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PAPER
Pramipexole in patients with Parkinson’s disease and
marked drug resistant tremor: a randomised, double
blind, placebo controlled multicentre study
O Pogarell, T Gasser, J J van Hilten, S Spieker, S Pollentier, D Meier, W H Oertel
.............................................................................................................................
J Neurol Neurosurg Psychiatry
2002;72:713–720
Objective
:
To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to
those of placebo as add on medication in patients with Parkinson’s disease.
Methods
:
Eighty four patients with early or advanced Parkinson’s disease and marked, drug resistant
tremor under a stable and optimised antiparkinsonian medication were included in a double blind,
randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose
titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as
adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor
related items (16, 20, 21) of the unified Parkinson’s disease rating scale (UPDRS) in “on” periods. Sec-
ondary end points included the percentage change in tremor score, the absolute and percentage
changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and
tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs.
Results: Pramipexole was significantly superior to placebo with a difference between treatment groups
in the mean absolute change in tremor score of −4.4 (95% confidence interval (95% CI) −6.2 to −2.5)
(p<0.0001), corresponding to a difference in the mean percentage change of −34.7% in favour of
pramipexole. The secondary end points were consistent with the significant change in tremor score and
provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG
registration as an objective measure showed a difference in mean absolute change in tremor
occurrence of −15.2% (95%CI −21.4 to −9.0) (p<0.0001), and a difference in the mean percentage
change of −45.7% in favour of pramipexole. The treatment effects increased during dose titration and
remained stable during the 4 week maintenance dose period until the end of the study. The average
daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an
increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, com-
parable with previous studies.
Conclusion
:
Pramipexole proved to be an effective agent for patients with Parkinson’s disease and
drug resistant tremor.
T
remor at rest is one of the cardinal symptoms of
Parkinson’s disease and the first sign in about 75% of
patients. A minority of patients will present with tremor
as the predominant symptom throughout the course of the
disease (tremor dominant Parkinson’s disease).
1
Antiparkin-
sonian drugs usually provide effective treatment for bradyki-
nesia and rigidity, whereas drug treatment of tremor may be
more difficult: parkinsonian tremor is sometimes resistant to
cur rently available medication or sufficient pharmacotherapy
may cause intolerable side effects and lead to discontinuation
of treatment (drug resistant tremor).
2
Stereotactic neurosur-
gery with deep brain stimulation (nucleus ventralis interme-
dius thalami, subthalamic nucleus) or thalamotomy may lead
to excellent tremor reduction, but is—at least in the short
ter m—an expensive approach with rare but potentially severe
side effects,
3–6
and is limited to specialised centres. Therefore,
new antiparkinsonian compounds are to be investigated with
respect to their efficacy on predominant and drug resistant
parkinsonian tremor.
Pramipexole is a novel non-ergoline dopamine agonist with
high binding specificity for the dopamine D2 receptor family
and with preferential affinity to the dopamine D3 receptor
subgroup.
7–9
Clinical trials with pramipexole as monotherapy
and as an adjunct to levodopa have shown the compound to be
safe, well tolerated, and efficacious.
10–14
Recently, sudden onset
of somnolence (sleep attacks) was reported to occur in a few
patients with pramipexol.
15
This topic is presently under
further investigation.
Compared with placebo, pramipexole treated patients
showed an improvement in both activities of daily living
(ADL) and motor scores as assessed by the unified Parkinson’s
disease rating scale (UPDRS) in early and advanced Parkin-
son’s disease, and a reduction of duration and severity of “off”
periods in advanced Parkinson’s disease.
10–14
In most of these
trials, tremor items were not analysed separately or there were
no systematic investigations of patients with predominant
tremor. However, descriptive analyses of placebo controlled
trials of pramipexole showed that the incidence of tremor,
reported as a newly occurring symptom during the studies
(507 patients, 251 under pramipexole, 256 under placebo) was
less frequent in patients taking pramipexole compared with
placebo.
16
Based on an exploratory subanalysis of patients
from one study centre of a placebo controlled multicentre trial
in advanced Parkinson’s disease, pramipexole seemed to have
potent tremorlytic activity: besides overall antiparkinsonian
.............................................................
Abbreviations: UPDRS, Unified Parkinson’s disease rating scale; ADL,
activities of daily living; LOCF, last observation carried forward; SAEs,
serious adverse events
See end of article for
authors’ affiliations
.......................
Correspondence to:
Dr O Pogarell, Department
of Psychiatry, University
Hospital,
Ludwig-Maximilians-
University of Munich,
Section of Clinical
Neurophysiology,
D-80336 Munich,
Germany; oliver.pogarell@
psy.med.uni-muenchen.de
Received 13 April 2001
In final revised form
7 November 2001
Accepted
20 November 2001
.......................
713
www.jnnp.com
effects, pramipexole led to a statistically significant improve-
ment in UPDRS tremor scores in a subgroup of 16 patients
with previously drug resistant tremor.
17
As a consequence of these findings, the present trial was
conducted to investigate the tremorlytic properties of prami-
pexole compared with placebo as an add on therapy in
patients with early or advanced Parkinson’s disease presenting
with marked and previously drug resistant tremor.
METHODS
Study design
The study followed a double blind, placebo controlled,
randomised, multicentre, parallel group comparative design.
The trial was conducted according to the principles of good
clinical practice and was approved by local ethics committees
at each centre. Written informed consent had to be given by all
participants. A total of four study sites were involved in two
European countries. Trial duration was up to 12 weeks. The
treatment groups were pramipexole and placebo as add on
therapy to a stable and optimised antiparkinsonian medi-
cation. The study dr ugs were administered as tablets with
identical appearance and taste. A computer generated
randomisation plan that included stratification by centre and
block (with a block size of four) was used to ensure a balanced
distribution (1:1) of treatment groups within centres. No per-
son directly involved in management or analysis of the trial
had access to the treatment assignment during the conduct.
After a blinded repor t planning meeting where the analysis
plan was finalised, the database was locked, treatment assign-
ment was added, and no further changes were made to the
database.
Inclusion/exclusion criteria
Patients of both sexes with Parkinson’s disease (Hoehn and
Yahr stage I-IV as assessed after at least 12 hours off
medication) according to the United Kingdom Parkinson’s
disease brain bank criteria were included.
18
Patients had to
fullfill the cr iteria of marked and drug resistant tremor during
their medical history—subjects either failed to experience a
clinically relevant and useful improvement in tremor under an
optimised antiparkinsonian therapy with various agents, or
side effects encountered under an effective antitremor therapy
were intolerable. Marked tremor was clinically defined by the
presence of a sum score of at least eight of 32 of the UPDRS
tremor items 16, 20, and 21 (referred to as tremor score) or, if
the tremor was present on one side only, by the presence of a
tremor score of at least six of 32. The generation of this sum
score is based on the validity of the UPDRS regarding
tremor,
19
and the clinical experience, that the UPDRS tremor
items reflect different but similarly important aspects of Par-
kinsonian tremor, including the impairment of activities of
daily living by tremor.
Tremor was assessed during “on” periods—that is, 2 to 3
hours after the last intake of antiparkinsonian medication.
Patients with atypical parkinsonian syndromes (multiple
system atrophy, progressive supranuclear palsy, etc), severe
dementia, epilepsy, previous neurosurgery, electroconvulsive
therapy within 90 days before randomisation, or severe other
physical diseases were excluded. Also excluded were patients
with symptomatic orthostatic hypotension—that is, a decline
in systolic (diastolic) blood pressure at 1 minute after standing
by 20 mm Hg or more compared with supine blood pressure
obtained after 5 minutes of quiet rest. Female patients of
childbearing potential were required to use medically accepted
means of contraception.
The patients had to receive a stable antiparkinsonian medi-
cation with levodopa/decarboxylase inhibitor preparations,
and/or selegiline, and/or amantadine for at least 30 days
before randomisation. Before study inclusion, the medication
had to be optimised regarding the symptomatic effects on
parkinsonian signs and symptoms and the dose related side
effects in each individual patient. Optimisation was mainly
perfor med by adjusting the levodopa dose either by increasing
the number of doses or increasing the dosage in each dose.
Concomitant treatment with the following agents was not
allowed during the past month (neuroleptic drugs and meto-
clopramide: the past 2 months) before randomisation:
dopamine agonists, MAO inhibitors except for selegiline, anti-
cholinergic drugs, budipine, reserpine, (classic) neuroleptic
drugs, metoclopramide, methylphenidate hydrochloride, am-
phetamine derivatives, α methyldopa, cinnarizine, and fluna-
rizine.
Efficacy criteria
The primary end point was the absolute change in tremor
score during “on” periods from baseline to the end of mainte-
nance. Secondary end points were (1) absolute and relative
(percentage) changes in separate tremor score items, and
other UPDRS scores, (2) changes in two tremor self rating
scales based on a patient’s diary, (3) absolute and relative
(percentage) changes in “tremor occurrence” as measured by
a long term EMG registration, and (4) a global assessment of
the effect on tremor.
Tremor score
Tremor score was calculated as the sum of UPDRS items 16,
20, and 21. Evaluation was done during an “on” period.
“On”periods were defined as 2 to 3 hours after the last intake
of study medication together with levodopa preparations
and/or other antiparkinsonian drugs, if applicable.
UPDRS scores
UPDRS part II (ADL) was evaluated for “on” and “off” periods
and the average calculated, a procedure consistent with other
Parkinson’s disease studies.
10 11
UPDRS par t III (motor exam-
ination) was evaluated during “on” periods. The sum of both
was calculated as the combined UPDRS II/III score.
Patient’s diary
The patient’s diary consisted of two tremor self rating scales
19
:
(1) Impairment of daily living by tremor and (2) severity of
tremor.
(1) Impairment of daily living by tremor is a 21 item check-
list of daily living tasks (for example, cutting with a knife,
using a spoon, brushing teeth etc). The best performance for
each item per day is rated using a four point scale (0, no diffi-
culty; 1, slight difficulty; 2, considerable effort; and 3, cannot
be fulfilled). The maximum score is 63 points.
(2) Severity of tremor is rated on a five point scale (0, miss-
ing; 1, mild; 2, moderate but occasionally occurring; 3, moder-
ate but per sisting; and 4 severe) with the items rest tremor,
postural tremor, and impairment by tremor (maximum score
12 points). Ratings were performed every 2 hours of the wak-
ing day. In both scales a reduction in total score indicates
improvement. Each scale was used on the 3 consecutive days
preceding each visit. The scores of these 3 days were averaged.
Long term EMG
A long term EMG tremor reg istration at baseline and end of
maintenance was used as an objective measure to quantify the
occur rence of tremor, expressed as a time percentage of a
registration period of 10 waking hours. The tremor recording
was performed with a long term EMG appliance via skin elec-
trodes placed bilaterally over the muscle venters of extensor
carpi radialis and flexor carpi ulnaris muscles with reference
electrodes placed 10 cm distally. Registration and tremor
analysis were performed according to a standardised protocol
of EMG tremor registration.
20 21
Only the side with the most
pronounced tremor was evaluated. The analysed time periods
were identical at baseline and end of maintenance in
individual patients.
714 Pogarell, Gasser, van Hilten, et al
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Global assessment
The effect on tremor at the end of the trial was assessed
globally on a three point scale (clear improvement, no clear
effect, clear deterioration) by both investigators and patients,
with the end points clear improvement versus no clear effect
or deterioration used in the analysis.
Safety criteria
Safety was assessed by physical examination, supine and
standing blood pressure measurements, laboratory tests (red
blood cells, white blood cells, enzymes, electrolytes, urinaly-
sis), 12 lead ECG, documentation of adverse events, and the
investigators’ global impression of tolerance.
Study procedures
At the screening visit medical history, physical examination,
vital signs, laboratory tests, ECG, modified Hoehn and Yahr
scale (“on” and “off”), UPDRS part II and III with derived
tremor scores were performed and the patients’ diaries with
self rating scales distributed.
Aftera2weekscreening period the patients were randomly
assigned to either pramipexole or placebo under double blind
conditions in a 1:1 ratio (baseline visit). Baseline assessments
comprised those for all end points, adverse events, and
changes in concomitant medication.
Subsequently the patients underwent an ascending dose
interval up to 7 weeks (weekly visits) with individual dose
adjustments from 0.375 mg to 4.5 mg/day pramipexole or
matching placebo using a three times a day regimen (3×0.125,
0.25, 0.5, 0.75, 1.0, 1.25, and 1.5 mg). The dosage was
increased in weekly steps until the patient showed a stable
and optimal improvement or received the maximally tolerated
dose (up to a maximum dose of 4.5 mg daily). Dose
adjustment was followed bya4weekmaintenance period. At
the end of maintenance there was a 1 week dose reduction
period to gradually withdraw study medication.
Additional antiparkinsonian medication (levodopa/
decarboxylase inhibitor preparations and/or selegiline and/or
amantadines) had to remain stable from 30 days before
randomisation and throughout the course of the study.
The following assessments were performed at each visit
after baseline—that is, at weekly visits during the ascending
dose interval, at the end of the maintenance period, and after
dose reduction: tremor score, UPDRS II (“on” and “off”),
UPDRS III (“on”), evaluation of patients’ diaries, adverse
events, changes in concomitant non-antiparkinsonian medi-
cation. Just before the end of maintenance there was a second
EMG registration of at least 10 hours of waking time. After
dose reduction physical examination, vital signs, laboratory
tests, and ECG were reassessed.
Statistical analysis
Baseline comparability of treatment groups was exploratively
assessed by χ
2
test (sex), two way analysis of variance
(ANOVA; age, UPDRS), Mantel-Haenszel test (Parkinson’s
disease duration, Hoehn and Yahr stage) and Wilcoxon-Mann-
Whitney test (levodopa dose) with factors treatment and cen-
tre.
Analysis of variance with f actors treatment and centre (for
nor mally distributed data), and the Wilcoxon-Mann-Whitney
test as alternative were applied for statistical evaluation of
differences in efficacy between the treatment groups regard-
ing the primary end point, the UPDRS derived secondary end
points, the self rating scales, and EMG tremor registration. As
the interaction treatment×centre was not significant (p=0.12)
this factor was removed from the ANOVA and only the main
effects remained. 95% Confidence intervals and p values were
calculated for differences in the mean absolute changes
between the treatment groups. The patients’and investigators’
global assessments of the effect on tremor of pramipexole or
placebo were compared using the Mantel-Haenszel test (clear
improvement v deterioration or no clear improvement), confi-
dence intervals for the differences of proportions were calcu-
lated using normal approximation. The null hypothesis for
statistical tests was that there is no difference between the
mean change from baseline to the end of maintenance in the
pramipexole and placebo treatment groups (intent to treat
population) and was tested for primary and secondary end
points. Post hoc subgroup analyses to determine the influence
of antiparkinsonian drugs other than study medication,
adverse events (fatigue), presence of “off” periods at baseline,
low or high tremor scores were performed for the primary end
point. Incidences of adverse events were descriptively evalu-
ated using Fisher’s exact test for the occurrence per treatment
group.
The intent to treat population included all patients who
were randomised to treatment, received at least one dose of
medication, and had at least one postbaseline efficacy assess-
ment. Missing data of the intent to treat population were esti-
mated using the “last observation carried forward” technique.
Previous power calculations had suggested that a sample size
of 42 in each treatment arm would be required to detect a sta-
tistically significant difference with 80% probability at the 5%
Received pramipexole:
n = 44
Did not receive pramipexole
as allocated: n = 0
Not randomised: n = 6
• Withdrawal of consent
before randomisation n = 1
• Violation of inclusion-exclusion criteria
during screening period n = 5
Registered: n = 90
Follow up: n = 44 (ITT)
Timing: baseline,
on treatment at week:
• 1–7 (ascending dose)
• 11 (end of maintenance)
• 12 (after dose reduction)
(EMG recording at baseline
and week 11 only)
Withdrawn: n = 0
Completed pramipexole
treatment: n = 44
(ITT population n = 44)
Received placebo: n = 40
Did not receive placebo
as allocated: n = 0
Follow up: n = 39 (ITT)
Timing: baseline,
on treatment at week:
• 1–7 (ascending dose)
• 11 (end of maintenance)
• 12 (after dose reduction)
(EMG recording at baseline
and week 11 only)
Withdrawn: n = 2
• Intervention ineffective n = 1
• Before follow up due to
preexisting disease n = 1
Completed placebo
treatment: n = 38
(ITT population n = 39)
Randomisation:
n = 84
Figure 1 Profile of the randomised trial: flow diagram with the
progress of the patients throughout the trial.
Pramipexole in patients with Parkinson’s disease with predominant tremor 715
www.jnnp.com
level of significance, if the difference in the mean change of
tremor score between treatment groups was 2.2 units.
RESULTS
Treatment population
Eighty four patients gave informed consent, were included,
and were randomised. One patient was withdrawn after the
first treatment dose (placebo) without postbaseline efficacy
measurements, as immediate cardiac surgery for an hitherto
undetected aortic valve stenosis was required. Thus the inten-
tion to treat population consisted of 83 patients (60 male, 23
female), 44 in the pramipexole group, 39 in the placebo group.
Eighty two (44 pramipexole, 38 placebo) patients completed
the trial according to protocol. One placebo patient discontin-
ued during the ascending dose period because of an
unsatisfactory therapeutic effect (fig 1).
The mean age of the intention to treat population was 63.6
(SD 8.9) years with a range from 35 to 80 years and a mean
disease duration of 6.3 (SD 3.8) years. The mean duration of
drug treatment was 3.8 (SD 3.3) years. Seventy three patients
were treated with levodopa with a median daily dose of 300
mg. Forty three patients (52%) received daily dosages of 300
mg levodopa or less, and 30 (36%) of more than 300 mg. Sel-
egiline and amantadine were used by 12 (10 pramipexole, two
placebo) and 14 (nine pramipexole, five placebo) patients,
respectively.
The sever ity of Parkinson’s disease was estimated at screen-
ing by Hoehn and Yahr staging dur ing “on” and “off” periods.
In “on” periods most of the patients were in Hoehn and Yahr
stages 2 and 2.5. Thirty seven patients had no “off” periods at
screening and most of the 46 patients with fluctuations were
in Hoehn and Yahr “off” stages 2.5 and 3.
At baseline the mean UPDRS II scores (average of “on” and
“off”) were 13 (SD 6.4) in the pramipexole group and 11.5 (SD
4.6) in patients on placebo. Mean UPDRS III (“on”) baseline
scores were 34.2 (SD 15.3) compared with 32.1 (SD 11),
pramipexole and patients with placebo, respectively. The mean
tremor score in “on” was 11.9 (SD 5) in the pramipexole ver-
sus 10.9 (SD 3.5) in the placebo group with a mean proportion
of the tremor score relative to the UPDRS II and III sum scores
of 28% and 27%, respectively. Both treatment groups were
comparable with respect to demographic and clinical features.
Exploratory and descriptive analyses were not suggestive of
significant differences at baseline (table 1).
Table 1 Demographics and baseline characteristics of the intent to treat population
(n=83) with mean (SD), n (%), or median, where appropriate
Pramipexole
(n=44)
Placebo
(n=39) Total (n=83)
Sex (n (%)):
Male 30 (68) 30 (77) 60 (72)
Female 14 (32) 9 (23) 23 (28)
Age (y):
Mean (SD) 62.0 (10.1) 65.4 (7.1) 63.6 (8.9)
Range 35–80 47–80 35–80
Duration of PD (y):
Mean (SD) 6.5 (4.0) 6.0 (3.5) 6.3 (3.8)
Range 0.9–17 2.0–16 0.9–17
Duration of drug treatment (y):
Mean (SD) 3.9 (3.1) 3.6 (3.5) 3.8 (3.3)
Levodopa dose (mg):
Median 300 300 300
Range 50–700 100–1700 50–1700
Patients (n (%)):
With no levodopa 5 (11) 5 (13) 10 (12)
<300 mg 25 (57) 18 (46) 43 (52)
>300 mg 14 (32) 16 (41) 30 (36)
Patients without “off” periods (at baseline) (n (%)) 22 (50) 16 (41) 38 (46)
Hoehn and Yahr Stage: in “on” periods (n (%)):
I 6 (14) 4 (10) 10 (12)
I.5 4 (9) 5 (13) 9 (11)
II 22 (50) 20 (51) 42 (51)
II.5 10 (23) 7 (18) 17 (20)
III 2(4) 3(8) 5(6)
IV 000
Hoehn and Yahr Stage: in “off” periods (n (%)):
I 0 1(3) 1(1)
I.5 0 2 (5) 2 (2)
II 3 (7) 6 (15) 9 (11)
II.5 12 (27) 10 (26) 22 (27)
III 7 (16) 4 (10) 11 (13)
IV 0 1 (3) 1 (1)
Tremor score (mean (SD)) 11.9 (5) 10.9 (3.5) 11.4 (4.3)
Item 16 (reported) 2.2 (0.8) 2.1 (0.7) 2.2 (0.7)
Item 20 (rest) 6.3 (3.4) 5.8 (2.2) 6.1 (2.9)
Item 21 (action/postural) 3.3 (1.6) 3.0 (1.8) 3.2 (1.7)
UPDRS (mean (SD)):
UPDRS II/III sum score 47.2 (21.1) 43.6 (14.4) 45.5 (18.2)
UPDRS II(mean “on/off”) 13 (6.4) 11.5 (4.6) 12.3 (5.7)
UPDRS III (“on”) 34.2 (15.3) 32.1 (11) 33.2 (13.4)
Patient’s diary (mean (SD)):
Daily living 20.2 (14.9) 17.3 (10.8) 18.8 (13.1)
Severity 6.1 (2.9) 5.7 (2.3) 5.9 (2.6)
Long term EMG:
Tremor occurrence (%, mean (SD)) 41.8 (21.5) 49.5 (21.6) 45.5 (21.8)
716 Pogarell, Gasser, van Hilten, et al
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Efficacy
Primary end point
The change in tremor score showed a statistically significant
difference between pramipexole and placebo group
(p<0.0001). The difference in the mean absolute change
between the treatment groups was −4.4 (95% confidence
interval −6.2 to −2.5), corresponding to a difference in the
mean relative change of −34.7% in favour of pramipexole
(table 2, fig 2). The visit by visit analysis of the change in
tremor score showed that the improvement under pramipex-
ole increased in a dose dependent manner during the ascend-
ing dose interval and seemed to remain stable between the
beginning and end of maintenance (fig 3).
Single tremor items
The separate analysis of the single UPDRS tremor items
(UPDRS II item 16 “on”: reported tremor in the ADL, UPDRS
III items 20 and 21: tremor at rest and action or postural
tremor, resp) disclosed similar results, with a statistically sig-
nificant difference in favour of pramipexole for rest tremor
and postural tremor (p<0.0001), as well as for reported
tremor (p<0.01). The differences in the mean absolute change
between the treatment groups were −2.6 (95% CI −3.8 to −1.4)
and −1.2 (95% CI −1.8 to −0.6) for items 20 and 21,
respectively, and −0.6 (95% CI −0.9 to −0.2) for item 16.
Subgroup analyses
The change in tremor score (primary end point) was further
evaluated according (1) to the presence or absence of “off”
periods at baseline, (2) to low or high baseline tremor scores,
and (3) to the presence or absence of fatigue (table 3). In
addition, the influence of antiparkinsonian medication other
than pramipexole or placebo was analysed.
(1) Pramipexole treatment was significantly superior to
placebo in both patients with and without “off “ periods at
baseline, with a difference in the mean change in tremor score
between the treatment groups by −5.8 (p=0.0001), and −3.2
(p=0.006), respectively. Interaction tests (ANOVA with factors
treatment and “off” status) disclosed that the reduction in
Table 2 Synopsis of primary and secondary end points for the intent to treat population (last observation carried
forward technique): absolute changes from baseline to end of maintenance
Pramipexole
(n=44)
Placebo
(n=39)
Difference between
groups (95% CI)
Difference in mean relative
changes (%)
Tremor scores (UPDRS):
Tremor score −5.8 (5) −1.5 (3.2) −4.4 (−6.2 to −2.5) −34.7 p<0.0001
Item 16 −0.7 (0.9) −0.2 (0.7) −0.6 (−0.9 to −0.2) −21.5 p<0.01
Item 20 −3.6 (3.3) −1.0 (2.2) −2.6 (−3.8 to −1.4) −37.9 p<0.0001
Item 21 −1.5 (1.6) −0.3 (1.1) −1.2 (−1.8 to −0.6) −35.6 p<0.0001
UPDRS scores:
UPDRS II/III (sum score) −18.8 (13.9) −3.8 (8.3) −15 (−20 to −10) −30.9 p<0.0001
UPDRS II (average “on”-”off”) −3.6 (3.8) −0.1 (2.6) −3.5 (−4.9 to −2.0) −25.2 p<0.0001
UPDRS III (“on”) −15.2 (11.6) −3.7 (6.8) −11.5 (−15.7 to −7.4) −34.1 p<0.0001
Patient’s diary:
Daily living −4.7 (8.6) 3.4 (8.0) −8.1 (−11.7 to −4.5) −43.4 p<0.0001
Severity −1.6 (2.1) 0.6 (2.2) −2.2 (−3.1 to −1.3) −39.5 p<0.0001
Long term EMG:
Tremor occurrence (%) −19.3 (14.8) −4.1 (13.2) −15.2 (−21.4 to −9.0) −45.7 p<0.0001
Global assessment (patients with improvement (%)):
Investigator’s assessment 56.8 12.8 44.0 (26.1 to 61.9) NA p<0.0001
Patient’s assessment 56.8 17.9 38.9 (20.0 to 57.7) NA p<0.0001
Values are mean (SD) or n (%) for pramipexole and placebo group; differences in the mean absolute changes between groups (mean and 95% confidence
intervals (95% CIs); and differences in mean relative changes between groups ((%)); p values are given for the differences in the mean absolute changes
(controlled for differences between study centres); NA, not applicable.
14
10
6
8
4
0
2
–2
–4
–8
–6
End of
maintenance
– baseline
End of
maintenance
Pramipexole
Tremor score
Baseline
12
11.9 (5)
10.9 (3.5)
6.1 (5)
9.4 (4.1)
–5.8 (5)
–1.5 (3.2)
Placebo
p < 0.0001
Figure 2 Mean tremor score (SD) at baseline (left) and end of
maintenance (middle) of pramipexole (n=44) and placebo (n=39)
group. Right: mean change from baseline to end of maintenance.
14
12
8
10
6
4
0
2
12978645
Weeks on treatment
Pramipexole (n = 44)
Placebo (n = 39)
Tremor score
3201 10 11
End of
maintenance
Figure 3 Development of the mean tremor score per week on
treatment with pramipexole (ppx) and placebo (pbo) (intent to treat,
last observation carried forward), at week 0 (baseline), weeks 1–7
(ascending dose interval), weeks 7–11 (maintenance period), week
11–12 (dose reduction).
60
40
50
30
10
20
0
–10
–30
–20
End of
maintenance
– baseline
End of
maintenance
Pramipexole
% Time with tremor
Baseline
41.8 (21.5)
49.5 (21.6)
22.5 (20)
45.4 (21.6)
–19.3 (14.8)
–4.1 (13.2)
Placebo
p < 0.0001
Figure 4 Mean occurrence of tremor by long term EMG
registration (% time of waking hours (SD)) at baseline (left) and end
of maintenance (middle) of pramipexole and placebo group. Right:
Mean change from baseline to end of maintenance.
Pramipexole in patients with Parkinson’s disease with predominant tremor 717
www.jnnp.com
tremor was significantly greater in the subgroup with “off”
periods at baseline (p=0.038, “with off” v “without off”).
(2) As the median tremor score at baseline was 11, a high
score was defined as>11 and a low score as<11. The
difference between the treatment groups in the mean change
in tremor score was −6.1 (p=0.0001) in the high score group,
and −2.2 (p=0.03) in the low score group, both in favour of
pramipexole. The interaction between the factors treatment
and baseline tremor score was statistically significant
(p=0.01, “high” v “low score”)—that is, the improvement
under pramipexole was stronger in patients with a high base-
line tremor score.
(3) To investigate whether the reduction in tremor was
influenced by side effects such as increased tiredness or
fatigue, the pramipexole treated patients without these
adverse events (n=34) were descriptively compared to those
patients, who experienced fatigue or increased tiredness dur-
ing treatment (n=10). There was no significant difference in
the mean change in tremor score from baseline to end of
maintenance between these subgroups (p=0.73). The im-
provement was even slightly more pronounced in the group
without compared with the group with fatigue/tiredness
(mean change by −6 (SD 4.8) v −5.4 (SD 5.6)), so there is no
evidence that additional fatigue during the trial contributed to
a reduction in tremor.
Further post hoc analyses indicated that levodopa, sel-
egiline, or amantadine use did not influence treatment
outcome; neither did levodopa dose, when stratified as>300
mg versus<300 mg.
UPDRS parts II and III
The mean improvement in the combined UPDRS II/III sum
score was significantly superior under pramipexole
(p<0.0001). The difference in the mean absolute change
between the treatment groups was −15 (95% CI −20 to −10)—
that is, a percentage difference in UPDRS II/III sum scores of
−30.9% in favour of pramipexole. The single UPDRS II and III
scores also showed a significant improvement (p<0.0001) in
the pramipexole group compared with the placebo group. The
differences between groups were −3.5 (95% CI −4.9 to −2.0) for
UPDRS II and −11.5 (95% CI −15.7 to −7.4) for UPDRS III,
indicating an overall efficacy of pramipexole on activities of
daily living and motor performance.
Patients’ diaries
The tremor self rating with respect to impairment of daily liv-
ing and severity of tremor, as based on the patients’ diaries
disclosed a difference in the mean improvement between the
treatment groups of −8.1 (95% CI −11.7 to −4.5) and −2.2 (95%
CI −3.1 to −1.3) in favour of pramipexole (p<0.0001), respec-
tively.
Long term EMG
The EMG recordings of tremor activity were consistent with
the patients’ subjective estimation (fig 4): Long term EMG
during waking hours displayed a mean occurrence of tremor
(as percentage of a time interval of 10 consecutive hour s) at
baseline of 41.8 (SD 21.5)% in the pramipexole group and 49.5
(SD 21.6)% in the placebo group. To the end of maintenance
the mean tremor occur rence decreased with a group
difference of −15.2 (95% CI −21.4 to −9.0) (p<0.0001), corre-
sponding to a difference in the mean relative change of -45.7%
in favour of pramipexole.
Global assessment
The investigators’ assessment of the effect on tremor showed
a clear improvement in 25 (56.8%) pramipexole patients ver-
sus five (12.8%) placebo patients. This corresponded with the
patients’ estimation: clear improvement was reported by 25
patients (56.8%) of the pramipexole and seven patients
(17.9%) of the placebo group. The differences between prami-
pexole and placebo groups were 44.0% (95% CI 26.1 to 61.9)
and 38.9% (95% CI 20.0 to 57.7) in favour of the pramipexole
group (p<0.0001), respectively.
Safety
The safety population consisted of all 84 patients who have
received at least one administration of the test dose (44
pramipexole, 40 placebo). Safety and tolerance were generally
assessed as good in most cases. Global clinical impression of
tolerance was rated as good in 94% of the patients and did not
differ between treatment groups. No deaths were reported.
The mean duration of treatment was comparable in the
treatment groups: 48.8 (SD 9.5) versus 46.4 (SD 9.1) days
ascending dose interval, 31.2 (SD 4.8) versus 29.4 (SD 3.9)
days maintenance, and 4.9 (SD 1.4) versus. 4.7 (SD 1.3) days
dose reduction phase, pramipexole and placebo group, respec-
tively. The average daily dose in the pramipexole group was 4.1
(SD 0.9) mg and 4 (SD 0.8) mg in the placebo group.
A descriptive analysis of adverse events showed a higher
overall incidence of side effects in patients treated with
pramipexole. A total of 72 patients (85.7%) reported at least
one adverse event, 41 (93.2%) and 31 (77.5%) in the
pramipexole and placebo group, respectively (p=0.06). Com-
mon treatment emergent adverse events—that is, with an
incidence of at least 10% in either treatment group were
Table 3 Subgroup analyses of primary end point data (tremor score): stratification
of the intent to treat population according to the presence or absence of “off”periods
at baseline, high or low tremor scores, and patients with and without fatigue,
reported as adverse event
Pramipexole Placebo
Mean difference
between groups
(p value)
Interaction test
(treatment×subgroup
qualifier)
“Off” status (yes/no) 22/22 patients 23/16 patients p=0.038
Patients with “off” −8.1 (5.4) −2.3 (3.6) −5.8 (p=0.0001)
Patients without “off” −3.6 (3.3) −0.4 (2.3) −3.2 (p=0.006)
Tremor score (high/low) 24/20 patients 18/21 patients p=0.01
Tremor score >11 −8.0 (5.4) −1.9 (3.7) −6.1 (p=0.0001)
Tremor score <11 −3.3 (2.6) −1.1 (2.8) −2.2 (p=0.03)
Fatigue (yes/no) 10/34 patients 4/35 patients NA
Patients with fatigue −5.4 (5.6)* −0.8 (3.3) NA
Patients without fatigue −6 (4.8)* −1.6 (3.3) NA
*p=0.73 for pramipexole treated patients.
NA; not applicable; change in tremor score from baseline to end of maintenance; difference in the mean
change between treatment groups (p value for the difference between treatment groups); and interaction tests
with factors treatment×subgroup qualifiers (“off” status, tremor score). Change in tremor score in patients with
or without fatigue per treatment group.
718 Pogarell, Gasser, van Hilten, et al
www.jnnp.com
fatigue (10 pramipexole/4 placebo patients), dizziness (8/6),
insomnia (9/3), nausea (7/3), aggravated parkinsonism (4/4),
abdominal pain (6/1), tremor (2/5), and headache (6/1).
Except for aggravated parkinsonism and tremor each of these
adverse events were reported more often in the pramipexole
group (table 4). Adverse events with a risk difference in excess
of 5% (more than two patients) between treatment groups,
were fatigue, insomnia, nausea, abdominal pain, and head-
ache. Tremor was reported in more placebo patients (12.5%
versus 4.5%). The differences between the treatment groups in
the incidence of these adverse events did not reach statistical
significance. In this trial, new occurrence of dyskinesias was
not seen in the pramipexole group and hallucinations were
reported in two (4.5%) patients on pramipexole. Serious
adverse events (SAEs) occurred in four (4.8%) patients, two in
each treatment group. Only one SAE (orthostatic hypotension
with a short loss of consciousness in a pramipexole treated
patient) was assessed as drug related. One patient (placebo
group) dropped out due to a serious adverse event (cardiac
surgery for hitherto undetected aortic valve stenosis), but this
was not related to the study drug. No other adverse events led
to discontinuation. Laboratory assessments, ECG, vital signs,
and physical findings seemed not to be systematically changed
by pramipexole treatment.
DISCUSSION
The present study shows that pramipexole is not only an
effective antiparkinsonian agent with respect to improvement
in ADL or UPDRS motor scores as a whole, but also leads to a
statistically significant reduction of parkinsonian tremor
when added to a stable antiparkinsonian medication. With
respect to the tremor scores, the difference in mean relative
improvement between the treatment groups was −34.7% in
favour of pramipexole. The corresponding difference in the
change in UPDRS II/III sum score was −30.9%. Accordingly,
there could be a slightly pronounced efficacy of pramipexole
on tremor in these patients, and it seems that the reduction in
tremor is not merely due to an overall antiparkinsonian effect.
However, our findings are only descriptive, and in the
literature there are no comparable data on selective efficacy of
antiparkinsonian agents.
The long term EMG recordings as an objective measure of
tremor activity over time were consistent with the change in
tremor score, showing a difference in the mean relative reduc-
tion in tremor occurrence by −45.7% in favour of pramipexole.
Furthermore, both patients’ and investigators’ assessments as
well as the patients’ self rating scales showed superiority of
pramipexole in this trial and thus underlined the clinical rel-
evance and benefit in daily living of the observed effects.
The differences between pramipexole and placebo increased
dose dependently during titration and were maintained until
the end of the study. As indicated by the analysis of the single
tremor score items, pramipexole favorably influenced not
only—as might have been anticipated—rest tremor, but also
both action and postural components of tremor.
Subgroup analyses disclosed that patients with “off”
periods, indicating an advanced stage of the disease, and
patients with higher tremor scores at baseline derived best
benefit from pramipexole treatment. However, the treatment
effect of pramipexole remained significant in the subgroups
without “off” periods, or with lower baseline tremor scores.
Pramipexole has been reported to cause “sleep attacks”.
15
A
non-specific sedative effect could, conceivably, be responsible
for the improvement of tremor. As there was no correlation
between the reduction in tremor and the presence or absence
of fatigue or increased tiredness in the subgroup analysis, effi-
cacy end points do not seem to be influenced by this side effect
profile of the study drug.
Two points should be made concerning the inclusion crite-
ria and study population. Firstly, there is, unfortunately, no
accepted UPDRS derived measure to define “tremor domi-
nant”, so that certainly some patients with mixed type
Parkinson’s disease and severe tremor were included. By clini-
cal impression, though, most patients were characterised as
tremor dominant Parkinson’s disease. As the mean tremor
score was 11.4 at baseline, all patients had at least marked
parkinsonian tremor in “on”, regardless of being tremor
dominant or not.
Secondly, patients were required to receive an optimised
antiparkinsonian therapy before inclusion. As the median
levodopa dose was relatively low (300 mg in all study arms),
this condition does not seem to be fulfilled at first glance.
However, most patients had Hoehn and Yahr scores of 2 in the
“on” periods and only 2.5 in the “off” periods indicating a suf-
ficient global therapeutic response, and a mild to moderate
disease severity of the study population. In addition, before
study inclusion, antiparkinsonian therapy was optimised by
balancing the best possible ratio of symptomatic benefit to
side effects provided at an individual base, which might favour
lower levodopa doses.
The improvement in tremor in this patient group is remark-
able, as the patients enrolled into the trial had shown a
marked to severe parkinsonian tremor throughout their
medical history, despite an otherwise optimised medication.
Add on therapy with pramipexole led to a further significant
improvement in parkinsonian symptoms and particularly in
tremor throughout the study. Upon discontinuation of the
trial medication, the tremor scores rapidly returned to baseline
values (fig 3), consistent with a drug relation of the observed
effect. A maintenance period of 4 weeks as in this study is
relatively short. However, other clinical trials with longer
observation periods proved a sustained treatment effect of
pramipexole.
10 11 13
The safety data showed a good overall tolerability, although
the number of patients with at least one adverse event was
higher in the pramipexole group (93.2% v 77.5%, p=0.06). The
most prominent adverse events were fatigue, insomnia,
nausea, abdominal pain, and headache, which is in line with
previous studies and similar to those of other dopamine
agonists.
2101214
None of these single adverse events showed a
statistically significant difference between treatment groups;
however, these exploratory analyses are limited by the few
patients and should not be overrated. There were no
unexpected safety results or deaths. “Sleep attacks”, recently
reported in patients under non-ergoline dopamine agonists,
15
did not occur during this trial, and increased tiredness or
fatigue did not contribute to the treatment effects. Pramipex-
ole was regarded as safe and tolerable within the tested dose
range from 0.375 to 4.5 mg daily with an average daily dose of
4.1 mg in the population studied.
Table 4 Occurrence of adverse events
(AEs)/treatment group
pramipexole
(n=44)
placebo
(n=40) p Value
Any AE 41 (93.2) 31 (77.5) 0.06
Fatigue 10 (22.7) 4 (10) 0.15
Dizziness 8 (18.2) 6 (15) 0.78
Insomnia 9 (20.5) 3 (7.5) 0.12
Nausea 7 (15.9) 3 (7.5) 0.32
Aggravation of parkinsonism 4 (9.1) 4 (10) 1.00
Abdominal pain 6 (13.6) 1 (2.5) 0.11
Tremor 2 (4.5) 5 (12.5) 0.25
Headache 6 (13.6) 1 (2.5) 0.11
Serious AE 2 (4.5) 2 (5) 1.00
Assessed as drug related 1 (2.3) 0 1.00
Values are number of patients (%) with at least one AE; common
treatment emergent adverse events, occurring in at least 10% of
patients in either treatment group; and serious adverse events; p
values (Fisher’s exact test) for the differences between treatment
groups
Pramipexole in patients with Parkinson’s disease with predominant tremor 719
www.jnnp.com
Positive effects of dopamine agonists as adjunct to levodopa
therapy on parkinsonian tremor have been reported
earlier.
22–24
Pergolide improved parkinsonian tremor in an open
label trial in patients unresponsive to bromocriptine therapy
(retrospective analysis),
22
and in a placebo controlled double
blind trial
23
as part of an overall antiparkinsonian effect. Both
lisuride and bromocriptine showed a significant improvement
in tremor when added to long term levodopa treatment in
patients with wear ing off phenomena.
24
None of these studies
were designed to investigate the effects on tremor separately
in a homogeneous sample of patients.
The reported trial is the first controlled, double blind study
of a dopamine agonist focusing on this cardinal symptom,
including tremor scales and objective EMG recordings. The
study was planned to test previous—methodologically
limited—findings that have suggested tremorlytic properties
of pramipexole and was designed to compare pramipexole
with placebo.
17
As no other dopamine agonist has been inves-
tigated with a special attention to tremor, the magnitude of
the tremorlytic response of pramipexole cannot be directly
compared with other substances. Data available on budipine, a
butyldiphenylpiperidine with affinities to various neurorecep-
tors and an antiparkinsonian agent, suggested to be tremor-
lytic, have shown an improvement of 33.7%
25
and 40%
26
as
measured with long term EMG. Our result of 45.7% difference
in relative tremor reduction between pramipexole and placebo
is even more pronounced. Thus further active comparator
studies are warranted to directly compare pramipexole to
other substances with tremorlytic potential. Nevertheless, we
conclude that in patients with early or advanced Parkinson’s
disease and insufficient control of tremor, add on pramipexole
is an effective dopamine agonist and thus seems to provide a
therapeutic option for this subgroup of patients with Parkin-
son’s disease.
ACKNOWLEDGEMENTS
This study was supported by Boehringer Ingelheim Pharma KG,
Ingelheim, Germany. The following coinvestigators were involved in
patient recruitment and data collection: A Ihsche, S Redies, and F
Schnorpfeil, Marburg, Germany; M Singer, and C Macher, Munich,
Germany;WJTvandeBeek, Leiden, The Netherlands; S Breit,
Tuebingen, Germany. We thank Dr J Koester, Ingelheim, Germany, for
statistical planing, analysis, and review. DM and SP are employees of
Boehringer Ingelheim, the manufacturer of pramipexole. JJvH has
received a fund from Boehringer Ingelheim for research. TG and WHO
have been reimbursed by Boehr inger Ingelheim for attending several
symposia, at which they gave presentations. In addition WHO received
an unrestricted grant of US$15 000 for studying sudden onset
somnolence in Parkinson’s disease in the year 2000.
.....................
Authors’ affiliations
O Pogarell, W H Oertel, Department of Neurology, Philipps-University
of Marburg, Marburg, Germany
T Gasser, Department of Neurology, University of Munich, Munich,
Germany
J J van Hilten, Department of Neurology, Leiden University Medical
Center, Leiden, The Netherlands
S Spieker, Department of Neurology, University of Tuebingen,
Tuebingen, Germany
S Pollentier, D Meier, Boehringer Ingelheim Pharma KG, Clinical
Research, Ingelheim, Germany
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