Role of nuclear medicine in evaluating patients with suspected gastrointestinal motility disorders

Role of Nuclear Medicine in Evaluating Patients With Suspected Gastrointestinal Motility Disorders Henry P. Parkman, Mark A. Miller, and Robert S. Fisher Functional symptoms caused by gastrointestinal motility disorders are relatively common in the general population. Knowledge of the relationship between symptoms and the underlying gastrointestinal dysmotUity provides physicians with a framework for successful evaluation and treatment of patients with possible motor disorders of the gastrointestinal tract. Scintigraphy provides for noninvasive and quantitative assess-

ment of physiological transit throughout the gastrointestinal tract, and it is extremely useful for diagnosing gastrointestinal motor dysfunction. The wide range of scintigraphic studies now available supplement other diagnostic tests for evaluation of all segments of the gastrointestinal tract.

CINTIGRAPHIC TECHNIQUES using gamma-emitting radionuclides provide useful tests for evaluating gastrointestinal motor function. These techniques can be helpful in both evaluating patients with suspected gastrointestinal motor dysfunction and understanding normal motor function. In contrast to radiographic studies using barium and manometric studies inserting tubes by nasal or oral intubation, scintigraphy is noninvasive, quantitative, can be performed under physiological conditions, and is associated with low radiation exposure. Scintigraphic techniques using orally administered radionuclides are currently available for quantifying esophageal transit, gastroesophageal reflux, gastric emptying, small intestinal transit, and colonic transit (Table 1). Intravenous administration of hepatobiliary radionuelides can also be used to assess hepatic function, gallbladder uptake and emptying, biliary leaks, anatomic abnormalities, and enterogastric reflux. This article will provide review of three areas: (1) the symptoms that occur because of gastrointestinal motor dysfunction; (2) the pathophysiological mechanisms for these symptoms; and (3) a clinical perspective on how scintigraphy is used to evaluate patients with symptoms of gastrointestinal motor dysfunction.

tion are diagnosed as having functional gastrointestinal disorders, primarily endoscopy-negative gastroesophageal reflux disease (GERD), nonulcer dyspepsia, and irritable bowel syndrome (IBS). 4 These functional disorders are often caused by gastrointestinal motility disorders. There are a variety of symptoms associated with impaired gastrointestinal motility (Table 2). Symptoms caused by gastrointestinal motor disorders range from gastroesophageal reflux-induced heartburn, with a prevalence of approximately 15% in the general population, to chronic constipation produced by colonic dysfunction, which occurs in up to 24% in an aging population. 5For the physician, understanding the pathophysiology of a patient's symptom will often facilitate a rational approach to patient management. For the patient, anxiety concerning symptoms can be reduced when an explanation for symptoms can be given and when education is provided about the natural outcome of the specific condition.

S

OVERVIEW OF SYMPTOMS CAUSED BY GASTROINTESTINAL DYSMOTILITY

Functional symptoms are those for which no structural, infectious, or biochemical cause can be found. 1 Overall, it has been estimated that symptoms of functional gastrointestinal disorders occur to some degree in nearly one quarter of apparently healthy people. 2,3 Of patients seeking physician consultation, a significant por-

Copyright 9 1995 by W.B. Saunders

Company

ESOPHAGUS

Symptoms of EsophagealMotorDysfunction The primary symptoms associated with esophageal motor dysfunction are dysphagia, heartburn, regurgitation, and chest pain (Table 2). 6 Dysphagia. Dysphagia, or difficulty swallowing, denotes the subjective sensation of solid food or liquid encountering difficulty in its passage from the mouth, down the esophagus, From the Gastroenterology Section, Department of Medicine, Temple UniversitySchool o[ Medicine, Philadelphia, PA. Address reprint requests to Henry P. Parkman, MD, Gastroenterology Section, Department of Medicine, Parkinson Pavilion, 8th Fir, Temple UniversityHospital, 3401 North Broad St, Philadelphia, PA 19140. Copyright 9 1995 by W.B. Saunders Company 0001-2998/95/2504-000155.00/0

Seminars in Nuclear Medicine, Vol XXV, No 4 (October), 1995: pp 289-305

289

290

PARKMAN, MILLER, AND FISHER

Table 1. Scintigraphic Testing of Gastrointestinal Motility

Esophageal transit Gastroesophageal reflux Gastric emptying Gallbladder evacuation Enterogastric reflux Small intestinal transit Colonic transit Combined testing Esophageal transit/gastroesophageal reflux Cholecystogastric (enterogastric reflux) scintigraphy Gastroenterocolonic (whole gut) scintigraphy

and into the stomach. Dysphagia encompasses a spectrum of sensations from difficulty initiating the swallow to the feeling of food sticking in the esophagus. Dysphagia can be caused by a number of disorders that can be clinically and anatomically divided into two major categories: (1) oropharyngeal dysphagia-difficulty in the initial phase of swallowing caused by abnormalities affecting the proximal striated muscles that are under voluntary control; and (2) esophageal dysphagiadifficulty with food sticking in the chest after swallowing caused by disorders affecting the esophageal smooth muscle or lower esophageal sphincter (LES) that are under involuntary control. Dysphagia in either case results from either an obstructive lesion causing luminal narrowing or an impairment of esophageal motor coordination. A Zenker's (pharyngo-esophageal) Table 2. Symptoms of Gastrointestinal Motor Dysfunction

Esophageal motor dysfunction Dysphagia Heartburn Chest pain Regurgitation Gastric motor dysfunction Early satiety Abdominal distension/bloating Nausea/vomiting Postprandial abdominal discomfort/pain Small-intestinal motor dysfunction Abdominal distension/bloating Nausea/vomiting Postprandial abdominal discomfort Colonic motor dysfunction Constipation Diarrhea Fecal incontinence Lower abdominal pain Gallbladder motor dysfunction Right upper quadrant abdominal pain

diverticulum, although an anatomic abnormality, may result from incomplete upper esophageal sphincter opening leading to increased hyopharyngeal pressures during swallowing. 7 The most frequent mechanical disorders resulting in esophageal dysphagia are peptic esophageal stricture, Schatzki's ring, and esophageal carcinoma. The most frequent esophageal motility disorders that lead to dysphagia are achalasia, diffuse esophageal spasm, and scleroderma.6 Achalasia is perhaps the best understood esophageal motor disorder. 8 Dysphagia for both solid and liquid foods typically worsens slowly over time, usually over several years. Obstruction at the LES is often correctly perceived by the patient as food sticking near the xiphoid area. Dysphagia in achalasia is caused by both the high pressure, incompletely relaxing LES that results in a functional obstruction between the esophagus and the stomach, and the ineffective propulsive force of esophageal contractions because of the simultaneous, usually lowamplitude esophageal contractions. Dysphagia may also occur in up to 30% of patients with GERD. 9,1~ It may be caused by mechanical obstruction caused by a peptic stricture (peptic stenosis) from long-standing reflux esophagitis and esophageal adenocarcinoma arising in a Barrett's esophagus. GERD is often associated with esophageal dysmotility, causing dysphagia. The esophageal dysmotility may be in the form of low-amplitude esophageal contractions, simultaneous contractions, or failed peristalsis in which the contractions do not traverse the entire esophagus. 1~ In addition, esophagitis from GERD may narrow the luminal diameter because of the edema and inflammation without true stricture formation. Heartburn. Heartburn, or pyrosis, is a retrosternal burning sensation that usually radiates in a cephalad direction upward from the xiphoid toward the neck. It is commonly aggravated in the reclining position or when bending over. Uncomplicated heartburn is often relieved promptly, albeit transiently, by antacid ingestion. Heartburn is a common symptom, and is present in about 7% of the general population on a daily basis, 15% on a weekly basis, and 40% on a monthly basis. 11 Heartburn results from reflux of acidic gastric secretions into the esophagus. Incompetence of

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

the antireflux barrier at the gastroesophageal junction, the LES, is the major factor contributing to GERD. The traditional view is that a weak or low-pressure LES allows reflux to occur from the stomach into the esophagus) 2 In severe GERD with esophagitis, the LES pressure is usually very low. The low LES pressure predisposes the patient to reflux; however, chronic inflammation from acid reflux may secondarily cause the low LES pressure. Of interest, in idiopathic GERD, diminished resting LES pressures are present in a minority of patients. The majority of gastroesophageal reflux episodes are caused by transient spontaneous, or inappropriate, relaxations of the LES that occur independent of swallowing. 13,14These transient LES relaxations may result from reflexes induced by esophageal or gastric distension. Other factors that may contribute to reflux include transient increases in intra-abdominal pressure, impaired clearance of acid from the esophagus because of diminished or absent peristalsis, and delayed gastric emptying. Chest Pain. Esophageal disorders are a major cause of noncardiac chest pain. Of patients who undergo cardiac catheterization for chest pain, up to 25% have normal coronary arteries without evidence of coronary spasmJ 5,16In some studies, as many as 50% of these patients with chest pain and normal coronary arteries have been found to have esophageal dysfunction as the cause of their symptoms. ~6 Chest pain of esophageal origin is usually caused by an esophageal motor disorder or GERD. Diffuse esophageal spasm (DES) is the classic esophageal motility disorder presenting as chest pain. The chest pain in DES may result from the intermittent simultaneous (nonpropulsive) contractions that occur after many swallows. However, this classic esophageal motility disorder accounts for fewer that 5% of the cases of noncardiac chest pain. ~7,~8In DES, the chest pain is often a squeezing substernal pain that can radiate to the back, neck, jaw, or arms. Often, it occurs with swallowing. At times, it is indistinguishable from cardiac angina, 19 probably because the sensory innervation of the esophagus is similar to the heart. Chest pain caused by esophageal spasm can also be relieved by nitroglycerin or calcium channel blockers. Clues suggesting that chest pain is of

291

esophageal rather than cardiac origin include the following: (1) other esophageal symptoms such as heartburn, dysphagia, or odynophagia; (2) pain associated with ingestion of hot or cold foods; and (3) pain relief with antacids. Esophageal manometry is considered by many to be the gold standard test for diagnosing esophageal motility disorders. Disorders of esophageal motility are classified into several categories: achalasia, DES, scleroderma esophagus, hypertensive LES dysfunction, and nonspecific esophageal motility disorders (NSEMD). 2~ The majority of patients with noncardiac chest pain will actually have a normal baseline manometric study or only a nonspecific abnormality. 17 Provocation tests with acid perfusion of the esophagus and intravenous infusion of edrophonium, a cholinesterase inhibitor, are used during esophageal manometry to induce symptoms in a patient and associate these symptoms with acid reflux and/or esophageal dysmotility, respectively. The most frequent nonspecific esophageal manometric abnormality consists of high-amplitude peristaltic contractions, a disorder that has been termed a hypertensive squeeze or a nutcracker esophagus. 18,2~ Because most patients with nutcracker esophagus are asymptomatic during the manometric recording of high-amplitude esophageal contractions, and because there is a poor correlation between reduction of contraction amplitude and improvement of chest pain, it is not clear that the high-amplitude peristaltic contractions are the actual cause of the chest pain. 21 GERD seems to underlie many cases of noncardiac chest pain. Ambulatory 24-hour monitoring of both esophageal pH and motility have shown that acid reflux is more commonly associated with noncardiac chest pain than motility abnormalities. 22 There are several mechanisms whereby gastroesophageal reflux may cause chest pain including esophageal inflammation from chronic acid exposure, acute acid stimulation of esophagus chemoreceptors, and reflux-induced esophageal spasm. Many chest pain episodes in patients with noncardiac chest pain may not correlate with either acid reflux or esophageal motor dysfunction, as recorded with ambulatory esophageal pH and pressure monitoring. 22 This finding suggests either that the esophagus is not actu-

292

ally the cause of the chest pain or that there is increased sensitivity of the esophagus to normal pressure contractions. Studies using esophageal balloon distension as a provocative test for esophageal chest pain have found that some patients have a lower sensory pain threshold, suggesting that they perceive pain abnormally in response to normal physiological events. 23 An alteration of the afferent sensory nerves may explain the symptoms in these patients.

Scintigraphic Evaluation of Esophageal Dysmotility Esophageal transit scintigraphy. Esophageal scintigraphy was developed as a noninvasive and quantitative method for assessing esophageal transit and motility. Initially, esophageal scintigraphy merely calculated the amount of radionuclide retention in the esophagus at specified time intervals after swallowing an initial bolus with a radionuclide. 24 This test has been subsequently refined in several ways. Esophageal transit time can be easily measured with frequent imagingY Esophageal transit time is influenced both by the coordination between esophageal contractions (peristalsis) and by the amplitude of esophageal contractions. Transit is delayed by simultaneous, nontransmitted, retrograde, or low-amplitude contractions. 26 It may be normal when esophageal contractions are repetitive or high in amplitude, as long as they are Peristaltic, such as may occur in NSEMD and nutcracker esophagus. Further refinements in esophageal scintigraphy were made to assess regional transit by dividing the esophageal region of interest into subdivisions representing the proximal, middle, and distal esophagus and assessing bolus progression through each region. 27 Regional transit can be viewed by examining a cinematic display, time-activity curves of regional esophageal transit, or composite imaging using condensed dynamic imagesY Often specific diagnoses of achalasia, DES, and scleroderma can be made by assessing bolus movement and coordination of transit through the esophagus. 28 Major esophageal motility disorders, such as achalasia and scleroderma, can readily be detected with esophageal scintigraphy. Esophageal retention in the supine position is markedly abnormal in patients with achalasia and sclero-

PARKMAN, MILLER, AND FISHER

derma. 24Achalasia is differentiated from scleroderma by repeating the test in the upright position. 27The retention seen in the supine position in scleroderma improves dramatically because of the effect of gravity, whereas in achalasia, it does not. Dynamic imaging is essential for detecting DES, NSEMD, and LES dysfunction. In DES, repetitive retrograde-antegrade-retograde movement of the radiolabeled bolus can be seen throughout the esophagus in the cinematic display. In a graphic display of proximal, middle, and distal esophageal transit, multiple peaks of activity representing disorganized bolus transit are seen. 27 However, because DES, as defined manometrically, is intermittent with simultaneous, nonpropagated swallows interspersed with normal peristaltic swallows, several swallows with a radiolabeled bolus may need to be performed to detect this disorder scintigraphically. Other less severe motility disorders, such as isolated LES dysfunction and NSEMD, are detected less reliably with scintigraphy because of the lack of clear-cut differentiation between the scintigraphic findings in these disorders and normal-control subjects. In LES dysfunction, there is normal transit down the esophagus until the gastroesophageal junction, where retention may be seen before entry of the radiolabeled bolus into the stomach. Patients with NSEMD may have slightly prolonged esophageal transit time compared with controls, especially with solids. 29 However, there is overlap between the values seen in control subjects and in NSEMD, such that many patients with manometrically determined NSEMD will have normal esophageal clearance and transit. The lack of clear separation between normal and NSEMD and, therefore, low detection rate of NSEMD is not surprising. First, nutcracker esophagus and some of the NSEMD, including repetitive and/or prolonged durations contractions, are associated with normal esophageal peristaltic function. z6 Second, NSEMDs are intermittent and show considerable variation in manometric and radiographic pattern from swallow to swallow and from study to study in the same patient. Third, the range of normal swallowing function, as assessed by scintigraphy, has some findings that may be labeled as abnormal. 3~ For ex-

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

ample, although most swallows in normal subjects during scintigraphy show progressive transit down the esophagus, an occasional swallow may detect perturbations in the lower third of the esophagus, such as retrograde transit. Occasionally, there is mild retention of radioactivity in normals at the aortic arch because of either the external compression of the aorta or the lower-amplitude contractions seen in this transition zone between striated and smooth muscle. Multiple swallows, anywhere from three to six, are usually used to detect the presence of the subtle motility disorders (NSEMD and LES dysfunction) and to help differentiate these from normal variation. At Temple University Hospital, we use three liquid swallows and three gelatin swallows. Some studies have suggested that gelatin boluses may unmask esophageal transit abnormalities. 29,32 Esophageal scintigraphy fell into disfavor because of this low sensitivity in detecting esophageal motor disorders, primarily N S E M D s . 26,33'34 Recently, a number of gastroenterologists have questioned whether the manometric findings of NSEMD have true clinical significance, because it is not clear that the esophageal manometric abnormalities observed in NSEMD and nutcracker esophagus actually produce symptoms, and if diagnosing NSEMD has an effect on patient management and o u t c o m e . 21'35 Esophageal scintigraphy is not a first-line test to evaluate dysphagia, because esophageal anatomy is important to interpret the results of scintigraphy. For example, distal esophageal stricture and esophageal cancer may both cause markedly delayed transit and increased retention as seen in achalasia. A barium swallow or upper endoscopy should be performed first in patients with dysphagia before considering either esophageal manometry or scintigraphy. Esophageal scintigraphy has several uses that are helpful for evaluation of patients. Quantitation of esophageal transit by scintigraphy has been valuable in assessing the response to therapeutic interventions in a number of conditions, especially achalasia. 36-38Esophageal transit time or esophageal retention will objectively quantitate esophageal function both before and after treatment. The low-radiation burden and patient tolerance associated with scintigraphy makes it useful when serial studies are needed.

293

We have also found scintigraphy to be helpful in patients who are not able to complete esophageal manometry or when other studies, such as esophageal manometry and videoesophagography, provide conflicting or indeterminant results. For example, it is occasionally difficult to differentiate manometrically between scleroderma and achalasia, especially in patients i n whom the motility catheter cannot be passed through the gastroesophageal junction into the stomach because of a tight stricture or the presence of a sigmoid esophagus. Esophageal transit scintigraphy may help in this situation. Finally, scintigraphy is occasionally helpful in evaluating patients with dysphagia with normal results in other studies to further document that there is normal swallowing function. This may be helpful in patients with globus sensation and in patients with possible psychiatric disturbances. Gastroesophageal reflux scintigraphy. Gastroesophageal reflux scintigraphy was first developed in 1976, as a convenient, noninvasive, and quantitative test for gastroesophageal reflux. 39 Unfortunately, other studies have not duplicated the original high sensitivity for gastroesophageal reflux scintigraphy.4~ Prolonged, 24-hour intraesophageal pH monitoring is presently considered the best test for diagnosing GERD and correlating gastroesophageal reflux episodes to symptoms. In contrast to gastroesophageal reflux scintigraphy, esophageal pH monitoring can be performed for prolonged periods (usually 24 hours) under relatively normal physiological conditions to detect intermittent episodes of reflux during fasting, meals, and postprandial periods with the patient in upright and supine (usually during sleeping) positions. Esophageal transit scintigraphy can detect spontaneous reflux, but only during the relative short duration of the study. 39'42 Gastroesophageal reflux scintigraphy also uses artificial provocative maneuvers to induce reflux, such as inflation of a binder around the patient's abdomen or performance of the Valsalva maneuver.39,42 Theoretically, these maneuvers increase abdominal pressure above the LES pressure to cause retrograde flow in patients with GERD. Because low basal LES pressure actually accounts for a minority of causes of reflux episodes, 13,14 one would expect that this test would not to be very sensitive.

294

However, it should be noted that esophageal pH monitoring detects gastroesophageal reflux only when the reflux episodes are acidic with a pH of less than 4.43 Reflux episodes are not registered if gastric acid secretion is suppressed by medication or buffered by food. An increasing number of patients are being seen with persistent symptoms while on gastric antisecretory agents, especially proton pump inhibitors and high-dose histamine receptor antagonists, which keep the gastric pH greater than 4. These patients may experience regurgitation that may not be detected by pH monitoring. Esophageal pH monitoring may not detect reflux events that occur during the early postprandial period when the pH of the gastric contents is buffered by the meal (ie, pH > 4). 44 Alkaline intestinal fluid containing bile and pancreatic enzymes may reflux into the stomach (enterogastric reflux) and then into the esophagus and cause heartburn. This is seen primarily in patients with prior gastric surgery. Duodenogastroesophageal reflux can be detected by measuring alkaline reflux into the esophagus with a pH probe 45 and, more recently, by monitoring bilirubin concentrations into the esophagus as an index of bile reflux.46In these conditions, gastroesophageal scintigraphy may be helpful because scintigraphy measures reflux events independent of intraesophageal pH, being primarily a measurement of volume of r e f l u x . 44 The gastroesophageal reflux scan may be helpful in patients with achalasia after treatment by dilation or myotomy when dysphagia recurs; it may not be clear whether the dysphagia is caused by achalasia or gastroesophageal reflux-induced stricture. 47 Gastroesophageal reflux scintigraphy can be used to detect the presence of reflux. However, the radionuclide usually must be placed directly in the stomach by a nasogastric tube. Gastroesophageal reflux scintigraphy is used in pediatric patients to investigate if chronic gastroesophageal reflux may be responsible for chronic pulmonary disorders, recurrent vomiting and esophagitis, failure to thrive with poor weight gain, and patients at risk for sudden infant death. 48 It can be combined with esophageal scintigraphy to measure esophageal transit, or with a gastric emptying scan. Prolonged observation after a mixed or liquid meal allows

PARKMAN, MILLER, AND FISHER

for evaluation of immediate postprandial reflux of gastric contents. 49 Pulmonary aspiration of gastric contents in infants may be detected by placing a radionuclide in milk contained in a bottle. Interpretation of a milk scan to assess aspiration of gastric contents may be difficult to distinguish from aspiration of the radiolabeled material during the initial ingestion of the radionuclide.5~ STOMACH

Symptoms of Gastric Motor Dysfunction Symptoms suggestive of gastric and/or small bowel dysmotility include early satiety, nausea, vomiting, abdominal bloating and distension, indigestion, and abdominal pain (Table 2). Dyspepsia and indigestion. Dyspepsia and indigestion are terms that are used widely, but inexactly with a variety of different meanings. Dyspepsia originates from the Greek language: dys- and pepsin, meaning poor and digestion, respectively. Dyspepsia generally refers to vague chronic upper-abdominal pain or discomfort, which is exacerabated with eating. 5a Dyspepsia affects approximately 20% of the general population. 52 In about 40% of dyspeptic patients, a cause can be found with careful initial evaluation consisting of history, physical examination, blood tests (complete blood count, chemistry profile, amylase), upper endoscopy, and abdominal ultrasonography. The term functional or nonulcer dyspepsia is used when no underlying disease process has been identified on this initial evaluation. In the majority of patients with a negative conventional work-up, further studies tailored to the individual patient, such as esophageal pH monitoring, lactose-tolerance testing, and gastric emptying scintigraphy, may identify a cause for symptoms. Functional dyspepsia probably represents a heterogeneous group of conditions. Subcategories of functional dyspepsia have been proposed and may be clinically useful.51,53For example, in ulcer-like dyspepsia (occasionally termed nonulcer dyspepsia), predominant symptoms include well localized epigastric pain and relief with food and antacids. This symptom pattern is suggestive of an ulcer but no ulcers are found on examination with upper endoscopy or upper gastrointestinal radiographic series. In reflux-

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

like dyspepsia, symptoms of dyspepsia are accompanied by heartburn and regurgitation. In dysmotility-like dyspepsia, prominent symptoms include bloating, distension, and early satiety. In some cases, dyspepsia may be induced by drugs including nonsteroidal anti-inflammatory drugs, theophylline, digoxin, antibiotics (ampicillin or erythromycin), and potassium or iron supplements. Scintigraphic studies have shown that delayed gastric emptying may be seen in nearly half of patients with dyspepsia: 4-56 Most often, the delayed gastric emptying is for solids rather than liquids. Detection of delayed gastric emptying in patients with dyspepsia may have some prognostic importance because these patients may respond better to prokinetic agents than dyspeptic patients with normal gastric emptying.56 Recent studies suggest that abnormal visceral afferent sensory pathways may be a major mechanism of symptom production in some patients with functional dyspepsia. 57-59 When balloons are inflated in the stomach or small intestine, dyspeptic patients experience more abdominal discomfort than healthy individuals at the same volume of gastric and/or small intestine distension. That is, symptoms in patients with functional dyspepsia may develop from an altered visceral perception of distension. Nausea and vomiting. There are multiple causes of vomiting:~ The acute onset of vomiting with diarrhea and fever suggests a viral infection. Episodic abrupt explosive vomiting suggests a central disorder with increased intracranial pressure. Vomiting preceded by colicky abdominal pain and abdominal distension may suggest gastrointestinal tract obstruction. Vomiting of large volume with partly digested food particles suggests impaired gastric emptying as may be seen in gastric outlet obstruction or functional gastric obstruction (gastroparesis). The common causes of chronic vomiting are structural lesions affecting the mucosa of the gastrointestinal tract (such as peptic ulcer disease), gastric motility disorders (such as gastroparesis), and psychogenic disorders. Gastroparesis refers to delayed gastric emptying caused by a chronic motility disorder of the stomach in the absence of mechanical obstruction. 61 Symptoms of gastroparesis include early

295

satiety, postprandial abdominal bloating, abdominal distension, nausea often accompanied by vomiting, and abdominal pain. The final diagnosis of gastroparesis is based on a compatible clinical picture: the absence of obstruction or mucosal disorders on endoscopy or upper gastrointestinal series, and delayed gastric emptying by scintigraphy. It must be remembered that an abnormal gastric emptying test suggests, but does not prove, that the symptoms are caused by gastroparesis. A patient with delayed gastric emptying may have other disorders. The three most common causes of gastroparesis are diabetes mellitus, prior surgery for peptic ulcer disease, and idiopathic (ie, gastroparesis with no obvious etiology) (Table 3). The actual mechanism for a delay in gastric emptying is not identifiable by gastric emptying scintigraphy. Impaired or altered motility in different anatomic regions of the stomach may result in delayed gastric emptying. For example, decreased fundic tone, decreased antral peristalsis, alterations in the gastric pacemaker, antropyloroduodenal incoordination, pyloric spasm, and even intestinal dysmotility have all been reported to delay gastric emptying.61 Further Table 3. Causes of Gastroparesis (Nonobstructive Delayed Gastric Emptying) Idiopathic Metabolic Diabetes Thyroid disease Renal insufficiency Postgastric surgery Neuromuscular disorders Polymyositis/dermatomyositis Connective tissue diseases Scleroderma Infiltrative disorders Lymphoms Amyloidosis Diffuse gastrointestinal motility disorder Intestinal Pseudo-obstruction Medication-induced Narcotic analgesics Antidepressants Anticholinergics Calcium channel blockers Somatostatin or octreotide Aluminum-containing antacids Electrolyte imbalance Potassium Calcium Magnesium

296

testing may be performed with antroduodenal manometry and electrogastrography.62 Intraluminal pressure recordings have shown that antral hypomotility is often present with delayed gastric emptying.63,64 Antral hypomotility may be caused by a decreased frequency of contractions and/or decreased amplitude of phasic pressures. Nausea and vomiting have also been associated with small intestinal dysmotility (hypermotility), which may result in increased resistance (ie, an augmented duodenal "break"), with secondary delay in gastric emptying into the small bowel. 63 Gastric myoelectrical abnormalities are frequently associated with gastroparesis. 65 These can be recorded using cutaneous electrodes to record gastric myoelectric activity, the electrogastrogram. Tachygastria, bradygastria, and a fiat line pattern have been described in patients with gastroparesis and/or nonulcer dyspepsia. 65 These dysrhythmias may induce nausea and vomiting by the development of dysfunctional, antral-phasic contractions resulting in impaired gastric emptying. Both antroduodenal manometry and electrogastrography record gastric motor function, not only in the postprandial period as does gastric emptying scinitgraphy, but also in the fasting state. 62 Fasting gastric motor function may also be important in producing patient's symptoms. Delayed gastric emptying is present in up to 50% of patients with insulin-dependent diabetes mellitus. Poor correlation has been reported between symptoms and the degree of gastric stasis in diabetes. 66 Many patients with grossly delayed gastric emptying have few or no symptoms. Severe symptoms may even remit with no documented change in gastric emptying. One study, examining the effect of the prokinetic agent domperidone in diabetic gastroparesis, suggested that symptomatic improvement with treatment correlated better with resolution of gastric dysrhythmias, than with improvement in gastric emptying.67Thus, delayed gastric emptying may represent a marker for gastroduodenal motor dysfunction rather than as a direct cause of symptoms.68 Idiopathic gastroparesis is the single most common cause of gastroparesis, representing almost 50% of gastroparetic patients at our institution; it is more common in women. In the literature, depending on the definitions used,

PARKMAN, MILLER, AND FISHER

these patients may be classified as having dysmotility-like dyspepsia, or idiopathic nausea and vomiting. 69 The evaluation of patients with suspected gastroduodenal motility problems after gastric surgery is particularly challenging. Symptoms may occur in the immediate or early postoperative period, and often resolve spontaneously. If symptoms suggesting a motility disorder persist, a dedicated radiological contrast study may help delineate the postsurgical anatomy and allow detection of stomal obstruction. Upper endoscopy may detect mucosal abnormalities such as recurrent or anastomotic ulcer. Gastric emptying scintigraphy may provide additional information, but interpretation may be difficult if extensive surgery has occurred. Truncal vagotomy abolishes the adaptive relaxation reflex that occurs with eating. This results in increased pressure in the fundus and an increased gastroduodenal pressure gradient leading to rapid emptying of liquids. A truncal vagotomy also interrupts excitatory neural pathways to the antrum leading to decreased amplitude of antral contractions, with resultant decreased trituration of solid food and prolonged emptying of solids from the stomach. In these postgastric surgery patients, gastric scintigraphy using both radiolabeled solids and liquids may be helpful, because liquid emptying is a reflection of proximal gastric function and solid emptying is a reflection of distal gastric function. Postsurgical gastroparesis can be particularly severe. Chronic gastric atony results primarily from the loss of gastric vagal innervation. 7~The incidence of postsurgical gastroparesis is highest with truncal vagotomy and relatively rare with parietal cell vagotomy. About 5% of patients who undergo vagotomy with antral resection develop a severe gastric motility impairment, termed postsurgical gastroparesis. The combination of vagotomy, distal gastric resection, and Roux-en-Y gastrojejunostomy predisposes patients to gastric stasis. This Rouxen-Y stasis syndrome is characterized by symptoms of postprandial epigastric pain or fullness, nausea, and vomiting. 71 Barium studies often show significantly delayed emptying from an atonic stomach with endoscopy showing a patent anastomosis. 7: Gastric scintigraphy shows markedly delayed emptying. Gastric stasis develops

EVALUATION OF GASTROINTESTINAL DYSMOTILi'rY

as a result of both gastroparesis in the vagotomized gastric remnant and motor dysfunction in the Roux-en-Y efferent loop. 7~ Excessive enterogastric reflux may produce the syndrome of alkaline (or bile) reflux gastritis. 73 It has been reported to occur after almost any form of distal gastric resection and/or drainage procedure, most commonly distal gastrectomy with Billroth II gastrojejunostomy. Procedures such as a pyloroplasty or pyloric resection that destroy the sphincteric properties of the pylorus also predispose to enterogastric reflux. Careful evaluation of these patients is needed as the symptoms (epigastric pain exacerbated by meals, nausea with bilious vomiting, and weight loss) and endoscopic findings of hyperemic mucosa, superficial gastritis, and even bile pooling are nonspecific.74 Enterogastric reflux scintigraphy may detect enterogastric reflux.75,76 Newer techniques that may improve diagnostic capabilities for enterogastric reflux include gastric pH monitoring (assessing periods with pH > 4) 45 and use of a bilirubin probe to detect and quantitate episodes of bilirubin reflux.46 Scintigraphy to Evaluate Gastric Motor Dysfunction Gastric emptying scintigraphy is currently the gold standard test for quantitating gastric emptying and documenting gastroparesis. The use of a typical or physiological meal, ease of quantitation, accuracy, and noninvasiveness have made it acceptable for patients and physicians alike. Gastric scintigraphy can be used to evaluate patients suspected of having a variety of conditions including gastroparesis, postgastric surgery syndromes, functional (nonulcer) dyspepsia, chronic intestinal pseudo-obstruction, and GERD (Table 4). Whereas there is some overlap within these clinical categories, the clinician often tries to distinguish between them. 99mTechnetium-sulfur colloid (99mTc-SC) and 111indium-DTPA are the radiopharmaceuticals usually used to label the solid and liquid components of the test meal, respectively. Because emptying of solids is generally a more sensitive and earlier indicator of impaired stomach function, 77 measurement of liquid gastric emptying is seldom necessary in clinical practice. The gold standard for radiolabeled solid meals is

297 Table 4. Uses of Gastric Emptying Sclntlgraphy Evaluation of Functional (nonulcer) dyspepsia Symptoms suggesting gastroparesis Postgastrectomy syndromes Evaluation for diffuse gastrointestinal dysmotility Symptoms of chronic intestinal pseudoobstruction Preceeding colon resectionfor colonic inertia Considering surgery for GERD Evaluate responses to prokinetic drug in patients with persistent symptoms Evaluate normal gastric physiology

radioactive chicken liver obtained after injecting 99mTc-SC into the wing vein of a live chicken. 78 The 99mTc-SC is taken up by hepatic Kupffer cells resulting in an intracellular trapped radiolabel. 79 Because the requirement for housing and injecting chickens is cumbersome, many centers substitute in vitro labeled scrambled eggs with 99mTc-SC. Binding of the radioactive tracer into the solid phase is stable on cooking it with the eggs simultaneously. Other meals, such as in vitro labeled chicken liver with cold beef stew, are acceptable if the binding of the radiopharmaceutical in the solid phase has been documented in the presence of acid and pepsin as occurs in the stomach. Poor labeling of the solid phase of the meal, may result in separation of the radionuclide from the solid phase into the liquid phase, and result in recording the relatively faster emptying of liquids. This could result in a normal gastric emptying value in a patient with gastroparesis. Normal values for gastric emptying are affected by specific meal composition, the technique of incorporating the radiolabel into the solid meal, and the method used for data acquisition and processing. Studies obtained at different institutions are not often comparable, especially if different meals are used. Each nuclear medicine facility should define its own normal ranges for men and women. Patient preparation is very important for gastric emptying tests. Although the radiation burden is low, gastric emptying scintigraphy does involve radiation exposure. As with any radiological test, one should rule out pregnancy in women before performing the test. To avoid possible pregnancy, it is safest to perform the gastric emptying tests in women during the early part of the follicular phase of the menstrual

298

cycle, before ovulation. Gastric emptying scintigraphy should be performed in the morning to eliminate the diurnal variability in emptying and to help minimize the presence of residual gastric material at the beginning of the study. Two important points that are frequently neglected in interpreting the test are: (1) medications the patient is taking may modify the results and (2) for premenopausal women, the phase of the menstrual cycle may modify the results. Patients should be instructed to discontinue medications that may affect gastric emptying for 3 days before the study (Table 3). Medications that might delay gastric emptying include narcotic analgesics, antidepressants, calcium channel blockers, and even octreotide, which is used to increase small intestinal transit. 8~ Medications that may increase gastric emptying include the prokinetic agents, metoclopramide, cisapride, erythromycin, and bethanechol, sl Occasionally, for clinical evaluation it is necessary to perform the test while a patient is on a prokinetic agent to determine why there is no response to what seems to be appropriate treatment. Diabetic patients should take their usual morning insulin dosage just before the test meal because hyperglycemia itself may delay gastric emptying.82 In patients with poor glucose control, the inhibitory effect of hyperglycemia on gastric emptying may need to be considered. The normal range for gastric emptying is very wide. Many physiological factors affect gastric emptying such as age, gender, and phase of the menstrual cycle.83-86Each of these factors should ideally be accounted for in the normal ranges of results; unfortunately, in many centers, they are often neglected. Gastric emptying in women is slower in the luteal phase, the final 2 weeks of the menstrual cycle, when serum progesterone levels are high. 83 This is important to realize because normal control values are often derived using standards for men only. Furthermore, because functional gastrointestinal disorders are more common in women, patients can be identified with delayed gastric emptying, when in fact, the delay may be because of the normal fluctuation of gastric emptying seen in the later stages of the menstrual cycle. Gastric scintigraphy can be readily modified to provide additional information for a particu-

PARKMAN, MILLER, AND FISHER

lar patient. 62 As already mentioned, by using two different isotopes, gastric emptying of solids and liquids can be measured simultaneously (eg, 99mTc-SC for solids and mindium-DTPA for liquids). For the patient intolerant to solid food, gastric emptying of liquids alone may be measured. Scintigraphy can also be modified to include evaluation of gastric emptying and enterogastric reflux in patients suspected of bile reflux gastritis. 75 This is performed using a dual-isotope method using 99mTc iminodiacetic acid (IDA) derivatives as hepatobiliary agents and lnindiumoxine labeled-eggs as the solid-phase marker for gastric emptying. In enterogastric reflux scintigraphy, the hepatobiliary agent is injected intravenously approximately 45 minutes before ingestion of the radiolabeled meal. Because 111indium and 99mTc have different energies, both can be imaged separately, to identify gastric emptying and excreted bile, respectively. This allows enterogastric reflux to be detected and quantitated. This test may be particularly important for postgastric surgery patients with chronic postprandial epigastric pain, nausea, and vomiting, suggesting the possibility of bile reflux gastritis. In some patients, there may be overlap of the stomach with small bowel or liver, making adequate interpretation difficult. Several centers are using small-bowel scintigraphy for clinical evaluation of selected patients. Small-bowel transit may be useful to detect diffuse gastrointestinal motor dysfunction or isolated small-bowel dysfunction. In chronic intestinal pseudo-obstruction, there is often a delay in both gastric emptying and small-bowel transit. 87 Small-bowel transit may be altered in IBS, suggesting this disorder involves the small intestine in addition to the colon. Transit of food through the small intestine and colon is faster than normal in IBS patients who have diarrhea but slower than normal in IBS patients who have constipation, s8 Small-intestinal transit can be measured as an adjunct to the gastric emptying test, by using more prolonged imaging and dual isotopes: 99mTc-SC-labeled eggs for solid-phase gastric emptying and nlindium-DTPA in water to measure liquid gastric emptying and small-bowel transit. 79 Measurement of small-bowel transit

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

requires an additional 4 hours of imaging over the normal 2-hour imaging for gastric emptying. 89,9~However, small-bowel transit is difficult to interpret, both technically and practically. 91 The delivery of the orally ingested radionuclide into the small bowel is variable because it depends on gastric emptying. 92 Except in patients with severe gastroparesis, the Hlindiumlabeled water empties relatively quickly from the stomach without a lag phase. The meal, consisting of chyme and liquid, spreads out as it moves through the small intestine; thus, the meal arrives in the colon as a spectrum rather than a bolus. 92 The identification of the cecum or terminal ileum scintigraphically may be difficult to determine because of variations in anatomy. There is a tremendous variation in smallbowel transit in normal subjects, which makes it difficult practically to detect abnormal smallbowel transit in individual patients. Lactulose breath test provides an alternative way to measure orocecal transit 93without the wide variability as seen scintigraphically. However, lactulose itself has an accelerating effect on small-bowel transit 94 and can be difficult to interpret in the setting of bacterial overgrowth. Small-bowel, or antroduodenal, manometry is another method to detect disorders of smallbowel motility. 62Antroduodenal manometry can record motility patterns in both the fasting and postprandial periods. Furthermore, the abnormalities seen may suggest either a neuropathic or a myopathic abnormality, which may be useful to tailor treatment for an individual patient. 95 Myogenic abnormalities are generally characterized by low-amplitude antral and duodenal contractions. Neurogenic abnormalities are characterized by normal amplitude, but abnormally propagated phasic contractions. These abnormalities are often identified by examining phase III of the migrating motor complex that occurs in the fasting pattern. 62The shortcoming of antroduodenal manometry is that it records motility only from the proximal small bowel, and it is somewhat invasive, requiring passage of a manometry catheter and use of fluoroscopy to ensure proper position of the catheter.

299

COLON

Symptoms of Colonic Motor Dysfunction The common symptoms of colonic dysmotility include constipation, diarrhea, fecal incontinence, and lower abdominal pain (Table 2). Constipation occurs in approximately 2% of the general population who seek medical attention, with an increase after the age of 65 years to 4% in men and 8% in women. 96In some surveys, constipation is the most common digestive complaint. 96 Population studies, interviewing seemingly healthy people that are not necessarily seeking medical attention, suggest the prevalence of constipation is actually much higher) The prevalence of constipation depends on the definition that is used. 5 The most common definition for research studies is less than three spontaneous bowel movements per week. Patients often view constipation differently than physicians. 97 Constipation as defined by straining at stool, hard stools, and a feeling of incomplete evacuation are present in 24% of elderly persons. 5 Usually, constipation is selflimiting or it responds to diet alteration and/or the addition of fiber. The condition most commonly diagnosed in these patients with mild constipation is the IBS. Although IBS has a variety of definitions, it generally refers to a symptom complex characterized by abdominal pain and altered bowel habit (constipation and/or diarrhea) that occurs in the absence of identifiable structural disease. 9a In evaluation of patients with constipation, careful review of underlying illnesses, medications, diet, activity, and other potential contributors to constipation is important. Initial diagnostic testing is to exclude underlying causes of constipation, such as malignancy, intestinal obstruction, or hypothyroidism. On occasion, constipation may be the presenting sign for colon cancer, especially if the change of bowel habits is of recent onset. However, most often the barium enema or colonoscopy does not show organic lesions. Several patterns of gastrointestinal motility abnormalities may be observed in patients with severe chronic constipation. 991~ In addition to IBS, these patterns consist of the following: (1) isolated anal sphincter dysfunction, suggesting the possibility of adult-onset Hirschsprung's disease; (2) an isolated motility disorder of the

300

rectosigmoid colon (functional rectosigmoid obstruction); (3) slow transit through the entire colon (colonic inertia); (4) a generalized disorder of gastrointestinal motor dysfunction, as occurs in chronic intestinal pseudo-obstruction; and (5) secondary causes of constipation, such as hypothyroidism. Differentiation among these different types of constipation is useful clinically. For instance, the prokinetic agent cisapride has been shown to be helpful in constipation from colonic inertia, but not from anal sphincter dysfunction or functional rectosigrnoid obstruction. 1~ The finding of colonic inertia, in some studies, was associated with a poorer clinical outcome. 1~176 If surgery is contemplated, patients with total colonic inertia will need a colectomy, whereas patients with anorectal dysfunction may only need an anorectal myectomy1~ and patients with functional rectosigmoid obstruction may require a left hemicolectomy. Unfortunately, colonic and rectal symptoms by themselves do not reliably differentiate these physiological subgroups of patients with severe idiopathic constipation. 1~ A sensation of anal blockage during defecation suggests pelvic floor dysfunction, but this symptom may also be seen in patients with slow-transit constipation and normal transit. 1~ Therefore, physiological testing is an important area in evaluation when management strategies for patients with severe constipation are being planned.! ~ Defecography and anal manometry are useful tests specifically for anorectal anatomy and function. In addition to determining rectal diameter and emptying, defecography may detect anatomic abnormalities either at rest or with straining. These include rectoceles, intussusceptions, poor relaxation of the puborectalis muscle, and perineal descent. 97 Anal manometry is used to evaluate the anorectal inhibitory reflex, to exclude disorders such as Hirschsprung's disease, and to evaluate for abnormalities in rectal sensation. Chronic diarrhea is also a common gastrointestinal symptom in the general population, with prevalence of 14% in patients older than 65 years of age. 5 The prevalence also depends on the definition used: passing loose, watery stools (12.9%) and/or stool frequency of more than three stools per day (2.5%). 5 For research

PARKMAN, MILLER, AND FISHER

studies, diarrhea is objectively defined by daily stool weights of more than 200 grams, and chronic diarrhea is for a duration of greater than 4 weeks. 1~ Evaluation of patients with chronic diarrhea generally entails studies to evaluate for infectious etiologies, inflamatory bowel disease, malabsorption disorders, and surreptitious laxative abuse. I~ However, after careful evaluation, 10% to 25% of patients with chronic diarrhea remain without a diagnosis and are often labeled with functional or idiopathic diarrhea. 1~ Fecal incontinence is an important problem in the elderly, with stool leakage of more than once per week present in 3.7% of elderly subjects. 5 Evaluation of fecal incontinence consists primarily, initially, with flexible sigmoidoscopy to evaluate for inflammation, melanosis coli, tumors, and even fecal impaction, which may result in overflow incontinence. 97 Anorectal manometry not only assesses anal sphincter pressure and rectal sensation, but may be used for treatment using biofeedback techniques. For patients who meet the criteria (motivation, ability to comprehend directions, and some degree of rectal sensation), success has been achieved with anal manometry biofeedback in up to 70%, including patients with incontinence caused by prior sphincter surgery or anorectal disease, idiopathic incontinence, and diabetes mellitus. 97

Scintigraphy to Evaluate Colonic Motor Dysfunction Colonic transit studies using either radiopaque markers (Sitz marks) or radiopharmaceuticals are useful to evaluate patients primarily with severe chronic constipation (Table 5). 106'107The use of radiopaque markers is relatively simple, inexpensive, and nearly universally available. However, it involves pellets or Table 5. Uses for Colonic-Transit Scintigraphy Clinicai evaluation of Constipation Suspected pseudoobstruction IBS Evaluate putative therapeutic agents Laxatives Prokinetic agents Smooth muscle relaxants Study normal colonic physiology

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

other solid markers that are nonphysiological and may not move through the colon in the same manner as native material? 08 Furthermore, the location of the markers in the gastrointestinal tract may be difficult to determine, because there is overlap of the colon and small intestine on abdominal plain filmsJ ~ Radiopaque marker studies is limited in interpreting regional transit through the colon because only infrequent radiographs are obtained, and localization of the markers in the colon may not be accurate as they are inferred from the intraabdominal location of the markers relative to boney landmarks, not from the true position in the colon. 1~

Colonic scintigraphy assesses colonic transit as a whole and regional transit through the colon, u~ Scintigraphy, in addition to permitting greater subdivision of the colon itself, allows more frequent imaging without increased radiation burden. The initial scintigraphic tests to measure colonic transit involve intubating the cecum with an oral tubeJ ~ Today, tests use orally administered radionuclides such as nqndium-labeled water 9~ or time-release capsules containing mindium-labeled resin pellets that dissolve and release radiolabeled material in the distal ileum or proximal colon, a9'11~Wholegut scintigraphy (gastroenterocolonic transit scintigraphy) simplifies patient evaluation because it makes use of the radioactivity as it traverses each section of the gastrointestinal tract, permitting measurement of gastric emptying, small-bowel transit, and colonic transit with no additional radiation exposure. 109This is helpful in patient evaluation because it is important to know if motility disturbances are isolated to the colon or more diffuse, as in intestinal pseudo-obstruction.~11 Subjects undergoing colonic scintigraphy and gastroenterocolonic scintigraphy should have a normal diet for several days before and during testing. Medications known to affect intestinal transit are stopped for 48 to 72 hours before the study. Subjects should not be undergoing other diagnostic studies that require sedation or gastrointestinal tract cleansing because colonic content, type, and frequency of meals, narcotic analgesics and sedatives, and enemas will influence colonic transit, u2 Scintigraphic tests are interpreted using percent time activities in dif-

301

ferent regions of the colon and the overall progression of the geometric center of radioactivity through the colon over 24 to 72 hours. Scintigraphy can document delayed colonic transit (ie, document that the patient does indeed have constipation) and if the abnormality is diffuse or localized to a specific region of the colon. Several patterns are seen in constipated patients. 1~176 These same patterns have been described using the more conventional radiopaque marker studies. 1~176 First, colonic inertia is suggested by delay in transit throughout the entire colon, especially the proximal colon. Second, functional rectosigmoid obstruction is shown with normal transit in the proximal colon, but with accumulation of activity in the descending and rectosigmoid colon, proximal to the anal sphincters. Third, normal colonic transit can be seen in some patients complaining of constipation, n0 Differentiation of functional rectosigmoid obstruction from normal colonic transit may be possible scintigraphically only if prolonged imaging'of 72 to 96 hours is obtained. 1~176 If shorter time periods are used ( < 4 8 hours), then patients with constipation from functional rectosigmoid obstruction cannot be differentiated from normal unconstipated control subjectsJ ~ Thus, a normal colonic transit using scintigraphic imaging < 48 hours does not necessarily imply that the patient has normal colorectal transit and does not imply that the patient is not actually constipated. A normal colorectal transit scan suggests the possibility of IBS, misrepresentation of bowel habits, misconception of normal frequency of bowel movements, or a psychosocial disturbanceJ ~176 Patients with normal coloreetal transit and complaints of constipation seem to suffer more from depression than patients with either slow transit or pelvic floor dysfunctionJ ~ The documentation of normal colorectal transit enables the physician to re-educate the patient concerning normal bowel function. The shortcomings of colonic scintigraphy are the following: (1) relatively high cost of the test; (2) it is a 3-day test requiring daily imaging during which other tests may interfere with the results of colonic transit; and (3) difficulty in detecting functional rectosigmoid obstruction, which in some series makes up one third of

302

PARKMAN, MILLER, AND FISHER

p a t i e n t s w i t h t r u e c o n s t i p a t i o n . 99,1~ S t u d i e s h a v e noted wide variations in colonic transit times b o t h b e t w e e n a n d w i t h i n i n d i v i d u a l s , n3 C o l o n i c t r a n s i t is slightly s l o w e r i n w o m e n t h a n m e n a n d has g r e a t e r n o r m a l v a r i a b i l i t y i n w o m e n ) 14 T h i s

d i f f e r e n c e m a y reflect t h e effects o f r e p r o d u c tive h o r m o n e s o n g a s t r o i n t e s t i n a l f u n c t i o n . T h e d i f f e r e n c e in c o l o n i c t r a n s i t b e t w e e n m e n a n d women, suggests that different n o r m a l ranges m a y n e e d to b e a p p l i e d for m e n a n d w o m e n .

REFERENCES

1. Lennard-Jones JE: Functional gastrointestinal disorders. N Engl J Med 308:431-435, 1983 2. Thompson WG, Heaton KW: Functional bowel disorders in apparently healthy people. Gastroenterology 79:283288, 1980 3. Drossman DA, Sandier RS, McKee DC, et al: Bowel patterns among subjects not seeking health care: Use of a questionnaire to identify a population with bowel dysfunctions. Gastroenterology 83:529-534, 1982 4. Harvey RF, Salih SY, Read AE: Organic and functional disorders in 2000 gastroenterology outpatients. Lancet 1:632-634, 1983 5. Talley NJ, O'Keefe EA, Zinsmeister AR, et al: Prevalence of gastrointestinal symptoms in the elderly: A population-based study. Gastroenterology 102:895-901, 1992 6. Parkman HP, Cohen S: Heartburn, regurgitation, odynophagia, chest pain, and dysphagia, in Haubrich WS, Schaffner F, Berk JE (eds): Bockus Gastroenterology, 5th edition. Philadelphia, PA, Saunders, 1995, pp 30-40 7. Cook IJ, Gabb M, Panagopoulos V, et al: Pharyngeal (Zenker's) diverticulum is a disorder of upper esophageal sphincter opening. Gastroenterology 103:1229-1235, 1992 8. Reynolds JC, Parkman HP: Achalasia. Gastroenterol Clin North Am 18:223-255, 1989 9. Triadafilopoulos G: Nonobstructive dysphagia in reflux esophagitis. Am J Gastroentero184:614-618, 1989 10. Jacob P, Kahrilas PJ, Vanagunas A: Peristaltic dysfunction associated with nonobstructive dysphagia in reflux disease. Dig Dis Sci 1990;35:939-942 11. Nebel OT, Fornes MF, Castell DO: Symptomatic gastroesophageal reflux: Incidence and precipitating factors. Dig Dis Sci 21:953-956, 1976 12. Cohen S: Motor disorders of the esophagus. N Engl J Med 301:184-192, 1979 13. Dodds WJ, Dent J, Hogan WJ, et al: Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 307:1547-1552, 1982 14. Dent J, Holloway RH, Toouli J, et al: Mechanisms of lower oesophageal sphincter incompetence in patients with symptomatic gastrooesophageal reflux. Gut 29:1020-1028, 1988 15. Nievens F, Janssens J, Piessens J, et al: Prospective study on prevalence of esophageal chest pain in patients referred on an elective basis to a cardiac unit for suspected myocardial infarction. Dig Dis Sci 36:229-235, 1991 16. DeMeester TR, O'Sullivan GC, Bermudez G, et al: Esophageal function in patients with angina-type chest pain and normal coronary angiograms. A n n Surg 196:488-492, 1982 17. Parkman HP, Cohen S: Esophageal chest pain: A diagnostic and management approach. J Crit Illness 6:695708, 1991

18. Katz PO, Dalton CB, Richter JE, et al: Esophageal testing in patients with noncardiac chest pain or dysphagia. Ann Intern Med 106:593-597, 1987 19. London RL, Ouyang A, Snape WJ Jr, et al: Provocation of esophageal pain by ergonovine or edrophonium. Gastroenterology 81:10-14, 1981 20. Castell DO, Castell JA: Esophageal motility testing (ed 2). Norwalk, CT, Appleton & Lange, 1994 21. Cohen S: Esophageal motility disorders and their response to calcium channel antagonists. The sphinx revisited. Gastroenterology 93:201-203, 1987 22. Peters L, Maas L, Petty D, et al: Spontaneous noncardiac chest pain: Evaluation by 24 hour ambulatory esophageal motility and pH monitoring. Gastroenterology 94:878-886, 1988 23. Richter JE, Barish CF, Castell DO: Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 91:835-852, 1986 24. Tolin RD, Malmud LS, Reilley J, et al: Esophageal scintigraphy to quantitate esophageal transit. Gastroenterology 76:1402-1408, 1979 25. Klein HA, Wald A: Esophageal transit scintigraphy, in Freeman LM, Weissmann HS (eds): Nuclear Medicine Annual 1988: New York, NY, Raven, 1988, pp 79-124 26. Richter JE, Blackwell JN, Wu WC, et al: Relationship of radionuclide liquid bolus transport and esophageal manometry. J Lab Clin Med 109:217-224, 1987 27. Russell COH, Hill LD, Holmes ER, et al: Radionuclide transit: A sensitive screening test for esophageal dysfunction. Gastroenterology 80:887-892, 1981 28. Miller DL, Parkman HP, Maurer AH, et al: Is esophageal manometry necessary to diagnose esophageal motility disorders? Am J Gastroentero188:1492, 1993 (abstr) 29. Hsu JJ, O'Connor MK, Kang YW, et al: Nonspecific motor disorder of the esophagus: A real disorder or a manometric curiosity? Gastroenterology 104:1281-1284, 1993 30. Bartlett RJV, Parkin A, Ware FW, et al: Reproducibility of oesophageal transit studies: Several 'single swallows" must be performed. Nucl Med Commun 8:317-326, 1987 31. Klein HA, Wald A: Normal variation in radionuclide esophageal transit studies. Eur J Nucl Med 13:115-120, 1987 32. Kjellen G, Svedberg JB, Tibbling L: Solid bolus transit by esophageal scintigraphy in patients with dysphagia and normal manometry and radiography. Dig Dis Sci 29:1-5, 1984 33. Holloway RH, Lange RC, Plankey MW, et al: Detection of esophageal motor disorders by radionuclide transit studies: A reappraisal. Dig Dis Sci 34:905-912, 1989 34. de Caestecker JS, Blackwell JN, Adam RD, et al: Clinical value of radionuclide oesophagal transit measurement. Gut 27:659-666, 1986

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

35. Kahrilas PJ: Nutcracker esophagus: An idea whose time has gone? Am J Gastroenterol 88:167-169, 1993 36. O'Connor MK, Byrine PJ, Keeling P, et al: Esophageal scintigraphy: Applications and limitations in the study of esophageal disorders. Eur J Nucl Med 14:133-136, 1988 37. Robertson CS, Harky JG, Atkinson M: Quantitative assessment of the response to therapy in achalasia of the cardia. Gut 30:768-777, 1989 38. Pasricha PJ, Ravich WJ, Hendrix TR, et al: Intrasphincteric botulinum toxin for the treatment of achalasia. N Engl J Med 322:774-778, 1995 39. Fisher RS, Malmud LS, Roberts GS, et al: Gastroesophageal (GE) scintiscanning to detect and quantitate GE reflux. Gastroenterology 70:301-308, 1976 40. Jenkins AG, Cowan R J, Richter JE: Gastroesophageal scintigraphy: Is it a sensitive screening test for gastroesophageal reflux disease? J Clin Gastroenterol 7:127-131, 1985 41. Hoffman GC, Vansant JH: The gastroesophageal scintiscan: Comparison of methods to demonstrate gastroesophageal reflux. Arch Surg 114:727-728, 1979 42. Velasco N, Pope CE, Gannan RM, et al: Measurement of esophageal reflux by scintigraphy. Dig Dis Sci 29:977-982, 1984 43. Richter JE: Ambulatory esophageal pH monitoring-Practical approach and clinical applications. New York, NY, Igaku-Shoin, 1991 44. Shay SS, Eggli D, Johnson LF: Simultaneous esophageal pH monitoring and scintigraphy during the postprandial period in patients with severe reflux esophagitis. Dig Dis Sci 36:558-564, 1991 45. Stein HJ, Hinder RA, DeMeester TR, et al: Clinical use of 24-hour gastric pH monitoring vs o-diisopropyl iminodiacetic acid (DISIDA) scanning in the diagnosis of pathologic duodenogastric reflux. Arch Surg 125:966-971, 1990 46. Champion G, Richter JE, Vaezi MF, et al: Duodenogastric reflux: Relationship to pH and importance in Barrett's esophagus. Gastroenterology 107:747-754, 1994 47. Parkman HP, Ogorek CP, Harris AD, et al: Nonoperative management of esophageal strictures following esophagomyotomy for achalasia. Dig Dis Sci 39:2102-2108, 1994 48. Heyman S: Esophageal scintigraphy (milk scans) in infants and children with gastroesophageal reflux. Radiology 144:891-893, 1982 49. Heyman S, Kirkpatrick JA, Winter HS, et ai: An improved radionuclide method for the diagnosis of gastroesophageal reflux and aspiration in children (milk scan). Radiology 131:479-482, 1979 50. Sondheimer JM: Gastroesophageal reflux: Update on pathogenesis and diagnosis. Ped Clin North Am 35:103116, 1988 51. Barbara L, Camilleri M, Corinaldesi R, et al: Definition and investigationof dyspepsia: Consensus of an international ad hoc working party. Dig Dis Sci 34:1272-1276, 1989 52. Malagelada JR: When and how to investigate the dyspeptic patient. Scand J Gastroentero126 182:70-74, 1991 (suppl) 53. Heading RC: Definitions of dyspepsia. Scand J Gastroentero126 183:1-6, 1991 (suppi)

303

54. Scott AM, Keliow JE, Shuter B, et al: Intragastric distribution and gastric emptying of solids and liquids in functional dyspepsia. Dig Dis Sci 38:2247-2254, 1993 55. Wegener M, Borsch G, Schaffstein J, et al: Frequency of idiopathic gastric stasis and intestinal transit disorders in essential dyspepsia. J Clin Gastroenterol 11:163-168, 1989 56. Jian R, Ducrot F, Ruskone A, et al: Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspepsia. Dig Dis Sci 34:657-664, 1989 57. Mearin F, Cucala M, Azpiroz F, et al: Ther origin of symptoms on the brain-gut axis in functional dyspepsia. Gastroenterology 101:999-1006, 1991 58. Lemann M, Dederding JP, Flourie B, et ai: Abnormal perception of visceral pain in response to gastric distension in chronic idiopathic dyspepsia. Dig Dis Sci 36:1249-1254, 1991 59. Bradette M, Pare P, Douville P, et al: Visceral perception in health and functional dyspepsia. Dig Dis Sci 36:52-58, 1991 60. Malagelada J-R, Camilleri M: Unexplained vomiting: A diagnostic challenge. Ann Intern Med 101:211-218, 1984 61. Parkman HP, Fisher RS: Gastroparesis: Diagnostic and therapeutic management. Practical Gastroenterology 17:18-27, 1993 62. Parkman HP, Harris AD, Krevsky B, et al: Gastroduodenal motility and dysmotility: Update on techniques for evaluation. Am J Gastroenteroi 90:869-892, 1995 63. Malagelada J-R, Stanghellini V: Manometric evaluation of functional upper gut symptoms. Gastroenterology 88:1223-1231, 1985 64. Waldron B, Cullen PT, Kumar R, et al: Evidence for hypomotility in non-ulcer dyspepsia: A prospective multifactorial study. Gut 32:246-251, 1991 65. Chen JDZ, McCallum RW: Clinical applications of electrogastrography. Am J Gastroentero188:1324-1336,1993 66. Horowitz M, Edelbroek M, Fraser R, et al: Disordered gastric motor function in diabetes mellitus--Recent insights into prevalence, pathophysioiogy, clinical relevance, and treatment. Scand J Gastroentero126:673-684, 1991 67. Koch KL, Stern RM, Stewart WR, et al: Gastric emptying and gastric myoelectric activity in patients with diabetic gastroparesis: Effect of long-term domperidone treatment. Am J Gastroentero184:1069-1074, 1989 68. Malagelada J-R: Gastroparesis--Commonly diagnosed but uncommonly responsible, in Barkin JS, Rogers AL (eds): Difficult Decisions in Digestive Diseases (ed 2). St Louis, MO, Mosby, 1994, pp 53-58 69. Wengrower D, Zaltzman S, Karmeli F, Goldin E: Idiopathic gastroparesis in patients with unexplained nausea and vomiting. Dig Dis Sci 34:397-401, 1991 70. Eagon JC, Miedema BW, Kelly KA: Postgastrectomy syndromes. Surg Clin North Am 72:445-465, 1992 71. Cullen JJ, Kelly KA: Gastric motor physiology and pathophysiology. Surg Clin North Am 73:1145-1160, 1993 72. Schirmer BD: Gastric atony and the Roux syndrome. Gastroenterol Clin North Am 23:327-343, 1994 73. Ritchie WP: Alkaline reflux gastritis. Gastroenterol Clin North Am 23:327-343, 1994 74. Burden WR, Hodges RP, Hsu M, et al: Alkaline reflux gastritis. Surg Clin North Am 71:33-44, 1991

304

75. Tolin RD, Malmud LS, Stelzer F, et al: Enterogastric reflux in normal subjects and patients with Bilroth II gastroenterostomy--Measurement of enterogastric reflux. Gastroenterology 77:1027-1033, 1979 76. Xynos E, Vassilakis JS, Fountos A, et al: Enterogastric reflux after various types of antiulcer gastric surgery: Quant!tation by 99m-Tc-HIDA scintigraphy. Gastroenterology 101:991-998, 1991 77. Chaudhuri TK, Fink S: Gastric emptying in human disease states. Am J Gastroenterol 86:533-538, 1991 78. Meyer JH: 99m-Tc-tagged chicken liver as a marker of solid food in the human stomach. Am J Dig Dis 21:296-304, 1976 79. Maurer AH, Fisher RS: Scintigraphy, in Shuster MM (ed): Atlas of Gastrointestinal Motility in Health and Disease. Baltimore, MD, Williams & Wilkins, 1993, pp 85-105 80. Schiller LR: Agents that delay gastrointestinal transit, in Fisher RS, Krevsky B (ed): Motor disorders of the gastrointestinal tract: What's new and what to do. New York, NY, Academy Professional Information Services, 1993, pp 25-28 81. Reynolds JC: Prokinetic agents. Gastroenterol Clin North Am 21:567, 1992 82. Fraser RJ, Horowitz M, Maddox AF, et al: Hyperglycemia slows gastric emptying in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 33:675-680, 1990 83. Hutson WR, Roehrkasse RL, Wald A: Influence of gender and menopause on gastric emptying and motility. Gastroenterology 96:11-17, t989 84. Moore JG, Tweedy C, Christian PE, et al: Effect of age on gastric emptying of liquid-solid meals in man. Dig Dis Sci 28:340-344, 1983 85. Datz FL, Christian PE, Moore J: Gender-related differences in gastric emptying. J Nucl Med 28:1204-1207, 1987 86. Evans MA, Triggs EJ, Cheung M, et al: Gastric emptying rate in the elderly: Implications for drug therapy. J Am Geriatric Soc 29:201-205, 1981 87. Camilleri M, Brown ML, Malagelada J-R: Impaired transit of chyme in chronic intestinal pseudoobstruction: Correction by cisapride. Gastroenterology 91:619-626, 1986 88. Cann PA, Read NW, Brown C, et al: Irritable bowel syndrome: Relationship of disorders in the transit of a single solid meal to symptom patterns. Gut 24:405-411, 1983 89. Charles F, Camilleri M, Phillips SR, et al: Scintigraphy of the whole gut: Clinical evaluation of transit disorders. Mayo Clin Proc 70:113-118, 1995 90. Krevsky B, Maurer AH, Niewiarowski T, et al: Effect of verapamil on human intestinal transit. Dig Dis Sci 37:919-924, 1992 91. v o n d e r Ohe MR, Camilleri M: Measurement of small bowel and colonic transit: Indications and methods. Mayo Clin Proc 67:1169-1179, 1992 92. Malagelada J-R, Robertson JS, Brown ML, et al: Intestinal transit of solid and liquid components of a meal in health. Gastroenterology 87:1255-1263, 1984 93. Caride VJ, Prokop EK, Troncale FJ, et al: Scintigraphic determination of small intestinal transit time: Com-

PARKMAN, MILLER, AND FISHER

parison with the hydrogen breath technique. Gastroenterology 86:714-720, I984 94. Miller MA, Parkman HP, Brown KL, et al: The lactulose breath test is not a physiologic standard for orocecal transit: Lactulose delays gastric emptying and accelerates small bowel transit. Gastroenterology 108:A650, 1995 (abstr) 95. Camilleri M: Study of human gastroduodenojejunal motility--Applied physiology in clinical practice. Dig Dis Sci 38:785-794, 1993 96. Sonnenberg A, Koch TR: Epidemiology of constipation in the United States. Dis Col Rect 32:1-8, 1989 97. Wald A: Constipation and fecal incontinence in the elderly. Gastroenterol Clin North Am 19:405-418, 1990 98. Schuster MM: Irritable bowel syndrome, in Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease-Pathophysiology/Diagnosis/Management. Philadelphia, PA, Saunders 1993, pp 917-933 99. Reynolds JC, Ouyang A, Lee CA, et al: Chronic severe constipation. Prospective motility studies in 25 consecutive patients. Gastroenterology 92:414-420, 1987 100. Wald A: Colonic transit and anorectal manometry in chronic idiopathic constipation. Ann Intern Med 146:17131716, 1986 101. Krevsky B, Maurer AH, Fisher RS: Patterns of colonic transit in chronic idiopathic constipation. Am J Gastroentero184:127-132, 1989 102. Krevsky B, Maurer AH, Malmud LS, et al: Cisapride accelerates colonic transit in constipated patients with colonic inertia. Am J Gastroentero184:882-887, 1989 103. Martelli H, Devroede G, Arhan P, et al: Mechanisms of idiopathic constipation: Outlet obstruction. Gastroenterology 75:623-631, 1978 104. Grotz RL, Pemberton JH, Talley NJ, et al: Discriminant value of psychological distress, symptoms profiles, and segmental colonic dysfunction in outpatients with severe idiopathic constipation. Gut 35:798-802, 1994 105. Donowitz M, Kokke FT, Saidi R: Evaluation of patients with chronic diarrhea. New Engl J Med 332:725729, 1995 106. Metcalf AM, Phillips SF, Zinsmeister AR, et al: Simplified assessment of segmental colonic transit. Gastroenterology 92:40-47, 1987 107. van der Simp JRM, Kamm MA, Nightingale JMD, et al: Radioisoptoe determination of regional colonic transit in severe constipation: comparison with radioopaque markers. Gut 34:402-408, 1993 108. Krevsky B, Malmud LS, D'Ercole F, et al: Colonic transit scintigraphy: A physiologic approach to the quantitative measurement of colonic transit in humans. Gastroenterology 91:1102-1119, 1986 109. Roberts JP, Newell MS, Deeks JJ, et al: Oral [Uqn]DTPA scintigraphic assessment of colonic transit in constipated subjects. Dig Dis Sci 38:1032-1039, 1993 110. Stivland T, Camilleri M, Vassallo M, et al: Scintigraphic measurement of regional gut transit in idiopathic constipation. Gastroenterology 101:107-115, 1991 111. Talley NJ: Measurement of whole-gut transit: A new test comes of age? Mayo Clin Proc 70:193-194, 1995 (editorial)

EVALUATION OF GASTROINTESTINAL DYSMOTILITY

112. Kaufman PN, Richter JE, Chilton HM, et al: Effects of liquid versus solid diet on colonic transit in humans: Evaluation by standard colonic transit scintigraphy. Gastroenterology 98:73-81, 1990 113. Price JMC, Davis SS, Wilding IR: Characterization

305

of colonic transit of nondisintegrating tablets in healthy subjects. Dig Dis Sci 38:1015-1021, 1993 114. McLean RG, Smart RC, Lubowski DZ, et al: Oral colon tranist scintigraphy using indium-111 DTPA: variability in healthy subjects, lnt J Colorect Dis 7:173-176, 1992