Subthalamic deep brain stimulation with a constant-current device in Parkinson's disease: an open-label randomised controlled trial

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Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial Michael S Okun, Bruno V Gallo, George Mandybur, Jonathan Jagid, Kelly D Foote, Fredy J Revilla, Ron Alterman, Joseph Jankovic, Richard Simpson, Fred Junn, Leo Verhagen, Jeff E Arle, Blair Ford, Robert R Goodman, R Malcolm Stewart, Stacy Horn, Gordon H Baltuch, Brian H Kopell, Frederick Marshall, DeLea Peichel, Rajesh Pahwa, Kelly E Lyons, Alexander I Tröster, Jerrold L Vitek, Michele Tagliati, for the SJM DBS Study Group*

Summary Lancet Neurol 2012; 11: 140–49 Published Online January 11, 2012 DOI:10.1016/S14744422(11)70308-8 This online publication has been corrected. The corrected version first appeared at thelancet.com/ neurology on February 15, 2012 See Comment page 121 *For study group members see end of Article Department of Neurology, Center for Movement Disorders and Neurorestoration (M S Okun MD) and Department of Neurological Surgery (K D Foote MD), University of Florida College of Medicine, Gainesville, FL, USA; Department of Neurology (B V Gallo MD) and Department of Neurosurgery (J Jagid MD), School of Medicine, University of Miami, Miami, FL, USA; Department of Neurosurgery, The Neuroscience Institute/ Mayfield Clinic, University of Cincinnati College of Medicine, Cincinnati, OH, USA (G Mandybur MD); Department of Neurology, University of Cincinnati Academic Health Center, Cincinnati, OH, USA (F J Revilla MD); Department of Neurosurgery, Mount Sinai School of Medicine, New York, NY, USA (R Alterman MD); Department of Neurology, Cedars-Sinai, Los Angeles, CA, USA (M Tagliati MD); Department of Neurology, Baylor College of Medicine, Houston, TX, USA (J Jankovic MD); Department of Neurosurgery, The Methodist Hospital Physician Organization, Houston, TX, USA (R Simpson MD); Department of Neurosurgery, Oakwood Hospital and Health System, Dearborn, MI, USA (F Junn MD); Rush University

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Background The effects of constant-current deep brain stimulation (DBS) have not been studied in controlled trials in patients with Parkinson’s disease. We aimed to assess the safety and efficacy of bilateral constant-current DBS of the subthalamic nucleus. Methods This prospective, randomised, multicentre controlled trial was done between Sept 26, 2005, and Aug 13, 2010, at 15 clinical sites specialising in movement disorders in the USA. Patients were eligible if they were aged 18–80 years, had Parkinson’s disease for 5 years or more, and had either 6 h or more daily off time reported in a patient diary of moderate to severe dyskinesia during waking hours. The patients received bilateral implantation in the subthalamic nucleus of a constant-current DBS device. After implantation, computer-generated randomisation was done with a block size of four, and patients were randomly assigned to the stimulation or control group (stimulation:control ratio 3:1). The control group received implantation without activation for 3 months. No blinding occurred during this study, and both patients and investigators were aware of the treatment group. The primary outcome variable was the change in on time without bothersome dyskinesia (ie, good quality on time) at 3 months as recorded in patients’ diaries. Patients were followed up for 1 year. This trial is registered with ClinicalTrials.gov, number NCT00552474. Findings Of 168 patients assessed for eligibility, 136 had implantation of the constant-current device and were randomly assigned to receive immediate (101 patients) or delayed (35 patients) stimulation. Both study groups reported a mean increase of good quality on time after 3 months, and the increase was greater in the stimulation group (4·27 h vs 1·77 h, difference 2·51 [95% CI 0·87–4·16]; p=0·003). Unified Parkinson’s disease rating scale motor scores in the off-medication, on-stimulation condition improved by 39% from baseline (24·8 vs 40·8). Some serious adverse events occurred after DBS implantation, including infections in five (4%) of 136 patients and intracranial haemorrhage in four (3%) patients. Stimulation of the subthalamic nucleus was associated with dysarthria, fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. Interpretation Constant-current DBS of the subthalamic nucleus produced significant improvements in good quality on time when compared with a control group without stimulation. Future trials should compare the effects of constant-current DBS with those of voltage-controlled stimulation. Funding St Jude Medical Neuromodulation Division.

Introduction Deep brain stimulation (DBS) is a powerful treatment for patients with Parkinson’s disease and medication-resistant motor fluctuations, dyskinesia, or refractory tremor.1–3 DBS of the subthalamic nucleus can improve not only the primary motor symptoms of Parkinson’s disease and levodopa-induced motor complications, but also overall quality of life, albeit with some associated adverse events.2,4–9 DBS is widely administered with voltage-controlled devices, in which current is variable.10 Constant-current stimulation might provide more accurate control of the spread of the electrical field than do voltage-controlled devices, because adjustments can be made to account for the potential heterogeneity in tissue impedance.11

The aim of this study was to assess the safety and efficacy of constant-current DBS by random assignment of patients with Parkinson’s disease to either immediate or 3-month delayed DBS after implantation of a stimulation device into the subthalamic nucleus. This design also enabled us to assess the clinical effect of lead implantation (ie, the microlesion effect).12–16 The primary outcome variable was change in the duration of on time without dyskinesia or with non-bothersome dyskinesia as noted by a detailed on-off fluctuation diary score recorded over 2 days. The diary has been validated in patients with Parkinson’s disease and used as a gold standard in many pharmacological trials, but was used as a primary outcome variable in only one large DBS www.thelancet.com/neurology Vol 11 February 2012

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study.17–19 These diaries potentially provide a better assessment of daily motor fluctuations than does the unified Parkinson’s disease rating scale (UPDRS).20,21

Methods Participants and study design We did a prospective, randomised, controlled, multicentre study at 15 university or hospital centres specialised in movement disorders in the USA. Included patients were 18–80 years old, were diagnosed with Parkinson’s disease according to the UK Parkinson’s Disease Society Brain Bank criteria,22 and had the disease for 5 years or more. Patients had either 6 h or more daily off time reported in the patient diary or moderate to severe dyskinesia during waking hours. To be included in the study, patients had to undergo diary training on how to rate their motor function or quality, including how to define the conditions of off, on, on with non-bothersome dyskinesia (scored mild), and on with bothersome dyskinesia (scored moderate or severe). After training, the patient was asked to remain in the clinic to complete his or her diary while being monitored and rated by designated study personnel. After a minimum of 3 h, the study personnel compared their diary information to the responses from the patient. If the patient’s responses matched those of the study personnel a minimum of 75% of the time, the patient met the diary proficiency inclusion criterion. An improvement in the UPDRS motor score (part 3) of 33% or more when comparing off medication (overnight) to best on medication score was required at baseline. All drugs for Parkinson’s disease remained unchanged for 1 month before implantation. Exclusion criteria were major illness or medical comorbidities, depression that was untreated but judged to be clinically significant by an investigator, cochlear implants, cardiac pacemakers, need for diathermy, repeat MRI scanning, anticoagulant therapy, previous neurosurgical procedure or ablative therapy, frank dementia according to cognitive screening, drug or alcohol abuse, being a women of child-bearing potential, having a positive pregnancy test, or presence of a terminal illness. The study protocol was submitted and approved by the US Food and Drug Administration (FDA) and all sites received institutional review board approval before the start of this study. Written informed consent was obtained from all patients before any study procedures were started.

Randomisation and masking Patients were randomly assigned to receive either immediate stimulation (stimulation group) or 3-month delayed stimulation (control group) after implantation of the DBS device in the subthalamic nucleus. The randomisation ratio of 3:1 was chosen to maximise the number of patients exposed to stimulation. Randomisation was computer-generated (SAS version 9.2) with a block size of four at each site before the site www.thelancet.com/neurology Vol 11 February 2012

started the trial. The sponsor converted the randomisation scheme for each site into sealed envelopes. Upon entry of a site into the study, the study coordinator was given a set of sealed envelopes with consecutive numbers printed on the outside; once a patient had undergone full device implantation, the study coordinator opened the envelope corresponding to the number of the individual, and the group to which the patient was assigned was indicated inside. Patients and raters were aware of group assignment.

Procedures Bilateral lead implantations were done either in one surgery (simultaneous bilateral implantation) or in a staged procedure with the two lead implantations separated by 2–4 weeks, according to the preferred practice of every surgical team. DBS devices (Libra DBS device [St Jude Medical Neuromodulation Division, Plano, TX, USA]) were implanted by use of MRI or CT-MRI fusion for targeting and microelectrode recording for target refinement, followed by intraoperative test stimulation of the DBS lead. The pulse generators were placed in a subclavicular position either on the same day or within a maximum of 6 weeks of lead implantation. All participating centres used microelectrode recording to refine targeting and DBS placement, but it was not logistically and economically possible to standardise the head frames and physiology equipment used at every centre. All participating centres were allowed to use existing DBS surgery equipment and were asked to physiologically refine the DBS targets based on their best medical practices. Devices implanted into patients in the stimulation group were programmed within 7 days after surgical implantation (day 0); those in the control group were not programmed until 3 months after implantation (day 90). Primary and secondary endpoints were tested at baseline and 3 months after surgery in both groups. After DBS activation in the control group, patients were again assessed at 6 and 12 months after surgery in four conditions (off medication, off stimulation; off medication, on stimulation; on medication, off stimulation; and on medication, on stimulation). The primary outcome was change in duration of on time without dyskinesia or with non-bothersome dyskinesia as measured in patients’ diaries,17,18 after 3 months of stimulation and in the medication on condition compared with the control group. We defined on medication as roughly 30 min after a patient takes antiparkinsonian medication when both the clinician and the patient indicate that the medication dose is effective. Management of medication was the responsibility of the investigators at each site and was not protocol driven. Secondary outcome variables were changes in UPDRS part 3 (motor), part 2 (activities of daily living), and total scores, quality of life, quality of sleep, severity of illness, levodopa equivalent dose,23 and the rate of

Medical Center Neurological Sciences, Chicago, IL, USA (L Verhagen MD); Department of Neurosurgery, Lahey Clinic, Burlington, MA, USA (J E Arle MD); Movement Disorder Group (B Ford MD) and The Neurological Institute of New York (R R Goodman MD), Columbia University Medical Center, New York, NY, USA; Texas Health Presbyterian Dallas Movement Disorder Center, Dallas, TX, USA (R M Stewart MD); Department of Neurology (S Horn DO) and Department of Neurosurgery (G H Baltuch MD), Parkinson’s Disease and Movement Disorders Center, UPHS: Pennsylvania Hospital, Philadelphia, PA, USA; Department of Neurosurgery, Medical College Wisconsin, Milwaukee, WI, USA (B H Kopell MD); Neurology Department, University of Rochester, Rochester, NY, USA (F Marshall MD); Clinical Research Department, St Jude Medical Neuromodulation Division, Plano, TX, USA (D Peichel BS); Parkinson’s Disease and Movement Disorder Center, University of Kansas Medical Center, Kansas City, KS, USA (R Pahwa MD, K E Lyons PhD); Department of Neurology, University of North Carolina - Chapel Hill, Chapel Hill, NC, USA (A I Troster PhD); and Department of Neurology, University of Minnesota School of Medicine, Minneapolis, MN, USA (J L Vitek MD) Correspondence to: Dr Michael S Okun, University of Florida College of Medicine, Center for Movement Disorders and Neurorestoration, 3450 Hull Road, 4th Floor, Gainesville, FL 32607, USA [email protected]fl.edu

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patient satisfaction. We measured the primary endpoints at 3 months, and the secondary endpoints at 3 months, 6 months, and 12 months after implantation.

Statistical analysis The sample size was based on the standard deviation (SD) of changes from pre-implantation in the duration of on time without dyskinesias, which was estimated to be 4·9 h from a previous clinical trial.24 On this basis, 116 patients randomly assigned in a 3:1 ratio were expected to provide 80% power to detect a 3·0-h difference in on time between treatment groups at the 0·05 level of significance. This calculation was done with the two-sample t test option of PASS 2002. To allow for a 15% dropout rate, we aimed to randomly assign 136 patients to study groups (102 to active stimulation and 34 to the control group). All statistical analyses were done by a consultant statistician. A second statistician at an academic institution also performed and verified all statistical analyses and all the tabular results reported for this study. The analysis of the primary outcome was based on the difference between groups (stimulation vs control) in the duration of on time measured by patients’ diaries at 3 months. This change was done by a two-way analysis of covariance that included the effects of treatment, study centre, and good quality on time at baseline. Study centres with fewer than four patients (n=2) were pooled to create a composite center. Treatment effect was tested by a two-sided test at a significance level of 5%.

168 patients assessed for eligibility

32 excluded 21 did not meet inclusion criteria 8 declined to participate 3 other reasons 136 randomised

A secondary analysis of the primary endpoint was done as a responder analysis, with 2 h or more above baseline in good quality on time arbitrarily defined as a clinically relevant response. This endpoint was analysed by a logistic regression model including effects of treatment, study centre, and baseline good quality on time. Changes from baseline in all continuous secondary endpoints were analysed by a two-way ANCOVA and included effects of treatment, study centre, and the corresponding baseline measure. Analyses at 6 and 12 months were done using preimplantation baseline data for all patients, regardless of their assigned treatment. The results are shown as means and standard deviations, to examine whether stimulation provided any additional benefit at 6 and 12 months for control patients (control group) when compared with the continuously stimulated group. This trial is registered with ClinicalTrials.gov, number NCT00552474.

Role of the funding source St Jude Medical Neuromodulation Division financially supported the study, contributed to the design and conduct of the study, and contributed to the collection, monitoring, and management of the data. The Division also provided support to both statisticians who performed independent analyses of the same dataset. The Clinical Research Department of St Jude Medical also provided administrative and technical support for preparation of the manuscript; however the manuscript was solely written by the authors and the content generated by the authors. The sponsor reviewed the manuscript but did not make changes to the data or their interpretation. MO, BVG, GM, and MT had full access to all the data in the study and take full responsibility for the integrity of the data, the accuracy of the data analysis, and the decision to submit the paper for publication.

Results 101 allocated to intervention (stimulation group), device was programmed within 7 days

35 allocated to intervention (control group), device was not activated until after the 3 month visit

1 discontinued intervention after 6 months and before 12 month visit (infection)

100 followed up at 1 month, 3 months*, 6 months, and 12 months

Study visits occurred at 1 month, 3 months*, 6 months, and 12 months

1 excluded from analysis (patient did not complete diary)

101 analysed

Figure 1: Trial profile *Primary endpoint assessed at 3 months.

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34 analysed

Between Sept 26, 2005, and Aug 13, 2010, 136 patients were randomly assigned to intervention (figure 1). 115 (85%) of 136 patients had simultaneous bilateral implantations and 21 (15%) had two separated lead implantations. Baseline characteristics are presented in table 1. The primary analysis showed a significant difference between the treatment groups with respect to changes in on time without bothersome dyskinesia (good quality on time). At 3 months, both study groups reported an increase from baseline in good quality on time and this increase was significantly greater in the stimulation group (table 2). The responder rate (defined as at least 2 h increase from baseline in good quality on time) was 73 (72·3%) in the stimulation group compared with 13 (38·2%) in the control group (p<0·001; 1·96–11·28). www.thelancet.com/neurology Vol 11 February 2012

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At 3 months, UPDRS part 1 (mentation) and part 2 (activities of daily living) were not improved compared with baseline in either group in the on-medication condition. A significant mean improvement of 37% in the UPDRS part 3 (motor) was recorded when comparing the off-medication, on-stimulation condition with the baseline off-medication condition (24·8 vs 40·8). A small but significant improvement of the UPDRS part 3 was also observed in the on-medication, on-stimulation condition as compared with the baseline on-medication condition (table 2). A significant reduction of the mean UPDRS part 4 (complications of levodopa therapy) was reported as compared with Stimulation group (n=101)

Control group (n=35)

Age (years)

60·6 (8·3)

59·5 (8·2)

Men

63 (62%)

21 (60%)

Disease duration (years)

12·1 (4·9)

11·7 (4·1)

Ethnic origin White

91 (90%)

31 (89%)

African American

1 (1%)

0 (0%)

Hispanic

8 (8%)

3 (9%)

Other

1 (1%)

1 (3%)

Weight (kg)

80·6 (18·3)

74·8 (15·6)

Height (cm)

173·5 (11·2)

171·2 (10·4)

Data are n (%) or mean (SD).

Table 1: Baseline characteristics

Baseline

3-month assessment

Adjusted 3-month mean change from baseline*

Stimulation group (n=101)

Control group (n=35)

Stimulation group†

Control group

Mean (SD)

Mean (SD)

n

n

Duration of good quality on time‡ (h)

6·7 (3·1)

7·4 (2·5)

Total UPDRS on medication§

39·6 (13·0)

38·6 (14·4)

Mean (SD)

34

8·9 (2·9)

4·27

75

32·7 (14·8)

33

44·6 (13·6)

1·77 (1·69)

95

UPDRS part 2 on medication§

9·2 (5·6)

9·9 (6·3)

81

UPDRS part 3 off medication§ ¶

40·8 (10·8)

44·1 (14·0)

UPDRS part 3 off medication§**

40·8 (10·8)

UPDRS part 3 on medication§

18·3 (9·5)

UPDRS part 4 on medication§

8·8 (3·5)

2·02 (1·87)

33

Control group

1·97 (1·51)

2·51 (0·87 to 4·16)

0·003

–6·83

5·33

–12·16 (–17·32 to –6·99)

<0·0001

0·17

0·18

0·002 (–0·68 to 0·68)

0·996

10·3 (6·5)

34

11·7 (7·2)

1·02

1·93

–0·91 (–3·43 to 1·61)

0·475

100

38·5 (13·4)||

35

40·4 (11·6)

–1·97

–2·56

0·59 (–3·06 to 4·24)

0·751

44·1 (14·0)

100

24·8 (10·1)

35

40·4 (11·6)

17·8 (10·1)

99

15·1 (8·2)

35

22·3 (10·5)

–3·01

4·37

–7·38 (–10·18 to –4·57)

<0·0001

9·6 (3·6)

88

4·5 (2·9)

33

8·0 (4·1)

–4·40

–1·00

–3·41 (–4·62 to –2·19)

<0·0001

1459 (991)

101

864 (551)

35

1272 (608)

–16·1

–492

–2·1

<0·0001

–361 (–529 to –193)

<0·0001

9·3 (4·4, 15·3)

<0·0001

–9·14

–1·80

–7·34 (–12·37 to –2·31)

0·005

8·6 (3·6)

–1·90

–1·52

–0·38 (–1·39 to 0·63)

0·459

3·14 (0·95)

–0·64

–0·07

–0·57 (–0·81 to –0·32)

0·0003

76·5 (16·3)

99

86·1 ( 11·4)

34

76·8 (17·7)

8·8

Hamilton depression inventory (T score)

66·1 (13·2)

69·3 (13·7)

88

57·4 (13·7)

30

66·2 (11·9)

D-KEFS category fluency (scaled score)

10·6 (3·8)

9·9 (3·6)

92

8·7 (3·6)

33

3·30 (0·89)

99

2·38 (0·067)

35

–131

–14·0 (–17·5 to –10·5)

–0·5

77·6 (16·8)

2·94 (0·80)

p value

1·77

Schwab and England on medication

Hoehn and Yahr off medication§

Difference in mean change (95% CI)

Mean (SD)

11·2 (4·5)

1·97 (1·88)

1311 (615)

Stimulation group

101

UPDRS part 1 on medication§

Levodopa-equivalent dose (mg)

baseline for both groups, with a statistically significant difference in favour of the stimulation group (table 2). The total UPDRS score (on medication for both groups) significantly improved in the stimulation group and worsened in the control group (table 2). The daily levodopa equivalent dose decreased compared with baseline in both groups, and this decrease was significantly greater in the stimulation group (table 2). The Hamilton depression inventory improved to a greater extent at 3 months in the stimulation group than in the control group (table 2). The Delis-Kaplin executive function scale (D-KEFS) subcomponent category fluency and letter fluency, measuring verbal fluency, worsened similarly in both groups at 3 months (table 2). Patient diaries and UPDRS scores at 3 months in the control group were also used as baseline values for comparison with 6 and 12 months outcomes (ie, after 3 and 9 months of stimulation) to investigate further the effect of stimulation. Good quality on time improved by 3·44 h (SD 4·1) at 6 months and by 2·64 h (4·1) at 12 months. The off-medication, on-stimulation total UPDRS scores improved by 19·4 points (12·2) at 6 months and 17·1 points (7·5) at 12 months as compared with off-medication, off-stimulation scores at 3 months. Parkinson’s disease drugs (levodopa equivalent dose) were reduced by 319 mg (535) at 6 months and by 391 mg (547) at 12 months compared with baseline. The results for the stimulation group and the control group were assessed separately to identify any treatment

UPDRS=unified Parkinson’s disease rating scale. D-KEFS=Delis-Kaplan executive function scale. *Adjusted for study site and baseline. †On stimulation unless noted. ‡Primary endpoint. §Secondary endpoint. ¶Comparison of baseline off medication with 3 months stimulation off and medication off. ||Off stimulation. **Comparison of baseline off medication with 3 months stimulation on and medication off.

Table 2: Changes from baseline at 3 months between stimulation and control groups

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trends over time. At the 12-month visit, the patients in the stimulation group experienced 12 months of stimulation and those in the control group had 9 months. According to the diary responses, the stimulation group had a continued small improvement in good quality on time over the 12-month study. The control group showed a greater improvement of good quality on time at the 6-month visit when compared with the 3-month visit (figure 2A). Good quality on time remained improved for both groups from 6 to 12 months. A significant improvement of the UPDRS part 3 was noted when the off-medication, on-stimulation A

condition was compared with the baseline offmedication condition after 3 months of stimulation for the control group at the 6-month visit (figure 2B). The levodopa equivalent dose also showed a significant reduction in the control group after 3 months of stimulation at the 6 month visit compared with values from the 3 month visit for the control group (figure 2C). According to the Hamilton depression inventory, the control group showed a continued improvement in depression T score at the 12-month visit (figure 2D). Both groups showed improvement in depression over B

Duration of “Good quality on time” Stimulation Control

20 18

45 40

16

35

Dose (mg)

30 Score

12 10 8

25 20

6

15

4

10

2

5

0

0

D

Levodopa equivalent dose

E

Hamilton depression inventory

90

2400 2200 2000 1800 1600 1400 1200 1000 800 600 400 200 0

80 70 60 T score

Time (h)

14

C

UPDRS III off medication, on stimulation

50

50 40 30 20 10 0

F

Delis-Kaplan letter fluency

PDQ-39

110

16 14

91 Total score

Scaled score

12 10 8 6

72 53 34

4 15

2

–4

0 0

3

6 Month

9

12

0

3

6 Month

9

12

Figure 2: Mean response over time for stimulation and control groups The stimulation group started stimulation within 7 days of device implant. The control group started stimulation after the 3-month visit. (A) Duration of good quality on time per treatment group over the 12-month study. The primary endpoint variable was measured at the 3-month visit. (B) UPDRS III, off medication, on stimulation per treatment group over the 12-month study. (C) Levodopa equivalent dose in mg per treatment group over the 12-month study. (D) Hamilton depression inventory T score per treatment group over the 12-month study. (E) Delis-Kaplan letter fluency scaled score per treatment group over the 12-month study. (F) PDQ-39 total score per treatment group over the 12-month study.

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All serious adverse events (n=50)

Stimulation group (0–3 months, n=101)

Control group (0–3 months, n=35)

All patients (3–12 months, n=136)

Number of events (%)

Number of patients (%)

Number of Number of events (%) patients (%)

Number of events (%)

Number of patients (%)

20 (40%)

14 (14%)

7 (14%)

4 (11%)

23 (46%)

23 (17%)

1 (2%)

1 (1%)

0

0

0

0

Resolved

Confusion

Event outcome at 1 year visit

..

CSF leakage

1 (2%)

1 (1%)

0

0

0

0

Improved

Depression

0

0

0

0

1 (2%)

1 (<1%)

Resolved

Erosion of hardware through the skin

0

0

0

0

1 (2%)

1 (<1%)

Improved

Gait disorder including balance problems

1 (2%)

1 (1%)

0

0

3 (6%)

3 (2%)

2 resolved, 1 improved, 1 unchanged

Hardware problem (lead)

1 (2%)

1 (1%)

0

0

0

0

Resolved

Infection

3 (6%)

2 (2%)

1 (2%)

1 (3%)

2 (4%)

2 (1%)

Resolved

Intracranial haemorrhage

3 (6%)

3 (3%)

1 (2%)

1 (3%)

0

0

Resolved

Lead migration

2 (4%)

2 (2%)

0

0

0

0

Resolved

Loss of stimulation

0

0

0

0

1 (2%)

1 (<1%)

Resolved

Motor fluctuations

1 (2%)

1 (1%)

0

0

0

0

Resolved

Worsening of PD symptoms

1 (2%)

1 (1%)

1 (2%)

1 (3%)

1 (2%)

1 (<1%)

2 resolved, 1 improved

Pneumonia

0

0

1 (2%)

1 (3%)

0

0

Resolved

Psychiatric changes or disturbances

0

0

0

0

1 (2%)

1 (<1%)

Resolved

Seizures or convulsions

1 (2%)

1 (1%)

0

0

0

0

Resolved

Tremor

1 (2%)

1 (1%)

0

0

0

0

Improved

Unrelated events

4 (8%)

3 (3%)

3 (6%)

2 (6%)

13 (26%)

13 (10%)

13 resolved, 4 improved, 3 unchanged

CSF=cerebrospinal fluid. PD=Parkinson’s disease.

Table 3: Summary of serious adverse events

time. D-KEFS scores, measuring verbal fluency, did not worsen further after 3 months but did not recover by 12 months (figure 2E). Total PDQ-39 scores improved from 100·7 (SD 20·3) in the control group and 97·9 (23·5) in the stimulation group at baseline to 81·2 (19·5) and 82·8 (23·8), respectively, at 6 months (3 months on stimulation in control group) and 81·9 (17·0) and 83·1 (23·4), respectively, at 12 months (9 months on stimulation in control group; figure 2F). Changes in device parameters occurred according to the standard operating procedures at each site. All parameters could be fine-tuned according to patients’ needs for symptom control. At the 12-month visit, the mean parameters used were: left side 151·1 Hz, 74 μs, 2·31 mA, and right side 151·1 Hz, 74·3 μs, 2·32 mA. Table 3 summarises all serious adverse events that occurred after device implantation, including five (4%) patients with infections and four (3%) patients with intracranial haemorrhages. Table 4 summarises all adverse events that occurred on four or more occasions over the 12 months of follow-up. Dysarthria, fatigue, falls, postoperative pain and discomfort, and oedema occurred more frequently in patients who had stimulation than in control patients at 3 months.

Discussion The results of this study show that a constant-current DBS device was relatively safe and efficacious for the www.thelancet.com/neurology Vol 11 February 2012

treatment of advanced Parkinson’s disease. The use of diaries for the primary outcome variable enable better estimation of the quantity and quality of effective on time, which is usually a patient’s major concern when seeking surgical therapy. In line with previous DBS trials (panel), constant-current stimulation of the subthalamic nucleus improved good quality on time by over 4 h to a total of 12 h per day as measured 1 year after surgery. Constant-current devices, such as the one used in this study, have theoretical advantages over voltage-driven devices in that the field of stimulation within brain tissue should be stable in size,27 whereas stimulation fields produced by voltage-driven devices are susceptible to changes in size caused by changing tissue impedance. This study did not offer a comparison with a voltagedriven device, and future studies should further explore the relative values of these different approaches. It should be noted that the stability of tissue impedance in various human brain regions, and therefore how this factor might affect the response to constant-current and constant-voltage devices, remains unknown. The study design used here offers a new look at the effects of device implantation by random assignment of a quarter of the patients to delayed stimulation. 3 months after surgery, on time had improved on average almost 2 h in the non-stimulated group. Despite the sustained implantation effect, there was clear evidence of substantial 145

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Stimulation group (0–3 months, n=101)

Control group (0–3 months, n=35)

All patients (3–12 months, n=136)

Number of events (%)

Number of patients (%)

Number of Number of events (%) patients (%)

Number of Number of events (%) patients (%)

135 (38%)

53 (52%)

20 (6%)

204 (57%)

Anxiety

4 (1%)

4 (4%)

1 (<1%)

1 (3%)

3 (<1%)

3 (2%)

7 resolved, 1 unchanged

Confusion

3 (<1%)

3 (3%)

1 (<1%)

1 (3%)

3 (<1%)

2 (1%)

4 resolved, 1 improved, 2 unchanged

Depression

4 (1%)

4 (4%)

0

0

12 (9%)

3 resolved, 6 improved, 5 unchanged, 2 worsened

Disequilibrium

6 (2%)

5 (5%)

1 (<1%)

1 (3%)

5 (1%)

5 (4%)

Dysarthria

9 (3%)

9 (9%)

0

0

8 (2%)

8 (6%)

6 resolved, 1 improved, 10 unchanged

Dyskinesia

6 (2%)

5 (5%)

1 (<1%)

1 (3%)

5 (1%)

5 (4%)

8 resolved, 4 improved

Dysphasia

3 (<1%)

3 (3%)

1 (<1%)

1 (3%)

3 (<1%)

3 (2%)

3 resolved, 1 improved, 3 unchanged

Dystonia

2 (<1%)

1 (1%)

0

0

3 (<1%)

3 (2%)

2 resolved, 3 unchanged

Oedema

8 (2%)

7 (7%)

0

0

5 (1%)

5 (4%)

Falls

9 (3%)

9 (9%)

0

0

19 (5%)

17 (12%)

All non-serious adverse events (n=359)

13 (37%)

12 (3%)

80 (59%)

Event outcome at 1 year visit

..

11 resolved, 1 unchanged

11 resolved, 2 improved 16 resolved, 7 improved, 4 unchanged, 1 worsened

Fatigue

5 (1%)

5 (5%)

0

0

2 (<1%)

2 (1%)

2 resolved, 2 improved, 3 unchanged

Gait disorder including balance problems

4 (1%)

4 (4%)

1 (<1%)

1 (3%)

4 (1%)

3 (2%)

4 resolved, 4 improved, 1 unchanged

Hallucinations

1 (<1%)

1 (1%)

1 (<1%)

1 (3%)

5 (1%)

5 (4%)

3 resolved, 2 improved, 2 unchanged

Headache

4 (1%)

4 (4%)

1 (<1%)

1 (3%)

2 (<1%)

2 (1%)

6 resolved, 1 improved

Infection

3 (<1%)

3 (3%)

0

0

1 (<1%)

1 (<1%)

3 resolved, 1 improved

Jolting or shocking sensation

1 (<1%)

1 (1%)

0

0

4 (1%)

3 (2%)

4 resolved, 1 improved

Paraesthesia

4 (1%)

4 (4%)

0

0

3 (<1%)

2 (1%)

5 resolved, 1 improved, 1 unchanged

Postoperation pain, stress, or discomfort

5 (1%)

5 (5%)

0

0

0

0

3 resolved, 1 improved, 1 unchanged

Psychiatric changes or disturbances

4 (1%)

3 (3%)

0

0

4 (1%)

4 (3%)

6 resolved, 1 improved, 1 unchanged

Sleep disturbances

3 (<1%)

3 (3%)

0

0

7 (2%)

7 (5%)

Subcutaneous haemorrhage or seroma

3 (<1%)

3 (3%)

1 (<1%)

1 (3%)

0

0

Resolved

0

0

0

0

5 (1%)

5 (4%)

Resolved

5 resolved, 2 improved, 3 unchanged

Unrelated events Cold or influenza symptoms Back pain

1 (<1%)

1 (1%)

1 (<1%)

1 (3%)

3 (<1%)

3 (2%)

Urinary tract infection

3 (<1%)

3 (3%)

1 (<1%)

1 (3%)

3 (<1%)

1 (<1%)

1 resolved, 4 unchanged Resolved

*Non-serious adverse events with incidence of 4 or more during the 1-year study.

Table 4: Summary of all non-serious adverse events*

benefits from DBS when control patients were reassessed after 3 months of active stimulation. Part of the initial effects seen could also be accounted for by a placebo effect (the fact that patients had a successful surgery and that they knew they would be stimulated soon might have contributed). In addition to motor function and motor complications, DBS seemed to benefit depressive symptoms at 3 months, whereas verbal fluency scores consistently worsened in both the stimulated and the control groups. These results indicate that verbal fluency deficits, the most frequent cognitive side-effect after DBS of the subthalamic 146

nucleus, are probably secondary to surgical implantation, as previously suggested by the unilateral National Institutes of Health COMPARE DBS cohort.9 Quality of life improved after bilateral DBS of the subthalamic nucleus, paralleling other large studies.7,8,24,29,30 The adverse event profile and safety profile were similar to those in other recent randomised studies of DBS.8,9,19,31 The comparison of stimulation versus control at 3 months offered unique insights into which sideeffects were related more to the application of electrical current than to an implantation effect. Stimulation of the subthalamic nucleus was associated with dysarthria, www.thelancet.com/neurology Vol 11 February 2012

Articles

Panel: Research in Context Systematic review We searched PubMed with the terms “DBS” and “deep brain stimulation” for randomised control trials and metaanalyses. Outcomes of bilateral DBS of the subthalamic nucleus were reviewed in a 2006 meta-analysis.25 Wide variations in outcome variables were reported in the 37 groups included. The variations were thought to be due to the uncontrolled and open-label designs.26 At the time of this meta-analysis, large well powered randomised controlled DBS trials had not been done; the largest sample size for a DBS study was 96 patients. The reported DBS outcomes before 2006 revealed data variability issues, effect size issues, and problems with standardisation. Data at that time included UPDRS part 3 (motor) outcomes (31–72% improvement with stimulation), levodopa equivalent dose (16–100% reduction), and quality of life improvements (of 34·5% mean improvement). Up to 2006, only one study had used diary based outcomes (49% improvement),27 and reporting of adverse events was not standardised. Another follow-up meta-analysis on DBSrelated cognitive issues27 revealed that there was a “difficulty in identification of factors underlying changes in verbal fluency”. The investigators pointed out that verbal fluency deficits were the most commonly reported side-effect of DBS, and that current studies did not account for factors such as surgical or implantation effects.26 In late 2006, a German study7 used a primary outcome of a PDQ39 quality-of-life measure in a cohort of patients with Parkinson’s disease receiving bilateral DBS of subthalamic nucleus who were also paired with a non-DBS medication control group. This study revealed significant benefits of stimulation.7 Later, the UK PD SURG trial8 similarly showed quality-of-life improvements, and included a control group; it also showed probable improvements of DBS over apomorphine pumps.8 Finally, the Veterans Administration Cooperative DBS Study, which included a best medication therapy control group, showed an improvement in UPDRS motor score, which was the primary outcome variable.19 The change was seen in both the bilateral subthalamic nucleus, and the bilateral globus pallidus pars interna DBS groups.19 Interpretation Our study is the first well powered randomised trial examining a constant-current DBS device. Additionally, it used a diary based motor outcome, the lack of which was noted as a shortcoming in previous meta-analyses.25 The present study also included a delayed DBS activation group. This study design facilitated important observations about implantation effects associated with DBS surgery. Finally, this study has addressed an important question raised by one of the meta-analyses27 concerning cognitive related outcomes. Data revealed that the most common cognitive side-effect of DBS surgery was induced mainly by surgery, and not by stimulation.

www.thelancet.com/neurology Vol 11 February 2012

fatigue, paraesthesias, and oedema, whereas gait problems, disequilibrium, dyskinesia, and falls were reported in both groups. These findings have great clinical relevance to clinicians and to patients, who should be aware that programming the DBS device might have unanticipated effects, despite substantial improvement of other motor symptoms and overall increases in on time and quality of life. It is interesting to note that although there were improvements with the implantation effect, the UPDRS on-medication scores worsened in the control group at 3 months. The study was not designed to address whether adjustments in programming or other forms of medical management could have alleviated these adverse events. Several important limitations should be discussed. Although statistically well powered, the study was not blinded and patients were informed of their random allocation to a control group or to the stimulation group. Despite the expected disappointment of control patients, we did not observe an inverse placebo effect and, instead, recorded a small but significant improvement in some measures 3 months after surgery. The study design could have reduced expectations and the possible influence of a placebo effect in the control group. Because of the absence of blinding, the cause and the magnitude of benefit in the control group could not be precisely interpreted. Disappointment about being randomly assigned to the delayed-stimulation group might have resulted in a nocebo effect. Future studies will need to examine this issue more closely, as a placebo effect could still have been present in this cohort. Recent gene therapy and transplantation trials have raised the important issue of a placebo effect in surgical cohorts, making sham or implantation-only groups important to differentiate the true effects of any intervention. Another important limitation is that we were unable to standardise the surgical procedures across centres. In conclusion, constant-current bilateral DBS of the subthalamic nucleus for Parkinson’s disease produced significant improvements in motor function and daily fluctuations of response to levodopa when compared with a control group with implanted but not activated leads, and these improvements were maintained at 1 year after implantation. Contributors All authors contributed to the recruitment of patients or performance of surgery and were members of the writing committee. RP, AIT, and KEL assisted with study concept and protocol design. KEL, AIT, and JLV were members of the data safety and monitoring board (DSMB) and therefore had no part in the study between the start and end of data collection. KEL, AIT, and JLV assisted in the interpretation of the outcome data and extensively revised the first and several additional drafts of the report. MSO drafted the first version of the manuscript. All authors contributed to the revisions of the manuscript and made substantial contributions to the final manuscript. St Jude Medical (SJM) DBS Study Group Investigators Diana Apetauerova (Lahey Clinic, Burlington, MA, USA), Roy A E Bakay (Rush University Medical Center, Chicago, IL, USA),

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Articles

J Michael Desaloms (Texas Health Presbyterian Dallas, TX, USA), Jeff Elias and Madaline Harrison (University of Virginia Health Systems, Charlottesville, VA, USA), Serena Hung (Medical College of Wisconsin, Milwaukee, WI, USA), Frank Hsu and David Swope (Loma Linda University Medical Center, Loma Linda, CA, USA), Jason Schwalb (Henry Ford Hospital System, Detroit, MI; University of Rochester, Rochester, NY), and Richard Trosch (Oakland University William Beaumont School of Medicine, Southfield, MI, USA). Conflicts of interest BVG, RP, KEL, MT, AIT, and JLV are paid consultants for St Jude Medical Neuromodulation Division. MSO is a consultant for the National Parkinson Foundation; has received grants from National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS), National Parkinson Foundation, Parkinson Alliance; has received no industry-related honoraria for more than 24 months; and has publication Royalties in Demos, Cambridge, Manson, Human. BVG is a consultant for Cyberonics Inc, Medtronic Inc, Novartis Pharmaceuticals, St Jude Medical Neuromodulation Division, and TEVA pharmaceuticals; has received grants from Medtronic Inc, Pfizer Pharma, GlaxoSmithKline, and St Jude Medical Neuromodulation Division. GM, JJag, KDF, and RA have received honoraria from Medtronic Inc. FJR is a consultant for Lundbeck. JJan is a consultant for Allergan, Chelsea Therapeutics, EMD Serono, Lundbeck Inc, Merz Pharmaceuticals, and Teva Pharmaceutical Industries Ltd; has received grants from Allergan, Allon Therapeutics, Ceregene Inc, Chelsea Therapeutics, Diana Helis Henry Medical Research Foundation, EMD Serono, Huntington’s Disease Society of America, Huntington Study Group, Impax Pharmaceuticals, Ipsen Limited, Lundbeck Inc, Michael J Fox Foundation for Parkinson Research, Medtronic, Merz Pharmaceuticals, NIH, National Parkinson Foundation, Neurogen, St Jude Medical Neuromodulation Division, Teva Pharmaceutical Industries Ltd, University of Rochester, and Parkinson Study Group; and has royalties in Elsevier, Lippincott Williams and Wilkins, and UpToDate. LV is a consultant for Impax Pharma, Boston Scientific, and Medtronic Inc. JA has received honoraria from Medtronic; is a consultant for Allen Medical, Boston Scientific, Globus Medical, and St Jude Medical Neuromodulation Division (not related to DBS); and is a shareholder and scientific adviser at SpineBridge. BF is in the advisory board for Medtronic Inc. RG is a consultant for Medtronic Inc and NeuroPace. RMS is a consultant for St Jude Medical Neuromodulation Division for internal training purposes. BK is a consultant for Medtronic Inc and Neurostream/Victholm Bionics. FM received travel support from St Jude Medical Neuromodulation Division to attend the investigator start-up meeting for this trial; is a site-investigator for a St Jude Medical Neuromodulation Divisionsponsored study in essential tremor; is a member of the Data and Safety Monitoring Board for trials sponsored by the Veterans Administration, and by Toyama Pharmaceuticals; and receives grant support as a site investigator for studies sponsored by the NINDS, the Fox Foundation, TEVA pharmaceuticals, Medivation Inc, CHDI, the Batten Disease Support and Research Association, and the FDA. He has received unrestricted educational grant support in the past from Medtronic Inc. DP is an employee of St Jude Medical Neuromodulation Division. RP is a consultant for St Jude Medical Neuromodulation Division (study design and blind reviewer), Teva Neuroscience, GlaxoSmithKline, GE Healthcare, EMD Serono, Boehinger Ingelheim, Medtronic Inc, Impax Pharma, Novartis, Adamas Pharma, and Biogen. KL is a consultant for Acorda, Medtronic Inc, St Jude Medical Neuromodulation Division (study design and DSMB), and Teva Neuroscience. AT has received grants and honoraria from Medtronic Inc; is a consultant for Medtronic Inc, Boston Scientific, and St Jude Medical Neuromodulation Division (Neuropsychological Testing recommendations and Data Safety Monitoring Board). JLV is a consultant for Boston Scientific, Medtronic Inc, and St Jude Medical Neuromodulation Division (DSMB) and a member of the DSMB for Ceregene. MT has received honoraria from Medtronic Inc and is a consultant for St Jude Medical Neuromodulation Division for internal training purposes. RS, FJ, SH, GHB, declare that they have no conflicts of interest.

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Acknowledgments Eugene Heyman provided statistical analysis as a consultant for St Jude Medical Neuromodulation Division. Michael Kutner also conducted and verified all of the statistical analysis and all of the tabular results reported in this manuscript, paid as a consultant by St Jude Medical Neuromodulation Division. We also thank all the investigators who contributed to the study and all the patients who agreed to participate in this study. We would like to thank Robert E Gross, Chairman of our DSMB. We also thank all the research teams including the study coordinators, device programmers, neuropsychologists, and research nurses for all the time and support enrolling and assessing the patients and collecting all data for this study at the following centres in the USA: Baylor College of Medicine, Houston, TX; Columbia University Medical Center, New York, NY; Lahey Clinic, Burlington, MA; Loma Linda University Medical Center, Loma Linda, CA; Medical College of Wisconsin, Milwaukee, WI; Mount Sinai Medical Center, New York, NY; Oakwood Hospital and Health Systems, Dearborn, MI; Texas Health Presbyterian Dallas, TX; Oakland University William Beaumont School of Medicine, Southfield, MI; Rush University Medical Center, Chicago, IL; University of Florida, Gainesville, FL; University of Miami, Miami, FL; University of Pennsylvania Hospital Systems, Philadelphia, PA; Henry Ford Hospital System, Detroit, MI; University of Rochester, Rochester, NY; and University of Virginia Health Systems, Charlottesville, VA. References 1 Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med 2003; 349: 1925–34. 2 Lang AE, Houeto JL, Krack P, et al. Deep brain stimulation: preoperative issues. Mov Disord 2006; 21 (suppl 14): S171–96. 3 Lang AE, Widner H. Deep brain stimulation for Parkinson’s disease: patient selection and evaluation. Mov Disord 2002; 17 (suppl 3): S94–101. 4 Okun MS, Fernandez HH, Pedraza O, et al. Development and initial validation of a screening tool for Parkinson disease surgical candidates. Neurology 2004; 63: 161–63. 5 Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs. subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 2005; 62: 554–60. 6 Follett KA. Comparison of pallidal and subthalamic deep brain stimulation for the treatment of levodopa-induced dyskinesias. Neurosurg Focus 2004; 17: E3. 7 Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355: 896–908. 8 Williams A, Gill S, Varma T, et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol 2010; 9: 581–91. 9 Okun MS, Fernandez HH, Wu SS, et al. Cognition and mood in Parkinson’s disease in subthalamic nucleus versus globus pallidus interna deep brain stimulation: the COMPARE trial. Ann Neurol 2009; 65: 586–95. 10 Cheung CT, Tagliati M. Deep brain stimulation: can we do it better? Clin Neurophysiol 2010; 121: 1979–80. 11 Lempka SF, Johnson MD, Miocinovic S, Vitek JL, McIntyre C. Current-controlled deep brain stimulation reduces in-vivo voltage fluctuations observed during voltage-controlled stimulation. Clin Neurophysiol 2010; 121: 2128–33. 12 Morishita T, Foote KD, Wu SS, et al. Brain penetration effects of microelectrodes and deep brain stimulation leads in ventral intermediate nucleus stimulation for essential tremor. J Neurosurg 2010; 112: 491–96. 13 Mann JM, Foote KD, Garvan CW, et al. Brain penetration effects of microelectrodes and DBS leads in STN or GPi. J Neurol Neurosurg Psychiatry 2009; 80: 794–97. 14 Granziera C, Pollo C, Russmann H, et al. Sub-acute delayed failure of subthalamic DBS in Parkinson’s disease: the role of micro-lesion effect. Parkinsonism Relat Disord 2008; 14: 109–13. 15 Derrey S, Lefaucheur R, Chastan N, et al. Alleviation of off-period dystonia in Parkinson disease by a microlesion following subthalamic implantation. J Neurosurg 2010; 112: 1263–66.

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