Abstract
Comparative outcomes among different monogenic forms of Parkinson disease after subthalamic nucleus deep brain stimulation (STN DBS) remain unclear. To compare clinical outcomes in patients with the most common monogenic forms of Parkinson disease treated with STN DBS. 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. 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. 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. 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.
Highlights
The traditional view of Parkinson disease as a single idiopathic disorder has been useful for the development of symptomatic treatments, such as dopaminergic oral medications
Treatment with STN deep brain stimulation (DBS) for patients with Parkinson disease with LRRK2, GBA, or homozygous or compound heterozygous PRKN mutations (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
Clinical and Demographic Data We found a total of 518 patients (135 with monogenic forms of Parkinson disease and 383 controls) from 17 studies of Parkinson disease–associated genetic mutations (Table 1)
Summary
The traditional view of Parkinson disease as a single idiopathic disorder has been useful for the development of symptomatic treatments, such as dopaminergic oral medications. Treatment with STN DBS can yield greater than 50% of motor improvement,3-5 60% amelioration of levodopa-related motor complications,4,5 40% to 60% improvement in quality of life,[6,7] and 50% reduction in the levodopa equivalent daily dose (LEDD).[8] the clinical outcomes after STN DBS have remained variable,[9] with nearly half of patients with Parkinson disease developing stimulation-resistant symptoms such as gait impairment, postural instability, falls, cognitive impairment, and other nonmotor deficits within 5 years from the procedure.[9] This variability in outcomes warrants an examination of clinical and biologic factors. We sought to examine whether different monogenic forms of Parkinson disease are associated with different responses to STN DBS in motor, functional, and pharmacologic end points
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