EARLYSTIM
Neurostimulation for Parkinson's Disease with Early Motor Complications
Year of Publication: 2013
Authors: Schuepbach WMM, Rau J, Knudsen K, ..., for the EARLYSTIM Study Group
Journal: New England Journal of Medicine
Citation: N Engl J Med 2013;368:610-622
Link: https://doi.org/10.1056/NEJMoa1205158
PDF: https://www.nejm.org/doi/pdf/10.1056/NEJ...ticleTools=true
PDF: Clinical Question
Does bilateral subthalamic nucleus deep brain stimulation improve quality of life in patients with Parkinson's disease and early motor complications compared to medical therapy alone?
Study Overview
Objective
To determine whether subthalamic deep brain stimulation improves quality of life at an earlier stage of Parkinson's disease, before severe motor complications develop
Study Summary
- RCT of bilateral STN-DBS plus medical therapy vs medical therapy alone in 251 patients with early motor complications
- Younger patients (mean 52 years) with shorter disease duration (mean 7.5 years) than typical DBS candidates
- Quality of life improved 26% with DBS vs 1% worsening with medical therapy alone (P=0.002)
Intervention
Bilateral STN deep brain stimulation (Medtronic) plus optimized medical therapy vs medical therapy alone for 2 years
Patients per Arm
Neurostimulation: 124, Medical therapy: 127
Bottom Line
In patients with PD and early motor complications (mean disease duration 7.5 years), bilateral STN-DBS plus medical therapy was superior to medical therapy alone in improving quality of life (8.0-point between-group difference on PDQ-39, P=0.002), motor disability, levodopa-induced complications, and time with good mobility at 2 years, though with higher rate of serious adverse events including suicides.
Major Points
- Largest randomized trial of STN-DBS in early Parkinson's disease with motor complications (mean disease duration 7.5 years, fluctuations/dyskinesia present ~1.7/1.5 years); an earlier pilot RCT (Schüpbach 2007, ref 15) had already tested the concept in a smaller cohort
- Neurostimulation improved PDQ-39 quality of life by 7.8 points vs worsening of 0.2 points with medical therapy (between-group difference 8.0 points, 95% CI 4.2–11.9, P=0.002)
- Off-medication UPDRS-III motor scores improved by 53% (17.5 points) in the DBS group; medical-therapy scores did not meaningfully change (within-group change of only 1.2 points; paper states 'scores did not change'); between-group difference 16.4 points favoring neurostimulation (P<0.001); confirmed on blinded video review (between-group difference 8.6 points, P<0.001)
- Activities of daily living (UPDRS-II worst condition, between-group difference 6.2 pts, P<0.001) and levodopa-induced complications (UPDRS-IV, between-group difference 4.1 pts, P<0.001) improved with neurostimulation; time with good mobility and no troublesome dyskinesia increased by 1.9 hours/day (P=0.01)
- No significant between-group differences in cognitive assessments (Mattis DRS); mood measures (MADRS, BDI-II) favored neurostimulation
- Serious adverse events more frequent in neurostimulation group (68 patients, 54.8%; 123 events) vs medical therapy (56 patients, 44.1%; 128 events); 26 events related to surgery/device in 22 patients (17.7%)
- Two suicides in neurostimulation group vs one in medical therapy group (total 3); suicide attempts similar (2 vs 2)
- Levodopa-equivalent daily dose reduced by 39% in DBS group but increased by 21% in medical therapy group (between-group difference 609 mg, P<0.001)
Design
Study Type: Randomized controlled trial
Randomization: 1
Blinding: Blinded video assessments; expert raters unaware of study assignments except for rigidity assessment
Enrollment Period: July 2006 to November 2009
Follow-up Duration: 24 months
Centers: 17
Countries: Germany, France
Sample Size: 251
Analysis: Intention-to-treat (primary); per-protocol (secondary). Mixed-model analysis with baseline adjustment. Hochberg's procedure for sequential testing.
Inclusion Criteria
- Age 18 to 60 years
- Parkinson's disease duration of 4 years or more
- Hoehn and Yahr stage <3 in the on-medication condition
- Early motor complications: fluctuations or dyskinesia present for ≤3 years (mean ~1.7 and 1.5 years)
- ≥50% improvement in UPDRS-III with dopaminergic medication
- Functional/social impairment despite medical treatment: UPDRS-II activities-of-daily-living score >6 in the worst condition OR mild-to-moderate impairment on the Social and Occupational Functioning Assessment Scale (51–80%)
- No dementia (Mattis DRS score >130)
- No major depression with suicidal thoughts (BDI-II ≤25)
- No acute psychosis
Exclusion Criteria
- Disease duration less than 4 years
- Dementia (Mattis DRS score ≤130)
- Major depression with suicidal thoughts (BDI-II >25)
- Acute psychosis
- Any medical/psychological problem interfering with study protocol
Baseline Characteristics
| Characteristic | Medical Therapy | Neurostimulation |
|---|---|---|
| N | 127 | 124 |
| Age (years) | 52.2±6.1 | 52.9±6.6 |
| Male sex (%) | 66.9 | 75.8 |
| Duration of PD (years) | 7.7±2.7 | 7.3±3.1 |
| Dyskinesia (n patients) | 94 | 84 |
| Motor fluctuations (n patients) | 124 | 121 |
| Levodopa-equivalent daily dose (mg) | 966.9±416.5 | 918.8±412.5 |
Arms
| Field | Control | Neurostimulation |
|---|---|---|
| Intervention | Optimized pharmacological treatment according to EFNS guidelines | Bilateral STN-DBS (electrodes model 3389, Medtronic; pulse generator Kinetra or Soletra, Medtronic) plus medical therapy |
| Duration | 24 months | 24 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| PDQ-39 summary index score (quality of life, 0-100, higher = worse); between-group difference in mean change from baseline to 24 months (ITT) | Primary | Worsened by 0.2 points (change -0.2±1.1) | Improved by 7.8 points (change 7.8±1.2, 26%) | 0.002 | |
| UPDRS-II (activities of daily living) in the worst condition — mean change from baseline | Secondary | Worsened by 1.7 points (change -1.7±0.6) | Improved by 4.5 points (change 4.5±0.6, 30%); between-group difference 6.2±0.9 (4.5 to 8.0) | <0.001 | |
| UPDRS-III motor score, off medication — mean change from baseline (Table 2 footnote: positive values indicate improvement) | Secondary | Essentially unchanged (within-group change 1.2±1.0, 4%; paper states 'scores did not change') | Improved by 17.5 points (change 17.5±1.0, 53%); between-group difference 16.4±1.4 (13.7 to 19.1) | <0.001 | |
| UPDRS-III off medication, blinded video review (rigidity excluded) | Secondary | Essentially unchanged (change 1.0±0.8, 4%) | Improved by 9.6±0.8 (38%); between-group difference 8.6±1.1 (6.4 to 10.9) | <0.001 | |
| UPDRS-IV (levodopa-induced motor complications) — mean change from baseline | Secondary | Worsened by 0.7 points (change -0.7±0.3) | Improved by 3.4 points (change 3.4±0.3, 61%); between-group difference 4.1±0.4 (3.2 to 4.9) | <0.001 | |
| Time with good mobility and no troublesome dyskinesia (hours/day) — mean change from baseline | Secondary | Increased by 0.2 hours (change 0.2±0.5) | Increased by 2.1 hours (change 2.1±0.5, 20%); between-group difference 1.9±0.8 (0.4 to 3.4) | 0.01 | |
| Levodopa-equivalent daily dose | Secondary | Increased by 21% | Reduced by 39% (between-group difference 609 mg) | <0.001 | |
| Serious adverse events (total) | Adverse | 56 patients (44.1%); 128 events | 68 patients (54.8%); 123 events | ||
| Death (all by suicide) | Adverse | 1 (0.8%) | 2 (1.6%) | ||
| Event related to surgery or device | Adverse | 0 | 26 events in 22 patients (17.7%) | ||
| Worsening of mobility | Adverse | 11 (8.7%) | 5 (4.0%) | ||
| Motor fluctuations | Adverse | 7 (5.5%) | 0 | ||
| Depression | Adverse | 1 (0.8%) | 6 (4.8%) | ||
| Suicide attempt | Adverse | 2 (1.6%) | 2 (1.6%) |
Subgroup Analysis
No formal subgroup analyses reported. Authors noted DBS may select patients with higher suicide risk.
Criticisms
- Higher rate of serious adverse events in neurostimulation group (54.8% vs 44.1%)
- Two suicides in neurostimulation group vs one in medical therapy group
- Blinding was incomplete — patients knew their treatment assignment (only video-based motor assessments were blinded)
- Relatively young patient population (mean age 52 years) compared to typical advanced PD trials
- Disease duration relatively short (7.5 years) with motor complications present for mean of only 1.7 years
- Cannot exclude placebo effects or differences in medical management
- Surgery/device-related serious adverse events occurred in 17.7% of neurostimulation patients
Funding
German Ministry of Research (Klinische Studien 01KG0502), French PHRC National (P050909), Medtronic
Based on: EARLYSTIM (New England Journal of Medicine, 2013)
Authors: Schuepbach WMM, Rau J, Knudsen K, ..., for the EARLYSTIM Study Group
Citation: N Engl J Med 2013;368:610-622
Content summarized and formatted by NeuroTrials.ai.