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Apomorphine infusion in advanced Parkinson’s patients with subthalamic stimulation contraindications
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.
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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.
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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,
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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.
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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.
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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.
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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,
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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.
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