contractions in those regions of the stomach and small bowel that come in contact with food. The caloric content of the meal is the major determinant of the duration of this so-called fed pattern. The maximum frequency of contractions is below that noted during phase III of the migrating motor complex.
The colon serves as a reservoir to facilitate the absorption of fluids, electrolytes, and short-chain fatty acids produced by bacterial metabolism of unabsorbed carbohydrates. This reservoir function is centered predominantly in the ascending and transverse colonic regions. The descending colon functions as a conduit for the relatively rapid transit of feces to the sigmoid colon, which acts as a second reservoir. The control and function of contractions in the colon are not fully understood; some irregular contractions serve to mix its contents, whereas high-amplitude propagated contractions (HAPCs), which on average occur four to six times a day, are sometimes associated with mass movement of colonic residue and lead to defecation. After meals of at least 500 kcal, there is a greater propensity for HAPCs to develop and for the tone (i.e., the background state of contractility) of the colon to increase, resulting in bowel movements in the first 2 hours after meals.
Emptying of the sigmoid colon and rectum is largely under volitional control. The defecatory process requires the Valsalva maneuver to raise intra-abdominal pressure, which is transmitted to the rectal contents, and relaxation of the puborectalis (or pelvic floor) and external anal sphincter, which necessitates a coordinated series of functions. This facilitates the opening or straightening of the rectoanal angle and expulsion of stool.
Gastric Motility Disorders
Gastroparesis is a chronic motility disorder characterized by delayed gastric emptying in the absence of a mechanical cause of obstruction. Most patients with gastroparesis are women.2
Gastroparesis is being increasingly recognized, and management of this condition is challenging. Symptoms do not closely correlate with gastric emptying, which is the customary indicator of gastroparesis. Although current management strategies are often suboptimal for improving patients' symptoms, advances are being made in the evaluation and treatment of this disorder.3,4 New treatments currently under investigation may result in a more favorable outlook for patients with this condition.
Gastroparesis can occur in many clinical settings, with a wide variation in and severity of symptoms [see Table 1]. In one series of 146 patients with gastroparesis, 36% of the cases were idiopathic, 29% were associated with diabetes, and 13% occurred in postsurgical patients; the remaining 22% of cases had miscellaneous causes.2
Gastroparesis is a well-recognized complication of diabetes mellitus. Classically, gastroparesis occurs in patients with long-standing type 1 diabetes mellitus who have other associated complicantions of diabetes, such as retinopathy, nephropathy, and peripheral neuropathy.5Many affected patients may have other signs of autonomic dysfunction, including postural hypotension. Gastroparesis may also occur in patients with type 2 diabetes.
The prevalence of gastroparesis in patients with either type 1 or type 2 diabetes ranges from 30% to 50%, although the magnitude of gastric delay is modest in many cases.5 Patients who have had diabetes for a relatively short time may have accelerated emptying. In those with accelerated emptying, impairment of fundic relaxation, which is necessary to accommodate a meal, may be the underlying defect; this may be caused by vagal dysfunction.6
Fluctuations in gastric emptying in patients with diabetic gastroparesis appear to influence postprandial blood glucose concentrations.7 In diabetic patients, delayed gastric emptying contributes to erratic glycemic control because of unpredictable delivery of food into the duodenum.8 Delayed gastric emptying of nutrients in conjunction with parenteral insulin administration may produce hypoglycemia. Conversely, acceleration of the emptying of nutrients has been reported to cause early postprandial hyperglycemia.9 Difficulty in the control of blood glucose levels may be an early indication that a diabetic patient is developing gastric motor dysfunction.2
Hyperglycemia itself can reversibly interfere with gastric motility in several ways: (1) by decreasing antral contractility; (2) by causing decreases in phase III of the migrating motor complex; (3) by increasing pyloric contractions; (4) by causing disturbances in gastric myoelectric activity; (5) by delaying gastric emptying; and (6) by modulating fundic relaxation.8 Hyperglycemia also appears to impair vagal efferent function.
Gastroparesis may occur as a complication of a number of abdominal surgical procedures. In the past, most cases resulted from vagotomy performed in combination with gastric drainage to correct medically refractory or complicated peptic ulcer disease. Since the advent of laparoscopic techniques for the treatment of GERD, gastroparesis has become a more common complication of fundoplication (possibly from vagal injury from the surgery). Approximately 5% of patients undergoing vagotomy with antrectomy and gastrojejunostomy (Bilroth I procedure) develop severe postsurgical gastroparesis.10 In these patients, the antrum is not present to triturate solids, and the proximal stomach is unable to generate sufficient pressure to empty solid food residue.
The combination of vagotomy, distal gastric resection, and Roux-en-Y gastrojejunostomy predisposes to severe gastric stasis resulting from slow emptying from the gastric remnant and delayed small bowel transit in the denervated Roux efferent limb. The Roux-en-Y stasis syndrome—characterized by postprandial abdominal pain, bloating, nausea, and vomiting—is particularly difficult to manage.
Table 1 Causes of Gastroparesis
Most patients with idiopathic gastroparesis are women, typically young or middle aged.11 The anatomic basis of idiopathic gastroparesis is not fully known. In one case of idiopathic gastroparesis, myenteric plexus hypoganglionosis and reductions in the number of interstitial cells of Cajal were observed.12 A viral etiology has also been postulated for a subset of cases of idiopathic gastroparesis. Some patients with idiopathic gastroparesis report an initial onset of symptoms suggestive of a viral prodrome.13 In this patient subset, previously healthy patients experience the sudden onset of nausea, vomiting, diarrhea, fever, abdominal cramps, or a combination of these symptoms—suggestive of a GI viral infection; however, the symptoms do not resolve, as would be the case in a viral infection. In these patients, nausea, vomiting, and early satiety become chronic, with resolution of symptoms possibly occurring after several years. The course of idiopathic gastroparesis may fluctuate between acute symptomatic episodes and periods in which symptoms are relatively quiescent. Patients who experience idiopathic gastroparesis without a viruslike onset show less improvement over time. Viruses that have been implicated in idiopathic gastroparesis include cytomegalovirus, Epstein-Barr virus, and varicella-zoster virus.
The diagnosis of gastroparesis is confirmed by the demonstration of delayed gastric emptying in a symptomatic patient, in the absence of other potential causes.
Symptoms of gastroparesis are variable and nonspecific and include early satiety, nausea, vomiting, bloating, and upper abdominal discomfort. In one series of 146 patients with gastroparesis, nausea and vomiting were the most frequently reported symptoms (occurring in 92% and 84% of patients, respectively), followed by abdominal bloating (75%) and early satiety (60%).2 Patients may also experience distention and anorexia.
Correlation of symptoms with delayed gastric emptying is variable in diabetic gastropathy, idiopathic gastroparesis, and functional dyspepsia. In patients with diabetes, abdominal fullness and bloating were found to be associated with delayed gastric emptying. Symptoms of idiopathic gastroparesis overlap with those of functional dyspepsia; in some patients, it may be difficult to distinguish between the two disorders. In functional dyspepsia, the predominant symptoms typically are abdominal pain and discomfort; in idiopathic gastroparesis, the predominant symptoms are typically nausea, vomiting, early satiety, and bloating. However, early satiety, postprandial fullness, and vomiting have been reported to be associated with delayed emptying in patients with functional dyspepsia.14
Family history and medication history are essential to identify underlying etiologic factors that may result in a motility disorder. In patients with diabetic gastroparesis, diabetes has generally been present for at least 5 years. A careful review of systems will help reveal an underlying collagen vascular disease (e.g., scleroderma) or disturbances of extrinsic neural control that also may be affecting the abdominal viscera. Such symptoms include orthostatic dizziness; difficulties with erection; dryness of mouth, eyes, or vagina; difficulties with visual accommodation in bright lights; and an absence of sweating. Raynaud phenomenon may suggest the presence of scleroderma.
On physical examination, the presence of a succussion splash is usually indicative of a region of stasis within the GI tract, typically the stomach. The hands and mouth may show signs of scleroderma. Testing of pupillary responses to light and accommodation, blood pressure in the lying and standing positions, general features of a peripheral neuropathy, and external ocular movements can identify patients with an associated neurologic disturbance, such as those with a long history (usually longer than 10 years) of diabetes mellitus or oculogastrointestinal muscular dystrophy.
A motility disorder should be suspected whenever undigested solid food or large volumes of liquids are observed during esophagogastroduodenoscopy, which is performed after an overnight fast. Barium studies rarely identify the etiology of the motor disorder except in small bowel systemic sclerosis, which is characterized by megaduodenum and thickened valvulae conniventes in the small intestine. Barium x-ray, however, serves the important function of excluding mechanical obstruction. The diagnosis of a gastric motility disorder, therefore, depends on a careful history and confirmation by transit tests.
If the patient's history includes an obvious etiologic factor, such as long-standing diabetes mellitus, it is usually unnecessary to pursue further investigations.
Routine laboratory testing is not useful for the diagnosis of gastric stasis, although it may help to identify diseases that are associated with delayed gastric emptying or to rule out other disorders [see Table 2]. A complete blood count and metabolic profile (e.g., fasting plasma glucose, potassium, creatinine, serum total protein, albumin, and calcium) are useful to assess the nutritional status of the patient.
Table 2 Evaluation of Patients Suspected of Having Gastroparesis4
Transit tests, which can be performed relatively simply and inexpensively, enable good discrimination between healthy and disease states. The most widely available approach is scintigraphy with scans taken immediately after ingestion of the radiolabeled meal, as well as 1, 2, and 4 hours later.15,16 Gastric emptying scintigraphy of a solid-phase meal is considered the gold standard for the diagnosis of gastroparesis because this test quantifies the emptying of a physiologic caloric meal.17 The test meal must have a sufficient caloric content (typically more than 200 kcal) and solid consistency to induce the increased contractions in the stomach and small intestine that occur postprandially. Many centers use a technetium-99m (99mTc) sulfur colloid-labeled egg sandwich as a test meal.
When the cause of the gastric transit disorder is unclear, referral to a specialized center for upper GI manometry, electrogastrography, and autonomic tests may be needed. Gastroduodenal manometry may identify a myopathic or neuropathic disorder or an unsuspected mechanical obstruction resulting from simultaneous prolonged contractions at several levels of the intestine. Electrogastrography may identify disorders of gastric electrical activity signifying a gastric motility disorder.
Symptoms of gastroparesis may simulate symptoms of other structural disorders of the stomach and proximal GI tract, such as peptic ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders. There also is an overlap between the symptoms of gastroparesis and those of functional dyspepsia. In fact, idiopathic gastroparesis can be considered one of the causes of functional dyspepsia.
Delayed gastric emptying may be caused by conditions other than gastroparesis; the conditions to be differentiated are mechanical obstruction, functional GI disorders such as functional dyspepsia and IBS, and eating disorders such as anorexia nervosa and rumination syndrome. The degree of impairment of gastric emptying in eating disorders is relatively minor compared with diabetic and postvagotomy gastric stasis.
The treatment goals for patients with symptomatic gastroparesis are as follows: (1) to control symptoms; (2) to correct fluid, electrolyte, and nutritional deficiencies; and (3) to identify and treat the underlying cause of gastroparesis, if possible. For relatively mild disease, dietary modifications and a low-dose antiemetic or prokinetic agent might provide satisfactory control of symptoms. Patients with severe manifestations of gastroparesis, such as refractory vomiting, pronounced dehydration, or chaotic glucose control, may require hospitalization for intravenous hydration, insulin administration, intravenous administration of antiemetic and prokinetic agents, or a combination of these measures.
In patients with gastroparesis, the liquid nutrient component of the ingested meal should be increased because gastric emptying of liquids often is preserved. The intake of fats and fiber should be minimized because they tend to slow gastric emptying. Indigestible fiber and roughage also may predispose to gastric bezoar formation. Foods that cannot be reliably chewed into small pieces should be avoided. Multiple frequent meals are often recommended to limit the caloric intake with each meal.
Correction of dehydration and electrolyte and nutritional depletion is particularly important during acute exacerbations of gastroparesis. Nutritional support should be tailored to the severity of the deficiencies of trace elements and dietary constituents in each patient. Dietary measures include the use of low-fiber and low-fat caloric supplements that contain iron, folate, calcium, and vitamins D, K, and B12. Patients who have more severe conditions, such as severe diabetic gastroparesis, may need parenteral or enteral nutrition supplementation.
Glycemic control in diabetic patients
To date, no long-term studies have confirmed the beneficial effects of maintenance of near-normal glycemia on gastroparetic symptoms in diabetic patients. Nevertheless, the findings of physiologic studies in healthy volunteers and diabetic patients and other obvious benefits of glycemic control provide a compelling argument for striving to achieve near-normal blood glucose levels in affected diabetic patients.3
Antiemetic agents may be useful in relieving symptoms of gastroparesis. Antiemetic drugs may serve as primary therapy for patients with gastroparesis; they may also be used as adjunctive therapy when combined with medications that promote gastric emptying [see Table 3]. Phenothiazines (e.g., prochlorperazine) are commonly prescribed as antiemetic agents; these agents are available in oral, suppository, I.M., and I.V. formulations. For patients with severe symptoms, suppositories or injectable formulations may be more beneficial. Side effects from phenothiazines are common and include sedation and extrapyramidal reactions. Serotonin (5-HT3) receptor antagonists, such as ondansetron, may be helpful in some cases. Ondansetron is available in oral and I.V. formulations.
Table 3 Therapy for Gastroparesis
Prokinetic medications are often used to enhance gut contractility and promote motility. Some prokinetic agents, notably metoclopramide and domperidone, also exhibit antiemetic properties and may be useful in relieving symptoms of gastroparesis [see Table 3]. The response to treatment is usually judged clinically rather than by repeating gastric emptying tests.
Metoclopramide, with its antinausea and indirect cholinomimetic actions, is widely used for the treatment of gastroparesis, though evidence of its efficacy is limited. Controlled trials report that metoclopramide provides symptomatic relief and accelerates gastric emptying of solids and liquids in patients with idiopathic, diabetic, and postvagotomy gastroparesis.18,19 Metoclopramide is approved for the treatment of diabetic gastroparesis and for the prevention of postoperative and chemotherapy-induced nausea and vomiting. The usual dosage is 10 mg four times a day. Metoclopramide is also available for parenteral use; the usual dose is 10 mg I.M. or I.V. Metoclopramide should be used with caution; it may be useful to administer a test dose (1 to 2 mg) to exclude dystonic reactions resulting from an idiosyncratic reaction. Metoclopramide is effective for the short-term treatment of gastroparesis for up to several weeks; however, symptomatic improvement does not necessarily accompany improvement in gastric emptying. The long-term utility of metoclopramide has not been proven. Neuropsychiatric side effects, such as dystonias, are not infrequent, and rare cases of tardive dyskinesia have been reported.
Erythromycin, a macrolide antibiotic that stimulates motilin receptors partly through a cholinergic mechanism, has been shown to stimulate gastric emptying in patients with diabetic gastroparesis, idiopathic gastroparesis, and postvagotomy gastroparesis; however, studies have been small and have not been carefully controlled.20 In a systematic review of studies on oral erythromycin, improvement in symptoms was noted in 43% of patients.20 Oral administration of erythromycin should be initiated at low doses (e.g., 125 mg to 250 mg three or four times daily).3 Intravenous erythromycin (100 mg every 8 hours) is used for hospitalized patients with severe refractory gastroparesis. Side effects of erythromycin at higher doses include nausea, vomiting, and abdominal pain.
Cisapride, a substituted benzamide that acts as a serotonin agonist, has been used to treat altered motility, such as impaired gastric emptying, in patients with both gastroparesis and CIP.21 The availability of cisapride has been severely restricted in the United States, because it has been associated with important drug interactions (causing cardiac arrhythmias and death).
Domperidone, a peripheral dopaminergic antagonist, has been shown to be efficacious in the treatment of diabetic gastroparesis22; symptom improvement was similar to that observed for metoclopramide and cisapride but with fewer CNS side effects. Domperidone is not approved in the United States but may be obtained with the use of a Federal Drug Administration Investigational New Drug Application and Institutional Review Board approval. The usual dosage is 30 to 80 mg/day in three or four divided doses.
Tegaserod is a partial 5-HT4 receptor agonist that has been shown to accelerate gastric and intestinal transit in healthy persons and intestinal transit in patients with constipation-predominant IBS.23,24 In a preliminary controlled trial, tegaserod was shown to accelerate solid-phase emptying in patients with gastroparesis; gastric emptying normalized in 80% of patients who received 18 mg of tegaserod daily, as compared with 50% of those receiving placebo.25 Tegaserod is chemically different from the benzamides and does not cause cardiac dysrhythmias.
Pyloric botulinum toxin injection
Botulinum toxin is a potent inhibitor of neuromuscular transmission and has been used to treat spastic somatic muscle disorders as well as achalasia. Pilot studies have tested the effects of pyloric injection of botulinum toxin in patients with diabetic and idiopathic gastroparesis. These preliminary studies indicated that treatment with botulinum toxin results in mild improvements in gastric emptying and modest reductions in symptoms for several months.26,27 Double-blind controlled studies are needed to support the efficacy of this treatment.
Gastric electric stimulation
Gastric electric stimulation is an emerging treatment for refractory gastroparesis. It involves an implantable neurostimulator that delivers a high-frequency (i.e., 12 cpm), low-energy signal with short pulses. A randomized, controlled trial indicated that gastric electrical stimulation decreased vomiting frequency and GI symptoms in patients with severe refractory gastroparesis.28 The gastric electric neurostimulator has been approved by the Food and Drug Administration for the treatment of chronic, refractory nausea and vomiting secondary to diabetic or idiopathic gastroparesis. The response rate to gastric electric stimulation is 50% to 70%. Diabetic patients respond better than patients with idiopathic gastroparesis. In addition, patients with primary symptoms of nausea and vomiting do better than patients with abdominal pain. The main complication of the implantable neurostimulator has been infection, which has necessitated removal of the device in approximately 5% to 10% of cases. Further investigation is needed to confirm the effectiveness of gastric stimulation in the treatment of gastroparesis.
Surgery is rarely indicated for patients with nonobstructive gastric stasis except for the provision of decompression (e.g., gastrostomy or jejunostomy) or for completion gastrectomy for patients with stasis syndrome after gastric surgery.29 For patients with gastroparesis who are unable to maintain nutrition with oral intake, surgical or endoscopic placement of a feeding jejunostomy tube may provide adequate nutrition. Switching from oral to small bowel nutrient delivery may decrease symptoms and reduce hospitalizations. Jejunostomy tubes are effective for providing nutrition, fluids, and medications if there is normal small intestinal motor function. Except in cases of profound malnutrition or electrolyte disturbance, enteral feedings are preferable to total parenteral nutrition (TPN) because of the risks of infection, venous thrombosis, and liver disease with TPN. If small bowel dysmotility is suspected, a trial of nasojejunal feedings should precede placement of a permanent jejunostomy tube. Jejunostomy tubes can be placed endoscopically or surgically during laparoscopy or laparotomy. Carefully regulated enteral nutrient infusions may improve glycemic control in diabetic patients with refractory vomiting. Nocturnal feedings may permit daytime employment and functioning.
Rapid Gastric Emptying (Dumping Syndrome)
Rapid gastric emptying (often referred to as dumping) can result from impaired relaxation of the stomach upon ingestion of food. Postprandial intragastric pressure is relatively high and results in active propulsion of liquid foods from the stomach. A high caloric (usually carbohydrate) content of the liquid phase of the meal evokes a rapid insulin response with secondary hypoglycemia. These patients may also have impaired antral contractility and gastric stasis of solids, which may paradoxically result in a clinical picture of both gastroparesis (for solids) and dumping (for liquids).30
Symptomatic rapid gastric emptying may also occur as a result of prior gastric surgery, damage to the pylorus, or gastric denervation. Symptoms of the dumping syndrome include sweating, weakness, occasional orthostasis, tachycardia, and diarrhea. The syndrome is often characterized by early dumping or late dumping. Early dumping results from rapid filling of the intestine with hypertonic fluid leading to bloating, crampy abdominal pain, and diarrhea with tachycardia and lightheadedness. Late dumping refers to symptoms primarily of hypoglycemia (i.e., weakness, palpitations, and diaphoresis) occurring 2 to 3 hours after a meal. Although dumping syndromes can usually be diagnosed clinically, scintigraphic studies using both solid and liquid phase markers can help establish the diagnosis of rapid gastric emptying.31
Management of dumping includes patient education (particularly regarding the avoidance of high-nutrient liquid drinks) and, possibly, the addition of guar gum or pectin to retard liquid emptying.30 If these measures are ineffective, pharmacologic approaches may be effective. For example, the use of subcutaneous octreotide (50 to 100 µg) 15 minutes before meals decreases many of the vasomotor symptoms and also retards gastric emptying and small bowel transit, thereby relieving associated hypoglycemia and diarrhea.32 Long-term use of octreotide is somewhat limited by side effects, particularly diarrhea and steatorrhea. A long-acting-release octreotide (Sandostatin-LAR) appears to be as effective as octreotide and may be better tolerated.33
Disorders of Small Bowel Motility
Motility disorders of the small bowel may be characterized by decreased contractility or by increased or uncoordinated contractility. Symptoms that may arise from the slow propagation of small intestinal contents include postprandial abdominal pain, bloating, nausea, vomiting, and early satiety. These symptoms can also be consistent with mechanical obstruction; the most important question to address initially is whether the symptoms result from obstruction or from a motility disorder. Bacterial overgrowth of the small intestine may occur as a consequence of slow intestinal transit caused by diminished activity during phase III of the migrating motor complex.
Diarrhea is generally the result of rapid intestinal transit; with an accelerated transit time, the amount of time during which the luminal contents are in contact with the mucosa decreases, thereby preventing absorption. Patients may also have maldigestion and malabsorption resulting from poor mixing of the dietary material with the digestive enzymes and bile salts. Accentuated borborygmi may also disturb the patient.
Chronic Intestinal Pseudo-Obstruction
CIP is a syndrome characterized by recurrent clinical symptoms suggestive of intestinal obstruction in the absence of a mechanical blockage of the lumen. The symptoms of pseudo-obstruction are caused by ineffective peristalsis; they are similar to those of gastroparesis and include nausea, vomiting, and abdominal pain with abdominal distension. Radiologic findings consist of air-fluid levels within the small intestinal lumen. CIP is a chronic condition, whereas the syndrome of adynamic ileus is acute and self-limited. The disorder can be caused by several systemic diseases, including scleroderma, amyloidosis, myxedema, and long-standing diabetes. Often, however, there is no known cause; such cases are categorized as chronic idiopathic intestinal pseudo-obstruction (CIIP). The diagnosis of CIIP is often delayed until several years after the onset of symptoms. At one center, a median of 8 years lapsed between onset of symptoms and diagnosis34; in these patients, manometry invariably showed abnormal motor patterns. Long-term outcome is generally poor despite surgical and medical therapies.
The two main forms of idiopathic pseudo-obstruction are myopathic (involving the intestinal musculature) and neurogenic (involving the neural apparatus).35 The bowel wall in patients with the myopathic form (e.g., hollow visceral myopathy) shows thinning and degeneration of the smooth muscle with replacement by fibrous tissue. Patients with the neurogenic form (e.g., visceral neuropathy) have abnormalities in neurons and glial cells within the splanchnic ganglia, the myenteric plexus, or both. In patients with the neurogenic form, the intestinal smooth muscle is normal.
Steps in the evaluation of a patients with suspected CIP include the following: radiographic imaging to eliminate a structural cause of blockage; assessment of the patient's nutritional state; confirmation of dysmotility by means of a transit test; and performance of specialized testing, such as gastroduodenojejunal manometry.36 In patients with intestinal myopathy, manometry typically reveals low-amplitude contractions that propagate normally. In patients with intestinal neuropathy, individual contractions may be of normal amplitude but are disorganized. Other manifestations include disruption of phase III of the migrating motor complex, bursts of nonpropagating activity during fasting, and failure to convert from the fasting to the fed pattern with a meal.
The natural history of CIP depends on the underlying cause of the syndrome. The management of CIP involves multiple modalities: dietary manipulations, parenteral nutrition, pharmacotherapy, and endoscopic and surgical therapy.35 Nutritional support by enteral or, if necessary, by parenteral means is an important aspect of management. Pharmacotherapy consists of prokinetic agents and, if indicated, antibiotics for bacterial overgrowth (see below). Venting jejunostomy may be helpful in relieving obstructive symptoms. Small bowel transplantation has been used in some centers.
Small Intestinal Bacterial Overgrowth
Normally, gastric acid secretion and intestinal motility play crucial roles in preventing significant numbers of bacteria from accumulating in the upper GI tract. Intestinal dysmotility is an important factor contributing to the development of clinically significant small intestinal bacterial overgrowth. Diarrhea, steatorrhea, and malabsorption are consequences of bacterial overgrowth. Diagnosis can be made with small intestinal aspiration of luminal contents with quantitation of bacteria or by use of the lactulose hydrogen breath test. In the latter test, an early hydrogen peak represents metabolism of the orally administered lactulose by bacteria in the small intestine and indicates bacterial overgrowth. Treatment is with broad-spectrum antibiotics directed against aerobic and anaerobic enteric bacteria.37 Because of microbial resistance to tetracycline, this agent is no longer effective in many patients. Adequate antimicrobial coverage can be achieved with amoxicillin-clavulanate, metronidazole, rifaximin, and gentamicin.37
Ileus is an acute decrease or absence of small bowel motility. Although ileus is most commonly seen in the postoperative setting, it is being increasingly recognized in nonsurgical conditions, usually in the context of severe metabolic or systemic illness. Ileus also occurs in association with peritonitis or following spinal cord injury or pelvic fractures. Postoperative ileus tends to be self-limiting (e.g., lasting up to 3 days after laparotomy). Available evidence suggests that sympathetic inhibitory overactivity from the spinal cord, possibly in conjunction with a decrease in parasympathetic activity, may be important in its development, particularly during the acute postoperative phase.38Factors that may prolong postoperative ileus include electrolyte and metabolic abnormalities (especially hypokalemia), medications (such as opiates), and infections (such as peritonitis). Currently, a multimodal approach (e.g., continuous epidural analgesia with local anesthetics, early feeding, and enforced mobilization) is taken in the prevention and management of postoperative ileus.39
Rapid-Transit Dysmotilities of the Small Bowel
Rapid transit through the small bowel is a minor component of IBS in some patients. However, it is a major component of other diseases and results in a significant loss of fluid and osmotically active solutes that overwhelm colonic capacitance and reabsorptive capacity and result in severe diarrhea. Examples include postvagotomy diarrhea, short bowel syndrome, diabetic diarrhea, and carcinoid diarrhea.40 These disturbances of small bowel transit can best be identified by use of scintigraphy or, if scintigraphy is not available, by use of the lactulose-hydrogen breath test.
The objectives of treatment are restoration of hydration and nutrition and retardation of small bowel transit. Dietary interventions include avoidance of hyperosmolar drinks (e.g., virtually all soft drinks), use of iso-osmolar or hypo-osmolar rehydration solutions, and reduction of the fat content in the diet to around 50 g a day to avoid delivery of unabsorbed fat to the colon (where their metabolites are cathartic). Correction of nutritional deficiencies (commonly, calcium, magnesium, potassium, and water- and fat-soluble vitamins) is often required. Pharmacotherapy should be delivered in a stepwise fashion. First, an opioid agent in high dosage (e.g., loperamide, 4 mg) is given one-half hour before each meal and at bedtime to suppress the small bowel transit and colonic response to feeding. Next, verapamil (40 mg b.i.d.) or clonidine (0.1 to 0.2 mg orally or by patch) should be given, and if these are ineffective or produce unacceptable side effects (usually hypotension), subcutaneous octreotide, starting at 50 µg before meals, should be prescribed.32 A long-acting-release octreotide (Sandostatin-LAR) that is administered intramuscularly is being evaluated as therapy for short bowel syndrome; preliminary evidence suggests that this form of therapy is effective and well tolerated.41
Patients with less than 1 m of residual small bowel may be unable to sustain fluid and electrolyte homeostasis without parenteral support. However, it is almost invariably possible to maintain patients with more than 1 m of residual small bowel with oral nutrition, pharmacotherapy, and supplements.
Colorectal Motility Disorders
Slow-transit constipation42 is a motility disorder of the colon that results in prolonged transit. The diagnosis of slow-transit constipation should be made only after exclusion of mucosal diseases, such as tumors and strictures. The diagnosis is most conveniently made by assessing mean colonic transit time through use of abdominal radiography and radiopaque markers. There are two commonly used variations of this method. The first type involves ingestion of 24 radiopaque markers in a soluble medication capsule on 4 successive days; plain abdominal radiography is performed on day 5. The number of markers in the colon approximates the mean colonic transit time in hours (normal: < 72 hours). The second variation requires that the patient ingest 20 markers on day 1; an abdominal x-ray is obtained on day 5. Normally, there should be fewer than five markers remaining in the colon. In all patients with delayed colonic transit, the possibility of outlet obstruction to defecation or a pangastrointestinal motility disorder must be ruled out.
Treatment of slow-transit constipation consists of increasing dietary bulk or fiber and administering osmotic laxatives (e.g., magnesium salts when not contraindicated) and stimulant laxatives or colonic prokinetic agents. A more severe variant of slow-transit constipation is colonic inertia. In this disorder, the colon fails to produce a motor response to physiologic stimuli, such as a meal, or to pharmacologic stimulation, as would occur, for example, after administration of neostigmine, 0.5 mg I.M., or intraluminal bisacodyl, 2 to 4 mg.
Megacolon is a cecal dilatation of the colon. Motility disorders arising from dilatation of the colon may be acute (Ogilvie syndrome) or chronic. Chronic megacolon may be congenital (Hirschsprung disease) or may represent the end stage of any form of refractory constipation (e.g., slow-transit constipation or pelvic floor dysfunction).
Acute Megacolon (Ogilvie Syndrome)
In Ogilvie syndrome, colonic dilatation is attributed to a sympathetically mediated reflex response to a number of serious medical or surgical conditions in elderly patients. The initial tasks facing the clinician are to exclude mechanical obstruction (with a hypaque enema), to discontinue enabling medications, and to correct metabolic disturbances.43 Dilatation of the cecum to a diameter of greater than 12 cm is cause for grave concern. The rectum should be decompressed with an indwelling tube and tap water enemas. Intravenous neostigmine is generally effective and safe for patients with colonic distention that is unresponsive to more conservative therapies. Endoscopic decompression is necessary for patients who do not respond to neostigmine therapy.
Hirschsprung disease, the congenital form of megacolon, is thought to be caused by the failure of neural crest cells to migrate completely during colonic development. The affected segment of the colon fails to relax, which results in blockage and retention of stool. Hirschsprung disease occurs in one in every 5,000 births. In the majority of patients, the disease is evident in the neonatal period and manifests in symptoms of distal intestinal obstruction such as vomiting, abdominal distension, and failure to pass stool. In patients with less severe disease, the diagnosis may not be made until childhood or adulthood. The clinical presentation usually suggests the diagnosis, which may be supported by findings on abdominal radiography, contrast enema, and anorectal manometry. The gold standard for the diagnosis of Hirschsprung disease is rectal biopsy, which can be performed safely by means of rectal mucosal suction.44 Surgery is the mainstay of treatment. Various surgical procedures are available; the choice of technique is usually made on the basis of surgeon preference because overall complication rates and long-term results are similar. Enterocolitis is a major complication of surgical repair, affecting as many as 55% of patients.45 Overall, mortality in patients with Hirschsprung disease is less than 10%.46
In chronic idiopathic megacolon, medical measures such as colonic evacuation with enemas, fiber supplementation, and laxatives may suffice. If severe motor dysfunction is confined to the colon, either a subtotal colectomy with an ileorrectal anastomosis or an ileostomy may occasionally be necessary.
Fecal incontinence is the involuntary passage of fecal material recurring for more than 3 months in a person older than 4 years of age. A review of 16 studies estimated that the prevalence of fecal incontinence ranges from 11% to 15% among community-dwelling adults; however, these values may reflect various biases in the available studies.47 Fecal incontinence is a common problem in the geriatric population, affecting 12% of community-dwelling adults48 [see 8:IX Management of Common Clinical Disorders in Geriatric Patients].
The most common causes of fecal incontinence are (1) weakness of the anal sphincter muscles that restrain passage of a bowel movement; (2) impaired rectal sensation; (3) decreased rectal compliance, which leads to increased frequency and urgency of bowel movements because the ability of the rectum to store fecal matter is reduced; and (4) fecal impaction, which produces constant inhibition of the tone of the internal anal sphincter, permitting leakage of liquid stool around the impaction. The latter is a frequent cause of fecal incontinence in older patients.
The evaluation of patients with fecal incontinence should begin with the taking of a medical history, followed by a thorough physical examination. Many patients find fecal incontinence a difficult topic to discuss, and specific questioning is often required. True incontinence must be distinguished from a sense of urgency without loss of stool—a symptom that may be associated with such disorders as IBS, pelvic irradiation, and inflammatory disease. The patient should be questioned about the onset, duration, frequency, and severity of symptoms, as well as precipitating events. It is important to determine whether there is a history of prior vaginal delivery, anorectal surgery, pelvic irradiation, diabetes, and neurologic disease, as well as whether symptoms occur in association with diarrhea. The physical examination should include inspection of the perianal area and an internal digital examination with assessment of pelvic floor descent while the patient is bearing down in simulation of a bowel movement.
The history and physical examination may suggest a possible cause of incontinence and thereby direct the choice of diagnostic tests. Sigmoidoscopy and anoscopy may be used to exclude mucosal inflammation, masses, or other pathology as the underlying cause of incontinence. Infrequently, identifying the cause of fecal incontinence requires specialized testing, including anorectal manometry to measure intraluminal pressure, anal endosonography to identify mass lesions, pudendal nerve conduction measurement to diagnose neuropathy, or defecography to define intrinsic lesions.
The treatment of fecal incontinence involves three approaches: medical therapy, biofeedback, and surgery. Medical therapy is aimed at reducing stool frequency and improving stool consistency. Limited evidence indicates that antidiarrheal agents (e.g., loperamide and diphenoxylate) and drugs that enhance anal sphincter tone (e.g., valproate sodium) reduce fecal incontinence in patients with watery stool.49 Stimulant laxatives (e.g., senna and bisacodyl), hyperosmolar laxatives (e.g., sorbitol and lactulose), rectal suppositories (e.g., glycerin and bisacodyl), or enemas (e.g., tap water) are often sufficient to treat constipation. Biofeedback therapy, a noninvasive means of cognitively retraining the pelvic floor and the abdominal wall musculature, is used to treat fecal incontinence50; the American College of Gastroenterology recommends its use in patients with weak sphincter muscles and impaired rectal sensation.51 Surgery should be considered in patients whose condition does not respond to medical therapy. A number of surgical approaches have been used to treat fecal incontinence, including sphincter repair, implantation of an artificial sphincter, and muscle transfer procedures with or without electrical stimulation. Stoma formation should be reserved for patients who do not respond to any other form of therapy.52
Functional Gastrointestinal Disorders
Functional GI disorders share common pathogenetic features, including abnormal motility and heightened visceral sensation. The abnormal motility may be characterized by rapid or slow transit of food or residue through the bowel or abnormal gastric relaxation to accommodate the meal. Abnormal contractile patterns have been described, but more importantly, patients perceive a sensation of excessive gut contractions. In some patients, these syndromes are preceded by an episode of gastroenteritis. In some patients with these conditions, frequently there is evidence of psychological comorbidity, such as anxiety, depression, or both; these symptoms appear to influence the decision of patients to consult their physicians.
Dyspepsia is characterized by upper abdominal symptoms that occur primarily during the postprandial period; they include nausea, vomiting, pain, bloating, anorexia, and early satiety. Dyspepsia that is not caused by ulcers, obstruction, or cancer is referred to as nonulcer or functional dyspepsia. It affects about 20% of the population of the United States.
An international committee of clinical investigators defined functional dyspepsia (Rome III criteria) as (1) the presence of one or more of four features (i.e., bothersome postprandial fullness, early satiation, epigastric pain, and epigastric burning) for the previous 3 months, with onset of symptoms at least 6 months before diagnosis; and (2) an absence of evidence of structural disease to explain the symptoms.53
Three main identified factors contribute to the pathophysiologic alterations present in functional dyspepsia: altered gastric emptying, increased gastric sensitivity, and impaired accommodation.54,55 The pathogenesis in many patients remains unclear. The role thatHelicobacter pylori infection plays in dyspepsia is uncertain; current epidemiologic evidence and the results of eradication studies provide insufficient evidence to support a causal relationship.56,57 A subgroup of patients may suffer nonerosive reflux esophagitis.
History and physical examination
The history usually provides information on the specific symptoms or the spectrum of symptoms experienced by the patient. However, the symptoms appear to have little discriminative value for predicting the physiologic alterations in an individual patient. The symptoms that appear to be most closely related to impaired gastric relaxation or accommodation are early satiety and weight loss.54 Studies have suggested that the presence of postprandial fullness may be indicative of delayed gastric emptying54,55; however, another study found only a weak correlation.58 Early satiety occurring soon after starting a meal has been associated with reduced gastric accommodation.54,55Weight loss of more than 5 kg is more frequent in patients with reduced gastric accommodation than in those with delayed gastric emptying.54
The presence of heartburn suggests a component of gastroesophageal reflux.59 Regurgitation from reflux needs to be differentiated from rumination,60 which results in the effortless regurgitation of undigested food within 30 minutes after oral ingestion; rumination occurs with virtually every meal and is not associated with nausea.
The physical examination is usually normal. On rare occasions, there may be a succussion splash in the epigastrium from the retention of food in the stomach. An epigastric mass, hepatomegaly, or supraclavicular lymphadenopathy may suggest that the dyspepsia is the result of malignancy. In the presence of alarm features such as dysphagia, bleeding, or weight loss in association with dyspepsia, it is essential to exclude mucosal diseases, such as ulcer or cancer. Cancer may still be present, however, even when these alarm features are absent. Patients are reassured by a negative endoscopic examination.
In most cases, the underlying cause of dyspepsia will not be obvious from the history and physical examination. For new-onset dyspepsia, endoscopy and testing for H. pylori infection are generally recommended.
Simple, cost-effective tests for mucosal disease, abnormal gastric emptying,61,62 and impaired gastric accommodation55,62 provide a rational alternative to the use of sequential empirical trials for identifying the mechanism causing dyspepsia.
There is great interest in identifying ways to demonstrate gastric hypersensitivity before therapy is initiated, because such knowledge would have a bearing on choice of therapy. Tests in which the patient drinks water or a nutrient beverage have been devised to evaluate the maximal tolerated volume and the symptoms of fullness, satiety, bloating, nausea, and pain at a defined period after ingestion (typically 30 minutes).54,63,64 These tests are noninvasive and inexpensive, and they have been introduced into clinical practice in some centers. However, they do not necessarily differentiate disturbances in the accommodation response from hypersensitivity per se. Until recently, measurement of accommodation required the placement of an intragastric balloon to measure fasting and postprandial volumes54; however, gastric accommodation can now be measured noninvasively by means of single-photon emission computed tomography.55,65
In clinical practice, dyspepsia is often treated with acid-suppressing regimens consisting of proton pump inhibitors or H2 receptor antagonists; however, the relative efficacy of these drugs remains uncertain.66 Temporary acid suppression with a proton pump inhibitor or an H2 receptor agonist may delay diagnosis of cancer.67
In cases of dyspepsia associated with H. pylori infection, eradication of the H. pylori infection results in resolution of the syndrome in only a small number of patients (1 in 5 or fewer)68; the general consensus is that in the absence of erosions or ulcers, attempted eradication of H. pylori is not indicated for the treatment of dyspepsia, though H. pylori infection is usually attempted anyway because of concern with the development of gastric atrophy or even gastric cancer in the long term.69
Irritable Bowel Syndrome
IBS is the most commonly diagnosed functional disorder of the GI tract. IBS affects 10% to 15% of the population of the United States, and patients with this disorder account for up to 25% of visits to gastroenterologists.1,70,71 As generally defined, IBS is characterized by chronic or recurrent abdominal pain associated with altered bowel function (i.e., constipation, diarrhea, or alternating constipation and diarrhea). The diagnosis of IBS is made on the basis of characteristic history, an absence of significant physical findings, an absence of abnormalities on standard laboratory tests, and normal gross and histologic findings on flexible sigmoidoscopy or colonoscopy. The Rome III criteria define IBS as the presence of two or more of the following symptoms occurring for at least 12 weeks in the preceding 12 months: (1) abdominal pain or discomfort that is relieved with defecation; (2) the onset of abdominal pain associated with a change in the frequency of bowel movements; and (3) the onset of pain associated with a change in form (appearance) of stool.72
Although classically, motility abnormalities are considered a disorder of the colon, such disorders can also be detected in the small intestine in a majority of patients with IBS. Motor abnormalities in the alimentary tract have been reported in IBS, including altered myoelectric activity and prolonged irregular small bowel and colonic contractions; these abnormalities include duodenal and jejunal clustering, ileal high-pressure waves, and a disturbed postprandial motor response. Abnormal visceral perception, as detected by a lower pain threshold in response to bowel distension, may also represent one of the key physiologic disturbances.
Constipation in patients with IBS may respond to treatment with fiber or simple laxatives, including osmotic agents.73,74 Serotoninergic agents that activate the 5-HT4 receptor may be approved for the treatment of constipation-predominant IBS. Tegaserod, the first of this class of drugs, appears to be modestly effective in women with constipation-predominant IBS.75,76 The 5-HT3 antagonist alosetron was found to provide adequate relief of pain, improved stool frequency, decreased urgency, and consistency for many patients whose predominant bowel disturbance was diarrhea.77 Alosetron was withdrawn from the market because of side effects (e.g., severe constipation and ischemic colitis), but it was reintroduced; the FDA has approved it for the treatment of women with severe diarrhea-predominant IBS whose condition failed to respond to conventional treatment.
IBS patients also tend to use complementary and alternative medicine more frequently than patients with organic bowel diseases.78Physicians should be aware of this, both with regard to the potential for adverse interactions and as an indication of emotional unease in these patients.
The Rome criteria III define functional constipation as the presence of two or more of the following symptoms occurring for at least 12 weeks in the preceding 12 months: (1) straining during at least 25% of defecations; (2) lumpy or hard stool in at least 25% of defecations; (3) a sensation of incomplete evacuation in at least 25% of defecations; (4) a sensation of anorectal obstruction or blockage in at least 25% of defecations; (5) manual maneuvers to facilitate defecation used in at least 25% of defecations; and (6) fewer than three bowel movements in a week.42 The Rome III guidelines also stipulate two additional conditions for the diagnosis of functional constipations, namely: (1) that loose stools are rarely present without the use of laxatives and (2) that there is insufficient evidence to support a diagnosis of IBS.42
Increasing dietary fiber and decreasing dietary fat, as well as the use of biofeedback and medication aimed at symptom relief, may be helpful in the treatment of functional constipation.42,79 Tegaserod has been approved by the FDA for the treatment of functional constipation; in one randomized trial, 43% of patients taking tegaserod (6 mg twice daily) responded to therapy, compared with 25% of patients taking placebo.80 Recently, lubiprostone was approved for the treatment of chronic idiopathic constipation. Lubiprostone is a chloride channel opener; its use leads to increased fluid secretion into the small intestine, which in turn leads to an increase in GI transit.
The Rome III criteria classify functional diarrhea separately from IBS. The Rome III criteria define functional diarrhea as the presence of loose or watery stool in at least 75% of episodes of stool passage for at least 12 weeks in the preceding 6 months.42 However, the diagnosis depends upon the evaluation of other potential causes; for this reason, the definition is somewhat limited in guiding clinical evaluation. The appropriate evaluation and treatment of these patients have not been appropriately delineated. Diagnostic measures often include evaluation of the stool for infectious causes and for the presence of fat, which would suggest malabsorption. Blood studies can now screen for celiac sprue and for inflammatory bowel disease. Rectal biopsies are performed during flexible sigmoidoscopy or colonoscopy to evaluate for microscopic colitis.
Outlet Obstruction to Defecation
Outlet obstruction to defecation (evacuation disorders) occurs when the patient has difficulty expelling a stool as a result of poorly functioning defecation dynamics.81
The patient may present with constipation or the inability to have spontaneous and complete bowel movements, as well as left-sided abdominal pain. A careful clinical history is useful in identifying failure of evacuation; specifically, patients may experience the need for digital disimpaction of the rectum or digital pressure on the posterior wall of the vagina or the perineum to expel stool. Enemas may not be emptied. The rectal examination identifies an immobile perineum during the process of straining and a tight, unyielding puborectalis sling muscle abutting the rectum posteriorly. This tight pelvic floor persists during attempts to evacuate. In rare instances, the anal sphincter itself is spastic or the entire perineum balloons or herniates down as a result of years of straining or of multiple childbirths, which weaken the ligaments and muscles that normally support the pelvic floor and rectoanal angle.
Occasionally, outlet obstruction is caused by an anatomic defect such as a rectocele or rectal internal mucosal prolapse; these are amenable to surgical correction. A spastic pelvic floor or spastic anal sphincter muscles usually respond to biofeedback and muscle relaxation exercises.82 Some patients with outlet obstruction to defecation have a profound psychological disorder or a history of abuse that requires identification and subsequent therapy.81
The author and editors gratefully acknowledge the contributions of the previous author, Michael Camilleri, M.D., to the development and writing of this chapter.
Editors: Dale, David C.; Federman, Daniel D.