Ronald F. Pfeiffer
Introduction
James Parkinson indicated quite clearly his awareness of intestinal dysfunction in the set- ting of Parkinson’s disease (PD) in his remark- able 1817 treatise, An Essay on the Shaking Palsy. In addition to characterizing other gastro- intestinal (GI) features of PD, his description of bowel dysfunction codi fi es in crystal clarity both constipation (“the bowels which had all along been torpid, now in most cases, demand stimulating medications of very considerable power”) and defecatory dysfunction (“the expul- sion of the feces from the rectum sometimes requiring mechanical aid”) [ 1 ] .
However, little else was placed in print regard- ing parkinsonian intestinal dysfunction in the post-Parkinson neurological literature until 1965, when Eadie and Tyrer published their analysis of GI dysfunction in 107 patients with parkinsonism. Of these, 76 had been diagnosed with idiopathic PD, whereas the majority of the remainder carried a diagnosis of postencepha- litic parkinsonism [ 2 ] . A group of comparably aged persons with “acute orthopedic” disorders served as controls. Constipation (no distinction was made between decreased frequency and dysfunctional defecation), along with other GI features, such as dif fi culty in chewing, drooling, dysphagia, and frequent “heartburn,” were noted to be present more often in individuals with par- kinsonism than in controls.
Little else was published for the next 25 years, until Korczyn wrote about autonomic dysfunc- tion in PD and suggested that GI dysfunction is the most frequent autonomic manifestation of the disorder and that constipation is the most com- mon GI feature; he also noted that constipation may precede the development of the motor mani- festations of PD [ 3 ] . In 1991, when Edwards et al. reported their survey of 98 patients with PD and 50 comparably aged spousal controls [ 4 ] , additional information regarding GI dysfunction in PD became available. The GI features they identi fi ed closely paralleled those described by Eadie and Tyrer, by Korczyn, and by Parkinson himself, including disordered salivation (drooling),
dysphagia, nausea, constipation (decreased bowel movement frequency), and defecatory dysfunction (dif fi culty with the actual act of defecation). In a series of subsequent reports that focus largely (although not exclusively) on bowel dysfunction in PD, these authors further investigated, cataloged, and characterized this surprisingly common, yet complex and troublesome aspect of PD [ 5– 12 ] .
Recent years have witnessed a sustained and ever-growing literature on the subject of intesti- nal dysfunction in PD (see [ 13– 18 ] for recent reviews). Using a large retrospective claims data- base, Makaroff et al. examined the association between the presence of GI disorders and PD-related outcomes and reported that the major- ity of people diagnosed with PD ultimately acquire at least one GI disorder (65% at 4 years post PD diagnosis) and that PD patients with GI disorders have worse health outcomes and incur higher annual healthcare costs than individuals with PD who do not develop GI disorders [ 19 ] .
This chapter will focus primarily on bowel dysfunction in PD, along with a brief review of the scarce literature regarding small intestinal function in PD.
Small Intestine
Anatomy and Physiology
The intestine is divided into two primary compo- nents, the small and large intestine (or colon), which possess de fi nite similarities, but also serve clearly different functions. In adults, the small intestine reaches the rather astounding length of approximately 4–6 m [ 20, 21 ] and is divided into three segments: duodenum, jejunum, and ileum.
The small intestine is responsible for absorption of nutrients, salt, and water. Motility within the small intestine is produced by contractions of the circular and longitudinal muscle layers that com- pose the intestinal walls. Interstitial cells of Cajal (ICCs), which are part of the enteric nervous sys- tem (ENS), generate electrical slow waves that serve a pacemaker function and migrate in an aborad direction [ 21, 22 ] . When spike bursts are superimposed on a slow wave, actual muscle
contraction occurs, which then travels in either direction along the small intestine. It previously was considered that slow waves traveled only short distances, with small intestinal motility organizing into segmental contractions serving to slowly mix and spread the chyme for digestion [ 21, 22 ] . However, a more recent study found that many of the slow waves actually propagated the length of the small intestine [ 21, 23 ] and it is likely that the characteristic segmentation pat- terns of small intestinal motility are the result of limited propagation of individual spikes occur- ring in the wake of slow waves [ 24 ] . The digest- ing contents within the small intestine are propelled forward at a rate of 5–20 mm/s and it typically takes 3–5 h for chyme to traverse the small intestine [ 21 ] .
Two distinct patterns of small intestinal motor function have been identi fi ed [ 25 ] . The fed (post- prandial) pattern, which appears within 10–20 min following a meal, is characterized by more seg- mental, and consequently less propulsive, con- tractions that assist in the mixing of digestive enzymes with the chyme and maximize mucosal contact, thus promoting nutrient absorption. The second pattern, the fasting (interdigestive) pat- tern, appears 4–6 h after a meal and is divided into three phases. First is a period of relative motor quiescence, followed by increasingly prominent contractions in the subsequent two phases that presumably serve to “ fl ush” solid residues from the small intestine into the colon, preventing bezoar formation and minimizing bacterial accu- mulation within the small intestine. This complex pattern of small intestinal motility is under the direct control of the ENS, but modulated by both autonomic and hormonal in fl uences.
Small Intestinal Dysfunction in PD Little attention has been focused on whether any changes in small intestinal function occur in the setting of PD. Thorough assessment of small intestinal function is rendered very dif fi cult because of its inaccessibility and length; undoubt- edly, this has discouraged dedicated investiga- tion. However, some information is available.
Orocecal transit time was shown to be mark- edly prolonged in 15 patients with PD when com- pared with 15 age- and sex-matched control individuals [ 26 ] . Yet, it must be recognized that this investigative method is a measure of com- bined gastric and small intestinal transit and does not assess small intestinal function in isolation.
Small intestinal manometry has also been employed in the study of PD patients and abnor- malities in small intestinal motor patterns have been demonstrated [ 27 ] . Small intestinal dilatation has also been observed radiographically [ 28 ] .
In the laboratory, disruption of the migrating myoelectric complex has been documented in rats following administration of 1-methyl-4-phe- nyl-1,2,3,6-tetrahydropyridine (MPTP), along with reduction in jejunal myenteric plexus dop- amine levels [ 29 ] . Also in rats, salsolinol, a cate- chol dopaminergic toxin, does not appear to alter fasting small intestinal myoelectric activity, but it does block changes induced by gastric distension [ 30 ] . Studies that evaluate whether similar changes occur in PD have not been undertaken.
The recent development and employment of newer technologies, such as the wireless motility capsule and video capsule endoscopy [ 31 ] , may permit the accumulation of more detailed infor- mation regarding small intestinal function in individuals with PD, but such studies have not yet been reported.
The clinical consequences of small intestinal dysfunction in PD, if it indeed occurs, have not been systematically investigated. Some individu- als with PD experience a very uncomfortable abdominal bloating sensation, which is suf fi ciently severe at times to compel the anguished individual to loosen trousers, even when they are clearly not even tight. This typi- cally develops during “off” periods and resolves with the re-emergence of levodopa bene fi t. It is conceivable that this uncomfortable sensation might be related to small intestinal dysmotility, but no study has actually addressed this issue.
If there is an association, agents that accelerate small intestinal transit time (e.g., the serotonin-4 receptor agonist prucalopride) [ 32 ] might provide symptomatic relief for patients with these symp- toms. Another potential consequence of delayed
small intestinal transit might be an alteration in intestinal nutrient absorption. This also has not speci fi cally been studied, but some recent inves- tigations have suggested possible roles for both small intestinal bacterial overgrowth (SIBO) and Helicobacter pylori infection (which occurs pri- marily in the stomach, but may also cause duode- nal ulceration) in producing problems for persons with PD.
Individuals with impaired intestinal motility are at risk for the development of SIBO. Recently, Gabrielli et al. [ 33 ] documented the presence of SIBO in 54% (26/48) of patients with PD, com- pared with only 8% (3/36) of a comparably aged control group. The presence of SIBO correlated with disease severity, as measured by both Hoehn and Yahr stage and UPDRS-III score. They, too, suggested that SIBO might be responsible for bloating and fl atulence and speculated that SIBO-related malabsorption with consequent impaired nutrient absorption might help to explain the weight loss that often occurs in indi- viduals with PD.
Basing his conjecture on a 1965 report by Strang [ 34 ] that there was a higher incidence of ulcers in patients with PD compared with con- trols and the subsequent identi fi cation of H.
pylori as an etiologic agent for peptic ulcer dis- ease (both gastric and duodenal) [ 35 ] , Altschuler hypothesized that H. pylori might play a role in the genesis of PD [ 36 ] . In a subsequent extended series of reports, Dobbs et al. have suggested that H. pylori infection triggers an autoimmune response, which may be further potentiated by the development of SIBO, that may initially dam- age the ENS and subsequently be transmitted to the central nervous system and produce PD (for review see [ 37 ] ). Although this theory has not been widely accepted, a recent epidemiological study using nationwide Danish registers provided increased fuel for the idea by demonstrating that prescriptions for H. pylori -eradication drugs and proton pump inhibitors fi ve or more years prior to the diagnosis of PD were associated with a 45%
and 23% increased PD risk, respectively [ 38 ] . A role for H. pylori infection in producing erratic levodopa absorption within the duodenum with consequent motor response fl uctuations has
also been proposed [ 39, 40 ] . Subsequent clinical studies reported that eradication of H. pylori infection improved levodopa absorption, short- ened the delay to turning “on” and lengthened
“on” time in patients with levodopa-induced motor fl uctuations [ 41, 42 ] . It has been specu- lated that H. pylori may interfere with levodopa absorption as a consequence of delayed gastric emptying, gastroduodenal in fl ammation, or even by direct utilization of levodopa by H. pylori itself [ 42, 43 ] . A recent review, however, con- cluded that there is insuf fi cient evidence that H.
pylori eradication improves absorption of levodopa and improves motor symptoms [ 44 ] .
Colon
Anatomy and Physiology
The colon, approximately 1.0–1.5 m in length in adults, is composed of the same two muscle layers—circular and longitudinal—found in the small intestine [ 20, 45 ] . The ileocecal valve, which divides the colon from the small intestine, is not a true sphincter but still effectively regu- lates colonic fi lling and prevents colo-ileal re fl ux.
The colon stores material marked for excretion and performs an important role in the regulation of fl uid, electrolyte, and short-chain fatty acid absorption. It can increase fl uid absorption up to fi vefold in appropriate circumstances. As in the stomach and small intestine, ICCs perform a pacemaker function in the generation of pressure waves that regulate colonic motility. Motor con- trol of colonic motility is mostly mediated directly through the ENS with modulation via the autonomic nervous system. Parasympathetic innervation of the ascending and transverse colon is vagal in origin, whereas the descending and rectosigmoid regions receive their innerva- tion by the pelvic nerves. Sympathetic supply to the colon originates in the thoracic spinal cord and reaches the colon via the inferior mesenteric and pelvic plexuses. Sympathetic activity pro- duces vasoconstriction of mucosal and submu- cosal blood vessels, downregulates motility, and inhibits secretion (thus limiting water loss);
parasympathetic activity increases enteric motor activity and colonic motility [ 45 ] .
Colonic Dysfunction in PD
To the lay public, constipation is a somewhat nonspeci fi c term that may connote both decreased bowel movement frequency (usually with hard stool) and dif fi culty completing a bowel move- ment, often with excessive straining, sometimes with inability to evacuate fecal contents entirely, and occasionally with associated pain [ 46 ] . However, these two problems are actually quite different, with distinctive physiology and clinical characteristics; hence, a separate classi fi cation and discussion of each is needed to fully under- stand bowel dysfunction in PD. Decreased bowel movement frequency is primarily a consequence of colonic dysmotility and is discussed in this section, whereas defecatory dysfunction is pri- marily an anorectal anomaly and is discussed in the following section.
Divergence between the public concept and formal medical de fi nition of what constitutes normal bowel movement frequency has also evolved in recent years, representing a source of confusion and sometimes consternation, both within the literature and inside the clinic. In the past, it was standard to label anything less fre- quent than a daily bowel movement as abnormal, constituting constipation, and this continues to be the concept embraced by many patients, particu- larly the elderly. The current formal medical boundary of constipation (or colonic inertia), however, has been rede fi ned as fewer than three bowel movements weekly. Some investigators have employed an even more strict de fi nition of constipation as one or fewer evacuations per week [ 47, 48 ] . Clinicians realize that not all patients are willing to accept the medical estab- lishment’s wisdom in this regard. To further com- plicate matters, the observation has also been made that estimations of bowel movement fre- quency reported by patients often con fl ict with their own diary records, typically in the direction of underestimating frequency [ 49 ] .
Recognition of this change in what actually constitutes normal bowel movement frequency is important when reviewing reports in the medical literature of constipation in PD. Estimates of the percentage of patients with PD experiencing con- stipation have descended from the 50–67% range of earlier reports to levels of 20–29% in more current publications. In 1958, Schwab and England reported the presence of constipation in two-thirds of their patients [ 50 ] , whereas in 1965, Eadie and Tyrer noted that 51% of their study sample of patients with PD did not have daily bowel movements, compared with 13% of their controls with orthopedic disease [ 2 ] . They also reported that over 50% of their patients were using laxatives on a regular basis. In notable con- trast, using a de fi nition of constipation as fewer than three bowel movements per week, Edwards et al. reported in 1991 the presence of constipa- tion in only 29% of their 98 patients with PD in comparison to 10% of their spousal controls [ 4 ] . Siddiqui et al. found its presence in only 20% of patients with PD in their 2002 survey report [ 51 ] . In contrast, in a group of PD patients studied recently by Stocchi et al., bowel movement fre- quency of fewer than three times per week was described by 77% of the 17 patients [ 52 ] . The explanation for this divergence is not readily apparent.
In survey studies, the presence of constipation in PD has correlated with disease duration and severity [ 2, 53 ] . However, in clinical practice, it is not unusual for patients with PD to recollect the development of some degree of bowel dys- function even prior to the appearance of the more typical motor features of PD [ 8 ] . Constipation occurring early in the course of PD has also been documented by Bassotti et al. [ 47 ] .
A report derived from data accumulated in the Honolulu-Asia Aging Study has propelled this a step further by suggesting that diminished bowel movement frequency may actually constitute a risk factor for PD development [ 54 ] . An associa- tion was documented between the frequency of bowel movements and risk of developing PD.
Men who reported a bowel movement frequency of less than one per day were found to have a risk of developing PD that was 2.7 times greater than
men who had daily bowel movements and fourfold higher than those with two or more bowel move- ments daily. The same group of investigators sub- sequently have reported an association between reduced bowel movement frequency and the pres- ence of incidental Lewy bodies [ 55 ] and between reduced bowel movement frequency and reduced substantia nigra neuronal counts (which was inde- pendent of the presence of Lewy bodies in the substantia nigra or locus ceruleus and a clinical diagnosis of PD) [ 56 ] .
Other investigators have added to the recogni- tion that constipation may constitute a risk factor for the development of PD. Using the medical records-linkage system of the Rochester Epidemiology Project in a study involving 196 case-control pairs that included both men and women, Savica et al. reported that constipation occurring as early as 20 or more years before the onset of motor symptoms is associated with an increased risk of PD and may represent a premo- tor manifestation of the disease [ 57 ] . In another study that identi fi ed 402 incident female PD cases drawn from the Nurses’ Health Study and 156 male PD cases from the Health Professionals Follow-up Study, Gao et al. found that men who have a bowel movement every 3 days or less have an almost fi vefold (4.98) increased risk of devel- oping PD in the next 6 years; the corresponding risk in women was 2.15 [ 58 ] .
Although these fi ndings may simply re fl ect the fact that the appearance of constipation can pre- cede the emergence of conventional PD motor features, other explanations are possible. Perhaps, rapid transit of material through the GI tract, implied by frequent bowel movements, limits exposure to, and absorption of, toxic substances capable of damaging dopaminergic neurons.
Further studies investigating this possibility might prove to be very interesting and informative.
Considerable evidence has now accumulated that implicates slowed colon transit of fecal mate- rial as the physiological basis for decreased bowel movement frequency in PD. Employing radiopaque markers, colon transit studies have indicated that as many as 80% of persons with PD may have abnormally prolonged transit times [ 59 ] . Jost and Schimrigk initially reported an
average colon transit time (CTT) of 5–7 days (120–168 h) in a group of 20 persons with PD, [ 59 ] and in a subsequent study of 22 subjects in whom CTT could be measured, the average time was 130 h [ 60 ] . Edwards et al. also documented slowed CTT in a study of 13 participants with PD, but the CTT they documented was consider- ably shorter than that noted by Jost and Schimrigk, fi nding a mean of 44 h, compared with 20 h in spousal controls [ 7 ] . A more recent study further con fi rms that CTT is slowed in PD, although the times reported (82.4 min in PD patients and 39 min in controls) appear to be incorrectly labeled in minutes rather than hours [ 61 ] . Therefore, despite the variance in average CTT in published reports, there seems to be ample agree- ment that CTT is prolonged in PD. The reason for the widely varying CTTs reported by the various investigators is not clearly evident.
In addition to the earlier survey studies, another study by Jost and Schimrigk in recently diagnosed patients with PD seems to support the idea that constipation becomes more severe as PD progresses. In this study, the average CTT in patients with PD was 89 h [ 62 ] , in comparison to the considerably longer CTTs reported in their earlier studies cited previously, which included individuals with more advanced disease.
Prolongation of CTT in untreated individuals strongly suggests that it develops as part of the disease process itself; yet the demonstration by Ashraf et al. shows that not all persons with pro- longed CTT experience clinically symptomatic constipation [ 63 ] . This evidence seems to indi- cate that delayed CTT may not be the sole deter- mining factor for stool frequency. Other factors certainly may have a role in the genesis of consti- pation in some individuals, but it is not clear what these factors might be. Medications—not only anticholinergic drugs but also levodopa and dop- aminergic agonists—may be responsible for diminished bowel movement frequency in some individuals, but not all individuals with PD who experience constipation are receiving these medications.
The pathophysiologic basis of constipation in PD has not been de fi nitively de fi ned. Evidence has accumulated for both central and peripheral