DISORDERS OF THE ANORECTLJM 0889-8553/01 $15.00 + .OO

SLOW TRANSIT CONSTIPATION

Adil E. Bharucha, MD, and Sidney F. Phillips, MD

Preston and Lennard-JoneP introduced the term idiopathic slow transit cons tipution to describe a clinical syndrome characterized by in- tractable constipation poorly responsive to fiber and laxatives. Other gastrointestinal manifestations include abdominal pain, bloating, mal- aise, nausea, anorectal symptoms suggestive of difficult fecal expulsion, and delayed colonic transit without megacolon. Extragastrointestinal symptoms in this syndrome included painful or irregular menses, hesi- tancy in initiating micturition, and somatic symptoms such as cold hands or blackout. Lane43 advocated colonic resection for treating a similar symptom complex in the early 1900s. With the widespread avail- ability of tests to measure colonic transit and pelvic floor function, concepts of slow transit constipation evolved. Patients with chronic constipation are categorized as follows: normal transit or irritable bowel syndrome, pelvic floor dysfunction, and slow transit constipation.'l, 56

Although colonic transit often is delayed in patients with pelvic floor dysfunction or obstructed defe~ation,5~, 65 the term slow transit Constipation in the scientific literature generally refers to patients who primarily complain of constipation and have delayed colonic transit but no under- lying systemic disorder or pelvic floor dysfunction that explains these symptoms (Box 1). The implication is that slow transit constipation represents a disorder of colonic motor function.

EPIDEMIOLOGY

The proportion of patients with functional constipation who have slow transit constipation depends on the sample. In a retrospective study

From the Division of Gastroenterology and Hepatology, Gastroenterology Research Unit and Enteric Neurosciences Program, Mayo Clinic, Rochester, Minnesota

~ ~~~

GASTROENTEROLOGY CLINICS OF NORTH AMERICA

VOLUME 30 * NUMBER 1 * MARCH 2001 77

78 BHARUCHA & PHILLIPS

Box 1. Causes of Constipation With Delayed Colonic Transit

Without pelvic floor dysfunction Idiopathic slow transit constipation Intestinal pseudo-obstruction Associated with autonomic neuropathies-diabetes, porphyria, multiple

Parkinson’s disease* system atrophy,* paraneoplastic conditions, idiopathic

With pelvic floor dysfunction

*May be associated with pelvic floor dysfunction.

of 70 patients with chronic constipation at a tertiary center, 37% had slow transit constipation; irritable bowel syndrome and pelvic floor dysfunction were identified in 27% and 23% of patients, re~pectively.~~ The corresponding figures for a community-based sample are unavail- able because those surveys did not assess colonic transit or pelvic floor function in a comprehensive manner. A US. Householder survey esti- mated the prevalence of chronic constipation as 3%, basing this diagnosis on infrequent and difficult-to-pass stools; nearly half of these subjects visited a physician.32 The proportion of these subjects with slow transit constipation is unknown because self-reported stool frequency correlates poorly with colonic transit. The correlation between extremes of stool form and colonic transit is better.21 Probert et aP3 calculated whole-gut transit from the defecation frequency, stool form score, and interdefeca- tory time interval using a previously derived formula. Although the prevalence of constipation as defined by patient perception, Rome crite- ria, and delayed transit was similar, the overlap between these three groups was poor. Of subjects classified as constipated by the subjective definition, only 37% had delayed transit; the remainder presumably had irritable bowel syndrome. In another study, total colonic transit times were similar in elderly subjects with functional constipation (n = 52), elderly subjects with irritable bowel syndrome (n = 55) and controls (n = 93). Elderly constipated subjects had delayed rectosigmoid transit compared with controls, howeverE; it is unknown if the delay is primary or secondary to pelvic floor dysfunction.

PATHOPHYSIOLOGY

Conceptually the term slow transit constipation refers to a clinical syndrome attributable to ineffective colonic propulsion. In the individual patient, the syndrome may be associated with one or more of a variety of disturbances-of colonic contractile activity, upper gut motility, post- prandial gastrointestinal hormone responses, or altered psychologic pro- files. None of these abnormalities is pathognomonic for the disorder.

SLOW TRANSIT CONSTIPATION 79

Increased mucosal absorption may occur as a consequence of delayed transit but does not cause slow transit constipati~n.~~

In health, the right colon usually functions as a reservoir, mixing contents, and the left colon functions as a conduit. Colonic motor activity in humans is notoriously irregular and unpredictable; periods of activity may be interspersed with quiescence lasting for hours. Intraluminal assessments of motor activity by a barostat-manometric assembly (Fig. 1) show more prominent phasic motor activity in the sigmoid colon than in the transverse or descending colon (Fig. 2). Combined assessments of motor activity and transit in the cleansed colon of healthy subjects reveal that transit is associated with nonpropagated and propagated contractions; propagated contractions propel contents over longer dis- tances than nonpropagated contractions.16 Only one third of propagated contractions are accompanied by propulsion of colonic contents, how- ever.16 There is considerable interest in high-amplitude propagated con- tractions (HAPCs) (275 to 90 mm Hg amplitude), which perhaps are more likely to induce mass migration of colonic contents. HAPCs gener- ally occur during the day, often occur after meals, and may be accompa-

Figure 1. Barostat-manometric assembly. The barostat is a rigid piston within a cylinder that can adjust the pressure or volume within the bag using a servomechanism. According to Boyle’s law, the product of pressure and volume within a closed system is constant. Therefore, when the balloon is inflated to a low, constant pressure until it is opposed to the colonic mucosa, increased colonic tone is accompanied by expulsion of air from the balloon to the cylinder. The barostat balloon is more sensitive than water-perfused transducers for recording colonic contraction, and in contrast to manometric sensors, also records colonic relaxation.

80 BHARUCHA & PHILLIPS

Manometry Descending Colon LLL-

I I, 1 d *IU - , , - , - . , ~ L ~ - ~ ~ M c 50 mm Hg

, ' L L d L L & , i U k b 0

~rnoidColon~~"~.~~~~"li~~~,~~~~.~~~ - A b . . " d U d U ! ! . , &

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~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ l ~ ~ ~ ~ ~ ~ ~ ~ ~ . ~ ~ ~ ~ ~ ~ , , ~ ~ - ~ , " ~ ~ ~ ~ [ mL f I

Neostigmine 30 minutes t

Meal

Figure 2. Preserved colonic contractile response to a meal in a patient with slow transit constipation. Colonic balloon volume declines, reflecting increased colonic tone accompa- 'nied by a prominent increase in phasic pressure activity after a meal and neostigmine.

nied by the urge to defecate. Nonetheless, even low-amplitude propa- gated contractions (<40 mm Hg amplitude) can induce mass migration of colonic contents.16

In constipated patients, measurement of colonic transit may reveal segmental (i.e., right-sided, left-sided, or rectosigmoid) or generalized delays in colonic transit.5O. 74 The significance of segmental transit delays to regional colonic motor function is incompletely understood. Most patients with obstructed defecation have delayed left colonic perhaps attributable to a rectocolonic inhibitory reflex.& Connell15 raised the possibility of a sigmoid brake by showing that the duration but not average amplitude of phasic motor activity in the sigmoid colon was greater in constipated subjects but lower in patients with functional diarrhea compared with controls. Similarly, Preston and Lennard-Jones61 suggested that phasic pressure activity in the sigmoid colon was higher in normal transit constipation than in controls or patients with slow transit constipation. Subsequent studies have not shown excessive sig- moid colonic phasic activity in constipated patients, relying instead on the colonic contractile response to a meal and HAPCs to distinguish health from disease. Prolonged ambulatory colonic manometry studies show that circadian variation of colonic motor activity is preserved in slow transit constipationlM although the increment in motor activity associated with awakening or meals is impaired when compared with healthy subjects. Similar findings have been reported in colonic barostat studies (Fig. 3).4, 57 The postprandial colonic contractile response is of limited diagnostic utility, however, in distinguishing between normal transit constipation, slow transit constipation, and pelvic floor dysfunc-

SLOW TRANSIT CONSTIPATION 81

I Manometry I HArtifact I

[ :0 mm Hg

-- ~_~I-

Pneumobelt Barostat

Colon Pressure

Colon Volume ~~ . _ ~ ~ ~~ . . ~ . ~ _ _ _ - . . . . . - - - L - l *

60 minutes

Meal Artifact Neostigmine

Figure 3. Impaired colonic contractile response to a meal in a patient with slow transit constipation. Barostat balloon volume and phasic activity did not increase after the meal but did increase after neostigmine.

tion because there is significant overlap in the meal response between these ~ategories.~~ Patients with normal or slow transit constipation also have fewer HAPCs (approximately 2 HAPCs/24 h) than controls (approximately 6 HAPCs/24 h).3 These observations do not clarify the mechanism of delayed transit.

Preston and Lennard-JoneP compared the colonic motor response to topical bisacodyl in patients with normal and slow transit constipa- tion; patients with slow transit constipation in the study had features of pelvic floor dysfunction. Bisacodyl induced a prominent, generally propagated colonic contractile response in all controls but in only some (11 of 18) patients with slow transit constipation. Other workers have shown impaired colonic motor responses to the cholinesterase inhibitors neostigmine and edrophonium,2 leading to the concept of colonic inertia. The term colonic inertia refers to the failure of a meal and a stimulant, such as bisacodyl or neostigmine, to enhance colonic phasic pressure activity. Colonic inertia probably reflects a severe disorder of colonic motor function that is not likely to respond to currently available laxa- tives and, in the absence of pelvic floor dysfunction, is an indication for colonic resection. Chronic megacolon, not secondary to Hirschsprung’s disease, generally represents the end stage of slow transit constipation, characterized by persistent colonic dilation.6 Although chronic megaco- lon suggests severe colonic dysfunction, intraluminal recordings often reveal a preserved phasic colonic motor response to a meal,@ a contrac- tile response to intravenous neostigmine, or both (unpublished observa- tions); the tonic contractile response to a meal inevitably is impaired.

By convention, symptoms such as abdominal bloating, discomfort,

82 BHARUCHA & PHILLIPS

and nausea are attributed to delayed colonic transit with backup of contents and perhaps bowel distention. Alternatively, disturbances in visceral perception may be partly responsible for these symptoms, as is speculated to occur in irritable bowel syndrome. Mertz et aPO observed a low threshold for discomfort during rapid rectal balloon distention, suggestive of visceral hypersensitivity, in approximately 66% of patients with slow transit or normal transit constipation. In contrast, the thresh- old for the sensation of stool during slow or ramp distention may be higher and associated with the symptomatic lack of the desire to defe-

These observations need to be confirmed in larger studies and suggest, as observed previously, that different neural mechanisms are responsible for perception of rapid and slow balloon di~tent ion.~~

Any of the disorders associated with autonomic neuropathy listed in the box earlier may cause slow transit constipation. Idiopathic slow transit constipation is associated infrequently with significant distur- bances of autonomic function, when defined by stringent The precise significance of disturbances of sweating identified by semiquanti- tative methods; or orthostatic hypotension, which may result from dehy- dration', 39; or modest reductions in rectal mucosal blood flow in slow transit constipation is un~lear.2~

It has been suggested that slow transit constipation occasionally represents the presenting or primary feature of a more generalized dysmotility,52, 73 resulting from any cause of pseudo-obstruction. Al- though clinicians need to be cognizant to this unusual possibility, the disturbances of upper gastrointestinal motility described in patients with typical slow transit constipation are minor, difficult to interpret, and may be secondary to rectal distention. These disturbances include rela- tively subtle abnormalities of esophageal peristalsis, delayed gastric emptying, and delayed small intestinal transit. The methods used to assess gastric emptylng and small bowel transit have been suboptimal. Other studies have described intestinal motor disturbances (i.e., non- propagated bursts or contractions) that are of doubtful significance be- cause they frequently occur during late phase 2 of the fasting migrating motor complex in normal subjects. Nonetheless, gastric emptying may be delayed secondary to viscerovisceral inhibitory reflexes, activated by retained stool in the colon or rectum. Rectal distention has been shown to inhibit colonic motor activity, inhibit phasic contractility in the jeju- num, and delay gastric emptying in healthy subjects.36, 85

Histology

A review highlights the variability in pathologic findings among studies of patients with slow transit constipation.38 Routine light micros- copy of colonic tissue often is unrevealing except for melanosis coli. Special stains may disclose fewer argyrophilic neurons in the colonic myenteric plexus,4l decreased neurofilaments in enteric and variable alterations in nerves containing vasoactive intestinal peptide,

SLOW TRANSIT CONSTIPATION 83

substance P, pituitary adenylate-cyclase activating peptide (PACAP), or nitric oxide.18, 26, 70, 79 A study showed significantly fewer nerve fibers and interstitial cells of Cajal (ICCs) in the sigmoid colon in slow transit constipation, using antibodies directed against protein gene product 9.5 and c-kit that are expressed by nerve fibers and ICCS.~O The reduction in number of ICCs may be of pathophysiologic significance because ICCs are required for generating electric slow waves in the smooth muscle and for transducing and amplifying signals between nerves and smooth muscle.66 These findings need to be confirmed by larger studies and do not indicate that the lack of ICCs is responsible for the disturbance of colonic motor function.

Preston et a160 reported abnormal hormonal (gastrin, motilin, and plasma pancreatic polypeptide) responses to an ingested water load in patients with constipation and diarrhea. These hormonal responses were significantly impaired in slow transit constipation and exaggerated in functional diarrhea. The significance of these findings is unclear.

CI i n ical Features

Most patients with the clinical syndrome of slow transit constipation are women. In the series of 64 patients reported by Preston and Lennard-

the symptoms began insidiously, often before the age of 10 years. In 10 patients, symptoms reportedly began after an appendectomy, a hysterectomy, or a fall with injury to the perineum. The symptom com- plex included infrequent defecation together with symptoms that are consistent with irritable bowel syndrome (i.e., abdominal pain, bloating, and nausea), pelvic floor dysfunction (i.e., digital evacuation of stool from the rectum, rectal bleeding, and rectal prolapse), urogynecologic symptoms (i.e., irregular menses, nocturia, and hesitancy), and systemic features (i.e., malaise). Most patients thought that the beneficial effect of laxatives declined over time.

Self-reported stool frequencies correlate poorly with colonic transit and cannot be used to distinguish between normal and slow transit constipation. Carefully recorded stool diaries noting stool form and frequency correlate reasonably well with transit, however, and can be used to facilitate the distinction between normal and slow transit consti- pation on clinical grounds. In particular, stool consistencies at the ex- treme end of the scale (i.e., lumpy stools) on the 7-point Bristol stool consistency scale are suggestive of delayed colonic transit and are not confounded by indices of upper gastrointestinal transit in healthy sub- jects.20

Slow transit constipation may impair day-to-day functioning and account for absences from work in approximately 75% of patients.62 A study by Bennett et a15 compared psychologic status using detailed psychometric measures in patients with functional gastrointestinal disor- ders associated with a variable degree of delayed transit. The distin- guishing features of patients with transit delays in two or more of three regions (i.e., stomach, small intestine, and colon) were female gender,

84 BHARUCHA & PHLLIPS

low levels of hypochondriasis, and high levels of depression and anger control. The low level of hypochondriasis runs counter to the notion that referral for illness is prompted by inappropriate illness concerns.

Differential Diagnosis

Having excluded organic disorders, such as colonic obstruction, hypothyroidism, or hypocalcemia, or drug-induced constipation, the major differential diagnoses include obstructed defecation, normal tran- sit constipation, and chronic intestinal pseudo-obstruction. The distinc- tion of obstructed defecation from isolated slow transit constipation is crucial because biofeedback therapy is the treatment of choice for ob- structed defecation. Symptoms that are suggestive, but not specific, of obstructed defecation include frequent straining, a sensation of incom- plete evacuation, dyschezia, and digital evacuation of feces. Symptom assessment by questionnaire, psychologic profiles, and rectosigmoid transit times are neither sufficiently sensitive nor specific for distinguish- ing between outlet obstruction and slow transit constipation.B Careful listening to the patient’s symptoms, a rectal examination with particular attention to pelvic floor motion and puborectalis relaxation during simu- lated defecation, and tests to assess pelvic floor function are the keys to identifying pelvic floor dysfunction.

The symptoms of slow transit, also termed painless, and normal transit, or painful, constipation overlap, blurring the distinction between these disorders. Patients with painful constipation are more likely to experience abdominal distention and the feeling of incomplete evacua- tion after defecation.44 In contrast, slow transit constipation generally can be distinguished from chronic intestinal pseudo-obstruction. Although patients with slow transit constipation may have nausea, abdominal bloating, distention, or delayed upper gastrointestinal transit, patients with intestinal pseudo-obstruction have more prominent abdominal dis- tention and vomiting and florid abnormalities on small bowel manome- try.

DIAGNOSTIC TESTS

Radiopaque Marker Methods

Since the original description by Hinton et alPoa several refinements have been made to the radiopaque marker technique for measuring colonic transit.5l In the modification described by Metcalf et a1,5l a capsule containing 20 radioactive markers is ingested at the same time on each of 3 consecutive days; a plain abdominal radiograph is taken on the fourth day. The number and distribution of markers in the abdomen provide a measure of overall and regional colonic transit. The maximum whole-gut transit time with a single plain radiograph on day

SLOW TRANSIT CONSTIPATION 85

4 is 72 hours, which is barely 2 SDs above the population mean. This upper limit can be extended to 120 hours by administering a capsule containing 24 radiopaque markers once daily for 5 days and taking a plain abdominal radiograph on the sixth day, 24 hours after the last capsule.40

Scintigraphic Techniques

To avoid dispersion of the radiolabel during passage through the gastrointestinal tract, the isotope is delivered into the colon by orocecal intubation or a delayed-release capsule. The delayed-release capsule contains activated charcoal or polystyrene pellets radiolabeled with tech- netium-99m or indium-111 coated by a pH-sensitive polymer methacry- late, which dissolves at an alkaline pH within the distal ileum, releasing the radioisotope within the ascending colon. The colonic distribution of radioisotope on scans taken 24 and 48 hours after administration of the capsule is highly sensitive and specific for identifying slow colonic transit?, l2 Colonic transit measurements by radiopaque markers and scintigraphic techniques are correlated to each other,2l are sensitive for identifying colonic transit delays in patients with slow transit constipa- tion, and involve similar total body radiation exposure (i.e., 0.08 rad for the radioactive capsule and for each abdominal rad i~graph) .~~ The larger radiopaque particles (average size 6 mm) travel faster and provide a shorter absolute value for transit time through the ascending and trans- verse colon than the smaller radiolabeled pellets (average size 1 mm).

TREATMENT

Medical Treatment

A careful history and, if necessary, formal evaluation of caloric intake is mandatory because deficient caloric intake can cause or exacer- bate c~nstipation.'~ Although deficient caloric intake is recognized to occur in patients with formal eating disorders such as anorexia nervosa, other patients may have an atypical eating disorder without overt criteria for anorexia nervosa or bulimia. Refeeding is accompanied by accelera- tion of colonic transit in these patients.13 Likewise, careful exclusion of metabolic disorders (hypothyroidism, hypocalcemia), drug-induced constipation, and colonic obstruction is necessary. A literature review of articles dealing with dietary fiber supplements and laxatives for constipation from 1966 through 1995 recovered 733 articles, of which only 36 were randomized trials lasting more than 1 week that assessed clinical outcomes; 23 trials were 1 month or shorter in duration.78 A therapeutic trial of dietary fiber supplements, which are known to accel- erate colonic transit, should be considered as part of any regimen, although fiber supplements administered alone probably are more effec-

86 BHARUCHA & PHILLIPS

tive in normal transit or fiber deficiency constipation than in slow transit constipation or pelvic floor dysfunction. In a study of 149 patients treated with plantago for 6 weeks, symptoms improved in 85% patients with normal transit but in only 15% of patients with slow transit consti- p a t i ~ n . ~ ~ An empirical trial of fiber supplementation should be consid- ered for patients with functional constipation at the initial presentation. Pelvic floor function and colonic transit should be assessed in patients unresponsive to dietary fiber or with clinical features suggestive of pelvic floor dysfunction. Bloating may be reduced by gradually titrating the dose of dietary fiber to the recommended dose or by switching to a synthetic fiber preparation, such as methylcellulose. The available fiber preparations and laxatives are summarized in Table 1.

Commonly used laxatives include lactulose, sorbitol, and milk of magnesia.67 In a trial of constipated men 65 years old and older, sorbitol, administered as a 70% syrup (10.5 g/15 mL; 15 to 60 mL daily) was equivalent to lactulose in improving symptoms but cheaper and better tolerated during a 4-week Polyethylene glycol 3350 (PEG) is a large polymer that is not degraded by bacteria and serves as an osmotic laxative. An 8-week, double-blind, placebo-controlled study showed that

' an isosmotic PEG electrolyte solution in chronic constipation increased stool frequency and accelerated left colonic transit, without inducing abdominal cramps or b10ating.I~ Glycerol cannot be taken by mouth because it is absorbed by the small intestine. Intracolonic administration of glycerol (10 mL) induces colonic HAPCS.~~ The stirnuzant Zaxatives have effects on mucosal transport and motility and include surface active agents, diphenylmethane derivatives, ricinoleic acid, and anthraqui- nones. Surface active agents such as docusates are relatively expensive and of little use as stool softeners in slow transit constipation. Of the diphenylmethane derivatives, phenolphthalein was withdrawn from the U.S. market after animal studies suggested the compound may be carcin- ogenic; there is no epidemiologic evidence to support this claim. Bisaco- dyl produces defecation, probably by inducing HAPCs, within 6 to 8 hours of taking the tablet or 15 to 30 minutes after the suppository. Bisacodyl is an effective rescue medication for chronic constipation.

The anthraquinones senna, cascara, sagrada, aloe, and rhubarb are common constituents of herbal and over-the-counter laxatives. They pass unchanged to the colon, where bacterial metabolism converts them to active forms. Therapeutic effects may require absorption, hepatic conju- gation, and secondary excretion in bile (enterohepatic cycling); urinary excretion of metabolites may facilitate detection of laxative use. Side effects include allergic reactions, electrolyte depletion, melanosis coli, and cathartic colon. Melanosis coli is brownish black colorectal pigmen- tation of unknown composition that is associated with apoptosis of colonic epithelial cells, reflecting cell death resulting from laxative action rather than programmed cell death. The term cathartic colon refers to alterations in colonic anatomy observed on barium enema associated with chronic stimulant laxative use, including colonic dilation, loss of haustral folds, strictures, colonic redundancy, and wide gaping of the

SLOW TRANSIT CONSTIPATION 87

ileocecal valve.s0 Cathartic colon initially was attributed to destruction of myenteric plexus neurons by laxatives71; more recent studies do not confirm those findings.37 The apparent decline in case reports of cathartic colon since the 1960s has been interpreted to suggest that the condition was secondary to other neurotoxic agents, such as podophyllin,54 which are no longer available, but not all investigators agree.% Anthraquinones have been proposed to have mutagenic effects, or to induce colorectal tumors in animal models. Several cohort studies and a case-control study failed to find an association between anthraquinones and colon cancers; a single case reporP and a prospective study did find an a~sociation.~~ The preponderance of evidence does not indicate a higher risk of colon cancer associated with long-term anthraquinone use.

Colchicine and misoprostol are two drugs that have been tried for con~tipation.~~, 82 Diarrhea is a common side effect of colchicine, a microtubule formation inhibitor used to treat gouty arthritis and familial Mediterranean fever. Colchicine (0.6 mg orally 3 times per day) increased stool frequency; reduced symptoms of abdominal pain, nausea, and bloating; and accelerated colonic transit in an open-labeled study of 7 patients with normal transit constipation treated for 8 weeks.82 Colchi- cine should be used cautiously, if at all, for treating constipation because long-term use may be associated with a neuromyopathy? The prosta- glandin El analog misoprostol(l200 kg/d) also increased stool frequency and accelerated colonic transit in a 3-week, double-blind, randomized placebo-crossover study, during which patients were treated for 1 week.” Misoprostol is expensive, it may exacerbate abdominal bloating, and its beneficial effects appear to decline over time. These agents may act by increasing secretion and motility, among other actions.

The serotonin 5-HT, receptor agonist cisapride has limited efficacy for treating constipation.s* Several novel prokinetic agents are undergo- ing phase 11-111 trials for treating constipation-predominant irritable bowel syndrome. Preliminary results suggest that the serotonin 5-HT, receptor agonists, prucalopride and tegaserod, provide superior symp- tom relief compared with placebo in patients with constipation-predomi- nant irritable bowel syndr0rne.3~~ 53 Prucalopride also accelerates colonic transit in these patients’O; tegaserod accelerates orocecal transit but has relatively mild effects on colonic tran~it.5~ Another novel approach involves using neurotrophins, including recombinant brain-derived neu- rotropic factor (r-metHuBDNF) and neurotrophin-3 (NT-3) to treat con- tipa at ion.'^ These agents promote survival and maturation of subpop- ulations of sensory neurons and modulate synaptic transmission at developing neuromuscular junctions in Xenopus nerve muscle cultures. Serendipitous observations of enhanced stool frequency in trials using r-metHuNT-3 for diabetic neuropathy led to studies of their effects on gut transit in healthy subjects and subjects with constipation. Prelimi- nary studies suggest that these agents administered subcutaneously increase stool frequency and accelerate overall colonic transit in healthy subjects and constipated patients. Long-term studies of these agents in slow transit constipation are awaited.

Tabl

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SLOW TRANSIT CONSTPATION 91

Surgical Treatment

Colonic resection should be considered for patients with medically refractory severe slow transit constipation or colonic inertia. Impaired colonic contractile responses to a meal or provocative stimuli such as neostigmine or bisacodyl may tilt the scales in favor of surgical therapy versus continued medical management (unpublished observations). Sev- eral surgical studies, beginning with Lane’s experience43 seem to prefer a subtotal colectomy with an ileorectal anastomosis; there is little enthu- siasm in the surgical community for a segmental or hemicolectornyz, 48

A subtotal colectomy for constipation is safe with virtually no operative mortality. Patients may prefer the cosmetic benefit of a laparoscopic cole~tomy.~~ Minor postoperative complications include postoperative ileus and wound infections. Questionnaire-based assessments suggest that approximately 80% to 90% of patients are satisfied after a subtotal colectomy for constipation; 10% may need short-term treatment with antidiarrheal agents after the ~pe ra t ion .~~ Less favorable success rates in other reports emphasize the importance of careful patient selection.35 The importance of a careful clinical assessment and diagnostic studies for pelvic floor dysfunction cannot be overemphasized. Pelvic floor dysfunction is not an absolute contraindication for subtotal colectomy. Although patients with pelvic floor dysfunction who undergo biofeed- back therapy before the operation do those who do not may continue to experience abdominal discomfort, bloating, and difficult evacuation after

Special Circumstances: Colonic Dysfunction After Spinal Cord Injury

Urinary bladder dysfunction and intractable constipation are com- mon manifestations of spinal cord injury. In a long-term follow-up study, approximately 40% of patients with spinal cord injury complained of ~onstipation.4~ In these patients, constipation may be due to delayed colonic transit, inability to generate adequate abdominal pressure when the spinal lesion is between T8-L2, or pelvic floor dysfunction. Colonic motility studies reveal variable changes in resting motility, a reduced colonic contractile response to feeding, and a preserved response to neostigmine, suggesting that myogenic function is relatively preserved.27 Therapy is directed toward maintaining soft, bulky stool and inducing reflex evacuation by digital stimulation and a rectal suppository after breakfast. Patients who are refractory to these measures may benefit from a colostomy or antegrade continence enemas delivered through a catheterizable appendicocecostomy77 Sacral nerve (S2-4) stimulators may accelerate transit in the left colon but have limited efficacy, and studies with direct colonic stimulation in humans are a ~ a i t e d . ~ ,

92 BHARUCHA & PHILLIPS

SUMMARY

Slow transit constipation is a clinical syndrome predominantly af- fecting young women, characterized by constipation and delayed colonic transit, occasionally associated with pelvic floor dysfunction. The disor- der spans a spectrum of variable severity, ranging from patients who have relatively mild delays in transit but who are otherwise indistin- guishable from irritable bowel syndrome patients at one extreme, to patients with colonic inertia or chronic megacolon at the other extreme. Potential mechanisms for impaired colonic propulsion include fewer colonic HAPCs or a reduced colonic contractile response to a meal. The cause of the syndrome is unclear. The treatment is primarily medical; surgery is reserved for patients with severe disease or colonic inertia. Recognition and treatment of pelvic floor dysfunction is crucial for patients treated medically or surgically. Collaborative studies are neces- sary to determine the pathophysiology of this disorder and to ascertain the efficacy of novel prokinetic agents.

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Address reprint requests to Adil E. Bharucha, MD

Gastroenterology Research Unit Mayo Clinic

Rochester, MN 55905