Article

Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson's disease

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Abstract

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in advanced Parkinson's disease (PD). However, considerable inter-individual variability has been observed for QoL outcome. Hypothesis: We hypothesized that demographic and preoperative NMS characteristics can predict postoperative QoL outcome. Methods: In this ongoing, prospective, multicenter study (Cologne, Manchester, London) including 88 patients, we collected the following scales preoperatively and on follow-up 6 months postoperatively: PDQuestionnaire-8 (PDQ-8), NMSScale (NMSS), NMSQuestionnaire (NMSQ), Scales for Outcomes in PD (SCOPA)-motor examination, -complications, and -activities of daily living, levodopa equivalent daily dose. We dichotomized patients into "QoL responders"/"non-responders" and screened for factors associated with QoL improvement with (1) Spearman-correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions using aforementioned "responders/non-responders" as dependent variable. Results: All outcomes improved significantly on follow-up. However, approximately 44% of patients were categorized as "QoL non-responders". Spearman-correlations, linear and logistic regression analyses were significant for NMSS and NMSQ but not for SCOPA-motor examination. Post-hoc, we identified specific NMS (flat moods, difficulties experiencing pleasure, pain, bladder voiding) as significant contributors to QoL outcome. Conclusions: Our results provide evidence that QoL improvement after STN-DBS depends on preoperative NMS characteristics. These findings are important in the advising and selection of individuals for DBS therapy. Future studies investigating motor and non-motor PD clusters may enable stratifying QoL outcomes and help predict patients' individual prospects of benefiting from DBS.

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... This puzzling situation has generated considerable interest in the search for preoperative predictors of postoperative QoL improvement 8 . Preoperative baseline QoL has been identified as the most consistent predictor of such an improvement with greater preoperative QoL burden being associated with greater postoperative QoL gains 5,[9][10][11] . However, other studies have found the opposite relationship between pre-and postoperative scores 12,13 , thereby suggesting that other factors than the baseline patient status may influence postoperative QoL. ...
... Each electrode contact recording was then re-referenced to the uppermost contact. For our model, we used periodic activity in different frequency bands: theta (3-7 Hz), alpha (8)(9)(10)(11)(12), lower beta (13)(14)(15)(16)(17)(18)(19)(20) and upper beta (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). We refined the power spectral density at each recording site by removing 1/f components (dashed lines), which facilitated the isolation of distinct oscillatory activity peaks (solid lines) (Fig. 3b). ...
... Consistent with prior research, our study confirms the strong predictive value of preoperative QoL on postoperative changes, surpassing other baseline patient information like age, sex, or disease duration. We observed that patients with greater preoperative QoL burdens tend to experience more substantial QoL gains post-intervention, similar to previous studies 5,7,[9][10][11]30 . Notably, lower preoperative QoL burden was more predictive of QoL deterioration at an average of 20 months after surgery than any of the other features examined (Fig. 5c), providing valuable information for patient counseling. ...
Article
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Improving health-related quality of life (QoL) is crucial for managing Parkinson’s disease. However, QoL outcomes after deep brain stimulation (DBS) of the subthalamic nucleus (STN) vary considerably. Current approaches lack integration of demographic, patient-reported, neuroimaging, and neurophysiological data to understand this variability. This study used explainable machine learning to analyze multimodal factors affecting QoL changes, measured by the Parkinson’s Disease Questionnaire (PDQ-39) in 63 patients, and quantified each variable’s contribution. Results showed that preoperative PDQ-39 scores and upper beta band activity (>20 Hz) in the left STN were key predictors of QoL changes. Lower initial QoL burden predicted worsening, while improvement was associated with higher beta activity. Additionally, electrode positions along the superior-inferior axis, especially relative to the z = −7 coordinate in standard space, influenced outcomes, with improved and worsened QoL above and below this marker. This study emphasizes a tailored, data-informed approach to optimize DBS treatment and improve patient QoL.
... Even though non-motor symptoms (NMS) of PD like: pain, fatigue, changes of in blood pressure, restless legs, bladder and bowel problems, skin sweating, sleep alterations, swallowing, and saliva control, communication issues and eye control remain essential, until recently were not in the main field of research. 6,7,8,9,10 NMS can be measured in a repeatable manner with the NMS scale provided by the Movement Disorders Society where: cardiovascular symptoms, alertness, mood, cognition, hallucinations, attention, memory, gastrointestinal tract symptoms, urinary and sexual functions, pain, taste and smell, weight changes and excessive sweating are evaluated. 11 The extra basal ganglia pathological changes of the brain are considered to be responsible for the NMS that influences the quality of PD patient's life. ...
... 3,4,5,2 Long-term studies provided evidence that DBS -induced motor improvement was evident at 8year follow-up. 15,8 However, it has to be kept in mind that DBS does not modify the speed of PD progression. With time, patients can develop disabling motor and NMS symptoms. ...
... This study confirms the positive effect of STN DBS on NMS. 23,7,8,9,10 The results for patient domains of the NMS Scale vary. In contrast to Dafsari et al, who reported no significant difference at a three years follow-up in domain I (Cardiovascular including falls) in the short -term study (three to six months) presented here, an improvement was registered in this domain mainly due to a decreased number of falls. ...
Article
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The effect of subthalamic deep brain stimulation (STN DBS) on motor symptoms of Parkinson's disease (PD) has been thoroughly analyzed. The influence of STN DBS on non-motor symptoms (NMS) is still debatable. We analyzed the effect of STN DBS on NMS in PD. Materials and methods 17 PD patients were qualified for STN DBS according to CAPSIT-PD criteria. Demographic data and clinical status according to the Hoehn–Yahr (H–Y) were recorded. The efficacy of STN DBS on NMS was measured with the NMS Scale before surgery and twelve months after surgery. Results Global NMS Scale score decreased by 1–75 points (mean 25,67) in 12 patients. No improvement or deterioration was reported in 5 patients (29%). The mean age of the improved group was 56 years and 59,8 years in the non-improved group. The mean duration of PD in the improved group was 11 years and 21 years in the non-improved group. In the non-improved group, four patients were rated 4 and one patients 3 according to the H–Y Scale. In the improved group, two patients were rated 4, six patients 3 and four patients 2 according to the H–Y Scale The most significant improvement of the NMS Scale was recorded in the domain IV- Perceptual problems/Hallucinations- (by 77%), domain I- Cardiovascular including falls- (by 68%) and domain III- Mood/Cognition- (by 58%). Deterioration of the NMS Scale was reported in the domain IX- Miscellaneous- (by 10%) and the domain VII- Urinary- (by 6%). Conclusions STN DBS has a positive impact on NMS among PD patients. The most important factors that influence improvement are: young age, short disease duration, and good clinical status measured with the H–Y Scale. The NMS Scale domains that tend to respond the best are the domains I, III and IV. The NMS Scale domains that might deteriorate after STN DBS are the domains VII and IX.
... To create clinical and socioeconomic impact via preoperative selection, the relation between preoperative variables and postoperative outcome must be strongly predictive despite the absence of surgical factors, such as lead positioning, which are unknown in the preoperative phase. Preoperative significant quality of life (QoL) impairment, severe motor symptoms, greater levodopa response, better cognitive performance, tremor-dominancy, and younger age have been correlated with better postoperative motor function improvement and QoL [15][16][17][18][19]. It is important to note that there is no consensus about all relevant preoperative predictors, and some of them specifically are a matter of debate [20]. ...
... It is important to note that there is no consensus about all relevant preoperative predictors, and some of them specifically are a matter of debate [20]. Unlike the studies reporting these correlations [16][17][18][19], 2 studies developed a machine learning model to decrease the number of suboptimal responders with individual motor response predictions ( Fig. 1) [21,22]. Both proof-of-concept studies described a good prediction of a binary outcome in a retrospective single-center STN DBS cohort. ...
... Better understanding of the STN itself can lead to more stable motor improvements as well [11]. Moreover, increasing insights in the clinical non-motor characteristics, genetic profiles, and neurophysiological characteristics and their relation with DBS outcome have promising potential to improve patient selection, counseling, and outcome prediction [18,42]. All these approaches do not exclude each other and can improve DBS outcome in PD in a complementary way in the future. ...
Article
Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort. Methods: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes. Results: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%. Conclusion: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.
... To create clinical and socioeconomic impact via preoperative selection, the relation between preoperative variables and postoperative outcome must be strongly predictive despite the absence of surgical factors, such as lead positioning, which are unknown in the preoperative phase. Preoperative significant quality of life (QoL) impairment, severe motor symptoms, greater levodopa response, better cognitive performance, tremor-dominancy, and younger age have been correlated with better postoperative motor function improvement and QoL [15][16][17][18][19]. It is important to note that there is no consensus about all relevant preoperative predictors, and some of them specifically are a matter of debate [20]. ...
... It is important to note that there is no consensus about all relevant preoperative predictors, and some of them specifically are a matter of debate [20]. Unlike the studies reporting these correlations [16][17][18][19], 2 studies developed a machine learning model to decrease the number of suboptimal responders with individual motor response predictions ( Fig. 1) [21,22]. Both proof-of-concept studies described a good prediction of a binary outcome in a retrospective single-center STN DBS cohort. ...
... Better understanding of the STN itself can lead to more stable motor improvements as well [11]. Moreover, increasing insights in the clinical non-motor characteristics, genetic profiles, and neurophysiological characteristics and their relation with DBS outcome have promising potential to improve patient selection, counseling, and outcome prediction [18,42]. All these approaches do not exclude each other and can improve DBS outcome in PD in a complementary way in the future. ...
Article
Full-text available
Background: Subthalamic nucleus deep brain stimulation (STN DBS) is an established therapy for Parkinson's disease (PD) patients suffering from motor response fluctuations despite optimal medical treatment, or severe dopaminergic side effects. Despite careful clinical selection and surgical procedures, some patients do not benefit from STN DBS. Preoperative prediction models are suggested to better predict individual motor response after STN DBS. We validate a preregistered model, DBS-PREDICT, in an external multicenter validation cohort. Methods: DBS-PREDICT considered eleven, solely preoperative, clinical characteristics and applied a logistic regression to differentiate between weak and strong motor responders. Weak motor response was defined as no clinically relevant improvement on the Unified Parkinson's Disease Rating Scale (UPDRS) II, III, or IV, 1 year after surgery, defined as, respectively, 3, 5, and 3 points or more. Lower UPDRS III and IV scores and higher age at disease onset contributed most to weak response predictions. Individual predictions were compared with actual clinical outcomes. Results: 322 PD patients treated with STN DBS from 6 different centers were included. DBS-PREDICT differentiated between weak and strong motor responders with an area under the receiver operator curve of 0.76 and an accuracy up to 77%. Conclusion: Proving generalizability and feasibility of preoperative STN DBS outcome prediction in an external multicenter cohort is an important step in creating clinical impact in DBS with data-driven tools. Future prospective studies are required to overcome several inherent practical and statistical limitations of including clinical decision support systems in DBS care.
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) with levodopa induced motor complications. Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. ...
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) with levodopa induced motor complications. Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. ...
... Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. However, no study has so far studied NMS in PD patients beyond 36 months post STN-DBS [7,8]. ...
Article
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Background: Even though a significant fraction of Parkinson's disease (PD) patients presents with only minor or no motor asymmetry, the motor symptoms in PD typically start on one side of the body and worse symptoms on the side of the disease onset usually persist long after the disease has become clinically bilateral. The asymmetric presentation of PD has been studied over the years, with some studies showing slower progression in PD subjects with asymmetric disease presentation. In other studies, however, it was not possible to relate the asymmetry to disease progression. Objective: The main objective of the present study was to assess the effect of asymmetry at disease onset on disease progression. Methods: Using the data available in the Parkinson's Progression Markers Initiative (PPMI) database, at baseline, 423 subjects with de-novo PD were included in the study. Instead of dichotomizing the subjects in asymmetric and symmetric, we kept the asymmetry index and the non-motor, disability, and motor progression at one-, three-, and five-year follow-up continuous. Linear regression was used to correlate asymmetry indices and disease progression. Results: There was no correlation between neither clinically, nor DatSCAN defined asymmetry and non-motor, motor, and disability progression in the de-novo PD subjects with a 5-year follow-up. Conclusion: Asymmetry does not predict progression of PD. Further studies are needed to investigate whether early detection of asymmetry on clinical grounds could successfully distinguish between PD and symmetric types of atypical parkinsonism in the early stages of the disease.
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) with levodopa induced motor complications. Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. ...
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) with levodopa induced motor complications. Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. ...
... Bilateral STN-DBS not only improves motor symptoms, but also a variety of non-motor symptoms (NMS) [1][2][3][4][5][6][7], as well as health-related quality of life (HRQoL) [3]. Short term positive effects of STN-DBS on NMS have been shown in several studies [1][2][3][4][5][6]. However, no study has so far studied NMS in PD patients beyond 36 months post STN-DBS [7,8]. ...
Article
Background: Several studies have shown beneficial effects of bilateral stimulation of the subthalamic nucleus (STN-DBS) on motor as well as on non-motor symptoms (NMS) up to 36 months post-surgery in advanced Parkinson's disease (PD) patients. We set to explore the long-term effect of STN-DBS on NMS in a four-year follow-up, prospective, observational study. Methods: Forty patients were enrolled and assessed at baseline. Twenty-eight were followed-up at 6, 12, 24, 36 and 48 months after the operation. The effect of post-operative time on NMS was analyzed by six-level repeated measures ANOVA. In a post-hoc analysis the follow-up scores were compared to baseline using a paired t-test. Results: The following scores stayed improved up to 24 months after surgery, presented as baseline/24 months, p-value (t-test): total Non-Motor Symptoms Scale score (54.0 ± 5.6/44.9 ± 5.0, p = 0.029), Hamilton Anxiety Scale (14.3 ± 1.3/11.3 ± 1.2, p = 0.019) and PDQ39 (53.4 ± 4.5/40.2 ± 2.9, p = 0.012). PD Sleep Scale 2 remained improved throughout the study (17.4 ± 2.0/12.8 ± 1.3 at 48 months, p = 0.032), while Beck Depression Inventory only at six months post-surgery (9.5 ± 1.2/6.7 ± 0.7 at 6 months, p = 0.006). Montreal Cognitive Assessment remained stable up to 24 months and then declined at 36 months (26.3 ± 0.5/25.4 ± 0.5 at 36 months, p = 0.003), Starkstein Apathy Scale deteriorated throughout the study (7.6 ± 0.7/12.7 ± 0.9 at 48 months, p = 0.006). Conclusions: We observed beneficial effect of STN-DBS in several but not all domains of NMS at least up to 24 months post-op in advanced PD. Further long-term studies on larger cohorts of PD patients and longer follow-up need to be conducted to better understand the long-term effect of STN-DBS on NMS.
... 7,[14][15][16] Reports on the predictive value of disease duration at surgery, daily levodopa dosage, postural and gait impairment, and non-motor symptoms all show conflicting results. 12,15,17,18 Comparison of reported motor outcome is hampered due to variance in assessment scales and assessments during varying dopaminergic states. 19 These non-conclusive results maintain the need for a simple tool which neurologists can use in clinical practice to predict motor outcome after STN DBS for individual patients. ...
... Likewise, the absence of a proper non-motor symptom scale hampered potential reproduction of the recently described importance of non-motor symptoms. 17 The reported influences of the preoperative variables on the outcome probability are partly consistent with the literature, and are partly contradicting literature. We stress that these influences cannot be seen outside the scope of this model. ...
... This categorization resulted in 30% weak responders, which is comparable to reported improvement ratios on quality of life after STN DBS. 5,14,17,18 Especially since we regarded postoperative differences in on-medication conditions instead of off-medication conditions; and postoperative surgical results are often comparable to the best state in on-medication condition. 12 The strong and weak responder groups significantly differed on all UPDRS changes, except for UPDRS III scores in the on-stimulation and off-medication condition compared to the preoperative off-medication condition (table 1). ...
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Introduction: Despite careful patient selection for subthalamic nucleus deep brain stimulation (STN DBS), some Parkinson's disease patients show limited improvement of motor disability. Non-conclusive results from previous prediction studies maintain the need for a simple tool for neurologists that reliably predicts postoperative motor response for individual patients. Establishing such a prediction tool facilitates the clinician to improve patient counselling, expectation management, and postoperative patient satisfaction. Predictive machine learning models can be used to generate individual outcome predictions instead of correlating pre- and postoperative variables on a group level. Methods: We developed a machine learning logistic regression prediction model which generates probabilities for experiencing weak motor response one year after surgery. The model analyses preoperative variables and is trained on 90 patients using a ten-fold cross-validation. We intentionally chose to leave out pre-, intra- and postoperative imaging and neurophysiology data, to ensure the usability in clinical practice. Weak responders (n = 27) were defined as patients who fail to show clinically relevant improvement on Unified Parkinson Disease Rating Scale (UPDRS) II, III or IV. Results: The model predicts weak responders with an average area under the curve of the receiver operating characteristic of 0.88 (standard deviation: 0.14), a true positive rate of 0.85 and a false positive rate of 0.25, and a diagnostic accuracy of 78%. The reported influences of the individual preoperative variables are useful for clinical interpretation of the model, but cannot been interpreted separately regardless of the other variables in the model. Conclusion: The very good diagnostic accuracy of the presented prediction model confirms the utility of machine-learning based motor response prediction one year after STN DBS implantation, based on clinical preoperative variables. After reproduction and validation in a prospective cohort, this prediction model holds a tremendous potential to be a supportive tool for clinicians during the preoperative counseling.
... 3) Other non-motor aspects: The Parkinson's Disease Sleep Scale-1 (PDSS), ranging from 0 to 150 (lower scores represent more severe impairment) [29], the Non-Motor Symptoms Questionnaire (NMSQ), ranging from 0 to 30 [30], and the Non-motor Symptom Scale (NMSS), ranging from 0 to 360 which surveys nine different domains of non-motor symptoms (higher scores represent more severe impairment for both) [31][32][33]. 4) Motor disorder: The Unified PD Rating Scale (UPDRS) -II, -III, and -IV were used to assess activities of daily living, motor examination, and motor complications. The UPDRS-II, -III, and IV range from 0 (no impairment) to 52,108, and 23 respectively (maximum impairment) [34]. ...
... Furthermore, the predictive potential of candidate parameters identified in this step (p<0.1) was tested with step-wise linear regressions with baseline scores as independent and PDQ-8 SI change score as dependent variables. This method has been employed previously by our group and other research groups [33,42,43]. A predictor model was calculated. ...
... Furthermore, baseline PDQ-8 SI (F (1,34) =34.86, p<0.001, r²=0.506) and TAS-20 (F (1,34) =8.212, p=0.007, r²=0.195) were significant predictors of PDQ-8 SI change score. A model summarizing both parameters predicted 50.9% of the variance in the PDQ-8 SI change at follow-up (F (2,33) =11.62, p<0.001). ...
Article
Background In advanced Parkinson's disease (PD), subthalamic neurostimulation (STN‐DBS) improves quality of life (QoL), motor, and non‐motor symptoms. However, its effect on alexithymia and its relationship to other neuropsychiatric symptoms and quality of life in PD is unclear. Methods In this prospective, observational study of 39 PD patients undergoing STN‐DBS, we examined PDQuestionnaire‐8 (PDQ‐8), Toronto Alexithymia Scale‐20 (TAS‐20), Hospital Anxiety and Depression Scale (HADS), Self‐Report Manic Inventory (SRMI), Apathy Evaluation Scale (AES), Unified PD Rating Scale‐activities of daily living, ‐motor examination, and ‐complications (UPDRS‐II/‐III/‐IV), and levodopa‐equivalent daily dose (LEDD) preoperatively and at 5‐month follow‐up. Outcome changes were tested with Wilcoxon signed‐rank or paired t‐test, when parametric tests were applicable, and corrected for multiple comparisons. The relationship between outcome changes was explored with bivariate correlations. Additionally, partial correlations between PDQ‐8 and TAS‐20 were computed controlling for HADS, SRMI, and AES change scores. Predictor analyses for PDQ‐8 improvement were calculated for all baseline parameters. Results Alexithymia baseline prevalence was 17.9%. We observed significant beneficial effects of STN‐DBS on PDQ‐8, TAS‐20, HADS, UPDRS‐II, ‐III, and –IV and significant LEDD reduction. The correlation between TAS‐20 and PDQ‐8 improvements remained significant after controlling for all other aforementioned outcomes. Predictor analyses for PDQ‐8 improvement were significant for PDQ‐8 and TAS‐20. Conclusions This is the first report of beneficial effects of STN‐DBS on alexithymia. Alexithymia was significantly associated with QoL outcome independently from anxiety, depression, mania, and apathy. Our study highlights the importance of alexithymia for holistic assessments of DBS outcomes. This article is protected by copyright. All rights reserved.
... Parkinson's disease (PD) is a common neurodegenerative disease, 1 and the advanced PD patients need the Deep brain stimulation of the subthalamic nuclei(STN-DBS) which improves motor and non-motor symptoms, [2][3][4] and enhance the quality of life. [3][4][5] Unfortunately, as one of the most common neuropsychiatric complications following DBS surgery, 6 the incidence of delirium was 22% to 42.6% of patients after DBS surgery. ...
... Parkinson's disease (PD) is a common neurodegenerative disease, 1 and the advanced PD patients need the Deep brain stimulation of the subthalamic nuclei(STN-DBS) which improves motor and non-motor symptoms, [2][3][4] and enhance the quality of life. [3][4][5] Unfortunately, as one of the most common neuropsychiatric complications following DBS surgery, 6 the incidence of delirium was 22% to 42.6% of patients after DBS surgery. 7,8 Postoperative delirium (POD) is common, serious, costly, under-recognized, and often fatal. ...
Article
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Objective This study aimed to explore possible biomarkers of postoperative delirium (POD) of Parkinson’s disease (PD) patients received deep brain stimulation (DBS) of the subthalamic nuclei. Materials and methods This nested case control study analyzed perioperative plasma and cerebral spinal fluid (CSF) of patients (n = 40) who developed POD undergone DBS surgery (n = 10) and those who did not (n = 30). Blood sample was collected before surgery and on the first day postoperative, CSF sample was collected at the beginning of the operation. POD was assessed by the Confusion Assessment Method (CAM) twice a day between 7:00 am and 7:00 pm after the surgery until discharge. Plasma and CSF sample from the two groups were analyzed to investigate possible biomarkers for POD in PD patients. Results There was no difference between POD and Non-POD groups on the concentration of Interleukin 6 and Tumor Necrosis Factor-α in CSF, preoperative plasma and postoperative plasma. There was no difference between POD and Non-POD groups on the concentration of S100 calcium-binding protein β protein (S100β) and Neurofilament light chain (NFL) in preoperative plasma and postoperative plasma. The concentration of C-reactive protein (CRP), NFL and S100β were significant higher in POD group than non-POD group in CSF. The concentration of CRP was significantly higher in POD group than non-POD group in preoperative plasma and postoperative plasma. CSF concentration of S100β might be a potential biomarker for POD via the receiver operating characteristic curve analysis and the area under the curve value of 0.973. Conclusion For PD patients received DBS surgery, CSF S100β might be a marker for aiding detection of high-risk patients with delirium. This requires further confirmation in clinical trials.
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced PD patients. Bilateral STN-DBS not only improves motor symptoms but also a variety of nonmotor symptoms [2][3][4], as well as health-related quality of life [2,5]. DBS could also reduce the levodopa medication dose and ameliorate the side effects associated with levodopa therapy [4]. ...
... Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced PD patients. Bilateral STN-DBS not only improves motor symptoms but also a variety of nonmotor symptoms [2][3][4], as well as health-related quality of life [2,5]. DBS could also reduce the levodopa medication dose and ameliorate the side effects associated with levodopa therapy [4]. ...
Article
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Background: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is a standard treatment option for advanced Parkinson's disease (PD) patients. Delirium following DBS electrode implantation is common, by several studies, and cognitive impairment is a risk factor for developing postoperative delirium (POD). This prospective observational study was conducted to identify whether preoperative baseline cognitive status has an association with POD in PD patients undergoing DBS surgery. Methods: Preoperatively, neuropsychiatric and neuropsychological assessments of the patients were performed including clinical dementia rating (CDR) score, instrumental activities of daily living (IADL) score, mini-mental state exam (MMSE) score, Montreal cognitive assessment (MoCA) score, Hamilton anxiety (HAMA) and Hamilton depression (HAMD) scores, and numerical cancellation test. POD was identified by the confusion assessment method (CAM) twice per day on postoperative day 1 until discharge. Results: Twenty-seven (21.6%) of 125 patients developed POD. Among the variables screened, age, CDR score, MMSE score, and HAMA score were indicated to be independent influence factors of POD. The cutoff score, AUC, sensitivity, and specificity of age, CDR score, MMSE score, and HAMA score associated with POD was 58.5, 0.751, 92.6%, 52.0%; 0.5, 0.848, 77.8%, 91.8%; 27.5, 0.827, 88.9%, 62.2%; and 12.5, 0.706, 85.2%, 54.1%, respectively. Conclusions: We observed age, CDR score, MMSE score, and HAMA score were independent influence factors of POD in PD patients who received DBS. It is necessary to assess the cognitive status of PD patients before surgery to identify high-risk patients.
... Previous research also demonstrated beneficial effects of STN-DBS on QoL compared to medical treatment [6][7][8] . However, on the individual level, 43-49% of patients experience no clinically relevant improvement of QoL postoperatively at 6-month follow-up 6,9,10 . Furthermore, there is Class I evidence that in 36% of pairs of patients treated either with best medical treatment alone or with STN-DBS, medical treatment alone results in better QoL outcomes than STN-DBS 2 . ...
... To our knowledge, this is the first report of a significant relationship between more severe preoperative QoL impairment and greater postoperative QoL improvement at 36-month followup 3 . This is in line with previous studies, that reported a relationship between these parameters at 6-month and 24month follow-up 3,9 . Every additional point in the PDQ-8 SI at baseline increased the odds of favorable long-term QoL outcome by 5%. ...
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To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable “QoL responders”/“non-responders”. At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as “QoL non-responders”. Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as ‘difficulties experiencing pleasure’ and ‘problems sustaining concentration’. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.
... After a mean follow-up of 13.2 ± 2.6 months (13.6 ± 2.9 for benign vs. 12.9 ± 2.3 for malignant patients; p: 0.485), the malignant phenotype showed a significantly higher probability of losing independence in the ADL when compared to the benign phenotype (OR: 16 The adjusted GLM analysis confirmed the significantly worse S&E score performances in malignant patients (F: 5.887; p: 0.018), independently from age at PD onset, disease duration, and motor response to DBS (Fig. 1A and Table 2). ...
... Previous studies investigating the effect of DBS on non-motor symptoms showed that some of them could improve after surgery, with a direct correlation with quality of life improvement [16]. However, the role of pre-surgical non-motor symptoms in predicting the STN-DBS outcome is still poorly investigated. ...
Article
Background Heterogeneity of Parkinson’s Disease (PD) phenotype may influence deep brain stimulation (DBS) outcome. However, DBS response in the malignant end of the PD spectrum has been poorly investigated. Objective To evaluate and compare DBS outcomes in malignant and benign PD patients, defined according to motor and non-motor symptom presentation at the presurgical selection. Methods We categorized a cohort of 154 parkinsonian patients fulfilling criteria for subthalamic nucleus (STN)-DBS into malignant, benign, and intermediate subtypes, according to a recently validated clinical PD classification. DBS efficacy on daily living independence (Schwab and England -S&E-score ≥70%), motor symptoms, and motor fluctuations (Unified Parkinson’s Disease Rating Scale -UPDRS- part-III and -IV, and Ambulatory Capacity Measure) were compared between malignant and benign patients, using corrected binary logistic regressions and repeated measure general linear model. Results One year after surgery, the probability of losing daily life independence was 16-fold higher in malignant patients, even after adjusting for age at PD onset, PD duration, and percentage of motor improvement after STN-DBS (OR: 16.233; p: 0.035). Conversely, malignant and benign patients showed a similar extent of improvement after STN-DBS (p > 0.05) in motor symptoms, motor fluctuations, and ambulatory capacity, both in medication-ON and medication-OFF conditions. Conclusion DBS candidates in the malignant end of the PD spectrum may profit from a similar improvement of motor symptoms and fluctuations after STN-DBS when compared to benign PD. However, patients of the malignant group have a lower probability of maintaining independence in daily life early after surgery.
... Nevertheless, less than 50% of the studies reported the DBS stimulation parameters and for more than 60% of the studies was not clear if the participants were recruited consecutively or selectively chosen. Two studies disclosed a conflict of interest [16,41] and one reported on the role of the funding source [16]. ...
... Nevertheless, less than 50% of the studies reported the DBS stimulation parameters and for more than 60% of the studies was not clear if the participants were recruited consecutively or selectively chosen. Two studies disclosed a conflict of interest [16,41] and one reported on the role of the funding source [16]. ...
Article
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Introduction While efficacy of deep brain stimulation for motor symptoms of neurological disorders is well accepted, its effects on the autonomic system remain controversial. We aimed to systematically assess all available evidence of deep brain stimulation effects on lower urinary tract function. Methods This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies were identified by electronic search of Cochrane Central Register of Controlled Trials, Embase, Medline, Scopus, and Web of Science (last search July 12, 2019) and by screening of reference lists and reviews. Results After screening 577 articles, we included 29 studies enrolling a total of 1293 patients. Deep brain stimulation of the globus pallidus internus (GPi), pedunculopontine nucleus (PPN), and subthalamic nucleus (STN) had an inhibitory effect on detrusor function, while deep brain stimulation of the ventral intermediate nucleus of the thalamus (VIM) showed an excitatory effect. In the meta-analysis, deep brain stimulation of the STN led to a significant increase in maximum bladder capacity (mean difference 124 mL, 95% confidence interval 60–187 mL, p = 0.0001) but had no clinically relevant effects on other urodynamic parameters. Adverse events (reported in thirteen studies) were most commonly respiratory issues, postural instability, and dysphagia. Risk of bias and confounding was relatively low. Conclusions Deep brain stimulation does not impair lower urinary tract function and might even have beneficial effects. This needs to be considered in the deep brain stimulation decision-making process helping to encourage and to reassure prospective patients.
... 1,2 Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the globus pallidus internus (GPi) is a wellestablished therapy for levodopa (L-dopa)-responsive PD with disabling motor complications and is able to improve motor 3 and nonmotor symptoms 4 as well as QoL. 5,6 Although STN may be the first choice as a DBS target in many centers, as reflected by the striking numerical predominance of STN-DBS studies over GPi-DBS studies 7 and the belief that STN target leads to better motor outcomes, 3,8,9 there is an ongoing debate about the optimal DBS target for PD. 3 The results of the only 2 randomized controlled trials (RCT) directly comparing these 2 targets did not provide conclusive evidence to support the superiority of either GPi-DBS or STN-DBS, 10,11 although 1 of these trials 11 demonstrated greater improvement in motor signs and activities of daily living (ADL) in off-medication phase with STN-DBS than with GPi-DBS. As a result, there is still a ...
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Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an accepted therapy for Parkinson's disease (PD) with disabling motor complications. For elderly patients with poorer cognition and postural instability, GPi has been proposed as the preferable DBS target based on expert opinion, arguing GPi‐DBS may be less complicated by depression, apathy, worsened verbal fluency, and executive dysfunction, resulting in greater improvement in quality of life (QoL). However, data supporting such patient‐tailored approach are lacking. Objectives The aims were to analyze whether the DBS target influences QoL in a PD cohort and a matched subgroup of frail patients with poor cognitive status and reduced postural stability, and whether other factors affect the QoL outcomes. Methods In this retrospective study, we analyzed a single‐center cohort of 138 PD patients who received bilateral STN‐DBS (117) or GPi‐DBS (21) using the mentioned approach for target selection. All patients underwent standardized clinical evaluations of motor‐ and nonmotor signs as well as QoL before and 1 year after surgery. Results DBS of both targets improved motor signs, dyskinesias, and pain. QoL improved without significant difference between the targets, but with a trend for greater improvement across all QoL domains in favor of the STN, even in an STN subgroup matched to the GPi group. Conclusion Our results contradict the prevailing belief that GPi‐DBS is superior in frail PD patients with cognitive decline and postural instability, questioning the proposed patient‐tailored approach of DBS target selection. Further studies are needed for a data‐driven approach.
... Deep brain stimulation (DBS) of the subthalamic nuclei is a standard treatment option for advanced PD patients. Bilateral STN-DBS improves motor and a variety of non-motor symptoms [1,2], as well as health-related quality of life [3,4]. DBS can also reduce the levodopa medication dose and ameliorate the side effects associated with levodopa therapy [5]. ...
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Background: The selection of the maintenance of general anesthesia may affect the development of postoperative delirium (POD), notably for Parkinson's disease (PD) patients, due to their lower cognitive reserve. The present study was designed to compare the potential impact of propofol vs. sevoflurane based general anesthesia maintenance methods on the development of POD in PD patients following deep brain stimulation (DBS) surgery. Methods: A total of 125 PD patients who were scheduled to undergo DBS surgery were randomly divided into the propofol (n = 63) and the sevoflurane groups (n = 62). The patients in the two groups randomly received propofol- or sevoflurane-based general anesthesia. The Confusion Assessment Method (CAM) was employed by an investigator who was blinded to the anesthesia regimen and was administered twice per day from postoperative day 1 until discharge. Results: The incidence of POD was 22.22% (14/63) with propofol anesthesia and 20.97% (13/62) with sevoflurane anesthesia (p = 0.865). In addition, no difference was noted in the duration and severity of delirium between the propofol and sevoflurane groups. Conclusions: In the present study, propofol- and sevoflurane-based general anesthesia exhibited comparable results with regard to the POD incidence in PD patients undergoing deep brain stimulation surgery.
... Finally, ten articles were included in the present study. 4,6,[12][13][14][15][16][17][18][19] These studies assessed a total number of 563 patients with the NMSS questionnaire and 336 patients with the NMSQ questionnaire. 8 studies were multicentric, 4,6,14-19 one conducted in Czech 13 and the other one in Hungary. ...
Article
Deep brain stimulation (DBS) is a well‐defined treatment for motor symptoms in advanced PD. Although several studies have investigated the DBS effect on non‐motor symptoms (NMS), controversial results exist regarding this matter. The aim of this meta‐analysis and systematic review was to assess the bilateral subthalamic nucleus (STN) DBS effect on NMS of PD. We conducted a systematic search on the literature of Web of Science (WOS), PubMed/MEDLINE, Scopus, Cochrane, and Embase. An additional hand search was also done. Finally, a meta‐analysis was conducted on 10 studies containing pre‐ and post‐bilateral STN‐DBS data regarding NMS acquired using Non‐Motor Symptoms Scale for Parkinson's Disease (NMSS) or Non‐Motor Symptoms Questionnaire (NMSQ). A random‐effects model was used to determine weighted mean differences, and the heterogeneity index was evaluated using Cochrane's Q test. Our study results indicated that bilateral STN‐DBS significantly reduced total NMSS and NMSQ score (WMD −17.73; 95% confidence interval [CI] −20.28 to −15.18, WMD −2.19; 95% CI −2.98 to −1.40), respectively, and no publication bias was found. Regarding each of the NMSS domains, DBS significantly reduced the scores of following domains: sleep (WMD ‐5.98; 95% CI ‐6.82 to −5.15), miscellaneous (WMD −4.19; 95% CI −4.96 to −3.43), urinary (WMD −2.99; 95% CI −3.78 to −2.19), sexual (WMD −0.65; 95% CI −1.16 to −0.14), and attention/memory (WMD −0.59; 95% CI −1.15 to −0.03). This meta‐analysis demonstrated that bilateral STN‐DBS has beneficial effects on NMS of PD.
... Quality of life (QoL) is one of the most critical patient-reported outcome measures to evaluate treatment efficacy in patients with advanced Parkinson's disease (PD) [1][2][3]. Clinical studies mainly assess QoL using the disease-specific Parkinson's disease questionnaires (PDQ) or the more generic European Quality of Life Questionnaire with 5 dimensions (EQ-5D) [4][5][6][7]. However, these tools do not consider the concept of "life satisfaction" which has been described as a relevant component to assess QoL holistically [8]. ...
Article
Background: The satisfaction with life and, in particular, with treatment in Parkinson's disease (PD) is understudied. Objective: To explore a new 7-item rating tool assessing satisfaction with life and treatment (SLTS-7) in PD. Methods: In this cross-sectional, multi-center study, including patients screened for advanced therapies, psychometric characteristics of the SLTS-7 were analyzed. An exploratory factor analysis identified the underlying factorial structure of the SLTS-7. Results: 117 patients were included, and the data quality of the SLTS-7 was excellent (computable data 100%), and acceptability measures satisfied standard criteria. Besides the global assessment (item 1), the exploratory factor analysis produced item 2 (physical satisfaction) as an independent item and two factors among the remaining items: items 3-5 (psycho-social satisfaction), and items 6 and 7 (treatment satisfaction). Cronbach's alpha was 0.89, indicative of high internal consistency. The SLTS-7 total score correlated moderately with motor symptoms and weakly with non-motor symptoms total scores. SLTS-7 showed the highest correlations with the European Quality of Life with 5 items (EQ-5D) visual analog scale (0.43-0.58, p < 0.01), indicating a moderate convergent validity. The SLTS-7 significantly increased with higher non-motor symptoms burden levels (p = 0.002). Conclusion: Life satisfaction in PD covers three specific aspects, namely physical, psycho-social, and treatment satisfaction. The new SLTS-7 is a valid, reliable, and easy-to-use tool to assess satisfaction with life and treatment in patients with PD screened for advanced therapies. Longitudinal studies analyzing the effect of advanced PD treatment on life and treatment satisfaction are warranted.
... Because patients in the fluctuating pain group were able to improve pain in response to dopaminergic medication, they are suggested to be a population that requires more aggressive treatment intervention. In addition to oral medication, device-assisted therapies such as deep brain stimulation and levodopa-carbidopa intestinal gel can relieve pain or pain fluctuation and improve the patient's QOL [39,40]. It is necessary to evaluate pain before and after the treatment and consider the evidence. ...
Article
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Pain is a common non-motor symptom in Parkinson's disease (PD) patients, and the incidence of fluctuating pain may be improved by taking levodopa. There are only a few detailed reports regarding fluctuating pain. In this study, 331 PD patients were classified into three groups: no-pain group (67.4%), non-fluctuating pain group (22.1%), and fluctuating pain group (10.6%). We evaluated patients' background and its impact on the quality of life (QOL) of each group. The pain group exhibited higher levels of depression (p < 0.0001), had a higher frequency of visual hallucinations (p = 0.007), and lower QOL (p < 0.0001) compared with the no-pain group. The fluctuating pain group had a younger onset (p = 0.006), higher Hoehn & Yahr stage (p = 0.018), and higher frequency of wearing-off (p < 0.001) and dyskinesia (p = 0.007) than the other groups. We compared the Parkinson's Disease Questionnaire-8 summary index (PDQ-8 SI) in each pain group to the no-pain group using analysis of variance. As a result, PDQ-8 SI was significantly higher in both the non-fluctuating and fluctuating pain groups (p < 0.0001). Pain is regarded as a non-negligible symptom that affects the QOL of PD patients, and given the unique characteristics, fluctuating pain might be considered as an independent clinical subtype of PD.
... This cohort-derived threshold was used in several previous studies. 1 30 Patients who experienced no clinically relevant improvement or worsening of QUIP-RS changes were not included in this analysis. Differences between these two groups were tested using Mann-Whitney U tests. ...
Article
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Background The effects of subthalamic stimulation (subthalamic nucleus-deep brain stimulation, STN-DBS) on impulsive and compulsive behaviours (ICB) in Parkinson’s disease (PD) are understudied. Objective To investigate clinical predictors of STN-DBS effects on ICB. Methods In this prospective, open-label, multicentre study in patients with PD undergoing bilateral STN-DBS, we assessed patients preoperatively and at 6-month follow-up postoperatively. Clinical scales included the Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP-RS), PD Questionnaire-8, Non-Motor Symptom Scale (NMSS), Unified PD Rating Scale in addition to levodopa-equivalent daily dose total (LEDD-total) and dopamine agonists (LEDD-DA). Changes at follow-up were analysed with Wilcoxon signed-rank test and corrected for multiple comparisons (Bonferroni method). We explored predictors of QUIP-RS changes using correlations and linear regressions. Finally, we dichotomised patients into ‘QUIP-RS improvement or worsening’ and analysed between-group differences. Results We included 55 patients aged 61.7 years±8.4 with 9.8 years±4.6 PD duration. QUIP-RS cut-offs and psychiatric assessments identified patients with preoperative ICB. In patients with ICB, QUIP-RS improved significantly. However, we observed considerable interindividual variability of clinically relevant QUIP-RS outcomes as 27.3% experienced worsening and 29.1% an improvement. In post hoc analyses, higher baseline QUIP-RS and lower baseline LEDD-DA were associated with greater QUIP-RS improvements. Additionally, the ‘QUIP-RS worsening’ group had more severe baseline impairment in the NMSS attention/memory domain. Conclusions Our results show favourable ICB outcomes in patients with higher preoperative ICB severity and lower preoperative DA doses, and worse outcomes in patients with more severe baseline attention/memory deficits. These findings emphasise the need for comprehensive non-motor and motor symptoms assessments in patients undergoing STN-DBS. Trial registration number DRKS00006735.
... 1,2 It is a common and disabling non-motor symptom (NMS) in Parkinson's disease (PD) patients with a prevalence that ranges from 33 to 80% and that can be evident even during the premotor stage. 3 Fatigue has a clear impact on quality of life, for both patients and caregivers [4][5][6][7] and approximately one-third of PD patients consider fatigue as one of the most disabling symptom of their disease. 8,9 It is important to distinguish fatigue from other NMS as they may be confused with fatigue, such as depression with the main difference being that in fatigue the mood need not necessarily be low, and excessive daytime sleepiness where people are sleepy, but not disproportionally exhausted, and finally apathy where the will to perform activities is lacking. ...
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Background Fatigue is a common and disabling non-motor symptom (NMS) in Parkinson’s disease (PD) patients. However, the effect of subthalamic nucleus (STN) deep brain stimulation (DBS) on fatigue has not been widely studied. Objective To determine the effect of STN DBS on fatigue in PD patients, measured by the Non-motor symptoms scale (NMSS). Methods Cross-sectional analysis of 50 patients with PD who underwent STN DBS at King’s College Hospital and Salford Royal Hospital with fatigue scores (measured by question number 4 from domain 2 (sleep/fatigue) of the NMSS as the primary outcome measure. Secondary outcome measures included the PD Sleep Scale (PDSS), Scales for Outcome in PD (SCOPA)-motor examination, activities of daily living, motor complications, Hoehn and Yahr (HY) stage and changes in Levodopa Equivalent Daily Dose (LEDD). Results 50 patients with a mean follow-up period of 1.98 ± 1.36 years were studied. Significant improvement in median fatigue scores (4.00 (0.75–9.00) to 1.00 (0.00–4.50); p = .001) was observed. In addition, improvements in question 5 (sleep maintenance and fragmentation; 8.00 (4.00–12.00) to 0.00 (0.00–4.00); p < .001) and in domain 2 total score (sleep/fatigue; 20.00 (8.75–27.25) to 6.00 (0.75–16.00); p < .001) were also significant, together with improvements in NMSS total score, SCOPA scores and HY stage (p ≤ .02). Moreover, LEDD but especially dopamine agonists LEDD was significantly reduced after DBS (310.00 (0.00–480.00) to 150.00 (0.00–300.00); p < .020). Conclusions Even though open label and not using a validated fatigue scale, this observational analysis suggest that fatigue improves significantly after STN DBS with persisting benefits at two years follow-up.
... London: National Research Ethics Service SouthEast London REC3-10/H0808/141, 000010084). Results from the apomorphine, levodopa infusion therapy, and STN-DBS arms have previously been published [18,19]. All patients gave written consent prior to study procedures. ...
Article
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Background Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson’s disease (PD). However, few studies have compared their nonmotor effects. Objective To compare nonmotor effects of STN-DBS and GPi-DBS. Methods In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, –III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. Results In both groups, PDQ, UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. Conclusions To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients’ individual motor and nonmotor profiles.
... Sleep disturbances and depressive symptoms are amongst the most common nonmotor symptoms (NMS) in patients with Parkinson's disease (PD) and are major predictors of negative health-related quality of life (QoL) [1]. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in improving medication-refractory motor impairment [2], QoL [3,4], and a wide range of NMS [5,6] in patients with PD. Long-term effects of STN-DBS on NMS have only been studied to a limited extent. ...
Article
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Background: Sleep disturbances and neuropsychiatric symptoms are some of the most common nonmotor symptoms in Parkinson's disease (PD). The effect of subthalamic stimulation (STN-DBS) on these symptoms beyond a short-term follow-up is unclear. Objective: To examine 36-month effects of bilateral STN-DBS on quality of sleep, depression, anxiety, and quality of life (QoL) compared to standard-of-care medical therapy (MED) in PD. Methods: In this prospective, controlled, observational, propensity score matched international multicenter study, we assessed sleep disturbances using the PDSleep Scale-1 (PDSS), QoL employing the PDQuestionnaire-8 (PDQ-8), motor disorder with the Scales for Outcomes in PD (SCOPA), anxiety and depression with the Hospital Anxiety and Depression Scale (HADS), and dopaminergic medication requirements (LEDD). Within-group longitudinal outcome changes were tested using Wilcoxon signed-rank and between-group longitudinal differences of change scores with Mann-Whitney U tests. Spearman correlations analyzed the relationships of outcome parameter changes at follow-up. Results: Propensity score matching applied on 159 patients (STN-DBS n = 75, MED n = 84) resulted in 40 patients in each treatment group. At 36-month follow-up, STN-DBS led to significantly better PDSS and PDQ-8 change scores, which were significantly correlated. We observed no significant effects for HADS and no significant correlations between change scores in PDSS, HADS, and LEDD. Conclusions: We report Class IIb evidence of beneficial effects of STN-DBS on quality of sleep at 36-month follow-up, which were associated with QoL improvement independent of depression and dopaminergic medication. Our study highlights the importance of sleep for assessments of DBS outcomes.
... In der Zukunft kann das Wissen über die einzelnen Subtypen mit Fokus auf dem Krankheitsverlauf zusätzliche Informationen für eine Therapieentscheidung bieten. Wichtiger scheint aktuell die präoperative Evaluation von NMS mit Wirkung auf die postoperative Lebensqualität [81] und das Outcome, wobei die Wirkungen auf die NMS auch hier mit der Positionierung der Elektroden bzw. der Stimulationslokalisation zusammenhängen [82]. ...
Article
Zusammenfassung Während Parkinson mit seiner vielfältigen und sehr individuellen Kombination aus motorischen und nichtmotorischen Symptomen zunehmend genauer charakterisiert ist, nicht zuletzt durch die Untersuchung von großen Patientenkohorten mit Deep-Phenotyping-Approach, folgt die Therapie weiterhin einem einheitlichen Schema. Durch bessere Stratifikation bieten Präzisionsmedizin-Ansätze die Möglichkeit, die Behandlung und patientenzentrierte Versorgung zu verbessern. Spezifische Therapien für den Einsatz bei monogenetischen Parkinson-Formen, die aktuell untersucht werden, könnten helfen, Krankheitsmechanismen zu verstehen und dadurch auch zum Verständnis des idiopathischen Parkinson-Syndroms beitragen, sowie neue Behandlungsziele aufzeigen. Wir zeigen Daten zur Vorhersage von Wirksamkeit und Langzeit-Vorteil von aktuellen medikamentösen Behandlungen sowie von Tiefer Hirnstimulation (THS) im Kontext von wachsendem pharmakogenetischen Wissen. Konfrontiert mit asymptomatischen Trägern genetischer Mutationen (monogenetische Erkrankung) von variabler Penetranz und prodromalen Stadien wie REM-Schlaf-Verhaltensstörungen, zeichnen sich erste präventive Therapiestrategien ab. Ihr Einfluss auf die Krankheitsprogression und Aussichten für die klinische Praxis müssen adressiert werden.
... Identifying individuals whose olfactory system could have functionality restored also identifies candidates for potential OD therapy. While motor symptom treatment is a primary concern in PD, improving non-motor symptoms like OD will improve patient quality of life (13,183). Simple strategies to improve OD are lacking presently. ...
Article
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This minireview discusses our current understanding of the olfactory dysfunction that is frequently observed in sporadic and familial forms of Parkinson's disease and parkinsonian syndromes. We review the salient characteristics of olfactory dysfunction in these conditions, discussing its prevalence and characteristics, how neuronal processes and circuits are altered in Parkinson's disease, and what is assessed by clinically used measures of olfactory function. We highlight how studies of monogenic Parkinson's disease and investigations in ethnically diverse populations have contributed to understanding the mechanisms underlying olfactory dysfunction. Furthermore, we discuss how imaging and system-level approaches have been used to understand the pathogenesis of olfactory dysfunction. We discuss the challenging, remaining gaps in understanding the basis of olfactory dysfunction in neurodegeneration. We propose that insights could be obtained by following longitudinal cohorts with familial forms of Parkinson's disease using a combination of approaches: a multifaceted longitudinal assessment of olfactory function during disease progression is essential to identify not only how dysfunction arises, but also to address its relationship to motor and non-motor Parkinson's disease symptoms. An assessment of cohorts having monogenic forms of Parkinson's disease, available within the Genetic Epidemiology of Parkinson's Disease (GEoPD), as well as other international consortia, will have heuristic value in addressing the complexity of olfactory dysfunction in the context of the neurodegenerative process. This will inform our understanding of Parkinson's disease as a multisystem disorder and facilitate the more effective use of olfactory dysfunction assessment in identifying prodromal Parkinson's disease and understanding disease progression.
... Protected by http://jnnp.bmj.com/ and highlights the relative importance of NMS. 43 QoL changes were significantly correlated to mood/apathy and attention/ memory changes, indicating that although group level clinical effects per se were not significant, these non-motor outcomes were significantly related with postoperative QoL outcome on an individual level. ...
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Objective To examine 36-month effects of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on non-motor symptoms (NMS) compared with standard-of-care medical treatment (MED) in Parkinson’s disease (PD). Methods Here we report the 36-month follow-up of a prospective, observational, controlled, international multicentre study of the NILS cohort. Assessments included NMSScale (NMSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). Propensity score matching resulted in a pseudo-randomised sub-cohort balancing baseline demographic and clinical characteristics between the STN-DBS and MED groups. Within-group longitudinal outcome changes were analysed using Wilcoxon signed-rank and between-group differences of change scores with Mann-Whitney U test. Strength of clinical responses was quantified with Cohen’s effect size. In addition, bivariate correlations of change scores were explored. Results Propensity score matching applied on the cohort of 151 patients (STN-DBS n=67, MED n=84) resulted in a well-balanced sub-cohort including 38 patients per group. After 36 months, STN-DBS significantly improved NMSS, PDQ-8, SCOPA-motor examination and -complications and reduced LEDD. Significant between-group differences, all favouring STN-DBS, were found for NMSS, SCOPA-motor complications, LEDD (large effects), motor examination and PDQ-8 (moderate effects). Furthermore, significant differences were found for the sleep/fatigue, urinary (large effects) and miscellaneous NMSS domains (moderate effects). NMSS total and PDQ-8 change scores correlated significantly. Conclusions This study provides Class IIb evidence for beneficial effects of STN-DBS on NMS at 36-month follow-up which also correlated with quality of life improvements. This highlights the importance of NMS for DBS outcomes assessments.
... However, we were interested in a pragmatic assessment of a wide range of sleep-wake disturbances including complex symptoms, such as nocturia, nocturnal psychosis, motor state-related sleep 1 3 symptoms, and sleep refreshment, which cannot be captured by polysomnography. Due to the design of our database as a prospective, observational study, motor assessments were recorded in ON states (MedON/StimON) [15]. Although the current study did not find a relationship/correlation between change in motor exam and change in sleep, this is still an important potential contributor to the improvement in sleep and the relationship may have been masked because participants were only evaluated in ON states. ...
Article
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Background Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and sleep symptoms in Parkinson’s disease (PD). However, the long-term effects of STN-DBS on sleep and its relationship with QoL outcome are unclear.Methods In this prospective, observational, multicenter study including 73 PD patients undergoing bilateral STN-DBS, we examined PDSleep Scale (PDSS), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, -activities of daily living, and -complications (SCOPA-A, -B, -C), and levodopa-equivalent daily dose (LEDD) preoperatively, at 5 and 24 months follow-up. Longitudinal changes were analyzed with Friedman-tests or repeated-measures ANOVA, when parametric tests were applicable, and Bonferroni-correction for multiple comparisons. Post-hoc, visits were compared with Wilcoxon signed-rank/t-tests. The magnitude of clinical responses was investigated using effect size.ResultsSignificant beneficial effects of STN-DBS were observed for PDSS, PDQ-8, SCOPA-A, -B, and -C. All outcomes improved significantly at 5 months with subsequent decrements in gains at 24 months follow-up which were significant for PDSS, PDQ-8, and SCOPA-B. Comparing baseline and 24 months follow-up, we observed significant improvements of PDSS (small effect), SCOPA-A (moderate effect), -C, and LEDD (large effects). PDSS and PDQ-8 improvements correlated significantly at 5 and 24 months follow-up.Conclusions In this multicenter study with a 24 months follow-up, we report significant sustained improvements after bilateral STN-DBS using a PD-specific sleep scale and a significant relationship between sleep and QoL improvements. This highlights the importance of sleep in holistic assessments of DBS outcomes.
... Subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective treatment option for patients with advanced Parkinson's disease improving quality of life, motor symptoms, and non-motor symptoms (Krack et al., 2003;Deuschl et al., 2006;Dafsari et al., 2018d). However, a considerable degree of interindividual variability has been reported for these outcomes (Floden et al., 2014;Dafsari et al., 2018e). A previous study by our group provided evidence that the position of active DBS contacts significantly contributed to the interindividual variability of quality of life, motor and non-motor outcomes after STN-DBS in Parkinson's disease (Dafsari et al., 2018a). ...
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Deep brain stimulation of the subthalamic nucleus is an effective and established therapy for patients with advanced Parkinson's disease improving quality of life, motor symptoms and non-motor symptoms. However, there is a considerable degree of interindividual variability for these outcomes, likely due to variability in electrode placement and stimulation settings. Here, we present probabilistic mapping data from a prospective, open-label, multicentre, international study to investigate the influence of the location of subthalamic nucleus deep brain stimulation on non-motor symptoms in patients with Parkinson's disease. A total of 91 Parkinson's disease patients undergoing bilateral deep brain stimulation of the subthalamic nucleus were included, and we investigated NMSScale, NMSQuestionnaire, Scales for Outcomes in Parkinson's disease-motor examination, -activities of daily living, and -motor complications, and Parkinson's disease Questionnaire-8 preoperatively and at 6-month follow-up after surgery. Leads were localized in standard space using the Lead-DBS toolbox and individual volumes of tissue activated were calculated based on clinical stimulation settings. Probabilistic stimulation maps and non-parametric permutation statistics were applied to identify voxels with significant above or below average improvement for each scale and analysed using the DISTAL atlas. All outcomes improved significantly at follow-up. Significant spatial distribution patterns of neurostimulation were observed for NMSScale total score and its mood/apathy and attention/memory domains. For both domains, voxels associated with below average improvement were mainly located dorsal to the subthalamic nucleus. In contrast, above average improvement for mood/apathy was observed in the ventral border region of the subthalamic nucleus and in its sensorimotor subregion and for attention/memory in the associative subregion. A trend was observed for NMSScale sleep domain showing voxels with above average improvement located ventral to the subthalamic nucleus. Our study provides evidence that the interindividual variability of mood/apathy, attention/memory, and sleep outcomes after subthalamic nucleus deep brain stimulation depends on the location of neurostimulation. This study highlights the importance of holistic assessments of motor and non-motor aspects of Parkinson's disease to tailor surgical targeting and stimulation parameter settings to patients' personal profiles.
... Deep Brain Stimulation Deep brain stimulation has been shown to improve motor and non-motor symptoms and quality of life of patients with movement disorder such as Parkinson's disease (PD). DBS can be implanted in various deep locations of the brain such as the subthalamic nucleus [37], pedunculopontine nucleus (STN) [38], or globus pallidus pars interna (GPi). The Netherlands SubThalamic and Pallidal Stimulation (NSTAPS) study evaluated functional improvements following GPi versus STN DBS implantation in PD patients and showed only slight preference of STN in regard to off-drug phase and some motor examination scores [39]. ...
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Purpose of Review Voiding dysfunction (VD) is morbid, costly, and leads to urinary tract infections, stones, sepsis, and permanent renal failure. Evaluation and diagnosis of VD in non-obstructed patients can be challenging. Potential diagnostic and therapeutic options beyond the bladder, such as brain centers involved in voiding have been proposed as promising targets. This review focuses on current and future applications of functional neuroimaging in human in voiding and in patients with VD. Recent Findings The current understanding of brain centers and their roles in initiating, maintaining, and/or modulating voiding is rudimentary in humans and in patients with VD. With the advent and advancement in functional neuroimaging, we are gaining more insight into specific brain regions involved in the voiding phase of micturition. In healthy individuals, right dorsomedial pontine tegmentum, periaqueductal gray, hypothalamus, and the inferior, medial, and superior frontal gyrus have been identified as regions of interest in voiding. Summary Functional neuroimaging could suggest new diagnostic methods and provides crucial steps towards therapeutic options for the morbid and intractable VD condition, in patients with neurogenic (e.g., MS or strokes) or non-neurogenic VD (e.g., underactive bladder or Fowler’s syndrome).
... As a general trend in the STN-DBS group, patient selection resulted in the lowest mean age at intervention, shortest disease duration, and least impairment for baseline clinical outcome parameters. Consistent with previous studies that have identified the relative importance of these factors, 13,15,18 in this highly selected group, improvements were observed for QoL, motor, nonmotor outcomes. As mentioned previously, our results indicate that the beneficial effects of STN-DBS may be particularly favorable if a reduction of dopaminergic medication may result in an improvement of specific nonmotor outcomes. ...
Article
Objective Real‐life observational report of clinical efficacy of bilateral subthalamic stimulation (STN‐DBS), apomorphine (APO), and intrajejunal levodopa infusion (IJLI) on quality of life, motor, and nonmotor symptoms (NMS) in Parkinson's disease (PD). Methods In this prospective, multicenter, international, real‐life cohort observation study of 173 PD patients undergoing STN‐DBS (n = 101), IJLI (n = 33), or APO (n = 39) were followed‐up using PDQuestionnaire‐8, NMSScale (NMSS), Unified PD Rating Scale (UPDRS)‐III, UPDRS‐IV, and levodopa equivalent daily dose (LEDD) before and 6 months after intervention. Outcome changes were analyzed with Wilcoxon signed‐rank or paired t test when parametric tests were applicable. Multiple comparisons were corrected (multiple treatments/scales). Effect strengths were quantified with relative changes, effect size, and number needed to treat. Analyses were computed before and after propensity score matching, balancing demographic and clinical characteristics. Results In all groups, PDQuestionnaire‐8, UPDRS‐IV, and NMSS total scores improved significantly at follow‐up. Levodopa equivalent daily dose was significantly reduced after STN‐DBS. Explorative NMSS domain analyses resulted in distinct profiles: STN‐DBS improved urinary/sexual functions, mood/cognition, sleep/fatigue, and the miscellaneous domain. IJLI improved the 3 latter domains and gastrointestinal symptoms. APO improved mood/cognition, perceptual problems/hallucinations, attention/memory, and the miscellaneous domain. Overall, STN‐DBS and IJLI seemed favorable for NMSS total score, and APO favorable for neuropsychological/neuropsychiatric NMS and PDQuestionnaire‐8 outcome. Conclusions This is the first comparison of quality of life, nonmotor. and motor outcomes in PD patients undergoing STN‐DBS, IJLI, and APO in a real‐life cohort. Distinct effect profiles were identified for each treatment option. Our results highlight the importance of holistic nonmotor and motor symptoms assessments to personalize treatment choices. © 2019 International Parkinson and Movement Disorder Society
... Nonmotor symptoms are important for quality-of-life scores and might predict overall DBS outcomes. 65 Electronic health (eHealth) and mobile health (mHealth) applications and telemonitoring concepts have been recently integrated into PD care and contain the aforementioned missing features. [66][67][68][69] Most of these developments are achieved in order to improve PD care and ensure its accessibility and cost-effectiveness. ...
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Advancing conventional open‐loop DBS as a therapy for PD is crucial for overcoming important issues such as the delicate balance between beneficial and adverse effects and limited battery longevity that are currently associated with treatment. Closed‐loop or adaptive DBS aims to overcome these limitations by real‐time adjustment of stimulation parameters based on continuous feedback input signals that are representative of the patient's clinical state. The focus of this update is to discuss the most recent developments regarding potential input signals and possible stimulation parameter modulation for adaptive DBS in PD. Potential input signals for adaptive DBS include basal ganglia local field potentials, cortical recordings (electrocorticography), wearable sensors, and eHealth and mHealth devices. Furthermore, adaptive DBS can be applied with different approaches of stimulation parameter modulation, the feasibility of which can be adapted depending on specific PD phenotypes. Implementation of technological developments like machine learning show potential in the design of such approaches; however, energy consumption deserves further attention. Furthermore, we discuss future considerations regarding the clinical implementation of adaptive DBS in PD. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
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Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for motor impairment due to Parkinson's disease (PD) progression. While treated subjects mostly experience significant amelioration of symptoms, some still report adverse effects. In particular, changes in gait patterns due to the electrical stimulation have shown mixed results across studies, with overall gait velocity improvement described as the core positive outcome. This retrospective study investigates changes in the gait parameters of 50 PD patients before and 6 months after STN-DBS, by exploiting a purely data-driven approach. First, unsupervised learning identifies clusters of subjects with similar variations in the gait parameters after STN-DBS. This analysis highlights two dominant clusters (Silhouette score: 0.45, Dunn index: 0.18), with one of them associated to a worsening in walking. Then, supervised machine learning models (i.e., Support Vector Machine and Ensemble Boosting models) are trained using pre-surgery gait parameters, clinical scores, and demographic information to predict the two gait change clusters. In a Leave-One-Subject-Out validation, the best model achieves balanced accuracy 80.05 $\pm$ 3.52 %, denoting moderate predictability of both clusters. Moreover, feature importance analysis reveals the variability in the step width and in the step length asymmetry during the preoperative gait test as promising biomarkers to predict gait response to STN-DBS.
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Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established treatment for motor impairment due to Parkinson's disease (PD) progression. While treated subjects mostly experience significant amelioration of symptoms, some still report adverse effects. In particular, changes in gait patterns due to the electrical stimulation have shown mixed results across studies, with overall gait velocity improvement described as the core positive outcome. This retrospective study investigates changes in the gait parameters of 50 PD patients before and 6 months after STN-DBS, by exploiting a purely data-driven approach. First, unsupervised learning identifies clusters of subjects with similar variations in the gait parameters after STN-DBS. This analysis highlights two dominant clusters (Silhouette score: 0.45, Dunn index: 0.18), with one of them associated to a worsening in walking. Then, supervised machine learning models (i.e., Support Vector Machine and Ensemble Boosting models) are trained using pre-surgery gait parameters, clinical scores, and demographic information to predict the two gait change clusters. In a Leave-One-Subject-Out validation, the best model achieves balanced accuracy over 82%, denoting moderate predictability of both clusters. Moreover, feature importance analysis reveals the variability in the step width and in the step length asymmetry during the preoperative gait test as promising biomarkers to predict gait response to STN-DBS.
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Objectives The aim of this study was to investigate the impact of nonmotor symptoms (NMS) on the quality of life (QoL) outcome after subthalamic nucleus deep brain stimulation (STN-DBS) at the 1-year follow-up. Methods Ninety-three patients diagnosed with Parkinson's disease (PD), who underwent subthalamic nucleus deep brain stimulation (STN-DBS) between April 2020 and August 2021, were included in this study. Demographic information was gathered through a self-designed questionnaire. The severity of both motor and non-motor symptoms, along with the quality of life (QoL), was assessed using the Unified Parkinson's Disease Rating Scale-III (UPDRS-III), Nonmotor Symptoms Scale (NMSS), and 8-item Parkinson's Disease Questionnaire (PDQ-8), respectively. Results Significant differences were observed in the UPDRS-III score, NMSS summary index (SI), and subscores of six domains (sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, urinary, and sexual function) between the baseline and the 6- and 12-month follow-ups. The correlation analysis revealed positive correlations between the preoperative NMSS SI and subscores of seven domains (cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/memory, gastrointestinal, and urinary) and ΔPDQ-8. Moreover, the preoperative PDQ-8 SI (β = 0.869, P < 0.001) and the preoperative attention/memory subscore (β = −0.154, P = 0.026) were predictive of the postsurgery improvement in quality of life (QoL). Conclusion Deep brain stimulation (DBS) led to an improvement in the patients' nonmotor symptoms (NMS) at the 1-year follow-up, along with a correlation observed between NMS and the patients' quality of life (QoL). Notably, the severity of preoperative attention/memory problems emerged as the most significant predictor of NMS influencing the QoL outcome after STN-DBS at the 1-year follow-up.
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Background Subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) improves quality of life (QoL), motor and non-motor symptoms (NMS). However, in previous studies, 43%–49% of patients did not experience clinically relevant postoperative QoL improvement. To inform individualised prediction of postoperative QoL improvement, we developed a stratification analysis of QoL outcomes based on preoperative non-motor total burden, severity of motor progression and motor response in levodopa challenge tests. Methods This was a prospective, open-label, multicentre, international study with a 6-month follow-up. A distribution-based threshold identified ’QoL responders’ in the PDQuestionnaire-8 Summary Index (PDQ-8 SI). After baseline stratification based on the NMS Scale, Hoehn and Yahr Scale and levodopa response assessed with the Unified PD Rating Scale-III, we compared postoperative QoL response between these strata. To assess the clinical usefulness and statistical feasibility of stratifications, we compared cumulative distribution function curves, respectively PDQ-8 within-stratum variation. Results All main outcomes improved postoperatively. Based on the 8.1 points threshold for clinically meaningful PDQ-8 SI improvement, only 80/161 patients were classified as ’QoL responders’. The absolute risk reductions for QoL non-response among respective non-motor, motor progression and levodopa response strata were 23%, 8% and 3%, respectively. Only non-motor stratification reduced PDQ-8 within-stratum variation compared with the overall cohort. Conclusions Non-motor stratification, but not motor progression or levodopa response stratification, is clinically useful and statistically feasible for personalised preoperative prediction of postoperative QoL outcome of STN-DBS for PD. Our findings highlight that non-motor assessments are necessary components of a case-based, holistic approach of DBS indication evaluations geared towards optimising postoperative QoL outcomes. Trial registration number GermanClinicalTrialsRegister: #6735.
Chapter
Omics data create several computational challenges related to their volume, high dimensionality, and complexity. A subfield of the computational intelligence area that can address part of this complexity is bioinspired algorithms. These methods are gaining importance by strategies upon modeling the behavior of living organisms to create an algorithmic process that solves optimization problems. There is a remarkable progress in the application of bioinspired algorithms in neurodegeneration diseases from omics data, such as in Parkinson’s disease, a progressive disorder that affects the nervous system and the parts of the body controlled by the nerves. In this chapter, we address the main cutting-edge bioinspired optimization methods applied to PD omics datasets driven by high-throughput analytical workflows offering a significant clinical contribution and providing a more comprehensive outcome across multiple biological layers.
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Beyond the established effects of subthalamic nucleus deep brain stimulation (STN-DBS) in reducing motor symptoms in Parkinson’s disease, recent evidence has highlighted the effect on non-motor symptoms. However, the impact of STN-DBS on disseminated networks remains unclear. This study aimed to perform a quantitative evaluation of network-specific modulation induced by STN-DBS using Leading Eigenvector Dynamics Analysis (LEiDA). We calculated the occupancy of resting-state networks (RSNs) in functional MRI data from 10 patients with Parkinson’s disease implanted with STN-DBS and statistically compared between ON and OFF conditions. STN-DBS was found to specifically modulate the occupancy of networks overlapping with limbic RSNs. STN-DBS significantly increased the occupancy of an orbitofrontal limbic subsystem with respect to both DBS OFF(p = 0.0057) and 49 age-matched healthy controls (p = 0.0033). Occupancy of a diffuse limbic RSN was increased with STN-DBS OFF when compared to healthy controls (p = 0.021), but not when STN-DBS was ON, which indicates rebalancing of this network. These results highlight the modulatory effect of STN-DBS on components of the limbic system, particularly within the orbitofrontal cortex, a structure associated with reward processing. These results reinforce the value of quantitative biomarkers of RSN activity in evaluating the disseminated impact of brain stimulation techniques and the personalization of therapeutic strategies.
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Background: Deep brain stimulation (DBS) is a well-established procedure for treating Parkinson's disease (PD). Although its mechanisms of action are still unclear, improvements in motor symptoms and reductions in medication side effects can be achieved for a significant proportion of patients, with consequent enhancement of quality of life. Objective: To investigate the impact of DBS on the quality of life of PD patients. Methods: This was a retrospective longitudinal study with collection of historical data in a neurosurgery center, from June 2019 to December 2020. The sample was obtained according to convenience, and the Parkinson's Disease Questionnaire (PDQ-39), Unified Parkinson's Disease Rating Scale (UPDRS) III and IV, Trail-Making Test and Verbal Fluency Test were used. Results: Data were collected from 17 patients (13 with subthalamic nucleus DBS and 4 with globus pallidus pars interna DBS). Significant improvement (p=0.008) on the UPDRS III was observed in comparing the preoperative without DBS with the postoperative with DBS. About 47.0% of the patients showed post-surgical improvement in QoL (p=0.29). Thirteen patients were able to complete part A of the Trail-Making Test and four of these also completed part B. Almost 60% of the patients scored sufficiently on the semantic test, whereas only 11.8% scored sufficiently on the orthographic evaluation. No association between implant site and test performance could be traced. Conclusions: Improvements in quality of life and motor function were observed in the majority of the patients enrolled. Despite the limitations of this study, DBS strongly benefits a significant proportion of PD patients when well indicated.
Article
Background Proactive interference (PI) refers to the interference of previously learned materials with new learning and reflects the failure of inhibitory processes in memory. Retroactive interference (RI) refers to the unfavorable effect of new learning on the later recall of previously learned information. Although subthalamic nucleus deep brain stimulation (STN‐DBS) does not affect global cognition in Parkinson's disease (PD), it has negative effects on specific aspects of cognition, including verbal fluency and executive inhibitory control of action.To this end, we set to test the acute effect of STN‐DBS on PI and RI during verbal learning. Methods Twenty PD patients with STN‐DBS were tested on the California Verbal Learning Test‐II using an ON/OFF stimulation design. Results The results showed that stimulation increased PI ON stimulation (P = 0.012) but had no effect on RI (P = 0.816). Conclusions Our results extend the role of STN to the inhibitory control that is required during memory encoding or recall for prevention of PI. © 2020 International Parkinson and Movement Disorder Society
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Introduction Despite careful patient selection for subthalamic nucleus deep brain stimulation (STN DBS), some Parkinson's disease patients show limited improvement of motor disability. Innovative predictive analysing methods hold potential to develop a tool for clinicians that reliably predicts individual postoperative motor response, by only regarding clinical preoperative variables. The main aim of preoperative prediction would be to improve preoperative patient counselling, expectation management, and postoperative patient satisfaction. Methods We developed a machine learning logistic regression prediction model which generates probabilities for experiencing weak motor response one year after surgery. The model analyses preoperative variables and is trained on 89 patients using a five-fold cross-validation. Imaging and neurophysiology data are left out intentionally to ensure usability in the preoperative clinical practice. Weak responders (n = 30) were defined as patients who fail to show clinically relevant improvement on Unified Parkinson Disease Rating Scale II, III or IV. Results The model predicts weak responders with an average area under the curve of the receiver operating characteristic of 0.79 (standard deviation: 0.08), a true positive rate of 0.80 and a false positive rate of 0.24, and a diagnostic accuracy of 78%. The reported influences of individual preoperative variables are useful for clinical interpretation of the model, but cannot been interpreted separately regardless of the other variables in the model. Conclusion The model's diagnostic accuracy confirms the utility of machine learning based motor response prediction based on clinical preoperative variables. After reproduction and validation in a larger and prospective cohort, this prediction model holds potential to support clinicians during preoperative patient counseling.
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The Subthalamic Nucleus (STh) is an oval-shaped diencephalic structure located ventrally to the thalamus, playing a fundamental role in the circuitry of the basal ganglia. In addition to being involved in the pathophysiology of several neurodegenerative disorders, such as Huntington’s and Parkinson’s disease, the STh is one of the target nuclei for deep brain stimulation. However, most of the anatomical evidence available derives from non-human primate studies. In this review, we will present the topographical and morphological organization of the nucleus and its connections to structurally and functionally related regions of the basal ganglia circuitry. We will also highlight the importance of additional research in humans focused on validating STh connectivity, cytoarchitectural organization, and its functional subdivision.
Article
Objective: This study was to analyze and compare the effects of subthalamic nucleus (STN)-Deep brain stimulation (DBS) and Globus pallidus internus (GPi)-DBS on Parkinson's disease (PD)-related pain. Methods: A retrospective study was performed of 64 patients (28 underwent GPi-DBS, 36 underwent STN-DBS) with PD-related pain in our hospital from January 2017 to July 2019. Numerical Rating Scale (NRS) was used to evaluate the degree of pain preoperatively and 4 months after operation, and the unified PD scale Ⅲ (UPDRS-III) was completed to assess the motor symptoms simultaneously. Results: The average NRS score of all 64 patients after operation was 1.09±1.39, which was significantly lower than that before operation (4.44±1.67) (p<0.0001). The improvement rate of NRS was 75%±27% in 28 GPi-DBS patients and 79%±27% in 36 STN-DBS patients, with no significant difference (p=0.577). The improvement rate of NRS and UPDRS-III were significantly correlated in STN-DBS group (r=0.3707, p=0.026), while not significantly correlated in GPi-DBS group (p=0.516). Conclusions: Both GPi-DBS and STN-DBS were effective for PD-related pain and seemed to have similar efficacy. This study provided an important first-step towards different DBS targets for controlling PD-related pain. Follow-up prospective research is an appropriate next-step on the path towards multicenter clinical trials.
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Background: Several studies examined the influence of subthalamic nucleus-deep brain stimulation (STN-DBS) on quality of life (QoL) in patients with Parkinson's disease (PD). However, it is unclear whether this effect differs between age groups and disease durations and whether it stays consistent over time. Objectives: We assessed the influence of stimulation duration, disease duration, and age at surgery on QoL after STN-DBS. Methods: We systematically searched for studies reporting the results of the Parkinson's Disease Questionnaire 39 or 8. Studies were included if they investigated the time passed since STN-DBS or if their study cohort fell into the range of one of the following age groups: younger than 60 years or between 60 and 70 years. For each condition, a standardized mean difference meta-analysis was performed. Furthermore, all studies were categorized into short or long disease duration at surgery using a median split. Results: A total of 23 studies reporting the cumulative outcome of 76 to 802 PD patients were included in this analysis. The results demonstrate a substantial improvement of QoL after DBS that remains stable over 36 months. QoL falls to preoperative scores 60 months after surgery. However, only 3 studies could be included in this analysis. Both younger and older PD patients profit in QoL from STN-DBS, independent of the disease duration. Conclusions: The results of this analysis show an impressive improvement in QoL after STN-DBS, with a loss of QoL 60 months after DBS surgery. This highlights the need to explore the factors influencing QoL after STN-DBS to prevent or delay a decline in QoL.
Article
Background Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in Parkinson's disease (PD). Few studies have investigated the influence of the location of neurostimulation on NMS. Objective To investigate the impact of active contact location on NMS in STN-DBS in PD. Methods In this prospective, open-label, multicenter study including 50 PD patients undergoing bilateral STN-DBS, we collected NMSScale (NMSS), NMSQuestionnaire (NMSQ), Hospital Anxiety and Depression Scale (anxiety/depression, HADS-A/-D), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, motor complications, activities of daily living (ADL), and levodopa equivalent daily dose (LEDD) preoperatively and at 6 months follow-up. Changes were analyzed with Wilcoxon signed-rank/t-test and Bonferroni-correction for multiple comparisons. Although the STN was targeted visually, we employed an atlas-based approach to explore the relationship between active contact locations and DBS outcomes. Based on fused MRI/CT-images, we identified Cartesian coordinates of active contacts with patient-specific Mai-atlas standardization. We computed linear mixed-effects models with x-/y-/z-coordinates as independent, hemispheres as within-subject, and test change scores as dependent variables. Results NMSS, NMSQ, PDQ-8, motor examination, complications, and LEDD significantly improved at follow-up. Linear mixed-effect models showed that NMS and QoL improvement significantly depended on more medial (HADS-D, NMSS), anterior (HADS-D, NMSQ, PDQ-8), and ventral (HADS-A/-D, NMSS, PDQ-8) neurostimulation. ADL improved more in posterior, LEDD in lateral neurostimulation locations. No relationship was observed for motor examination and complications scores. Conclusions Our study provides evidence that more anterior, medial, and ventral STN-DBS is significantly related to more beneficial non-motor outcomes.
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Objective: The objective of this study was to investigate whether directional deep brain stimulation (DBS) of the subthalamic nucleus in Parkinson's disease (PD) offers increased therapeutic windows, side-effect thresholds, and clinical benefit. Methods: In 10 patients, 20 monopolar reviews were conducted in a prospective, randomized, double-blind design to identify the best stimulation directions and compare them to conventional circular DBS regarding side-effect thresholds, motor improvement, and therapeutic window. In addition, circular and best-directional DBS were directly compared in a short-term crossover. Motor outcome was also assessed after an open-label follow-up of 3 to 6 months. Results: Stimulation in the individual best direction resulted in significantly larger therapeutic windows, higher side-effect thresholds, and more improvement in hand rotation than circular DBS. Rigidity and finger tapping did not respond differentially to the stimulation conditions. There was no difference in motor efficacy or stimulation amplitudes between directional and circular DBS in the short-term crossover. Follow-up evaluations 3 to 6 months after implantation revealed improvements in motor outcome and medication reduction comparable to other DBS studies with a majority of patients remaining with a directional setting. Conclusion: Directional DBS can increase side-effect thresholds while achieving clinical benefit comparable to conventional DBS. Whether directional DBS improves long-term clinical outcome needs to be investigated in the future. © 2017 International Parkinson and Movement Disorder Society.
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Objective: The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinson's disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods: PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results: There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have "much" or "very much" improved CGIS. Conclusions: Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS.
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The benefit of deep brain stimulation (DBS) in controlling the motor symptoms of Parkinson’s disease is well established, however, the impact on the non-motor symptoms (NMS) remains to be elucidated, although the growing investigative efforts are promising. This article reviews the reported data and considers the level of evidence available with regard to the effect of DBS on NMS total burden and on the cognitive, neuropsychiatric, sleep, pain, dysautonomic, and weight domains. Multiple case series suggest that DBS improves the burden of NMS by reducing prevalence, intensity, and non-motor fluctuations. There is level I evidence on the effect of DBS on cognition and mood. Slight cognitive decline has been reported in most class I studies, although the functional effect is probably minimal. Two randomized prospective studies reported no change in depression while improvement of anxiety has been reported by a class I trial. Prospective cohort studies point to improvement of hyperdopaminergic behaviors, such as impulse control disorders, while others report that hypodopaminergic states, like apathy, can appear after DBS. There is only class III evidence supporting the benefit of DBS on other NMS such as nocturnal sleep, pain, dysautonomia (urinary, gastrointestinal, cardiovascular, and sweating), and weight loss. Although preliminary results are promising, randomized prospectively controlled trials with NMS as primary end points are necessary to further explore the effect of DBS on these often invalidating symptoms and offer conclusions about efficacy.
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Long-term impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) on health-related quality of life (HRQOL) and associated factors in patients with Parkinson’s disease (PD) are not clear. In this prospective study, we included 69 PD patients (64 % men, mean age 61.3 ± 7.4 and disease duration 13.2 ± 5.7 years) undergoing STN-DBS. They were evaluated preoperatively (baseline), 1 and 5 years postoperatively assessing 39-item Parkinson’s Disease Questionnaire (PDQ-39), Schwab and England Activities of Daily Living Scale (SEADL), Unified Parkinson’s Disease Rating Scale (UPDRS) off- and on-medication, patient diaries, dopaminergic treatment, mortality and surgical complications. Five years postoperatively, off-medication, there were improvements from baseline in UPDRS-II and III total (27.2 and 26.7 %, respectively) and SEADL (18.6 % more completely independent patients) (p < 0.05) scores, while on-medication, there was a deterioration in UPDRS-III (37.8 %, mainly axial signs) (p < 0.05) and minor improvements in SEADL (3.7 %). While at 1 year PDQ-39, the summary index improved substantially (36.5 %) (p < 0.05), at 5 years patients regressed (only 8.8 %) (p < 0.05), though changes in PDQ-39 subscores remained significant, with improvements in ADL (18.8 %), emotional well-being (19.0 %), stigma (36.4 %) and discomfort (20.6 %), despite worsening in communication (47.8 %) (p < 0.05). Lower preoperative PDQ-39 summary index and greater 1-year UPDRS-III-off total score gain predicted better long-term HRQOL. STN-DBS produces long-term improvements in HRQOL in PD. Preoperative HRQOL and short-term postoperative changes in off-medication motor status may predict long-term HRQOL in PD following STN-DBS.
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Parkinson’s disease (PD) is a common, degenerative disorder of the central nervous system. Individuals experience predominantly extrapyramidal symptoms including resting tremor, rigidity, bradykinesia, gait abnormalities, cognitive impairment, depression, and neurobehavioral concerns. Cognitive impairments associated with PD are diverse, including difficulty with attention, processing speed, executive functioning, memory recall, visuospatial functions, word-retrieval, and naming. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is FDA approved and has been shown to be effective in reducing motor symptoms of PD. Studies have found that stimulating STN and GPi are equally effective at improving motor symptoms and dyskinesias; however, there has been discrepancy as to whether the cognitive, behavioral, and mood symptoms are affected differently between the two targets. The present study used random-effects meta-analytic models along with a novel p-curve analytic procedure to compare the potential cognitive and emotional impairments associated with STN-DBS in the current literature to those associated with GPi-DBS. Forty-one articles were reviewed with an aggregated sample size of 1622 patients. Following STN-DBS, small declines were found in psychomotor speed, memory, attention, executive functions, and overall cognition; and moderate declines were found in both semantic and phonemic fluency. However, GPi-DBS resulted in fewer neurocognitive declines than STN-DBS (small declines in attention and small-moderate declines in verbal fluency). With regards to its effect on depression symptomatology, both GPi-DBS and STN-DBS resulted in lower levels of depressive symptoms post-surgery. From a neurocognitive standpoint, both GPi-DBS and STN-DBS produce subtle cognitive declines but appears to be relatively well tolerated.
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To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. clinicaltrials.gov Identifier: NCT01809613. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
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OBJECTIVE: To prospectively evaluate the effect of subthalamic nucleus deep brain stimulation (STN-DBS) on the different characteristics of pain and other nonmotor symptoms (NMS) in patients with Parkinson disease (PD). METHODS: Forty-four patients with PD and refractory motor symptoms were screened for STN-DBS. Patients were evaluated before and 1 year after surgery. The primary outcome was change in pain prevalence after surgery. Secondary outcome measures were changes in motor function (Unified Parkinson's Disease Rating Scale), characteristics of pain and other NMS using specific scales and questionnaires, and quality of life. RESULTS: Forty-one patients completed the study. The prevalence of pain changed from 70% to 21% after surgery (p < 0.001). There were also significant improvements in pain intensity, NMS, and quality of life after STN-DBS (p < 0.05). Dystonic and musculoskeletal pain responded well to DBS, while central pain and neuropathic pain were not influenced by surgery. There was a strong correlation between the change in pain intensity and the improvement in quality of life (r = 0.708, p < 0.005). No correlation was found between pain improvement and preoperative response to levodopa or motor improvement during stimulation (r = 0.247, p = 0.197 and r = 0.249, p = 0.193, respectively) or with changes in other NMS. CONCLUSIONS: STN-DBS decreased pain after surgery, but had different effects in different types of PD-related pain. Motor and nonmotor symptom improvements after STN-DBS did not correlate with pain relief. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with idiopathic PD with refractory motor fluctuations, STN-DBS decreases the prevalence of pain and improves quality of life. © 2014 American Academy of Neurology. PMID: 25217059 [PubMed - as supplied by publisher]
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Typical body weight changes are known to occur in Parkinson’s disease (PD). Weight loss has been reported in early stages as well as in advanced disease and malnutrition may worsen the clinical state of the patient. On the other hand, an increasing number of patients show weight gain under dopamine replacement therapy or after surgery. These weight changes are multifactorial and involve changes in energy expenditure, perturbation of homeostatic control, and eating behavior modulated by dopaminergic treatment. Comprehension of the different mechanisms contributing to body weight is a prerequisite for the management of body weight and nutritional state of an individual PD patient. This review summarizes the present knowledge and highlights the necessity of evaluation of body weight and related factors, as eating behavior, energy intake, and expenditure in PD.
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Changes in sensory function that have been described in patients with Parkinson disease (PD) can be either 'pure' disorders of conscious perception such as elevations in sensory threshold, or disorders of sensorimotor integration, in which the interaction between sensory input and motor output is altered. In this article, we review the extensive evidence for disrupted tactile, nociceptive, thermal and proprioceptive sensations in PD, as well as the influences exerted on these sensations by dopaminergic therapy and deep brain stimulation. We argue that abnormal spatial and temporal processing of sensory information produces incorrect signals for the preparation and execution of voluntary movement. Sensory deficits are likely to be a consequence of the dopaminergic denervation of the basal ganglia that is the hallmark of PD. A possible mechanism to account for somatosensory deficits is one in which disease-related dopaminergic denervation leads to a loss of response specificity, resulting in transmission of noisier and less-differentiated information to cortical regions. Changes in pain perception might have a different explanation, possibly involving disease-related effects outside the basal ganglia, including involvement of peripheral pain receptors, as well as structures such as the periaqueductal grey matter and non-dopaminergic neurotransmitter systems.
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It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
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To find predictors of cognitive decline and quality of life 1&emsp14;year after bilateral subthalamic nucleus deep brain stimulation (STN DBS) in Parkinson's disease (PD). A total of 105 patients were evaluated with a comprehensive neuropsychological assessment before and 12 months after surgery. A control group of 40 PD patients was included to control for effects of repeated testing and disease progression. The authors determined individual changes in cognition, mood and quality of life using a statistical method that controls for multiple comparisons, and performed logistic regression analyses to assess predictors of cognitive changes and quality of life. 12 months after surgery, the improvement in motor function was 41% (Unified Parkinson's Disease Rating Scale Part 3 score in off). The STN group showed a large improvement in quality of life compared with the control group (Cohen d=0.9). At the individual level, 32% (95% CI 22 to 40) of the STN group showed a substantial improvement in quality of life. 36% (95% CI 27 to 46) of the STN patients showed a profile of cognitive decline compared with the control group. Mood improved in 16 STN patients and declined in 16 subjects. Impaired attention, advanced age and a low l-dopa response at baseline predicted cognitive decline, whereas a high l-dopa response at baseline predicted an improvement in quality of life. Postoperative decrease in dopaminergic medication was not related to cognitive decline. STN DBS improves quality of life. However, a profile of cognitive decline can be found in a significant number of patients. l-dopa response, age and attention at baseline are predictors of cognitive and psychosocial outcome.
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to briefly outline the development and validation of the Parkinson's Disease Questionnaire (PDQ-39) and then to provide evidence for the use of the measure as either a profile of health status scores or a single index figure. the PDQ-39 was administered in two surveys: a postal survey of patients registered with local branches of the Parkinson's Disease Society of Great Britain (n = 405) and a survey of patients attending neurology clinics for treatment for Parkinson's disease (n = 146). Data from the eight dimensions of the PDQ-39 were factor-analysed. This produced a single factor on the data from both surveys. the eight dimensions of the PDQ-39 and the new single index score-the Parkinson's disease summary index (PDSI), together with clinical assessments (the Columbia rating scale and the Hoehn and Yahr staging score). in the postal survey 227 patients returned questionnaires (58.2%). AH 146 patients approached in the clinic sample agreed to take part. Higher-order principal-components factor analysis was undertaken on the eight dimensions of the PDQ-39 and produced one factor on both datasets. Consequently it was decided that the scores of the eight domains could be summed to produce a single index figure. The psychometric properties of this index were explored using reliability tests and tests of construct validity. The newly derived single index was found to be both internally reliable and valid. data from the PDQ-39 can be presented either in profile form or as a single index figure. The profile should be of value in studies aimed at determining the impact of treatment regimes upon particular aspects of functioning and well-being in patients with Parkinson's disease, while the PDSI will provide a summary score of the impact of the illness on functioning and well-being and will be of use in the evaluation of the overall effect of different treatments. Furthermore, the PDSI reduces the number of statistical comparisons and hence the role of chance when exploring data from the PDQ-39.
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To evaluate the sleep symptoms and polysomnographic architecture in advanced Parkinson's disease after chronic bilateral subthalamic stimulation (STN-DBS). Sleep was studied in 11 patients (six women and five men; mean (SD) age 63.6 (7.8) years) who underwent STN-DBS. Subjective sleep evaluation was assessed by clinical sleep interview and the Pittsburgh sleep quality index (PSQI) questionnaire, and sleep architecture by polysomnography with audiovisual recording. Nocturnal mobility was evaluated. Before surgery, eight patients rated their sleep quality as unsatisfactory; seven of these had a marked improvement after surgery, and the PSQI questionnaire showed significantly improved sleep quality. After surgery, polysomnography showed an increase in the longest period of uninterrupted sleep and a decrease in the arousal index. There was an increase in nocturnal mobility after surgery, but no change in REM sleep behaviour disorder. In advanced Parkinson's disease, chronic STN-DBS is associated with subjective improvement in sleep quality, probably through increased nocturnal mobility and reduction of sleep fragmentation.
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Although the short-term benefits of bilateral stimulation of the subthalamic nucleus in patients with advanced Parkinson's disease have been well documented, the long-term outcomes of the procedure are unknown. We conducted a five-year prospective study of the first 49 consecutive patients whom we treated with bilateral stimulation of the subthalamic nucleus. Patients were assessed at one, three, and five years with levodopa (on medication) and without levodopa (off medication), with use of the Unified Parkinson's Disease Rating Scale. Seven patients did not complete the study: three died, and four were lost to follow-up. As compared with base line, the patients' scores at five years for motor function while off medication improved by 54 percent (P<0.001) and those for activities of daily living improved by 49 percent (P<0.001). Speech was the only motor function for which off-medication scores did not improve. The scores for motor function on medication did not improve one year after surgery, except for the dyskinesia scores. On-medication akinesia, speech, postural stability, and freezing of gait worsened between year 1 and year 5 (P<0.001 for all comparisons). At five years, the dose of dopaminergic treatment and the duration and severity of levodopa-induced dyskinesia were reduced, as compared with base line (P<0.001 for each comparison). The average scores for cognitive performance remained unchanged, but dementia developed in three patients after three years. Mean depression scores remained unchanged. Severe adverse events included a large intracerebral hemorrhage in one patient. One patient committed suicide. Patients with advanced Parkinson's disease who were treated with bilateral stimulation of the subthalamic nucleus had marked improvements over five years in motor function while off medication and in dyskinesia while on medication. There was no control group, but worsening of akinesia, speech, postural stability, freezing of gait, and cognitive function between the first and the fifth year is consistent with the natural history of Parkinson's disease.
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To evaluate the reliability and validity of the Short Parkinson's Evaluation Scale (SPES)/SCales for Outcomes in Parkinson's disease (SCOPA)-a short scale developed to assess motor function in patients with Parkinson's disease (PD). Eighty five patients with PD were assessed with the SPES/SCOPA, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn and Yahr (H&Y) scale, and Schwab and England (S&E) scale. Thirty four patients were examined twice by two different assessors who were blinded to each other's scores and test executions. Additionally, six items of the motor section of the SPES/SCOPA were assessed in nine patients and recorded on videotape to evaluate inter-rater and intra-rater reliability. The reproducibility of the sum scores in the clinical assessments was high for all subscales of the SPES/SCOPA. Inter-rater reliability coefficients for individual items ranged from 0.27-0.83 in the motor impairment section, from 0.58-0.82 in the activities of daily living section, and from 0.65-0.92 in the motor complications section. Inter-rater reliability of the motor items in the video assessments ranged from 0.70-0.87 and intra-rater reliability ranged from 0.81-0.95. The correlation between related subscales of the SPES/SCOPA and UPDRS were all higher than 0.85, and both scales revealed similar correlations with other measures of disease severity. The mean time to complete the scales differed significantly (p<0.001) and measured 8.1 (SD 1.9) minutes for the SPES/SCOPA and 15.6 (SD 3.6) minutes for the UPDRS. The SPES/SCOPA is a short, reliable, and valid scale that can adequately be used in both research and clinical practice.
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The SCOPA-Motor Scale (S-MS) for assessment of Parkinson's disease (PD), contains 21 items in three domains: Motor examination, Disability, and Complications. Our objective was to validate the S-MS Spanish version. This validation study was based on a multicenter, cross-sectional, one-point-in-time evaluation design. The applied measures were: Unified Parkinson's Disease Rating Scale-3.0 (UPDRS); S-MS; PD Global Evaluation (PDGE); and Clinical Global Impression of severity (CGI). Completeness of data collection, floor and ceiling effect, internal consistency, precision, and construct and discriminative validity were analyzed in 151 PD patients. Scores from S-MS were fully computable. Floor effect was high for Complications (43.7%). Cronbach's alpha was > 0.90 for every domain, and item-total correlation was > 0.70 except for Examination. Standard error of measurement (SEM) ranged from 0.40 to 2.4. Convergent validity with corresponding UPDRS sections yielded coefficients > 0.90. Discriminative validity across Hoehn and Yahr (HY) and CGI stages was significant (Kruskal-Wallis, P < .0001). Insofar as internal consistency was concerned, alpha-values of the Examination sections were marginally higher for the UPDRS than for the S-MS (a finding perhaps accounted for by redundancy in this part of the UPDRS). The S-MS is a consistent and valid scale, shorter by almost half than the UPDRS.
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We investigated gender-differences in clinical phenomenology and response to deep brain stimulation (DBS) of the subthalamic nucleus (STN) in a group of patients with advanced Parkinson's disease (PD). Thirty-eight consecutive patients with PD (22 men and 16 women), bilaterally implanted for DBS of the STN, were evaluated 1 month before and 11 to 14 months after surgery. Gender differences in severity of the disease (HY and UPDRS), ability in the activities of daily living (ADL, UPDRS II), tremor and rigidity (UPDRS III), bradykinesia (UPDRS III and hand tapping test), levodopa-induced dyskinesias (LIDs, UPDRS IV), and levodopa equivalent daily dosage (LEDD) were analyzed before and after intervention. We found a predominantly male population, with no gender-related differences in age at onset, disease progression rate, or severity of disease. Nevertheless, women had more severe LIDs than men, only before the intervention. Bradykinesia was significantly less responsive to any kind of treatment (pharmacologic and neurosurgical) in women than in men. Finally, although STN-DBS induced similar total benefits in both genders, postoperative assessment suggested that the ADL improved more in women than in men. Women and men with advanced PD appear to differ in some clinical features and in response to dopaminergic and STN-DBS treatment.
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Chronic bilateral subthalamic stimulation leads to a spectacular clinical improvement in patients with motor complications. However, the post-operative body weight gain involved may limit the benefits of surgery and induce critical metabolic disorders. Twenty-four Parkinsonians (61.1 +/- 1.4 years) were examined 1 month before (M - 1) and 3 months after (M + 3) surgery. Body composition and energy expenditure (EE) were measured (1) over 36 h in calorimetric chambers (CC) with rigorous control of food intakes and activities [sleep metabolic rate, resting activities, meals, 3 or 4 sessions of 20 min on a training bicycle at 13 km/h and daily EE] and (2) in resting conditions (basal metabolic rate) during an acute L-dopa challenge (M - 1) or according to acute 'off' and 'on' stimulation (M + 3). Before surgery, EE was compared between the Parkinsonian patients and healthy subjects matched for height and body composition (metabolic rate during sleep, daily EE) or matched to predicted values (basal metabolic rate). Before surgery, in Parkinsonian men but not women, (1) daily EE was higher while sleep metabolic rate was lower compared to healthy matched men (+9.2 +/- 3.9 and -8.2 +/- 2.3%, respectively, P < 0.05) and (2) basal metabolic rate (L-dopa 'on') was higher than predicted basal metabolic rate (+11.5 +/- 4.0%, P < 0.05) but was further increased without L-dopa (+8.4 +/- 3.2% vs L-dopa 'on', P < 0.05). EE during daily activities was higher during 'off' periods compared to 'on' periods for both men (+19.3 +/- 3.3%, P < 0.0001) and women (+16.1 +/- 4.7%, P < 0.01). After surgery, there was a 3.4 +/- 0.6 kg (P < 0.0001) body weight increase together with fat mass (P < 0.0001) and fat-free mass (P < 0.05) in Parkinsonian men and a 2.6 +/- 0.8 kg (P < 0.05) body weight increase together with fat mass (P < 0.05) in Parkinsonian women. Sleep metabolic rate increased in men (+7.5 +/- 2.0%, P < 0.01) to reach control values but remained unchanged in women. Daily EE decreased significantly in both men and women (-7.3 +/- 2.2% and -13.1 +/- 1.7%, respectively, P < 0.01) but there was no correlation between daily EE changes and body weight gain. Parkinson's disease is associated with profound alterations in the central control of energy metabolism. Normalization of energy metabolism after DBS-STN implantation may favour body weight gain, of which quality was gender specific. As men gained primarily fat-free mass, a reasonable weight gain may be tolerated, in contrast with women who gained only fat. Other factors such as changes in free-living physical activity may help to limit body weight gain in some patients.
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In addition to motor symptoms, patients with Parkinson's disease (PD) show deficits in sensory processing. These deficits are thought to result from deficient gating of sensory information due to basal ganglia dysfunction in PD. Deep brain stimulation of the subthalamic nucleus (STN-DBS) has been shown to improve sensory deficits in PD, e.g. STN-DBS normalizes the perception of urinary bladder filling in patients with PD. This study aimed at investigating how STN-DBS modulates the processing of urinary bladder information to elucidate the (patho-)physiology of sensory gating mechanisms in PD. Nine PD patients with bilateral STN-DBS switched on (STN-DBS ON) or off (STN-DBS OFF) were studied during dynamic bladder filling and an empty bladder condition (for control), while changes in regional cerebral blood flow (rCBF) were measured by PET. Urinary bladder filling led to an increased rCBF in the periaqueductal grey (PAG), the posterior thalamus, the insular cortex as well as in the right frontal cortex and the cerebellum bilaterally. A significant interaction between bladder condition and STN-DBS was observed in the posterior thalamus and the insular cortex, with enhanced modulation of these areas during STN-DBS ON compared to STN-DBS OFF. Furthermore, regression analyses revealed a modulation of the neural activity in the thalamus and the insular cortex by the PAG activity during STN-DBS ON only. Thus, STN-DBS led to a significant enhancement of afferent urinary bladder information processing. The data suggest that STN-DBS facilitates the discrimination of different bodily states by supporting sensory perception and the underlying neural mechanisms. Furthermore, this is the first imaging study, which shows an effect of STN-DBS on sensory gating in PD patients and its neural basis.
Article
Background Subthalamic nucleus (STN) deep brain stimulation (DBS) improves quality of life (QoL), motor, and non-motor symptoms (NMS) in Parkinson's disease (PD). Few studies have investigated the influence of the location of neurostimulation on NMS. Objective To investigate the impact of active contact location on NMS in STN-DBS in PD. Methods In this prospective, open-label, multicenter study including 50 PD patients undergoing bilateral STN-DBS, we collected NMSScale (NMSS), NMSQuestionnaire (NMSQ), Hospital Anxiety and Depression Scale (anxiety/depression, HADS-A/-D), PDQuestionnaire-8 (PDQ-8), Scales for Outcomes in PD-motor examination, motor complications, activities of daily living (ADL), and levodopa equivalent daily dose (LEDD) preoperatively and at 6 months follow-up. Changes were analyzed with Wilcoxon signed-rank/t-test and Bonferroni-correction for multiple comparisons. Although the STN was targeted visually, we employed an atlas-based approach to explore the relationship between active contact locations and DBS outcomes. Based on fused MRI/CT-images, we identified Cartesian coordinates of active contacts with patient-specific Mai-atlas standardization. We computed linear mixed-effects models with x-/y-/z-coordinates as independent, hemispheres as within-subject, and test change scores as dependent variables. Results NMSS, NMSQ, PDQ-8, motor examination, complications, and LEDD significantly improved at follow-up. Linear mixed-effect models showed that NMS and QoL improvement significantly depended on more medial (HADS-D, NMSS), anterior (HADS-D, NMSQ, PDQ-8), and ventral (HADS-A/-D, NMSS, PDQ-8) neurostimulation. ADL improved more in posterior, LEDD in lateral neurostimulation locations. No relationship was observed for motor examination and complications scores. Conclusions Our study provides evidence that more anterior, medial, and ventral STN-DBS is significantly related to more beneficial non-motor outcomes.
Article
Background: The objective of this study was to investigate 24-month of effects of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on nonmotor symptoms in Parkinson's disease (PD). Methods: In this prospective, observational, multicenter, international study including 67 PD patients undergoing bilateral STN-DBS, we examined the Non-motor Symptom Scale, Non-Motor Symptoms Questionnaire, Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-motor examination, -activities of daily living, and -complications, and levodopa-equivalent daily dose preoperatively and at 5 and 24-month of follow-up. After checking distribution normality, longitudinal outcome changes were investigated with Friedman tests or repeated-measures analysis of variance and Bonferroni correction for multiple comparisons using multiple tests. Post hoc, Wilcoxon signed rank t tests were computed to compare visits. The strength of clinical responses was analyzed using effect size. Explorative Spearman correlations of change scores from baseline to 24-month follow-up were calculated for all outcomes. Results: The Non-motor Symptom Scale and all other outcome parameters significantly improved from baseline to the 5-month follow-up. From 5 to 24-month, partial decrements in these gains were found. Nonetheless, comparing baseline with 24-month follow-up, significant improvements were observed for the Non-motor Symptom Scale (small effect), Scales for Outcomes in PD-motor examination showed a moderate effect, and Scales for Outcomes in Parkinson's Disease-complications and levodopa-equivalent daily dose showed large effects. Non-motor Symptom Scale change scores from baseline to 24-month follow-up correlated significantly with Parkinson's Disease Questionnaire-8, Scales for Outcomes in Parkinson's Disease-activities of daily living, and -motor complications change scores. Conclusions: This study provides evidence of beneficial effects of bilateral STN-DBS on nonmotor symptoms at 24-month follow-up. The extent of nonmotor symptom improvement was directly proportionate to improvements in quality of life, activities of daily living, and motor complications. This study underlines the importance of nonmotor symptoms for holistic assessments of DBS outcomes. © 2017 International Parkinson and Movement Disorder Society.
Article
Objective: The optimal timing of subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) is a topic of ongoing debate. In patients with short disease duration an improvement of quality of life (QoL) has been demonstrated for patients aged younger than 61 years. However, this has not been systematically investigated in older patients yet. We hypothesized that patients aged 61 years or older experience a significant QoL improvement after STN-DBS with no difference in effect sizes for groups of patients with short and longer disease duration. Materials and methods: From four centers (Cologne, London, Manchester, Venice) we identified "older patients" aged 61 years or older with short (≤8 years) or longer disease duration and compared QoL, motor impairment, complications, medication requirements, and Mini-Mental State Examination (MMSE) on baseline and five months after surgery. Results: Mean age/disease duration in 21 subjects with shorter disease duration were 65.5/6.3 years compared to 66.8/14.6 in 33 subjects with longer disease duration. The short disease duration group was affected by less baseline motor complications (p = 0.002). QoL in the short/longer disease duration group improved by 35/20% (p = 0.010/p = 0.006), motor complications by 40/44% (p = 0.018/p < 0.001), and medication requirements by 51/49% (both p < 0.001). MMSE remained unchanged in both groups. Conclusion: Patients aged 61 years or older benefited from STN-DBS regardless of short (≤8 years) or longer (>8 years) disease duration. Our results contribute to the debate about DBS selection criteria and timing and call for prospective confirmation in a larger cohort.
Article
Objective: The purpose of this study was to investigate how quality of life outcome after bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in Parkinson's disease (PD) depends on age. Methods: In this prospective, open-label, multicenter study including 120 PD patients undergoing bilateral STN-DBS, we investigated the PDQuestionnaire-8 (PDQ-8), Unified PD Rating Scale-III, Scales for Outcomes in PD-motor examination, complications, activities of daily living, and levodopa equivalent daily dose preoperatively and at 5 months follow-up. Significant changes at follow-up were analyzed with Wilcoxon signed-rank test and Bonferroni correction for multiple comparisons. To explore the influence of age post hoc, the patients were classified into 3 age groups (≤59, 60-69, ≥70 years). Intragroup changes were analyzed with Wilcoxon signed-rank and intergroup differences with Kruskal-Wallis tests. The strength of clinical responses was evaluated using effect size. Results: The PDQuestionnaire-8, Scales for Outcomes in PD-motor complications, activities of daily living, and levodopa equivalent daily dose significantly improved in the overall cohort and all age groups with no significant intergroup differences. However, PDQuestionnaire-8 effect sizes for age groups ≤59, 60 to 69, and ≥70 years, respectively, were strong, moderate, and small. Furthermore, PDQuestionnaire-8 domain analyses revealed that all domains except cognition and emotional well-being significantly improved in patients aged ≤59 years, whereas only communication, activities of daily living, and stigma improved in patients aged 60-69 years, and activities of daily living and stigma in patients aged ≥70 years. Conclusions: Although quality of life, motor complications, and activities of daily living significantly improved in all age groups after bilateral STN-DBS, the beneficial effect on overall quality of life was more pronounced and affected a wider range of quality of life domains in younger patients. © 2017 International Parkinson and Movement Disorder Society.
Article
Background: It is vital for clinicians to understand and interpret correctly medical statistics as used in clinical studies. In this review, we address current issues and focus on delivering a simple, yet comprehensive, explanation of common research methodology involving receiver operating characteristic (ROC) curves. ROC curves are used most commonly in medicine as a means of evaluating diagnostic tests. Methods: Sample data from a plasma test for the diagnosis of colorectal cancer were used to generate a prediction model. These are actual, unpublished data that have been used to describe the calculation of sensitivity, specificity, positive predictive and negative predictive values, and accuracy. The ROC curves were generated to determine the accuracy of this plasma test. These curves are generated by plotting the sensitivity (true-positive rate) on the y axis and 1 - specificity (false-positive rate) on the x axis. Results: Curves that approach closest to the coordinate (x = 0, y = 1) are more highly predictive, whereas ROC curves that lie close to the line of equality indicate that the result is no better than that obtained by chance. The optimum sensitivity and specificity can be determined from the graph as the point where the minimum distance line crosses the ROC curve. This point corresponds to the Youden index (J), a function of sensitivity and specificity used commonly to rate diagnostic tests. The area under the curve is used to quantify the overall ability of a test to discriminate between 2 outcomes. Conclusion: By following these simple guidelines, interpretation of ROC curves will be less difficult and they can then be interpreted more reliably when writing, reviewing, or analyzing scientific papers.
Article
Background STN-DBS is well established to improve motor symptoms and quality of life in patients with PD. While non-motor symptoms are crucial for quality of life in these patients, only neuropsychiatric and neuropsychological symptoms have been systematically studied in a longitudinal design so far. However, these are only a part of the non-motor symptoms spectrum. Hypothesis We hypothesized that STN-DBS is associated with a beneficial effect on a range of non-motor symptoms. Methods In this multicenter, open, prospective, international study (EuroInf-study, UKCRN10084/DRKS00006735) we investigated non-motor effects of STN-DBS in “real-life” use. We evaluated Non-motor Symptom Scale, and Questionnaire, PD Questionnaire-8, Scales for Outcomes of PD motor examination and complications, and activities of daily living preoperatively and at 6 months follow-up in 60 consecutive patients (35 male, mean age: 61.6 ± 7.8 years, mean disease duration: 10.4 ± 4.2 years). Results All outcomes improved significantly at 6 months follow-up (PD Questionaire-8, p = 0.006; activities of daily living, p = 0.012; all others, p < 0.001; Wilcoxon signed-rank, respectively paired t-test; Bonferroni-correction). Post-hoc analyses of Non-motor Symptom Scale domains showed a significant reduction of sleep/fatigue and miscellaneous domains (p ≤ 0.001), perceptual problems/hallucinations (p = 0.036), and urinary (p = 0.018) scores. Effect sizes were “moderate” for Non-motor Symptom Scale, and motor complications, “large” for motor examination, and “small” for other outcomes. Conclusions This study provides evidence that bilateral STN-DBS improves non-motor burden in patients with PD and opens the door to a more balanced evaluation of DBS outcomes. Further randomized studies are needed to confirm these findings and compare DBS non-motor effects to other invasive therapies of advanced PD.