Parkinson’s Patients Long-Term Survival After Deep Brain Stimulation
Overview
This study investigates the long-term outcomes of patients undergoing deep brain stimulation of the subthalamic nucleus (STN-DBS) for Parkinson’s disease (PD) in comparison to medical treatment (MT) alone. A cross-sectional analysis of 115 STN-DBS patients was conducted, assessing the evolution of PD symptoms and health-related quality of life (HRQoL) through both rater-based scales and self-reported questionnaires. The results demonstrate that in the first year of STN-DBS, levodopa equivalent dose decreased, motor function improved, and nonmotor symptoms and cognition remained stable. Morbidity milestones, including falls, hallucinations, dementia, and nursing home placement, occurred approximately 13 years after diagnosis. Following the onset of any milestone, motor function, cognition, and HRQoL significantly worsened, limiting mean survival time to around 5.8 years. Despite living with PD for a more extended period, patients with STN-DBS experienced morbidity milestones later in the disease course compared to those with MT alone, suggesting that morbidity remains concentrated in the final five years of life for PD patients with STN-DBS.
Introduction
This study addresses challenges in evaluating the long-term outcomes of deep brain stimulation (DBS) due to the absence of an adequate control group and limitations in using health-related quality of life (HRQoL) as the sole measure. Existing randomized trials often lack proper controls, and comparing patients who undergo DBS with those who meet criteria but choose not to undergo surgery is hindered by selection bias. The study proposes applying the concept of “compressed morbidity” to assess long-term outcomes in subthalamic nucleus DBS (STN-DBS) patients.
This concept, introduced by Fries in 1980 for aging populations, suggests that despite a longer lifespan, significant health issues and disabilities occur only in the late stages of life.
The study focuses on morbidity milestones (recurrent falls, hallucinations, dementia, and nursing home placement) as indicators of disease progression. By evaluating the occurrence of these milestones and death in PD patients with STN-DBS therapy, the study aims to provide insights into the clinical outcome. Additionally, motor and cognitive function, along with HRQoL, were prospectively assessed in a cross-sectional design to validate the functional relevance of the identified milestones.
Methods
Between 2001 and 2019, a total of 195 Parkinson’s disease (PD) patients underwent subthalamic nucleus deep brain stimulation (STN-DBS) surgery at the University Hospital Carl Gustav Carus, Technical University Dresden, Germany. Pre-surgery, PD diagnosis confirmation followed the International Parkinson and Movement Disorder Society criteria, and standard criteria for DBS implantation were applied. The Register of Patients with Advanced Parkinson’s Disease (READ-PD) study, approved by the local ethics committee (IRB00001473, EK 487122016), involved 115 STN-DBS patients enrolled between 2017 and 2020. Informed consent was obtained from patients or their caretakers in the prospective cohort. A flowchart detailing patient enrollment is provided. The assessment, including demographics, medical history, medication, and symptom evaluations, utilized various validated clinical scales and questionnaires. This included a self-developed fall questionnaire, UPDRS Parts II, III, and IV, Tinetti Mobility Test, Short Physical Performance Battery, PD Non-Motor Symptoms Questionnaire, Montreal Cognitive Assessment, Parkinson’s Hallucinations Score, and PDQ-39.
In addition to the prospective analysis, patient records were utilized to identify morbidity milestones in those undergoing STN-DBS. For patients unable to visit the hospital, telephone interviews were conducted to assess morbidity milestones. Of the initially identified 195 patients, data for 162 patients were obtained, with 39 patients having passed away at the time of data analysis (March–May 2021).
Statistical Analysis
Statistical analyses were conducted using SPSS (IBM Corp, Armonk, NY) and relevant R plugins, while GraphPad Prism (GraphPad Software, San Diego, CA) was used for creating graphs. A significance level of <0.05 was considered statistically significant, with appropriate corrections for multiple comparisons. Participants were categorized into 5 groups based on the time between deep brain stimulation (DBS) implantation and the first study visit (0-1 years, 2-4 years, 5-7 years, 8-10 years, and >10 years). Cross-sectional comparisons at each time point post-surgery were made with preoperative data. One-way analysis of variance (ANOVA) and Kruskal–Wallis test were utilized for normal and non-normally distributed data, respectively.
For comparisons between preoperative and postoperative data (0-1 years after surgery), paired t-tests and Mann–Whitney U tests were employed for normally and non-normally distributed data. The frequency of morbidity milestones in the cohort was compared with a cohort on medical treatment using the χ2 test. Independent-sample t-tests with Welch’s correction were used to compare baseline characteristics and milestone onset between the two cohorts. To assess milestone functional relevance, patients were divided into groups based on milestone presence at the first follow-up after DBS, and differences in scores for various assessments were calculated using the Mann–Whitney U test. Data obtained during the study are available from the corresponding author upon reasonable request.
Results
The READ-PD cohort, consisting of 162 participants, was analyzed along with a comparison to the Kempster et al cohort, revealing significant differences in demographic and clinical characteristics. In the prospective assessment of 115 patients who underwent STN-DBS surgery between 2001 and 2019, improvements in motor fluctuations, dyskinesias, Hoehn and Yahr stage, and motor function were observed one year post-surgery. However, long-term analysis demonstrated that these effects were not permanent, and certain aspects, such as motor function, tended to deteriorate several years after surgery.
The study also explored morbidity milestones in STN-DBS patients, revealing a mean of 1.4 milestones per patient. The first milestone occurred approximately 13.7 years after PD diagnosis, and the mean survival time after diagnosis was 20.31 years. These milestones occurred significantly later in the STN-DBS cohort compared to a cohort on medical treatment described by Kempster et al. Hallucinations, falls, and nursing home placement occurred less frequently in the STN-DBS cohort, while dementia occurred at a similar frequency and hallucinations increased. Survival after milestone onset in the subset of 39 patients who died during the study was 5.4 years.
Functional validation of morbidity milestones demonstrated significantly higher impairment in patients with milestones, as reflected in PDQ-39, UPDRS Part III, SPPB, Tinetti, and MoCA scores, compared to patients without milestones. UPDRS Part IV scores showed no difference, indicating sustained improvement in motor fluctuations after DBS. Additionally, analyses identified predictors of morbidity milestones, with better Tinetti scores correlating with a reduced risk of falls.
These findings emphasize the benefits of STN-DBS but highlight the non-permanence of certain improvements and the importance of considering long-term outcomes and milestones in evaluating the efficacy of DBS in PD patients.
Conclusion
This study presents findings from a representative cohort of patients with STN-DBS, demonstrating a reduction in disease burden post-surgery and an increase with the occurrence of morbidity milestones. HRQoL improves after surgery but declines following the onset of a morbidity milestone. Morbidity milestones, occurring approximately 5 years before death, suggest a compression of morbidity to the final stage of the disease in STN-DBS patients, indicating an extended overall survival with favorable disease burden.
Patients selected for STN-DBS differ from those on MT, with differences in age at diagnosis and longer survival after diagnosis. The study highlights the functional relevance of morbidity milestones, correlating strongly with disease severity measures and HRQoL, particularly after the first milestone. Despite the inclusion of only STN-DBS patients in the analysis, the functional relevance of milestones appears equivalent in patients on MT.
The study acknowledges limitations, including single-center data collection, relatively small sample size, and the need for larger cohorts for more generalizable conclusions. Prospective follow-up was limited to 1 to 3 years, impacting the longitudinal analysis. The study proposes a concept of compressed morbidity, suggesting that disability remains limited in the last 5 years of life for STN-DBS patients, indicating prolonged survival with relatively little disability. The findings underscore the potential significance of morbidity milestones as endpoints for assessing outcomes in routine data studies.
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