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EARLYSTIM

Neurostimulation for Parkinson's Disease with Early Motor Complications

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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

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?

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
        First randomized trial of DBS in early Parkinson's disease with motor complications (mean disease duration 7.5 years)
Neurostimulation improved PDQ-39 quality of life score by 7.8 points vs worsening of 0.2 points with medical therapy (P=0.002)
Off-medication UPDRS-III motor scores improved 16.4 points in DBS group vs favored neurostimulation (P<0.001)
Activities of daily living (UPDRS-II), levodopa-induced complications (UPDRS-IV), time with good mobility all significantly improved (P<0.001)
No significant differences in cognitive assessments (Mattis DRS) or emotional outcomes between groups
Serious adverse events more frequent in neurostimulation group (54.8% vs 44.1%); 26 events related to surgery/device
Two suicides in neurostimulation group vs one in medical therapy group
Levodopa-equivalent daily dose reduced by 39% in DBS group but increased by 21% in medical therapy group

      

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 off-medication
Early motor complications (mean duration ~1.7 years)
≥50% improvement with dopaminergic medication
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/Solterra) plus medical therapy
Duration	24 months	24 months

Outcomes

Outcome	Type	Control	Intervention	P-value
PDQ-39 summary index score (quality of life, 0-100, higher = worse)	Primary	Worsened by 0.2 points (-0.2±1.2)	Improved by 7.8 points (7.8±1.2)	0.002
UPDRS-II (activities of daily living) without medication	Secondary	Mean±SE: 23±1.0	Mean±SE: 9.5±1.0	<0.001
UPDRS-III motor score, off medication (blinded assessment)	Secondary	Worsened (mean change -1 to 0)	Improved by 16.4 points	<0.001
UPDRS-IV (levodopa-induced motor complications)	Secondary	Mean±SE: 0±0.5	Mean±SE: 0.2±0.5	0.01
Time with good mobility and no troublesome dyskinesia (hours/day)	Secondary	Mean±SE: 1.0±0.8	Significantly increased	<0.001
Levodopa-equivalent daily dose	Secondary	Increased by 21%	Reduced by 39%	<0.001
Serious adverse events (total)	Adverse	56 (44.1%)	68 (54.8%)
Death (all by suicide)	Adverse	1 (0.8%)	2 (1.6%)
Event related to surgery or device	Adverse	0	26 (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
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-related complications occurred in 17.7% of neurostimulation patients

Funding

German Ministry of Research (Klinische Studies 01KG0502), French PHRC National (P050909), Medtronic

Based on: EARLYSTIM (New England Journal of Medicine, 2013)