Gastrointestinal Features of Parkinson’s Disease
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- Cloud, L.J. & Greene, J.G. Curr Neurol Neurosci Rep (2011) 11: 379. doi:10.1007/s11910-011-0204-0
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Gastrointestinal (GI) symptoms are among the most common nonmotor manifestations of Parkinson’s disease (PD), and they have many important ramifications for patients. The purpose of this review is to raise awareness of the full spectrum of GI symptoms in PD which include weight loss, sialorrhea, dysphagia, nausea, constipation, and defecatory dysfunction. We will discuss their practical significance, and outline a clear approach to their evaluation and management. A brief discussion about the impacts of commonly used medical and surgical PD therapies on GI symptom manifestation is also included.
KeywordsGastrointestinalNonmotor symptomsParkinson’s diseaseWeight lossSialorrheaDysphagiaAspirationGastroparesisNauseaVomitingBloatingRefluxEarly satietyConstipationDefecatory dysfunctionLaxativesGlycopyrrolateAtropineIpratropium bromideBotulinum toxinPolyethylene glycolPsylliumDomperidoneApomorphine
In addition to the cardinal motor features of the disease, Parkinson’s disease (PD) patients suffer from a variety of nonmotor symptoms, of which gastrointestinal (GI) symptoms are among the most common. In recent years, these GI symptoms have received increased attention in the medical literature and have been the focus of several reviews [1, 2•, 3, 4, 5•, 6]. The most common GI symptoms in PD are weight loss, sialorrhea, dysphagia, nausea, constipation, and defecatory dysfunction, all of which reflect dysregulation of GI motility at all levels of the GI tract.
These diverse GI symptoms have important ramifications for PD patients. Recent studies have underscored their significance in determining quality of life [7–10]. Furthermore, GI symptoms have been associated with severe and potentially life-threatening complications, including malnutrition, pulmonary aspiration, megacolon, intestinal obstruction, and even perforation [11–16]. They rank among the most common causes of emergency admission in the PD population . Lastly, they can impact on other PD symptoms. For example, several studies have indicated that gastroparesis and subsequent late arrival at intestinal absorption sites can lead to erratic absorption of levodopa with resultant motor fluctuations [18–20].
Recognition of GI symptoms requires vigilance on the part of clinicians. Health care providers should routinely ask direct questions about GI symptoms during office visits so that efforts can be directed at appropriate management of these distressing manifestations.
There is a paucity of clinical trial data to guide the treatment of GI dysfunction in PD. In fact, until very recently, there were no randomized, double-blind, placebo-controlled trials of symptomatic GI medications. Six recent studies have provided level I evidence for symptomatic treatment of sialorrhea and constipation. Despite this recent progress, our armamentarium of treatments for dysphagia, nausea, and defecatory dysfunction remains severely limited. The clinical presentation, evaluation, and treatment options of individual GI symptoms common in PD will be discussed.
Unintended weight loss is common in PD [21–23], with one study reporting PD patients to be four times more likely to experience a weight loss of greater than 10 lb since their diagnosis than matched controls over the same time period . Other studies have found women to be more vulnerable than men to unintended weight loss and undernutrition in PD [23, 24]. The amount of weight loss is usually modest but can sometimes be more dramatic (exceeding 12.8 kg) . The etiology of this unintended weight loss is not known. Potential contributing factors include impaired olfaction and taste perception, dysphagia, increased energy expenditure from dyskinesias, and side effects (nausea and anorexia) from dopaminergic drugs. For PD patients experiencing dramatic or ongoing weight loss, evaluation for an alternative medical cause should be undertaken. Consultation with a registered dietician to evaluate daily energy intake and expenditure and to make dietary modifications is important to ensure adequate nutritional status and curtail weight loss.
Excessive saliva in the mouth with or without overt drooling is common in PD, occurring in more than 70% of patients [25, 26]. In addition to social embarrassment, sialorrhea can lead to aspiration and subsequent pneumonia. Recent studies have shown that saliva production is not increased in PD but is actually diminished . Sialorrhea in PD is thought to be the result of infrequent and inefficient swallowing .
Pharmacologic treatment of gastrointestinal symptoms in Parkinson’s disease (in order of suggested use)
Level of evidencea
Side effect considerations
Sublingual ipratropium bromide spray
1–2 sprays (containing 21 μg per metered dose spray) as needed up to 4x/day
Dry nasal passages and nose bleed reported
Sublingual atropine ophthalmic, 1% solution
1 drop (containing 5 mg atropine) 2x/day
Systemic side effects occurred in some patients (delirium and hallucinations)
1 mg 3x/day Maximum dose: 8 mg/day
Constipation, dry mouth, blurred vision, urinary retention, anhidrosis, palpitations, dysgeusia, drowsiness, confusion
Botulinum toxin B
500–1000 U per parotid gland, 250 U per submandibular gland
Dry mouth, dysphagia
Botulinum toxin A
15–40 U per parotid gland, 10–15 U per submandibular gland
Dry mouth, dysphagia
20 mg 4x/day
Elevated prolactin levels, rare adverse cardiac events
5.1 g 2x/day
GI obstruction possible if not taken with adequate liquid
Polyethylene glycol 3350
Up to 17 g daily
Electrolyte abnormalities may occur with chronic use
3–10 mg subcutaneous
Hypotension, pretreatment with an antiemetic is necessary
Botulinum toxin A
100 U into puborectalis muscle using transrectal ultrasound guidance
While survey studies suggest that approximately 50% of PD subjects report dysphagia [26, 34], clinical assessments of swallowing such as modified barium swallow testing reveal abnormalities may be present in more than 75% [15, 16]. This suggests that as with many other GI symptoms in PD, objective abnormalities often precede subjective complaints. The clinical severity of PD does not predict the presence or severity of dysphagia [35, 36]. Although all phases of swallowing (oral, pharyngeal, and esophageal) can be affected, the oral phase is most often abnormal, followed by the pharyngeal and esophageal phases, respectively . Using modified barium swallow studies and videofluoroscopy, multiple abnormalities in the oropharyngeal phase have been documented, including vallecula and piriform sinus residues, delayed swallowing reflex, and deficits in laryngeal movement [38–40]. The aforementioned abnormalities culminate in increased risk of aspiration, which may occur asymptomatically in as many as 15% to 33% of PD patients, and can lead to pneumonia [11, 38, 40]. Using videoradiography and esophageal manometry, multiple abnormalities in the esophageal phase have been identified, including incomplete upper esophageal sphincter relaxation and reduced opening, high intrabolus pressure, complete aperistalsis, multiple simultaneous contractions (diffuse esophageal spasms), high-amplitude contractions, prolonged esophageal phase, and reduced lower esophageal sphincter pressure [35, 36, 41]. These esophageal abnormalities can result in both dysphagia and gastroesophageal reflux.
PD patients complaining of coughing or choking during meals should undergo evaluation with a modified barium swallow study. If normal, further evaluation with videofluoroscopy should be considered to evaluate esophageal function. Treatment of dysphagia in PD can be challenging. Optimizing dopaminergic medications can be beneficial for some patients [38, 42]. Swallowing training to learn voluntary airway protection techniques may also be beneficial . Rarely, it may be necessary to pursue gastrostomy feeding tube placement.
Although nausea is a common side effect of dopaminergic medications, it also occurs in untreated PD patients , possibly due to underlying gastroparesis. In addition to nausea, gastroparesis can cause other vexing GI symptoms such as postprandial bloating, abdominal pain, early satiety, and weight loss, all of which have been well described in PD . Objective evidence for gastroparesis has been well documented in PD, with some studies suggesting its prevalence may approach 100% . Gastroparesis has been reported to be more severe in PD patients treated with levodopa , which has important pharmacokinetic implications because levodopa must reach the small intestine to be absorbed. Several studies have suggested that delayed or erratic gastric emptying is responsible for motor fluctuations in patients taking levodopa [18, 19]. For PD patients suspected of having gastroparesis, gastric scintigraphy is most often used to assess gastric emptying, and consultation with a gastroenterologist may be necessary to assist with management.
When it is mild, treatment of gastroparesis in PD should begin with a conservative, nonpharmacologic approach. Patients can adopt a gastroparesis diet, which may serve to reduce symptoms and maintain proper nutrition and hydration status. The gastroparesis diet encourages small, frequent meals, along with avoidance of foods high in fat and fiber, taking fluids throughout meals, and remaining upright or walking for 1 to 2 h after meals. When pharmacologic treatments are required, the use of metoclopromide (a central and peripheral dopamine receptor antagonist often used in the treatment of gastroparesis) is contraindicated in PD because it worsens parkinsonism by blocking central dopamine receptors. Domperidone is a peripheral dopamine receptor blocker that does not cross the blood–brain barrier and can be used safely in the PD population to improve gastric emptying and associated GI symptoms . Although widely available in other parts of the world, domperidone is currently not available in the United States. Prokinetic agents such as cisapride and mosapride have been shown to improve gastric emptying in PD [47, 48] but have been removed from the US market due to associated cardiotoxicity. Other treatments for gastroparesis such as erythromycin and gastric pacemaker placement may be beneficial but have not been tested specifically in the PD population.
Decreased bowel movement frequency, generally defined as less than three bowel movements per week, may occur in more than 50% of PD patients . The proposed mechanism is slowed transit through the colon. Colon transit time has been found to be up to twice as long in PD patients than controls [49–51]. Constipation often occurs early in the disease course and may predate motor features by several years . A study of more than 6,000 men without PD enrolled in the Honolulu Heart Program found that the risk of future PD increases fourfold in men who had less than one bowel movement a day when compared with men having more than one . Subsequent autopsy studies on subjects with no clinical signs of parkinsonism or dementia prior to death confirmed that late life constipation is associated with incidental Lewy bodies in the substantia nigra and locus caeruleus as well as decreased substantia nigra neuron density [53, 54]. These clinical and pathologic findings suggest that constipation may in some cases represent incipient PD.
Treatment of constipation in PD should begin with conservative, nonpharmacologic approaches. Patients should be advised to increase fluid intake, maximize dietary fiber, and increase daily activity levels. Medications known to exacerbate constipation should be discontinued if possible.
Should conservative measures fail, there are a number of oral agents that can be used to manage chronic constipation. Psyllium, used alone or in combination with a stool softener such as docusate sodium, is a safe and effective initial approach . Should a more aggressive regimen be required, osmotic agents are preferred over other categories of laxatives due to their safety profile with long-term use. Polyethylene glycol is an osmotic laxative found to be safe and effective for PD patients [56, 57•]. It is available in the United States without a prescription and can be used daily or on an as-needed basis. Although studied in PD and found to be effective in the treatment of constipation, the prokinetic agents such as cisapride , mosapride , and tegaserod  have been removed from the US market due to the aforementioned safety concerns. Table 1 summarizes suggested pharmacologic treatment options for constipation in PD, including dosages, level of evidence supporting their use in PD, and relevant side effect considerations.
Defecatory dysfunction, which is often experienced as excessive straining, pain, or a feeling of incomplete evacuation during defecation, has been reported to occur in up to 67% of PD patients  and can occur very early in the course of PD. Defecation requires the coordinated action of multiple muscle groups. Muscles that maintain fecal continence (internal and external anal sphincters and puborectalis) must relax, while the abdominal and diaphragmatic muscles that increase intra-abdominal pressure contract. Multiple abnormalities in this complex process have been described in PD patients, including paradoxical contraction of the puborectalis and external anal sphincter during defecation [61, 62].
Although anorectal function can be formally evaluated using defecography and/or anorectal manometry, these studies are not routinely used in clinical practice. Unfortunately, despite its frequency and severity, no treatments for defecatory dysfunction have been rigorously studied in the PD population. Use of routine laxatives and stool softeners is generally not effective and may actually worsen symptoms . Improvement in defecatory dysfunction has been reported to occur after subcutaneous injection of the dopamine agonist apomorphine [61–63]; however, subjects receiving apomorphine injections must be pretreated with an antiemetic, and adverse effects include orthostatic hypotension along with other dopaminergic effects. Botulinum toxin injections into the external anal sphincter and/or puborectalis muscle have also been reported to improve defecatory dysfunction in PD [64, 65]; however, these injections can be technically challenging, require ultrasound guidance, and must be repeated periodically. Biofeedback techniques have not been specifically evaluated in the PD population, although they may be helpful for some patients. More effective and practical treatments for defecatory dysfunction are desperately needed. Table 1 summarizes suggested pharmacologic treatment options for defecatory dysfunction in PD, including dosages, level of evidence supporting their use in PD, and relevant side effect considerations.
Effects of PD Therapies on GI Symptoms
Dopaminergic medications remain the mainstay of medical therapy for the motor manifestations of PD, and they may impact GI symptom manifestation both positively and negatively. First, nausea and vomiting are common side effects of all of the dopaminergic medications, which can sometimes limit their use. Second, dopaminergic medications have a known inhibitory effect on upper GI motility  and may therefore worsen underlying gastroparesis , thereby contributing to nausea, vomiting, and other GI symptoms. Conversely, dopaminergic medications may actually improve other GI symptoms such as sialorrhea, dysphagia, and anorectal dysfunction in PD [38, 42, 63]. Lastly, excessive weight gain has been reported to occur in patients taking dopamine receptor agonists as a result of compulsive eating .
Deep brain stimulation (DBS) may also influence GI symptom expression. Improvements in deglutition and constipation have been reported after subthalamic nucleus DBS [68, 69]. Weight gain has also been observed after both bilateral and unilateral subthalamic nucleus DBS surgery [70, 71]. The cause of weight gain following DBS is thought to be related to suppression of chronic tremor and/or dyskinesia, although further study is needed to clarify the underlying mechanism.
GI symptoms are highly prevalent in PD, occur early in the disease course, and have important consequences for patients. It is essential for clinicians to be aware of the full spectrum of GI symptoms in PD, understand how commonly used PD therapies may influence their expression, and be familiar with basic approaches to the evaluation and treatment of the more common GI features of PD. Treatment of dysphagia, gastroparesis, and defecatory dysfunction are particularly challenging in this population. More clinical trials are needed to guide clinicians in the management of these symptoms, and more research is needed to clarify the mechanisms underlying deranged gut motility in PD, which may in turn lead to improved, disease-specific therapies.
Conflicts of interest: L.J. Cloud: has participated in a scientific advisory board for UCB Pharma and expenses were paid for the travel to this meeting; J.G. Greene: none.