Increased risk of acute stroke among patients with severe COVID-19: a multicenter study and meta-analysis.

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 I2 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 (I2  = 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.

[Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) for assessment of non-motor symptoms in dystonia : Intercultural adaptation in the German language]. / Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest) zur Erhebung nichtmotorischer Symptome bei Dystonie : Interkulturelle Adaptation in deutscher Sprache.

BACKGROUND: Non-motor symptoms (NMS) in patients with dystonia have a relevant impact on health-related quality of life; however, a comprehensive easy to use NMS assessment tool for clinical bedside use is currently not available. OBJECTIVE: The validated German version of the dystonia non-motor symptoms questionnaire (DNMSQuest) for assessing NMS in craniocervical dystonia is presented. METHODS: The DNMSQuest in the German language was developed based on internationally recognized standards for intercultural adaptation of self-completed patient questionnaires. Translation of the original English questionnaire into the German language as well as back translation to English was carried out independently by four bilingual specialists in neurological movement disorders. In each case a consensus version accepted by each translator was created by another neurologist. The back translated English version was compared with the original English questionnaire for relevant linguistic and content discrepancies by a neurologist who was significantly involved in the development of the original questionnaire. The final German version was used in 130 patients with cervical dystonia and 48 healthy controls in an international, multicenter validation study. RESULTS: An interculturally adapted validated version of the DNMSQuest in the German and English languages was developed for rapid bedside assessment and evaluation of NMS in cervical dystonia. CONCLUSION: The DNMSQuest successfully bridges the current gap of a validated disease-specific, patient self-administered, short, comprehensive questionnaire for NMS assessment in routine clinical practice in craniocervical dystonia. It is envisaged that this tool will be useful for the clinical practice and trials.

Rasagiline improves polysomnographic sleep parameters in patients with Parkinson's disease: a double-blind, baseline-controlled trial.

BACKGROUND AND PURPOSE: The aim was to study the effects of rasagiline on sleep quality in patients with Parkinson's disease (PD) with sleep disturbances. Sleep disorders are common in PD. Rasagiline is widely used in patients with PD, but double-blind polysomnographic trials on its effects on sleep disturbances are missing. METHODS: This was a single-center, double-blind, baseline-controlled investigator-initiated clinical trial of rasagiline (1 mg/day) over 8 weeks in patients with PD with sleep disturbances. Blinding was achieved by running a strategic matched placebo parallel group. Co-primary outcome measures were the changes between baseline and end of the treatment period in sleep maintenance/efficiency as assessed by polysomnography and the Parkinson's Disease Sleep Scale Version 2 (PDSS-2) score. RESULTS: A total of 20 of 30 patients were randomized to rasagiline (mean ± SD age, 69.9 ± 6.9 years; 10 male; Hoehn-Yahr stage, 1.9 ± 0.8). Compared with baseline, sleep maintenance was significantly increased at the end of the treatment period (relative change normalized to baseline, +16.3 ± 27.9%; P = 0.024, paired two-sided t-test) and a positive trend for sleep efficiency was detected (+12.1 ± 28.6%; P = 0.097). Treatment with rasagiline led to significantly decreased wake time after sleep onset, number of arousals, percentage of light sleep and improved daytime sleepiness as measured by the Epworth Sleepiness Scale. We did not observe changes in the co-primary endpoint PDSS-2 score, and no correlations of polysomnographic sleep parameters or PDSS-2 score with motor function (Unified Parkinson's Disease Rating Scale motor score). Rasagiline was well tolerated with no unexpected adverse events. CONCLUSIONS: In patients with PD with sleep disturbances, rasagiline showed beneficial effects on sleep quality as measured by polysomnography. These effects were probably not related to motor improvement or translated into improved overall sleep quality perception by patients.

Perfusion computed tomography in posterior circulation stroke: predictors and prognostic implications of focal hypoperfusion.

BACKGROUND AND PURPOSE: The aim was to determine the predictors of focal hypoperfusion on computed tomography (CT) perfusion (CTP) in patients with acute posterior circulation stroke and its association with long-term outcome. METHODS: Patients with posterior circulation stroke were selected from the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) who underwent CTP within 24 h of stroke onset as part of the stroke imaging protocol. Hypoperfusion was defined as an area of visually well demarcated mean transit time prolongation corresponding to an arterial territory on standard reconstruction CTP imaging maps. Areas of hypoperfusion were assessed with the posterior circulation Acute Stroke Prognosis Early CT Score. Clinical and imaging associations with focal hypoperfusion were identified using multiple imputation analyses, and the adjusted functional outcome measured by the modified Rankin Scale at 3 and 12 months was determined. RESULTS: Of the 3595 consecutive patients from the ASTRAL registry between 2003 and 2014, 1070 (29.7%) had a posterior circulation stroke and 436 of these (40.7%) patients had a good quality baseline CTP. 23.1% had early ischaemic changes and 37.4% had focal hypoperfusion. In multiple imputation analysis, visual field deficits, reduced level of consciousness, cardiac and multiple stroke mechanisms, significant vessel pathology and ischaemic changes visible on plain CT were associated with focal hypoperfusion. Focal hypoperfusion was independently associated with outcome at 12 months (odds ratio 2.04, 95% confidence interval 1.22-3.42, P < 0.01). CONCLUSIONS: In posterior circulation stroke patients undergoing acute CTP, multiple clinical, aetiological and radiological variables were associated with focal hypoperfusion. Patients with focal hypoperfusion had a worse 12-month outcome.

Levodopa/carbidopa intestinal gel (LCIG) infusion as mono- or combination therapy.

Levodopa/carbidopa intestinal gel (LCIG) infusion is an effective escalating therapy in patients with Parkinson disease (PD) suffering from motor fluctuations and dyskinesia. Levodopa/carbidopa given continuously as infusion provides an optimized application of the most effective and best tolerable antiparkinsonian drug. It has been proven to have a superior motor effect compared with oral levodopa and to improve also non-motor symptoms. However, invasiveness, discomfort resulting from carrying an external device, and side effects associated with the way of administration limit its application in PD patients. At present, there are no guidelines that delineate to which patients LCIG should be offered as monotherapy, in combination with oral and/or transdermal medication, or as additional therapy to deep brain stimulation (DBS). Based on clinical studies, we propose an expert consensus for neurologists addressing the question when LCIG therapy should be recommended and in which cases LCIG infusion is suggested in combination with other antiparkinsonian drugs and/or DBS. We describe how LCIG should be initiated and what we consider necessary for clinical follow-up. We suggest an algorithm facilitating decision-making with respect to the currently available invasive PD therapies, namely infusion with subcutaneous apomorphine, LCIG, and DBS.

Parkinson's disease as a multisystem disorder.

This article summarises the noteworthy contribution of Professor Jellinger to the understanding of Parkinson's disease (PD) as a disease affecting multiple body- and neurotransmitter-systems. Phosphorylated alpha-synuclein and the formation of Lewy pathology as neuropathological hallmarks of PD seem to spread from the enteric nervous system and the olfactory bulb in a rostrocranial direction to the CNS. Subsequently, a progressive degeneration of the dopaminergic-nigrostriatal system and widespread extranigral pathology affecting different anatomical structures and neurotransmitters are induced causing the various non-motor and motor symptoms of PD.

[The Geriatric Patient with Parkinson's Disease - a Neurological Challenge]. / Der geriatrische Parkinson-Patient - eine neurologische Herausforderung.

Geriatric patients with Parkinson's disease (PD) represent a particular challenge in terms of diagnostics and treatment. This overview article addresses age-related characteristics of this patient group and discusses particularities in PD symptoms in this age group, frequent comorbidities and the resulting polypharmacy. Questions regarding the availability of specialist and therapist care as well as end-of-life aspects are discussed. While comprehensive care structures are not always available, this patient group requires a multidisciplinary treatment team supervised by neurologists with ample experience in PD treatment.

[Perioperative Management of PD Patients]. / Perioperatives Management von Parkinson-Patienten.

Both patients and caregivers but also treating physicians are concerned about complications along with surgical interventions. A major problem is abrupt cessation of anti-Parkinson medication, which leads to manifold disturbances, sometimes even to an akinetic crisis. There are several means to guarantee continuous dopaminergic stimulation even in patients that are not allowed to take medication orally before they undergo surgery. Amongst others rectally applied levodopa, amantadine infusions, and especially the use of a rotigotine patch are good means to overcome oral intake. Perioperative management is important due to the fact that in Germany alone each year more than 10 000 PD patients undergo surgery. Main reasons for this are fractures, but also elective interventions. Further emergency situations that cause treatment as an inpatient are psychosis, motoric disability, but also pneumonia and cardiovascular disturbances. In contrast PD patients suffer less often from cancer.

New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.

BACKGROUND: The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS: We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS: In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS: Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.

Night-time sleep in Parkinson's disease - the potential use of Parkinson's KinetiGraph: a prospective comparative study.

BACKGROUND AND PURPOSE: Night-time sleep disturbances are important non-motor symptoms and key determinants of health-related quality of life (HRQoL) in patients with Parkinson's disease (PD). The Parkinson's KinetiGraph (PKG) can be used as an objective measure of different motor states and periods of immobility may reflect episodes of sleep. Our aim was to evaluate whether PKG can be used as an objective marker of disturbed night-time sleep in PD. METHODS: In this prospective comparative study, data from PKG recordings over six consecutive 24 h periods are compared with Hauser diaries and scales focusing on motor state, sleep and HRQoL in PD patients. Thirty-three 'non-sleepy' PD patients (PD-NS) were compared with 30 PD patients presenting with excessive daytime sleepiness (PD-EDS). The groups were matched for age, gender and Hoehn and Yahr state. RESULTS: In the PD-EDS group subjective sleep reports correlated with the PKG's parameters for quantity and quality night-time sleep, but not in the PD-NS group. There were no significant correlations of the night-time sleep quantity parameters of the Hauser diary with subjective sleep perception, neither in the PD-EDS nor in the PD-NS group. CONCLUSIONS: This first PKG based study of night-time sleep in PD suggests that PKG could be used to provide an easy to use and rough evaluation of aspects of night-time sleep and one that could flag patients where polysomnography may be required. In sleepy PD patients for instance, quantity and quality PKG parameters correlate with different aspects of sleep such as insomnia, parasomnia and restless legs syndrome.

[Organized Post-Stroke Care through Case Management on the Basis of a Standardized Treatment Pathway : Results of a Single-Centre Pilot Study]. / Koordinierte Schlaganfallnachsorge durch Case Management auf der Basis eines standardisierten Behandlungspfades : Ergebnisse einer monozentrischen Pilotstudie.

BACKGROUND: Post-stroke care programs based on a standardized treatment pathway supported by case management may prevent secondary stroke and minimize risk factors. OBJECTIVES: We aimed to determine the feasibility of a standardized treatment pathway and its impact on risk factor control, life-style changes and adherence to secondary prevention medication. METHODS: We conducted a prospective pilot study in consecutive stroke patients. The 12-month post-stroke care program included regular perosnal and phone contact with a certified case manager. Target values for vascular risk factors following current recommendations of stroke guidelines were monitored and treated if necessary. In the case of deviations from the treatment pathway the case manager intervened. Patients were screened for recurrent stroke at the end of the program after 12 months. RESULTS: We enrolled 101 patients: 57.4 % were male, the median age was 72 (IQR, 62-80) years, median baseline NIHSS score was 2(IQR, 1-5), 79.2 % had an ischemic stroke, 3 % a hemorrhagic stroke, and 17.8 % a transient ischemic attack (TIA). Eighty-six (85.1 %) patients completed the program, 12 (11.9 %) withdrew from the program and 3 died of malignant diseases. In total, 628 personal (6.2/patient) and 2,683 phone contacts (26.6/patient) were conducted by the case manager. Three hundred-seventy-nine specific interventions were necessary mostly because of missing medication, non-compliance, and social needs. After 12 months, target goals for blood pressure, body mass index, nicotine use, and cholesterol were more frequently (p < 0.05) achieved than at baseline. No recurrent stroke occurred during the program. CONCLUSIONS: Our pilot data demonstrate that case management-based post-stroke care is feasible and may contribute to effective secondary prevention of stroke.

Mitochondrial abnormalities in the myofibrillar myopathies.

Myofibrillar myopathies are a genetically diverse group of skeletal muscle disorders, with distinctive muscle histopathology. Causative mutations have been identified in the genes MYOT, LDB3, DES, CRYAB, FLNC, BAG3, DNAJB6, FHL1, PLEC and TTN, which encode proteins which either reside in the Z-disc or associate with the Z-disc. Mitochondrial abnormalities have been described in muscle from patients with a myofibrillar myopathy. We reviewed the literature to determine the extent of mitochondrial dysfunction in each of the myofibrillar myopathy subtypes. Abnormal mitochondrial distribution is a frequent finding in each of the subtypes, but a high frequency of COX-negative or ragged red fibres, a characteristic finding in some of the conventional mitochondrial myopathies, is a rare finding. Few in vitro studies of mitochondrial function have been performed in affected patients.

Effects of rotigotine transdermal patch in patients with Parkinson's disease presenting with non-motor symptoms - results of a double-blind, randomized, placebo-controlled trial.

BACKGROUND AND PURPOSE: Non-motor symptoms (NMS) of Parkinson's disease (PD) have a major impact on health-related quality of life. This is the first randomized controlled trial to use the NMS Scale (NMSS) as a primary outcome to assess treatment effects on NMS in PD. METHODS: In this double-blind trial (NCT01300819), patients with PD and a total NMSS score ≥40 were randomized (2:1) to rotigotine or placebo, titrated over 1-7 weeks to optimal dose (≤8 mg/24 h for patients not receiving levodopa, ≤16 mg/24 h for patients receiving levodopa), maintained for 12 weeks. The primary outcome was change in NMSS total score from baseline to end of maintenance. Secondary outcomes were the nine NMSS domains, Unified Parkinson's Disease Rating Scale (UPDRS) III (motor) and the 39-item Parkinson's Disease Questionnaire (PDQ-39). RESULTS: In total, 283/349 (81.1%) randomized patients completed the trial; 211 rotigotine and 122 placebo were included in the full analysis set. The NMSS total score decreased by 23 (rotigotine) and 19 (placebo) points; the treatment difference was not statistically significant (-3.58; 95% confidence interval -8.43, 1.26; P = 0.147). Numerically greater than placebo improvements were detected in the 'mood/apathy' and 'miscellaneous' NMSS domains (P < 0.05). Treatment differences in UPDRS III (-2.60; -4.27, -0.92; P = 0.002) and PDQ-39 (-2.79; -5.21, -0.37; P = 0.024) favoured rotigotine. Adverse events reported more frequently with rotigotine were nausea, application site reactions, somnolence and headache. CONCLUSIONS: Rotigotine improvement in the multi-domain NMSS total score was not superior to placebo. A different sensitivity of individual NMSS domains to dopaminergic therapy and a large placebo effect may have contributed to these findings.

Cabergoline protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture.

In the present study, primary mesencephalic cell cultures prepared from embryonic mouse mesencephala were used to investigate the neuroprotective effect of cabergoline, an ergoline D2 receptor agonist, against the pesticide and neurotoxin rotenone relevant to Parkinson disease (PD). Treatment of cultures with cabergoline alone significantly increased the number of tyrosine hydroxylase immunoreactive (THir) neurons and reduced the release of lactate dehydrogenase (LDH) into the culture medium compared to untreated controls. Against rotenone toxicity, cabergoline significantly rescued degenerating THir neurons, reduced the release of LDH into the culture medium and improved the morphology of surviving THir neurons. The neuroprotective effects afforded by cabergoline were independent of dopaminergic stimulation as blocking of dopamine receptors by the dopamine receptor antagonist sulpiride did not prevent them. Furthermore, rotenone-induced formation of reactive oxygen species (ROS) was significantly reduced by cabergoline. Although cabergoline increased the glutathione (GSH) content in the culture, the protective effect for dopaminergic neurons seemed not to be predominantly mediated by increasing GSH, as depletion of GSH by L-buthionine-(S,R)-sulfoximine (BSO), a GSH biosynthesis inhibitor, did not prevent cabergoline-mediated neuroprotection of THir neurons in rotenone-treated cultures. Moreover, cabergoline significantly increased the ATP/protein ratio in primary mesencephalic cell cultures when added alone or prior to rotenone treatment. These results indicate a neuroprotective effect of cabergoline for dopaminergic neurons against rotenone toxicity. This effect was independent of dopamine receptor stimulation and was at least partially mediated by reducing ROS production and increasing the ATP/protein ratio.

[Axon-reflex based nerve fiber function assessment in the detection of autonomic neuropathy]. / Axon-Reflex-basierte Nervenmessverfahren in der Diagnostik autonomer Neuropathie.

Axon-reflex-based tests of peripheral small nerve fiber function including techniques to quantify vasomotor and sudomotor responses following acetylcholine iontophoresis are used in the assessment of autonomic neuropathy. However, the established axon-reflex-based techniques, laser Doppler flowmetry (LDF) to assess vasomotor function and quantitative sudomotor axon-reflex test (QSART) to measure sudomotor function, are limited by technically demanding settings as well as interindividual variability and are therefore restricted to specialized clinical centers. New axon-reflex tests are characterized by quantification of axon responses with both temporal and spatial resolution and include "laser Doppler imaging (LDI) axon-reflex flare area test" to assess vasomotor function, the quantitative direct and indirect test of sudomotor function (QDIRT) to quantify sudomotor function, as well as the quantitative pilomotor axon-reflex test (QPART), a technique to measure pilomotor nerve fiber function using adrenergic cutaneous stimulation through phenylephrine iontophoresis. The effectiveness of new axon-reflex tests in the assessment of neuropathy is currently being investigated in clinical studies.