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Abstract Different stages of Parkinson’s disease (PD) are defined by clinical criteria, while late-stage PD is marked by the onset of morbidity milestones and rapid clinical deterioration. Based on neuropathological evidence, degeneration in the dopaminergic system occurs primarily in the early stage of PD, raising the question of what drives disease progression in late-stage PD. This study aimed to investigate whether late-stage PD is associated with increased neurodegeneration dynamics rather than functional decompensation using the blood-based biomarker serum neurofilament light chain (sNfL) as a proxy for the rate of neurodegeneration. The study included 118 patients with PD in the transition and late-stage (minimum disease duration 5 years, mean (SD) disease duration 15 (±7) years). The presence of clinical milestones (hallucinations, dementia, recurrent falls, and admission to a nursing home) and mortality were determined based on chart review. We found that sNfL was higher in patients who presented with at least one clinical milestone and increased with a higher number of milestones (Spearman’s ρ = 0.66, p

Background We studied the association of bridging intravenous thrombolysis (IVT) before thrombectomy for anterior circulation large‐vessel occlusion and functional outcome and scrutinized its dependence on grade of reperfusion and distal thrombus migration. Methods and Results We included consecutive patients with anterior circulation large‐vessel occlusion from our prospective registry of thrombectomy‐eligible patients treated from January 1, 2017 to January 1, 2023 at a tertiary stroke center in Germany in this retrospective cohort study. To evaluate the association of bridging IVT and functional outcome quantified via modified Rankin Scale score at 90 days we used multivariable logistic and lasso regression including interaction terms with grade of reperfusion quantified via modified Thrombolysis in Cerebral Infarction (mTICI) scale and distal thrombus migration adjusted for demographic and cardiovascular risk profiles, clinical and imaging stroke characteristics, onset‐to‐recanalization time and distal thrombus migration. We performed sensitivity analysis using propensity score matching. In our study population of 1000 thrombectomy‐eligible patients (513 women; median age, 77 years [interquartile range, 67–84]), IVT emerged as a predictor of favorable functional outcome (modified Rankin Scale score, 0–2) independent of modified mTICI score (adjusted odds ratio, 0.49 [95% CI, 0.32–0.75]; P=0.001). In those who underwent thrombectomy (n=812), the association of IVT and favorable functional outcome was reproduced (adjusted odds ratio, 0.49 [95% CI, 0.31–0.74]; P=0.001) and was further confirmed on propensity score analysis, where IVT led to a 0.35‐point decrease in 90‐day modified Rankin Scale score (ß=–0.35 [95 CI%, −0.68 to 0.01]; P=0.04). The additive benefit of IVT remained independent of modified mTICI score (ß=–1.79 [95% CI, −3.43 to –0.15]; P=0.03) and distal thrombus migration (ß=–0.41 [95% CI, −0.69 to –0.13]; P=0.004) on interaction analysis. Consequently, IVT showed an additive association with functional outcome in the subpopulation of patients undergoing thrombectomy who achieved successful reperfusion (mTICI ≥2b; ß=–0.46 [95% CI, −0.74 to –0.17]; P=0.002) and remained beneficial in those with unsuccessful reperfusion (mTICI ≤2a; ß=–0.47 [95% CI, −0.96 to 0.01]; P=0.05). Conclusions In thrombectomy‐eligible patients with anterior circulation large‐vessel occlusion, IVT improves functional outcome independent of grade of reperfusion and distal thrombus migration.

ObjectivePatients’ olfactory function after autoimmune encephalitis (AE) involving limbic structures may be impaired. This study aimed to characterize olfactory function in patients after autoimmune encephalitides.MethodsA case–control study was performed including 11 AE patients with antibodies against NMDAR (n = 4), GAD (n = 3), VGKC (n = 3) and antibody-negative AE (n = 1) and a control group of 12 patients with pneumococcal meningo-encephalitis (PC). In subgroup analyses, AE patients with and without NMDAR-antibodies were compared. Olfactory function was assessed using the Sniffin Sticks test and the resulting TDI-score (threshold, discrimination, identification). Involvement of limbic structures was evaluated on imaging data (MRI). Statistical analyses were performed to test for correlations of TDI-score and MRI results.ResultsThe overall olfactory function of the AE-group and the PC-group was comparable (mean TDI 32.0 [CI 27.3–36.7], 32.3 [CI 28.5–36.0)]. The proportions of hyposmic patients were similar compared to the general population. However, AE patients of the non-NMDAR group had significantly lower TDI-scores (28.9 ± 6,8) than NMDAR patients (37.4 ± 3.5) (p = 0.046) and a significantly lower discrimination capability than the NMDAR patients (9.9 ± 2.0 vs. 14.5 ± 0.6) (p = 0.002). The non-NMDAR patients had significantly more limbic MRI pathologies (6/7) compared to the NMDAR patients (0/4) (p = 0.015). Furthermore, a correlation between limbic MRI pathologies and worse capability of smelling discrimination was found (p = 0.016, r = −0.704, n = 11).ConclusionOur results indicate that patients with NMDAR autoimmune encephalitis have normal long term olfactory function. However, patients with non-NMDAR autoimmune encephalitis appear to have a persistently impaired olfactory function, probably mediated by encephalitic damage to limbic structures.

Parkinson's disease (PD) is characterized by a variety of motor and non-motor symptoms. As disease progresses, fluctuations in the response to levodopa treatment may develop, along with emergence of freezing of gait (FoG) and levodopa induced dyskinesia (LiD). The optimal management of the motor symptoms and their complications, depends, principally, on the consistent detection of their course, leading to improved treatment decisions. During the last few years, wearable devices have started to be used in the clinical practice for monitoring patients' PD-related motor symptoms, during their daily activities. This work describes the results of 2 multi-site clinical studies (PDNST001 and PDNST002) designed to validate the performance and the wearability of a new wearable monitoring device, the PDMonitor®, in the detection of PD-related motor symptoms. For the studies, 65 patients with Parkinson's disease and 28 healthy individuals (controls) were recruited. Specifically, during the Phase I of the first study, participants used the monitoring device for 2–6 h in a clinic while neurologists assessed the exhibited parkinsonian symptoms every half hour using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, as well as the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia severity assessment. The goal of Phase I was data gathering. On the other hand, during the Phase II of the first study, as well as during the second study (PDNST002), day-to-day variability was evaluated, with patients in the former and with control subjects in the latter. In both cases, the device was used for a number of days, with the subjects being unsupervised and free to perform any kind of daily activities. The monitoring device produced estimations of the severity of the majority of PD-related motor symptoms and their fluctuations. Statistical analysis demonstrated that the accuracy in the detection of symptoms and the correlation between their severity and the expert evaluations were high. As a result, the studies confirmed the effectiveness of the system as a continuous telemonitoring solution, easy to be used to facilitate decision-making for the treatment of patients with Parkinson's disease.

Abstract Deep brain stimulation (DBS) is a potent symptomatic therapy for Parkinson’s disease, but it is debated whether it causes or prevents neurodegeneration. We used serum neurofilament light chain (NFL) as a reporter for neuronal damage and found no difference between 92 patients with chronic STN-DBS and 57 patients on best medical treatment. Serum NFL transiently increased after DBS surgery whereas the initiation of STN stimulation did not affect NFL levels, suggesting that DBS surgery can be associated with neuronal damage whereas stimulation itself is not.

ObjectiveA total of 48% of patients with Parkinson's disease (PD) present symptoms of gastrointestinal dysfunction, particularly constipation. Furthermore, gastrointestinal tract (GIT)-related non-motor symptoms (NMSs) appear at all stages of PD, can be prodromal by many years and have a relevant impact on the quality of life. There is a lack of GIT-focused validated tools specific to PD to assess their occurrence, progress, and response to treatment. The aim of this study was to develop and evaluate a novel, disease- and symptom-specific, self-completed questionnaire, titled Gut Dysmotility Questionnaire (GDQ), for screening and monitoring gastrointestinal dysmotility of the lower GIT in patients with PD.MethodsIn phase 1, a systematic literature review and multidisciplinary expert discussions were conducted. In phase 2, cognitive pretest studies comprising standard pretests, interviews, and evaluation questionnaires were performed in patients with PD (n = 21), age- and sex-matched healthy controls (HC) (n = 30), and neurologists (n = 11). Incorporating these results, a second round of cognitive pretests was performed investigating further patients with PD (n = 10), age- and sex-matched HC (n = 10), and neurologists (n = 5). The questionnaire was adapted resulting in the final GDQ, which underwent cross-cultural adaptation to the English language.ResultsWe report significantly higher GDQ total scores and higher scores in five out of eight domains indicating a higher prevalence of gastrointestinal dysmotility in patients with PD than in HC (p < 0.05). Cognitive pretesting improved the preliminary GDQ so that the final GDQ was rated as relevant (100/100%), comprehensive (100/90%), easy to understand concerning questions and answer options (100/90%), and of appropriate length (80/100%) by neurologists and patients with PD, respectively. The GDQ demonstrated excellent internal consistency (Cronbach‘s alpha value of 0.94). Evidence for good construct validity is given by moderate to high correlations of the GDQ total score and its domains by intercorrelations (rs = 0.67–0.91; p < 0.001) and with validated general NMS measures as well as with specific items that assess gastrointestinal symptoms.InterpretationThe GDQ is a novel, easy, and quick 18-item self-assessment questionnaire to screen for and monitor gastrointestinal dysmotility with a focus on constipation in patients with PD. It has shown high acceptance and efficacy as well as good construct validity in cognitive pretests.

BackgroundParkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. ObjectiveThis study tested methods to assess usability and determined prerequisites for successful use in patients with PD. MethodsWe performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). ResultsIn this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and better motor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. ConclusionseHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder with both motor and non-motor symptoms. Despite the progressive nature of PD, early diagnosis, tracking the disease’s natural history and measuring the drug response are factors that play a major role in determining the quality of life of the affected individual. Apart from the common motor symptoms, i.e., tremor at rest, rigidity and bradykinesia, studies suggest that PD is associated with disturbances in eating behavior and energy intake. Specifically, PD is associated with drug-induced impulsive eating disorders such as binge eating, appetite-related non-motor issues such as weight loss and/or gain as well as dysphagia—factors that correlate with difficulties in completing day-to-day eating-related tasks. In this work we introduce Plate-to-Mouth (PtM), an indicator that relates with the time spent for the hand operating the utensil to transfer a quantity of food from the plate into the mouth during the course of a meal. We propose a two-step approach towards the objective calculation of PtM. Initially, we use the 3D acceleration and orientation velocity signals from an off-the-shelf smartwatch to detect the bite moments and upwards wrist micromovements that occur during a meal session. Afterwards, we process the upwards hand micromovements that appear prior to every detected bite during the meal in order to estimate the bite’s PtM duration. Finally, we use a density-based scheme to estimate the PtM durations distribution and form the in-meal eating behavior profile of the subject. In the results section, we provide validation for every step of the process independently, as well as showcase our findings using a total of three datasets, one collected in a controlled clinical setting using standardized meals (with a total of 28 meal sessions from 7 Healthy Controls (HC) and 21 PD patients) and two collected in-the-wild under free living conditions (37 meals from 4 HC/10 PD patients and 629 meals from 3 HC/3 PD patients, respectively). Experimental results reveal an Area Under the Curve (AUC) of 0.748 for the clinical dataset and 0.775/1.000 for the in-the-wild datasets towards the classification of in-meal eating behavior profiles to the PD or HC group. This is the first work that attempts to use wearable Inertial Measurement Unit (IMU) sensor data, collected both in clinical and in-the-wild settings, towards the extraction of an objective eating behavior indicator for PD.

Abstract Parkinson’s disease (PD) is diagnosed when patients exhibit bradykinesia with tremor and/or rigidity, and when these symptoms respond to dopaminergic medications. Yet in the last years there was a greater recognition of additional aspects of the disease including non-motor symptoms and prodromal states with associated pathology in various regions of the nervous system. In this review we discuss current concepts of two major alterations found during the course of the disease: cytoplasmic aggregates of the protein α-synuclein and the degeneration of dopaminergic neurons. We provide an overview of new approaches in this field based on current concepts and latest literature. In many areas, translational research on PD has advanced the understanding of the disease but there is still a need for more effective therapeutic options based on the insights into the basic biological phenomena.

Abstract Background Hepatitis E infection affects over 20 million people worldwide. Reports of neurological manifestations are largely limited to the peripheral nervous system. We report a middle-aged genotype 3c male patient with acute hepatitis E virus (HEV) infection and severe neurological deficits with evidence of multiple disseminated inflammatory lesions of the central nervous system. Case presentation A 42-year-old male patient presented to our emergency department with musculoskeletal weakness, bladder and bowel retention, blurred vision and ascending hypoesthesia up to the level of T8. Serology showed elevated liver enzymes and positive IgM-titers of hepatitis E. Analysis of cerebrospinal fluid (CSF) showed mild pleocytosis and normal levels of glucose, lactate and protein. HEV-RNA-copies were detected in the CSF and stool. Within 3 days after admission the patient became paraplegic, had complete visual loss and absent pupillary reflexes. MRI showed inflammatory demyelination of the optic nerve sheaths, multiple subcortical brain regions and the spinal cord. Electrophysiology revealed axonal damage of the peroneal nerve on both sides with absent F-waves. Treatment was performed with methylprednisolone, two cycles of plasma exchange (PLEX), one cycle of intravenous immunoglobulins (IVIG) and ribavirin which was used off-label. Liver enzymes normalized after 1 week and serology was negative for HEV-RNA after 3 weeks. Follow-up MRI showed progressive demyelination and new leptomeningeal enhancement at the thoracic spine and cauda equina 4 weeks after admission. Four months later, after rehabilitation was completed, repeated MRI showed gliotic transformation of the spinal cord without signs of an active inflammation. Treatment with rituximab was initiated. The patient remained paraplegic and hypoesthesia had ascended up to T5. Nevertheless, he regained full vision. Conclusions Our case indicates a possible association of acute HEV infection with widespread disseminated central nervous system inflammation. Up to now, no specific drugs have been approved for the treatment of acute HEV infection. We treated our patient off-label with ribavirin and escalated immunomodulatory therapy considering clinical progression and the possibility of an autoimmune response targeting nerve cell structures. While response to treatment was rather limited in our case, detection of HEV in patients with acute neurological deficits might help optimize individual treatment strategies.

Abstract Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p

Identification of individual risk factors for motor complications in Parkinson’s disease (PD) can help to guide personalised medical treatment, particularly since treatment options are still limited. To determine whether common functional gene polymorphisms in the dopamine metabolism predict the onset of motor complications in PD, we performed a retrospective, observer-blinded follow-up study of 30 PD patients who underwent genotyping of dopa-decarboxylase (DDC; rs921451), monoamine oxidase B (MAOB; rs1799836), catechol-O-methyltransferase (COMT; rs4680), and dopamine transporter (DAT; variable number tandem repeat) polymorphisms. Onset of wearing-off and dyskinesias was determined by blinded clinical assessments. Predictive values of genotypes for motor complications were evaluated using Cox proportional hazard models. During a median follow-up time of 11.6 years, 23 (77%) of 30 PD patients developed wearing-off, 16 (53%) dyskinesias, and 23 (77%) any motor complication. The MAOB (rs1799836) polymorphism predicted development of dyskinesias with MAOBCC/(C)/CT genotypes (resulting in low/intermediate brain enzyme activity) being associated with lower hazard ratios (unadjusted HR [95% CI]: 0.264 [0.089–0.787]; p=0.012; adjusted HR [95% CI]: 0.142 [0.039–0.520]; p=0.003) than MAOBTT/(T) genotypes (resulting in high brain enzyme activity). DDC (rs921451), COMT (rs4680), and DAT (VNTR) polymorphisms were not predictive of motor complications. Together, the MAOB (rs1799836) polymorphism predicts the development of dyskinesias in PD patients. Our results need confirmation in larger cohorts. If confirmed, individual assessment of this polymorphism might be helpful for early risk stratification and could comprise a step towards patient-tailored therapeutic strategies to prevent or delay motor complications in the course of PD.

Background: While intravenous thrombolysis (IVT) in ischemic stroke can be safely applied in telestroke networks within 3 h from symptom onset, there is a lack of evidence for safety in the expanded 3- to 4. 5-h time window. We assessed the safety and short-term efficacy of IVT in acute ischemic stroke (AIS) in the expanded time window delivered through a hub-and-spoke telestroke network.Methods: Observational study of patients with AIS who received IVT at the Stroke Eastern Saxony Telemedical Network between 01/2014 and 12/2015. We compared safety data including symptomatic intracerebral hemorrhage (sICH; according to European Cooperative Acute Stroke Study II definition) and any intracerebral hemorrhage (ICH) between patients admitted to telestroke spoke sites and patients directly admitted to a tertiary stroke center representing the hub of the network. We also assessed short-term efficacy data including favorable functional outcome (i.e., modified Rankin Scale ≤ 2) and National Institutes of Health Stroke Scale (NIHSS) at discharge, hospital discharge disposition, and in-hospital mortality.Results: In total, 152 patients with AIS were treated with IVT in the expanded time window [spoke sites, n = 104 (26.9%); hub site, n = 48 (25.9%)]. Patients treated at spoke sites had less frequently a large vessel occlusion [8/104 (7.7) vs. 20/48 (41.7%); p < 0.0001], a determined stroke etiology (p < 0.0001) and had slightly shorter onset-to-treatment times [210 (45) vs. 228 (58) min; p = 0.02] than patients who presented to the hub site. Both cohorts did not display any further differences in demographics, vascular risk factors, median baseline NIHSS scores, or median baseline Alberta stroke program early CT score (p > 0.05). There was no difference in the frequency of sICH (4.9 vs. 6.3%; p = 0.71) or any ICH (8.7 vs. 16.7%; p = 0.15). Neither there was a difference regarding favorable functional outcome (44.1 vs. 39.6%; p = 0.6) nor median NIHSS [3 (5.5) vs. 2.5 (5.75); p = 0.92] at discharge, hospital discharge disposition (p = 0.28), or in-hospital mortality (9.6 vs. 8.3%; p = 1.0). Multivariable modeling did not reveal an association between telestroke and sICH or favorable functional outcome (p > 0.05).Conclusions: Delivery of IVT in the expanded 3- to 4.5-h time window through a telestroke network appears to be safe with equivalent short-term functional outcomes for spoke-and-hub center admissions.

Background: Neuroprotective and neurorestorative effects have been postulated for selective serotonin-reuptake inhibitors (SSRI). We hypothesized that sertraline, which is characterized by less severe adverse effects and more stable pharmacokinetics than classic SSRI, is associated with improved functional recovery in acute ischemic stroke patients with motor deficits.Methods: Prospective observational study of consecutive acute ischemic stroke patients who received sertraline for clinically suspected post-stroke depression (PSD) or at high risk for PSD. Eligibility comprised acute motor deficit caused by ischemic stroke (≥2 points on NIHSS motor items) and functional independence pre-stroke (mRS ≤1). Decision to initiate treatment with SSRI during hospital stay was at the discretion of the treating stroke physician. Patients not receiving sertraline served as control group. Favorable functional recovery defined as mRS ≤2 was prospectively assessed at 3 months. Multivariable logistic regression analysis was used to explore the effects of sertraline on 3-months functional recovery. Secondary outcomes were frequency of any and incident PSD (defined by BDI ≥10) at 3 months.Results: During the study period (03/2017–12/2018), 114 patients were assigned to sertraline (n = 72, 62.6%) or control group (n = 42, 37.4%). At study entry, patients in sertraline group were more severely neurologically affected than patients in the control group (NIHSS: 8 [IQR, 5–11] vs. 5 [IQR, 4–7]; p = 0.002). Also, motor NIHSS scores were more pronounced in sertraline than in control group (4 [IQR 2–7] vs. 2 [IQR 2–4], p = 0.001). After adjusting for age and baseline NIHSS, multivariable regression analysis revealed a significant association between sertraline intake and favorable functional outcome at 3 months (OR 3.10, 95% CI 1.02–9.41; p = 0.045). There was no difference between both groups regarding the frequency of any depression at 3 months (26/53 [49.1%] vs. 14/28 [50.0%] patients, p = 0.643, BDI ≥10). However, fewer incident depressions were observed in sertraline group patients compared to patients in control group (0/53 [0%] vs. 5/28 [17.9%] patients, p = 0.004).Conclusions: In this non-randomized comparison, early treatment with sertraline tended to favor functional recovery in patients with acute ischemic stroke. While exploratory in nature, this hypothesis needs further investigation in a clinical trial.

Abstract Background Non‐motor symptoms (NMS) are integral to Parkinson's Disease (PD) and management remains a challenge. Safinamide is a novel molecule in relation to addressing NMS due to its multifocal mechanism of action with both dopaminergic and non‐dopaminergic properties. Objective To investigate the efficacy of safinamide on NMS and its burden in PD patients with motor fluctuations after 6 months of treatment. Methods This observational, multicenter, open‐label, pilot study assessed a wide range of NMS using the following rating scales, NMSS (non‐motor symptom scale), KPPS (King's PD pain scale), HADS (hospital anxiety and depression scale), PDQ‐8 (Parkinson's disease quality of life questionnaire), and PDSS‐2 (Parkinson's disease sleep scale), EuroQol‐5D 3 level version (EQ‐5D‐3L), CGI‐I (clinical global impression of improvement), and PGI‐C (patient global impression of change). Motor examination using UPDRS part III (Unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) and Hoehn and Yahr staging were also obtained. Results 27 patients were included in the analysis and were evaluated at baseline and ≥ 6 months after safinamide treatment. 26 patients had a daily maintenance dose of 100 mg and 1 patient a daily dose of 50 mg. Significant improvements in UPDRS IV, KPPS item 5 (region‐specific “off” dystonia), KPPS domain 3 (items 4–6, fluctuation related pain) and KPPS total score were observed after treatment with safinamide, while maintaining stable dopaminergic medication. No statistically significant differences were found in NMSS, HADS, PDSS‐2, EQ‐5D‐3L, and PDQ‐8 after treatment. Conclusions Our results suggest that safinamide may have a beneficial effect on pain, a key unmet need in fluctuating PD patients.

An amendment to this paper has been published and can be accessed via the original article.

Abstract Objective To develop and validate a novel 14‐item self‐completed questionnaire (in English and German) enquiring about the presence of non‐motor symptoms (NMS) during the past month in patients with craniocervical dystonia in an international multicenter study. Methods The Dystonia Non‐Motor Symptoms Questionnaire (DNMSQuest) covers seven domains including sleep, autonomic symptoms, fatigue, emotional well‐being, stigma, activities of daily living, sensory symptoms. The feasibility and clinimetric attributes were analyzed. Results Data from 194 patients with CD (65.6% female, mean age 58.96 ± 12.17 years, duration of disease 11.95 ± 9.40 years) and 102 age‐ and sex‐matched healthy controls (66.7% female, mean age 55.67 ± 17.62 years) were collected from centres in Germany and the UK. The median total NMS score in CD patients was 5 (interquartile range 3–7), significantly higher than in healthy controls with 1 (interquartile range 0.75–2.25) (P

Abstract Background The clinical effect of copper accumulation on the heart of patients suffering from Wilson’s disease (WD) is not completely understood. We aimed to determine if patients with WD show signs of cardiac involvement, structural heart disease or autonomic dysfunction. In this prospective trial, we studied 61 patients (mean age 44.3 ± 15.2 years, 51% males) with WD and compared them to 61 age- and gender-matched healthy controls. All subjects underwent clinical examination, blood tests, echocardiography and 24 h electrocardiographic (ECG) recording. Results Left- and right ventricular systolic function did not differ significantly between WD patients and controls. However, 5 of the 61 patients had a reduced left ventricular ejection fraction (LVEF). Furthermore, diastolic dysfunction was more prevalent in WD patients (9 of 61 vs. 0 of 61, p = 0.001). The severity of WD based on the Unified Wilson’s Disease Rating Scale was significantly correlated to NT-pro BNP (r = 0.34, P = 0.013). Patients with an exacerbation of WD in medical history had higher troponin levels compared to those without (11.3 ± 4.7 vs 4.6 ± 1.2). The autonomic function assessed by triangular index (TI) and SDNN-index was significantly reduced in WD patients compared to controls in most in almost every age category (p-value TI and SDNN: age 20–29, p

Background: Neurocardiac dysfunction worsens clinical outcome and increases mortality in stroke survivors. We hypothesized that heart rate variability (HRV) biofeedback improves neurocardiac function by modulating autonomic nervous system activity after acute ischaemic stroke (AIS).Methods: We randomly allocated (1:1) 48 acute ischaemic stroke patients to receive nine sessions of HRV- or sham biofeedback over 3 days in addition to comprehensive stroke unit care. Before and after the intervention patients were evaluated for HRV via standard deviation of normal-to-normal intervals (SDNN, primary outcome), root mean square of successive differences between normal heartbeats (RMSSD), a predominantly parasympathetic measure, and for sympathetic vasomotor and sudomotor function. Severity of autonomic symptoms was assessed via survey of autonomic symptom scale total impact score (TIS) at baseline and after 3 months.Results: We included 48 patients with acute ischaemic stroke [19 females, ages 65 (4.4), median (interquartile range)]. Treatment with HRV biofeedback increased HRV post intervention [SDNN: 43.5 (79.0) ms vs. 34.1 (45.0) ms baseline, p = 0.015; RMSSD: 46.0 (140.6) ms vs. 29.1 (52.2) ms baseline, p = 0.015] and alleviated autonomic symptoms after 3 months [TIS 3.5 (8.0) vs. 7.5 (7.0) baseline, p = 0.029], which was not seen after sham biofeedback (SDNN: p = 0.63, RMSSD: p = 0.65, TIS: 0.06). There were no changes in sympathetic vasomotor and sudomotor function (p = ns).Conclusions: Adding HRV biofeedback to standard stroke unit care led to improved neurocardiac function and sustained alleviation of autonomic symptoms after acute ischaemic stroke, which was likely mediated by a predominantly parasympathetic mechanism.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03865225.

ObjectiveHopelessness and depression are strongly associated with suicidality. Given that physical and psychological outcomes can be altered with hope, hope is a therapeutic goal of increasing importance in the treatment of brain tumor patients. Moreover, it is not yet understood which factors affect the perception of hope in brain tumor patients. In addition, it remains uncertain whether lower-grade brain tumor patients suffer less from psycho-oncological distress than higher-grade brain tumor patients.MethodsNeuro-oncological patients were examined perioperatively with the Distress Thermometer (DT) and the Herth Hope Index (HHI). In addition, psychological comorbidities (anxiety GAD-2, depression PHQ-2) and an assessment of general psycho-oncological distress were recorded.ResultsSixty-six brain tumor patients were included (median age 53 years, 35% higher-grade brain tumors, i.e., WHO grade III/IV). No differences between higher- and lower-grade brain tumor patients were observed for general psycho-oncological distress and hope. However, higher-grade brain tumor patients showed a significantly higher level of depression (p ≤ 0.001) and more negative expectations regarding therapeutic success (H = 4.873, p ≤ 0.050). The extent of depression correlated negatively with hope.ConclusionUnexpectedly, higher-grade brain tumor patients remained as hopeful as lower-grade brain tumor patients despite the devastating diagnosis, higher levels of depression, and a worse expectation of therapeutic success. Conversely, lower-grade brain tumor patients experience as much psycho-oncological distress as patients with a higher-grade brain tumor, underpinning the imperative need for comprehensive psycho-oncological screening. For all brain tumor patients, considering hope is important to avoid suicides resulting from hopelessness and depression.

Background: We hypothesized that autotitrating bilevel positive airway pressure (auto-BPAP) favorably affects short-term clinical outcomes in hyperacute ischemic stroke.Methods: In a multicenter, randomized, controlled trial patients with large vessel steno-occlusive stroke and clinically suspected sleep apnea were allocated to auto-BPAP or standard stroke care alone. Auto-BPAP was initiated within 24 h from stroke onset and performed over 48 h during diurnal and nocturnal sleep. Sleep apnea was assessed using cardiorespiratory polygraphy. Primary endpoint was early neurological improvement on National Institutes of Health Stroke Scale (NIHSS) score at 72 h. Safety and tolerability of BPAP, functional independence [modified Rankin Scale (mRS) 0–2], stroke recurrence, and mortality at 90 days were assessed.Results: Due to low recruitment, the trial was prematurely stopped after 24 patients had been randomized (auto-BPAP, n = 14; control, n = 10): median baseline NIHSS 13 (5.5–18), 88% large vessel occlusion, and 12% large vessel stenosis. Polygraphy confirmed sleep apnea in 64% of auto-BPAP and 88% of control patients (p = 0.34). Adherence to auto-BPAP was achieved by 9 of the 14 (64%) patients. Between auto-BPAP and control patients, no differences were observed in early neurological improvement (median NIHSS change: −2.0, IQR = 7 points vs. −0.5, IQR = 3 points), 90 days functional independence (21 vs. 30%, p = 0.67), stroke recurrence (0 vs. 20%, p = 0.16), and death (14 vs. 20%, p = 1.0). No safety concerns were identified.Conclusions: In this prematurely terminated trial, auto-BPAP was safe but did not show an effect on short-term clinical outcomes in selected ischemic stroke patients. Its tolerability, however, may be limited in hyperacute stroke care and needs to be improved before larger trials are conducted.Clinical Trial Registration:ClinicalTrials.gov, identifier: NCT01812993.

Introduction: Our goal was to investigate whether biomarkers of cerebral damage are found in autoimmune-mediated epilepsy (AIE) and whether these can differentiate AIE from other seizure disorders.Methods: We retrospectively searched our cerebrospinal fluid (CSF) database for patients with definite AIE, hippocampal sclerosis due to other causes (HS), genetic generalized epilepsy (GGE), and psychogenic, non-epileptic seizures (PNES). We measured serum and CSF tau, neurofilament 1 (NFL), glial fibrillary acid protein (GFAP), and ubiquitin-carboxy-terminal hydrolase L1 with a single-molecule array.Results: We identified suitable samples from patients with AIE (n = 13) with different antibodies and compared them to HS (n = 13), GGE (n = 7), and PNES (n = 8). The NFL levels were significantly elevated in the serum (p = 0.0009) and CSF (p < 0.0019) of AIE patients. The AIE group was significantly older, while the disease duration was significantly shorter than in the control groups. NFL correlated significantly with age in all groups, and the NFL levels of AIE patients were hardly higher than those of healthy elderly people published elsewhere.Conclusions: Our data indicate that the elevated NFL levels in AIE patients are most likely due to the higher age in this group and not due to the underlying inflammation. Unless larger prospective studies with intra-individual, longitudinal analyses and treatment responses would contradict our findings, NFL in serum might yet become a biomarker for disease activity and differential diagnosis.

Parkinson's disease (PD) is known to involve the peripheral nervous system (PNS) and the enteric nervous system (ENS). Functional changes in PNS and ENS appear early in the course of the disease and are responsible for some of the non-motor symptoms observed in PD patients like constipation, that can precede the appearance of motor symptoms by years. Here we analyzed the effect of the pesticide rotenone, a mitochondrial Complex I inhibitor, on the function and neuronal composition of the ENS by measuring intestinal contractility in a tissue bath and by analyzing related protein expression. Our results show that rotenone changes the normal physiological response of the intestine to carbachol, dopamine and electric field stimulation (EFS). Changes in the reaction to EFS seem to be related to the reduction in the cholinergic input but also related to the noradrenergic input, as suggested by the non-adrenergic non-cholinergic (NANC) reaction to the EFS in rotenone-exposed mice. The magnitude and direction of these alterations varies between intestinal regions and exposure times and is associated with an early up-regulation of dopaminergic, cholinergic and adrenergic receptors and an irregular reduction in the amount of enteric neurons in rotenone-exposed mice. The early appearance of these alterations, that start occurring before the substantia nigra is affected in this mouse model, suggests that these alterations could be also observed in patients before the onset of motor symptoms and makes them ideal potential candidates to be used as radiological markers for the detection of Parkinson's disease in its early stages.

Human-Computer Interaction (HCI) and games set a new domain in understanding people’s motivations in gaming, behavioral implications of game play, game adaptation to player preferences and needs for increased engaging experiences in the context of HCI serious games (HCI-SGs). When the latter relate with people’s health status, they can become a part of their daily life as assistive health status monitoring/enhancement systems. Co-designing HCI-SGs can be seen as a combination of art and science that involves a meticulous collaborative process. The design elements in assistive HCI-SGs for Parkinson’s Disease (PD) patients, in particular, are explored in the present work. Within this context, the Game-Based Learning (GBL) design framework is adopted here and its main game-design parameters are explored for the Exergames, Dietarygames, Emotional games, Handwriting games, and Voice games design, drawn from the PD-related i-PROGNOSIS Personalized Game Suite (PGS) (www.i-prognosis.eu) holistic approach. Two main data sources were involved in the study. In particular, the first one includes qualitative data from semi-structured interviews, involving 10 PD patients and four clinicians in the co-creation process of the game design, whereas the second one relates with data from an online questionnaire addressed by 104 participants spanning the whole related spectrum, i.e., PD patients, physicians, software/game developers. Linear regression analysis was employed to identify an adapted GBL framework with the most significant game-design parameters, which efficiently predict the transferability of the PGS beneficial effect to real-life, addressing functional PD symptoms. The findings of this work can assist HCI-SG designers for designing PD-related HCI-SGs, as the most significant game-design factors were identified, in terms of adding value to the role of HCI-SGs in increasing PD patients’ quality of life, optimizing the interaction with personalized HCI-SGs and, hence, fostering a collaborative human-computer symbiosis.

BackgroundSleep disturbances and impairment of cognitive function are among the most frequent non-motor symptoms in Parkinson’s disease (PD) with negative implications on quality of life of patients and caregivers. Despite the fact that sleep disturbances are a major issue in PD patients, only limited data are available regarding interactions of sleep disturbances and cognitive performance.ObjectiveThis post hoc analysis of the RaSPar trial was therefore designed to further elucidate sleep disturbances and their impact on cognition in PD.MethodsTwenty-six PD patients with sleep disturbances were evaluated thoroughly including assessments of patients’ subjective and objective sleep quality by interview, questionnaires, and polysomnography (PSG). Cognitive performance was assessed by Parkinson Neuropsychometric Dementia Assessment (PANDA) and Test of Attentional Performance (TAP), and associations of sleep and cognitive function were evaluated.ResultsWe did not detect differences in cognitive performance between patients with and without rapid eye movement (REM) sleep behavior disorder (RBD). Instead, cognitive impairment, particularly affecting cognitive domains attention, executive function/working memory, and semantic memory, was associated with impaired PSG-measured sleep quality (e.g., sleep efficiency) and sleep disordered breathing (SDB) (Apnea-Hypopnea Index > 5/h). Global cognitive performance was decreased in patients with SDB (PANDA score 23.2 ± 3.5 vs. 26.9 ± 2.2, P = 0.020, unpaired two-sided t-test).ConclusionSleep apnea and other sleep disturbances impair cognitive performance in PD and should be evaluated in routine care, and treatment options such as continuous airway pressure therapy should be considered.

Being the second most common neurodegenerative disease, Parkinson's disease (PD) can be symptomatically treated, although, unfortunately, it cannot be cured yet. Moreover, diagnosing and assessing PD patients is a complex process, requiring continuous monitoring. In this vein, the design, development, and validation of innovative assessment tools may be helpful in the management of patients with PD, in particular. Based on intelligent ICT interventions, the i-PROGNOSIS project intends to mitigate PD's specific symptoms, such as neurological movement disorders of gait, balance, coordination, and posture, already characterized in the early phase of the disease. From this perspective, an innovative iPrognosis motor assessment tool is presented here, taking into consideration the Unified Parkinson Disease Rating Scale (UPDRS) Part III motor skills testing items, for evaluating the motor skills status. The efficiency of the proposed Assessment Tests to reflect the motor skills status, similarly to the UPDRS Part III items, was validated via 27 participants (18 males; mean age = 62 years, SD = 10.36 years; range, 43–79 years) with early (n = 10) and moderate (n = 17) PD who performed the Assessment Tests. Features from the latter were then correlated with the corresponding clinically assessed UPDRS Part III items, and statistically significant negative correlations (range, −0.364 to −0.802) were identified between the median values of the Assessment Tests and the UPDRS Part III items. In this vein, the iPrognosis Assessment Tests were integrated within the personalized interventions of the i-PROGNOSIS project, providing alternative means of assessing their effect on the PD patient's motor skills enhancement. The promising results presented here elaborate on the concept of using ICT-based assessment means to achieve comparable outcomes with the clinical standards in motor skills assessment.

We aimed to assess how evidence-based stroke care changed over the two waves of the COVID-19 pandemic. We analyzed acute stroke patients admitted to a tertiary care hospital in Germany during the first (2 March 2020–9 June 2020) and second (23 September 2020–31 December 2020, 100 days each) infection waves. Stroke care performance indicators were compared among waves. A 25.2% decline of acute stroke admissions was noted during the second (n = 249) compared with the first (n = 333) wave of the pandemic. Patients were more frequently tested SARS-CoV-2 positive during the second than the first wave (11 (4.4%) vs. 0; p < 0.001). There were no differences in rates of reperfusion therapies (37% vs. 36.5%; p = 1.0) or treatment process times (p > 0.05). However, stroke unit access was more frequently delayed (17 (6.8%) vs. 5 (1.5%); p = 0.001), and hospitalization until inpatient rehabilitation was longer (20 (1, 27) vs. 12 (8, 17) days; p < 0.0001) during the second compared with the first pandemic wave. Clinical severity, stroke etiology, appropriate secondary prevention medication, and discharge disposition were comparable among both waves. Infection control measures may adversely affect access to stroke unit care and extend hospitalization, while performance indicators of hyperacute stroke care seem to be untainted.

Abstract Background Moderate hypothermia after decompressive surgery might not be beneficial for stroke patients. However, normothermia may prove to be an effective method of enhancing neurological outcomes. The study aims were to evaluate the application of a pre-specified normothermia protocol in stroke patients after decompressive surgery and its impact on temperature load, and to describe the functional outcome of patients at 12 months after treatment. Methods We analysed patients with space-occupying middle cerebral artery (MCA) infarction treated with decompressive surgery and a pre-specified temperature management protocol. Patients treated primarily with device-controlled normothermia or hypothermia were excluded. The individual temperature load above 36.5 °C was calculated for the first 96 h after hemicraniectomy as the Area Under the Curve, using °C x hours. The effect of temperature load on functional outcome at 12 months was analysed by logistic regression. Results We included 40 stroke patients treated with decompressive surgery (mean [SD] age: 58.9 [10.1] years; mean [SD] time to surgery: 30.5 [16.7] hours). Fever (temperature > 37.5 °C) developed in 26 patients during the first 96 h after surgery and mean (SD) temperature load above 36.5 °C in this time period was 62,3 (+/− 47,6) °C*hours. At one year after stroke onset, a moderate to moderately severe disability (modified Rankin Scale score of 3 or 4) was observed in 32% of patients, and a severe disability (score of 5) in 37% of patients, respectively. The lethality in the cohort at 12 months was 32%. The temperature load during the first 96 h was not an independent predictor for 12 month lethality (OR 0.986 [95%-CI:0.967–1.002]; p

Abstract We aimed to explore the effects of bilateral subthalamic nucleus stimulation and levodopa on cardiovascular autonomic function in Parkinson’s disease. Twenty-six Parkinson’s disease patients with bilateral subthalamic nucleus stimulation in a stable state were tested under stimulation off and dopaminergic medication off (OFF-OFF), stimulation on and dopaminergic medication off (ON-OFF), and stimulation on and medication (levodopa) on (ON-ON) conditions by recording continuously blood pressure, ECG, and respiration at rest, during metronomic deep breathing, and head-up tilt test. Thirteen patients were diagnosed as orthostatic hypotension by head-up tilt test. Baroreflex sensitivity and spectral analyses were performed by trigonometric regressive spectral analysis. Subthalamic nucleus stimulation and levodopa had multiple influences. (1) Systolic blood pressure during tilt-up was reduced by subthalamic nucleus stimulation, and then further by levodopa. (2) Subthalamic nucleus stimulation and levodopa had different effects on sympathetic and parasympathetic regulations in Parkinson’s disease. (3) Levodopa decreased baroreflex sensitivity and RR interval only in the orthostatic hypotension group, and had opposite effects on the non-orthostatic hypotension group. These findings indicate that subthalamic nucleus stimulation and levodopa have different effects on cardiovascular autonomic function in Parkinson’s disease, which are modulated by the presence of orthostatic hypotension as well.

Background: The optimal sedative regimen with general anesthesia (GA) or conscious sedation for patients undergoing endovascular therapy (EVT) remains controversial. Apart from sedative regimen, the duration of anesthetic exposure may affect clinical outcomes. We aimed to determine whether there is an association between anesthetic exposure time and clinical outcomes in mechanically ventilated stroke patients undergoing EVT for large vessel occlusion.Methods: This was an observational study of consecutive ischemic stroke patients who underwent EVT for anterior circulation large vessel occlusion under GA from January 2016 to March 2018. To minimize confounding by indication, we restricted our analysis to patients whose anesthetic exposure lasted

Background: Cerebral venous drainage might influence brain edema characteristics and functional outcome of patients with severe ischemic stroke. The purpose of the study was to evaluate whether hypoplasia of transverse sinuses or the internal jugular veins is associated with poor functional outcome in patients with space-occupying middle cerebral artery (MCA) infarction who underwent decompressive surgery.Methods: We performed a retrospective analysis of patients with space-occupying MCA infarction treated with decompressive surgery at our university hospital. The transverse sinuses and the internal jugular veins were evaluated on baseline images and categorized as normal, hypoplastic or occluded. We defined composite variables for ipsilateral, contralateral or any abnormal cerebral venous drainage. We assessed the functional outcome at 12 months with the modified Rankin scale (mRS) score and defined poor functional outcome as mRS scores 5 and 6.Results: We analyzed 88 patients with available baseline imaging data [mean [SD] patient age 53 (±9) years; median[IQR] time to decompressive surgery 31(22-51) h]. At 12 months 44 patients (50%) had a poor outcome. In univariate analysis neither ipsilateral (OR 1.98;95%CI: 0.75–5.40), nor contralateral (OR 1.56;95%CI: 0.59–4.24) or any (OR 1.6; 95%CI: 0.68–3.79) hypoplasia or occlusion of venous drainage were significantly associated with poor functional outcome. In multivariate analyses, higher patient age (OR 1.07;95%CI 1.01–1.14) and baseline stroke severity (OR 3.42;95%CI 1.31–9.40) were independent predictors of poor functional outcome, but not ipsilateral hypoplasia or occlusion of venous drainage (OR 1.31;95%CI 0.47–3.67).Conclusions: The cerebral venous drainage pattern was not significantly associated with poor functional outcome in our cohort of patients with space-occupying MCA infarction who underwent decompressive surgery.

Background: The diagnostic value of cerebrospinal fluid (CSF) analysis in juvenile stroke, i.e., stroke in young adult patients, is not well studied. We sought to determine the therapeutic impact of routine CSF-analysis in young adults with acute ischemic stroke or transient ischemic attack (TIA).Methods: We abstracted data from patients with acute cerebral ischemia aged 18–45 years who were consecutively admitted to our stroke center between 01/2008 and 12/2015. We routinely performed CSF-analysis in patients with hitherto unknown stroke etiology after complete diagnostic work up. We assessed the frequency and underlying causes of abnormal CSF-findings and their impact on secondary stroke prevention therapy.Results: Among 379 patients (median [IQR:IQR3-IQR1] age 39 [10:43-33] years, 48% female) with acute ischemic stroke (n = 306) or TIA (n = 73), CSF analysis was performed in 201 patients (53%). Of these, 25 patients (12.4 %) had CSF pleocytosis (leucocyte cell count ≥ 5 Mpt/L), that was rated as non-specific (e.g., traumatic lumbar puncture, reactive pleocytosis) in 22 patients. Only 3 patients (1.5% of all patients who underwent CSF-analysis) with CSF-pleocytosis had specific CSF-findings that were related to stroke etiology and affected secondary stroke prevention therapy. Imaging findings had already suggested cerebral vasculitis in two of these patients.Conclusions: The diagnostic yield of routine CSF-analysis in juvenile stroke was remarkably low in our study. Our data suggest that CSF-analysis should only be performed if further findings raise the suspicion of cerebral vasculitis.

Objectives: Wilson's disease is reported to have autonomic dysfunction, but comprehensive evaluation of autonomic function is lacking. Additionally, little is known about the change of autonomic function of Wilson's disease during continuous therapy. We assumed that patients with Wilson's disease had both sympathetic and parasympathetic autonomic impairments, and the autonomic dysfunction might be stable across a 3-year follow-up after years of optimal treatment.Methods: Twenty-six patients with Wilson's disease and twenty-six healthy controls were recruited. Twenty patients in the Wilson's disease group were examined again after a 3-year follow-up. All the participants were evaluated by a questionnaire on dysautonomia symptoms, 24-h blood pressure and heart rate monitoring, and cardiovascular autonomic function examination in various conditions including at rest, deep breathing, Valsalva maneuver, isometric handgrip test and passive tilting. Baroreflex sensitivity and spectral analyses were performed via trigonometric regressive spectral analysis.Results: Patients with Wilson's disease showed autonomic dysfunction mainly in the following aspects: (1) the heart rate was higher than the controls. (2) Valsalva ratio was lower in patients with Wilson's disease compared with the controls. (3) Heart rate increase during isometric hand gripping was smaller in the Wilson's disease patients than the controls. (4) Baroreflex sensitivity was lower during nearly all the cardiovascular autonomic function examinations compared with healthy controls. When tested 3 years later, baroreflex sensitivity at rest decreased compared with baseline. (5) There were mild declines of resting DBP and low frequency component of heart rate variability during the follow-up examination compared with baseline. (6) Subgroup analysis showed that patients initially presenting with neurological symptoms had a higher night-time heart rate, lower expiration: inspiration RR interval ratio (E/I ratio), lower expiration: inspiration RR interval difference (E-I difference), less increase of heart rate and diastolic blood pressure during the handgrip test, and lower baroreflex sensitivity during deep breathing than the control group. (7) Correlation analysis showed that the severity of neurological symptoms was associated with E/I ratio, E-I difference, Valsalva ratio, heart rate change during the handgrip test, and baroreflex sensitivity during deep breathing.Conclusions: The present study reveals cardiovascular autonomic dysfunction involving both sympathetic and parasympathetic branches in Wilson's disease patients, which is especially significant in the patients with neurological onset. Autonomic function is generally stable undergoing optimal maintenance treatment in patients with Wilson's disease. Though there might be mild changes of specific parameters.

BackgroundIn Parkinson’s disease (PD), alpha-synuclein accumulation in cutaneous autonomic pilomotor and sudomotor nerve fibers has been linked to autonomic nervous system disturbances even in the early stages of the disease. This study aims to assess the association between alpha-synuclein-mediated structural autonomic nerve fiber damage and function in PD, elucidate the role of neuropathy progression during the early disease stages, and test reproducibility and external validity of pilomotor function assessment using quantitative pilomotor axon-reflex test and sudomotor function via quantitative direct and indirect test of sudomotor function.Methods/designA prospective controlled study will be conducted at four study sites in Europe and the USA. Fifty-two male and female patients with idiopathic PD (Hoehn and Yahr 1–2) and 52 age- and sex-matched healthy controls will be recruited. Axon-reflex-mediated pilomotor erection will be induced by iontophoresis of phenylephrine on the dorsal forearm. Silicone impressions of the response will be obtained, scanned, and quantified for pilomotor muscle impressions by number, impression size, and area of axon-reflex spread. Axon-reflex-mediated sweating following acetylcholine iontophoresis will be quantified for number and size of droplets and axon-reflex spread. Sympathetic skin responses, autonomic and motor symptoms will be evaluated. Tests will be performed at baseline, after 2 weeks, 1, 2, and 3 years. Skin biopsies will be obtained at baseline and after 3 years and will be analyzed for nerve fiber density and alpha-synuclein accumulation.DiscussionWe anticipate that progression of autonomic nerve dysfunction assessed via pilomotor and sudomotor axon-reflex tests is related to progression of autonomic symptom severity and alpha-synuclein deposition. Potential applications of the techniques include interventional studies evaluating disease-modifying approaches and clinical assessment of autonomic dysfunction in patients with PD.Clinical trail registrationTRN NCT03043768.

In patients with Parkinson’s disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson’s disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.

Effective management and development of new treatment strategies for response fluctuations in advanced Parkinson's disease (PD) largely depends on clinical rating instruments such as the PD home diary. The Parkinson's kinetigraph (PKG) measures movement accelerations and analyzes the spectral power of the low frequencies of the accelerometer data. New algorithms convert each hour of continuous PKG data into one of the three motor categories used in the PD home diary, namely motor Off state and On state with and without dyskinesia.To compare quantitative motor state assessment in fluctuating PD patients using the PKG with motor state ratings from PD home diaries.Observational cohort study on 24 in-patients with documented motor fluctuations who completed diaries by rating motor Off, On without dyskinesia, On with dyskinesia, and asleep for every hour for 5 consecutive days. Simultaneously collected PKG data (recorded between 6 am and 10 pm) were analyzed and calibrated to the patient's individual thresholds for Off and dyskinetic state by novel algorithms classifying the continuous accelerometer data into these motor states for every hour between 6 am and 10 pm.From a total of 2,040 hours, 1,752 hours (87.4%) were available for analyses from calibrated PKG data (7.5% sleeping time and 5.1% unclassified motor state time were excluded from analyses). Distributions of total motor state hours per day measured by PKG showed moderate-to-strong correlation to those assessed by diaries for the different motor states (Pearson's correlations coefficients: 0.404-0.658), but inter-rating method agreements on the single-hour-level were only low-to-moderate (Cohen's κ: 0.215-0.324).The PKG has been shown to capture motor fluctuations in patients with advanced PD. The limited correlation of hour-to-hour diary and PKG recordings should be addressed in further studies.

OBJECTIVE: Decrease of olfactory function in Parkinson's disease (PD) is a well-investigated fact. Studies indicate that pharmacological treatment of PD fails to restore olfactory function in PD patients. The aim of this investigation was whether patients with PD would benefit from "training" with odors in terms of an improvement of their general olfactory function. It has been hypothesized that olfactory training should produce both an improved sensitivity towards the odors used in the training process and an overall increase of olfactory function. METHODS: We recruited 70 subjects with PD and olfactory loss into this single-center, prospective, controlled non-blinded study. Thirty-five patients were assigned to the olfactory training group and 35 subjects to the control group (no training). Olfactory training was performed over a period of 12 weeks while patients exposed themselves twice daily to four odors (phenyl ethyl alcohol: rose, eucalyptol: eucalyptus, citronellal: lemon, and eugenol: cloves). Olfactory testing was performed before and after training using the "Sniffin' Sticks" (thresholds for phenyl ethyl alcohol, tests for odor discrimination, and odor identification) in addition to threshold tests for the odors used in the training process. RESULTS: Compared to baseline, trained PD patients experienced a significant increase in their olfactory function, which was observed for the Sniffin' Sticks test score and for thresholds for the odors used in the training process. Olfactory function was unchanged in PD patients who did not perform olfactory training. CONCLUSION: The present results indicate that olfactory training may increase olfactory sensitivity in PD patients.

Impairment of olfaction is a characteristic and early feature of Parkinson's disease. Recent data indicate that >95% of patients with Parkinson's disease present with significant olfactory loss. Deficits in the sense of smell may precede clinical motor symptoms by years and can be used to assess the risk for developing Parkinson's disease in otherwise asymptomatic individuals. This paper summarizes the available information about olfactory function in Parkinson's disease, indicating the advantageous use of olfactory probes in early and differential diagnosis.

BACKGROUND: Differences in spontaneous and drug-induced baroreflex sensitivity (BRS) have been attributed to its different operating ranges. The current study attempted to compare BRS estimates during cardiovascular steady-state and pharmacologically stimulation using an innovative algorithm for dynamic determination of baroreflex gain. METHODOLOGY/PRINCIPAL FINDINGS: Forty-five volunteers underwent the modified Oxford maneuver in supine and 60° tilted position with blood pressure and heart rate being continuously recorded. Drug-induced BRS-estimates were calculated from data obtained by bolus injections of nitroprusside and phenylephrine. Spontaneous indices were derived from data obtained during rest (stationary) and under pharmacological stimulation (non-stationary) using the algorithm of trigonometric regressive spectral analysis (TRS). Spontaneous and drug-induced BRS values were significantly correlated and display directionally similar changes under different situations. Using the Bland-Altman method, systematic differences between spontaneous and drug-induced estimates were found and revealed that the discrepancy can be as large as the gain itself. Fixed bias was not evident with ordinary least products regression. The correlation and agreement between the estimates increased significantly when BRS was calculated by TRS in non-stationary mode during the drug injection period. TRS-BRS significantly increased during phenylephrine and decreased under nitroprusside. CONCLUSIONS/SIGNIFICANCE: The TRS analysis provides a reliable, non-invasive assessment of human BRS not only under static steady state conditions, but also during pharmacological perturbation of the cardiovascular system.

Patients undergoing long-term therapy for PD often experience motor fluctuations and nocturnal disturbances. In a post-hoc analysis, we explored effects of ropinirole prolonged release on sleep, night-time awakenings, and “on” time over 24 hours. Patients with advanced PD suboptimally controlled with L-dopa were randomized to adjunctive ropinirole prolonged release (2–24 mg/day) or placebo for 24 weeks. Awake/asleep and, if awake, “on”/“off” status was recorded via diary cards. At week 24 last observation carried forward, changes in nighttime or daytime sleep duration were not significantly different between treatments. Of patients with baseline awakenings, a significantly higher proportion in the ropinirole prolonged release group had a reduction in awakenings versus placebo. Patients receiving ropinirole prolonged release had a significantly greater increase in amount/percentage of awake time “on”/“on” without troublesome dyskinesia during all periods assessed (including night-time and early morning), versus placebo, and higher odds for being “on” on waking. Adjunctive once-daily ropinirole prolonged release may help provide 24-hour symptom control in patients with advanced PD not optimally controlled with L-dopa.

Hyposmia is one of the early signs in Idiopathic Parkinson´s Disease (PD). Olfactory stimuli were applied during fMRI scanning to show disease-related modulation of central nervous system structures and to advance our understanding of olfactory dysfunction in PD patients. All participants received either unpleasant stimuli smelling like rotten eggs or pleasant ones smelling like roses. Using a block design at a 1.5 T scanner we investigated a total of 8 PD patients (mean age 60 ± 10.9 years) and 13 age matched controls (mean age 58 ± 9.6 years). PD duration ranged from 1 to 9 years (mean 6.63 years); patients had an average “Unified Parkinson’s Disease Rating Scale III” score of 23.25 (range, 6-46). Olfactory function was established using the “Sniffin’ Sticks” test battery. Patients tended to rate the stimuli presented during fMRI scans as less intense, but also as more pleasant than controls. FMRI results revealed differences between PD patients and controls which depended on the type of stimulation. While both pleasant and unpleasant stimulation was associated with lower activation in the amygdalo-hippocampal complex in patients compared to controls, increased activity in response to pleasant stimuli was observed in the striatum and the left inferior frontal gyrus. In contrast, unpleasant stimulation led to hypoactivation of the ventral striatum in patients (but not in controls) and did not enhance left inferior frontal activity. These results may partly reflect differences between PD patients and healthy controls in the processing of primary dimensions of odors, intensity and valence.

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]

BACKGROUND: The assessment of baroreflex sensitivity (BRS) has emerged as prognostic tool in cardiology. Although available computer-assisted methods, measuring spontaneous fluctuations of heart rate and blood pressure in the time and frequency domain are easily applicable, they do not allow for quantification of BRS during cardiovascular adaption processes. This, however, seems an essential criterion for clinical application. We evaluated a novel algorithm based on trigonometric regression regarding its ability to map dynamic changes in BRS and autonomic tone during cardiovascular provocation in relation to gender and age. METHODOLOGY/PRINCIPAL FINDINGS: We continuously recorded systemic arterial pressure, electrocardiogram and respiration in 23 young subjects (25+/-2 years) and 22 middle-aged subjects (56+/-4 years) during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex- and spectral analysis was performed using the algorithm of trigonometric regressive spectral analysis. There was an age-related decline in spontaneous BRS and high frequency oscillations of RR intervals. Changes in autonomic tone evoked by cardiovascular provocation were observed as shifts in the ratio of low to high frequency oscillations of RR intervals and blood pressure. Respiration at 0.1 Hz elicited an increase in BRS while head-up tilt and Valsalva manoeuvre resulted in a downregulation of BRS. The extent of autonomic adaption was in general more pronounced in young individuals and declined stronger with age in women than in men. CONCLUSIONS/SIGNIFICANCE: The trigonometric regressive spectral analysis reliably maps age- and gender-related differences in baroreflex- and autonomic function and is able to describe adaption processes of baroreceptor circuit during cardiovascular stimulation. Hence, this novel algorithm may be a useful screening tool to detect abnormalities in cardiovascular adaption processes even when resting values appear to be normal.

Although extrapyramidal diseases are commonly thought to solely affect the extrapyramidal motor system, nonmotor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also frequently observed. Autonomic dysfunction as an important clinical component of extrapyramidal disease (idiopathic Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, dementia with Lewy bodies) is often not formally assessed and thus frequently misdiagnosed. Symptoms of autonomic dysfunction in general impact more on quality of life than motor symptoms. Appropriate symptom-oriented diagnosis and symptomatic treatment as part of an interdisciplinary approach can greatly benefit the patient. Unfortunately, double-blind, randomized, controlled studies are scarce with the consequence that most recommendations are not based on the highest level of evidence. This review elaborates a limited overview on the treatment of cardiovascular, gastrointestinal, urogenital and sudomotor autonomic dysfunction in various extrapyramidal syndromes.