Neurostimulation for Parkinson’s

Disease with Early Motor

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

Research Appraisal
Alreem Al-Naimi
 Publication
• Published by the New England Journal of Medicine (NEJM)
• Date
• Published on 14th of February 2013
• Setting
Impact Factor
• Germany and France (2018)

• Duration 70.670
• Two years
• Authors
W.M.M. Schuepbach, J. Rau, K. Knudsen, J. Volkmann, P. Krack, L. Timmermann, T.D. Hälbig, H.
Hesekamp, S.M. Navarro, N. Meier, D. Falk, M. Mehdorn, et al.
 Background
• Parkinson’s disease is a progressive
neurodegenerative disease; affects
dopaminergic neurotransmission → rigidity,
bradykinesia, and rest tremor.

• Levodopa-induced motor complications →

compromise quality of life.

• Neurostimulation has become an established

treatment for advanced Parkinson’s disease and
has shown long-term efficacy.
 Objective of Study

• To assess whether neurostimulation plus medical therapy would be

beneficial (improves quality of life) at an earlier stage of Parkinson's
disease compared to receiving medical therapy only.
 Study Design

• Investigator-initiated, randomized, multicenter, parallel-group design

comparing neurostimulation plus medical therapy (neurostimulation group)
with medical therapy alone (medical-therapy group).

• Approved by the ethics committee.

• All patients provided written informed consent before randomization.
 Patients - Inclusion Criteria
• Age → 18 - 60 yrs old

• Disease duration → 4 yrs or more

• Disease severity → rating < stage 3 in on-medication conditions; according to Hoehn & Yahr Scale with scores (0-
5),↑scores = ↑ severe disease

• Improvements of motor signs of 50% or more with dopaminergic medication; assessed with use of UPDRS-III
with scores (0-18), ↑scores = worse functioning

• Fluctuations or dyskinesia present for → 3 yrs or less

• Activities of daily living in the worst condition despite medical treatment → score >6; assessed by UPDRS-II with
scores (0-52), ↑scores = worse functioning

OR

• Mild-to-moderate impairment in social & occupational functioning → score (51-80%); on social & occupational
functioning assessment scale with score of (1-100), ↓ score, worse functioning
 Patients - Exclusion Criteria
• Duration of disease of < 4 years.

• Dementia (a score ≤130); assessed using Mattis Dementia Rating scale

(0-144), ↑scores = better functioning

• Major depression with suicidal thoughts (a score >25); assessed using

Beck Depression Inventory II with score (0 to 63), ↑scores = worse
functioning

• Acute psychosis, and any medical or psychological condition.

 Methods

• Patients assigned to neurostimulation underwent bilateral stereotactic

surgery of the subthalamic nucleus with the implantation of electrodes and
a pulse generator within 6 weeks after randomization.

• A levodopa challenge test was performed at baseline and at 24 months.

• Blinded assessments were based on preoperative and postoperative
standardized video recordings obtained at baseline and at 24 months.
• A specific procedure for monitoring the risk of suicidality, established
after two suicides had occurred during the study, consisted of a baseline
assessment of the general risk and a semi-structured telephone interview
every 2 months to assess status, with psychiatric follow-up as needed.
 Outcome Measures
• The primary outcome: mean difference between groups in quality of life from
baseline to 2 years

• Assessed using the summary index of the Parkinson's Disease

Questionnaire (PDQ-39).

• The secondary outcome: motor functions and activities of daily living

• UPDRS score and patients diary.

• Adverse events were reported and defined as any events that led to death,
disability, or prolonged or new hospitalization with serious health impairment.
 Characteristics of Patients
• 251 patients were enrolled

• 124 patients assigned to the

neurostimulation group

• 120 underwent implantation

and completed the study

• 127 patients assigned to the

medical-therapy group

• 125 underwent medical therapy

• 123 completed the study

 Quality-of-life, Activities of daily living, and Motor
outcomes

Improved by 26%; assess QOL

Severity of parkinsonian motor
improved by 53%
Levodopa-induced complications
(dyskinesia) improved by 61%
Assess psychosocial
consequences of
Parkinson's Disease; 28%
• The primary outcome (PDQ-39 summary index score) was improved from baseline to 24
months by 26% in the neurostimulation group but worsened by 1% in the medical-therapy
group.

• The SCOPA-PS score for psychosocial performance was also significantly better in the
neurostimulation group than in the medical-therapy group (P=0.02).

• UPDRS-III scores for the severity of parkinsonian motor improved by 53% in the
neurostimulation group.

• UPDRS-IV scores for levodopa-induced complications, including motor fluctuations and

dyskinesia, improved by 61% in the neurostimulation group, with a 4.1-point difference
between treatment groups (P<0.001).

• Levodopa-equivalent daily dose was reduced by 39% in the neurostimulation group but was
increased by 21% in the medical-therapy group, with a between-group difference of 609 mg
(P<0.001).
 Scores in all domains of the Parkinson's Disease
The maximum effect was reached at 5 months and remained Questionnaire (PDQ-39) except for communication and
stable for up to 24 months (Figure 1A). social support showed significant improvement in favor
of neurostimulation (Figure 1B).
 Adverse Events

• 68 patients in neurostimulation and 56 in

medical-therapy group had at least one
serious adverse event.

• Numbers of all adverse events were similar in

the two groups.

• 3- 26 serious adverse events related to

surgery or the implanted device, including a
brain abscess and a case of unspecific
edema, all but 1 resolved completely; the
exception was a case of impaired wound
healing, which resulted in mild scarring.
 Conclusion

• Neurostimulation was superior to medical therapy alone at a relatively

early stage of Parkinson's disease, before the appearance of severe
disabling motor complications.

• Neurostimulation may be a therapeutic option for patients at an earlier

stage than current recommendations suggest.
 Research Appraisal

• Strengths:

• Weakness:
 Citation

• Schuepbach, W., Rau, J., Knudsen, K., Volkmann, J., Krack, P., &
Timmermann, L. et al. (2013). Neurostimulation for Parkinson's Disease
with Early Motor Complications. New England Journal Of Medicine, 368(7),
610-622. doi: 10.1056/nejmoa1205158