Gastroenterology motility disorders

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Gastroenterology Motility Disorders

The motor activity of the gastrointestinal tract is responsible for transporting swallowed food into the stomach, breaking solid food into small articles, mixing it with digestive enzymes, assisting in the absorption of digested food and transporting the undigested residue toward the rectum for eventual evacuation. Motility disorders of the gastrointestinal system affect transport and are generally not attributable to anatomic or biochemical defects (although they may cause anatomic derangements). Symptoms may include dysphagia, gastroesophageal reflux, abdominal pain, early satiety, nausea, bloating, distention and various symptoms of disordered defecation. Regarded by some as the ¡§last frontier¡¨ of luminal digestive diseases the diagnosis and (pharmacologic) treatment of motility disorders have continued to attract research and clinical interest.

Today I would like to review a medley of developments and controversies in the field of gastrointestinal motility. This is an ambitious undertaking given the breadth of the field so I will concentrate on seven areas of present and future clinical importance.

1.)     The assessment of upper esophageal sphincter function and dysfunction.
2.)     What¡¦s new in the diagnosis and treatment of achalasia?
3.)     Practice guidelines for the evaluation and mangement of non-cardiac (esophageal) chest pain.
4.)     How do motility abnormalities contribute to the pathogenesis of gastroesophageal reflux disease?
5.)     The emerging methodology and clinical application of antroduodenal manometry.
6.)     New perspectives on the irritable bowel syndrome
7.)     The role of colonic motility in guiding therapy for patients with constipation.
The Assessment of Upper Esophageal Sphincter Function and Dysfunction.

Like all sphincters of the digestive tract, the upper esophageal sphincter (UES) separates two functional segments, the pharynx and the esophagus. Recent technical advances have provided new insights into the function of this area. Videoradiographic studies (with images recorded at 30 frames/second) have helped clarify the timing of the events that occur during pharyngeal contraction and UES opening. As a result of these analyses of swallowing function it has become apparent that UES relaxation and UES opening are not identical. Relaxation of the muscle is only one component of the opening process and it is best measured manometrically. In contrast, opening can only be identified and assessed radiographically. Manometric studies have shown that radial asymmetry exists with the UES in that pressures recorded in the anterior and posterior directions are usually two or three times greater than pressures recorded laterally. Maximal pharyngeal pressures during swallowing occur just proximal to the UES, in the anatomical hypopharynx. If the pharyngeal wave does not occur within the UES relaxation period then it is either misplaced or the UES relaxation itself is abnormal. Either of these two situations may cause ¡§transfer dysphagia¡¨ a term used to describe abnormal bolus transfer from the mouth to the esophagus. Generally speaking, transfer dysphagia occurs from any of the following defects: 1.) poor oral preparation; 2.) weak pharyngeal contraction 3.) inadequate UES opening and 4.) incoordination between pharyngeal contraction and UES relaxation.
Causes of Oropharyngeal Dysphagia
     Zenker¡¦s diverticulum/cricopharyngeal bar
     Local tumor
     Anterior osteophyte
     Post-cricoid web
     Motor neuron disease
     Parkinson¡¦s disease
     Cerebral palsy
     Brain tumor
     Multiple sclerosis
     Wilson¡¦s disease
     Muscular dystrophies
     Myasthenia gravis
     Thyroid dysfunction

Symptoms associated with oropharyngeal dysphagia include nasal regurgitation, coughing (due to laryngeal penetration and/or tracheal aspiration), drooling and speech difficulties.

The issue of the utility of UES manometry frequently arises with several commonly encountered clinical diagnoses.

Zenker¡¦s Diverticulum
This is a posterior outpouching of one or more layers of the hypopharyngeal wall located immediately above the UES. When the pharyngeal sac becomes large enough to contain food, patients develop a variety of symptoms, including dysphagia, persistent cough, fullness in the neck, gurgling in the throat, postprandial regurgitation and aspiration. It is no longer believed that discoordination between pharyngeal contraction and UES relaxation is an important component in the genesis of Zenker¡¦s diverticulum. Combined videoradiography and manometry studies in patients with Zenker¡¦s diverticulum have demonstrated a loss of elasticity of the UES in these patients resulting in a restricted opening of the sphincteric segment during bolus passage despite normal muscle relaxation. UES manometry is not necessary in these patients. There has been almost universal acceptance of cricopharyngeal myotomy as the treatment of choice for this condition (despite the controversy surrounding its use in other conditions of the UES). Some have favored an endoscopic technique for this procedure but it is not universally accepted or performed.

¡§Cricopharyngeal Achalasia¡¨ and Abnormal UES Function

Increased resting UES pressure per se may be demonstrated radiographically and manmetrically but it is not the equivalent of achalasia (from the Greek, absent relaxation). The term is more appropriately applied to patients with oropharyngeal dysphagia who have varying degrees of failure of the UES to relax (elevated residual pressure). In such cases, manometric study of the UES can help to clarify that which may be confusing radiographically.

Oculopharyngeal Muscular Dystrophy

Patients with this hereditary condition develop pharyngeal weakness and poor UES relaxation with the onset of oropharyngeal dysphagia occurring in middle age. UES manometry can be helpful in this situation.

Parkinson¡¦s Disease

The pathogenesis of dysphagia and drooling of saliva in these patients is multifactorial. When studied, abnormalities of UES relaxation and coordination (as well as manometric abnormalities of the esophageal body and LES) have been documented but UES manometry is seldom clinically indicated in this patient population.

Aging and Swallowing Function

Studies on age-related changes in pressure dynamics in the UES and pharynx have shown an inverse correlation between age and UES resting pressure and a direct correlation between age and UES residual pressure, that is, the pressure remaining in the UES at the nadir of a swallow induced relaxation. These changes are consistent with a reduction in the compliance of the muscles that comprise the UES in elderly individuals.

The treatment of patients with oropharyngeal dsyphagia is complex and multifactorial. Dysphagia associated with systemic illnesses such as Parkinson¡¦s disease, myasthenia gravis, polymyositis, and thyroid dysfunction often improves with treatment of the underlying disorder. Consultation with occupational therapists and speech pathologists may be appropriate to teach patients maneuvers to improve swallowing efficiency and safety. Diet modification including the thickening of liquids may be helpful. Cricopharyngeal myotomy works best for Zenker¡¦s diverticulum and true ¡§cricopharyngeal achalasia¡¨ but has been used with limited success in patients with stroke, oculopharyngeal muscular dystrophy, motor neuron disease, head trauma, polio, and neoplastic or post-surgical nerve injury. Bougie dilatation of the UES with a large (18-20 mm) bougie has been used as empiric therapy by clinicians for many years and is currently under investigation in patients with a variety of diseases who have elevated resting UES pressure or incomplete UES relaxation.

What¡¦s New in the Diagnosis and Treatment of Achalasia?

Achalasia is an esophageal motility disorder of unknown cause, characterized clinically by dysphagia and regurgitation and diagnosed by manometry and/or barium esophagram with esophagogastroduodenoscopy findings being confirmatory (and used to exclude neoplasm). Manometric characteristics include abnormal lower esophageal sphincter (LES) relaxation and esophageal aperistalsis and histologically by myenteric plexus abnormalities.

Historically, the oldest available description of achalasia is from 1672 by Sir Thomas Willis. For 15 years he treated an achalasia patient with a dilator made from a whale bone with a sponge attached at the end with which the patient forced food into the stomach after each meal. Von Mikuliczi used the term cardiospasm in 1881 to describe this condition believing the disease was caused by spasm of the cardia because no organic cause for obstruction could be found. In 1929 Hurst and Rake concluded that the disease was due to failure of the sphincter to relax and termed the condition achalasia (¡§failure to relax¡¨).

Uncommon, but not rare, the incidence rate has been reported as 0.4-1.2/100,000 and the prevalence rate about 7-13/100,000 in Europe and the United States. Over 3,500 cases are diagnosed annually among Medicare beneficiaries. Typically the disease is diagnosed in adults between the ages of 25 and 60 years with less than 5% of cases occurring in children <15 years of age. (Childhood cases are likely to have associated anomalies such as adrenocorticotrophic hormone insensitivity, alacrima, autonomic and motor neuropathy, short stature, microcephaly and nerve deafness). Men and women are affected equally.

Although the etiology remains unknown our understanding of the pathology and pathophysiology is increasing. The finding of familial achalasia in <2% of cases has lead to the genetic theory that achalasia might be inherited as a rare autosomal recessive trait. The rarity of a hereditary form of this disorder was noted in a survey of 1,012 first-degree relatives (447 siblings and 247 children) of 159 patients with achalasia in which not a single case was found. According to Mendelian genetic principles, if achalasia was an autosomal recessive disorder 112 of the 447 siblings should be affected. Further evidence against a genetic theory is that achalasia has been reported in only one of a pair of monozygous twins.

The environmental theory of etiology is based upon demonstrated geographic variations in the prevalence of achalasia which might be due to an unknown environmental factor(s). Implicated factors include bacteria (diphtheria pertussis, clostridia, tuberculosis, syphilis), viruses (herpes, varicella zoster, polio and measles), toxic agents (poisonous gas), esophageal trauma and ischemic esophageal damage in utero during gut rotation. The strongest evidence to date suggests that a neurotropic infectious agent could be the involved factor. The evidence is:

1.)     The esophagus is the only portion of the gut where a smooth muscle is covered by squamous epithelium. (Herpes viruses, for example, have a predilection for squamous mucosa but rarely involve the columnar mucosa of the gastrointestinal tract. Trypanosoma cruzi can cause a form of achalasia
that has many of the features seen in idiopathic achalasia.
2.)     Many of the pathologic features of achalasia could be explained by an infectious process, particularly those caused by neurotropic viruses.
3.)     Serologic studies in achalasia patients, compared with age- and gender-matched controls, show an association with the measles and varicella zoster viruses. (In situ DNA hybridization demonstrated varicella zoster virus DNA in esophageal tissue obtained at cardiomyotomy in 3/9 achalasia patients but in only 1/20 control patients).
4.)     A recent case report showed an association between the development of achalasia and varicella infection.

The major arguments against an infectious etiology are the failure to demonstrate (by light microscopy electron microscopy, or by polymerase chain reaction techniques) an infectious agent in esophageal tissue samples from achalasia patients and the rarity of the disease in household members and relatives of patients with achalasia.
The autoimmune theory of achalasia has been supported by the finding of mononuclear cell and eosinophil infiltrates seen in the myenteric plexus of achalasia patients (possibly due to an autoimmune process?) and the association between the DQw1, class II histocompatibility antigen and Caucasian achalasia patients. (Class II antigens are associated with autoimmune diseases such as Sj„«gren¡¦s syndrome and sicca syndrome and achalasia has been described in case reports of patients with these syndromes). Recently, autoantibodies to the myenteric plexus were found using indirect immunofluorescence, in 29/49 achalaia patients but in only 3/29 healthy controls, further suggesting an autoimmune process. The degenerative theory suggests that a small population of patients may have achalasia secondary to degenerative neurologic disorders based upon epidemiologic studies from the United States suggesting that achalasia is associated with various neurological disorders such as Parkinson¡¦s disease, hereditary cerebellar ataxia, von Recklinghausen¡¦s neurofibromatosis and psychiatric disorders such as depression.

The major histopathologic changes in patients with achalasia are located in the myenteric plexus with most patients having inflammatory changes and a loss of ganglion cells. There are no good animal models for achalasia. Studies suggest that there is a selective loss of postganglionic myenteric plexus inhibitory neurons containing both nitric oxide (NO) and vasoactive intestinal peptide (VIP). The postganglionic, cholinergic neurons of the myenteric plexus are spared leading to unopposed cholinergic stimulation. This is believed to produce a high basal LES pressure and the loss of inhibitory input results in abnormal relaxation. The aperistalsis in the body of the esophagus seen in achalasia is not well understood but probably is related to the loss of the latency gradient along the esophageal body; a process mediated by NO.

Dysphagia, regurgitation, weight loss, chest pain, heartburn and cough are the most common symptoms of achalasia with symptoms often occurring for years before a diagnosis is established. Esophageal manometry remains the ¡§gold standard¡¨ for diagnosing achalasia. Aperistalsis is always present in the esophageal body. The term ¡§vigorous achalasia¡¨ is sometimes used when there is normal or even high amplitude simultaneous contractions. Some manometric abnormality of the LES is always present in achalasia. The LES resting pressure may be normal in up to 40% of achalasia patients but a low LES pressure is never seen in untreated achalasia patients. Abnormal LES relaxation is seen in all achalasia patients. Upper esophageal sphincter (UES) function as measured with solid state or sleeve techniques can be abnormal in achalasia. Increased UES pressure, shortened duration of relaxation and repetitive spontaneous UES contractions coinciding with simultaneous repetitive pressure increases in the esophageal body have been reported. A barium esophagram with fluoroscopy may be the single best diagnostic test for achalasia. Radionuclide emptying studies must be regarded as supplementary. Computed tomography (CT) has only a limited role while endoscopy should be performed in all patients to exclude a tumor of the gastroesophageal junction. Endoscopic ultrasonography provides only limited information (often in patients with ¡§pseudoachalasia¡¨¡Xsecondary achalasia due to malignancy) and cannot be recommended as a routine test in achalasia. Complications of achalasia have included esophageal inflammation, ulcerations, esophageal perforation and fistulas, bezoars and an increased risk in achalasia patients for the development of secondary squamous cell esophageal carcinoma.

There is no cure for achalasia. Ideally, treatment should restore peristalsis and restore LES function. This is not achievable with currently available treatment modalities. The medical and surgical treatments available all improve symptoms by lowering LES pressure thereby facilitating esophageal emptying by gravity, or in the case of radical surgery, creating a ¡§neo-esophagus¡¨ from a section of the colon. Medications exist to lower LES pressure but they do not improve LES function. These include anticholinergics (atropine, dicyclomine, cimetropium bromide), calcium channel blockers (diltiazem, nifedipine, verapamil), nitrates (amyl nitrate, sublingual nitroglycerin, isosorbide dinitrate), ƒÒ-adrenergic agonists (terbutaline) and theophylline. A recent Italian report cites efficacy of sildenafil (Viagra) in lowering resting LES pressure! The results of pharmacologic treatment in achalasia (most experience is reported with nifedipine and isosorbide dinitrate) are inconsistent and usually limited to mild to moderate degrees of disease. Pharmacologic treatment is best indicated for elderly achalasia patients or patients with significant coexisting medical problems making them poor candidates for pneumatic dilatation or surgery. Those who refuse other forms of therapy or have mild or intermittent symptoms may also be considered for this form of treatment.

Bougie dilatation with a large diameter Hurst or Maloney dilator can transiently relieve symptoms but pneumatic dilatation has become the dilatation procedure of choice. This technique uses air pressure to dilate and disrupt the circular muscle fibers of the LES while leaving the mucosa intact. The most commonly used dilators are endoscopically guided inflatable polyethylene catheters.

Using this type system good to excellent results can be anticipated in 88-95% of patients with a mean of 6-47 months follow up. 15-48% need repeat dilatations. Pneumatic dilatation does not improve LES relaxation but basal pressure is lowered by 43-70%. Partial return of peristalsis is reported manometricaly in about 20% of patients but this does not correlate with symptoms or esophageal emptying. Of interest is that there is a disparity between symptoms and objective manometric or radiologic findings of esophageal function, the reason for this being unclear. Perforation is the main complication being reported in up to 15% of pneumatic dilatations.

The modified Heller myotomy (single anterior myotomy incision) accounts for 99% of achalasia operations with half of the surgeons using the transthoracic approach. Good to excellent results are obtained in about 90% of achalasia patients followed 1 to 36 years. A 10% complication rate has been reported, the most common complication being gastroesophageal reflux. Since 1992 minimally invasive thorascopic or laparoscopic esophagomyotomy has grown in popularity. These techniques have a learning curve for success and prospective comparisons with open myotomy have not been performed.
Botulinum toxin is a potent neurotoxin produced by the anaerobic bacterium Clostridium botulinum whose paralytic action (botulism) is due to binding of the toxin to presynaptic cholinergic nerve terminals with subsequent inhibition of acetylcholine release. Since 1994 intrasphincteric injection of botulinum toxin has been used to reduce LES pressure. 18 month follow up has shown that 70% of patients have symptomatic and objective improvement. Up to 40% may require repeat injections. Older patients and those with vigorous achalasia (high amplitude nonperistaltic esophageal body contractions) tend to respond better to botulinum toxin injection. Long term efficacy, safety and success of this technique are not known but are under study. Retrograde transport of the toxin to the brain or spinal cord can occur and repeated injections can lead to antibody formation against the toxin and resistance to its effect.

The initial treatment of choice for otherwise healthy patients with achalasia is controversial. The majority will undergo one or more courses of pneumatic dilatation. Those not responding to (repeated) dilatations will undergo surgical myotomy probably by minimally invasive techniques if available. Patients at high risk for surgery or those refusing invasive forms of treatment can be treated with botulinum toxin and/or medications. Patients with megaesophagus who have failed pneumatic dilatation and/or myotomy should undergo esophagectomy and colonic interposition.

Practice Guidelines for the Evaluation and Management of non-Cardiac (Esophageal) Chest Pain.

Because of its location in the thorax and similar innervation, esophageal pain may mimic pain from coronary artery disease, even including an exertional component and relief with nitroglycerin. The etiology of recurring angina-like chest pain is: coronary artery disease, 70-80%; esophageal abnormality, 15-20%; musculoskeletal disorders, 5-10%; other ? Esophageal abnormalities causing chest pain include gastroesophageal reflux disease (GERD), esophageal motility disorders including ¡§nutcracker esophagus (NE¡Xhigh amplitude peristaltic contractions), diffuse esophageal spasm (DES¡Xlow or high amplitude non-peristaltic contractions causing diffuse spasm), non-specific esophageal motility disorder (NEMD), achalasia, hypertensive lower esophageal sphincter (LES). Any of these motility disturbances may be accompanied by a hiatal hernia.

The diagnostic approach for esophageal causes of chest pain include the associated history with particular regard to heartburn, regurgitation, dysphagia or odynophagia. Esophageal manometry is usually performed with the hope of finding motility abnormalities at baseline (a time when the patient is not having their usually intermittent pain). These motility abnormalities at baseline suggest that there is an abnormal motility event which causes the patient¡¦s chest pain. The even is rarely identified.

1.)     Nutcracker esophagus¡Xhigh amplitude (>180 mmHg) peristaltic contractions.
2.)     Diffuse esophageal spasm¡Xsimultaneous (non-peristaltic) contractions occurring with at least 20% of wet swallows intermixed with peristaltic contractions. Other associated findings include repetitive peaks (>2/wave), long duration (>6 sec), spontaneous contractions which may be high amplitude and an abnormal LES
3.)     Non-specific esophageal motility disorder¡Xlacks characteristic classifiable motility findings.
4.)     Achalasia
5.)     Hypertensive LES (considered by some to be a part of the NEMD). Elevated LES pressure (>45 mmHg), incomplete LES relaxation, normal peristalsis.

A variety of provocative tests have been devised to try to refine the diagnosis of esophageal motility disorders in addition to using other means of evaluating the esophagus.

1.)     Acid perfusion (Bernstein) test. 0.1 N HCl is infused into the mid-esophagus with a saline infusion control. A positive result is obtained when there is a reproduction of the patient¡¦s chest pain with relief provided by saline infusion. This indicates acid-sensitive mucosa, suggesting an esophageal cause of the patient¡¦s intermittent chest pain.
2.)     Edrophonium (Tensilon) test. A provocative test when 80 mcg/kg of edrophonium is given IV. A positive test reproduces the patient¡¦s typical pattern of chest pain. Some institutions require manometric abnormalities such as high amplitude prolonged contractions after swallowing in association with the chest pain.
3.)     Ambulatory 24 hour esophageal pH monitoring. This is the best means to evaluate possible GERD as a cause of chest pain; if episodes of pain are associated with episodes of esophageal acid exposure, then GERD is a likely etiology of the chest pain.
4.)     Esophagoscopy. Often performed to ¡§R/O significant pathology¡¨ such as unsuspected esophagitis, esophageal ulceration, etc.
5.)     Barium esophagram. A non-invasive test to R/O other pathology, but generally not indicated in the evaluation of chest pain alone. It is useful to support the diagnosis of achalasia, double contrast studies may show specific mucosal lesions in esophagitis, it can diagnose a large hiatal hernia, stricture as well as webs and rings.

There are several clinical concerns the gastroenterologist is faced with in dealing with non-cardiac esophageal chest pain. One must never accept an esophageal defect as the etiology of the chest pain until significant coronary disease is excluded. The presence of an esophageal motility abnormality is probably the cause of the patient¡¦s chest pain. Confirmation of this can do much to allay the patient¡¦s fear that they have cardiac disease. Esopahgeal stimulation with acid perfusion in a cardiac patient can compromise cardiac dynamics (increase the rate-pressure product). One must not fail to look for gastroesophageal reflux in patients with unexplained symptoms such as chest pain, laryngitis, hoarseness, unexplained cough, asthma (and other respiratory symptoms). Treatment for these esophageal motility disorders has included PPI therapy, nitrates, calcium channel blocker therapy, balloon and bougie dilatation where appropriate, extensive counseling, and at times surgical myotomy.

How do Motility Abnormalities Contribute to the Pathogenesis of Gastroesophageal Reflux Disease?

Many factors (*) are involved in the pathogenesis of gastroesophageal reflux disease (GERD), but the antireflux barrier at the gastroesophageal junction is the final determinant of reflux.

(*) Multifactorial pathogenesis of GERD
     Antireflux barrier at the gastroesophageal junction
          Lower esophageal sphincter (LES)
          Crural diaphragm
          Transient LES relaxations (TLESRs)
          Hiatal hernia
     Delayed esophageal clearance
          Low amplitude esophageal contractions
          Simultaneous esophageal contractions

Impaired esophageal mucosal defense mechanisms

Gastric factors
     Gastric acid hypersecretion
     Delayed gastric emptying
     Gastric distension
     Abnormal antropyloroduodenal antireflux mechanism
     Bile reflux
External factors
     High-fat content foods

In the majority of cases transient lower esophageal sphincter (LES) relaxations seem to be the necessary condition for reflux to occur. In severe cases of GERD, especially those with erosive esophagitis, ulceration, stricture, and Barrett¡¦s epithelium, diminished resting LES pressure plays a contributory role. Esophageal dysmotility may be an additive factor leading to increased esophageal acid contact time and predispose patients to develop erosive esophagitis. Also, delayed gastric emptying may further compromise the LES. Finally, the role of bile reflux across an incompetent gastroduodenal (pyloric) junction remains controversial.
The Emerging Methodology and Clinical Application of Antroduodenal Manometry.

Motility disorders of the stomach and small intestine represent a considerable diagnostic and therapeutic challenge. As symptoms are relatively nonspecific in many situations and include dyspepsia, early satiety and prolonged stomach fullness or bloating, discomfort and nausea in the postprandial period. The search for a possible motor disorder begins only following the exclusion of obstructive lesions or mucosal disease by history, physical examination, routine laboratory studies, ultrasound of the gallbladder and panreas as well as upper gastrointestinal endoscopy. The evaluation of these disorders has traditionally been based on radiological and nuclear medicine techniques such as ¡§barium burger¡¨ meals and solid-phase gastric emptying studies which detect gastroparesis rather than on direct measures of intestinal contractile or myoelectrical activity. Antroduodenal manometry is a relatively new technique for the assessment of gastric and small intestinal motor function. Advances in catheter, transducer and recorder design now permit prolonged recordings of intraluminal pressure activity from almost any part of the gastrointestinal tract. Because of its relative accessibility, antroduodenal manometry has emerged as a potential diagnostic tool. Antroduodenal manometry is performed using either a perfused catheter system (up to 8 catheters¡X5 in the antrum and 3 in the duodenum and proximal jejunum) or solid-state systems with analysis done by visual inspection of tracings or computerized interpretation of tracings done in both the fasting and postprandial state. Placement of these manometric assemblies is typically under fluoroscopic guidance. Given recent advances in sensor design and recording capabilities, the major hurdle which now faces the clinical applicability of antroduodenal manometry is its interpretation. The question that is raised is ¡§How useful is this technique in the clinical evaluation of patients with symptoms suggestive of upper gastrointestinal dysmotility?¡¨ Antroduodenal manometry is capable of detecting alterations in motor patterns among patients with non-ulcer dyspepsia, gastroparesis, intestinal obstruction, intestinal pseudo-obstruction, postsurgical states and the short bowel syndrome. Based upon current experience as found in a review of the literature the most clinically useful antroduodenal manometry study may be a normal one. While antroduodenal manometry may in the hands of some be able to differentiate, with some confidence, between what is truly normal and abnormal, its ability to provide specific diagnoses is rather limited because the features of several dysmotility syndromes appear to be relatively nonspecific. Therefore, for the moment, the principal value of an antroduodenal manometry study is to reassure the patient and clinician that foregut motility is, indeed, normal. Treatment approaches are limited at the present time and include dietary counseling and gastroprokinetic agents such as metoclopromide, the restricted use drug cisapride, domperidone where available and erythromycin. Increased understanding of the pathophysiology of disorders of gastric neuromuscular function wil lead to an improved and more rational armamentarium for the treatment of these disorders and the symptoms they produce.

New Perspectives on the Irritable Bowel Syndrome

The irritable bowel syndrome (IBS) has been the subject of this conference in the recent past. Physicians can often make a positive diagnosis of IBS using symptom criteria. IBS occurs in about 15% of adults in Western countries but only about 30% of affected people see their primary care physicians about it. Less than 30% of patients are referred to specialists and only a fraction of referred patients are seen at academic centers where almost all IBS research is done. The diagnosis of IBS is based on positive findings (Manning and Rome criteria) as well as after investigations to exclude other disorders. Symptoms are also chronic or recurrent, pain is variable in timing and location, and diarrhea and constipation (if present) may alternate. ¡§Red-flag¡¨ symptoms and age (<50 or >50) provide additional points of reference in considering and establishing the diagnosis. Medication side effect, lactose intolerance, giardiasis, inflammatory bowel disease (including ileitis), diverticulosis and thyroid disease are usually excluded. Repeated patient testing can undermine the patient¡¦s confidence in the diagnosis yet the diagnosis is not ¡§protective¡¨ from the development of other conditions, particularly as the patient ages. Most patients require no drug treatment. The prescription pad should not substitute for more important aspects of treatment such as listening, validating, educating and identifying and reinforcing coping strategies in a long-term therapeutic alliance. True constipation may benefit from fiber supplementation. True diarrhea may be alleviated with the use of mild and potent antidiarrheals. Antispasmodics can be used to modify colonic motility and therefore may decrease severe, acute abdominal pain associated with IBS, especially if it is postprandial. Bloating and distention may be problematic. Several ¡§motilinomimetic¡¨ drugs have been synthesized. Their development depends on their lack of antimicrobial activity and the absence of prokinetic effect during prolonged administration. 5-hydroxytrptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are in the works. These ¡§enterokinetic¡¨ compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that make them suitable for treatment of IBS.
Besides decreasing colonic sensitivity to distention these drugs prolong intestinal transit and may be particularly useful for patients with diarrhea-predominant IBS.


A novel 5-HT4 agonist enterokinetic compound. Anorectal function seems to be unaffected. It has a marked and consistent effect on stool frequency and consistency, and on colonic transit. It does not appear to affect visceral sensitivity or sphincter function. It hold promise for patients with slow transit constipation and is undergoing advanced clinical trials.


A serotonin (5-HT)4 partial agonist extensively investigated for the treatment of IBS patients with constipation-predominant symptoms. The most frequent adverse effects in patients studied to date include transient diarrhea and flatulence. Recommended for approval by the Food and Drug Administration¡¦s (FDA) Gastrointestinal Drugs Advisory Committee for the treatment of abdominal pain or discomfort and constipation in women with IBS. May also be used as a potential treatment for other gastrointestinal disorders of function such as gastroesophageal reflux disease (GERD) and functional dyspepsia. Awaiting finalization of FDA approval.


A potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated and FDA approved for the management of irritable bowel syndrome¡Xdiarrhea predominant variety in women. It blocks the fast 5-HT3-mediated depolarization of guinea-pig myenteric and submucosal neurons in vitro and attenuates the visceral nociceptive effect of rectal distention in conscious or anesthetized dogs. It increases the compliance of the colon to distention in patients with IBS and delays colonic transit in patients with IBS, carcinoid diarrhea and in healthy volunteers. It increases in vivo fluid absorption in the normal human small intestine. The most common adverse effect is constipation although ischemic colitis has been (rarely) reported in clinical trials.

Neostigmine Infusion: a new standard of care for acute colonic pseudo-obstruction?

Acute colonic distention with a cecal diameter of 10 cms. or more is a common feature of acute colonic pseudo-obstruction, a condition of post-operative or in hospital patients with a variety of conditions. Patients who fail to respond to conventional management of NPO, nasogastric suction, postural changes, IV fluids, electrolyte replacement and discontinuation of any drugs that may affect colonic motility are often considered for colonoscopic decompression (controversial role) and/or surgery (colostomy?). Neostigmine infusion 2 mgs. IV over 3-5 minutes with electrocardiogaphic monitoring (for bradycardia) often results in resolution of this condition. Side effects have included (usually mild) crampy abdominal pain.

The Role of Colonic Motility in Guiding Therapy for Patients with Constipation

Constipation is a common condition often defined by less than three bowel movements per week. As constipation is often secondary to altered motility of the colon, tests that measure colonic motility may lead the clinician to appropriate therapy. Colonic transit measured with either radionuclides or radio-opaque markers determine whether the transit through the colon is truly slow, and then identify the potential region(s) of the colon that impede(s) the movement of intraluminal contents. Patients with normal colonic transit do not require further evaluation of their colonic motor function. Colonic and anorectal manometry differentiate patients into 3 groups:

1.)     Functional anal outlet obstruction
2.)     Uncoordinated distal colonic phasic contractions
3.)     Colonic inertia (poor colonic contractions)

Functional outlet obstruction may be treated successfully by increasing the water content of the stools and by biofeedback. Antispasmodics including anticholinergics, nitrates and calcium channel blockers may decrease the functional obstruction cause by phasic colonic contractions. The prokinetics such as the restricted use drug cisapride have successfully improved constipation due to colonic inertia, Parkinson¡¦s disease or spinal cord injury as well as idiopathic inertia. Occasionally patients with colonic inertia may require colectomy with ileorectal anastomosis to treat severe constipation.

In patients with constipation without alarm symptoms or signs that suggest bowel obstruction or blood in the stool, standard therapy to increase the stool water content with supplements of water and dietary fiber and/or stool softeners may be adequate treatment. It the patient responds to this therapeutic trial, no further diagnostic tests are needed to define the motility pattern of the gastrointestinal tract or defecatory function. However, the unresponsive patient must be studied further to define the pathophysiology including changes in gut transit and in colonic contractile pattern. Patients with recent onset of constipation who are over the age of 40 years should have a colonoscopy to exclude diverticulosis, colonic tumors and colonic polyps.

Colonic Transit

Measurement of the rate of transit of intraluminal contents through the colon provides an efficient way to initiate the evaluation. When measuring colonic transit, patients should maintain their usual diet, refrain from using laxatives and respond to the urge to move their bowels. Although several methods exist, the most widely used method is to measure the transit of radio-opaque (or in some institutions radioisotope) markers through the colon. Both techniques allow the estimation of the regional movement of intraluminal contents, although the measurement of rapid flow through the colon may require the use of radionuclide markers and more frequent monitoring of the images. These tests allow the quantitation of the total colonic and regional transit times. If the total transit time is > 75 Hours, the patient has slow transit constipation caused by abnormal colonic motility or functional obstruction at the anal outlet. Therapy is then directed toward improving the transit of intraluminal contents. Patients with normal transit constipation may require re-education about normal bowel habits and further discussion to understand the exact problem causing their symptoms. Some patients with outlet obstruction may feel that evacuation is incomplete and still have a normal frequency of stools. Patients with constipation associated with delayed transit exhibit greater psychological well-being compared to those with constipation and normal colonic transit.

Colonic Motility

Many studies have focused on measuring changes in distal colonic motility since this region is in reach of the rigid sigmoidoscope. Patients with constipation caused by altered colonic motility can be differentiated by changes in colonic pressure profiles. In approximately 50% of chronically constipated patients there is an increase in postprandial colonic motiity. The other patients have an absent postprandial response (colonic inertia). Both groups of constipated patients have a decrease in the number of propagating contractions. The patients with inertia often have intermittent abdominal pain associated with nausea and vomiting in addition to their constipation. This may reflect either a generalized gastrointestinal motility disorder or reflex proximal gut inhibition by a distended colon or rectum. (The absence of high-amplitude propagated contractions in constipation is contrasted with the increased number of high-amplitude propagated contractions occurring after eating and during the fasting phase in patients with functional diarrhea or ulcerative colitis.)

Anorectal Motility

Patients with excessive straining to move their bowels and slow transit through only the distal colon may have outlet obstruction. Constipation may result from the patient¡¦s inability to effectively coordinate the defecation process by relaxing the external anal sphincter and straightening the angle between the rectum and the anal canal. The clinical tests, anorectal manometry and defecography, characterize the function of the internal and external anal sphincter and the dynamics of defecation. Manometry estimates the control of sphincter relaxation, the coordination of the muscles in the pelvic floor which are necessary for easy defecation and the visceral sensation necessary for the control of defecation. Videodefecography is a radiologic examination which extends the information on the function of the pelvic floor-anal sphincter complex. This test will show the presence of a significant non-emptying rectocele or an internal prolapse of the rectal mucosa which interferes with defecation. The angle between the anal canal and the rectum can also be measured from the video images. If the patient cannot straighten the anle between the rectum and the anal canal, constipation may result, since the passage of stool through the pelvic floor can be obstructed. Recent studies suggest that functional outlet obstruction secondary to spasm of the puborectalis muscle can easily be diagnosed by the failure to expel a small balloon (<25 cc).

Normal values for anal manometric studies:

Anal sphincter pressure >75 mm Hg
Anal sphincter relaxation >90%
First sensation of rectal distension <20 cc
Pelvic coordination Expulsion of balloon <25 cc

Overview of Treatment of Constipation

When different underlying pathophysiologic causes for constipation can be demonstrated, tailoring treatment to the underlying condition makes sense. The effectiveness of this philosophy in the medical literature is still quite preliminary but it serves as a starting point in patient management. Constipated patients with normal transit times and normal colonic motility should have other components of their disease carefully examined and effort should not be expended correcting a normal motor pattern. Normal motility testing in these patients allow the physician to concentrate on other aspects of the patient, including their psychological responses to bowel movements. Patients with slow transit and chronic constipation are equally split into groups with functional obstruction due to distal colonic segmenting contractions or colonic inertia. Current wisdom suggests that (1) colonic inertia should be treated with prokinetic drugs (restricted use cisapride) that will stimulate the colonic propulsion of intraluminal contents, and (2) the spastic segments of colon in functional constipation should be relaxed with antispasmodic drugs. Patients with constipation due to functional outlet obstruction have been successfully treated with retraining of their pelvic floor muscles by biofeedback. Patients with intractable constipation associated with inertia may require colectomy and ileorectal anastomosis. Surgery should only be considered after complete evaluation and an exhaustive trial of medical mangement.

Prokinetic Therapy

Prokinetic therapy includes non-specific irritant laxatives, cholinergic agonists such as bethanechol (side effects often preclude the routine use of this agent in constipation), metoclopramide minimally stimulates the colonic smooth muscle but has improved bowel movements in patients with constipation associated with diabetes mellitus, and cisapride which releases acetylcholine and improves physiologic function and symptoms in some patients with constipation. A small amount of data suggests that erythromycin may have promotility effects in the colon but this has not been found in all studies. Ursodiol, a dihydroxy bile salt, has been shown to induce diarrhea in some possibly by initiating high-amplitude propagating contractions, increasing the rate of transit of colonic contents. Tegaserod, discussed with the irritable bowel syndrome, constipated variety, is a promising new drug that has a high affinity to human 5-HT4 receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex with resultant acceleration of colonic transit and increased proximal colonic emptying in these patients. In those with intractable constipation, and slow colonic transit with normal anorectal manometry, surgical therapy¡Xcolectomy with an ileorectal anastomosis¡Xmay be offered.

Antispasmodic Therapy

A decrease in the amplitude and frequency of colonic contractions may improve bowel habit in those patients win whom segmenting contractions impede the forward movement of stool. None of the clinically available anticholinergic drugs has a specific effect on the colon or even on the gastrointestinal tract. There are multiple anticholinergics that may be used, including hyoscine, dicyclomine and prifinium bromide. Other drugs have been looked at as well. Since calcium channel blockers and nitrates have been used in treating esophageal motility disturbances, they have in a preliminary fashion been evaluated in colonic disorders without a true therapeutic role being identified.

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