Quality of life in Parkinson’s disease improved by apomorphine pump: the OPTIPUMP cohort study

Abstract

To report on OPTIPUMP, a cohort study, investigating the impact in real-life clinical settings of continuous subcutaneous apomorphine infusion (CSAI) on the quality of life (HRQoL) of patients with Parkinson's disease. OPTIPUMP was a prospective, open-label, observational cohort study involving 30 investigational sites in France. CSAI was proposed as part of routine clinical care to patients aged ≥18 years, in absence of dementia, with a PD diagnosis and based on the presence of motor fluctuations not controlled by oral treatments. The impact of APO-pump on quality of life was evaluated as the difference in PDQ-39 scores between the initiation treatment and the follow-up visit after 6 months' treatment. All adverse events were recorded. Hyper- and hypodopaminergic behavioral tolerance was assessed on the Ardouin Scale of Behavior in Parkinson's Disease. Between September 2011 and January 2013, we enrolled 142 patients: 42 patients were withdrawn due to pump removal (33), death (4), lost of follow-up (4), no available data (1). 100 completed the study. At 6 months, their HRQoL had significantly improved (p = 0.011), as had their total UPDRS score (p < 0.001). Regarding the safety profile, Ardouin scale scores indicated that their hyperdopaminergic behaviors had not increased. CSAI had a favorable impact on HRQoL, with benefits outweighing risks. The analysis of the withdrawn patients highlights the heterogeneity of the use of the pump having an impact on its efficacy and tolerability.

Full text

ORIGINAL COMMUNICATION
Quality of life in Parkinson’s disease improved by apomorphine
pump: the OPTIPUMP cohort study
Sophie Drapier
1,14
•
Alexandre Eusebio
2
•
Bertrand Degos
3
•
Marc Ve
´
rin
1
•
Franck Durif
4
•
Jean Philippe Azulay
2
•
Franc¸ois Viallet
5
•
Tiphaine Rouaud
6
•
Caroline Moreau
7
•
Luc Defebvre
7
•
Valerie Fraix
8
•
Christine Tranchant
9
•
Karine Andre
10
•
Christine Brefel Courbon
11
•
Emmanuel Roze
12
•
David Devos
13
Received: 17 November 2015 / Revised: 15 March 2016 / Accepted: 21 March 2016
Ó Springer-Verlag Berlin Heidelberg 2016
Abstract To report on OPTIPUMP, a cohort study, inves-
tigating the impact in real-life clinical settings of continuous
subcutaneous apomorphine infusion (CSAI) on the quality of
life (HRQoL) of patients with Parkinson’s disease. OPTI-
PUMP was a prospective, open-label, observational cohort
study involving 30 investigational sites in France. CSAI was
proposed as part of routine clinical care to patients aged
C18 years, in absence of dementia, with a PD diagnosis and
based on the presence of motor fluctuations not controlled by
oral treatments. The impact of APO-pump on quality of life
was evaluated as the difference in PDQ-39 scores between the
initiation treatment and the follow-up visit after 6 months’
treatment. All adverse events were recorded. Hyper- and
hypodopaminergic behavioral tolerance was assessed on the
Ardouin Scale of Behavior in Parkinson’s Disease. Between
September 2011 and January 2013, we enrolled 142 patients:
42 patients were withdrawn due to pump removal (33), death
(4), lost of follow-up (4), no available data (1). 100 completed
the study. At 6 months, their HRQoL had significantly
improved (p = 0.011), as had their total UPDRS score
(p \ 0.001). Regarding the safety profile, Ardouin scale
scores indicated that their hyperdopaminergic behaviors had
not increased. CSAI had a favorable impact on HRQoL, with
benefits outweighing risks. The analysis of the withdrawn
patients highlights the heterogeneity of the use of the pump
having an impact on its efficacy and tolerability.
OPTIPUMP Study Group. Members of the OPTIPUMP Study Group
are present in Acknowledgements.
Electronic supplementary material The online version of this
article (doi:10.1007/s00415-016-8106-3) contains supplementary
material, which is available to authorized users.
& Sophie Drapier
sophie.drapier@chu-rennes.fr
1
Department of Neurology, EA 4712, University Rennes 1,
CHU Pontchaillou, 2 Henri Le Guilloux,
35000 Rennes, France
2
Department of Neurology and Movement Disorders,
APHM Timone University Hospital and Institut de
Neurosciences de la Timone, AMU-CNRS UMR 7289,
Marseilles, France
3
Department of Neurology, Centre Expert et Inter-
Re
´
gional de Coordination de la Maladie de Parkinson,
Ho
ˆ
pital de la Pitie
´
-Salpe
ˆ
trie
`
re, APHP, 47-83 boulevard
de l’Ho
ˆ
pital, 75013 Paris, France
4
Department of Movement Disorders and Neurology,
CHU Clermont-Ferrand, 58 rue Montalembert,
63003 Clermont-Ferrand, France
5
Department of Neurology, University Hospital, Avenue
des Tamaris, 13616 Aix-En-Provence, France
6
Department of Neurology, CHU Nantes, boulevard Jacques-
Monod-Saint-Herblain, 44093 Nantes, France
7
Department of Movement Disorders and Neurology,
INSERM U1171, Lille University, CHU Lille, 2, avenue
Oscar Lambret, 59037 Lille, France
8
Department of Psychiatry and Neurology, CHU Grenoble,
Avenue Maquis du Gre
´
sivaudan, 38700 La Tronche, France
9
Department of Movement Disorders and Neurology, CHU
Strasbourg, 1 Place de L Ho
ˆ
pital, 67000 Strasbourg, France
10
CLINACT Groupe, Se
`
vre, France
11
Department of Clinical Pharmacology and Neurosciences,
UMR 825 Inserm, University Hospital Toulouse III,
31059 Toulouse, France
12
Department of Neurology, Assistance Publique Ho
ˆ
pitaux de
Paris, Inserm, U 1127, CNRS, UMR 7225, UMR S 1127,
Institut du Cerveau et de la Moelle e
´
pinie
`
re, ICM, Sorbonne
Universite
´
s, 47-83 boulevard de l’Ho
ˆ
pital, 75013 Paris,
France
123
J Neurol
DOI 10.1007/s00415-016-8106-3

Keywords Apomorphine pump  Parkinson’s disease 
Quality of life
Introduction
Severe Parkinson’s disease (PD) represents a therapeutic
challenge when patients develop levodopa-related motor
complications. Continuous subcutaneous apomorphine infu-
sion (CSAI) is one option recommended in many EU countries.
Several open-label studies have reported a constant, significant
reduction in motor fluctuations (increase in ‘‘on’’ time and
decreases of 50–70 % in ‘‘off’’ time), with a significantly
reduced L-DOPA daily dose [1–5] and a possible improvement
in dyskinesia [1, 4, 6, 7]. Although this treatment was intro-
duced back in the late 1980s, very little effort has been made to
better characterize the use and impact of apomorphine in a large
cohort of patients with PD in real-life clinical settings. So far,
most studies have been small, and the largest study (82 patients)
was retrospective [2]. A comprehensive meta-analysis of clin-
ical trials of CSAI in PD [8] concluded that apomorphine was
both safe and effective in the treatment of patients whose
symptoms were insufficiently controlled. However, these trials
were performed in a very idiosyncratic manner (e.g. waking-
day infusion, combined with levodopa therapy, prospective or
retrospective, different durations of therapy, etc.), and the lar-
gest one included just 45 patients, in an open-label setting. In
recent years, health-related quality of life (HRQoL) instruments
were developed to assess more comprehensively the functional
health status of PD patients and the effectiveness of medical
treatment to become the measure of choice [9, 10]. However,
very few studies have investigated their effects [11–13]. We
therefore prospectively collected data on a large group of 142
patients who underwent CSAI in France between September
2011 and January 2013. Our prospective cohort study per-
formed in real-life clinical settings observed (1) the impact of
CSAI on HRQoL at 6-month follow up, and (2) the risk/benefit
ratio (i.e. motor and nonmotor symptoms and tolerance).
Methods
Study design and patient selection
OPTIPUMP was a prospective, open-label, observational,
cohort study involving 30 investigational sites in France.
The study was approved by the relevant authorities
(CCTIRS: 11.223; CNIL: DR-2011-157; CNOM: FR/IH/
SRMI 11.110.064) prior to initiation, in accordance with
local applicable regulations for observational studies. Being
a current care study and having the AMM authorization, the
study did not need to undergo ethical procedures. All patients
gave informed consent to take part.
Patients were enrolled in the study if they had already
been selected to receive CSAI by their clinical teams as part
of their routine clinical care. Suitability for this therapy was
based on the presence of motor fluctuations and/or disabling
off periods and/or dyskinesias not optimally controlled by
oral treatments. All patients had to be aged C18 years,
nondemented according to the DCM-V (MMSE test and
semi structured interviews for evaluation of autonomy in
daily life), diagnosed with PD based on established criteria
[14], and capable of completing the PDQ-39 unaided.
Patients with hypersensitivity to apomorphine, hepatic
and/or renal failure, or any other medical or psychological
problem that might interfere with the HRQoL assessment
were excluded from the study.
Medication
All patients considered for the study had to be programmed
for initiation of apomorphine hydrochloride (APO) treat-
ment (Apokinon
Ò
, Aguettant, Lyon, France), to be given
subcutaneously as a continuous infusion via a pump.
CSAI was initiated and adjusted during a hospital stay,
as routinely done in each center. Patients were then dis-
charged from hospital and followed on an outpatient basis
by their physician. Follow-up of CSAI was also undertaken
by the home healthcare provider, via home visits by spe-
cialized nurses and outbound patient calls answered by an
expert call center.
Efficacy and safety assessments
To evaluate the impact of CSAI on HRQoL, the authors
observed the difference between PDQ-39 scores at the
initiation of APO-pump treatment and at the follow-up visit
after 6 months of APO-pump treatment.
The PDQ-39 is a PD-specific questionnaire covering
eight health dimensions that may be adversely affected by
the disease [15]. Each dimension is scored from 0 to 100,
with lower scores indicating better perceived health status.
To assess the efficacy of CSAI, the Clinical Global
Impression Improvement (CGI-I) scale [16]wasratedby
patients and physicians separately at the end of the observa-
tion period, and the Unified Parkinson’s Disease Rating Scale
(UPDRS) Parts I, II, III and IV [17] was rated by physicians.
We also evaluated the Minimal Clinically Important
Change (MCIC) on the UPDRS part II (activities of daily
13
Department of Medical Pharmacology, INSERM U1171,
Lille University, CHU Lille, 2, avenue Oscar Lambret,
59037 Lille, France
14
Neurology Department, University Hospital, 2 rue Henri Le
Guilloux, 35200 Rennes, France
J Neurol
123

living, ADL), part III (motor) and the total UPDRS. The
MCIC of the UPDRS was calculated as the mean change of
UPDRS score in those patients who were judged to be min-
imally improved on the physicians’ CGI-I (score = 3) [18].
All adverse events were recorded. In addition, hyper-
and hypodopaminergic behavioral tolerance was evaluated
with the Ardouin Scale of Behavior in Parkinson’s Disease
[19], a validated scale used to track changes in mood and
behavior related to dopaminergic medication [20]. It’s 21
items addressing nonmotor symptoms are grouped into four
dimensions: general psychological assessment, apathy,
nonmotor fluctuations and hyperdopaminergic behaviors.
The ratings on a 5-point scale ranging from 0 (Absent)to4
(Severe) are performed during a semistructured interview
and closed questions about the severity and intensity of
each symptom that occurred during the previous month. A
score C2 is considered to be an alert.
Statistics
All the scores on the scales and questionnaires assessing
changes in the patients’ status between the baseline and the
6-month follow up were analyzed for a per protocol popu-
lation (i.e., the population that completed the 6-month
assessment). Adverse events were reported for the safety
population (i.e., all the enrolled patients who initiated the
CSAI). For each PDQ-39 domain, the item scores were
summed and this score was transformed to percentage on the
maximum possible score. The PDQ-39 summary index was
the arithmetic mean of the eight domains score. Missing data
were imputed according to the predictive mean matching
method for continuous variables with a monotone pattern of
missing data (expectation–maximization, EM algorithm).
The monotone pattern was obtained after applying the
Markov chain Monte Carlo partial imputation method. The
PDQ-39 questionnaires were analyzed with and without
multiple imputations, to check the robustness of our find-
ings. No other missing data were replaced. When we
reached a sufficient sample size, comparative analyses were
performed, using Chi-square tests for qualitative parameters,
and Student’s t test for quantitative ones. Analyses were
conducted with SAS version 9.2, and the significance
threshold was set at p = 0.05. All statistical tests were two-
sided, with the probability of a Type I error set at .05.
Results
Baseline demographics and patients’ characteristics
A total of 142 patients were enrolled between 07/Sep/
2011 and 24/Jan/2013. Out of these patients, 100
completed the entire study up to the 6-month assessment.
One patient had a MMSE score of 15 and 13 patients had
a MMSE score between 20 and 24. For all these patients,
the autonomy in daily life was verified during semi-
structured interviews. Patients’ baseline clinical char-
acteristics are set out in Table 1. Regarding patients’
mode of daily life, 3/142 (2.1 %) were living in spe-
cialized institutes, 26/142 (18.3 %) lived alone, 64/142
(45.1 %) were living at home with part-time homecare
support, and 49/142 (34.5 %) were living at home with
fulltime homecare support. This homecare support could
be supplied by a patient’s relative and/or by external
providers.
Treatment discontinuation and reasons
Forty-two patients withdrew from the study due to drug
intolerance (12), lack of efficacy (6), other medical reasons
(6), intercurrent event (5), device intolerance (i.e., patients
found cumbersome the device: 4), death (4), lost of follow-
up (4), missing data (1) (Fig. 1).
The patient with an MMSE score of 15 and 3 patients
with an MMSE between 20 and 24 were among the 12
patients experiencing drug intolerance.
Table 1 Patients’ baseline characteristics and previous PD treatment
Baseline parameters n/mean ± SD (%)
Number of patients N = 142
Demographics
Female n = 83 (58.5 %)
Male n = 59 (41.6 %)
Age (years) 66.7 ± 10.8
Time from PD diagnosis (years) 11.6 ± 5.4
Motor status
Dyskinesia n = 123 (86.6 %)
Motor fluctuations n = 138 (97.2 %)
Hoehn and Yahr scale (ON) 2.3 ± 0.1
Hoehn and Yahr scale (OFF) 3.4 ± 1.1
PD treatment history
Total daily L-dopa equivalent dose (mg) 1154.1 ± 758.9
L-dopa n = 138 (97.2 %)
Dopamine agonists n = 90 (63.4 %)
Anticholinergics n = 4 (2.8 %)
Amantadine n = 38 (26.8 %)
MAO-B inhibitors n = 38 (26.8 %)
COMT inhibitors n = 46 (32.4 %)
Clozapine n = 7 (4.9 %)
Apomorphine pen n = 20 (14.1 %)
Antidepressants n = 42 (29.6 %)
Deep brain stimulation before CSAI n = 11 (7.8 %)
J Neurol
123

Therapeutic strategy
CSAI pump treatment
CSAI was initiated for daytime use in 87.3 % of the
patients, lasting on average for 12.7 ± 1.5 h a day (me-
dian: 12; range 9–18), while 24 h infusion was the primary
mode for the remaining 12.7 %. A single infusion rate was
implemented for almost all patients (Supplemental
Table 1). After a period of adaptation, the total daily
apomorphine dose was increased from a mean starting dose
of 22.7 ± 25.4 mg/day to a mean apomorphine dose of
58.5 ± 46.1 mg/day at hospital discharge (M0), and sub-
sequently kept within a similar range during the 6-month
observation period.
Impact on other treatments
Of the 142 patients in the overall population, 84 % were still
being treated with L-dopa at M6, compared with 97 % at
baseline, and their mean daily dose had decreased by 24 %
(p \ 0.0001). The proportion of patients treated with other
dopaminergic agonists decreased sharply from 63 % at
baseline to 24 % at M6, but there was no significant change
in the mean L-dopa equivalent daily dose for those still
receiving this type of medication (Supplemental -Fig. 1).
Effectiveness, safety and adverse events of CSAI
Effectiveness
Comparing the 6-month scores to the baseline ones on the
self-assessed PDQ 39 of the 100 patients who completed
the study; we observed statistically significant differences
in the overall score (-11.3 %, p = 0.011), evidencing
significant improvements on the bodily discomfort, stigma,
mobility and emotional well-being dimensions (Table 2).
At the 6-month assessment, CGI-I scores were collected
for 94 out of the 100 patients who completed the study.
According to this scale, 73.4 % of patients considered that
their state had improved (i.e., scores between 1 and 3),
9.6 % that it was unchanged (score of 4) and 17.0 % that it
had worsened (i.e., scores of 5–7) 6 months after initiation
of CSAI. Neurologists’ assessments of patients were very
consistent with these figures: 71.7 % improved, 15.2 %
unchanged, and 13.1 % worsened after CSAI initiation
(Fig. 2). For what concerns the MCIC: the number of
patients minimally improved (=3) was 28. For this group,
the mean change in UPDRS part II was -5.3 points (95 %
CI -7.7 to -2.8), in UPDRS part III was -4.7 (95 % CI
-8.1 to -1.3), and in total UPDRS was - 12.9 (95 % CI
-18.8 to -6.9).
The total UPDRS score at 6 months showed a statisti-
cally significant improvement for all 100 patients still in
the study (-17.5 %, p \ 0.0001). UPDRS-I showed no
such improvement (-10.9 %, p = 0.33), but all the other
domains we assessed showed statistically significant
improvements: UPDRS-II in on state (-10.5 %, p =
0.0448); UPDRS-II in off state (- 17.9 %, p \ 0.0001);
UPDRS-III in best on state (-16.3 %, p = 0.0002); and
UPDRS-IV (-31.3 %, p \ 0.0001) (Supplemental Fig. 2).
Safety
Comparing the 6-month scores to the baseline ones of the
100 patients who completed the study, we observed sta-
tistically significant decrease in the percentage of patients
exhibiting a score C2 on the Ardouin scale for the fol-
lowing three dimensions: anxiety, on-state nonmotor fluc-
tuations and off-state nonmotor fluctuations.
No significant difference evidencing overall impairment
was found in any of the areas we explored. In particular
there was no overall worsening of hyperdopaminergic
behaviors (Table 3).
Fig. 1 Patients distribution across study duration
J Neurol
123

Adverse events
All adverse events bellow were analyzed in the overall
cohort (N = 142). Injection site reactions were predomi-
nantly reported during the course of the study, with 90
(63.4 %) of the patients experiencing nodules at injection
sites, and 43 (30.2 %) of the patients reporting local pain at
injection sites. These nodules occurred in the first weeks of
therapy for most of the patients (86.7 %). The nodules
were not really considered painful, with a median rating of
2 on a 10-point pain scale. Only one patient was withdrawn
due to occurrence of nodules.
Other treatment-emergent adverse events occurring in
61.3 % of the patients included somnolence, reported for
33 patients (23.2 %), behavioral disorders for 31 patients
(21.8 %) (confusion, 7; agitation, 11; hallucinations 13),
gastrointestinal disorders for 25 patients (17.6 %), fatigue
for 18 patients (12.7 %), and sudoresis for 17 patients
(12 %). The patient having an MMSE score at 15 and one
patient having an MMSE score at 24 were among the 7
patients experiencing confusion.
Cardiac disorders, sialorrhea, and pallor were also
reported, but with a lesser frequency of occurrence (6.3, 6.3
and 2.1 % of the overall study population).
In total, 17 serious adverse events were reported in 13
patients, including reactions at injection sites with local
skin necrosis, panniculitis, or local skin inflammatory
reaction (5 cases), chest pain (2 cases), somnolence (1
case) and impulse control disorders in the form of patho-
logical gambling (1 case). Isolated cases of hypersensitiv-
ity, nausea, hypertension, falls, costal fracture,
hypereosinophilia, confusional syndrome, agitation were
also reported.
Discussion
OPTIPUMP was an observational, longitudinal, prospec-
tive cohort study conducted in France to collect exhaustive
data on patients affected with PD undergoing CSAI treat-
ment in their usual care environment. The cohort enrolled
142 patients. Out of them, 100 patients completed the
study. After 6 months of CSAI, an average improvement of
11.3 % in their quality of life was observed. More than
70 % of 100 patients reported an improvement on their
CGI-I. Motor symptoms decreased by 17.5 %, and were
associated with a positive impact on behavioral nonmotor
symptoms (around 90 % of patients remained stable or
improved on the Ardouin scale) and a good safety profile
(lower than expected dropout rate) thus showing a positive
impact on the risk/benefit ratio.
Given the lack of published data on the efficacy and
safety of CSAI for a large population in a real-life setting, as
well as on its different practical uses, we reasoned that a
prospective observational cohort study in a real-life clinical
setting would clarify the impact of this treatment on quality
of life and its role in therapeutic strategies for managing
patients with PD. The results of this cohort study are
externally valid, as apomorphine was given to patients
receiving different types of standard antiparkinsonian treat-
ment in a real-life clinical setting. Moreover, the large
number of patients and the multicenter nature of the study
increased the representativeness of the sample, thus enabling
us to truly evaluate the impact on the quality of life.
Table 2 Changes in mean
PDQ-39 scores
Dimension Baseline 6 months Magnitude of effect % p value
Mobility 63.8 ± 19.6 57.5 ± 24.4 -9.9 % 0.0026
Activities of daily living 51.2 ± 21.9 48.2 ± 22.5 -6.0 % 0.13
Emotional well-being 42.2 ± 21.6 38.2 ± 21.0 -9.6 % 0.0241
Stigma 39.6 ± 23.2 33.8 ± 22.4 -14.6 % 0.0019
Social support 20.8 ± 21.5 20.8 ± 20.5 -0.2 % 0.99
Cognitions 32.4 ± 20.6 33.8 ± 17.8 ?4.5 % 0.43
Communication 33.4 ± 20.3 30.9 ± 19.4 -7.5 % 0.33
Bodily discomfort 48.4 ± 26.0 42.9 ± 21.4 -11.4 % 0.0165
Global score 41.2 ± 15.5 36.5 ± 13.9 -11.3 % 0.0114
Fig. 2 Proportions of patients for each CGI-I score assessed by the
patients and the neurologists at 6 months
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123

Nevertheless, the study presented several limitations
related to its design being observational, open-label not
implying a control group. The calculation of the sample
size and the study design were pragmatic. We focused on
HRQoL as primary outcome in a real-life population where
conclusive data are missing. One-hundred forty-two
patients were included from 30 centers thus implying a
variability of data not comparable to the reports in litera-
ture. Nevertheless, more strict selection criteria would have
not allowed a real-life focus on this treatment.
The drop-out rate could indeed appear to be high as
compared with randomized clinical trials performed in
expert centers with selected smaller sample size of patients.
However, if we consider the drop out related to pump
system removal, the patients are only 33 (23 %). Further-
more, the purpose and the great interest of the current study
was to involve a large number of centers covering the
country and the highest number of patients in order to
capture the real life of the treatment. Thus, the study
involved all the motivated centers whatever the size and
the expertise in CSAI and clinical trials. These different
designs could mainly explain the different rates of drop out
and the risk of attrition regarding the loss of participants.
Because patients’ perceptions of the benefits of a given
treatment may differ from clinicians’ assessments, HRQoL
has become the outcome measure of choice [10]. In our
prospective study, the overall PDQ-39 score had improved
significantly at 6-month follow up, not only for the physical
aspects (mobility, bodily discomfort) but also for the
mental ones (stigma, emotional well-being), reflecting the
positive overall impact of CSAI on the different aspects of
the disease. Few studies have evaluated the effect of CSAI
on the quality of life of patients affected with PD. Rambour
et al. reported no improvement in HRQoL in a retrospec-
tive analysis of 18 patients receiving a low dose of apo-
morphine during the daytime (3.1 mg/h) [11]. In a clinical
observational ‘‘real life’’ study, Martinez-Martin et al. [12]
compared CSAI versus conventional treatment (control
group) over 1 year on the quality of life. During follow-up
the control group showed worsening in PDQ-8 while the
CSAI group showed highly significant improvements. In an
open-label, prospective, observational study featuring the
abbreviated PDQ-8 questionnaire, the same author [13]
showed an improvement of 30 % of HRQoL after
6 months of CSAI in a group of 43 PD patients receiving a
mean daily dose of 106 mg.
Table 3 Ardouin scale: changes in the proportion of patients with a score C2 for each item
Dimension Items Proportion of patients with a score C 2 (%) p
Baseline 6 mos
a
General psychological state Depressive mood 28.4 20.2 ns
Hypomanic or manic mood 3.4 3.4 ns
Anxiety 34.1 25.8 p = 0.025
Irritability 9.1 10.1 ns
Hyperemotivity 25.0 16.9 ns
Psychotic symptomatology 3.4 2.3 ns
Overall functioning in apathetic mode 13.6 14.6 ns
Nonmotor fluctuations Motor ON 12.6 4.5 p = 0.01
Motor OFF 43.7 27.0 p = 0.002
Hyperdopaminergic behaviors Nocturnal hyperactivity 12.5 9.0 ns
Diurnal somnolence 15.9 20.2 ns
Excessive eating behavior 8.0 10.1 ns
Creativity 9.1 5.6 ns
Hobbyism 10.2 9.0 ns
Punding 5.7 4.5 ns
Risk-seeking behavior 3.4 2.3 ns
Compulsive shopping 2.3 1.1 ns
Pathological gambling 1.1 2.3 ns
Hypersexuality 2.3 2.3 ns
Compulsive dopaminergic medication use 3.4 2.3 ns
Overall functioning in an appetitive mode 4.6 3.4 ns
a
mos months
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123

Our HRQoL results were reinforced by the CGI-I score
showing that 73 % of patients deemed that their state had
improved with CSAI. The positive effect of CSAI on
HRQoL can be explained by the profile of our patients and
the therapeutic strategies that were adopted. First, the mean
age of our population was 66 years, which is older than the
population commonly studied and reported in the literature
[2]. As a consequence of their greater age, 69 % of our
patients were retired and 17 % had a disability at study
enrolment. However, although the patients in our popula-
tion had different profiles, in France, CSAI is generally
only proposed when patients have reached an advanced
stage of severe levodopa-related motor complications
(LDRMCs), and as expected, nearly all (97 %) the patients
had motor fluctuations, and the vast majority (87 %) had
dyskinesias at inclusion. Our results therefore confirm that,
in suitably selected patients with severe LDRMCs, CSAI
has a beneficial effect on HRQoL. Second, the mean total
daily apomorphine dose was 58 mg/day, maintained either
for an average of 13 h/day or continuously, and was
accompanied by a significant reduction in dopaminergic
treatment, in a pattern suggesting that the patients’ neu-
rologists preferred to reduce the levodopa daily dose and to
withdraw other dopaminergic agents during the 6-month
adaptation period. Even if a small group of our patients had
different infusion regimens, ranging from apomorphine
monotherapy to continuous 24 h infusion, CSAI was
mainly proposed as an add-on during the waking day, with
a reduction in additional oral L-dopa therapy.
The positive impact on HRQoL was accompanied by a
significant improvement in UPDRS scores (-17.5 % for
the total score). These differences were clinically mean-
ingful, and translated into an improvement in daily life
activities, motor disability and motor fluctuations, as pre-
viously reported in smaller populations [2, 21, 22].
As reported by Manson et al. [3], Pietz et al. [4], and Di
Rosa et al. [7], the apomorphine treatment had a favorable
impact on dyskinesias reduction or stabilization since it
allowed a marked reduction of levodopa dosage. To be
highlighted, Manson et al. published a dyskinesia duration
reduced by 64 % at 12 months in the monotherapy patients’
group versus 30 % in the polytherapy one [3]. In our study,
we observed no significant change in dyskinesia under CSAI.
The lack of effectiveness on dyskinesia may relate to the need
for continuing oral levodopa-equivalent dose therapy, result-
ing in sustained pulsatile stimulation, which was the case for a
large proportion of patients in our study. Furthermore, the
apomorphine was delivered in average at 60 mg/day which is
probably not adequate level to have an effect on dyskinesia
reduction.
Interestingly, the improvements only became evident
after at least 3 months of CSAI, but the full benefit was
consistent after 6 months of treatment. This may represent
a clue to the optimization of CSAI, and suggests that
patients need to wait at least 3–6 months before judging the
risk/benefit ratio. Forty-two patients dropped out of CSAI
before the end of the observation period, most of them very
soon after pump initiation. The reasons for these dropouts
were mainly an unfavorable risk/benefit ratio. This result is
important, because withdrawal from treatment can only be
reliably recorded from prospective studies and, to our
knowledge, no data on these rates are provided in the lit-
erature for CSAI. Moreover, it emphasizes the importance
of the period just after hospital discharge, when patients
return home. At this point, very close follow up with the
physician and homecare support provider is crucial for
properly adjusting the treatment and, by so doing, avoiding
dropout. After the first 3 months, we found that CSAI
became more acceptable to patients, and the dropout rate
fell.
The reported side effects were in accordance with the
known safety profile of apomorphine, as described in the
summaries of product characteristics and in the literature
[23]. Cutaneous side effects, constituting the most common
adverse reactions, were generally not painful and did not
lead to treatment discontinuation, except for one patient.
The fact that we gave early information to patients on the
possible side effects and their management by homecare
providers could explain their very positive global impres-
sions. However, the key focus of this study in terms of
tolerance was a possible impact on hypo- and hyper-
dopaminergic mood and behavior, which could be disas-
trous for patients and their families, and remains a
challenge in the therapeutic management of PD [24, 25].
Results showed a significant decrease in anxiety and non-
motor fluctuations in both the off and on states, evidencing
partial alleviation of the symptoms induced by the other
anti-PD therapies, the disease itself, or both. Most of the
items tended to improve, without reaching a statistically
significant level, except for diurnal somnolence, which
tended to worsen. Hyperdopaminergic behaviors did not
increase for most of the patients, proving that a higher
incidence of psychiatric adverse effects after CSAI
implementation is not systematic. CSAI had a generally
favorable impact, despite the very variable nonmotor pro-
files of our PD patients. This favorable outcome may also
be explained by the treatment of these nonmotor symptoms
before beginning CSAI. At baseline, 29.6 % of patients
were receiving antidepressant therapy. Just 4.9 % of hal-
lucinated patients were treated with clozapine at baseline,
but this figure had reached 21 % by 6-month follow up.
In conclusion, CSAI, defined as the combination of a
drug, a pump and a support service at home, had a favor-
able impact on quality of life after a follow-up of 6 months,
with the benefits outweighing the risks in the studied
population, confirming its place in the treatment strategy
J Neurol
123

for PD patients with motor fluctuations. Further analyses of
patients with different PD profiles would make it possible
to establish the best therapeutic strategies and modalities of
CSAI, in order to derive maximum benefit from it.
Acknowledgments The authors are indebted to Se
´
bastien Woynar
for his experienced participation in the organization of the study and
technical support, Sara Calmanti for critical readings, manuscript
editing and submission, and Elisabeth Portier for advice in manuscript
editing.
Sophie Arguilliere, Ste
´
phanie Bannier, Philippe Busson, Vale
´
rie
Chauvire, The
´
odor Danaila, Pascal Derkinderen, Anne Doe De
Maindreville, Fre
´
de
´
rique Fluchere, Eric Gaujard, Julien Gere, Olivier
Ille, Paul Krack, Pierre Krystkowiak, Ame
´
lie Leblanc, Romain
Lefaucheur, Alain Legout, David Maltete, Fabienne Ory, Aure
´
lia
Poujois, Nicolaı
ˆ
e Rasvan Gosporady, Alain Razafindramboa, Anne
Salmon, Franc¸ois Tison, Fre
´
deric Torny, Tatiana Witjas, Farid
Yekhlef, Fabienne Zaetta.
Compliance with ethical standards
Study funding The study has been funded by Orkyn’ and
Aguettant.
Conflicts of interest Dr Sophie Drapier received speech honorar-
ium from Teva and Medtronic; and served on scientific advisory
boards for Aguettant and Britannia. Dr Alexandre Eusebio received
honoraria from UCB, GE Healthcare, Aguettant, is in the advisory
board for Orkyn and has received research grants from the French
Ministry of Health and the Agence Nationale de la Recherche.
Dr Bertrand Degos received research support from INSERM (COS-
SEC), patient’s association France Parkinson; received travel fund-
ings from Novartis, Teva, Lundbeck, MERZ-pharma; received speech
honorarium from Novartis and Medtronic; and served on scientific
advisory boards for Aguettant. Dr Marc Ve
´
rin has served on the
Scientific Advisory Board for Aguettant and Orkyn and received
speech honorarium from Teva and Medtronic. Dr Franck Durif has
served on the Scientific Advisory Board for Aguettant and Orkyn and
received speech honorarium from Teva and Medtronic. Dr Jean
Philippe Azulay received honoraria from Abbvie, Boehringer, UCB
and is in the advisory board for Abbvie, Zambon, UCB. Dr Franc¸ois
Viallet has served on the Scientific Advisory Board for Aguettant and
Orkyn. Dr Tiphaine Rouaud received speech honorarium from Teva.
Dr Caroline Moreau has served on the Scientific Advisory Board for
Aguettant. Dr Luc Defebvre served on the Scientific Advisory Board
for Novartis, Aguettant and Abbvie, and has received various hono-
raria from pharmaceutical companies (Abbott Abbvie and Boehrin-
ger) for consultancy and lectures on Parkinson’s disease at symposia.
Dr Valerie Fraix received honorarium from Medtronic France.
Dr Christine Tranchant received speech honorarium from Teva and
served on scientific advisory boards for Allergan and Abbvie. Karine
Andre reports no disclosure. Dr Christine Brefel Courbon served on
the Scientific Advisory Board for Novartis, Aguettant, UCB, Med-
tronic and received PHRC grants from the French Ministry of
Research. She has received various honoraria for consultancy and
lectures at symposia from pharmaceutical companies. Dr Emmanuel
Roze is the recipient of a grant ‘‘poste d’accueil’’ AP-HP/CNRS. He
received research support from INSERM (COSSEC), AP-HP (DRC-
PHRC), Fondation pour la Recherche sur le Cerveau (FRC), Merz-
Pharma, Orkyn, IP sante
´
, Ultragenyx; served on scientific advisory
boards for Orkyn, Ultragenyx and Merz-pharma; received speech
honorarium from Merz-pharma, Novartis, Ipsen-Pharma and Orkyn,
received travel funding from Ipsen-Pharma, Teva, Abbvie, Merz-
Pharma, Dystonia Europe, the Georgian Medical and Public Health
Association the International Federation of Clinical Neurophysiology,
and the Movement Disorders Society. Dr David Devos served on the
Scientific Advisory Board for Novartis and Aguettant and has
received PHRC grants from the French Ministry of Health and
research funding from the ARSLA charity. He has received various
honoraria from pharmaceutical companies for consultancy and lec-
tures on Parkinson’s disease at symposia.
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