Parkinsonism and Related Disorders 55 (2018) 18–25

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Parkinsonism and Related Disorders

journal homepage: www.elsevier.com/locate/parkreldis

Review article

Gastric emptying in Parkinson's disease – A mini-review T

∗
Karoline Knudsen , Martha Szwebs, Allan K. Hansen, Per Borghammer
Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Denmark

A R T I C LE I N FO A B S T R A C T

Keywords: Patients with Parkinson's disease (PD) experience a range of non-motor symptoms, including constipation and
Parkinson other gastrointestinal problems. These symptoms are sometimes present in the prodromal disease phase. An
Gastric emptying improved understanding of the underlying pathophysiology is needed considering that PD has been hypothe-
Non-motor symptom sized to originate in the gut. Delayed gastric emptying time (GET) is often listed as a prevalent gastrointestinal
Scintigraphy
symptom in PD, but the true prevalence is controversial.
Breath test
The aim of this short review was to investigate if GET in PD is dependent on the applied measuring meth-
odology. A systemic search of Pubmed identified 15 relevant studies, including six using gold standard method
gastric scintigraphy and nine using 13C-octanoate breath tests. Overall, gastric scintigraphy studies showed a
non-significant GET delay (standardized mean difference (SMD) 0.42) in PD patients. After exclusion of one
outlier study, GET was significantly increased (SMD 0.59). In contrast, highly significant GET delay (SMD 1.70)
was seen in breath test studies. A limitation of the meta-analyses was reuse of the same control group in some
studies. In summary, the marked GET delay observed in breath test studies is not confirmed by gold standard
gastric scintigraphy studies. This discrepancy can perhaps be explained by breath test being an indirect GET
measure, depending not only on mechanic stomach emptying but also intestinal absorption and liver metabo-
lism.
Thus, multi-modality studies under standardized conditions are needed to elucidate the prevalence and se-
verity of gastric dysmotility in PD, along with contributions from other factors including intestinal absorption
and permeability.

1. Introduction GI infections, microbiota, and other features, be triggers of such initial

Parkinson's disease (PD) is characterized by the presence of brady-
kinesia, rigidity, and tremor. However, the majority of PD patients
experience numerous non-motor symptoms (NMS) often several years
prior to diagnosis, including olfactory dysfunction, REM sleep behavior
disorder (RBD), and depression [1,2]. Moreover, NMS from the cardi-
ovascular, urogenital, gastrointestinal (GI), and thermoregulatory sys-
tems are also frequent, and most are probably related to dysfunction of
the autonomic nervous system [3].
These NMS are becoming increasingly important in the context of
early prodromal PD diagnosis, and they are also intricately associated
with the progression of the disease [1]. Moreover, the Braak hypothesis
posits that PD pathology in the form of aggregated α-synuclein may in
some cases originate in the olfactory bulb and peripheral GI para-
sympathetic nerve terminals, with secondary spreading to the brain-
stem through the autonomic nervous system [4]. Environmental factors
such as pesticides and toxins could, in addition to genetic vulnerability,
α-synuclein pathology formation [5–7]. Thus, an improved under-
standing of GI dysfunction is crucially needed to advance research into
etiopathogenesis of PD.
Several symptoms, believed to be caused by gastroparesis, have
been reported in PD patients, including nausea, fullness, and bloating,
and also, erratic gastric emptying may contribute to motor fluctuations
[8]. Two different methods are generally used to objectively estimate
gastric emptying time (GET). The gold standard scintigraphic method
evaluates GET after ingestion of a standardized radioactive meal [9].
This method yields a simple measure of biomechanical emptying of
stomach contents, and is relatively insensitive to patient movements
including dyskinesias. However, GET scintigraphy requires specialized
equipment and trained personnel, and exposes the patient to radiation
[10]. The alternative breath test was introduced as an indirect measure
of GET. In short, a meal containing 13C-Sodium Octanoate is ingested
and passes the stomach. The 13C-Sodium Octanoate is rapidly absorbed
from the intestine, and metabolised by hepatocytes. The time-

Abbreviations: GE, Gastric emptying; GET, Gastric emptying time; GI, Gastrointestinal; H&Y, Hoehn & Yahr; NMS, Non-motor symptoms; PD, Parkinson's disease; RBD, REM sleep
behavior disorder; SMD, Standard mean difference; T1/2, Half-emptying time
∗
Corresponding author. Department of Nuclear Medicine and PET Centre, Noerrebrogade 44, building 10 G, 6th floor, DK-8000, Aarhus C, Denmark.
E-mail address: karoknud@rm.dk (K. Knudsen).

https://doi.org/10.1016/j.parkreldis.2018.06.003
Received 26 February 2018; Received in revised form 30 April 2018; Accepted 3 June 2018
1353-8020/ © 2018 Elsevier Ltd. All rights reserved.
K. Knudsen et al.
dependent 13C-CO2/12C-CO2 ratio is then quantified in exhaled air.
Gastric emptying (GE) is defined as the rate-limiting step in the process,
but there are several additional contributing factors like small intestinal
motility and absorption as well as liver metabolism, which could po-
tentially impact the outcome [11–14]. Studies using these two methods
to assess GET in PD patients have shown somewhat contradictory re-
sults [15,16]. This raises the question, whether breath test and scinti-
graphy can be considered interchangeable measures of the same un-
derlying pathology in PD. Here, we review the available GET literature
in PD and present meta-analyses of published studies, which used either
gastric scintigraphy or breath tests.
2. Methods
During August 2017, Pubmed was searched using the following
terms “Parkinson's disease”, “gastric emptying”, “gastric scintigraphy”,
and “breath test”. The search was limited to English studies and the
inclusion criteria were (1) Parkinson's disease (2) GE scintigraphy (3)
GE breath test (4) a matched, representative control group. Only studies
with non-selected, representative patient groups were included. Studies
deliberately recruiting patient samples with overrepresentation of GI
symptoms and patients with motor fluctuations, believed to be caused
by erratic gastric emptying, were excluded. Results are presented as
mean ± SD. In cases where GET parameters were reported as median
and range, these were converted to an estimate of mean and SD [17].
The following data was extracted from each study: (1) method; (2)
sample size; (3) disease duration; (4) Hoehn & Yahr stage; (5) medi-
cation on/off at test; (6) emptying time parameters. Missing data from
Trahair et al. 2016 and Gjerløff et al. 2015 were obtained from the
corresponding authors [18,19].
2.1. Statistical analysis
Analyses and forest plots were performed using STATA 13 (College
Station, TX: StataCorp LP). Due to clinical and methodological diversity
between studies, the random-effect model was used. The level of het-
erogeneity in meta-analyses signifies the degree of variability in accu-
racy estimates. Thus, heterogeneity across studies was evaluated by chi-
square test and I2 (I2 = 0%; no heterogeneity, I2 < 30%; mild hetero-
geneity, 30% < I2 < 50%; moderate heterogeneity, and I2 > 50%;
substantial heterogeneity) [20]. Statistical significance was defined as
p < 0.05. The effect size, representing the difference in GET between
PD patients and controls, is presented as standardized mean difference
(SMD), since SMD is independent of the unit of measurement [21]. In
this review, a positive SMD represents delayed gastric emptying in the
PD group in a given analysis. The following interpretation of SMD has
been proposed: SMD = 0.2; small effect size, SMD = 0.5; medium effect
size, SMD = 0.8; large effect size [22].
3. Results
According to the search strategy, a total of 160 studies were iden-
tified, and 139 studies were excluded, as they did not include GET data
in PD patients. An additional six studies were excluded due to not
meeting inclusion criteria; four studies did not include a control group
[23–26] and two studies recruited highly selected PD patients, who
showed normal and delayed GET, respectively, and reported bloating
and constipation symptoms [27,28]. Thus, 15 studies were included in
the analyses (Table 1) [3,11,12,16,18,19,29–38]. One study subgroup
of PD patients from Djadetti et al. all experienced motor fluctuations
and was excluded. In the study by Tanaka from 2009, PD patients were
divided in two subgroups with- and without motor fluctuations. The
fluctuation subgroup was considered selected and thus excluded from
the analyses. In the Tanaka study from 2011, data from 40 late stage
patients were previously published in the 2009 study and therefore
excluded from the analyses. Five scintigraphy studies applied solid
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Parkinsonism and Related Disorders 55 (2018) 18–25
meals, and one study used a liquid meal. Five breath test studies applied
solid meals, and five studies used liquid meals. All studies presented
results as gastric half-emptying time (T1/2) except Shiina 2015 and
Tateno 2015, who reported data as peak time of the 13CO2/12CO2 ratio
(Tmax).
3.1. Scintigraphy versus breath test
Forest plots from meta-analyses of all scintigraphic studies com-
bined are presented in Fig. 1A. The analysis showed a non-significant
small-to-medium effect size GET delay in PD patients compared to
controls (SMD 0.42; CI (95%): −0.02, 0.87; p = 0.064). Two of seven
patient groups exhibited significantly delayed T1/2-GET, and one group
approached significance. A substantial amount of between-study het-
erogeneity was seen (70.1%). The study by Gjerløff and colleagues was
unusual in that the PD group showed decreased GET compared to HC.
Thus, we performed a post hoc analysis after excluding this study. The
remaining studies showed a significant delay of SMD 0.59 (CI (95%):
0.23, 0.95; p = 0.001) and a moderate heterogeneity of 48.5% (sup-
plementary Figure 1).
Forest plots from the meta-analyses of all breath test studies com-
bined are depicted in Fig. 1B. The analysis showed a very large effect
size and significant difference of SMD 1.70 (CI (95%): 1.16, 2.23;
p < 0.0001). Ten of 11 patient groups showed significantly delayed
GET in the individual study, but a substantial amount of heterogeneity
was also seen in these studies (84.9%). Exclusion of the two studies,
which presented GET data as Tmax did not change the overall result
(SMD: 1.86; CI (95%): 1.22, 2.50; p < 0.0001; I2 = 86.8%).
3.2. Solid versus liquid meal
Among scintigraphy studies, only Trahair 2016 used liquid meal,
and no significant GET delay was seen in this study. No significant GET
delay was found when combining all solid meal scintigraphy studies
(SMD: 0.47; CI (95%): −0.06, 0.99; p = 0.081; I2 = 73.7%), except
after exclusion of the aberrant Gjerløff study (SMD: 0.68; CI (95%):
0.29, 1.07; p = 0.001; I2 = 47.2%).
A subgroup analysis of the breath test studies using solid meals
showed a large significant effect size (SMD: 1.73, CI (95%): 1.15, 2.31;
p < 0.001; I2 = 74.4%) (Fig. 2A). The liquid meal breath test studies
showed a similar large SMD of 1.68 (CI (95%): 0.72, 2.63; p = 0.001;
I2 = 90%) (Fig. 2B).
3.3. Disease stage
We divided PD patients into early and late disease stage using a cut-
off value of ≤mean 6.5 years disease duration or Hoehn & Yahr stage
(H&Y) ≤2.5.
Among the scintigraphic studies, these cut-offs defined five studies
of early stage PD (eliminating Krygowska-Wajs, 2009 and the late-stage
PD subgroup from Hardoff, 2001). Compared to controls, no overall
delay in GET was seen in these early PD groups (SMD: 0.39; CI (95%):
−0.28, 1.05; p = 0.252; I2 = 79.7%), unless the Gjerløff study was
excluded (SMD: 0.66; CI (95%): 0.10, 1.21; p = 0.021; I2 = 67.4%).
Isolated analyses of solid meal studies did not change the result in any
of the cases. Since only two scintigraphic studies had investigated late-
stage PD patients, this was considered insufficient to perform a separate
analysis [30,31].
Among the breath test studies, the cut-offs defined ten data sets of
early-stage PD groups, and a highly significant GET delay was revealed
in these studies (SMD: 1.66; CI (95%): 1.13, 2.18; p < 0.001;
I2 = 81.2%). The results did not change significantly when separating
breath test studies of early PD patients into liquid- and solid meal, re-
spectively. Data from late-stage PD patients were only available from
the Tanaka 2009 study and two subgroups from the Goetze 2005 and
2006 studies. These data were considered insufficient to conduct a valid
K. Knudsen et al. Parkinsonism and Related Disorders 55 (2018) 18–25

Table 1
Demographic data and scintigraphic/breath test gastric emptying time (minutes) from studies of PD patients and healthy controls (HC).

N; number of patients, SD; standard deviation, H&Y; Hoehn & Yahr stage, DD; disease duration, On/off med; PD patients studied without/after withdrawal of
antiparkinsonian medication. Shaded areas mark studies including same HC reference groups.

20
K. Knudsen et al.
Fig. 1. A. Forest plot of all included studies using gastric emptying scintigraphy. B. Forest plot of all included studies using gastric emptying breath test.
SMD = standardized mean difference.
meta-analysis of late stage PD patients.
4. Discussion
The present analyses of available studies suggest that GE is delayed
in some PD patients. The tendency was present in all but one scinti-
graphy study, although a significant GET delay was seen only in two out
of seven individual papers. In contrast, a highly significant delay was a
much more robust finding in studies using breath test methodology,
where ten of 11 individual studies reported significantly delayed GET.
21
Parkinsonism and Related Disorders 55 (2018) 18–25
The included studies displayed several methodological differences, in-
cluding variations in inclusion criteria, meal composition, and patients
being on or off anti-parkinsonian treatment during GET evaluation.
These issues probably contributed to the substantial heterogeneity ob-
served in both scintigraphy and breath test studies. The validity of
combining such studies in meta-analyses can be questioned, and the
SMD values should be treated with some caution and mainly inter-
preted as an overall estimate of outcome differences. Nevertheless, the
present meta-analyses strongly suggest that scintigraphy and breath test
studies in PD patients are simply not comparable, and probably do not
K. Knudsen et al.
Fig. 2. A. Forest plot of studies using solid meal gastric emptying breath test. B. Forest plot of studies using liquid meal gastric emptying breath test.
SMD = standardized mean difference.
measure the same thing.
In all analyses, a large and substantially higher effect size was seen
for breath test studies compared to results from scintigraphic metho-
dology. Scintigraphy allows a direct and simple measure of mechanical
GE, whereas the breath test method involves several steps, including
mechanical GE, small intestinal absorption, and liver metabolism. It has
been shown that the majority of PD patients exhibit significantly de-
layed colonic transit time [16]. Also, small intestinal transit time is
significantly delayed in PD, although with larger variation among in-
dividual patients [39–41]. In addition, small intestinal bacterial
22
Parkinsonism and Related Disorders 55 (2018) 18–25
overgrowth has been reported in a significant fraction of PD patients
[42–44]. Thus, it could be hypothesized that small intestinal motility,
absorption, bacterial overgrowth, and perturbed liver metabolism of
fatty acids might all contribute to biased assessments of gastric emp-
tying time when using breath tests.
As mentioned, solid meal scintigraphy is considered the gold stan-
dard method for GET evaluation [9]. Thus, alternative methods should
be validated according to this standard. Choi et al. previously compared
solid meal breath test and gastric scintigraphy in healthy individuals
and reported considerable between-method variability. Also, breath test
K. Knudsen et al.
results could not be adjusted by a single constant according to scinti-
graphy GET data. In a later study by the same group, increased sam-
pling time resulted in a weak between-method correlation. Moreover,
breath test and scintigraphic results were reproducible within subjects,
but substantial between-method variation was seen [14,45]. Another
study performed GET scintigraphy and breath test in patients with
functional dyspepsia and found an average between-method GET dif-
ference of 58 min [10]. Of note, the examinations in the latter study
were performed on separate days. Nevertheless, the available evidence
suggests that the two methods are not always comparable, which may
be particularly true for disorders in which dysfunction is present in both
stomach and small intestinal motility and absorption.
In addition, previous studies have demonstrated intestinal in-
flammation and changes in permeability for pro-inflammatory bacteria
and endotoxins in PD patients, probably resulting in small intestinal
dys-absorption [46–48]. This might also potentially affect the absorp-
tion mechanism related to the breath test method. Therefore, studies
are needed which employ both scintigraphy and breath test GET in
addition to validated measures of intestinal absorption and motility in
PD patients.
Alternative methods for gastric emptying and motility assessment
like real-time MRI and ultrasonography has also been explored [42,49].
Also, novel endo-capsule methods have been introduced, having the
advantage of studying not only the stomach but also the individual
intestinal segments during a single examination [50,51]. These
methods need further validation in PD patients, but they hold potential
as non-radioactive markers of gastric emptying and motility.
4.1. Composition of test meal
Differences in liquid and solid meal formulations probably influence
GET results, and solid meal is generally considered the gold standard.
Only one scintigraphy study used liquid meal, but eliminating these
data did not change the overall SMD outcome. Also, division of breath
test studies into liquid and solid meal did not disclose differences in
overall SMD of GET delay in PD patients. Nevertheless, the significant
heterogeneity between studies should be considered, and these results
taken with caution.
Previous data have, however, shown contradicting results. Ziessman
and colleagues compared both solid and liquid meal GET scintigraphy
in healthy subjects and showed longer liquid GET [52]. Of note, the
liquid meal was ingested 30 min prior to the solid meal and not si-
multaneously, which could have influenced physiological gastric mo-
tility and induced a non-fasting state for the solid meal. The included
study by Goetze from 2006 evaluated both solid and liquid meal breath
test in PD patients compared to controls and found solid meal delay in
88% and liquid meal delay in only 38% of the patients [32]. However,
each meal composition was evaluated in separate subject groups, which
does not allow a direct comparison of results. It has also been shown
that caloric density and GET are positively correlated, as increased
caloric content probably promotes a slowing in gastric emptying rate
[53,54].
In summary, well-designed studies in PD patients are needed to
evaluate potential differences in meal composition using both the
scintigraphic and breath test method.
4.2. Medication status of patients
The included studies were highly heterogenous with respect to PD
medication status during GET examination. The majority of studies
showed delayed GET in PD patients. However, it is still not known if
this delay is caused by long-term levodopa treatment, disease involve-
ment, or a combination of both.
Even though previous studies of both young and elderly volunteers
reported a significant GET delay after levodopa administration [55,56],
the results from PD patient groups does not seem to consistently support
23
Parkinsonism and Related Disorders 55 (2018) 18–25
this finding. One scintigraphy study examined PD patients in the
medication on-state and found no significant difference in GET com-
pared to controls [16]. Also, Hardoff and colleagues did not detect
significant GET differences between treated and untreated PD patients,
and the same was evident when dividing the patients into groups of
mild and moderate disease stage [30]. Moreover, Shiina et al. in-
vestigated a group of drug-naïve PD patients before and approximately
1.5 years after initiation of levodopa treatment and found no difference
in breath test GET [37]. Also, the Gjerløff study reported accelerated
scintigraphic GET in moderate disease stage PD patients after a > 12-h
medication withdrawal period [19]. Participants in this study were
examined according to the exact same protocol as the study of early-to-
moderate disease stage PD patients by Knudsen and colleagues, but the
latter group was examined in the on-medication state [16].
To summarize, the potential GET effect of levodopa treatment is still
not fully understood and needs further investigation.
4.3. Disease stage
Only a few studies of later stage PD patients have been published.
Considering the potential bias caused by the type of methodology used,
it is unclear to what degree gastric dysmotility is exacerbated with
disease progression. The present analyses showed no difference in effect
size for any of the two methods when eliminating late-stage PD sub-
groups. However, this does not rule out that gastric dysmotility may
progress in advanced disease stages, and more data is needed to es-
tablish this issue.
Looking at the individual studies, Hardoff et al. did not find any
difference in scintigraphy GET between early and later stage PD pa-
tients [30]. In contrast, the two studies by Goetze and colleagues
showed a significant increase in breath test GET in later stage patients.
This was, however, only evident when applying solid meal, and no
differences according to disease stage was seen in the liquid meal
evaluation [11,32]. In a breath test study by Unger et al., patients with
RBD did not exhibit prolonged GET compared to controls, whereas a
significant increase was seen in de novo untreated PD patients. This
suggests that gastroparesis and/or other contributing factors to a pa-
thological breath test parallels the appearance of motor symptoms, and
that GET delay is apparently unrelated to antiparkinsonian treatment
[34]. The treated early stage PD group exhibited a further increase in
GET, but it is unknown whether this difference was related to disease
progression, medication, or both.
In summary, as methodologically standardized studies of late stage
PD patients are lacking, it is unclear to what degree gastric dysmotility
progresses with advancing disease, as well as the role played by chronic
dopaminergic replacement therapy. The one available study suggests
that delayed gastric emptying is not present in the prodromal phase.
4.4. Limitations
Some limitations must be mentioned. First, in several cases the same
control group was employed across different studies, which violates the
assumption of data independence. Nevertheless, the studies were in-
cluded as independent components of the analyses due to the scarcity of
published GET studies. Second, meal composition differed among stu-
dies, also within the solid and liquid categories. Third, several addi-
tional between-study differences were present, such as disease stage,
medication status, and analysis method, all of which contribute to a
substantial degree of heterogeneity. However, given the limited size of
published data on the subject, more strict inclusion criteria would have
made a direct comparison impossible. Thus, the presented meta-ana-
lyses results and forest plots should all be treated with caution and
interpreted more as an overall view on differences between GET scin-
tigraphy and breath tests.
K. Knudsen et al.
5. Conclusion
In conclusion, the available studies of GET in PD patients lack
standardization and thus exhibit substantial heterogeneity. A modest
overall delay was seen in scintigraphic GET in PD patients, which was
significant in only two of seven individual study groups. In contrast, a
marked delay in GET was robustly detected in studies employing the
13
C-octanoate breath test, with significant findings being reported in
ten of 11 individual patient groups. This discrepancy puts into question
the validity of breath tests as a measure of delayed gastric emptying in
PD and suggests that other factors, including small intestinal dysmoti-
lity and absorption, may play a perhaps underappreciated role in the
“gastroparesis story”. Thus, future multi-modality studies under stan-
dardized conditions are needed to assess the relative contributions of
each of these potentially pathogenic factors to upper gastrointestinal
dysfunction in PD.
Declarations of interest
None.
Funding sources
None.
Financial disclosures/conflicts of interest
None.
Author contributions
K Knudsen; Conception of study. Data acquisition, analysis, and
interpretation. Drafting the article. Critical revision. Final approval.
M Szwebs; Data acquisition, analysis, and interpretation. Drafting
the article. Final approval.
A K Hansen; Data analysis and interpretation. Critical revision.
Final approval.
P Borghammer; Conception of study. Data acquisition, analysis,
and interpretation. Critical revision. Final approval.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.
doi.org/10.1016/j.parkreldis.2018.06.003.
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