Review

Gastrointestinal dysfunction in Parkinson’s disease

Alfonso Fasano, Naomi P Visanji, Louis W C Liu, Antony E Lang, Ronald F Pfeiffer

Our understanding of dysfunction of the gastrointestinal system in patients with Parkinson’s disease has increased Lancet Neurol 2015; 14: 625–39
substantially in the past decade. The entire gastrointestinal tract is affected in these patients, causing complications Morton and Gloria Shulman
that range from oral issues, including drooling and swallowing problems, to delays in gastric emptying and Movement Disorders Clinic and
the Edmond J Safra Program in
constipation. Additionally, small intestinal bacterial overgrowth and Helicobacter pylori infection affect motor
Parkinson’s Disease, Toronto
fluctuations by interfering with the absorption of antiparkinsonian drugs. The multifaceted role of the Western Hospital, University
gastrointestinal system in Parkinson’s disease necessitates a specific and detailed assessment and treatment plan. Health Network, Division of
The presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates this system in Neurology, University of
Toronto, Toronto, Ontario,
the pathogenesis of Parkinson’s disease. Future studies elucidating the role of the gastrointestinal tract in the
Canada (A Fasano MD,
pathological progression of Parkinson’s disease might hold potential for early disease detection and development N P Visanji PhD,
of neuroprotective approaches. Prof A E Lang MD); Division of
Gastroenterology, Department
of Medicine, Toronto Western
Introduction treatment. We conclude by discussing the next crucial Hospital, Toronto, Ontario,
Progress in the understanding of the extent and role of steps that are needed in research, treatment, and Canada (L W C Liu MD); and
gastrointestinal dysfunction in Parkinson’s disease has understanding of gastrointestinal involvement in Department of Neurology,
increased substantially in the past decade.1 Not only is Parkinson’s disease. Oregon Health and Science
University, Portland, Oregon,
the gastrointestinal system impaired from both a motor USA (Prof R F Pfeiffer MD)
and dysautonomic standpoint, but it also plays an active Synucleinopathy in the gastrointestinal tract Correspondence to:
part in the pathophysiological changes that underlie The pathological changes of Parkinson’s disease are Dr Alfonso Fasano, University of
motor fluctuations through its effects on absorption of defined by abnormal α-synuclein accumulation in the Toronto, Movement Disorders
antiparkinsonian drugs. A wealth of evidence2–4 strongly brain in characteristic Lewy bodies or Lewy neurites. Centre, Toronto Western
Hospital, Toronto, ON M5T 2S8,
implicates pathophysiological changes in the gastro- However, evidence for abnormal α-synuclein Canada
intestinal tract in the pathogenesis of Parkinson’s accumulation outside the brain, including throughout alfonso.fasano@uhn.ca
disease, and many studies5 indicate that the enteric the enteric nervous system, is growing (figure 1).
nervous system might serve as a conduit for the α-Synuclein deposition occurs in the myenteric and
propagation of α-synuclein, initiating the characteristic submucosal plexuses and mucosal nerve fibres, with a
spread of degeneration through the CNS. clear rostrocaudal gradient in deposition throughout the
Here, we review current knowledge of gastrointestinal enteric nervous system.13 A study mapping the distri-
involvement in Parkinson’s disease. First, we assess the bution of phosphorylated α-synuclein2 reported the
growing body of experimental evidence supporting the highest concentrations of enteric phosphorylated
hypothesis that the gastrointestinal tract might be the α-synuclein in the submandibular gland and lower
site of initiation of Parkinson’s disease, along with oesophagus, lower concentrations in the stomach and
evidence for the potential use of gastrointestinal small intestine, and lowest concentrations in the colon
α-synuclein deposition (from the submandibular gland and rectum. The causes of this pattern of distribution are
to the appendix and the colon) as a diagnostic biomarker. unknown, although deposition follows the pattern of
Second, we discuss the effect of gastrointestinal dys- innervation from visceromotor projection neurons.
function on clinical symptoms, including oral difficulties, These neurons originate in the dorsal motor nucleus of
swallowing problems, and constipation. As a result of the vagus nerve (DMV) and innervate the longitudinal
their frequency, these salient gastrointestinal symptoms extent of the gastrointestinal tract, with vagal innervation
are important in disease progression and constitute a predominant in the upper gastrointestinal tract and
major source of disability. We also review evidence sympathetic and pelvic outflow projections predominant
describing the deleterious effect of small intestinal in more distal regions.
bacterial overgrowth (SIBO) and Helicobacter pylori The accumulating evidence describing early enteric
infection on the absorption of antiparkinsonian drugs nervous system pathological changes in Parkinson’s
and the potential effects on the pathophysiological disease, in regions far more accessible for direct study
changes in patients with Parkinson’s disease and motor than the brain, has prompted investigations assessing
fluctuations. enteric α-synuclein as a biomarker for Parkinson’s disease.
Owing to the substantial role of the gastrointestinal Many groups, including our own, chose colonic biopsies
system in Parkinson’s disease, we believe that thorough as a practical source of tissue. We previously reviewed the
assessment and treatment of gastrointestinal dysfunction advantages and challenges of the use of colonic
in patients with the disease is essential. To this end, we α-synuclein as a diagnostic biomarker13 and concluded
have designed a practical algorithm for the assessment of that colonic α-synuclein does not provide high specificity
the gastrointestinal system in patients with Parkinson’s for the diagnosis of Parkinson’s disease.11 Our findings
disease and provide an evidence-based approach to support other reports that have shown the presence of

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 Review

The appendiceal mucosa also has been proposed as a

Submandibular gland Oesophagus potential site of entry of α-synuclein because this region
• Phosphorylated α-synuclein • Phosphorylated α-synuclein in
present in postmortem tissue upper oesophagus in 0 of 8 and has the highest expression of α-synuclein in the enteric
from 28 of 28 patients with in lower oesophagus in 11 of nervous system in healthy individuals.15 Alternatively, our
Parkinson’s disease2 16 patients with Parkinson’s
• Phosphorylated α-synuclein disease8
finding9 of increased aggregated α-synuclein in the colon
present in biopsy tissue from • Lewy bodies in lower of control individuals prompted us to postulate that in
9 of 12 patients with oesophagus in 6 of 6 patients Parkinson’s disease, α-synuclein might disaggregate and
Parkinson’s disease6 with Parkinson’s disease and
3 of 8 controls9 infiltrate the CNS as soluble α-synuclein oligomers.
The distribution of synucleinopathy is associated with
gastrointestinal symptoms along the entire gastro-
Stomach intestinal tract.16 The extent of gastrointestinal dys-
• Phosphorylated α-synuclein in Colon
3 of 8 patients with Parkinson’s function, with corresponding widespread enteric nervous
• α-Synuclein in myenteric and
disease2 submucosal plexus in 10 of system synucleinopathy, could suggest that a disruption
• Lewy bodies in 2 of 7 patients
with Parkinson’s disease6
10 patients with Parkinson’s in the physiological function of α-synuclein might have a
disease and 40 of 77 controls3
• Phosphorylated α-synuclein in pivotal role in gastrointestinal dysfunction. The potential
submucosal plexus in 21 of existence of so-called strains of α-synuclein, some
29 patients with Parkinson’s
disease and 0 of 10 controls10
physiological and others with potentially deleterious
Appendix
• Appendiceal mucosa • α-Synuclein and properties, reinforces this association. However, several
phosphorylated α-synuclein reports show an absence of neuronal loss within the
had the most dense
present in mucosa in 19 of
α-synuclein expression in the
22 patients with Parkinson’s enteric nervous system in Parkinson’s disease,17 so
healthy enteric nervous
system; α-synuclein present in
disease and 11 of 11 controls11 further investigation is needed to establish whether
• α-Synuclein present in mucosa
10 of 10 individuals without
in 9 of 9 patients with
pathological α-synuclein disrupts gastrointestinal
Parkinson’s disease7
Parkinson’s disease and 0 of function in the disorder. In fact, neuronal loss in the
23 controls12 enteric nervous system might not be necessary; this
• Phosphorylated α-synuclein
present in 11 of 13 individuals finding underlines the suggested role of the DMV, a
without Parkinson’s disease with brain region that has a high level of synucleinopathy in
a possible increase with age4
Parkinson’s disease and where α-synuclein over-
expression has been shown to mediate impaired gastro-
Figure 1: Distribution of α-synuclein and phosphorylated α-synuclein in the enteric nervous system in intestinal motility in experimental parkinsonism.18
patients with Parkinson’s disease Although a clear pattern exists for the presence of
Increasing evidence suggests that abnormal α-synuclein accumulates outside the brain and throughout the enteric
synucleinopathy in regions of the gastrointestinal tract
nervous system.2–4,6–12 Adapted from Pfeiffer,1 by permission of Elsevier.
affected in Parkinson’s disease, no studies have shown a
causative link between this pathological abnormality and
α-synuclein in the colon in healthy individuals.13 Although the corresponding gastrointestinal deficit. Future work
good sensitivity for detection of α-synuclein in the colon enhancing our understanding of the association between
exists, the clear rostrocaudal gradient in α-synuclein enteric synucleinopathy and gastrointestinal dysfunction
deposition in the enteric nervous system, coupled with the might aid the development of treatments targeting
strong vagal innervation, has prompted the suggestion gastrointestinal symptoms.
that tissue from more proximal regions of the gastro-
intestinal tract might provide higher sensitivity and Oral difficulties
specificity for the diagnosis of Parkinson’s disease than Dental problems
tissue from the colon. The submandibular gland, in which Patients with Parkinson’s disease brush their teeth and
phosphorylated α-synuclein has been reported in all seek dental care less frequently than healthy individuals.19
patients with Parkinson’s disease and none of the healthy The ability of patients to brush their teeth effectively is
controls in a postmortem study, might have better hampered by decreased manual dexterity and difficulty
diagnostic potential.8 opening the jaw,20 leading to increased periodontal
The hypothesis that Parkinson’s disease might arise disease, an increased frequency of caries, and fewer
from the gut has received much attention. This idea, first remaining teeth.21 Excessive saliva (sialorrhoea) might
posited a decade ago,5 has gained attention because several change salivary pH and composition in some patients,
studies have suggested that the pathological progression of and xerostomia might impair the mouth’s self-cleaning
Parkinson’s disease might be mediated by the prion-like mechanism in others.21
properties of α-synuclein.14 The enteric nervous system is
affected early in Parkinson’s disease and the dense Drooling
innervation originating from the DMV might provide a Drooling is defined as excessive pooling of saliva in the
conduit for abnormal forms of α-synuclein to access the oral cavity due to overproduction of saliva or impaired
CNS.5 These vagal projection neurons are among the first salivary clearance, caused by swallowing difficulties or
cells in the CNS to exhibit abnormal α-synuclein deposits. inability to maintain saliva within the oral cavity. Drooling

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has several negative effects: social embarrassment, poor
oral hygiene, bad breath, increased intra-oral occult
bacteria, difficulty eating and speaking, increased risk of
aspiration pneumonia, and a profound effect on quality
of life.22 Furthermore, a 9·75 times increased risk of
respiratory infection over 1 year was documented in
patients with Parkinson’s disease with daily drooling and
silent aspiration or silent laryngeal penetration of food.23
Drooling prevalence in patients with Parkinson’s disease
ranges from 10% to 81% in controlled studies (table 1).29,34
Such variability can be attributed to the absence of
established diagnostic criteria, the use of different types
of screening questionnaires, and differences in the
characteristics of cohorts with Parkinson’s disease.22
Several features of Parkinson’s disease are associated
with drooling, including severity of motor symptoms
(especially dysarthria and dysphagia).54 Other motor
features (hypomimia with unintentional mouth opening
and stooped posture with dropped head) impair the
ability to maintain saliva within the oral cavity.55 Factors
indirectly related to disease severity have been associated
with drooling, including disease duration, use of anti-
depressants, hallucinations, orthostatic hypotension, and
ageing.56 The associations with severity of motor
symptoms and other motor features, and the clinical
observation of increased drooling during off-times (when
the effects of antiparkinsonian drugs wear off and
symptoms return), suggest that impaired swallowing
might be the cause of drooling, rather than over-
production of saliva.
Several experimental and clinical findings22 suggest
that salivary production is in fact reduced in many
patients with Parkinson’s disease, probably as a result of
dopamine depletion. Accordingly, dry mouth is present
in more than 60% of patients with Parkinson’s disease
and might coexist with drooling in 30% of these patients.57
Additional mechanisms might be the cause of drooling;
one study29 showed that salivary production in response
to a discrete stimulus is significantly higher in drooling
Proportion of Proportion of
patients with healthy controls
Parkinson’s disease

Proportion of Proportion of (Continued from previous column)

patients with healthy controls Constipation
Parkinson’s disease
Eadie and Tyrer24 61% (n=76) 13% (n=96)
Drooling Edwards et al25 29% (n=98) 10% (n=50)
Eadie and Tyrer24 50% (n=76) 5% (n=96) Singer et al41 7% (n=48) 6% (n=32)
Edwards et al25 70% (n=94) 6% (n=50) Wang et al42 71% (n=62) NA
Edwards et al26 77% (n=13) 14% (n=7) Edwards et al26 31% (n=13) 14% (n=7)
Siddiqui et al27 52% (n=44) 13% (n=24) Gonera et al43 4% (n=60) 8% (n=58)
Verbaan et al28 73% (n=420) 7% (n=150) Abbott et al44‡ 10% (n=96) 4% (n=6694)
Nicaretta et al29 10% (n=14) NA (n=8) Sakakibaraet al45 50% (n=12) 20% (n=10)
Kim et al30 26% (n=23) 4% (n=23) Chaudhuri et al46 47% (n=123) 26% (n=96)
Leibner et al31 59% (n=58) 14% (n=51) Kaye et al47 59% (n=156) 21% (n=148)
Yu et al32 46% (n=90) 13% (n=270) Verbaan et al28 22% (n=420) 2% (n=150)
Muller et al33 42% (n=207) 6% (n=175) Krogh et al48 27% (n=416) 5% (n=45)
Damian et al34 81% (n=62) 25% (n=287) Kim et al30 26% (n=23) 4% (n=23)
Picillo et al35* 16% (n=200) 2% (n=96) Savica et al49 36% (n=196) 20% (n=196)
Taste impairment Ramjit et al50 67% (n=58) 22% (n=51)
Shah et al36 27% (n=75) 1% (n=74) Yu et al32 70% (n=90) 48% (n=270)
Deeb et al37 22% (n=50) 1% (n=23) Muller et al33 39% (n=207) 14% (n=175)
Kashihara et al38 9% (n=285) 0% (n=61) Gaenslen et al51‡ 25% (n=93) 11% (n=93)
Pont-Sunyer et al39* 14% (n=109) 1% (n=107) Damian et al34 63% (n=62) 31% (n=286)
Swallowing disorders Picillo et al35* 16% (n=200) 14% (n=93)
Edwards et al25 52% (n=94) 6% (n=50) Szewczyk-Krolikowski et al52* 41% (n=490) 34% (n=176)†
Edwards et al26 77% (n=13) 14% (n=7) Pont-Sunyer et al39* 39% (n=109) 13% (n=107)
Clarke et al40 30% (n=64 4% (n=80) Schrag et al53‡§ 32% (n=7232)¶ 19% (n=40 541)¶
Siddiqui et al27 30% (n=44) 8% (n=24) 25% (n=4769)|| 15% (n=25 544)||
Verbaan et al28 55% (n=420) 19% (n=150) 20% (n=1680)** 14% (n=8305)**

Kim et al30 13% (n=23) 0% (n=23)† NA=not available. *Early disease stage, drug-naive patients.†Group comparisons
Yu et al32 28% (n=90) 21% (n=270)† were not statistically significant; all other differences between patients and
controls are significant. ‡Symptoms were assessed during the premotor phase.
Muller et al33 19% (n=207) 6% (n=175)
§Prevalence of gastrointestinal symptoms was assessed at different time intervals
Damian et al34 53% (n=60) 22% (n=290) before diagnosis: ¶2 years, ||2–5 years, and **5–10 years.
Picillo et al35* 9% (n=200) 3% (n=96)
Table 1: Prevalence of major gastrointestinal symptoms in patients with
(Table 1 continues in next column)
Parkinson’s disease reported in case-controlled studies

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 Review
patients with Parkinson’s disease than in healthy
individuals. The association between drooling and
α-synuclein deposition in the submandibular glands in
patients with Parkinson’s disease is unknown.2
Other aspects of oral function
Impaired olfaction is well established in Parkinson’s
disease, but impairment of taste has received less
attention. Several studies58 have documented impaired
taste in patients with Parkinson’s disease, with prevalence
ranging from 9% to 27% (table 1). Age, sex, disease
duration, and disease stage are not associated with
impaired taste, although some studies suggest that taste
is more likely to be impaired if cognitive functions are
affected.58 Painful burning mouth syndrome without any
obvious abnormality in the oral mucosa or other
structures has been reported in patients with Parkinson’s
disease and, in some instances, might be induced by
levodopa treatment.59
Swallowing disorders
Oropharyngeal and oesophageal dysphagia are frequently
reported in patients with Parkinson’s disease, with a
prevalence ranging from 9% to 77% (table 1). In a meta-
analysis,60 the pooled prevalence was estimated to be 35%
for subjective oropharyngeal dysphagia; however,
because many patients are unaware of symptoms,
objective testing resulted in a higher prevalence of 82%.60
Pharyngeal dysfunction and oropharyngeal transit
abnormalities increase the risk of aspiration, thus
contributing to risk of upper respiratory tract infection
and pneumonia.61 Aspiration is present in 15–56% of
patients with Parkinson’s disease and silent aspiration in
15–33% of patients.62
Dysphagia typically emerges in more advanced
Parkinson’s disease, but it can develop early, occasionally
even as the presenting feature.63 Oropharyngeal
dysphagia is often attributed to bradykinesia and rigidity
Figure 2: Delay in gastric emptying
Photograph taken during gastroscopy. Arrow points to a carbidopa tablet
remaining intact in a patient’s stomach about 1·5 h after intake.
628
secondary to basal ganglia dysfunction. However,
functional neuroimaging has shown hypometabolism in
the supplementary motor area and the anterior cingulate
cortex in these patients;64 peripheral mechanisms
including motor and sensory pharyngeal nerves might
also play a part in oropharyngeal dysphagia.65
Malnutrition
The prevalence of malnutrition in Parkinson’s disease
ranges from 0% to 24% and risk of malnutrition from
3% to 60%.66 Malnutrition is an established determinant
of health in elderly people and is linked to reduced
functional ability, quality of life, and survival in patients
with Parkinson’s disease.67 Motor impairment (dys-
phagia), fear of increased off-time, fasting associated
with drug administration, drug-induced nausea, and
anorexia can all affect food intake. Female sex, ageing,
loss of appetite, depression, apathy, and loss of olfaction
or taste might also contribute to malnutrition.
Dyskinesias contribute to weight loss by increasing
energy expenditure,68 and low bodyweight is associated
with an increased risk of dyskinesias, creating a vicious
circle.68,69 Administration of levodopa (normalised for
bodyweight and adjusted for age, sex, and disease
severity) has been associated with impaired nutritional
status in a dose-dependent manner.70 A direct effect of
levodopa on fat metabolism, skeletal muscle glucose
uptake, and hormones (such as prolactin) has also been
postulated.71 A cumulative levodopa dose is purportedly
associated with nutritional deficiency through changes
in homocysteine, vitamin B6, and B12 levels.72
Conversely, weight gain is associated with treatment
with dopamine agonists and neurosurgical procedures,
such as deep-brain stimulation of the subthalamic
nucleus, possibly due to effects on limbic areas.73
Stomach problems
Motility disorders
Recognition of impaired gastric emptying in Parkinson’s
disease is growing; prevalence ranges from 70% to 100%,
although not all affected individuals have symptoms.74
Gastroparesis can be present in both early and advanced
Parkinson’s disease, with delays in gastric emptying
more likely to be associated with solid meals.75 Nausea,
vomiting, early satiety, excessive fullness, bloating, and
abdominal distension characterise gastroparesis.76
Because levodopa is absorbed in the small intestine,
gastroparesis might result in delayed or complete loss of
benefit of the levodopa dose (figure 2).
The pathophysiological abnormalities of gastroparesis
in Parkinson’s disease probably include central and
enteric components. The DMV is involved early in the
course of disease5 and, in 6-hydroxydopamine-lesioned
animals, delayed gastric emptying is prevented by
vagotomy.77 However, involvement of the enteric nervous
system might occur even earlier in Parkinson’s disease,78
suggesting that peripheral factors also contribute to
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gastroparesis in these patients. The neuropeptide ghrelin
has a role in the modulation of gastric motility; ghrelin is
secreted when the stomach is empty, thus increasing
gastrointestinal motility in preparation for ingestion of
food. Abnormal ghrelin function might therefore be
implicated in gastroparesis in Parkinson’s disease,
suggesting that ghrelin or its receptor might be potential
treatment targets.79
Helicobacter pylori infection
The spiral Gram-negative bacterium H pylori is a highly
prevalent risk factor for peptic ulcers and gastric cancer. A
chronic systemic inflammatory response to H pylori could
be a common determinant in the onset, evolution, and
outcome of many neurological diseases, including
Parkinson’s disease. The authors of a Danish population-
based study80 reported that a diagnosis of H pylori gastritis
was associated with about a 45% increased risk of
Parkinson’s disease. The peripheral immune response,
triggered by H pylori, might disrupt the blood–brain
barrier, thus promoting microglia-mediated inflammation
and autoimmune neurotoxic effects.81 However, the
relevance of this association is unclear because many
shared risk factors for the development of H pylori
infection and Parkinson’s disease exist, and the prevalence
of H pylori in Parkinson’s disease is similar to that in the
general population.82
Strong evidence exists for a biological contribution of
H pylori to motor fluctuations in Parkinson’s disease,
owing to interference in the absorption of levodopa
(figure 3).83 Accordingly, in a diary-based study,87 H pylori
infection was associated with an increased delay in onset
of action of levodopa and decreased on-time (time during
which symptoms are adequately controlled). The findings
of a small clinical study88 did not lend support to these
results, but patients infected with H pylori were treated
with higher doses of levodopa than those not infected.
Studies investigating levodopa pharmacokinetics did not
find differences between patients with or without H pylori
infection.83,89 This inconsistency in clinical and pharma-
cokinetic findings could result from the tightly controlled
conditions of the levodopa challenge in pharmacokinetic
studies, which might not reflect the patient’s own
alimentary habits. Nevertheless, the strongest evidence
supporting a direct role of H pylori in the pathophysiological
changes associated with motor fluctuations comes from
H pylori eradication studies.
Small intestinal bacterial overgrowth
In healthy people, intrinsic mechanisms control the
number and composition of small intestine microbiota:
gastric acid destroys many bacteria entering the
stomach; biliary and pancreatic secretions limit bacterial
growth; the migrating motor complex (which has the
housekeeping function of gastrointestinal motility)
reduces luminal growth potential; the intestinal mucus
traps and fights bacteria; and the ileocaecal valve
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Review
Weight loss, iron or
vitamin deficiency
Malabsorption
Parkinson’s disease
Parkinson’s disease
H A G drugs A H
Helicobacter pylori BC
Slow gastrointestinal Small intestinal
B
motility bacterial overgrowth
Proton-pump inhibitors D
E
Motor fluctuations F
Figure 3: The complex association between Helicobacter pylori, small intestinal bacterial overgrowth, and
Parkinson’s disease
(A) H pylori and small intestinal bacterial overgrowth (SIBO) might affect the progression of Parkinson’s disease
through induction of the peripheral immune response, disruption of the blood–brain barrier, and mediation of
neuroinflammation.81,84 The dotted line represents no clear evidence. (B) H pylori and SIBO negatively affect
gastrointestinal motility by means of various mechanisms—eg, reduction in the production of ghrelin.85 (C) Slow
motility might lead to increased prevalence of SIBO.86 (D) The use of proton-pump inhibitors and hypochlorhydria
related to atrophic gastritis increases the likelihood of concomitant SIBO in patients infected with H pylori.
(E) H pylori can affect motor fluctuations by means of gastric hypochlorhydria (levodopa is highly soluble in an acidic
environment); the presence of adhesins on the bacteria surface that directly bind to levodopa; local production of
reactive oxygen species, which inactivate levodopa; levodopa acting as a nutrient for bacterial growth; impairment
of stomach motility, leading to a prolonged transit time and exposure of the drug to bacteria and enzyme activity;
and disruption of the mucosa in the small intestine, which is the main site of levodopa absorption.83 (F) SIBO can
affect motor fluctuations through levodopa malabsorption owing to changed chyme composition as a result of
mucosal injury (loss of activity of brush-border disaccharidases) or the bacterial fermentation of sugars and
deconjugation of bile acids (thus leading to the production of lithocholic acid, which is directly toxic to
enterocytes).82 (G) Parkinson’s disease affects motor fluctuations through its effects on gastric emptying
(like H pylori and SIBO). (H) H pylori and SIBO are common causes for malabsorption of important nutrients.
inhibits retrograde migration of bacteria from the colon
into the ileum.90 A prospective study86 provided evidence
for an increased prevalence of SIBO in patients with
Parkinson’s disease that was associated with the Hoehn
and Yahr stage and motor score from the unified
Parkinson’s disease rating scale. Another study focusing
on patients with fluctuating Parkinson’s disease82
showed a similar increased prevalence (55% vs 20% in
healthy controls), whereas an uncontrolled study in 103
consecutive patients noted a lower prevalence (25%),
probably due to patients having less severe disease and
exclusion of patients taking proton-pump inhibitors,
which increase the risk of SIBO in patients with
Parkinson’s disease.84
Patients with Parkinson’s disease with SIBO have been
reported to have more severe motor fluctuations (off-
time, delayed on-time, and no on-time) than those
without SIBO.82 This study also controlled for concurrent
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 Review
H pylori infection, which was linked to wearing-off
episodes and contributed with SIBO to severity of off-
time, absence of on-episodes (dose failure), and presence
of unpredictable fluctuations.82 Although the results of a
more recent study that adjusted for disease duration84 did
not confirm an association with motor fluctuations, a
significant association between SIBO and worse motor
function was identified.
Any causative link between SIBO and Parkinson’s
disease severity is difficult to ascertain. The peripheral
inflammatory state induced by SIBO might contribute to
increased intestinal permeability, thus promoting the
translocation of bacteria and endotoxins across the
intestinal epithelium, triggering microglial activation
and exacerbating the neurodegenerative process.84 There-
fore, SIBO might create a proinflammatory environ-
ment,91 as reported in newly diagnosed patients with
Parkinson’s disease, and supported by a study that
quantified local inflammation and enteric glial reaction
in gastrointestinal biopsies of patients with Parkinson’s
disease.92 Nonetheless, a clear negative effect of SIBO on
levodopa absorption is present (figure 3). SIBO might
change chyme composition as a result of mucosal injury
or the bacterial fermentation of sugars and deconjugation
of bile acids.82 SIBO might also impair drug absorption
as a result of inflammation or partial metabolism of
levodopa. SIBO might contribute to reduced gastric
emptying through inflammatory effects on entero-
chromaffin-like cells.93 As for H pylori, evidence sup-
porting a direct role of SIBO in the pathophysiological
changes associated with motor fluctuations comes from
eradication studies (see below).
Because the intestinal microbiota influence the immune
system and the absorption of nutrients, drugs, and toxic
compounds, a study was done to investigate the faecal
microbiome of 72 patients with Parkinson’s disease and
matched healthy controls.94 An under-representation of
the Prevotella-associated gut microbiome enterotype and
an abundance of Lactobacillaceae, Verrucomicrobiaceae,
Bradyrhizobiaceae, and Clostridiales incertae sedis IV
were independently associated with Parkinson’s disease.
Additionally, Enterobacteriaceae abundance was
associated with more severe axial motor symptoms. The
scarcity of Prevotellaceae is related to increased gut per-
meability and lower concentrations of vitamins such as
thiamine and folate, conditions previously reported in
Parkinson’s disease.94,95 A decreased abundance of Prevo-
tellaceae and an increased abundance of Lactobacillaceae
have also been associated with reduced concentrations of
the gut hormone ghrelin.94
Constipation
Constipation is the most common gastrointestinal
symptom in Parkinson’s disease, reported in 80–90% of
patients (table 1), and in view of its emergence long
before the onset of motor symptoms, is an especially
noteworthy gastrointestinal feature of the disease. A
630
population-based study reported that risk of
development of Parkinson’s disease increases with
constipation severity (hazard ratios ranged from 3·3 to
4·2).96 Not only is the risk increased in individuals with
constipation, but constipation is also emerging as one
of the earliest features of autonomic dysfunction in
Parkinson’s disease, developing as early as 15·3 years
before motor features.97 Thus, detection of constipation
might have potential sensitivity as a clinical biomarker
of prodromal Parkinson’s disease.
The mechanisms underlying constipation in
Parkinson’s disease are unknown. Reduced neuronal
density in the myenteric ganglion can be present in
patients with severe chronic constipation.98 However,
an absence of neuronal loss in the myenteric plexus in
Parkinson’s disease has been reported;99 in another
study,100 there was evidence of phosphorylated
α-synuclein in four of five colonic biopsy samples from
individuals with Parkinson’s disease and concurrent
chronic constipation, with no staining evident in those
with Parkinson’s disease or chronic constipation alone,
but these samples did not include investigation of the
myenteric plexus.
Constipation is a common adverse effect of many
Parkinson’s disease drugs, particularly anticholinergics
and dopamine agonists. Nevertheless, delayed colonic
transit has been reported in patients with Parkinson’s
disease independent of drugs.101 Patients might also have
dyssynergic defecation, which is characterised by the
inability, or paradoxical increase, of the pelvic floor
muscles to relax during attempted defecation. Although
dysfunction of the sacral parasympathetic nucleus and
pelvic ganglia is implicated in Parkinson’s disease, the
underlying pathogenesis of dyssynergic defecation
might involve dopaminergic dysfunction, because acute
administration of apomorphine improves symptoms of
dyssynergic defecation in a subset of patients with
Parkinson’s disease.26 Dyssynergic defecation has also
been reported in 25–30% of patients with idiopathic
chronic constipation and can be improved with bio-
feedback (pelvic floor rehabilitation training), suggesting
that maladaptive behaviour rather than an irreversible
structural defect might explain some cases.102
A practical algorithm for management
All patients with Parkinson’s disease with gastrointestinal
symptoms or with a suboptimum response to
dopaminergic drugs (possibly related to poor absorption)
should be assessed and treated (figure 4). Identification
of modifiable factors is a crucial first step in the manage-
ment of these patients. In some cases, Parkinson’s
disease treatment should be optimised—eg, because
drooling is common during off-times, treatment of
fluctuations should first be addressed, although this
must be weighed against the fact that many anti-
parkinsonian drugs can cause or exacerbate gastro-
intestinal symptoms. A multidisciplinary approach is key
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 Review

to the success of gastrointestinal management because
most of these conditions will need the coordinated
intervention of several health professionals, such as
speech pathologists, dietitians, neurologists, and gastro-
enterologists. This approach further emphasises the
importance of non-pharmacological and rehabilitative
management.
Dental problems and drooling
Because individuals with Parkinson’s disease who have
removable dentures might have difficulties mani-
pulating them, dental implants might be preferable and
should be considered earlier, rather than later, in the
course of disease.110 Treatment of drooling includes
behavioural interventions, including changes of head
position, use of swallow timers or chewing gum,111 and
pharmacological approaches (table 2).
Swallowing problems
Patients with Parkinson’s disease and dysphagia should
be considered for assessment of both oropharyngeal and
oesophageal dysphagia, guided by clinical history and
presentations. Videofluoroscopy is the gold standard in
the assessment of oropharyngeal dysfunction in patients
with Parkinson’s disease105 and an oesophageal mano-
metry study is the most accurate and sensitive test to
identify oesophageal dysmotility. Oesophageal dysphagia
has been reported in about 67% of patients with
Parkinson’s disease on the basis of oesophageal
manometry studies.106 In patients who are unable to
tolerate an oesophageal manometry study, barium
swallow can be used. Endoscopy should be considered if
structural or inflammatory lesions are suspected.
In an evidence-based review,107 preliminary evidence
was identified for the effectiveness of expiratory muscle
strength training and video-assisted swallowing therapy
for dysphagia. The role of dopaminergic drugs and
deep-brain stimulation surgery is controversial.135–137 No
studies have assessed the use of enterokinetic drugs in
oesophageal dysphagia; thus, treatment should be
dictated by the underlying dysmotility.
Malnutrition
For patients with Parkinson’s disease who have
substantial or persisting weight loss, assessment for an
alternative medical cause should be undertaken. Mal-
nutrition and its metabolic effects (vitamin deficiencies
and sarcopenia) should not be overlooked. Nutritional
intervention (individualised dietetic advice) might
contribute to improved quality of life.138
Gastroparesis
The best clinically validated assessment for gastro-
paresis is measurement of the gastric emptying time

Patients with Parkinson’s disease with gastrointestinal symptoms or suboptimal response to dopaminergic drugs

Occult infections Motility problems

Helicobacter pylori Small intestinal bacterial Dysphagia Gastroparesis Constipation

overgrowth

Assessments Assessments Assessments Assessments Assessments

• Urea breath test103 • Lactulose breath test82 • Oropharyngeal • Technetium-99-labelled • Outlet
• Stool antigen test103 • Glucose breath test82 • Videofluorography105 gastric emptying study108 • Anorectal manometry
• Serology • Jejunal aspirate90 • Oesophageal • Balloon expulsion test
• Gastroscopy83,89 • Oesophageal Treatments • Defecography109
Treatments manometry study106 • Dopamine antagonists* • Transit
Treatments • Antibiotic cycles90 • Upper gastrointestinal • 5-HT4 agonists • Radio-opaque marker
• Eradication therapies104 series barium • Macrolide antibiotics study

Treatments Treatments
• Oropharyngeal • Outlet
• Expiratory muscle • Biofeedback102
strength training • Botulium neurotoxin
• Video-assisted injection to anal
swallowing therapy107 sphincter101
• Transit102
• Fibre
• Laxatives (osmotic,
stimulant)
• Prokinetic drugs
• Secretagogues

Figure 4: A practical algorithm for the assessment of patients with Parkinson’s disease with gastrointestinal dysfunction
*All dopamine antagonists used for their anti-enteric effects (eg, metoclopramine) are contraindicated in Parkinson’s disease with the exception of domperidone.

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 Review

during the course of 4 h with a standard meal labelled
with Technetium-99.108 Treatment of gastroparesis in
Parkinson’s disease is challenging because levodopa
might delay gastric emptying. A widely used dopamine
antagonist, metoclopramide, is contraindicated in
Parkinson’s disease because it crosses the blood–brain
barrier and exacerbates motor dysfunction.
Domperidone, another dopamine antagonist, does not
cross the blood–brain barrier, but is not universally
available and increased risk of cardiac arrhythmia
needs diligent monitoring.139 The 5-HT4 receptor
agonists cisapride and tegaserod are effective, but have
been withdrawn from the market because of cardiotoxic
effects and are available only with restricted access in
some countries. Prucalopride is a newer 5-HT4 agonist
with no documented cardiotoxic effects and has been
studied in patients with chronic constipation; however,
its usefulness in gastroparesis has not been investigated.
The macrolide antibiotic erythromycin, although
effective, is not suitable for chronic use owing to drug

Dose Evidence in patients with Outcomes Side-effects

Systemic anticholinergics
Glycopyrrolate 1–2 mg twice or three times
daily
Topical anticholinergics
Sublingual atropine 0·5 mg twice daily (eg, 1 drop
of 1% atropine solution)
Sublingual ipratropium 21–42 μg (1–2 sublingual
bromide sprays) up to four times daily
Tropicamide Intra-oral films up to
3 mg, one dose
Systemic alpha-2 agonists
Clonidine 0·15 mg per day
Systemic alpha-1 agonists
Modafinil 100 mg per day
Botulinum neurotoxin serotype A and B
Onabotulinumtoxin A Parotid gland 5–50 U;
submandibular gland 5 U
Abobotulinumtoxin A Parotid gland 75–146·2 U;
submandibular gland 78·7 U
Rimabotulinumtoxin B Parotid gland 500–2000 U;
submandibular gland 250 U
Parkinson’s disease
4-week randomised double-blind,
placebo-controlled crossover trial in
23 patients112
1-week open-label study in six
patients114
5-week randomised double-blind,
placebo-controlled, crossover study in
17 patients115
Single-dose pilot study with a
randomised double-blind,
placebo-controlled, crossover design in
12 patients116
12-week double-blind,
placebo-controlled study in
32 patients117
A study in patients with Parkinson’s
disease and Hoehn and Yahr grade 2–3
with moderate to severe drooling;118
study type not available
A case series;119 three open-label
studies;120–122 an open-label case-control
study;123 a randomised
placebo-controlled study;124 and
a randomised double-blind,
placebo-controlled study125
A case series;127 two randomised
double-blind, placebo-controlled
studies;128,129 and a randomised
double-blind, crossover trial compared
with rimabotulinumtoxin B126
Two open-label studies;130,131 three
randomised double-blind,
placebo-controlled studies;132–134 and
a randomised double-blind, crossover
trial compared with
abobotulinumtoxin A126
Significant change in
sialorrhoea scoring scale
Improvement in objective
and subjective measures
No improvement in objective No difference from placebo
evaluation (primary (blood–brain barrier not
endpoint) but improvement crossed)
in subjective ratings
A non-significant
improvement was seen in
the 0·3 mg and 1 mg dosage
groups
Significant improvement of
the frequency of clearing
saliva
Reduction in drooling
severity score and
patient-reported
improvement
Similar positive outcomes for
botulinum neurotoxin A
(abobotulinumtoxin A) and
botulinum neurotoxin B, but
a faster effect after
botulinum neurotoxin B,
probably in view of an
increased affinity of
rimabotulinumtoxin B for
autonomic terminals126
No difference from placebo
(blood–brain barrier not
crossed); behavioural changes
reported in children and young
adults with cerebral palsy;113
could cause peripheral
side-effects (eg, constipation)
Can cross the blood–brain
barrier, producing the same
side-effects as systemic
administration, including
confusion114
No difference from placebo
Diurnal somnolence, dizziness,
and dry mouth
Positive effect on drooling
might be related to the
improvement of dysphagia22
Safe; only minimum side-
effects reported—dryness of
mouth and increased saliva
viscosity, which might depend
on the distribution of
botulinum neurotoxin in the
major salivary glands

Table 2: Pharmacological treatments for drooling in patients with Parkinson’s disease

632 www.thelancet.com/neurology Vol 14 June 2015

 Review

interactions and QT prolongation, and studies have
suggested that azithromycin might be a preferable
alternative.140 Further research is needed to assess the
clinical efficacy of nizatidine, a selective histamine
H2 receptor agonist,141 and ghrelin agonists.142
Botulinum neurotoxin injections into the pyloric
sphincter have been anecdotally reported to ameliorate
gastroparesis in patients with Parkinson’s disease, but
extensive investigation in patients without Parkinson’s
disease but with gastroparesis has not shown a clear
benefit.143 Improvement in gastric emptying after deep-
brain stimulation of the subthalamic nucleus has been
reported,144 but needs further study. Finally, although not
studied in patients with Parkinson’s disease, gastric
electrical stimulation might be effective in refractory
cases.145
Infections
Helicobacter pylori
Non-invasive tests for H pylori infection include the urea
breath test, the stool antigen test, and serological tests.
The positive predictive value of H pylori serological tests
is highly variable and dependent on the pre-test
probability of H pylori infection in the patient population;
the test can also remain positive long after H pylori
eradication. In patients who present with foregut
symptoms, gastroscopy is helpful to detect an active
H pylori infection and to quantify the severity of gastritis,
which is proposed to affect levodopa absorption.83,89 The
urea breath test and stool antigen test can be used to
assess continued infection after eradication therapy.103
The positive effect of eradication of a gastrointestinal
infection on the promotion of levodopa absorption was
originally described in one patient with Parkinson’s
disease with duodenitis caused by Strongyloides
stercoralis.146 The effect of H pylori eradication on motor
fluctuations has been confirmed in a double-blind
study;89 the improvement in motor fluctuations was
greater after 3 months than in shorter-term follow-up,
suggesting a time-dependent decrease in H pylori-related
inflammatory changes in gastrointestinal mucosa.87
Several meta-analyses and systematic reviews104 have
yielded inconsistent conclusions as to which first, second,
or third-line combination regimen is the most effective to
eradicate infection. The triple therapy regimen (proton-
pump inhibitors, amoxicillin 1 g [metronidazole 500 mg if

Rationale with regard to gastrointestinal Highest level of evidence Advantages Disadvantages

dysfunction
Orally dissolving levodopa Easily administered in patients with
swallowing difficulties (orally
disintegrating levodopa is swallowed with
saliva)
Levodopa methyl ester The liquid formulation limits the effect of
(melevodopa) delayed gastric emptying
effervescent tablets
Dispersible levodopa The liquid formulation limits the effect of
delayed gastric emptying
Levodopa-carbidopa Levodopa is delivered into the jejunum;
intestinal gel bypassing the stomach ensures a rapid and
reliable onset of action
Apomorphine Subcutaneous delivery of a strong
dopamine agonist, bypassing the
gastrointestinal system; can be given either
with intermittent (pen-jet) or continuous
infusion (micro-pump)
Rotigotine patch Subcutaneous delivery of a dopamine
agonist, bypassing the gastrointestinal
system
Deep-brain stimulation of Direct targeting of basal ganglia
the subthalamic nucleus dysfunction
Single-dose, double-blind, Can be taken without water
double-dummy, crossover study
in 20 patients 156
Randomised double-blind,
double-dummy, controlled
parallel-group trial in
221 patients157
Open-label crossover trial in
eight patients158
Randomised double-blind,
double-dummy trial
in 66 patients162
Double-blind, single-dose,
crossover trial in 62 patients160
Randomised double-blind,
controlled study of the
rotigotine patch vs placebo and
ropinirole in 561 patients159
Randomised controlled study of
deep-brain stimulation vs best
medical therapy in
251 patients161
Improvement of afternoon dose
failures (increased bioavailability and
decreased time to onset) compared
with standard levodopa163,164
Fast onset of action
Significant reduction of off-episodes
and disabling dyskinesias; simplification
of oral treatment, with reduction of
dopaminergic side-effects165
Effectively aborts off-episodes as a
rescue treatement;167 continuous
infusion reduces motor fluctuations
and dyskinesias168
Improvement of non-motor
symptoms; reduced incidence of
psychiatric complications;169 good
strategy when oral therapy cannot be
used (eg, pre-surgery and post-surgery)
Significant reduction of off-episodes
and disabling dyskinesias; reduction of
oral medications mainly possible with
deep-brain stimulation of the
subthalamic nucleus but not the globus
pallidus interna161,170
Not a true sublingual preparation;
absorbed in the gastrointestinal tract
rather than through the oral mucosa; only
a small pilot study is available with no
significant group differences156
No improvement of total off-time
besides a statistical trend (p=0·07)157
Few good-quality studies, pulsatile and
erratic delivery, and poor solubility in
water
Levodopa undergoes competition with
dietary aminoacids for transport across
the blood–brain barrier;166 high rate of
percutaneous endoscopic gastrostomy
complications; not approved for 24 h
continuous infusion
Few good-quality studies for continuous
infusion; side-effects might be both local
(subcutaneous nodules) and systemic
(nausea, hypotension, psychosis)
High rate of reactions at the application
site
Surgical risk (bleeding); postoperative
depression and suicide;
stimulation-induced side-effects
(hyphophonia)

Table 3: Treatments designed to account for the presence of gastrointestinal dysfunction in patients with Parkinson’s disease

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 Review
allergic to penicillin], and clarithromycin 500 mg twice
daily for 7 days) has been proposed as the first-line
treatment for H pylori eradication103 and has also been
used in patients with Parkinson’s disease. A meta-
analysis147 showed that lengthening the treatment duration
(7 days vs 10 days vs 14 days) increases the eradication rate
with only a marginal increase in adverse events between
7 days and 14 days, but the eradication rate did not differ
between 10 days and 14 days. The treatment course of
choice will depend on regional pharmacotherapy
availability, local H pylori antibiotic resistance profile, and
patient tolerability. Of note, quinolone-based therapy
should be used with caution owing to the risk of adverse
CNS effects in elderly people.148
Small intestinal bacterial overgrowth
Although the gold standard for the diagnosis of SIBO is
colony counts of cultured jejunal aspirate, this method is
invasive and its diagnostic reliability is highly variable.90
The lactulose breath test and the glucose breath test,
measuring breath hydrogen after oral administration of
lactulose or glucose, are widely used in clinical studies of
SIBO. Some patients with SIBO harbour microbiota that
produce methane gas rather than hydrogen (eg,
Staphylococcus aureus, Streptococcus viridans, Enterococci,
Serratia, or Pseudomonas). Thus, use of the glucose
breath test and the lactulose breath test to measure both
hydrogen and methane has been suggested to increase
the accuracy of diagnosis of SIBO.82
A intestinal symptom in patients with Parkinson’s disease,
D Results from an open-label observational study in ten
B laxative (macrogol 3350) was efficacious.150 A 2-week
E activator, is efficacious without substantial adverse effects,
C showed promise in the treatment of constipation in
Figure 5: Treatment options developed to bypass gastrointestinal
dysfunction in patients with Parkinson’s disease
(A) Liquid levodopa formulations, in the form of dispersible levodopa or soluble
melevodopa, might enable more rapid onset of drug action than standard
formulations.156–158 Parenteral administration routes including (B) the rotigotine
patch and (C) subcutaneous apomorphine are marketed in many countries.159,160
(D) Deep-brain stimulation of the subthalamic nucleus allows a reduction in
levodopa equivalent daily dose of about 50%, which might decrease
gastrointestinal related side-effects.161 (E) The stomach can be bypassed by
intrajejunal infusion of a levodopa-carbidopa gel through a tube inserted into a
percutaneous endoscopic gastrostomy.162
634
Eradication of SIBO improved motor fluctuations (off-
time and delayed on-time) without affecting the
pharmacokinetics of levodopa in an open-label study of
rifaximin 200 mg three times a day for 1 week.82 No
adverse effects related to the antibiotic therapy were
reported and 14 of 18 patients did not have SIBO after
1 month. However, in view of the persistence of
underlying predisposing factors (ie, the presence of
Parkinson’s disease), the rate of SIBO relapse at
6 months was, unsurprisingly, high, occurring in 6 of
14 individuals compared with 22 of 80 in another study
in patients without Parkinson’s disease.149
Many different antibiotic regimens have been advocated
for SIBO, including ciprofloxacin, metronidazole, neo-
mycin, norfloxacin, and doxycycline, with no consensus
about the most efficacious dose or duration of treatment.90
The common antibiotic treatment cycle is 1–2 weeks every
1–3 months based on clinical response. When available,
rifaximin (a non-absorbed rifamycin analogue) has the
most favourable tolerability.
Constipation
In patients with chronic constipation, a thorough history
and digital rectal examination is helpful to differentiate
colonic transit abnormality versus dyssynergic de-
fecation.102,109 The usefulness of the radio-opaque marker
study for colonic transit measurement, and of anorectal
manometry, the balloon expulsion test, and defecography
have been described in patients with idiopathic chronic
constipation.109 However, none of these motility tests
have been validated in patients with Parkinson’s disease.
Although constipation is the most common gastro-
trials to assess efficacy of various drugs have been scarce.
patients with Parkinson’s disease showed that an osmotic
randomised, placebo-controlled trial in 54 patients showed
that lubiprostone, a secretagogue and chloride channel
although nausea is common.151,152 Cisapride and tegaserod
Parkinson’s disease, but have been withdrawn because of
concerns about cardiotoxic effects.153 Prucalopride, an
enterokinetic drug with the same mechanism of action as
cisapride and tegaserod, and linaclotide, a guanylate
cyclase C agonist luminally active and minimally absorbed
gastrointestinal secretagogue, have not been studied in
patients with Parkinson’s disease.154 In view of the few
trials in patients with Parkinson’s disease with
constipation and transit dysfunction, we recommend use
of the same treatment algorithm as in patients with
idiopathic chronic constipation.102,109 In patients with
dyssynergic defecation,155 although botulinum neurotoxin
injections into the anal sphincter have been recom-
mended,101 further study is needed before recommending
this approach as standard practice.
www.thelancet.com/neurology Vol 14 June 2015

Bypassing the gastrointestinal tract
Gastrointestinal dysfunction clearly plays a part in the
development of motor fluctuations and dyskinesia in
Parkinson’s disease. Therefore, treatment options partly
or completely bypassing the gastrointestinal tract have
been developed (table 3 and figure 5). Because
absorption of levodopa in tablet form is affected by
unpredictable gastric emptying time (figure 2), many
liquid levodopa formulations have been developed and
are commercially available (table 3). Another alternative
is orally dissolving levodopa (swallowed with saliva), but
levodopa absorption still depends on the function of the
proximal intestine, and thus requires an intact small
bowel.171 Therefore, parenteral routes have been
investigated (table 3 and figure 5). The stomach can be
bypassed with functional neurosurgery, rotigotine trans-
dermal patch, apomorphine subcutaneous infusion or
injection, or a percutaneous endoscopic gastrostomy
with jejunal tube for intrajejunal levodopa infusion,162
making treatment possible in patients with severe
swallowing problems. Many patients nowadays are
started on parenteral treatment using rotigotine.
However, monotherapy with dopamine agonists often
does not suffice when motor signs progress. Thus, novel
levodopa formulations are already under development:
microspheres for drug delivery and esters or alkyl esters
for transdermal, intranasal, subcutaneous, or intra-
muscular administration, and microenemas for rectal
administration.
Conclusions
Understanding of the pivotal role of the gastrointestinal
system in the pathophysiology and possibly also the
cause of Parkinson’s disease has grown substantially
during the past decade. Although some progress has
been made in the development of effective treatments
for gastrointestinal dysfunction in these patients, much
remains to be accomplished. More effective treatment
modalities for dysphagia are sorely needed. Problems
with potential cardiotoxic effects have impeded the
introduction of effective medical treatments for
gastroparesis. However, newer drugs, such as the ghrelin
agonist relamorelin, hold great promise if positive
results in patients with diabetic gastroparesis can be
replicated in patients with Parkinson’s disease.172
Relamorelin is being assessed in a multicentre clinical
trial in patients with Parkinson’s disease and chronic
constipation, and effects on gastroparesis will also be
assessed in this study (ClinicalTrials.gov, NCT01955616).
Although various drugs are available for the treatment of
slow-transit constipation, more effective prokinetic
agents, such as relamorelin, are still needed. Additionally,
more research is needed into effective treatments for
dyssynergic defecation.
The potential roles of H pylori infection and SIBO in
the development of gastrointestinal dysfunction in
Parkinson’s disease might allow new treatment
www.thelancet.com/neurology Vol 14 June 2015
Review
Search strategy and selection criteria
We identified references for this Review from searches of our
personal files and textbooks. We also searched PubMed for
papers published in English from Jan 1, 1965, to Jan 26, 2015,
with the search terms “gastrointestinal dysfunction”, “weight
loss”, “dysphagia”, “gastroparesis”, “gastric emptying”, “small
intestine”, “colon”, “anorectal”, “dental”, “drooling”, “taste”,
“burning mouth”, “dry mouth”, “nutrition”, “helicobactor
pylori”, “small intestinal bacterial overgrowth”,
“constipation”, and “enteric synuclein” coupled with the term
“Parkinson’s disease”. We selected the final list of references
on the basis of specific relevance to this Review and focused
on advances from the past 10 years.
approaches, although the association between infection
status and motor function or response to treatment is
not straightforward and, in view of their high incidence
in the ageing population, H pylori and SIBO might be
unrelated to Parkinson’s disease. Future studies with
improved diagnostic capabilities should allow an
accurate estimation of prevalence. An improved
understanding of the interaction between H pylori and
SIBO is needed because the likelihood of concomitant
SIBO is very high in patients infected with H pylori and
some effects related to H pylori eradication might be
caused by concomitant SIBO eradication.82,89
Additionally, because only 10% of patients with
continuing H pylori infection have signs of atrophic
gastritis, future studies stratifying participants in
different subgroups should be undertaken.173 The roles
of hybrid and super-optimised H pylori eradication
therapies and probiotics also need to be explored.
Research into alternative routes of administration of
levodopa formulations that bypass the gastrointestinal
tract are underway, and potential innovations include
microspheres for drug delivery and esters or alkyl esters
for transdermal, intranasal, subcutaneous, and intra-
muscular administration, and microenemas for rectal
application. In the coming years, our understanding of
gastrointestinal dysfunction in Parkinson’s disease will
hopefully continue to accelerate and lead to improved
treatment strategies for patients.
Contributors
All authors contributed to the writing of the first draft of the manuscript
and editing thereafter.
Declaration of interests
AF has received honoraria from UCB, Medtronic, Boston Scientific,
Abbvie, and Teva Canada. LWCL has received honoraria from Abbvie,
Actavis Canada, Forest Laboratories Canada, and Takeda Canada. AEL
has served as an adviser for Abbvie, Allon Therapeutics, Avanir
Pharmaceuticals, Biogen Idec, Boerhinger Ingelheim, Ceregene, Lilly,
Medtronic, Merck, Novartis, NeuroPhage Pharmaceuticals, Teva, and
UCB; has received honoraria from Medtronic, Teva, UCB, and Abbvie;
has received grants from Brain Canada, Canadian Institutes of Health
Research, Edmond J Safra Philanthropic Foundation, the Michael J Fox
Foundation, the Ontario Brain Institute, National Parkinson
Foundation, Parkinson Society Canada, Tourette Syndrome Association,
635
 Review
and the W Garfield Weston Foundation; and has served as an expert
witness in cases related to the welding industry. RFP has received
honoraria from Teva, UCB, and US WorldMeds for lectures; from
Pfizer, Chelsea, and Acadia for consulting; and from UCB for research
grants and contracts. NPV declares no competing interests.
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