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
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
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
Causes of Oropharyngeal Dysphagia
Zenker¡¦s diverticulum/cricopharyngeal bar
Motor neuron disease
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.
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.
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
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
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
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
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.
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
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
Delayed esophageal clearance
Impaired esophageal mucosal defense mechanisms
Gastric acid hypersecretion
Delayed gastric emptying
Abnormal antropyloroduodenal antireflux
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
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
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
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 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
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
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
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.
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.)
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
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.
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