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Background: Parkinson's disease (PD) is associated with psychosocial distress that affects patients' quality of life. The distress thermometer (DT) is an 11-point visual analogue scale that is used as a screening tool for the assessment of psychosocial distress, originally developed for oncological diseases., Objectives: To validate the DT for PD and to explore contributing factors., Methods: The DT scale was administered to 105 people with Parkinson's Disease (PwPD). Along with it, we assessed motor symptoms (Unified Parkinson's Disease Rating Scale part III [UPDRS III], Hoehn and Yahr-stage [H&Y]), non-motor symptoms (Non-motor Symptom Questionnaire [NMSQ]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS], Fear of Progression-Questionnaire Short Form [FOP-Q-SF], Generalized Anxiety Disorder Scale-7 [GAD-7], 9-question Patient Health Questionnaire [PHQ-9]), the feeling of hope (Herth Hope Index [HHI]) and quality of life (Schedule for the Evaluation of Individual Quality of Life [SEIQoL])., Results: With a cut-off of 4, the DT identified PwPD with distress with a sensitivity of 97% and a specificity of 38%. With this cut-off, the DT will yield false negative results in 1 out of 100 cases. Factor analyses and a random forest regression of the dataset revealed that distress can be predicted by two factors, which we termed "anxiety" and "depression/resilience/motor symptoms"., Conclusion: The DT is an ultra-short and reliable screening tool for distress in PwPD. DT values below 4 rule out distress with a high degree of certainty. Anxiety and depression are important factors in distress but are counterbalanced by the individuals' psychological resilience., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

An important aim in long-term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co-administering it with inhibitors of peripheral dopa-decarboxylase and catechol-O-methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed-dose combinations as the branded formulation Stalevo ® (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual-enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient-years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non-dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance., (© 2023 The Author. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally., Methods: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years., Clinicaltrials: gov: NCT03043768., Results: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm 2 vs. 175 [68-200] mm 2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001)., Conclusions: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD). The long-term benefit in PD patients with STN-DBS in comparison to medical treatment (MT) alone has not yet been demonstrated conclusively., Objectives: To judge the long-term outcome of patients with STN-DBS., Methods: To assess the evolution of PD symptoms and health-related quality of life (HRQoL) after deep brain stimulation (DBS) surgery, we conducted a cross-sectional analysis of 115 patients with STN-DBS with rater-based scales and self-reported questionnaires. In addition, we screened records of all our STN-DBS patients (2001-2019, n = 162 patients) for the onset of the morbidity milestones (falls, hallucinations, dementia, and nursing home placement) to assess disability-free life expectancy., Results: In the first year of STN-DBS, levodopa equivalent dose was reduced and motor function improved. Nonmotor symptoms and cognition remained stable. These effects were similar to previous studies. Morbidity milestones occurred 13 ± 7 years after diagnosis. Motor function, cognition, and HRQoL significantly worsened after the occurrence of any milestone, confirming the clinical relevance of these milestones. After onset of the first milestone, mean survival time was limited to 5 ± 0.8 years, which is comparable with patients with PD but without STN-DBS., Conclusions: On average, PD patients with STN-DBS live with their disease for a longer time, and morbidity milestones occur later in the disease course than in PD patients with MT. As judged by morbidity milestones, morbidity remains compressed into the final 5 years of life in PD patients with STN-DBS., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: In Parkinson's disease, postural instability and falls are of particular socioeconomic relevance. Although effective fall prevention and the prophylaxis of fall-related injuries depend on low-threshold symptom monitoring, validated instruments are lacking., Objectives: To develop a self-report questionnaire for the assessment of falls, near falls, fear of falling, fall-related injuries, and causes of falls for patients with Parkinson's disease (PwPD)., Methods: A pool of potential items was generated from a literature review and by discussion in an expert panel. The first version of the Dresden Fall Questionnaire (DREFAQ) was tested in a group of German-speaking movement disorder specialists as well as PwPD. The resulting 5-item questionnaire was assessed in a validation cohort of 36 PwPD who documented fall events and near-fall events in a calendar for 3 months and completed the DREFAQ at the end of the study. The questionnaire was subsequently used in a separate cohort of 46 PwPD to determine test-retest reliability and confirm the factor structure., Results: The DREFAQ showed good internal consistency (Cronbach's α = 0.84) and good test-retest reliability (intraclass correlation coefficient, 0.76; 95% confidence interval, 0.60-0.86). The total DREFAQ score showed good concurrent validity with fall events (Spearman's ρ = 0.82) and near-fall events (Spearman's ρ = 0.78) as determined by fall and near-fall diaries. Factor analysis revealed a 2-factor structure composed of near falls with fear of falling and severe falls with injuries., Conclusions: The DREFAQ is a reliable and valid 5-item questionnaire for determining the incidence of falls, near falls, fear of falling, fall-related injuries, and causes of falls in PwPD., (© 2022 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of Movement Disorder Society.)

Background and Purpose: Hypothermia may be neuroprotective in acute ischemic stroke. Patients with anterior circulation large vessel occlusion (acLVO) are frequently hypothermic after endovascular therapy (EVT). We sought to determine whether this inadvertent hypothermia is associated with improved outcome., Methods: We extracted data of consecutive patients (January 2016 to May 2019) who received EVT for acLVO from our prospective EVT register of all patients screened for EVT at our tertiary stroke center. We assessed functional outcome at 3 months and performed multivariate analysis to calculate adjusted risk ratios (aRRs) for favorable outcome (modified Rankin Scale scores = 0-2) and mortality across patients who were hypothermic (<36°C) and patients who were normothermic (≥36°C to <37.6°C) after EVT. Moreover, we compared the frequency of complications between these groups., Results: Among 837 patients screened, 416 patients received EVT for acLVO and fulfilled inclusion criteria (200 [48.1%] male, mean age = 76 ± 16 years, median National Institutes of Health Stroke Scale score = 16, interquartile range [IQR] = 12-20). Of these, 209 patients (50.2%) were hypothermic (median temperature = 35.2°C, IQR = 34.7-35.7) and 207 patients were normothermic (median temperature = 36.4°C, IQR = 36.1-36.7) after EVT. In multivariate analysis, hypothermia was not associated with favorable outcome (aRR = 0.99, 95% confidence interval [CI] = 0.75-1.31) and mortality (aRR = 1.18, 95% CI = 0.84-1.66). More hypothermic patients suffered from pneumonia (36.4% vs. 25.6%, p = 0.02) and bradyarrhythmia (52.6% vs. 16.4%, p < 0.001), whereas thromboembolic events were distributed evenly (5.7% vs. 6.8%, not significant)., Conclusions: Inadvertent hypothermia after EVT for acLVO is not associated with improved functional outcome or reduced mortality but is associated with an increased rate of pneumonia and bradyarrhythmia in patients with acute ischemic stroke., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Recent observations linked coronavirus disease 2019 (COVID-19) to thromboembolic complications possibly mediated by increased blood coagulability and inflammatory endothelial impairment. We aimed to define the risk of acute stroke in patients with severe and non-severe COVID-19., Methods: We performed an observational, multicenter cohort study in four participating hospitals in Saxony, Germany to characterize consecutive patients with laboratory-confirmed COVID-19 who experienced acute stroke during hospitalization. Furthermore, we conducted a systematic review using PubMed/MEDLINE, Embase, Cochrane Library and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines including data from observational studies of acute stroke in COVID-19 patients. Data were extracted by two independent reviewers and pooled with multicenter data to calculate risk ratios (RRs) and 95% confidence intervals (95% CIs) for acute stroke related to COVID-19 severity using a random-effects model. Between-study heterogeneity was assessed using Cochran's Q and I 2 statistics. International Prospective Register of Systematic Reviews registration number: CRD42020187194., Results: Of 165 patients hospitalized for COVID-19 (49.1% males, median age = 67 years [57-79 years], 72.1% severe or critical) included in the multicenter study, overall stroke rate was 4.2% (95% CI: 1.9-8.7). Systematic literature search identified two observational studies involving 576 patients that were eligible for meta-analysis. Amongst 741 pooled COVID-19 patients, overall stroke rate was 2.9% (95% CI: 1.9-4.5). Risk of acute stroke was increased for patients with severe compared to non-severe COVID-19 (RR = 4.18, 95% CI: 1.7-10.25; P = 0.002) with no evidence of heterogeneity (I 2  = 0%, P = 0.82)., Conclusions: Synthesized analysis of data from our multicenter study and previously published cohorts indicates that severity of COVID-19 is associated with an increased risk of acute stroke., (© 2020 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Dopamine agonist withdrawal syndrome (DAWS) has been reported in patients with Parkinson's disease (PD) who rapidly decrease or stop their dopamine agonist (DA) treatment. Retrospective studies suggest a high prevalence of DAWS (14%-18%) in PD, but there are no prospective studies. We report data from the first pilot European multicenter prospective study addressing the frequency of probable DAWS (Rabinak-Nirenberg criteria) in PD patients. The self-completed Nonmotor Symptoms Questionnaire (which addresses the core features of DAWS) was administered at clinical follow-up at 1 month in 51 patients (33 male; mean age: 73.0 ± 9.9 years; PD duration: 12.2 ± 6.3 years) who had discontinued dopamine agonists. Twelve out of fifty-one patients (24%) met clinical criteria for DAWS, the most common symptoms of which were anxiety (91.7%), pain (50%), sweating (41.7%), and anhedonia (16.7%), after the withdrawal of a DA (ropinirole, pramipexole, or cabergoline). In this first prospective evaluation of DAWS in the clinic, preliminary data indicate a high rate after discontinuation of a range of DAs, particularly in the context of impulse control disorders. Larger, controlled studies are required to establish a definitive management pathway.

Background and Purpose: Dopamine agonists (DAs) are generally considered to be deprived of the highly dyskinetic effect of levodopa in Parkinson's disease (PD) patients. However, the risk for dyskinesia induced by DA monotherapy and the contribution of clinically significant factors in the development of this disorder have never been systematically assessed., Methods: A systematic literature search was conducted for randomized, levodopa-controlled trials of DAs in early PD. A meta-analysis was performed to calculate the combined odds ratio (OR) for dyskinesia. Meta-regressions were subsequently performed on dyskinesia OR including individually as covariates the effects of mean disease duration, treatment duration and DA dose. In an additional analysis the effect of adjunct levodopa on the odds for dyskinesia was investigated., Results: DA monotherapy resulted in an 87% lower risk for dyskinesia compared with treatment with levodopa (OR = 0.13, 95% confidence interval 0.09-0.19, P < 0.001). The risk for dyskinesia was independent of the dose of DA, disease duration and treatment duration. A dose-related pattern was revealed between adjunct levodopa in the DA group and dyskinesia. Nevertheless, the odds for dyskinesia in the DA group were constantly lower than in the levodopa group., Conclusion: Initial DA treatment encompasses a lower risk for dyskinesia even after the unavoidable introduction of levodopa that increases the risk for dyskinesia in a dose-related manner. As the dose and treatment duration with DAs are factors independent of the risk of dyskinesia, monotherapy with DAs in early PD is suggested at doses that ensure efficacy and delay the need for levodopa, always following an adequate evaluation of the risks DAs can pose in individual patients., (© 2013 The Author(s) European Journal of Neurology © 2013 EFNS.)

Phytanic acid alpha-oxidation was studied in cultures of skin fibroblasts and myoblasts from patients with various defects of the respiratory chain in order to obtain information on the subcellular site and the mechanism of this pathway. In fibroblasts from patients with complex IV (cytochrome c oxidase) deficiency or glutaricaciduria type II, phytanic acid alpha-oxidation was reduced to 14% of normal, whereas in myoblasts from patients with complex I (NADH-Q reductase) deficiency, it was normal. Apparently, at least one step of phytanic acid alpha-oxidation occurs in mitochondria and in this process electrons are transferred to the respiratory chain via the electron-transfer flavoprotein (ETF).