What predicts quality of life after subthalamic deep brain stimulation in Parkinson's disease? A systematic review.

BACKGROUND AND PURPOSE: Subthalamic deep brain stimulation (STN DBS) is an effective therapy against medication-refractory motor complications in patients with Parkinson's disease. However, it remains difficult to predict which baseline patient characteristics are associated with quality of life (QoL) after surgery. The objective was to identify preoperative factors associated with QoL after STN DBS by systematically reviewing publications of sufficient methodological quality. METHODS: Main databases were systematically searched up to March 2019 to identify studies that investigated factors associated with QoL after STN DBS in patients with idiopathic Parkinson's disease. RESULTS: In all, 869 studies were identified, of which 18 fulfilled the inclusion criteria. Higher QoL after DBS appears to be associated with a large preoperative difference between ON and OFF motor function in some studies, although there was no clear association of severity of motor function or motor complications with postoperative QoL. Lower severity of dyskinesias was associated with greater postoperative QoL improvement but has been insufficiently studied. Higher baseline QoL was suggestive of higher postoperative QoL. Four studies suggested that older age at surgery is associated with a lower improvement, although six other studies reported no association. No or limited evidence was found for cognitive impairment or psychiatric dysfunction. CONCLUSION: Various relative contraindications for STN DBS such as cognitive impairment and psychiatric dysfunction appear to be unrelated to postoperative QoL. However, the lack of clear correlations with disease-related variables suggests that QoL may be individually influenced by other factors, indicating that an ideal preoperative patient profile with regard to QoL improvement cannot be readily provided.

Onset and evolution of anxiety in Parkinson's disease.

BACKGROUND AND PURPOSE: Anxiety is common in Parkinson's disease (PD) and has a great influence on quality of life. However, little is known about risk factors for development of anxiety in PD. We investigated which factors were associated with longitudinal changes in severity of anxiety symptoms and development of future anxiety in patients who were not anxious at baseline. METHODS: Analyses were performed on data of the PROfiling PARKinson's disease (PROPARK) cohort, a 5-year hospital-based longitudinal cohort of over 400 patients with PD who have been examined annually. Linear mixed models were used to identify factors associated with longitudinal changes in Hospital Anxiety and Depression Scale - Anxiety (HADS-A) scores. Survival analysis using data of patients who were not anxious at baseline was performed to identify predictors of future anxiety (i.e. HADS-A ≥ 11). RESULTS: Of 409 patients who were included at baseline, 67 (16%) had anxiety, whereas 64 (19%) of the remaining 342 non-anxious patients developed anxiety after a mean (SD) follow-up of 2.6 (1.3) years. Seventy percent of the patients with anxiety were also depressed. Female gender, cognitive impairment, depressive symptoms, dysautonomia, insomnia and excessive daytime sleepiness (EDS) at baseline were associated with higher HADS-A scores over time and, except for female gender and EDS, all of these variables were independent predictors of development of anxiety in patients who were not anxious at baseline. CONCLUSIONS: Anxiety is highly prevalent in PD. Higher anxiety scores over time and future development of anxiety are associated with female gender, cognitive impairment, autonomic dysfunction, insomnia and EDS. Anxiety and depression usually coexist and share similar determinants, suggesting a common pathophysiological mechanism.

Multicentre randomized clinical trial to investigate the cost-effectiveness of an allogeneic single-donor fibrin sealant after coronary artery bypass grafting (FIBER Study).

BACKGROUND: Reduction of blood transfusion in cardiac surgery is an important target. The aim of this study was to investigate the cost-effectiveness of the use of CryoSeal®, an allogeneic single-donor fibrin sealant, in patients undergoing coronary artery bypass grafting (CABG). METHODS: This randomized clinical study involved seven cardiac surgery centres in the Netherlands. Patients undergoing elective isolated CABG with the use of at least one internal thoracic artery (ITA) graft were assigned randomly to receive either CryoSeal® (5 ml per ITA bed) or no CryoSeal®. Primary efficacy endpoints were units of transfused red blood cells, fresh frozen plasma and platelet concentrates, and duration of intensive care unit stay. Secondary efficacy endpoints were 48-h blood loss, reoperation for bleeding, mediastinitis, 30-day mortality and duration of hospital stay. RESULTS: Between March 2009 and January 2012, 1445 patients were randomized. The intention-to-treat (ITT) population comprised 1436 patients; the per-protocol (PP) population 1292. In both the ITT and the PP analysis, no significant difference between the treatment groups was observed for any of the primary and secondary efficacy endpoints. In addition, no significant difference between the groups was seen in the proportion of transfused patients. Estimated CryoSeal® costs were €822 (95 per cent c.i. €808 to €836) per patient, which translated to €72,000 per avoided transfusion (unbounded 95 per cent c.i.). CONCLUSION: The use of the fibrin sealant CryoSeal® did not result in health benefits. Combined with the high cost per avoided transfusion, this study does not support the implementation of routine CryoSeal® use in elective isolated CABG. REGISTRATION NUMBER: NTR1386 ( http://www.trialregister.nl).

Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson's disease: the LEAP-study.

BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857, EudraCT number 2011-000678-72.

[Risk factors for Parkinson's disease: possibilities for prevention and intervention]. / Risicofactoren voor de ziekte van Parkinson.

Considering age to be the primary risk factor for developing Parkinson's disease and the observation that the Dutch population is rapidly aging, the parkinson prevalence is expected to increase over the coming years, as there is still no cure available for the disease. This has been confirmed by epidemiological data, which show a steady increase of the disease prevalence in the Netherlands for the period 2010-2021. Genetic risk factors only partially explain the disease pathogenesis. Environmental factors, such as exposure to pesticides and trichloroethylene are associated with a higher risk for developing Parkinson's disease. Lifestyle factors such as exercise, caffeine intake and the Mediterranean diet are associated with a lower risk for developing the disease and possibly delay the disease progression. Policy makers and healthcare providers should employ stricter regulations for pesticide use and should stimulate a healthy lifestyle to slow down the increasing prevalence.

The observation of bleeding complications in haemato-oncological patients: stringent watching, relevant reporting.

BACKGROUND: The reported percentage of haemato-oncological patients experiencing bleeding complications is highly variable, ranging from 5 to 70%, posing a major problem for comparison of clinical platelet transfusion trials using bleeding complications as a primary endpoint. In a pilot study we assessed the impact of the design of scoring of bleeding on the percentage of patients with WHO grade 2 or higher bleeding grades. STUDY DESIGN AND METHODS: We performed a prospective, observational study using a rigorous bleeding observation system in thrombocytopenic patients with haemato-oncological disorders. Endpoints of the study were the percentage of patients and days with bleeding WHO grade ≥ 2 comparing designs in which skin bleeding represent a continuation of a previous bleed or a new bleed. RESULTS: In four participating hospitals 64 patients suffering 870 evaluable thrombocytopenic days (platelet count < 80 × 10(9) L(-1)) were included. At least one episode of bleeding grade ≥ 2 occurred in 36 patients (56%). Most grade 2 bleeding complications occurred mucocutaneously. The percentage of days with bleeding of grade ≥ 2 was 16% but decreases to 8% when only newly developed skin bleeding was included. CONCLUSION: Rigorous daily observation results in a bleeding incidence that is comparable to recent reportings applying the same method. The results of this study show that censoring for stable skin bleeding has a profound effect on bleeding incidence per day. The clinical relevance of rigorous or clinically judged bleeding scores as an endpoint remains to be defined.

Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease.

BACKGROUND: Levodopa initially provides good symptomatic control of the symptoms of Parkinson's disease, but motor complications often develop after long-term use. Other classes of antiparkinsonian drugs including dopamine agonists, catechol-O-methyl transferase inhibitors, or monoamine oxidase type B inhibitors are then added as adjuvant therapy. It is unclear whether one class of drug is more effective than another. This meta-analysis evaluates the comparative benefits and risks of these agents as adjuvant treatment in Parkinson's disease patients with motor complications. METHODS: A systematic review of the literature from 1966 to the end of June 2010 was conducted to identify randomized trials involving a dopamine agonist, catechol-O-methyl transferase inhibitor, or monoamine oxidase type B inhibitor versus placebo, as adjuvant to levodopa therapy. RESULTS: Forty-five trials involving nearly 9,000 participants were included. The meta-analysis confirms reports from individual trials that compared with placebo, adjuvant therapy significantly reduces patient off-time and levodopa dose, with improved symptom severity scores (e.g., Unified Parkinson's Disease Rating Scale). However, dyskinesia and numerous other side effects are increased with adjuvant therapy. Few randomized comparisons between drugs have been undertaken, but indirect comparisons suggest that dopamine agonist therapy may be more effective than catechol-O-methyl transferase inhibitor and monoamine oxidase type B inhibitor therapy, which have comparable efficacy. No differences between drugs within each class were observed other than the catechol-O-methyl transferase inhibitor tolcapone appearing more efficacious than entacapone. DISCUSSION: This meta-analysis highlights the need for direct head-to-head randomized trials to assess the impact of adjuvant therapy on patient-rated quality of life and health economic outcomes.

The effect of RBC transfusions on cytokine gene expression after cardiac surgery in patients developing post-operative multiple organ failure.

AIM: To determine the effect of red blood cell (RBC) transfusions during cardiac surgery on cytokine gene expression (GE) in relation to multiple organ failure (MOF) development after systemic inflammatory response syndrome (SIRS). BACKGROUND: RBC transfusion in cardiac surgery patients is dose-dependently associated with post-operative MOF, possibly acting as a second hit after cardiopulmonary bypass. METHODS: For this observational study, 29 patients divided into four groups of cardiac surgery patients were selected from a randomised controlled trial (RCT). Group 1: no-RBC, no-MOF (N = 8); group 2: MOF, no-RBC (N = 7); group 3: RBC, no-MOF (N = 6); group 4: RBC and MOF (N = 8). Selection was based on age, gender, number of (leukocyte-depleted) RBC transfusions, type and duration of surgery. A 114 cytokine GE array was applied to blood samples withdrawn before and 24 h after surgery. Expression of selected genes was confirmed with reverse transcriptase real time-polymerase chain reaction (RT-PCR). RESULTS: Nineteen of the 39 detectable genes showed a significant change in GE after surgery. Confirmed by RT-PCR, transfused MOF patients exhibit significantly less downregulation of CD40 ligand than control patients. Patients who would develop MOF show significantly larger increases in GE of transforming growth factor-α (TGF-α), tumour necrosis factor (TNF)-superfamily members 10 and 13B (TNFsf10/13B). CONCLUSIONS: When tested at 24 h after surgery, cytokine GE in peripheral blood leucocytes showed no significant differences between those transfused and those not transfused. Some alterations were seen in those developing MOF compared to those who did not, but the findings offer no role of leukocyte depleted (LD) RBC transfusion in the development of MOF.

Machine learning for automated EEG-based biomarkers of cognitive impairment during Deep Brain Stimulation screening in patients with Parkinson's Disease.

OBJECTIVE: A downside of Deep Brain Stimulation (DBS) for Parkinson's Disease (PD) is that cognitive function may deteriorate postoperatively. Electroencephalography (EEG) was explored as biomarker of cognition using a Machine Learning (ML) pipeline. METHODS: A fully automated ML pipeline was applied to 112 PD patients, taking EEG time-series as input and predicted class-labels as output. The most extreme cognitive scores were selected for class differentiation, i.e. best vs. worst cognitive performance (n = 20 per group). 16,674 features were extracted per patient; feature-selection was performed using a Boruta algorithm. A random forest classifier was modelled; 10-fold cross-validation with Bayesian optimization was performed to ensure generalizability. The predicted class-probabilities of the entire cohort were compared to actual cognitive performance. RESULTS: Both groups were differentiated with a mean accuracy of 0.92; using only occipital peak frequency yielded an accuracy of 0.67. Class-probabilities and actual cognitive performance were negatively linearly correlated (ß = -0.23 (95% confidence interval (-0.29, -0.18))). CONCLUSIONS: Particularly high accuracies were achieved using a compound of automatically extracted EEG biomarkers to classify PD patients according to cognition, rather than a single spectral EEG feature. SIGNIFICANCE: Automated EEG assessment may have utility for cognitive profiling of PD patients during the DBS screening.

No mutations in the voltage-gated NaV1.7 sodium channel alpha1 subunit gene SCN9A in familial complex regional pain syndrome.

BACKGROUND: Mutations in the voltage-gated Na(V)1.7 Na(+) channel alpha1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. METHODS: We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. RESULTS: No causal gene mutations were identified in the SCN9A gene in any of the patients. CONCLUSIONS: Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS.

Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI.

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Leucocyte depletion of perioperative blood transfusion does not affect long-term survival and recurrence in patients with gastrointestinal cancer.

BACKGROUND: Perioperative red blood cell (RBC) transfusion may be associated with a poor prognosis in cancer surgery. Allogeneic leucocytes are assumed to play a causal role. This study evaluated the long-term effect of transfusion with leucocyte-depleted (LD) blood in patients with gastrointestinal cancer. METHODS: The Transfusion Associated Complications = Transfusion Induced Complications? (TACTIC) study is a multicentre randomized controlled trial evaluating the short-term benefits of LD versus non-LD RBC transfusions. The present study evaluated 5-year survival and cancer recurrence among 512 patients with gastrointestinal cancer included in the TACTIC study. RESULTS: Some 89.2 per cent of patients had a primary tumour and 79.7 per cent underwent surgery with curative intent; 243 patients received perioperative RBC transfusion (median 3 units). The 5-year overall survival rate of patients with any type of gastrointestinal cancer was 50.8 per cent in the LD group and 45.8 per cent in the non-LD group (P = 0.191). Corresponding 5-year disease-free survival rates were 60.0 and 56.6 per cent (P = 0.482), and recurrence rates 32.9 and 34.3 per cent (P = 0.864). CONCLUSION: Leucocyte depletion is not associated with better long-term survival and lower recurrence rates in patients with gastrointestinal cancer.

Patterns of motor and non-motor features in Parkinson's disease.

OBJECTIVE: To evaluate the presence and nature of patterns of coherency among the motor and non-motor domains in Parkinson's disease (PD) and to examine which clinical parameters are related to the potential patterns. METHODS: A cohort of 397 patients with PD were randomly divided into two samples. Exploratory factor analysis (EFA) was performed on the motor and non-motor symptoms in PD in the first sample. Findings of the EFA were used to construct a model which was tested in the second sample by confirmatory factor analysis. Multiple regression analyses on the resulting factors were performed to evaluate the influence of clinical parameters on these factors. RESULTS: Four factors were identified. The first and strongest factor (cognitive impairment, autonomic dysfunction, psychotic symptoms, depression, daytime sleepiness and axial symptoms) reflected advancing disease. Another factor largely reflected motor complications of therapy and was related to dopaminergic medication. The other two factors reflected sleep/depression and tremor/bradykinesia/rigidity, and were only marginally related to disease severity or medication. CONCLUSIONS: The motor and non-motor features in PD can be characterised by four distinct patterns of coherency, which provide insight into the contributions of the primary disease process and antiparkinsonian medication to the broad clinical spectrum of PD. One factor, consisting of predominantly non-motor symptoms together with axial features, clearly reflected disease severity and may provide a new basis for monitoring disease progression in PD.

Selecting candidates for Deep Brain Stimulation in Parkinson's disease: the role of patients' expectations.

Patients with advanced Parkinson's Disease (PD) may be eligible for Deep Brain Stimulation (DBS) in case of medication-related motor fluctuations or tremor refractory to oral medication. However, several PD symptoms are unresponsive to DBS and constitute relative contra-indications for DBS. Patients referred for DBS undergo an eligibility screening during which motor functioning and contra-indications for surgery are assessed. During this pre-screening the potential benefits and drawbacks of surgery are discussed, together with patients' expectations of the results of DBS. Unrealistic expectations on the benefits of DBS may contribute to reduced patient satisfaction and poor clinical outcomes after surgery. The aim of this multicenter study (289 patients) was to assess the reasons for rejection after an outpatient-based pre-screening visit for DBS referrals, with particular emphasis on the role of patient expectations of DBS. The most frequent reason contributing to rejection was suboptimal oral treatment or satisfying symptom-control with oral medication (50% of rejections). Unrealistic expectations were identified in 38% of rejected patients and were the singular reason for rejection in 4%. Incorporating the assessment of unrealistic expectations increased the accuracy (Area Under the Curve) of determining DBS eligibility from 0.92 ((95% confidence interval (95%CI) 0.88-0.97) to 0.97 (95%CI 0.96-0.99). Patients' expectations of DBS are easily checked, and better education of patients and treating neurologists with regard to unrealistic expectations of this procedure may improve efficiency of referrals and avoid unnecessary stress and disappointments during screening.

Intraoperative test stimulation of the subthalamic nucleus aids postoperative programming of chronic stimulation settings in Parkinson's disease.

BACKGROUND: It is unknown whether intraoperative testing during awake Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) can be used to postoperatively identify the best settings for chronic stimulation. OBJECTIVE: To determine whether intraoperative test stimulation is indicative of postoperative stimulation results. METHODS: Records of consecutive Parkinson's Disease patients who received STN DBS between September 2012 and December 2017 were retrospectively analyzed. The best depth identified after intraoperative stimulation via the microelectrode's stimulation tip was compared with the depth of the contact selected for chronic stimulation after a standard monopolar contact review. Moreover, thresholds for induction of clinical effects (optimal improvement of rigidity and induction of side-effects) were compared between stimulation at the postoperatively selected contact and at the corresponding intraoperative depth. RESULTS: Records of 119 patients were analyzed (mean (SD) age 60.5 (6.5) years, 31.9% female, 238 STNs). In 75% of cases, the postoperatively selected contact corresponded with the intraoperative depth with the largest therapeutic window or was immediately dorsal to it. Higher stimulation intensities were required postoperatively than intraoperatively to relieve rigidity (p = 0.002) and induce capsular side-effects (p = 0.016). CONCLUSION: In the majority of cases, the postoperative contact for chronic stimulation was at a similar level or immediately dorsal with respect to the identified best intraoperative depth. Postoperatively, relief of rigidity and induction of capsular side-effects occur at higher stimulation intensities than during intraoperative test stimulation.

Stimulation challenge test after STN DBS improves satisfaction in Parkinson's disease patients.

OBJECTIVE: Although subthalamic Deep Brain Stimulation (STN DBS) is proven effective in improving symptoms of Parkinson's Disease (PD), previous literature demonstrates a discrepancy between objective improvement and patients' perception thereof. We aimed to examine whether postoperative stimulation challenge tests (SCT) alters patients' satisfaction after STN DBS for PD. METHODS: Fifty-four PD patients underwent preoperative levodopa challenge tests and were routinely invited for SCT 1-2 years postoperatively. SEverity of predominantly Nondopaminergic Symptoms in PD (SENS-PD) scores quantified non-dopaminergic disease severity. Motor functioning was quantified using Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores; a ratio between conditions ON and OFF (preoperative Med-ON vs. Med-OFF, and postoperative Med-ON/Stim-ON vs. Med-OFF/Stim-OFF) reflected treatment benefit. 'Global Impression of Change' (GIC) and 'Global Satisfaction with Surgery' (GSS) Likert scales were filled out before and immediately after SCT. RESULTS: Postoperative Med-ON/Stim-ON severity was lower than preoperative ON severity. Disease severity scores were not different between assessments. GIC and GSS scores were higher after SCT versus before (GIC: Z = -3.80, r = 0.37, subjects indicating maximum scores before SCT: 32.1%, after SCT: 57.1%; GSS: Z = -3.69, r = 0.35, maximum scores before SCT: 25.0%, after SCT: 46.4%). Higher non-dopaminergic disease severity was associated with lower GIC and GSS scores (GIC: OR 1.2 (95%CI 1.0-1.3); GSS: OR 1.2 (95%CI 1.1-1.3), while motor-scores and magnitude of DBS-effects were not. CONCLUSION: SCT improves patients' satisfaction and is recommended especially in case of suboptimal subjective valuations. This information should be considered in clinical practice and in the context of clinical trials.

A comprehensive model of health-related quality of life in Parkinson's disease.

BACKGROUND: Insight in how impairments and disabilities related to Parkinson's disease (PD) influence health-related quality of life (HRQoL) is required to review adequacy of current management strategies. METHODS: The Scales for Outcomes in Parkinson's disease (SCOPA) evaluation was used to assess impairments and disabilities. HRQoL was assessed with the EuroQol-5D Visual Analogue Scale. 378 patients with PD who participated in the SCOPA/PROPARK cohort were assessed while on their usual treatment. Multiple linear regression analysis and structural equation modelling were used to construct a model of factors that influence HRQoL. RESULTS: A model with good fit was constructed that identified various impairments and disabilities as important contributors to HRQoL in PD. Of the disabilities, psychosocial well-being had a larger impact on HRQoL than physical functioning. Of the impairments, depression had the largest contribution to HRQoL, followed by axial motor symptoms, gastrointestinal symptoms, and urinary symptoms. In addition, pain, psychiatric and motor complications, and daytime sleepiness had small but significant influences on HRQoL. CONCLUSION: Multiple factors, including disabilities, nonmotor symptoms and axial motor symptoms, affect HRQoL in patients with PD. In patients who are on symptomatic treatment aiming to alleviate mainly motor symptoms, there is a large impact on HRQoL of nonmotor and nondopaminergic symptoms. Research is warranted to develop and evaluate management strategies for the aspects that currently impact on HRQoL as psychosocial well-being, depressive symptoms, axial motor symptoms, gastrointestinal symptoms, and urinary symptoms. These findings call for a multidisciplinary approach in the care of these features.

Quantifying proprioceptive reflexes during position control of the human arm.

This study aimed to analyse the dynamic properties of the muscle spindle feedback system of shoulder muscles during a posture task. External continuous force disturbances were applied at the hand while subjects had to minimize their hand displacements. The results were analysed using two frequency response functions (FRFs) from which the model parameters were derived, being 1) the mechanical admittance and 2) the reflexive impedance. These FRFs were analysed by a neuromusculoskeletal model that implicitly separates the reflexive feedback properties (position, velocity and acceleration feedback gains) from intrinsic muscle visco-elasticity. The results show substantial changes in estimated reflex gains under conditions of variable bandwidth of the applied force disturbance or variable degrees of external damping. Position and velocity feedback gains were relatively larger when the force disturbance contained only low frequencies. With increasing damping of the environment, acceleration feedback gain decreased, velocity feedback gain remained almost constant and position feedback gain increased. It is concluded that under the aforementioned circumstances, the reflex system increases its gains to maximize the mechanical resistance to external force disturbances while preserving sufficient stability.

Dopamine agonist therapy in early Parkinson's disease.

BACKGROUND: Dopamine agonists are being used increasingly as first line treatment for Parkinson's disease, but there remains uncertainty about their clinical and cost-effectiveness relative to levodopa. OBJECTIVES: This meta-analysis aims to quantify more reliably the benefits and risks of dopamine agonists compared to placebo or levodopa in early Parkinson's disease. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library), MEDLINE, EMBASE, PubMed, LILACS and Web of Science, plus major journals in the field, abstract books, conference proceedings and reference lists of retrieved publications. SELECTION CRITERIA: Randomised trials comparing an orally administered dopamine agonist (with or without levodopa) versus placebo or levodopa or both placebo and levodopa in participants with early Parkinson's disease. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on clinician-rated disability, motor complications, other side-effects, treatment concordance, levodopa dose and mortality. MAIN RESULTS: Twenty-nine eligible trials, involving 5247 participants, were identified. Participants randomised to a dopamine agonist were less likely to develop dyskinesia (odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43 to 0.59; P < 0.00001), dystonia (OR 0.64, 95% CI 0.51 to 0.81; P = 0.0002) and motor fluctuations (OR 0.75, 95% CI 0.63 to 0.90; P = 0.002) than levodopa-treated participants. However, various 'non-motor' side-effects, including oedema (OR 3.68, 95% CI 2.62 to 5.18; P < 0.00001), somnolence (OR 1.49, 95% CI 1.12 to 2.00; P = 0.007), constipation (OR 1.59, 95% CI 1.11 to 2.28; P = 0.01), dizziness (OR 1.45, 95% CI 1.09 to 1.92; P = 0.01), hallucinations (OR 1.69, 95% CI 1.13 to 2.52; P = 0.01) and nausea (OR 1.32, 95% CI 1.05 to 1.66; P = 0.02) were all increased in agonist-treated participants (compared with levodopa-treated participants). Agonist-treated participants were also significantly more likely to discontinue treatment due to adverse events (OR 2.49, 95% CI 2.08 to 2.98; P < 0.00001). Finally symptomatic control of Parkinson's disease was better with levodopa than with agonists, but data were reported too inconsistently and incompletely to meta-analyse. AUTHORS' CONCLUSIONS: This meta-analysis confirms that motor complications are reduced with dopamine agonists compared to levodopa, but also establishes that other important side-effects are increased and symptom control is poorer with agonists. Larger, long-term comparative trials assessing patient-rated quality of life are needed to assess more reliably the balance of benefits and risks of dopamine agonists compared to levodopa.

Odour identification and discrimination in Dutch adults over 45 years.

OBJECTIVES: The aim of the study was to establish normative values for the two culture dependent components (odour identification and odour discrimination) of the "Sniffin' Sticks" test battery in the Dutch population over 45 years of age, and to assess the influence of age and sex on olfactory function in this population. METHODS: This study was performed in 150 healthy Dutch subjects (87 male and 63 female, mean age 59.2 years, range 45-78 years). Olfactory performance was assessed using the odour identification and discrimination parts of the "Sniffin' Sticks" test battery. RESULTS: In women, odour discrimination scores declined significantly with age, whereas there was no effect of age on odour discrimination performance in men. For odour identification, there were no effects of age or sex in this population. A moderate correlation was found between identification and discrimination test scores. CONCLUSION: Provisional population-specific normative data for olfactory testing using the identification and discrimination parts of the "Sniffin' Sticks" olfactory test battery have been established for the Dutch population over 45 years of age. The current data are applicable to the clinical evaluation of patients with olfactory disorders.