Nej Mo a 1205158

7/23/2019 Nej Mo a 1205158

1/13

original article

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 368;7 nejm.org february 14, 2013610

Neurostimulation for Parkinsons Diseasewith Early Motor Complications

W.M.M. Schuepbach, J. Rau, K. Knudsen, J. Volkmann, P. Krack, L. Timmermann,T.D. Hlbig, H. Hesekamp, S.M. Navarro, N. Meier, D. Falk, M. Mehdorn, S. Paschen,

M. Maarouf, M.T. Barbe, G.R. Fink, A. Kupsch, D. Gruber, G.-H. Schneider, E. Seigneuret,A. Kistner, P. Chaynes, F. Ory-Magne, C. Brefel Courbon, J. Vesper, A. Schnitzler,

L. Wojtecki, J.-L. Houeto, B. Bataille, D. Maltte, P. Damier, S. Raoul, F. Sixel-Doering,D. Hellwig, A. Gharabaghi, R. Krger, M.O. Pinsker, F. Amtage, J.-M. Rgis, T. Witjas,S. Thobois, P. Mertens, M. Kloss, A. Hartmann, W.H. Oertel, B. Post, H. Speelman,

Y. Agid, C. Schade-Brittinger, and G. Deuschl, for the EARLYSTIM Study Group*

The authors full names, degrees, and affili-ations are listed in the Appendix. Addressreprint requests to Dr. Deuschl at the De-partment of Neurology, University Hos-pital SchleswigHolstein, Campus Kiel,Christian-Albrechts University Kiel, Arnold-Heller Str. 3, 24105 Kiel, Germany, or [email protected].

Dr. Schuepbach, Mr. Rau, and Dr. Knudsenand Dr. Agid, Ms. Schade-Brittinger, andDr. Deuschl contributed equally to thisarticle.

* Additional investigators in the Con-trolled Trial of Deep Brain Stimulationin Early Patients with Parkinsons Dis-ease (EARLYSTIM) Study Group arelisted in the Supplementary Appendix,available at NEJM.org.

N Engl J Med 2013;368:610-22.

DOI: 10.1056/NEJMoa1205158

Copyright 2013 Massachusetts Medical Society.

A B S T RA C T

BACKGROUND

Subthalamic stimulation reduces motor disability and improves quality of life inpatients with advanced Parkinsons disease who have severe levodopa-induced motorcomplications. We hypothesized that neurostimulation would be beneficial at anearlier stage of Parkinsons disease.

METHODS

In this 2-year trial, we randomly assigned 251 patients with Parkinsons disease andearly motor complications (mean age, 52 years; mean duration of disease, 7.5 years)to undergo neurostimulation plus medical therapy or medical therapy alone. Theprimary end point was quality of life, as assessed with the use of the ParkinsonsDisease Questionnaire (PDQ-39) summary index (with scores ranging from 0 to 100

and higher scores indicating worse function). Major secondary outcomes includedparkinsonian motor disability, activities of daily living, levodopa-induced motor com-plications (as assessed with the use of the Unified Parkinsons Disease Rating Scale,parts III, II, and IV, respectively), and time with good mobility and no dyskinesia.

RESULTS

For the primary outcome of quality of life, the mean score for the neurostimulationgroup improved by 7.8 points, and that for the medical-therapy group worsened by0.2 points (between-group difference in mean change from baseline to 2 years, 8.0points; P = 0.002). Neurostimulation was superior to medical therapy with respectto motor disability (P

7/23/2019 Nej Mo a 1205158

2/13

ear ly Neurostimulation for Parkinsons Disease

n engl j med 368;7 nejm.org february 14, 2013 611

Parkinsons disease is a progressiveneurodegenerative disease that affects do-paminergic neurotransmission, resulting inbradykinesia, rigidity, and rest tremor. After aninitial honeymoon period, during which there isa sustained response to dopaminergic treatment,beneficial effects are hampered by levodopa-

induced motor complications,1progressively com-promising quality of life.2-4

Because levodopa-responsive parkinsoniansymptoms are improved by high-frequency stim-ulation of the subthalamic nucleus,5,6 neuro-stimulation has become an established treatmentfor advanced Parkinsons disease with medicallyintractable fluctuations and dyskinesia7-10 andhas shown long-term efficacy.11-13It is typicallyused after the disease has been present for 11 to13 years,7-10when quality of life, social adjust-ment (psychosocial competence),14 and profes-

sional activity are already severely impaired.Neurostimulation improves quality of life,7-10inaddition to motor symptoms. Moreover, later inthe course of the disease, features unresponsiveto dopaminergic treatment often predominate.Therefore, optimizing quality of life during theperiod when patients have the greatest responseto dopaminergic therapy (and therefore neuro-stimulation as well) should be considered a majorgoal of current treatment. We hypothesized thatneurostimulation improves quality of life at anearlier stage of Parkinsons disease, as suggestedby our pilot trial involving patients with early andmild motor complications.15

In the current study, we randomly assignedpatients with Parkinsons disease and a recentonset of motor complications to receive neuro-stimulation plus medical therapy or medicaltherapy only. Disease-related quality of life waschosen as the primary outcome, thereby allowinga global assessment of beneficial and adverseeffects in a way that subjectively matters to thepatient.

METHODS

PATIENTS

Patients with Parkinsons disease were eligiblefor the study if they met the following inclusioncriteria: an age of 18 to 60 years; disease durationof 4 years or more; a disease severity rating belowstage 3 in the on-medication condition, accord-ing to the Hoehn and Yahr scale, with scores

ranging from 0 to 5 and higher scores indicatingmore severe disease16; improvement of motor signsof 50% or more with dopaminergic medication,6as assessed with the use of the Unified Parkin-sons Disease Rating Scale, part III (UPDRS-III;scores range from 0 to 108, with higher scoresindicating worse functioning)17; fluctuations or

dyskinesia present for 3 years or less; and a scoreof more than 6 for activities of daily living in theworst condition despite medical treatment, as as-sessed with the use of the UPDRS-II (scores rangefrom 0 to 52, with higher scores indicating worsefunctioning), or mild-to-moderate impairmentin social and occupational functioning (score of51 to 80% on the Social and Occupational Func-tioning Assessment Scale,18with scores rangingfrom 1 to 100 and lower scores indicating worsefunctioning).

Exclusion criteria were dementia (a score of

130 on the Mattis Dementia Rating Scale,19with scores ranging from 0 to 144 and higherscores indicating better functioning), major de-pression with suicidal thoughts (a score of >25 onthe Beck Depression Inventory II,20with scoresranging from 0 to 63 and higher scores indicat-ing worse functioning), acute psychosis, and anymedical or psychological problem that would in-terfere with the conduction of the study protocol.21Patients with a duration of disease of less than4 years were excluded because atypical forms ofparkinsonism would be expected to be identifi-able before then. Details regarding the scales areprovided in Tables S1, S2, and S3 in the Supple-mentary Appendix, available with the full text ofthis article at NEJM.org.

STUDY DESIGN

Conducted in Germany and France, this studyfollowed an investigator-initiated, randomized,multicenter, parallel-group design comparingneurostimulation plus medical therapy (neuro-stimulation group) with medical therapy alone

(medical-therapy group). Randomization wasperformed centrally at the University of Marburgcoordinating center, Marburg, Germany, with theuse of randomization lists with randomly permut-ed block lengths stratif ied according to center.

The trial conformed to the Declaration of Hel-sinki, Good Clinical Practice guidelines, and theInternational Organization for Standardization14:155 (2003) standards and was approved by theethics committee for each participating center.

The New England Journal of Medicine

Downloaded from nejm.org on September 28, 2015. For personal use only. No other uses without permission.

Copyright 2013 Massachusetts Medical Society. All rights reserved.

7/23/2019 Nej Mo a 1205158

3/13



All patients provided written informed consentbefore randomization. An independent data andsafety monitoring committee provided review anddirection regarding the collection of safety data.

Full source-data verification was performed bymonitors from the German coordinating center(Koordinierungszentrum fr Klinische Studien)

for the German centers and by monitors from theFrench coordinating center (Department of Clin-ical Research, Assistance PubliqueHpitaux deParis) for the French centers. Data were collectedand analyzed by the German coordinating centerin Marburg. All the authors vouch for the accu-racy of the data and the analyses reported andfor the adherence of the study to the protocol,available at NEJM.org. The protocol committeedesigned the study, and the steering committeewrote the first draft of the manuscript. Medtron-ic provided additional funding for the study but

had no role in the study design, data accrual,data analysis, or manuscript preparation.

Patients assigned to neurostimulation under-went bilateral stereotactic surgery of the subtha-lamic nucleus with the implantation of electrodes(model 3389, Medtronic) and a pulse generator(Kinetra or Soletra, Medtronic) within 6 weeksafter randomization, according to operative stan-dards that address local anesthesia, imaging, tar-geting, microelectrode recording, and conf irma-tion of the f inal electrode position.21Patients inthe neurostimulation group then began receivingstimulation according to standards established forthis study (see the Supplementary Appendix).21

Assessments were scheduled at baseline and at5, 12, and 24 months. A levodopa challenge testwas performed at baseline and at 24 months (seethe Supplementary Appendix).21Blinded assess-ments were based on preoperative and postop-erative standardized video recordings obtainedat baseline and at 24 months. Videos were re-corded for each motor condition (according towhether the patient was or was not receiving

medication or stimulation). The UPDRS-III scorewas assessed by two expert raters who were un-aware of the study assignments,22except for theassessment of rigidity, which cannot be evaluatedon the basis of a video recording.

During follow-up, adjustments to medicationand stimulation were performed according to pre-defined standards.21These standards followed theEuropean Federation of Neurological Societiesguidelines for the treatment of advanced Parkin-sons disease23and a standardized sequence of

interventions.21An independent expert panel as-sessed whether medication therapy was consis-tent with guidelines for each patient (see theSupplementary Appendix).

A specific procedure for monitoring the riskof suicidality, established after two suicides hadoccurred during the study, consisted of a baseline

assessment of the general risk and a semistruc-tured telephone interview every 2 months to as-sess status, with psychiatric follow-up as needed(see the Supplementary Appendix).21

OUTCOME MEASURES

The primary end point was the between-groupdifference in mean change in quality of life frombaseline to 2 years, as assessed with the use ofthe summary index of the Parkinsons DiseaseQuestionnaire (PDQ-39).24,25After we obtained asignificant result for quality of life, the following

clinically relevant motor functions were testedsequentially as major secondary outcomes: ac-tivities of daily living (UPDRS-II score),17severityof motor signs (UPDRS-III score), severity oftreatment-related complications (UPDRS-IV score),and time with good mobility and no troublesomedyskinesia, as recorded by patients in a diary. Mi-nor secondary outcomes included scores on theScales for Outcomes in Parkinsons DiseasePsy-chosocial (SCOPA-PS) questionnaire (on a scalefrom 0 to 33, with higher scores indicating worsefunctioning), the Mattis Dementia Rating Scale19(on a scale of 0 to 144, with higher scores indicat-ing better functioning), the Brief Psychiatric RatingScale26 (on a scale of 18 to 126, with higherscores indicating worse functioning), the Mont-gomery and sberg Depression Rating Scale27(ona scale of 0 to 60, with higher scores indicatingworse functioning), the Beck Depression Inven-tory II20(on a scale of 0 to 63, with higher scoresindicating worse functioning), and the StarksteinApathy Scale28(on a scale of 0 to 42, with higherscores indicating worse functioning), as well as

the levodopa-equivalent daily dose.7,9,21,29

Theother minor secondary outcomes are listed in theSupplementary Appendix.

ADVERSE EVENTS

Adverse events in all patients were reported andcoded according to the Medical Dictionary for Regu-latory Activities, version 14.1. Serious adverseevents were defined as any events that led todeath, disability, or prolonged or new hospital-ization with serious health impairment.




7/23/2019 Nej Mo a 1205158

4/13

ear ly Neurostimulation for Parkinsons Disease

n engl j med 368;7 nejm.org february 14, 2013 613

STATISTICAL ANALYSIS

The sample size was calculated on the basis ofour previous studies.7,15We selected a power of80% for a two-sided MannWhitney test, assum-ing normally distributed data. To detect a stan-dardized effect size of 0.4 with an alpha level of5%, we calculated that we would need to enroll

208 patients. Assuming a 15% rate of loss tofollow-up, we determined that a total enrollmentof at least 246 patients would be required. Theintention-to-treat analysis was primary; the per-protocol analysis was secondary. No interimanalysis was planned. The MannWhitney testwas replaced by a flexible and robust linearmixed-model analysis with baseline adjustmentand included study center as a random effect,main effects for group and time, a group-by-timeinteraction term, and a generalized covariancematrix to account for serial dependency among

observations after verification of the assumptionof multivariate normality for the parametricmodel.21Differences in mean changes betweenassessments at baseline and at 24 months werecompared between the groups. Missing data dueto loss to follow-up were handled by means ofdirect likelihood analyses,30,31 with adjustmentfor the conditional expectation of the missingmeasurements, given the observed ones.

A serial gatekeeper procedure was planned. Ifthe primary end point was significant, the UPDRS-II, UPDRS-III, and UPDRS-IV scores and time withgood mobility and no troublesome dyskinesiawere tested sequentially with the use of Hoch-bergs multiple-comparison method32 at a sig-nificance level of 5%.

RESULTS

CHARACTERISTICS OF THE PATIENTS

Of 392 patients assessed for eligibility, 251 wereenrolled between July 2006 and November 2009at nine German and eight French university cen-

ters (Fig. S1 in the Supplementary Appendix).The intention-to-treat population consisted of124 patients assigned to the neurostimulationgroup (120 of whom underwent implantation andcompleted the study) and 127 patients assigned tothe medical-therapy group (of whom 125 under-went medical therapy and 123 completed the study).A total of 25 patients had major protocol devia-tions, including PDQ-39 assessment outside thepredefined time window, an absence of motorfluctuations or dyskinesia, insuff icient exposure

to treatment, and death during the study period.The per-protocol analysis included 116 patientsin the neurostimulation group and 110 in themedical-therapy group (Fig. S1 in the Supple-mentary Appendix). Baseline characteristics didnot differ significantly between the treatmentgroups (Table 1). The mean duration of Parkin-sons disease was 7.5 years, and patients wereincluded in the study a mean of 1.7 years afterthe onset of levodopa-induced motor complica-tions of any severity.

QUALITY-OF-LIFE, ACTIVITIES OF DAILY LIVING,

AND MOTOR OUTCOMES

The primary outcome (PDQ-39 summary indexscore) was improved from baseline to 24 months by26% in the neurostimulation group but worsenedby 1% in the medical-therapy group (Table 2). Inthe intention-to-treat population, the between-group difference in the mean change from base-line was 8.0 points (P = 0.002), which was similarto the between-group differences in the per-pro-tocol population and the group of patients whocompleted the PDQ-39 assessment. The maximum

Table 1.Baseline Characteristics of the Study Population.*

CharacteristicNeurostimulation

(N = 124)Medical Therapy

(N = 127)

Age yr 52.96.6 52.26.1

Sex no. (%)

Male 94 (75.8) 85 (66.9)

Female 30 (24.2) 42 (33.1)

Duration of Parkinsons disease yr 7.33.1 7.72.7

Dyskinesia

No. of patients 84 94

Duration yr 1.40.8 1.50.8

Motor fluctuations



Treatment with levodopa



Treatment with dopamine agonistNo. of patients 118 115


Levodopa-equivalent daily dose mg 918.8412.5 966.9416.5

* Plusminus values are means SD. There were no significant between-groupdifferences.

The presence of dyskinesias or fluctuations for 3 years or less was an eligibilitycriterion.




7/23/2019 Nej Mo a 1205158

5/13



Table2.

Primary,

Major,andMinorSecondaryEndPoints.*

EndPoint

Baseline

Within-TreatmentChangefrom

Baseline

to24Mo

nths

Between-Group

Difference

inChangefrom

Baseline

(95%C

I)

PValue

Neurostimulation

Med

icalTherapy

Neurostimulation

MedicalTherapy

no.of

patients

mean

SE

no.of

patients

mean

SE

mean

SE

%c

hange

fromb

aseline

mean

SE

%c

hange

fromb

aseline

meanS

E

Primaryendpoint

PDQ-39summaryindexscore,i

ntention-to-treat

population

124

30.21.3

127

30.21.3

7.81.2

26

0.21.1

1

8.01.6(4.2t

o11.9)

0.002

PDQ-39summaryindexscore,p

er-protocol

population

110

30.11.4

116

30.11.3

8.11.2

27

0.01.2

0

8.11.7(2.8t

o13.4)

0.02

Majorsecondaryendpoints

UPDRS-IIIscore,withoutmedic

ation

123

33.21.8

127

33.01.8

17.51.0

53

1.21.0

4

16.41.4(13.7

to19.1)

Documents

Nej Mo a 1205158