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Defecatory function in Parkinson's disease Response to apomorphine.

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Defecatory Function in Parkmson's Disease:
Response to Apomorphine
L. L. Edwards, MD," E. M. M. Quigley, MD,$ R. K. Harned, MD,$
Ruth Hofman, RN,"? and R. F. Pfeiffer, MD"
~
~
~~~
We evaluated the effects of the doparninergic agent apomorphine on defecation and anorectal function in patients
with Parkinson's disease (PD). A gastrointestinal symptom survey, extrapyramidal assessment, defecating proctogram,
and anorectal manometric study were performed in 8 subjects with PD. Basal studies showing abnormalities were
repeated following apornorphine administration. Prior defecographic abnormalities were normalized following apomorphine injection in 1 of 3 subjects and significant improvements in manometric parameters were observed in all 5
subjects who underwent repeat anorectal manometry. We conclude that apomorphine can correct anorectal dysfunction in PD, and that these abnormalities may be a consequence of dopamine deficiency secondary to the PD process.
These findings may also have therapeutic implications.
Edwards LL, Quigley EMM, Harned RK, Hofman R, Pfeiffer RF. Defecatory function in Parkinson's disease:
response to apomorphine. Ann Neurol 1993;33:490-493
Constipation and anorectal dysfunction are common in
Parkinson's disease (PD) 11-31. Their pathophysiology
in PD is incompletely understood 141, although results
of recent studies point toward a direct relationship with
the PD process 12-6). Both Wakabayashi and colleagues [7) and Kupsky and coworkers @] identified
Lewy bodies in the colonic myenteric plexus of patients
with PD. Mathers and associates [ S , 91 correlated ineffective defecation with paradoxical activation of the
puborectalis muscle and suggested this represented
dystonia of the pelvic floor musculature as a direct
manifestation of the PD process. Limited observations
suggest that this dysfunction improves following the
administration of apomorphine, a dopamine agonist
[5). Similar responses to apomorphine have been demonstrated in the urinary sphincter [lo, 111.
The purpose of this study was to characterize the
process of defecation and anorectal sphincter function
in PD both before and after the administration of apomorphine, to further assess the role of dopaminergic
mechanisms in the defecatory dysfunction in this disorder.
Materials and Methods
Subjects
Subjects with PD were recruited from the Movement Disorders Clinic at the University of Nebraska Medical Center
and from the Nebraska Chapter of the American Parkinson's
From the Sections of 'Neurology, $Digestive Diseases and Nutrition, and $Radiology, University of Nebraska Medical Center,
Omaha, NE.
f Deceased.
Disease Association, and were included in the study after
giving informed consent.
Protocol
Each subject underwent evaluation with a comprehensive
gastrointestinal (GI) survey 121, Unified Parkinson's Disease
Rating Scale (UPDRS) 1121, defecography, and anorectal manometry. In those patients demonstrating abnormalities on
defecography or anorectal manometry, the appropriate test
was repeated following the administration of apomorphine.
EXTRAPYRAMIDALFUNCTION ASSESSMENT. Extrapyramidal
function was assessed using the UPDRS 112). Neurological
evaluation was performed on all subjects by the same neurologist (R. F. P.). The severity of PD was determined using
both the Schwab and England score 1131 and the Hoehn and
Yahr stage [14].
A GI assessment
survey developed and validated in previous studies 13, 41
was administered to each subject by a single interviewer
(L. L. E.).
GASTROINTESTINAL SYMPTOM SURVEY.
Defecography was performed using a
technique similar to that originally described by Mahieu and
colleagues [Is]. With the patient in the left lateral decubitus
position, Anatrast (E-Zem) barium sulfate paste (100% wti
vol barium) was instilled into the rectum with a modified
caulking gun until a sensation of fullness developed (200500 gm). The subject then sat on a specially designed com-
DEFECOGRAPHY.
Received Sep 3 , 1992, and in revised form Nov 23. Accepted for
publication Dec 2, 1992.
Address correspondence to Dr Pfeiffer, University of Nebraska
Medical Center, Section of Neurology. 600 S. 42nd Street, Omaha,
NE 68198-2045.
490 Copyright 0 1993 by the American Neurological Association
mode and the process of defecation was monitored by
fluoroscopy. Radiographs were taken during a number of
maneuvers: at rest, during “squeeze” (i.e., voluntary maximal
contraction of the sphincter and pelvic floor muscles), during
straining (without defecation), and finally during defecation.
The defecography studies were performed and analyzed by
the same radiologist (R. K. H.).
Anorectal manometry was performed using an eight-lumen catheter assembly with individual side-holes arrayed at 0.5-cm intervals over the distal end
of the catheter assembly. The assembly also incorporated an
inflatable balloon at its distal end. Each catheter was perfused
at a rate of 0.1 cm3/min by an Arndorfer low-compliance
perfusion system (Arndorfer, Greendale, WS), and intraluminal pressure changes were monitored by strain-gauge transducers and recorded on a Sandhill TDS recorder (Sandhill
Scientific, Littleton, CO).
The catheter assembly was first inserted into the rectum
and two station pull-through procedures were performed to
define the basal sphincter pressure profile. Each pull-through
was performed in 1-crn steps, with at least 30 seconds being
spent at each station. Following definition of the basal sphincter profile, the catheter was reinserted so that the closely
spaced side-holes straddled the sphincter. With the catheter
in this location, the patient was asked to squeeze, and both
the maximum increment and the duration of the squeeze
response were defined. With the balloon in the rectum and
the side-holes straddling the sphincter, the balloon was rapidly inflated with 60 cm3 of air and the rectosphincteric reflex
(rectoanal inhibitory reflex) was defined on two separate occasions. Finally, with the balloon in the rectum, stepwise inflation of the balloon was performed at 10-cm3 increments
and the threshold for sensation defined. All anorectal manometric examinations were performed and analyzed by the
same gastroenterologist (E. M. M. Q.).
ANORECTAL MANOMETRY.
TESTING WITH APOMORPHINE.
Following analysis of the
baseline studies, patients were selected for repeat testing with
apomorphine based on the most abnormal study: Those with
abnormalities on baseline defecography underwent repeat
defecography and those with abnormalities on baseline anorectal manometry underwent repeat manometric studies.
To prevent nausea, each subject was pretreated with the
antiemetic domperidone (Janssen Pharmaceuticals, Piscataway, NJ), 20 mg 30 minutes before meals and at bedtime
for 3 days prior to the testing with apomorphine. On the day
of testing, antiparkinsonian medications were withheld, but
domperidone was continued.
Following completion of a baseline defecography or anorectal manometry, apomorphine (6 mg) was injected subcutaneously into the right deltoid area and the test repeated 10
to 20 minutes later. Blood pressure and heart rate were monitored frequently throughout the procedures.
Data Analysis
Cumulative scores from the UPDRS were collected for mentation, activities of daily living, and the motor examination.
Individual scores were used for tremor, rigidity, gait, postural
stability, and brad ykinesia. The Hoehn and Yahr stage and
the Schwab and England score were also tabulated.
From the GI survey, individual scores for each GI symptom assessed and a total GI score (the combination of scores
for abnormal salivation, dysphagia, nausea, bowel movement
frequency, and defecatory dysfunction) were tabulated.
Each defecating proctogram was analyzed for completeness
of evacuation, puborectalis contraction, and anorectal angles.
The anorectal angle was defined, the configuration of the anal
canal was assessed during each maneuver (rest, “squeeze,”
strain, and defecation), and the completeness of evacuation
evaluated. The anorectal angle was measured using the angle
formed by the longitudinal axis of the anal canal and the
longitudinal axis of the rectum { 15}.
From the anorectal manometry, the following measurements were taken: basal sphincter pressure, anal sphincter
length, initial squeeze increment, sustained squeeze incre ment and duration, as well as the presence or absence of
phasic fluctuations on squeeze, the rectosphincteric reflex,
and the threshold for sensation.
For statistical comparisons of the data from the basal and
the apomorphine studies, x2 and Student’s t test were used
as appropriate.
Results
Subjects
Eight subjects (5 men, 3 women) with PD participated
in this study. The mean age was 65.1 years (range,
53-74 years), and the mean duration of PD was 5.9
years (2.5-12.0 years).
Unified Parkinson’s Disease Rating Scale
The mean scores for the parameters of PD from the
UPDRS were as follows: tremor, 1.9 (0-10); rigidity,
5.5 (2-11); bradykinesia, 1.4 (0-3); and total motor
score, 19.9 (6-35). All subjects had a Hoehn and Yahr
stage of 2 and the mean Schwab and England score was
87.5 % (80- 100%).
GastrointestinalAssessment Survey
The frequencies of the GI symptoms were 75% for
abnormal salivation, 88% for dysphagia, 13% for indigestion, 13% for nausea, 0% for emesis, 38% for constipation (bowel movement <3 timedwk), and 75%
for defecatory dysfunction. The mean total GI score
was 5.4 (range, 2-11).
Test Results Prior to Apomorphine Administration
Defecography identified abnormal anorectal angles
(angle at rest >91.96 degrees & 1.52 [standard error
of mean)) [15] in 7 , abnormal puborectalis contraction
(no change in anorectal angle with strain) in 2, and
incomplete evacuation (<90%) in 5 subjects.
Anorectal manometry revealed decreased basal
sphincter pressures in 6, impaired squeeze in 7, prominent phasic fluctuations on squeeze in 5, and an abnormal rectosphincteric response in 3 subjects. This abnormal rectosphincteric response featured a prominent
hypercontraction with no evidence of relaxation.
Edwards et al: Apomorphine and Defecatory Function in PD
491
lnltlal Squeeze hssuro
0’
Sustalnad Squeeze Incromont
0 ‘
6bbn
rpanorphtn
A h
*pornorphln
ID-HS)
hlar
m h h w
(0
-
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rpomorphln
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Fig 2. Changes i n anorectal manometry after apomorphine administration. All 5 subjects experienced an increase in squeeze
pressures after apomorphine injection. Three had an increase in
both initial and sustained squeeze pressures. One subject showed
an increase in initial squeeze (46-67 mm H a with a decrease
in sustained squeeze (20-8 mm Hgi. Another subject exhibited
an increase in sustained squeeze (4-20 mm Hgj with a decrease
in initial squeeze (105-76 mm Hg).
A
Anorectal manometry was repeated in 5 subjects.
The initial and sustained squeeze response improved
in 4 subjects (Fig 2). Phasic fluctuations diminished in
3 subjects, but the frequency of an abnormal rectosphincteric reflex response was unchanged. Figure 3 is
an example of the manometric findings in 1 PD subject
before and after the administration of apomorphine.
Two subjects suffered symptomatic postural hypotension during defecography following the apomorphine injection. One subject experienced drowsiness
during anorectal manometry following apomorphine
administration.
B
Fig 1 Defecography in a parkinsonian subject during defecation. (A) Before apomorphine administration. There is a widened anorectal angle at rest (top left). Although the anorectal
angle decreases with “lzft,”it continues to widen (top right).
The subject is unable t o evacuate the rectum during this maneuver (bottom right). (B) After apomorphine administration.
Note the angle remains widened; howwer, the puborectalis contracts normally, and there is improved evacuation.
I
Test Results after Apomorphine Administration
Defecography was repeated following the administration of apomorphine in 3 subjects. There were no
changes in 2 while the third subject showed dramatic
improvement. As illustrated in Figure 1, apomorphine
abolished the paradoxical puborectalis contraction on
strain, widened the anal canal, and greatly improved
evacuation.
492 Annals of Neurology Vol 33 NO 5 May 1773
Discussion
The GI symptom profile of the subjects with PD in
this study was similar to that of previous large surveys
11, 2}, indicating that although limited in numbers,
these subjects were representative of people with PD.
Anorectal manometry revealed several abnormalities. After the administration of apomorphine, marked
improvements in both the initial and the sustained
squeeze pressures were noted in 4 P D subjects. Although these changes did not reach statistical significance, possibly due to the small number of subjects,
the improvement was clear and this suggests that dopamine receptors, either peripherally or centrally, play a
role in defecatory function. While the phasic fluctuations improved in most subjects after they took apomorphine, reversal of an abnormal rectosphincteric reflex response was not consistent. The importance of
this reflex in defecation has not been completely determined and its pathogenesis deserves further study.
Mathers and coworkers 15, 91 found that with the
-q
t
.ua
f
m
These findings may also provide a new therapeutic approach to defecatory dysfunction in PD. In addition to
further assessing the clinical utility of apomorphine,
the effectiveness of more readily available dopamine
agonists, such as bromocriptine and pergolide, should
also be investigated. Further study of defecatory function in relation to fluctuations in motor performance
in P D might also provide more thorough characterization and point the way to more specific and effective
treatment of GI symptoms in individuals with PD.
Dr Edwards is supported by the Nellie House Craven scholarship
from the University of Nebraska Medical Center.
We with to thank Carol Edmonds for her superb secretarial assistance.
References
.T
m
Fig 3. Example of anorectal manometry before (top) and after
(bottom) the administration of apomorphine. Improvements in
the initial squeeze pressure and sustained squeeze pressure are
seen.
administration of apomorphine, most of their subjects
who exhibited paradoxical puborectahs contraction in
the basal state improved dramatically. In the current
study, 1 subject receiving apomorphine exhibited this
dramatic improvement. One of the other 2 subjects
undergoing repeat defecography experienced a hypotensive episode 5 minutes after the completion of
defecography, raising the possibility that the study was
performed before the maximum effect of apomorphine
was reached.
Although domperidone, a peripheral dopamine receptor blocker that crosses the blood-brain barrier
poorly, was effective in blocking the emetic effect of
apomorphine at the chemoreceptor trigger zone, it did
not appear to block the effect of apomorphine on defecatory function, suggesting that the rectal dysfunction
observed in these patients is centrally mediated.
Two subjects experienced significant orthostatic
hypotension during defecography, which requires
changes in position from lying down to standing in
addition to straining. The dose of 6 mg of apomorphine
may have been excessive for this patient population,
considering the procedures being performed. A lower
dose might avoid the severe hypotension experienced
by some of our subjects.
The improvement in defecatory function seen after
the apomorphine injection suggests that GI symptoms
in PD are a consequence of dopamine deficiency.
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Edwards e t al: Apomorphine and Defecatory Function in PD
493
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