Abstract
Objective:
The deep brain stimulation (DBS) in early-stage Parkinson’s disease (PD) pilot clinical trial randomized 30 patients (Hoehn & Yahr II off; medication duration 0.5–4 years; without dyskinesia/motor fluctuations) to optimal drug therapy (early ODT) or bilateral subthalamic nucleus (STN) DBS plus ODT (early DBS+ODT). This study aims to report 11-year outcomes of patients who completed the DBS in early-stage PD pilot trial.
Methods:
Attempts were made to contact all 29 subjects who completed the two-year trial to participate in an 11-year follow-up study. Mixed-effects models compared overall trend in outcomes for randomization groups (fixed effects: assigned treatment, year, their interaction; random effect: subject) to account for repeated measures.
Results:
Twelve subjects participated in this 11-year follow-up study (n=8 early ODT, n=4 early DBS+ODT). Participating subjects were 70.0 ± 4.8 years old with a PD medication duration of 13.7 ± 1.7 years (early DBS duration 11.5 ± 1.3 years, n=4). Three early ODT subjects received STN-DBS as standard care (DBS duration 6.5 ± 2.0 years). Early ODT subjects had worse motor complications (UPDRS-IV) than early DBS+ODT subjects over the 11-year follow-up period (between-group difference=3.5 points; Pinteraction=0.03). Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to early ODT for other UPDRS domains, PDQ-39, and LEDD.
Conclusions:
Eleven years after randomization, early DBS+ODT subjects had fewer motor complications than early ODT subjects. These results should be interpreted with caution, because only 40% of pilot trial subjects participated in this 11-year follow-up study. The FDA has approved the conduct of a pivotal clinical trial evaluating DBS in early-stage PD (IDEG050016).
Search Terms: Parkinson’s Disease, Deep Brain Stimulation, Longitudinal Studies, Dyskinesias, Movement Disorders
INTRODUCTION
Patients living with Parkinson’s disease (PD) often battle the disease for 25 years or more, and investigations are needed to identify therapies that provide durable, long-term benefits. Subthalamic nucleus (STN) deep brain stimulation (DBS) is an FDA-approved adjunctive therapy that improves motor function and quality of life and reduces dyskinesia and motor fluctuations in mid- and advanced-stage PD (1–3). Sustained motor benefits of DBS after 5–10 years are reported in prospectively followed advanced-stage PD cohorts (4–7), but there are no published reports of long-term follow-up (≥5 years) of PD patients treated with STN-DBS from a randomized clinical trial. Furthermore, the long-term clinical success of DBS in later stages of PD motivates investigations to determine whether earlier intervention could expand or even improve its benefits.
A prospective, randomized pilot clinical trial evaluating STN-DBS in early-stage PD was conducted at Vanderbilt University from 2006–2012 (IDEG050016, NCT0282152, IRB040797). Thirty early-stage, idiopathic PD patients (Hoehn & Yahr II off therapy, age 50–75, medication duration six months to four years, without dyskinesia or other motor fluctuations) were randomized 1:1 to bilateral STN-DBS plus optimal drug therapy (“early DBS+ODT”) or optimal drug therapy alone (“early ODT”) and evaluated ON (on medications and stimulation, if applicable) and OFF therapy (week-long washout of medication and stimulation, if applicable) every six months for two years (8). Participants then enrolled in an additional annual follow-up study through five years after randomization (2012–2014) where they were only evaluated in the ON therapy state (9).
This safety and tolerability trial was designed to collect the first preliminary data on the effects of early DBS. The study met its primary safety endpoint at 24 months (8), and prior publications describe the study design (10), enrollment (11) and surgical (12) experiences, primary trial results (8), five-year outcomes (9), and post hoc analyses of a patient-centered composite outcome (13), effects on motor symptom progression (14), and medication costs (15,16). Based on the results of the pilot, the FDA has approved the conduct of a prospective, double-blind, placebo-controlled, pivotal multicenter safety and efficacy trial of DBS in early-stage PD (IDEG050016).
Since joining the trial as very early-stage patients (mean PD duration at enrollment: 2.2 ± 1.5 years), this cohort has progressed more than a decade to a PD stage where symptoms are increasingly resistant to effective medication management. Understanding the durability of DBS therapy becomes even more critical when considering its application in early-stage PD due to the added length of time patients will have the device implanted. The adoption of DBS in early PD as an adjunctive therapy will require not only demonstrating safety and efficacy in a multicenter, pivotal trial but also lasting benefit in studies evaluating the long-term effects of early DBS. This study reports 11-year outcomes of patients who enrolled in the DBS in early-stage PD pilot clinical trial.
METHODS
Standard Protocol Approvals, Registrations, and Patient Consents
The DBS in early PD pilot was a prospective, randomized, controlled, single-blind clinical trial (ClinicalTrials.gov NCT00282152) that was approved by the FDA (IDEG050016) and Vanderbilt IRB (IRB040797) (8). Attempts were made to contact all 29 subjects who completed the 5-year follow-up visit (9). All participants of this 11-year follow-up study provided written informed consent (Vanderbilt IRB180766).
Subjects
The pilot trial randomized 30 early-stage PD patients (Hoehn & Yahr stage II off therapy; medication duration 6 months – 4 years; without history or evidence of dyskinesia or motor fluctuations) to receive optimal drug therapy alone (early ODT) or bilateral subthalamic nucleus deep brain stimulation plus ODT (early DBS+ODT). After the two-year pilot trial completed, all participants were permitted to pursue any indicated PD therapy, including DBS. In this intention-to-treat analysis, early ODT subjects who later received DBS as standard care were evaluated in their assigned randomization group. Death status was determined by medical record review, family members reached during recruitment calls, or publicly searchable obituaries. Clinical characteristics at death were extracted from medical records and/or an IRB-approved form completed by family members.
Study Procedures
Subjects were asked to undergo the same week-long therapeutic washout that was completed by all 29 subjects at baseline and 6, 12, 18 and 24 months in the two-year pilot trial. Following the same washout protocol from the pilot trial, at the end of the day 1 study assessment, all PD medications and DBS were stopped while subjects were closely monitored inpatient at the Vanderbilt Clinical Research Center. An ON therapy only assessment (similar to outpatient study visits at years 3, 4, and 5) was performed for subjects unwilling to attempt the washout. Study assessments from the pilot trial were repeated in this 11-year study (8,9). The UPDRS-III motor examination was videotaped daily during the washout and scored in a randomized, blinded fashion by the same independent rater who evaluated videos for all prior study visits (K.R.C). Rigidity cannot be reported, because the UPDRS-III was videotaped for blinded evaluation, following the same protocol from the pilot trial. PDQ-39 was administered on day 1 while subjects were on therapy (on PD medications and on DBS, if applicable). Rest tremor was evaluated using item 20 of the UPDRS part III ON therapy. Polypharmacy per subject was defined as being prescribed more than one class of PD medication at the study visit (15,17). New assessments were administered in this 11-year study to explore caregiver burden (MCSI)(18), tremor quality of life (QUEST) (19), pain related to PD (20), health-related quality of life (EQ-5D) (21), and impulse control (QUIP) (22).
Statistical Analysis
No post-hoc power calculations were performed because this is a long-term follow-up study from a pilot clinical trial. Analyses were exploratory, and there were no adjustments for multiplicity. Longitudinal clinical outcomes collected at baseline, 0.5, 1, 1.5, 2, 3, 4, 5, and 11 years were evaluated using linear (continuous outcomes) or generalized (binary outcomes due to discrete and sparse values in the original measure) mixed-effects models to compare the overall trend in outcomes for the two randomization groups. Models included assigned treatment (early ODT vs early DBS+ODT), year, and their interaction as fixed effects and subject as a random effect to account for repeated measures from baseline to 11-year evaluations. Interaction term was removed from the model if non-significant (P>0.1). Based on mixed-effect model fitting results, partial-effects plots were created to visualize the interaction effect of treatment and time on UPDRS part IV, adjusted for other covariates. Characteristics of deceased pilot trial participants and outcomes collected only at the 11-year visit are descriptively reported. R Statistical Software Version 4.1.2 (Foundation for Statistical Computing, Vienna, Austria) was used for all statistical analyses.
RESULTS
Twelve subjects who completed the DBS in early-stage PD pilot clinical trial participated in this 11-year follow-up study (n=8 early ODT, n=4 early DBS+ODT; Figure 1). Eighteen pilot trial subjects did not participate for the following reasons: withdrew after the baseline visit (n=1 early ODT), too disabled (n=1 early ODT, n=1 early DBS+ODT), lost to follow-up (n=2 early DBS+ODT), declined (n=1 early DBS+ODT), deceased (n=5 early ODT, n=7 early DBS+ODT). Throughout the available follow-up visits, all subjects still carried the diagnosis of idiopathic Parkinson’s disease. None of the subjects later proved to have an alternate diagnosis causing their Parkinsonism. Participating subjects were 70.0 ± 4.8 years old and had been taking PD medications for 13.7 ± 1.7 years (mean early DBS duration 11.5 ± 1.3 years, n=4; Table 1). Three early ODT subjects who participated in this study received bilateral STN-DBS as standard of care (mean DBS duration 6.5 ± 2.0 years). Nine subjects (n=6 early ODT, n=3 early DBS+ODT) attempted the week-long washout, with four completing all seven days withdrawn from medications and DBS, if applicable (n=3 early ODT, n=1 early DBS+ODT). Mean washout duration was 4.9 ± 2.0 days (early ODT: 5.2 ± 2.0 days; early DBS+ODT: 4.3 ± 2.3 days).
Figure 1: Follow-up from the DBS in Early-Stage PD Pilot Clinical Trial.
(A) Thirty subjects were randomized 1:1 to early DBS+ODT or early ODT. One early ODT subject dropped out after the baseline visit. Subjects completed week-long washouts at baseline, 6, 12, 18, and 24 months and exited the clinical trial after the 24-month study visit. (B) All 29 subjects who completed the two-year trial enrolled in a follow-up study which included annual outpatient (on therapy only) assessments through five years. (C) Twelve subjects completed an 11-year study visit, with the option to participate in an additional week-long washout. Seventeen former trial participants did not participate due to the following reasons: deceased (n=12), too disabled (n=2), lost to follow-up (n=2), declined to participate (n=1), dropped out after the baseline visit (n=1).
Table 1:
Baseline and 11 Year Subject Characteristics
| Early ODT | Early DBS+ODT | |||
|---|---|---|---|---|
| Baseline | 11 Years | Baseline | 11 Years | |
| Sex (Male:Female) | 7:1 | 4:0 | ||
| Age (Years) | ||||
| Mean | 58.9 (5.3) | 70.6 (5.3) | 57.1 (3.5) | 68.7 (3.8) |
| Range | 52.7 – 68.1 | 63.7 – 78.5 | 54.0 – 62.1 | 65.5 – 73.6 |
| Time Since Baseline (Years) | n.a. | 11.7 (0.8) | n.a. | 11.6 (1.3) |
| Medication Use | ||||
| Duration (Years) | 2.33 (1.2) | 14.0 (1.64) | 1.5 (0.5) | 13.1 (1.77) |
| LEDD (mg) | 554 (229) | 904 (431) | 471 (290) | 565 (262) |
| UPDRS Scores | ||||
| UPDRS-III ONa | 22.4 (8.1) | 26.1 (14.5) | 14.0 (8.8) | 25.0 (17.1) |
| Totalb | 36.6 (11.8) | 54.3 (21.3) | 22.8 (8.9) | 46.5 (22.2) |
| PDQ-39 Summary Index | 14.7 (6.7) | 27.0 (10.1) | 11.2 (7.2) | 32.5 (18.3) |
Abbreviations:
DBS = deep brain stimulation;
ODT = optimal drug therapy;
LEDD = levodopa equivalent daily dose;
UPDRS = Unified Parkinson’s Disease Rating Scale
n.a. = not applicable
Values are mean (SD).
Excludes rigidity; single-blind rating
UPDRS total reported as the sum of parts I, II, III, and IV
Table 2 summarizes longitudinal clinical outcomes. Early DBS+ODT was well-tolerated after 11 years and showed comparable outcomes to ODT subjects for UPDRS-I, UPDRS-II, UPDRS-III ON, Total UPDRS, Hoehn & Yahr, Schwab & England, PDQ-39, and LEDD (Table 2). Early ODT subjects had worse UPDRS-IV scores (motor complications) than early DBS+ODT subjects over the 11-year follow-up period (Figure 2; Table 2; between-group difference = 3.5 points; Pinteraction=0.03). Between-group differences in UPDRS-III OFF could not be evaluated because too few subjects completed the week-long washout (n=3 early ODT; n=1 early DBS+ODT). New exploratory assessments collected at the 11-year study visit are presented in Table 3.
Table 2:
Annual Outcomes of the 11-Year Study Subjects
| Early ODT | Early DBS+ODT | ||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Year 1 | Year 2 | Year 3 | Year 4 | Year 5 | Year 11 | Δ Baseline to 11 years | Baseline | Year 1 | Year 2 | Year 3 | Year 4 | Year 5 | Year 11 | Δ Baseline to 11 years | MEM P-value | |
| No. | 8 | 8 | 8 | 3 a | 8 | 8 | 8 | 4 | 4 | 4 | 2 a | 4 | 4 | 4 | |||
| Hoehn & Yahr | 1.9 (0.2) |
2.0 (0.0) |
1.9 (0.4) |
2.3 (0.6) |
2.1 (0.2) |
2.3 (0.4) |
2.8 (0.6) |
0.9 | 1.3 (0.5) |
2.0 (0.0) |
2.0 (0.0) |
2.0 (0.0) |
2.0 (0.0) |
2.1 (0.3) |
2.5 (0.4) |
1.3 | 0.26 |
| Schwab & England | 91.3 (5.2) |
90.0 (0.0) |
88.8 (5.8) |
83.3 (11.5) |
88.1 (3.7) |
84.4 (11.2) |
77.5 (19.8) |
−13.8 | 92.5 (5.0) |
92.5 (5.0) |
96.3 (4.8) |
95.0 (7.1) |
95.0 (5.8) |
88.8 (6.3) |
85.0 (5.8) |
−7.5 | 0.17 |
| UPDRS-I | 1.7 (1.2) |
2.4 (1.5) |
2.5 (1.6) |
2.0 (1.7) |
1.8 (1.6) |
2.4 (1.3) |
2.9 (1.6) |
1.2 | 0.5 (0.6) |
2.8 (2.2) |
3.3 (3.3) |
2.5 (3.5) |
3.3 (2.5) |
3.0 (2.9) |
2.3 (1.9) |
1.8 | 0.79 |
| UPDRS-II | 9.3 (4.6) |
8.3 (3.9) |
9.3 (4.9) |
6.7 (6.7) |
11.0 (5.4) |
13.1 (5.5) |
19.6 (6.8) |
10.4 | 4.8 (4.0) |
6.8 (4.3) |
7.4 (7.5) |
7.0 (5.7) |
9.8 (5.1) |
13.8 (3.3) |
15.8 (7.0) |
11.1 | 0.45 |
| UPDRS-III ON | 22.4 (8.0) |
26.0 (7.6) |
24.0 (9.4) |
25.0 (11.3) |
22.5 (9.5) |
28.1 (8.6) |
26.1 (14.5) |
3.7 | 14.0 (8.8) |
16.3 (10.6) |
14.0 (10.0) |
15.5 (13.4) |
18.3 (11.1) |
12.8 (10.0) |
25.0 (17.1) |
11.0 | 0.11 |
| UPDRS-III OFF b | 32.8 (7.3) |
37.0 (4.5) |
40.8 (7.9) |
NA | NA | NA | 41.7 (8.0) |
NA | 22.0 (9.6) |
25.8 (14.6) |
30.8 (15.6) |
NA | NA | NA | NA | NA | NA |
| UPDRS-IV | 2.1 (2.2) |
2.5 (2.5) |
3.9 (2.8) |
4.3 (1.2) |
4.4 (2.6) |
4.9 (2.6) |
5.6 (3.6) |
3.5 | 3.5 (1.7) |
5.5 (5.2) |
2.8 (1.5) |
4.0 (0.0) |
4.3 (2.2) |
4.3 (1.7) |
3.5 (2.1) |
0.0 | 0.03 |
| Total UPDRS | 36.6 (11.8) |
39.1 (9.2) |
39.6 (14.9) |
38.0 (17.8) |
39.6 (12.3) |
48.5 (13.5) |
54.3 (21.3) |
17.7 | 22.8 (8.9) |
31.3 (8.5) |
27.4 (17.7) |
29.0 (4.2) |
35.5 (18.5) |
33.8 (11.8) |
46.5 (22.2) |
23.7 | 0.17 |
| LEDD, mg | 554 (229) |
753 (306) |
720 (283) |
982 (677) |
966 (531) |
1280 (731) |
904 (431) |
350 | 471.0 (290.0) |
483.0 (288.0) |
575.0 (485.0) |
1050.0 (1060.0) |
849.0 (785.0) |
918.0 (874.0) |
565.0 (262.0) |
94.0 | 0.23 |
| PDQ-39 Summary Index | 14.7 (6.7) |
13.9 (7.3) |
19.0 (14.7) |
28.0 (7.2) |
20.9 (11.9) |
22.9 (17.8) |
27.0 (10.1) |
12.3 | 11.2 (7.2) |
22.4 (16.5) |
14.7 (11.4) |
20.2 (8.0) |
24.8 (16.5) |
22.5 (16.3) |
32.5 (18.3) |
21.3 | 0.88 |
Due to a gap in study funding, only 5 of the 11-year study subjects completed the study visit at Year 3 (n=3 early ODT; n=2 early DBS+ODT).
Only four subjects completed the week-long washout at the 11-year follow-up assessment (n=3 early ODT; n=1 early DBS+ODT).
NA = not available; P-values were from linear mixed effects models (MEM).
Figure 2: Complications of Therapy (Unified Parkinson’s Disease Rating Scale, Part IV).
DBS = deep brain stimulation; ODT = optimal drug therapy.
Table 3:
Additional Assessments at the 11-Year Study Visit
| Early ODT (n=8) | Early DBS+ODT (n=4) | |
|---|---|---|
| MSCI a | 27.0 (9.2) | 17.0 (18.7) |
| QUEST | 30.9 (17.7) | 37.9 (30.9) |
| King’s PD Pain Scale | 4.5 (3.2) | 2.8 (1.0) |
| EQ-5D Health Scale | 69.7 (15.8) | 65.0 (10.8) |
| EQ-5D Utility Index | 0.8 (0.1) | 0.8 (0.1) |
| QUIP Total ICD | 1.5 (1.9) | 0.9 (1.6) |
Abbreviations:
MCSI = Multidimensional Caregiver Strain Index;
QUEST = Quality of Life in Essential Tremor Questionnaire;
EQ-5D = 5-level EuroQol;
QUIP = Questionnaire for Impulsive-Control Disorders;
ICD = Impulse Control Disorder
Missing data for MSCI: early ODT, n=5; early DBS+ODT, n=1
Since the five-year study completed, there were no surgical issues reported for either randomization group, and prior studies report adverse events after two and five years of follow-up (8, 9). Early DBS+ODT subjects were originally implanted with two single-channel internal pulse generators (IPGs) when the study began (2006–2009). Over the 11-year follow-up period, the 4 early DBS+ODT subjects in this study had 17 IPG replacement surgeries (across both left and right sides), with a mean battery life of 4.9 ± 2.3 years per IPG. One early ODT subject who later received DBS had three IPG replacements, with a mean battery life of 4.2 ± 0.5 years per IPG.
Twelve subjects were deceased (n=5 early ODT; n=7 early DBS+ODT). Table 4 describes the deceased participants and PD characteristics at death. Age at death was 72.3 ± 6.5 years and PD duration was 11.8 ± 3.2 years. Cause of death for early DBS+ODT subjects included: PD (n=1), SARS-COV2 (n=1), aspiration pneumonia (n=1), subdural hematoma following a fall unrelated to DBS which did not damage the DBS system (n=1), unknown (n=5). Cause of death for early ODT subjects included: cancer (n=1), Alzheimer’s dementia/hypertension (n=1), unknown (n=3).
Table 4:
Deceased Subjects from the DBS in Early PD Pilot Trial
| Baseline Characteristics | ||||||
|---|---|---|---|---|---|---|
| Early ODT | Early DBS+ODT | |||||
| Sex (Male:Female) | 5:0 | 7:0 | ||||
| Age | ||||||
| Mean | 62.0 (8.2) | 63.3 (5.4) | ||||
| Range | 50.2–69.8 | 58.8–74.0 | ||||
| Medication Use | ||||||
| Mean Duration (years) | 1.73 (0.8) | 2.77 (1.6) | ||||
| Mean LEDD (mg) | 382 (191) | 481 (367) | ||||
| Hoehn & Yahr | 1.6 (0.6) | 1.9 (0.4) | ||||
| Schwab & England | 90.0 (7.1) | 92.1 (3.9) | ||||
| UPDRS Scores | ||||||
| UPDRS-III ON | 21.8 (11.4) | 30.3 (11.1) | ||||
| Total | 32.4 (15.0) | 43.7 (14.3) | ||||
| PDQ-39 Summary Index | 12.4 (13.4) | 13.9 (7.4) | ||||
| Parkinson’s Disease Characteristics at Death | ||||||
| Early ODT | Early DBS+ODT | |||||
| Age | ||||||
| Mean | 70.4 (7.6) | 73.6 (5.7) | ||||
| Range | 62.0 – 78.8 | 67.8 – 84.4 | ||||
| PD Duration | 10.1 (2.2) | 13.0 (3.4) | ||||
| DBS Duration | n.a. | 10.1 (2.2) | ||||
| Time Since Baseline | 8.4 (2.3) | 10.3 (2.2) | ||||
| Yes | No | Unknown | Yes | No | Unknown | |
| Dementia | 2 (40%) | 1 (20%) | 2 (40%) | 4 (57%) | 3 (43%) | 0 (0%) |
| Depression | 4 (80%) | 0 (0%) | 1 (20%) | 4 (57%) | 2 (29%) | 1 (14%) |
| Dysphagia | 1 (20%) | 1 (20%) | 3 (60%) | 5 (71%) | 2 (29%) | 0 (0%) |
| Falls | 3 (60%) | 0 (0%) | 2 (40%) | 7 (100%) | 0 (0%) | 0 (0%) |
| Psychosis/Hallucinations | 2 (40%) | 0 (0%) | 3 (60%) | 3 (43%) | 3 (43%) | 1 (14%) |
| Incontinence | 1 (20%) | 0 (0%) | 4 (80%) | 2 (29%) | 3 (43%) | 2 (29%) |
| Insomnia | 3 (60%) | 0 (0%) | 2 (40%) | 4 (57%) | 2 (29%) | 1 (14%) |
| Nursing Home Admission | 2 (40%) | 1 (20%) | 2 (40%) | 2 (29%) | 4 (57%) | 1 (14%) |
Abbreviations: DBS = deep brain stimulation; ODT = optimal drug therapy; LEDD = levodopa equivalent daily dose; UPDRS = Unified Parkinson’s Disease Rating Scale
Values are mean (SD).
Excludes rigidity; single-blind rating
UPDRS total reported as the sum of parts I, II, III, and IV
DISCUSSION
This study reports 11-year outcomes from the pilot clinical trial of DBS in early-stage PD, which represents the longest follow-up of PD patients who received DBS as part of a randomized clinical trial at any stage of disease. Early DBS+ODT subjects had significantly fewer motor complications than early ODT subjects. These results should be interpreted with caution, however, because only 40% of pilot trial subjects participated in this 11-year follow-up study.
This study has several limitations, and these results are therefore exploratory and hypothesis-generating. The pilot clinical trial was restricted by the FDA to 30 participants, and only a limited number of subjects were available for follow-up 11 years after baseline due to death, disability, or loss to follow-up. This selection bias is noted as a limitation as is the small sample size. All study participants completed five week-long washouts as part of the original two-year pilot trial and given this prior experience with the washout protocol, efforts were made to repeat the week-long washout. Four participants successfully completed the washout and three declined to attempt it. There were no episodes of a neuroleptic malignant-like syndrome due to rapid reduction of dopaminergic medications (23) or a DBS withdrawal syndrome due to discontinuing DBS (24) during any of the 147 early-stage PD week-long washouts in the pilot trial or the 9 mid-/late-stage PD washouts in this 11-year follow-up study. Such reactions remain a possibility, and future studies should closely monitor PD patients withdrawn from dopaminergic medications and DBS. Despite the aforementioned limitations, it remains important to gather as much preliminary data as possible regarding the long-term effects of DBS when applied at the very earliest stages of PD.
STN-DBS is an established treatment for reducing dyskinesia and motor complications of mid- and advanced-staged PD (1–3). After 11 years of follow-up, early DBS+ODT was superior to early ODT for motor complications associated with medical therapy. Notwithstanding the limitations of this study, the preliminary finding that early DBS provides long-term reduction in motor complications aligns with the longstanding history of reported benefits of the therapy. Previous results from the pilot trial demonstrated that STN-DBS in early-stage PD may slow the progression of tremor (14) and reduce the risk of disease progression and polypharmacy (9); however, the small sample size of this study was not adequate to allow detection of significant differences on these measures. This cohort also completed a post-study interview, and that qualitative analysis indicates overall satisfaction with participating in the trial (25).
This study reports 11-year outcomes of participants from the DBS in early-stage PD pilot clinical trial and showed that early DBS+ODT subjects had fewer motor complications than ODT subjects. These results must be interpreted with caution due to the limitations of this study. Understanding the potential benefits of DBS in early-stage PD as an adjunctive therapy to medications will require not only demonstrating safety and efficacy in a future multicenter trial but also showing lasting benefit in studies evaluating the long-term effects of early DBS. The FDA has approved the conduct of a pivotal, multi-center, randomized clinical trial to evaluate DBS in early-stage PD (IDEG050016).
ACKNOWLEDGEMENTS
We extend our most sincere appreciation to the participants of this clinical trial. Their commitment to advancing research and time invested are an incredible gift to the Parkinson’s community. We thank Bryan Eoff for his work on this study.
Funding
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (R21NS107877) and the American Parkinson Disease Association awarded to Dr. Hacker and a CTSA award No. UL1 TR002243 from the National Center for Advancing Translational Sciences. This work was also supported by a generous gift from Phyllis G. Heard, and her children, Elizabeth Heard, and Tony Heard.
Conflict of Interest Statement
The pilot trial of DBS in early PD received partial support from Medtronic, Inc, which manufactures the DBS system. Dr. Hacker receives funding from the National Institute on Aging and is a shareholder of Arena Therapeutics. Ms. Meystedt, Mr. Turchan, Dr. Cannard, Ms. Harper, Ms. Fan, Dr. Ye, and Dr. Davis declare no Competing Financial Interests. Dr. Konrad has equity ownership in Neurotargeting LLC and receives research and fellowship grants paid to West Virginia University from Medtronic. Dr. Charles is a shareholder of Arena Therapeutics.
Footnotes
DISCLAIMER
The views expressed in this article are those of the author and do not necessarily reflect the official policy or position of Walter Reed National Military Medical center, the Department of Defense, or the U.S. Government. This publication does not imply any Federal/Department of Defense endorsement of any treatment or device.
REFERENCES
- 1.Deuschl GG, Schade-Brittinger C, Krack P, et al. A Randomized Trial of Deep-Brain Stimulation for Parkinson’s Disease. New England Journal of Medicine 2006;355:896–908. [DOI] [PubMed] [Google Scholar]
- 2.Schuepbach WMM, Rau J, Knudsen K, et al. Neurostimulation for Parkinson’s disease with early motor complications. New England Journal of Medicine 2013;368:610–22. [DOI] [PubMed] [Google Scholar]
- 3.Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthalamic deep-brain stimulation for Parkinson’s disease. New England Journal of Medicine 2010;362:2077–91. [DOI] [PubMed] [Google Scholar]
- 4.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. [DOI] [PubMed] [Google Scholar]
- 5.Harries AM, Kausar J, Roberts SAG, et al. Deep brain stimulation of the subthalamic nucleus for advanced Parkinson disease using general anesthesia: long-term results. J Neurosurg 2012;116:107–13. [DOI] [PubMed] [Google Scholar]
- 6.Castrioto A, Lozano A, Poon Y, Lang A, Fallis M, Moro E. Ten-Year Outcome of Subthalamic Stimulation in Parkinson Disease. Archives of Neurology 2011;68:1550–6. [DOI] [PubMed] [Google Scholar]
- 7.Fasano A, Romito L, Daniele A, et al. Motor and cognitive outcome in patients with Parkinson’s disease 8 years after subthalamic implants. Brain 2010;133:2664–76. [DOI] [PubMed] [Google Scholar]
- 8.Charles D, Konrad PE, Neimat JS, et al. Subthalamic nucleus deep brain stimulation in early stage Parkinson’s disease. Parkinsonism and Related Disorders 2014;20:731–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Hacker ML, Turchan M, Heusinkveld LE, et al. Deep brain stimulation in early-stage Parkinson disease: Five-year outcomes. Neurology 2020;95:E393–401. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Charles D, Tolleson C, Davis TL, et al. Pilot Study Assessing the Feasibility of Applying Bilateral Deep Brain Stimulation in Very Early Stages of Parkinson’s Disease: Study Design and Rationale. Journal of Parkinson’s Disease 2012;2:215–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Charles PD, Dolhun RM, Gill CE, et al. Deep brain stimulation in early Parkinson’s disease: Enrollment experience from a pilot trial. Parkinsonism and Related Disorders 2012;18:268–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kahn E, D’Haese P-F, Dawant B, et al. Deep brain stimulation in early stage Parkinson’s disease: operative experience from a prospective randomised clinical trial. J Neurol Neurosurg Psychiatry 2012;83:164–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Hacker ML, Tonascia J, Turchan M, et al. Deep brain stimulation may reduce the relative risk of clinically important worsening in early stage Parkinson’s disease. Parkinsonism and Related Disorders 2015;21:1177–83. [DOI] [PubMed] [Google Scholar]
- 14.Hacker M, Delong M, Turchan M, et al. Effects of deep brain stimulation on rest tremor progression in early stage Parkinson disease. Neurology 2018;91:e463–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hacker ML, Currie AD, Molinari AL, et al. Subthalamic Nucleus Deep Brain Stimulation May Reduce Medication Costs in Early Stage Parkinson’s Disease. Journal of Parkinson’s Disease 2016;6:125–31. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Hacker M, Cannard G, Turchan M, et al. Early subthalamic nucleus deep brain stimulation in Parkinson ‘ s disease reduces long-term medication costs. Clinical Neurology and Neurosurgery 2021;210:106976. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Weaver FM, Stroupe KT, Cao L, et al. Parkinson’s disease medication use and costs following deep brain stimulation. Movement Disorders 2012;27:1398. [DOI] [PubMed] [Google Scholar]
- 18.Oyama G, Okun MS, Schmidt P, et al. Deep brain stimulation may improve quality of life in people with Parkinson’s disease without affecting caregiver burden. Neuromodulation 2014;17:126–32. [DOI] [PubMed] [Google Scholar]
- 19.Louis ED, Machado DG. Tremor-related quality of life: A comparison of essential tremor vs.Parkinson’s disease patients. Parkinsonism and Related Disorders 2015;21:729–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Chaudhuri KR, Rizos A, Trenkwalder C, et al. King’s Parkinson’s disease pain scale, the first scale for pain in PD: An international validation. Mov Disord 2015;30:1623–31. [DOI] [PubMed] [Google Scholar]
- 21.Van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to EQ-5D-3L value sets. Value in Health 2012;doi: 10.1016/j.jval.2012.02.008. [DOI] [PubMed] [Google Scholar]
- 22.Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson’s Disease-Rating Scale. Movement Disorders 2012;27:242–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Adnet P, Lestavel P, Krivosic-Horber R. Neuroleptic malignant syndrome. Br J Anaesth 2000;85:129–35. [DOI] [PubMed] [Google Scholar]
- 24.Reuter S, Deuschl G, Berg D, Helmers A, Falk D, Witt K. Life-threatening DBS withdrawal syndrome in Parkinson’s disease can be treated with early reimplantation. Parkinsonism and Related Disorders 2018;56:88–92. [DOI] [PubMed] [Google Scholar]
- 25.Stoehr K, Pazira K, Bonnet K, Schlundt D, Charles D, Hacker M. Deep Brain Stimulation in Early-Stage Parkinson’s Disease: Patient Experience After 11 Years. Brain Sciences 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]