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Subthalamic deep brain stimulation and levodopa in Parkinson’s disease: a meta-analysis of combined effects

  • Joaquin A. Vizcarra
  • Miguel Situ-Kcomt
  • Carlo Alberto Artusi
  • Andrew P. Duker
  • Leonardo Lopiano
  • Michael S. Okun
  • Alberto J. Espay
  • Aristide Merola
Review

Abstract

Introduction

While subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa improve motor symptoms in Parkinson disease (PD) to a similar magnitude, their combined effect remains unclear. We sought to evaluate whether STN-DBS and levodopa yield differential effects on motor outcomes, dyskinesia, and activities of daily living (ADL) when combined compared to when administered alone.

Methods

We conducted a meta-analysis of all studies reporting motor, dyskinesia, and ADL outcomes after bilateral STN-DBS in PD with presurgical Unified Parkinson’s Disease Rating Scale (UPDRS-III) in Medication-OFF and Medication-ON states and postsurgical assessments in four conditions: Stimulation-ON/Medication-ON, Stimulation-ON/Medication-OFF, Stimulation-OFF/Medication-ON, and Stimulation-OFF/Medication-OFF. Dyskinesia duration (UPDRS item 32) and ADL (UPDRS-II) were compared between high and low postsurgical levodopa equivalent daily dose (LEDD) reduction. Random-effects meta-analyses using generic-inverse variance were conducted. Confidence in outcomes effect sizes was assessed.

Results

Twelve studies were included (n = 401 patients). Stimulation-ON/Medication-ON was associated with an UPDRS-III improvement of − 35.7 points [95% confidence interval, − 40.4, − 31.0] compared with Stimulation-OFF/Medication-OFF, − 11.2 points [− 14.0, − 8.4] compared with Stimulation-OFF/Medication-ON, and − 9.5 points [− 11.0, − 8.0] compared to Stimulation-ON/Medication-OFF within 5 years. The difference was maintained beyond 5 years by − 28.6 [− 32.8, − 24.4], − 8.1 [− 10.2, − 5.9], and − 8.0 [− 10.3, − 5.6], respectively. No difference was observed between Stimulation-ON/Medication-OFF and Stimulation-OFF/Medication-ON within and beyond 5 years. Dyskinesia duration and ADL outcomes were similar in high vs. low postsurgical LEDD reduction.

Conclusion

Subthalamic nucleus deep brain stimulation and levodopa independently lessened motor severity in PD to a similar magnitude, but their combined effect was greater than either treatment alone, suggesting therapeutic synergism.

Keywords

Subthalamic nucleus Deep brain stimulation Levodopa Synergism Parkinson 

Notes

Author contributions

Dr. JAV: conception, organization, and execution of research project; design and execution of statistical analysis; writing of the first draft of manuscript. Dr. MS-K: execution of research project; review and critique of the manuscript. Dr. CAA: execution of research project; review and critique of the manuscript. Dr. APD: review and critique of statistical analysis; review and critique of the manuscript. Dr. LL: review and critique of statistical analysis; review and critique of the manuscript. Dr. MSO: review and critique of statistical analysis; review and critique of the manuscript. Dr. AJE: conception of research project; review and critique of statistical analysis; review and critique of the manuscript. Dr. AM: conception and organization of research project; review and critique of statistical analysis; writing of the first draft and review and critique of the manuscript of manuscript.

Funding

Nothing to declare.

Compliance with ethical standards

Ethical standards

The manuscript does not contain clinical studies or patient data.

Conflicts of interest

Dr. Vizcarra reports no conflict of interest. Dr. Situ-Kcomt reports no conflict of interest. Dr. Artusi reports no conflict of interest. Dr. Duker has previously received honoraria but has not received industry support in the last 36 months. Dr. Lopiano has received honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. Dr. Okun serves as a consultant for the National Parkinson Foundation, and has received research grants from NIH, NPF, the Michael J. Fox Foundation, the Parkinson Alliance, Smallwood Foundation, the Bachmann-Strauss Foundation, the Tourette Syndrome Association, and the UF Foundation. His DBS research is supported by: R01 NR014852 and R01NS096008. He has previously received honoraria, but, in the past > 60 months, he has received no support from industry. He has received royalties for publications with Demos, Manson, Amazon, Smashwords, Books4Patients, and Cambridge (movement disorders books). He is an associate editor for New England Journal of Medicine Journal Watch Neurology. He has participated in CME and educational activities on movement disorders (in the last 36) months sponsored by PeerView, Prime, QuantiaMD, WebMD, Medicus, MedNet, Henry Stewart, and by Vanderbilt University. The institution and not Dr. Okun receives grants from Medtronic, Abbvie, Allergan, and ANS/St. Jude, and the PI has no financial interest in these grants. He has participated as a site PI and/or co-I for several NIH, foundation, and industry sponsored trials over the years but has not received honoraria. Dr. Espay has received grant support from the NIH, Great Lakes Neurotechnologies, and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, TEVA, Impax, Acadia, Acorda, Cynapsus/Sunovion, Lundbeck, and USWorldMeds; publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer; and honoraria from Abbvie, UCB, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society. He serves on the editorial boards of the Journal of Parkinson’s Disease and Parkinsonism and Related Disorders. Dr. Merola is supported by NIH (KL2 TR001426) and has received speaker honoraria from CSL Behring and Cynapsus Therapeutics. He has received grant support from Lundbeck.

Supplementary material

415_2018_8936_MOESM1_ESM.pdf (680 kb)
Supplementary material 1 (PDF 680 KB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Neurology, Gardner Family Center for Parkinson’s Disease and Movement DisordersUniversity of CincinnatiCincinnatiUSA
  2. 2.Department of NeurologyUniversity of CincinnatiCincinnatiUSA
  3. 3.Department of Neuroscience “Rita Levi Montalcini”University of TurinTurinItaly
  4. 4.Department of Neurology, Center for Movement Disorders and NeurorestorationMcKnight Brain InstituteGainesvilleUSA

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