How Does Deep Brain Stimulation Change the Course of Parkinson's Disease?

Abstract

A robust body of evidence from randomized controlled trials has established the efficacy of deep brain stimulation (DBS) in reducing off time and dyskinesias in levodopa-treated patients with Parkinson's disease (PD). These effects go along with improvements in on period motor function, activities of daily living, and quality of life. In addition, subthalamic DBS is effective in controlling drug-refractory PD tremor. Here, we review the available data from long-term observational and controlled follow-up studies in DBS-treated patients to re-examine the persistence of motor and quality of life benefits and evaluate the effects on disease progression, major disability milestones, and survival. Although there is consistent evidence from observational follow-up studies in DBS-treated patients over 5-10 years and beyond showing sustained improvement of motor control, the long-term impact of DBS on overall progression of disability in PD is less clear. Whether DBS reduces or delays the development of later motor and non-motor disability milestones in comparison to best medical management strategies is difficult to answer by uncontrolled observational follow-up, but there are signals from controlled long-term observational studies suggesting that subthalamic DBS may delay some of the late-stage disability milestones including psychosis, falls, and institutionalization, and also slightly prolongs survival compared with matched medically managed patients. These observations could be attributable to the sustained improvements in motor function and reduction in medication-induced side effects, whereas there is no clinical evidence of direct effects of DBS on the underlying disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: disease-modification; disease-modifying; mortality; neuroprotection; nursing home placement.

FIG 1

Responsiveness of PD symptoms to long‐term treatment with STN‐DBS. Studies reporting outcomes at two time points (ie, 5 years of follow‐up and beyond [range, 8–11 years]) are included for illustrative reasons and for better comparability of changes over long periods of follow‐up. Results are shown as percentage change from preoperative baseline indicated by the 100% line to no symptoms at 0%. The results of individual studies are represented by dots and the circles with bars show weighted mean values across studies (total n = 168). Activities of daily living scores (UPDRS‐II) and motor scores (UPDRS‐III) as well as motor subscores for tremor, rigidity, bradykinesia, and combined “axial” motor symptoms are measured in the stimulation ON and in the practically defined medication off state after overnight withdrawal (ie, >12 h) of dopaminergic medications. In addition, changes in motor fluctuations and dyskinesias (UPDRS‐IV) and in LEDDs are shown. LEDD = levodopa‐equivalent daily doses; PD = Parkinson's disease; UPDRS = Unified Parkinson's Disease Rating Scale. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 2

Progression of off medication, OFF stimulation motor scores in long‐term observational studies >5 years. All patients included in these long‐term studies (total n = 180) had subthalamic stimulation and were assessed in the practically defined off state after overnight withdrawal (ie, >12 h) of dopaminergic medications and at least 40 min after switching stimulation OFF. The weighted mean UPDRS‐III motor scores were 46.2 points pre‐surgery, 44.4 points 1 year post‐surgery, and 52.7 points at last follow‐up (8–10 years post‐surgery). Therefore, excluding the drop in UPDRS‐III scores seen up to year 1 (−1.8 points), there was an UPDRS‐III increase of 8.3 points from post‐surgery to last follow‐up, equaling a ~1.0 points increase per year. UPDRS‐III = Unified Parkinson's Disease Rating Scale motor score. [Color figure can be viewed at wileyonlinelibrary.com]

FIG 3

Meta‐analysis of controlled studies on survival in PD patient with versus without DBS. Across all five studies (upper panel A), STN‐DBS was associated with a trend for increased survival that was not statistically significant with substantial heterogeneity as per I2 index. Two of these studies have used controls from historical cohorts and there is no reporting of balancing patient groups or statistical adjustments according to important confounders such as comorbidities, age of onset, disease duration, or severity., Excluding these from the meta‐analysis (lower panel B) results in a significant survival benefit with DBS with a lower, but still substantial heterogeneity. Meta‐analysis was calculated with R software (version 3.6.3; R Foundation for Statistical Computing, Vienna, Austria) using the metaphor package (Random Effect Model).

FIG 4

Effects of STN‐DBS on motor symptoms and potential effects on late‐stage disability milestones and disease progression. Effects of STN‐DBS are shown in relation to the natural history of PD under conservative treatments without DBS (upper row) and according to the timing of DBS introduction. The second row “classic timing of DBS” refers to the majority of PD patients with DBS, who are operated when motor fluctuations and dyskinesias have led to substantial disability. In past clinical trials, and also observational studies (see Table 1 and Supplementary Tables S1 and S2) such patients are approximately 60 years of age, have mean disease durations of 10–13 years, and a long‐standing history of motor complications. The third row refers to the EARLYSTIM trial, where younger patients with a mean age of 52 years (<60 years), shorter mean disease duration of 7.5 years and motor complication history (<3 years) were included (Table 1). This trial has led to a trend toward progressively earlier surgical selection also in clinical practice. However, no follow‐up of the EARLYSTIM cohort has yet been published and the effects of earlier surgery on the very long‐term outcomes remain unclear. The last row “earliest stim DBS” refers to experimental use of DBS in early PD patients that do not yet experience motor complications. We refer to the main text for more details. [Color figure can be viewed at wileyonlinelibrary.com]