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Meta-Analysis
. 2019 Feb 1;2(2):e187800.
doi: 10.1001/jamanetworkopen.2018.7800.

Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease: A Systematic Review and Meta-analysis

Carlo Alberto Artusi  1 , Alok K Dwivedi  2 , Alberto Romagnolo  1 , Gian Pal  3 , Marcelo Kauffman  4 , Ignacio Mata  5 , Dhiren Patel  6 , Joaquin A Vizcarra  6 , Andrew Duker  6 , Luca Marsili  6 , Binith Cheeran  7   8 , Daniel Woo  6 , Maria Fiorella Contarino  9   10 , Leonard Verhagen  3 , Leonardo Lopiano  1 , Alberto J Espay  6 , Alfonso Fasano  11   12   13 , Aristide Merola  6
Affiliations
Meta-Analysis

Association of Subthalamic Deep Brain Stimulation With Motor, Functional, and Pharmacologic Outcomes in Patients With Monogenic Parkinson Disease: A Systematic Review and Meta-analysis

Carlo Alberto Artusi et al. JAMA Netw Open. .

Abstract

Importance: Comparative outcomes among different monogenic forms of Parkinson disease after subthalamic nucleus deep brain stimulation (STN DBS) remain unclear.

Objective: To compare clinical outcomes in patients with the most common monogenic forms of Parkinson disease treated with STN DBS.

Design, setting, and participants: Systematic review and meta-analysis in which a PubMed search of interventional and noninterventional studies of Parkinson disease with LRRK2, GBA, or PRKN gene mutations published between January 1, 1990, and May 1, 2018, was conducted. Among the inclusion criteria were articles that reported the Motor subscale of the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) before and after STN DBS treatment, that involved human participants, and that were published in the English language. Studies that used aggregated data from patients with different genetic mutations were excluded, and so were studies with assumed but not confirmed genetic data or incomplete follow-up data.

Main outcomes and measures: Changes in UPDRS-III scores and levodopa equivalent daily dose (LEDD) were analyzed for each monogenic form of Parkinson disease. Additional end points included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), and cognitive function.

Results: Of the 611 eligible studies, 17 (2.8%) met the full inclusion criteria; these 17 studies consisted of 8 cohort studies (47.1%), 3 case series (17.6%), and 6 case reports (35.3%), and they involved a total of 518 patients. The UPDRS-III score improved by 46% in LRRK2 (mean change, 23.0 points; 95% CI, 15.2-30.8; P < .001), 49% in GBA (20.0 points; 95% CI, 4.5-35.5; P = .01), 43% in PRKN (24.1 points; 95% CI, 12.4-35.9; P < .001), and 53% in idiopathic Parkinson disease (25.2 points; 95% CI, 21.3-29.2; P < .001). The LEDD was reduced by 61% in LRRK2 (mean change, 711.9 mg/d; 95% CI, 491.8-932.0; P < .001), 22% in GBA (269.2 mg/d; 95% CI, 226.8-311.5; P < .001), 61% in PRKN (494.8 mg/d; 95% CI, -18.1 to -1007.8; P = .06), and 55% in idiopathic Parkinson disease (681.8 mg/d; 95% CI, 544.4-819.1; P < .001). Carriers of the PRKN mutations showed sustained improvements in UPDRS-II and UPDRS-IV, whereas LRRK2 mutation carriers sustained improvements only in UPDRS-IV. Carriers of the GBA mutation showed worse postsurgical cognitive and functional performance.

Conclusions and relevance: Treatment with STN DBS for patients with Parkinson disease with LRRK2, GBA, or PRKN mutations appears to be associated with similar motor outcomes but different changes in dopaminergic dose, activities of daily living, motor complications, and cognitive functions.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Artusi reported receiving travel grants from Zambon and AbbVie. Dr Dwivedi reported receiving grants 1R01HL125016-01, 1 R21 HL143030-01, 1R21 AI133207, and R21 AI118228 from the National Institutes of Health (NIH); grants PP180003, PP170068, PP170004, PP140164, 140211, PP110156, PP150031, and PP130083 from the Cancer Prevention and Research Institute of Texas; K12 (consultant) award from the Center for Clinical and Translational Science and Training; and support as a coinvestigator from Coldwell and TMF. Dr Dwivedi also reported being a director of Biostatistics & Epidemiology Consulting Lab at the Texas Tech University Health Sciences Center El Paso. Dr Romagnolo reported receiving grant support and speaker honoraria from AbbVie; speaker honoraria from Chiesi Farmaceutici; and travel grants from Medtronic, Lusofarmaco, and UCB Pharma. Dr Pal reported receiving personal fees from ASIM, AbbVie, Boston Scientific, KeyQuest, Qessential, and SeaGrove; consulting and personal fees from Huron Consulting, Krog Partners, US WorldMeds, and Allergan as well as grant K23-NS097625-02 from the Parkinson Disease Foundation and the National Institute of Neurological Disorders and Stroke (NINDS). Dr Kauffman reported being an employee of CONICET and Ministry of Science of Buenos Aires, Argentina. Dr Mata reported receiving grant 1I211RX002553-01 from the US Department of Veterans Affairs, grant P50 NS06284 from the NIH, and other research funding from the Parkinson Disease Foundation and American Parkinson Disease Foundation. Dr Duker reported receiving grants from Medtronic and Abbott outside the submitted work. Dr Cheeran reported being the medical director for Abbott Laboratories and receiving travel support and unrestricted educational grants for organizing continuing professional development events from Medtronic, St. Jude Medical, and Boston Scientific (manufacturers of DBS electrodes). Dr Woo reported receiving grants NIH U10NS077311, U01NS036695, R01NS093870, and R01NS100417 from the NIH. Dr Contarino reported receiving travel support from Boston Scientific, being on the advisory board of Medtronic and Boston Scientific, being an independent research and educational consultant for Medtronic, and receiving a grant from the Stichting Parkinson Fonds. Dr Verhagen reported receiving personal compensation from Abbott and Medtronic. Dr Lopiano reported receiving honoraria for lecturing and travel grants from Medtronic, UCB Pharma, and AbbVie. Dr Espay reported receiving grant support from the NIH, Great Lakes Neurotechnologies, and the Michael J. Fox Foundation; personal compensation as a consultant or 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; honoraria from AbbVie, UCB Pharma, USWorldMeds, Lundbeck, Acadia, the American Academy of Neurology, and the Movement Disorders Society; and personal fees from AbbVie, Neuroderm, Impax, Acadia, Acorda, Sunovion, Lundbeck, Osmotica Pharmaceuticals, and USWorldMeds outside of the submitted work. Dr Fasano reported receiving grants, personal fees, and/or nonfinancial support from AbbVie, Boston Scientific, Medtronic, Chiesi Farmaceutici, Ipsen, UCB Pharma, and Sunovion all outside of the submitted work. Dr Merola reported receiving grant KL2 TR001426 from the NIH; speaker honoraria from CSL Behring, Cynapsus Therapeutics, and AbbVie; grant support from Lundbeck; and personal fees from Medtronic outside of the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
DBS indicates deep brain stimulation; GPi, globus pallidus pars interna. aTwenty-four patients were carriers of heterozygous PRKN mutation and were analyzed separately.,,,,,,
Figure 2.
Figure 2.. Meta-analysis of Motor Improvement and Levodopa Equivalent Daily Dose (LEDD) Reduction After Subthalamic Nucleus Deep Brain Stimulation
A, The DerSimonian and Laird (D-L) meta-analysis method produced slightly less precise estimates compared with the Hartung-Knapp-Sidik-Jonkman (HKSJ) method. Both methods produced similar findings, except for the GBA gene owing to the extremely high heterogeneity and small number of studies. The presurgical motor outcome (Unified Parkinson’s Disease Rating Scale Part III [UPDRS-III] score) associated with levodopa is reported in eTable 8 in the Supplement. B, Both D-L and HKSJ meta-analysis methods produced similar findings for all genes. Error bars represent the 95% CI of the mean changes reported.
See this image and copyright information in PMC

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