Parkinsonism and Related Disorders 18 (2012) 40e44
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Parkinsonism and Related Disorders
journal homepage: www.elsevier.com/locate/parkreldis
Apomorphine infusion in advanced Parkinson’s patients with subthalamic
stimulation contraindications
Sophie Drapier a, *, Anne-Sophie Gillioz b, Emmanuelle Leray c, Julie Péron a, Tiphaine Rouaud a,
Annaig Marchand a, Marc Vérin a
a
b
c
Department of Neurology, University Hospital, Service de Neurologie, CHU Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes Cedex, France
Department of Geriatric Medicine, University Hospital, Rennes, France
Department of Epidemiology and Public Health, University Hospital, Rennes, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 April 2011
Received in revised form
2 August 2011
Accepted 11 August 2011
Background: The efficacy of continuous subcutaneous apomorphine infusion (APO) has been evaluated in
advanced Parkinson’s disease in several open-label studies but never in a population of patients for
whom subthalamic nucleus deep brain stimulation (STN-DBS) was contraindicated.
Methods: The aim of this study was to evaluate the efficacy and cognitive safety of APO at 12-month followup in 23 advanced parkinsonian patients (mean age: 62.3 years; mean disease duration: 13.9 years)
whose dopa-resistant axial motor symptoms and/or cognitive decline constituted contraindications for
STN-DBS. Their motor and cognitive status were evaluated before APO and 12 months afterwards.
Results: After one year, patients expressed high levels of satisfaction, with a mean rating on the Visual
Analog Scale of 52.8% under APO. Daily OFF time, recorded in a 24-h diary, was reduced by 36% and ON
time improved by 48%. There was a significant reduction (26%) in mean oral levodopa equivalent dose.
Dopa-resistant axial symptoms and neuropsychological performance remained stable. No adverse event
was noted and none of the patients needed to take clozapine at any time.
Conclusions: APO is both safe and effective in advanced parkinsonian patients with untreatable motor
fluctuations, for whom STN-DBS is contraindicated due to dopa-resistant axial motor symptoms and/or
cognitive decline. As such, it should be regarded as a viable alternative for these patients.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Parkinson’s disease
Subcutaneous apomorphine infusion
Neuropsychological assessment
Axial motor symptoms
1. Introduction
Severe Parkinson’s disease (PD) represents a therapeutic challenge when patients become disabled by oneoff motor fluctuations
and dyskinesias that are refractory to medical treatment. One
available option at this stage is subthalamic nucleus deep brain
stimulation (STN-DBS), which is recognized as an effective treatment for these patients, improving akinesia and rigidity, and
reducing levodopa-induced dyskinesias [1,2].
There is, however, growing evidence that STN-DBS occasionally
causes axial motor side effects, cognitive impairment (frontal executive functions) and adverse changes in mood, especially in patients
with minor levodopa-resistant axial motor symptoms and/or cognitive decline prior to surgery [3e6]. Consequently, selection for STNDBS remains drastic, restricting the number of patients deemed
suitable for this technique. Continuous subcutaneous apomorphine
infusion (APO) is currently used in fluctuating PD patients and its
efficacy has been assessed in several open-label studies [7e10].
However, there is no specific information about the motor effect of
APO treatment in PD patients with contraindications for STN-DBS.
Moreover, cognitive tolerance has received little attention and
cognitive assessments in APO trials have often been limited to a few
basic tests [7,8,11]. To our knowledge, only one APO trial has so far
included a comprehensive battery of neuropsychological tests, and
this was administered to a very small sample of patients scheduled
for STN-DBS [3].
The aim of our study was to measure the continuing efficacy and
tolerability of APO after one year of therapy, using a comprehensive
battery of scales for both cognition and motor status, in advanced
PD patients unable to undergo STN-DBS because of axial motor
symptoms and/or cognitive disturbances.
2. Patients and methods
2.1. Patients
* Corresponding.author. Tel.: þ33 (0) 2 99 28 98 42; fax: þ33 (0) 2 99 28 41 32.
E-mail address: [email protected] (S. Drapier).
1353-8020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.parkreldis.2011.08.010
Twenty-three consecutive patients underwent APO between 2005 and 2008. All
met the clinical criteria of the United Kingdom Parkinson’s Disease Society brain
S. Drapier et al. / Parkinsonism and Related Disorders 18 (2012) 40e44
bank for idiopathic PD [12]. Due to severe and disabling motor fluctuations and
drug-induced dyskinesias refractory to optimal treatment, all of them were potential
candidates for STN-DBS and underwent a preoperative assessment featuring standard selection and exclusion criteria for surgery [13]. As described in a paper
recently published by our team [14], stimulation was contraindicated for all patients,
due to global cognitive impairment, as measured on the Mattis Dementia Rating
Scale [15] (MDRS 130), and/or dysexecutive syndrome (impaired scores on three or
more tests assessing executive functions, in comparison with expected values for
patients’ age and education level), and/or dopa-resistant axial motor signs, including
dysarthria, freezing and falls (preoperative UPDRS III axial subscore in the on-dopa
condition 3). APO was introduced as an alternative to STN-DBS, with the purpose
of achieving more constant dopaminergic stimulation. All procedures were carried
out with the adequate understanding and written consent of the subjects involved.
Ethical approval was waived. The study was conducted in accordance with the
Declaration of Helsinki.
Demographic and clinical data at baseline are provided in Table 1.
41
using Deuschl et al.’s method [17]. Self-scoring 24-h diaries were kept for 5 days at
baseline and again 12 months after the start of treatment to assess motor fluctuations and dyskinesia duration. Training on diary completion was conducted and
included instructions and example diaries. Total daily time in the “ON”, “INTERMEDIATE” and “OFF” states, and total dyskinesia duration were expressed as
a percentage of the waking day, on the basis of these diaries. At 12 months, global
self-perceived Improvement was measured with a single-item Visual Analog Scale
(VAS-I) ranging from 0% (no change) to 100% (best improvement) [18]. The question
was worded: “Compared to the time before your operation, how would you judge
your global improvement at the moment?”
A neuropsychological assessment including the MDRS (gauging attention,
initiation/perseveration, construction, conceptualization and memory) [15] and, to
probe frontal executive functions, the Stroop test [19], Trail Making test (TMT A, B,
and B-A) [20], Wisconsin Card Sorting test (WCSCT) [21] and literal and categorical
verbal fluency [22], was administered to patients in the ON DOPA motor condition.
2.4. Statistical analysis
2.2. Apomorphine treatment
APO was carried out using an infusion pump (Microjet Crono PAR, Cane Medical
Technology, Italy), starting with an initial dose of 1 mg/h, which was gradually
increased to obtain the best clinical response during the waking day. APO was discontinued at night.
Domperidone (60 mg/day) was given to prevent nausea and orthostatic hypotension, and oral PD medication was slowly reduced. APO was used during the day at
a mean hourly rate of 3.5 0.96 mg (range: 1.2e5.0) for a mean infusion duration of
15.1 2.0 h (range: 12.0e21.5), and a mean bolus number of 2.8 1.8 per day (range:
0e6), with a mean dose of 3.0 1.1 mg per bolus (range: 0e5). Total apomorphine
mean dose, including continuous infusion and bolus doses was 62.6 18.8 mg of
apomorphine per day (range: 30e90).
2.3. Clinical assessment
The clinical assessment was conducted in accordance with the Core Assessment
Program for Intracerebral Transplantation (CAPIT) [16] and included the UPDRS
Parts I (mentation, behavior, and mood), II (activities of daily living; ADL), III (motor
performance) with medication (ON DOPA), and IV (complications of therapy in the
past week), and the Hoehn and Yahr (H&Y) and Schwab and England (S&E) scales.
We also calculated an “axial III score” (out of 20), defined as the sum of Items 18
(speech), 27 (rising from chair), 28 (posture), 29 (gait) and 30 (postural stability) in
the UPDRS III. We also defined a “dyskinesia score” (out of 13) corresponding to the
sum of Items 32, 33, 34 and 35, and a “motor fluctuations score” (out of 6) corresponding to the sum of Items 36, 37, 38 and 39 of the UPDRS IV. Daily dopaminergic
treatment was defined as the mean oral levodopa equivalent dose (LED), calculated
In spite of the small sample size (23 patients), we were able to perform parametric
analyses, as the variable distributions were compatible with normal distribution. We
compared the motor and neuropsychological data collected at baseline and 12 months
after the start of APO using Student t-tests. Comparisons were significant at the 5%
level.
Statistical analysis was performed using SPSS 17.0 for Windows.
3. Results
3.1. Motor results (Table 2)
The mean VAS-I 12 months after APO was 52.8 16.4% (range:
25e75). The 24-h diaries indicated a significant improvement in “ON”
time, “OFF” time and “INTERMEDIATE” time. “ON” time increased
significantly (þ48%, p ¼ 0.004), whereas “OFF”, “INTERMEDIATE” and
cumulated “OFF þ INTERMEDIATE” time decreased (36%, p ¼ 0.04;
26%, p ¼ 0.05 and 31%, p ¼ 0.01, respectively). “DYSKINESIA”
duration remained stable. Motor scores also remained stable, with no
significant difference compared with baseline regarding S&E ON and
OFF DOPA, H&Y ON and OFF DOPA, UPDRS II ON and OFF DOPA, and
UPDRS III ON DOPA. There was a significant reduction in mean oral
LED (26%, p ¼ 0.001) with APO treatment.
Table 1
Demographic data before APO (baseline) and nature of STN-DBS contraindications.
Gender
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
Patient 7
Patient 8
Patient 9
Patient 10
Patient 11
Patient 12
Patient 13
Patient 14
Patient 15
Patient 16
Patient 17
Patient 18
Patient 19
Patient 20
Patient 21
Patient 22
Patient 23
Mean SD
M
M
M
M
M
M
F
F
M
F
M
M
M
F
M
M
F
M
F
M
F
M
M
16M/7F
Handedness
R
R
L
L
R
R
R
R
L
R
R
R
R
R
R
L
L
L
R
R
L
L
R
15R/8L
Age at disease
onset (years)
Disease duration
(years)
Contraindications for STN-DBS
Cognitive
dysfunction
Dopaeresistant
axial symptoms
49
59
52
14
41
43
58
44
60
65
47
48
45
46
32
51
63
51
49
49
43
49
55
48.4 10.5
20
19
12
44
16
17
6
6
6
10
12
9
22
14
13
15
8
14
10
14
20
8
5
13.9 8.2
102 (D)
128 (D)
134 (D)
124 (D)
138 (D)
132 (D)
110 (D)
130 (D)
142 (D)
133 (D)
134 (D)
135 (D)
123 (D)
142 (D)
133 (D)
137 (D)
131 (D)
138 (D)
118 (D)
122 (D)
137 (D)
137 (D)
135 (D)
130.2 9.9
5
14
8
3.5
5.5
7
3
9
3
5
4.5
5.5
1
6
7.5
7
7.5
4
10
7
3
2.5
2.5
5.3 3.4
Note. Cognitive dysfunction expressed as total Mattis score. D: dysexecutive syndrome; dopa-resistant axial symptoms expressed as UPDRS III axial subscore; SD: standard
deviation.
42
S. Drapier et al. / Parkinsonism and Related Disorders 18 (2012) 40e44
Table 2
Mean (standard deviation) motor scores of patients “off” and “on” dopa before
(baseline) and 12 months after start of APO.
VAS-I %
UPDRS II (/52) OFF
UPDRS II (/52) ON
UPDRS III (/108) ON
Axial III score (/20) ON
UPDRS IV (/24)
Dysk score (/13)
Mot fluct score (/6)
H&Y (/5) OFF
H&Y (/5) ON
S&E (/100%) OFF
S&E (/100%) ON
24 h diaries ON%
24 h diaries OFF%
24 h diaries INT%
24 h diaries OFF þ INT%
24 h diaries DYSK%
Oral LED without APO (mg/day)
Baseline
M12
e
24.1 9.5
10.2 6.8
18.3 8.3
5.3 3.4
7.7 3.8
3.7 3.4
3.9 1.7
4.2 1.0
2.3 0.9
39.1 19.5
77.8 14.1
32.7 17.8
23.8 13.7
21.6 14.5
45.4 16.7
21.8 16.0
1372.2 325.1
52.8
26.0
11.0
21.8
5.7
6.9
3.2
3.2
4.0
2.3
43.9
78.7
48.4
15.2
16.0
31.2
20.4
1021.3
4. Discussion
P
16.4
7.9
5.7
11.1
2.9
3.4
2.7
1.6
0.7
1.1
23.3
11.4
21.5
11.7
14.4
22.6
18.1
331.3
N/A
0.41
0.53
0.08
0.58
0.47
0.58
0.20
0.41
0.83
0.38
0.81
0.004
0.04
0.05
0.01
0.73
0.0001
Note. VAS-I: Visual Analog Scale-Improvement expressed as a percentage; UPDRS:
Unified Parkinson’s Disease Rating Scale; H&Y: Hoehn and Yahr; S&E: Schwab and
England; Dysk: dyskinesias; Mot fluct: motor fluctuations; 24 h diaries ON: 24 h
diaries ON time; 24 h diaries INT: 24 h diaries intermediate time. 24 h diaries
DYSK: 24 h diaries dyskinesia time; 24 h diaries OFF þ INT: 24 h diaries OFF plus
intermediate time; LED: levodopa equivalent dose. APO: apomorphine.
3.2. Neuropsychological results (Table 3)
Regarding the scores of UPDRS I, no worsening of psychiatric
status was observed at the 12-month assessment. Neuropsychological and especially MDRS (total and subscale) scores
remained stable after 12 months, with the exception of TMT A, which
significantly increased.
3.3. Adverse events
Small itchy nodules at the injection sites were observed in all
patients, but no case of cutaneous necrosis was noted. The presence
of these nodules did not lead to the discontinuation of apomorphine treatment. Other apomorphine-related adverse events, such
as nausea or orthostatic hypotension, were well controlled by
domperidone. None of the patients complained of sedation or
Table 3
Mean (standard deviation) neuropsychological scores before (baseline) and 12
months after start of APO.
UPDRS I
MDRS (/144)
Stroop
Word
Color
C/W
IS
TMT (s)
TMT A
TMT B
TMT B-A
Fluency
Categorical
Literal
WCST
Categories
Errors
P. errors
Baseline
M12
P
2.9 1.8
129.9 10.0
2.4 1.9
131.5 7.2
0.45
0.36
87.1
59.9
29.3
5.7
16.2
14.3
9.8
6.8
84.5
56.1
29.1
5.3
20.1
17.3
10.8
6.5
hallucination. No patient was treated with clozapine either at
baseline or after 12 months’ treatment.
0.39
0.04
0.70
0.83
75.4 27.7
199.0 90.0
129.4 64.7
94.1 51.1
220.9 114.7
136.7 82.0
0.02
0.18
0.62
16.8 6.2
11.5 6.2
16.2 5.1
11.3 5.3
0.69
0.84
4.0 1.9
14.9 9.1
5.4 5.6
3.4 2.8
29.4 8.0
4.6 4.4
0.43
0.40
0.47
Note. UPDRS: Unified Parkinson’s Disease Rating Scale; MDRS: Mattis Dementia
Rating Scale; C/W: Color/Word; IS: Interference score; TMT: Trail Making Test;
WCST: Wisconsin Card Sorting Test; P. errors: perseverative errors.
This study measured the motor and neuropsychological
outcomes of APO at 12 months in advanced parkinsonian patients
with contraindications for STN-DBS. All patients presented
disabling motor fluctuations that were refractory to optimal
medical treatment, and were excluded from STN-DBS on the
grounds of dopa-resistant axial motor symptoms and/or cognitive
decline. All underwent the same comprehensive and standardized
battery of tests at baseline and 12 months after the start of APO.
The main motor finding was a significant reduction in fluctuations, reflected by the increase in “ON” time, and decreases in “OFF”
and “INTERMEDIATE” times reported in the self-scoring diaries,
leading to a high level of patient satisfaction (mean VAS-I: 52.8%)
after one year’s therapy. Self-scoring diaries are very useful for
assessing motor status in fluctuating PD patients and, to date, most
Phase III trials in PD have used changes in “ON” and “OFF” time,
recorded in patient diaries, as their primary endpoints for evaluating drug efficacy [23]. While the catechol-O-methyl-transferase
inhibitor entacapone has been found to improve daily “ON” time
by approximately 1 h in PD patients with motor fluctuations when
taken with each dose of levodopa [24], ON time increased by 2 h in
our study (4.8 h at baseline vs. 6.7 h after APO). These results are in
line with previous studies [8] suggesting the beneficial role of APO
in motor fluctuations.
In contrast, we failed to observe any change in dyskinesia
duration under APO treatment, supporting the findings of recent
comparative trials [3,11]. The possible antidyskinetic effect of
apomorphine therefore remains a matter of debate [7,10,25,26]. The
lack of effectiveness on dyskinesia may relate to the need of
continuing oral LED therapy resulting in sustained pulsatile stimulation. Improvement of dyskinesia may be achieved only with APO
in high daily dose monotherapy [9]. In our study, APO was in
adjunction and, consistent with the literature [27], mean oral LED
was significantly reduced (26%) but probably not enough to
decrease dyskinesia.
Another interesting motor result was the absence of any worsening of dopa-resistant axial motor symptoms, as reflected by the
stability of the UPDRS III axial motor subscore at 12 months. By
contrast, axial motor impairment has been reported after STN-DBS
including postural instability and gait disability worsen at shortterm follow-up [28].
As described by Welter et al. [13], the severity of preoperative
axial motor symptoms evaluated at the time of maximum clinical
improvement under levodopa treatment, in particular the level of
gait disorders and postural instability, is a highly effective predictor
of poor outcome of treatment by STN-DBS at 6-month follow-up.
In our group of patients, we recorded a high pre-apomorphine
axial score in the ON condition and there was no significant
change after the pump treatment began, suggesting the “nonimpairment” of dopa-resistant axial motor signs, even for such
high-risk patients.
As far as the nonmotor results are concerned, our study
demonstrated a high level of neuropsychological safety for APO at
12-month follow-up, which is of particular importance for such
high-risk patients (i.e., displaying cognitive decline at baseline).
Patients who have undergone STN-DBS surgery are routinely
administered exhaustive neuropsychological assessments, but this
is very rarely the case for patients undergoing APO treatment [3,11].
In the present study, we used standardized tests, which yielded
extensive information about APO treatment tolerability and
possible cognitive side effects. Despite the fact that patients had
S. Drapier et al. / Parkinsonism and Related Disorders 18 (2012) 40e44
a poor cognitive status at baseline, contraindicating STN-DBS, we
did not find any change in their neuropsychological status after 12
months of APO, confirming that APO treatment is a safe therapy in
PD, in terms of patients’ cognitive status. These results are in
agreement with Alegret et al. [3] and De Gaspari et al. [11], who
compared STN-DBS with APO in two groups of fluctuating PD
patients and failed to find any cognitive change in the APO group. In
contrast, the effect of STN-DBS on neuropsychological status has
been of great concern in recent years [3,5] showing consistently
a significant decrease on the semantic fluency test in the postoperative condition.
Regarding the stability of the UPDRS I score and absence of
hallucination, sedation or use of Clozapine after APO, we concluded
at one-year follow-up that APO is safe, in terms of the psychiatric
tolerance displayed by our group. There are conflicting findings on
the frequency of psychiatric side effects under APO. Some authors
have observed an increased risk of psychiatric disturbances [10],
whereas others have described either no change [25] or a clear
reduction in psychiatric complications [29].
In conclusion, our study confirmed that APO is a good therapeutic alternative for patients when STN-DBS is contraindicated.
However, this does not necessarily mean that it is the best
alternative in every case.
Indeed, in these advanced stages of the disease, management is
a challenge and other therapeutic options, such as duodenal levodopa infusion (DLI) or GPI stimulation, have to be considered. DLI
ensures more continuous plasma levels than oral treatment,
resulting in effective control of motor complications [30] with
a reduction in disabling dyskinesia and a significant improvement
in quality of life [31]. Moreover, the cognitive improvement
observed after DLI needs to be confirmed [32]. Regarding GPI
stimulation, we recently published a study demonstrating the
efficacy and safety of GPi-DBS [14] in a population of advanced PD
patients for whom STN-DBS was contraindicated. At the 6-month
follow-up, we observed a mean improvement of 41.1% in the
UPDRS III motor score in the OFF DOPA condition. Motor fluctuations were reduced by 22.9% and dyskinesia duration by 68.6%.
Axial motor symptoms improved and neuropsychological performances remained stable.
In the context of severely disabled parkinsonian patients with
STN-DBS contraindications, GPi-DBS or LDI might be preferable for
those with severe dyskinesias, given the dramatic reduction in
dyskinesias during waking hours, while APO might be more suitable for patients with only mild dyskinesias. Taken together with
the new data on GPi-DBS [14] and LDI, the present results show that
there is an urgent need for well-designed, randomized clinical
trials, in order to compare these three therapeutic approaches and
determine which option is the most appropriate for each patient,
depending on baseline clinical characteristic, when STN-DBS is
contraindicated. Given the possibility that differences in efficacy
could be quite small, future studies comparing treatment-related
adverse events should, perhaps, take cognitive safety and quality
of life as their primary outcome measures, rather than changes in
UPDRS scores, except for dyskinesias, where the effect of APO has
yet to be determined.
5. Conclusion
APO has a positive therapeutic impact on refractory motor
fluctuations in severely disabled PD patients and appears to be
a valid alternative to STN-DBS, especially in cases of surgical
contraindications. It is a minimally invasive approach that has
beneficial effects on motor status, with a high degree of neuropsychological and psychiatric safety at one-year follow-up. Our
preliminary results highlight the need for a large-scale, prospective,
43
long-term, randomized trial including patients for whom STN-DBS
is contraindicated and who are therefore treated with either APO,
GPi-DBS or LDI, in order to comprehensively assess the pros and
cons of each technique.
Acknowledgment
We would like to thank Elizabeth Wiles-Portier for preparing
the manuscript.
References
[1] Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Fiveyear follow-up of bilateral stimulation of the subthalamic nucleus in advanced
Parkinson’s disease. N Engl J Med 2003;349(20):1925e34. Nov 13.
[2] Limousin P, Pollak P, Benazzouz A, Hoffmann D, Le Bas JF, Broussolle E, et al.
Effect of parkinsonian signs and symptoms of bilateral subthalamic nucleus
stimulation. Lancet 1995;345(8942):91e5. Jan 14.
[3] Alegret M, Valldeoriola F, Marti M, Pilleri M, Junque C, Rumia J, et al.
Comparative cognitive effects of bilateral subthalamic stimulation and
subcutaneous continuous infusion of apomorphine in Parkinson’s disease.
Mov Disord 2004;19(12):1463e9. Dec.
[4] Allert N, Volkmann J, Dotse S, Hefter H, Sturm V, Freund HJ. Effects of bilateral
pallidal or subthalamic stimulation on gait in advanced Parkinson’s disease.
Mov Disord 2001;16(6):1076e85. Nov.
[5] Drapier D, Drapier S, Sauleau P, Haegelen C, Raoul S, Biseul I, et al. Does
subthalamic nucleus stimulation induce apathy in Parkinson’s disease?
J Neurol 2006;253(8):1083e91. Aug.
[6] Funkiewiez A, Ardouin C, Caputo E, Krack P, Fraix V, Klinger H, et al. Long term
effects of bilateral subthalamic nucleus stimulation on cognitive function,
mood, and behaviour in Parkinson’s disease. J Neurol Neurosurg Psychiatry
2004;75(6):834e9. Jun.
[7] Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apomorphine
in the long term treatment of levodopa induced interdose dyskinesias in
Parkinson’s disease. J Neurol Neurosurg Psychiatry 1998;64(5):573e6. May.
[8] Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B, Castro Garcia A, Alonso Frech F,
Alvarez Lopez M, et al. Efficacy of long-term continuous subcutaneous
apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: a multicenter study. Mov Disord 2008;23(8):1130e6. Jun 15.
[9] Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treatment of
refractory motor complications of Parkinson’s disease: long-term follow-up
study of 64 patients. Mov Disord 2002;17(6):1235e41. Nov.
[10] Pietz K, Hagell P, Odin P. Subcutaneous apomorphine in late stage Parkinson’s
disease: a long term follow up. J Neurol Neurosurg Psychiatry 1998;65(5):
709e16. Nov.
[11] De Gaspari D, Siri C, Landi A, Cilia R, Bonetti A, Natuzzi F, et al. Clinical and
neuropsychological follow up at 12 months in patients with complicated
Parkinson’s disease treated with subcutaneous apomorphine infusion or deep
brain stimulation of the subthalamic nucleus. J Neurol Neurosurg Psychiatry
2006;77(4):450e3. Apr.
[12] Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of
idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases.
J Neurol Neurosurg Psychiatry 1992;55(3):181e4. Mar.
[13] Welter ML, Houeto JL, Tezenas du Montcel S, Mesnage V, Bonnet AM, Pillon B,
et al. Clinical predictive factors of subthalamic stimulation in Parkinson’s
disease. Brain 2002;125(Pt 3):575e83. Mar.
[14] Rouaud T, Dondaine T, Drapier S, Haegelen C, Lallement F, Peron J, et al.
Pallidal stimulation in advanced Parkinson’s patients with contraindications
for subthalamic stimulation. Mov Disord 2010;25(12):1839e46. Sep 15.
[15] Mattis Dementia Rating Scale. In: Psychological assessment. Odessa:
Ressources Inc; 1988.
[16] Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, et al. Core
assessment program for intracerebral transplantations (CAPIT). Mov Disord
1992;7(1):2e13.
[17] Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, Botzel K, et al.
A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J
Med 2006;355(9):896e908. Aug 31.
[18] de Boer AG, van Lanschot JJ, Stalmeier PF, van Sandick JW, Hulscher JB, de
Haes JC, et al. Is a single-item visual analog scale as valid, reliable and
responsive as multi-item scales in measuring quality of life? Qual Life Res
2004;13(2):311e20. Mar.
[19] Stroop JR. Studies of interferences in serial verbal reactions. J Exp Psychol
1935;18:643e62.
[20] Reitan RM. Validity of the trail making test as an indication of organic brain
damage. Percept Mot Skill 1958;8:271e6.
[21] Nelson HE. A modified card sorting test sensitive to frontal lobe defects.
Cortex 1976;12(4):313e24. Dec.
[22] Cardebat D, Doyon B, Puel M, Goulet P, Joanette Y. Evocation lexicale, formelle
et sémantique chez des sujets normaux: performances et dynamiques de
production en fonction du sexe, de l’âge et du niveau d’étude. Acta Neurol
Belg 1990;90:207e17.
44
S. Drapier et al. / Parkinsonism and Related Disorders 18 (2012) 40e44
[23] Korczyn AD, Nussbaum M. Emerging therapies in the pharmacological treatment of Parkinson’s disease. Drugs 2002;62(5):775e86.
[24] Group PS. Entacapone improves motor fluctuations in levodopa-treated
Parkinson’s disease patients. Parkinson Study Group. Ann Neurol 1997;
42(5):747e55. Nov.
[25] Di Rosa AE, Epifanio A, Antonini A, Stocchi F, Martino G, Di Blasi L, et al.
Continuous apomorphine infusion and neuropsychiatric disorders: a controlled
study in patients with advanced Parkinson’s disease. Neurol Sci 2003;24(3):
174e5. Oct.
[26] Katzenschlager R, Hughes A, Evans A, Manson AJ, Hoffman M, Swinn L, et al.
Continuous subcutaneous apomorphine therapy improves dyskinesias in
Parkinson’s disease: a prospective study using single-dose challenges. Mov
Disord 2005;20(2):151e7. Feb.
[27] Deleu D, Hanssens Y, Northway MG. Subcutaneous apomorphine: an evidencebased review of its use in Parkinson’s disease. Drugs Aging 2004;21(11):
687e709.
[28] van Nuenen BF, Esselink RA, Munneke M, Speelman JD, van Laar T, Bloem BR.
Postoperative gait deterioration after bilateral subthalamic nucleus stimulation in Parkinson’s disease. Mov Disord 2008;23(16):2404e6. Dec 15.
[29] Ellis C, Lemmens G, Parkes D, Abbott RJ, Pye IF, Nigel leigh P, et al. Use of
apomorphine in parkinsonian patients with neuropsychiatric complications to
oral treatment. Parkinsonism Relat Disord 1997;3(2):103e7. April.
[30] Nyholm D, Nilsson Remahl AI, Dizdar N, Constantinescu R, Holmberg B, Jansson R,
et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in
advanced Parkinson disease. Neurology 2005;64(2):216e23. Jan 25.
[31] Antonini A, Isaias IU, Canesi M, Zibetti M, Mancini F, Manfredi L, et al.
Duodenal levodopa infusion for advanced Parkinson’s disease: 12-month
treatment outcome. Mov Disord 2007;22(8):1145e9. Jun 15.
[32] Sanchez-Castaneda C, Campdelacreu J, Miro J, Juncadella M, Jauma S, Calopa M.
Cognitive improvement after duodenal levodopa infusion in cognitively
impaired Parkinson’s disease patients. Prog Neuropsychopharmacol Biol
Psychiatry 2010;34(1):250e1. Feb 1.