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ZUSAMMENFASSUNGDie komplexe Symptomatik der Parkinsonerkrankung erfordert einen langfristigen, individuellen und umfassenden Therapieansatz. Spezialisierte Netzwerke sind eine Möglichkeit, diesem Bedarf zu begegnen. In Deutschland ist keine flächendeckende, netzwerkbasierte Versorgung Parkinsonerkrankter etabliert. Es fehlen in Netzwerken organisierte und in der Parkinsonbehandlung geschulte Physiotherapeuten. Die im Heilmittelkatalog geregelten, ambulanten Leistungen der Physiotherapie beruhen auf konzeptbasierten Therapieformen, die nicht den Inhalten der europäischen Physiotherapieleitlinie entsprechen. Im Modellvorhaben PaNTher – Parkinson Netzwerk Therapie erhalten Parkinsonpatienten im Großraum München die Möglichkeit einer spezialisierten, leitlinienbasierten Physiotherapie. Vorgestellt wird das Chronic Care Modell auf dessen Basis PaNTher darauf abzielt, die Versorgungsqualität zu verbessern. Stadien- bzw. symptomspezifische Therapieprogramme, ein strukturiertes Schulungsprogramm zur Steigerung der Expertise der Physiotherapeuten und eine sektorenübergreifende Zusammenarbeit zwischen kooperierenden Fachärzten, Therapeuten und dem Projektzentrum an der Parkinson-Fachklinik sind Komponenten des Programms. Teilnehmende Patienten werden im Selbstmanagement ihrer Erkrankung gestärkt. Die Wirksamkeit des Modellvorhabens PaNTher wird durch eine unabhängige, begleitende wissenschaftliche Evaluation untersucht.

OBJECTIVE: Mepolizumab proved to be an efficacious treatment for eosinophilic granulomatosis with polyangiitis (EGPA) at a dose of 300 mg every 4 weeks in the randomized, controlled MIRRA trial. In a few recently reported studies, successful real-life experiences with the approved dose for treating severe eosinophilic asthma (100 mg every 4 weeks) were observed. We undertook this study to assess the effectiveness and safety of mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks in a large European EGPA cohort. METHODS: We included all patients with EGPA treated with mepolizumab at the recruiting centers in 2015-2020. Treatment response was evaluated from 3 months to 24 months after initiation of mepolizumab. Complete response to treatment was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a prednisolone or prednisone dose (or equivalent) of ���4 mg/day. Respiratory outcomes included asthma and ear, nose, and throat (ENT) exacerbations. RESULTS: Two hundred three patients, of whom 191 received a stable dose of mepolizumab (158 received 100 mg every 4 weeks and 33 received 300 mg every 4 weeks) were included. Twenty-five patients (12.3%) had a complete response to treatment at 3 months. Complete response rates increased to 30.4% and 35.7% at 12 months and 24 months, respectively, and rates were comparable between mepolizumab 100 mg every 4 weeks and 300 mg every 4 weeks. Mepolizumab led to a significant reduction in BVAS score, prednisone dose, and eosinophil counts from 3 months to 24 months, with no significant differences observed between 100 mg every 4 weeks and 300 mg every 4 weeks. Eighty-two patients (40.4%) experienced asthma exacerbations (57 of 158 [36%] who received 100 mg every 4 weeks; 17 of 33 [52%] who received 300 mg every 4 weeks), and 31 patients (15.3%) experienced ENT exacerbations. Forty-four patients (21.7%) experienced adverse events (AEs), most of which were nonserious AEs (38 of 44). CONCLUSION: Mepolizumab at both 100 mg every 4 weeks and 300 mg every 4 weeks is effective for the treatment of EGPA. The 2 doses should be compared in the setting of a controlled trial.

Objectives ANCA-associated vasculitis (AAV) can affect all age groups. We aimed to show that differences in disease presentation and 6 month outcome between younger- and older-onset patients are still incompletely understood. Methods We included patients enrolled in the Diagnostic and Classification Criteria for Primary Systemic Vasculitis (DCVAS) study between October 2010 and January 2017 with a diagnosis of AAV. We divided the population according to age at diagnosis: Results A total of 1338 patients with AAV were included: 66% had disease onset at Conclusion Within 6 months of diagnosis of AAV, patients >65 years of age display a different pattern of organ involvement and an increased risk of significant damage and mortality compared with younger patients.

Eosinophilic Granulomatosis with Polyangiitis (EGPA, Churg-Strauss syndrome) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) characterised by respiratory manifestations and systemic organ involvement [1]. Particularly, cardiac manifestations occur in 40–60% of patients, representing the leading cause of mortality [2]. Recent reports suggest that venous thromboembolic events might also represent a consistent burden of disease [3, 4], as already known for the other AAVs [5–7], possibly due to eosinophil-mediated vascular inflammation [5]. Nevertheless, the occurrence of arterial and venous thrombotic events (AVTE) has never been systematically explored in EGPA. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Alessandra Bettiol Conflict of interest: Renato Alberto Sinico Conflict of interest: Franco Schiavon Conflict of interest: Sara Monti Conflict of interest: Enrica Paola Bozzolo Conflict of interest: Franco Franceschini Conflict of interest: Marcello Govoni Conflict of interest: Claudio Lunardi Conflict of interest: Giuseppe Guida Conflict of interest: Giuseppe Lopalco Conflict of interest: Giuseppe Paolazzi Conflict of interest: Angelo Vacca Conflict of interest: Gina Gregorini Conflict of interest: Pietro Leccese Conflict of interest: Matteo Piga Conflict of interest: Fabrizio Conti Conflict of interest: Paolo Fraticelli Conflict of interest: Luca Quartuccio Conflict of interest: Federico Alberici Conflict of interest: Carlo Salvarani Conflict of interest: Silvano Bettio Conflict of interest: Simone Negrini Conflict of interest: Carlo Selmi Conflict of interest: Savino Sciascia Conflict of interest: Gabriella Moroni Conflict of interest: Loredana Colla Conflict of interest: Carlo Manno Conflict of interest: Maria Letizia Urban Conflict of interest: Alfredo Vannacci Conflict of interest: Maria Rosa Pozzi Conflict of interest: Paolo Fabbrini Conflict of interest: Stefano Polti Conflict of interest: Mara Felicetti Conflict of interest: Maria Rita Marchi Conflict of interest: Roberto Padoan Conflict of interest: Paolo Delvino Conflict of interest: Roberto Caporali Conflict of interest: Carlomaurizio Montecucco Conflict of interest: Lorenzo Dagna Conflict of interest: Adriana Cariddi Conflict of interest: Paola Toniati Conflict of interest: Dr. Tamanini reports other from Glaxo Smith Kline, outside the submitted work. Conflict of interest: Federica Furini Conflict of interest: Alessandra Bortoluzzi Conflict of interest: Elisa Tinazzi Conflict of interest: Lorenzo Delfino Conflict of interest: Iuliana Badiu Conflict of interest: Giovanni Rolla Conflict of interest: Vincenzo Venerito Conflict of interest: Florenzo Iannone Conflict of interest: Alvise Berti Conflict of interest: Roberto Bortolotti Conflict of interest: Vito Racanelli Conflict of interest: Guido Jeannin Conflict of interest: Angela Padula Conflict of interest: Alberto Cauli Conflict of interest: Roberta Priori Conflict of interest: Armando Gabrielli Conflict of interest: Milena Bond Conflict of interest: Martina Tedesco Conflict of interest: Giulia Pazzola Conflict of interest: Paola Tomietto Conflict of interest: Marco Pellecchio Conflict of interest: Chiara Marvisi Conflict of interest: Federica Maritati Conflict of interest: Alessandra Palmisano Conflict of interest: Christian Dejaco Conflict of interest: Johann Willeit Conflict of interest: Stefan Kiechl Conflict of interest: Iacopo Olivotto Conflict of interest: Peter Willeit Conflict of interest: Domenico Prisco Conflict of interest: Augusto Vaglio Conflict of interest: Giacomo Emmi

Humans' voice offers the widest variety of motor phenomena of any human activity. However, its clinical evaluation in people with movement disorders such as Parkinson's disease (PD) lags behind current knowledge on advanced analytical automatic speech processing methodology. Here, we use deep learning-based speech processing to differentially analyze voice recordings in 14 people with PD before and after dopaminergic medication using personalized Convolutional Recurrent Neural Networks (p-CRNN) and Phone Attribute Codebooks (PAC). p-CRNN yields an accuracy of 82.35% in the binary classification of ON and OFF motor states at a sensitivity/specificity of 0.86/0.78. The PAC-based approach's accuracy was slightly lower with 73.08% at a sensitivity/specificity of 0.69/0.77, but this method offers easier interpretation and understanding of the computational biomarkers. Both p-CRNN and PAC provide a differentiated view and novel insights into the distinctive components of the speech of persons with PD. Both methods detect voice qualities that are amenable to dopaminergic treatment, including active phonetic and prosodic features. Our findings may pave the way for quantitative measurements of speech in persons with PD.

This cross-sectional study investigates the potential of novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed progressive supranuclear palsy., Key Points Question Can tau–positron emission tomography imaging with the novel tau radiotracer 18F-PI-2620 differentiate patients with progressive supranuclear palsy (PSP) from healthy controls and controls with disease? Findings In this cross-sectional study of 60 patients with PSP, 10 healthy controls, and 20 controls with disease, there was significantly higher 18F-PI-2620 binding in target regions of patients with PSP compared with controls regardless of disease severity. Individual patients with PSP with Richardson syndrome were separated with high sensitivity and specificity. Meaning 18F-PI-2620 tau–positron emission tomography differentiates patients with PSP from controls at the single-patient level, potentially facilitating a more reliable diagnosis., Importance Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis. Objective To investigate the potential of the novel tau radiotracer 18F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. Design, Setting, and Participants In this cross-sectional study, participants underwent dynamic 18F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP–non-RS were excluded from final data analysis owing to incomplete dynamic PET scans. Data were collected from December 2016 to October 2019 and were analyzed from December 2018 to December 2019. Main Outcomes and Measures Postmortem autoradiography was performed in independent PSP-RS and healthy control samples. By in vivo PET imaging, 18F-PI-2620 distribution volume ratios were obtained in globus pallidus internus and externus, putamen, subthalamic nucleus, substantia nigra, dorsal midbrain, dentate nucleus, dorsolateral, and medial prefrontal cortex. PET data were compared between patients with PSP and control groups and were corrected for center, age, and sex. Results Of 60 patients with PSP, 40 (66.7%) had RS (22 men [55.0%]; mean [SD] age, 71 [6] years; mean [SD] PSP rating scale score, 38 [15]; score range, 13-71) and 20 (33.3%) had PSP–non-RS (11 men [55.0%]; mean [SD] age, 71 [9] years; mean [SD] PSP rating scale score, 24 [11]; score range, 11-41). Ten healthy controls (2 men; mean [SD] age, 67 [7] years) and 20 controls with disease (of 10 [50.0%] with Parkinson disease and multiple system atrophy, 7 were men; mean [SD] age, 61 [8] years; of 10 [50.0%] with Alzheimer disease, 5 were men; mean [SD] age, 69 [10] years). Postmortem autoradiography showed blockable 18F-PI-2620 binding in patients with PSP and no binding in healthy controls. The in vivo findings from the first large-scale observational study in PSP with 18F-PI-2620 indicated significant elevation of tracer binding in PSP target regions with strongest differences in PSP vs control groups in the globus pallidus internus (mean [SD] distribution volume ratios: PSP-RS, 1.21 [0.10]; PSP–non-RS, 1.12 [0.11]; healthy controls, 1.00 [0.08]; Parkinson disease/multiple system atrophy, 1.03 [0.05]; Alzheimer disease, 1.08 [0.06]). Sensitivity and specificity for detection of PSP-RS vs any control group were 85% and 77%, respectively, when using classification by at least 1 positive target region. Conclusions and Relevance This multicenter evaluation indicates a value of 18F-PI-2620 to differentiate suspected patients with PSP, potentially facilitating more reliable diagnosis of PSP.

Background Freezing of gait is a highly disabling symptom in persons with Parkinson's disease (PwP). Despite its episodic character, freezing can be reliably evaluated using the FOG score. The description of the minimal clinically relevant change is a requirement for a meaningful interpretation of its results. Objective To determine the minimal clinically relevant change of the FOG score. Methods We evaluated video recordings of a standardized freezing-evoking gait parkour, i.e., the FOG score just before and 30 minutes after the intake of a regular levodopa dose in a randomized blinded fashion. The minimal clinically relevant response was considered a value of one or more on a 7-step Likert-type response scale [-3; +3] that served as the anchor. The minimal clinically relevant change was determined by ROC analysis. Results 37 PwP (Hoehn & Yahr stages 2.5-4, 27 male, 10 female) were aged 68.2 years on average (range 45-80). Mean disease duration was 12.9 years (2-29 years). Minimum FOG score was 0 and Maximum FOG score was 29. Mean FOG scores before medication were 10.6, and 11.1 after medication intake, with changes ranging from -14.7 to +16.7. The minimal clinically relevant change (MCRC) for improvement based on expert clinician rating was three scale points with a sensitivity of 0.67 and a specificity of 0.96. Conclusions The FOG score is recognized as a useful clinical instrument for the evaluation of freezing in the clinical setting. Knowledge of the MCRC should help to define responses to interventions that are discernible and meaningful to the expert physician and to the patient.

Axial deformities such as camptocormia or Pisa syndrome in people with Parkinson’s disease (PwP) are poorly understood. The scarcity of information may result from the shortage of reliable and responsive evaluation instruments. We evaluated the body height loss (BHL) as a new measure for PwP with axial deformities. 50 PwP with axial deformity defined by an UPDRS item 28 value of at least 2 were included in this mono-center study. We measured body height while lying supine and after 1 min of standing, providing a percentage value of BHL, and compared this measure to other clinical variables. BHL depended on the Hoehn and Yahr clinical stage and correlated with clinical scales for function and mobility, but not with timely measures of the axial disorder such as age at diagnosis or duration of disease. ANOVA showed that only lumbar flexion explained the variability of BHL (F = 21.0, p

ZusammenfassungTrotz wachsender Möglichkeiten in der Pharmakotherapie und der tiefen Hirnstimulation können bei der Mehrzahl der Parkinson-Patienten im Verlauf wesentliche Funktionen wie Gleichgewicht, Gehen, Sprechen, Schlucken und Kognition langfristig nur unzureichend gebessert werden. Den aktivierenden Therapien wie Physio-, Sprech-, Schluck- und Ergotherapie kommt hierbei eine zunehmen de Rolle zu. Der Empfehlungsgrad in den S3-Leitlinien erreicht für die Haupttherapie-formen Level A (Physiotherapie) und B (Logopädie, Schlucktherapie, Ergotherapie). Für die Physiotherapie finden sich die meisten Studien. Neue Ansätze mit Krafttraining, Tanzen, Tai Chi sowie gerätegestützte Ansätze wie Laufbandtraining kombiniert mit neuen Entwicklungen wie virtueller Realität und Spielkonsolen („Exergaming“) weisen eine gute Studienevidenz auf. Die S3-Leitlinie der DGN fordert für alle Patienten in allen Stadien Zugang zu einer zeitlich ausreichenden Physiotherapie. Dieser CME Artikel fasst den Stand der aktivierenden Therapien in der Langzeitversorgung von Parkinson-Patienten zusammen.

The obliquus capitis inferior (OCI) muscle may be crucially involved in generating the tremulous component of spasmodic torticollis. This study was undertaken to evaluate the efficacy of a simplified ultrasonography-guided approach of botulinum neurotoxin injection into the OCI in the management of spasmodic torticollis. Here, a novel off-plane technique of ultrasonography-guided botulinum neurotoxin injection into the OCI is demonstrated on video. We investigated its effect in five patients with tremulous torticollis with only partial response to conventional injection technique not injecting OCI. On ultrasonography the OCI and its neighboring structures (greater occipital nerve, vertebrae C1 and C2) were clearly displayed. Unlike the previously proposed approach with axial OCI imaging and in-plane medio-lateral needle insertion, we applied here an off-plane needle insertion technique. With this, the ultrasonography guidance of needle insertion was easier using the sagittal imaging plane rather than the axial plane. Compared to botulinum neurotoxin injection into more superficial neck muscles only, additional ultrasonography-guided botulinum neurotoxin injection into the OCI led to a higher benefit (self-rated improvement of cervical dystonia, p = 0.026, Mann-Whitney test), especially of the tremulous component (p = 0.007), even though the total botulinum neurotoxin dose was not changed. We conclude that selected patients with tremulous torticollis may benefit from botulinum neurotoxin injection into the OCI.

Introduction: Pathogenesis in a subgroup of sarcopenic patients seems to be based on a reduced number of motor neurons. This study aimed at investigating the overlap between sarcopenia and neurodegeneration, as reflected by a low number of motor neurons in patients with Parkinsonian syndromes (PS). Methods: The motor unit number index (MUNIX) of the hypothenar muscle was used to assess the number and size (MUSIX) of motor units (MUs) in patients with idiopathic Parkinson disease (iPD, n = 53), patients with atypical Parkinsonian syndrome (aPS, n = 21), and a control group (n = 30). Mean age of participants was 70.3 years and 54.1% were female. Skeletal muscle mass by bioelectrical impedance analysis, hand-grip strength and gait speed were measured. Based on these assessments, sarcopenia was diagnosed according to the criteria of the European Working Group on Sarcopenia in Older People. Results: Sarcopenia criteria were met by 10 patients with PS (13.5%). The study group had significantly lower MUNIX values than the control group (109 [SD ±39.1] vs. 129 [SD ±45.1]; p = 0.020) even after adjustment for age and sex. Three of the 5 sarcopenic iPD patients (75%) had pathological low MUNIX values (Discussion/Conclusion: Sarcopenia is a frequent comorbidity in PS. The pathologically low MUNIX values found in 75% of our sarcopenic iPD patients provides further support for the existence of a neurodegenerative overlap syndrome with a reduced number of MUs potentially leading to sarcopenia. This finding warrants further evaluation.

SummarySmall RNA pathway components and small RNA profiles of flowering plant egg cells are largely unexplored, mainly because they are not easily accessible but deeply buried inside the ovary.We describe here the utilization of proliferating callus tissue that adopted transcriptome features of Arabidopsis egg cell as a tool to explore small RNA pathway components and small RNA profiles in egg cells. We furthermore complement our studies with mRNA-Seq data from isolated Arabidopsis egg cells and provide data validation by promoter-reporter studies and whole mount in situ hybridization.Sequencing of small RNA libraries demonstrate the predominance of TE-derived siRNAs in the egg cell-related callus. TE-features and expression profiles suggest post-transcriptional silencing of activated Gypsy-like LTR retrotransposons, whereas the majority of class II DNA transposons belonging to Copia, CACTA, hAT-like and Mutator superfamilies are subjected to transcriptional silencing.Small RNA-seq furthermore led to the identification of differentially expressed known and novel miRNAs whose expression in the egg cell was verified by small RNA whole mount in situ hybridization. Both the strong expression of miRNAs in the egg-cell-adjoining synergids and the secretion of miRNAs into the micropyle suggest hitherto undescribed roles for these accessory cells in intercellular communication with the egg cell and the arriving pollen tube.In conclusion, our datasets provide valuable and comprehensive resources to study small RNA pathways and small-RNA-mediated epigenetic reprogramming during egg cell differentiation and the onset of plant embryogenesis.

Gait festination is one of the most characteristic gait disturbances in patients with Parkinson’s disease or atypical parkinsonism. Although festination is common and disabling, it has received little attention in the literature, and different definitions exist. Here, we argue that there are actually two phenotypes of festination. The first phenotype entails a primary locomotion disturbance, due to the so-called sequence effect: a progressive shortening of step length, accompanied by a compensatory increase in cadence. This phenotype strongly relates to freezing of gait with alternating trembling of the leg. The second phenotype results from a postural control problem (forward leaning of the trunk) combined with a balance control deficit (inappropriately small balance-correcting steps). In this viewpoint, we elaborate on the possible pathophysiological substrate of these two phenotypes of festination and discuss their management in daily clinical practice. Electronic supplementary material The online version of this article (10.1007/s00415-018-9146-7) contains supplementary material, which is available to authorized users.

The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique.

Background Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage ≥3 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage ≥3 CKD in a large cohort of patients affected by T1DM. Methods A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage ≥3 CKD (eGFR 30% from baseline was evaluated. Results The mean estimated GFR was 98 ± 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions Albuminuria and eGFR reduction represent independent risk factors for incident stage ≥3 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening. Electronic supplementary material The online version of this article (10.1186/s12882-018-1136-6) contains supplementary material, which is available to authorized users.

ZusammenfassungDie Erfassung der Qualität medizinischer Dienstleistungen ist bei chronischen und komplexen neurologischen Erkrankungen wie der Parkinsonkrankheit eine Herausforderung. Wir führten im Jahr 2012 ein Qualitätssurvey mit dem Patientenfragebogen der neuen MDS-UPDRS-Skala (Movement Disorder Society Unified Parkinson Disease Rating Scale) durch. Der Patiententeil der Skala evaluiert motorische und nicht motorische Symptome mit 20 Items, die jeweils Werte von 0 bis 4 annehmen können. Von 1 097 stationären Patienten mit Parkinson-Syndrom im Jahr 2012 konnten korrespondierende Vorher-Nachher-Daten (bei Aufnahme und postalisch nach Entlassung) eines Samples mit 220 Patienten (20%) mit idiopathischer Parkinsonkrankheit erhoben werden. Der Mittelwert des Summenscore verbesserte sich in dieser Population um 3,2 Skalenpunkte (p < 0,001) zum Zeitpunkt zwei Wochen nach Entlassung. Der MDS-UPDRS erweist sich so als praktikables, objektives und valides Instrument, um die Qualität der stationären Behandlung von Parkinsonpatienten zu erfassen.

Botulinum neurotoxin A (BoNT A) is the first-line treatment for cervical dystonia. However, although BoNT A has a favorable safety profile and is effective in the majority of patients, in some cases the treatment outcome is disappointing or side effects occur when higher doses are used. It is likely that in such cases either the target muscles were not injected accurately or unintended weakness of non-target muscles occurred. It has been demonstrated in clinical trials for spastic movement disorders that sonography-guided BoNT A injections could improve treatment outcome. As the published evidence for a benefit of sonography-guided BoNT injection in patients with cervical dystonia is scarce, it is the aim of this review to discuss the relevance of sonography in this indication and provide a statement from clinical experts for its use. The clear advantage of sonography-guided injections is non-invasive, real-time visualization of the targeted muscle, thus improving the precision of injections and potentially the treatment outcomes as well as avoiding adverse effects. Other imaging techniques are of limited value due to high costs, radiation exposure or non-availability in clinical routine. In the hands of a trained injector, sonography is a quick and non-invasive imaging technique. Novel treatment concepts of cervical dystonia considering the differential contributions of distinct cranial and cervical muscles can reliably be implemented only by use of imaging-guided injection protocols.

Objective Turning and limitations to step length were shown to trigger progressive shortening of steps, which can lead to freezing of gait. By reducing the base area in which the turn had to take place, we aimed to evaluate the contribution of spatial constraints on 360° axial turns in people with Parkinson’s disease with and without freezing. Methods We evaluated 40 patients with and without freezing and 16 age-matched healthy subjects. We assessed clinical data, and used body-worn inertial sensors to describe stepping and turn duration of 360° in quadratic squares of different sizes marked on the floor. Results We found that, when subjects had to perform turns in smaller as compared to larger squares, this spatial constraint strongly affected the turning behavior, i.e. increased the number of steps, and the duration of turns. However, turning was significantly more impaired in patients as compared to controls, and patients with freezing were significantly worse as patients without freezing. Conclusion Our data show that spatial constraint during axial turning has the potential to deteriorate stepping performance, especially in patients reporting freezing of gait. Significance The size of the base area needs to be defined in any item or scale that makes diagnostic use of turning.

Continuous jejunal levodopa infusion is an increasingly used therapy option in patients with Parkinson's disease who experience severe fluctuations from oral levodopa. In a number of recent reports polyneuropathy in patients receiving jejunal levodopa infusion was referenced to cobalamin (vitamin B12) deficiency. We describe one of three cases from our hospital with severe subacute polyneuropathy that developed during jejunal levodopa infusion, and occurred despite vitamin substitution therapy and normal vitamin B12 and holotranscobalamin serum levels.

ZusammenfassungIm Schatten der anderen Therapieoptionen bei Parkinson-Syndromen hat sich die Injektion von Botulinumtoxin für eine Reihe von Indikationen zum unverzichtbaren Helfer gemacht. Hierzu gehören vor allem die Sialorrhoe des Parkinson-Patienten und therapierefraktäre Dystonien des Gesichtes (Blepharospasmus) sowie der Extremitäten (Off-Dystonien). Der Beitrag nennt die Indikation, die verfügbare Evidenz und eine pragmatische Herangehensweise. Die Empfehlung der Autoren zu jeder Indikation sowie deren Zulassungsstatus wird benannt.

BACKGROUND: Smoking has been linked to mucinous ovarian cancer, but its effects on other ovarian cancer subtypes and on overall ovarian cancer risk are unclear, and the findings from most studies with relevant data are unpublished. To assess these associations, we review the published and unpublished evidence. METHODS: Eligible epidemiological studies were identified by electronic searches, review articles, and discussions with colleagues. Individual participant data for 28,114 women with and 94,942 without ovarian cancer from 51 epidemiological studies were analysed centrally, yielding adjusted relative risks (RRs) of ovarian cancer in smokers compared with never smokers. FINDINGS: After exclusion of studies with hospital controls, in which smoking could have affected recruitment, overall ovarian cancer incidence was only slightly increased in current smokers compared with women who had never smoked (RR 1·06, 95% CI 1·01-1·11, p=0·01). Of 17,641 epithelial cancers with specified histology, 2314 (13%) were mucinous, 2360 (13%) endometrioid, 969 (5%) clear-cell, and 9086 (52%) serous. Smoking-related risks varied substantially across these subtypes (p(heterogeneity)

Festination and freezing of gait (FOG) are sudden episodic inabilities to initiate or sustain locomotion mostly experienced during the later stages of Parkinson's disease (PD) or other higher-level gait disorders. The aim of this study was to develop a clinical rating instrument for short-interval rating of festination and FOG. Foot movements of 33 patients were video taped and rated during 12 episodes in a standardized course on a four-level interval scale according to severity. Motor blocks were provoked in four situations and by three levels of dual-tasking (tasks). Addition of the item scores produced a FOG score. The assessment requires less than 15 min. The inter-rater and re-test reliability of the FOG score is high (Kendall kappa = 0.85-0.92, P < 0.0001). Variability of the item scale due to situations and tasks can be attributed to unidimensional group factors (Cronbach's alpha 0.84 and 0.94). Group comparisons and a logistic regression model show significant effects for both situations and tasks on the item scale (Friedman test: "situation": P < 0.0001, "task": P < 0.0001). Six patients with PD have significantly different scores during mobile (practical ON; 6.2 +/- 3.9) and immobile (practical OFF; 15.8 +/- 4.6) medication states (P < 0.05). The FOG score correlates with the 10 m number of steps (rho = 0.58; P = 0.001) and with the self-evaluation of FOG (rho = 0.51; P < 0.01). Our results encourage the further use of the FOG score to evaluate festination and FOG.

ZusammenfassungMotorische Blockaden während des Gehens sind als eine episodisch auftretende Störung der Ganginitiierung und des Lokomotionserhalts bei Parkinsonsyndromen und zentralen Gangstörungen definiert. Phänomenologisch werden Festination, trembling-in-place und total akinesia als Freezing-Formen unterschieden. Fünf differente Gangsituationen wurden als klassische Provokatoren für Freezing-Episoden benannt. Um eine Testung durch einen Beobachter klinisch einfach und aussagekräftig durchführen zu können, haben wir ein neues Testinstrument, den Freezing-ofgait-Score (FOG-Score) entwickelt, der im klinischen Alltag erprobt wird. Freezing bei Parkinsonpatienten ist meist dopasensitiv, kann aber auch im On-Zustand des Patienten auftreten und ist dann schwer zu therapieren.Wir diskutieren standardisierte Therapieschemata für Patienten mit On-Freezing, die wir an unserem Zentrum entwickelt haben.

Background: Severe generalized spastic movement disorders of various aetiologies often involve the jaw muscles and lead to a spastic trismus with masseter muscle hypertonia. We report a placebo-controlled randomized study on patients with spastic trismus. Methods: Eleven patients with masseter hypertonia because of stroke, hypoxic encephalopathy or traumatic brain injury were allocated to either botulinum toxin serotype B (BoNT/B) injections into the masseter muscles or placebo treatment. The dental gap, the amount of saliva, salivation scales, and a clinical goal attainment were evaluated. Results: Three weeks after injection the BoNT/B group showed a significantly increased mouth opening compared with placebo treatment (P

Freezing of gait (FOG) is a common disturbance in Parkinson's disease (PD) and other higher-level gait disorders. It appears most often during the later stages of PD but is seen also during the initial phases before oral substitution of levodopa has started. The disorder has its own pathophysiology and differs from bradykinesia. It can occur both on and off medication. It interferes with activities of daily life, reduces mobility, and is an important risk factor for falling. While patients with FOG during medication do not reliably respond to pharmacotherapy or deep brain stimulation, external cues have been demonstrated that influence FOG effectively. They are applied as auditory, visual, tactile, or mental cues. This article discusses available pharmacological and physiotherapeutic approaches to the treatment of FOG.

Cerebral palsy is the most common etiology of a spastic movement disorder in childhood. The present paper gives an introduction to the classification, the phenomenology, the diagnosis and current pathophysiological concepts of the cerebral palsies. It focusses on the interdisciplinary therapy approach of the motor disorder, especially on the functional therapies and the treatment with botulinum toxin.

SummaryBackgroundHalf the epidemiological studies with information about menopausal hormone therapy and ovarian cancer risk remain unpublished, and some retrospective studies could have been biased by selective participation or recall. We aimed to assess with minimal bias the effects of hormone therapy on ovarian cancer risk.MethodsIndividual participant datasets from 52 epidemiological studies were analysed centrally. The principal analyses involved the prospective studies (with last hormone therapy use extrapolated forwards for up to 4 years). Sensitivity analyses included the retrospective studies. Adjusted Poisson regressions yielded relative risks (RRs) versus never-use.FindingsDuring prospective follow-up, 12 110 postmenopausal women, 55% (6601) of whom had used hormone therapy, developed ovarian cancer. Among women last recorded as current users, risk was increased even with

Lamotrigine (LTG) was reported to have a positive profile especially regarding cognition. Our investigation focuses on whether the experiences of physicians and parents of children with long-term LTG treatment confirm this. All patients of two neuropaediatric departments in whose treatment course LTG had been administered, irrespective of the outcome of the therapy had been included in this study. By conducting semi-structured interviews with patients' parents and epileptologists, we collected qualitative epidemiological and epilepsy related data on seizure rate, adverse events and assessed changes of cognition and vigilance of LTG therapy on 119 patients. Each of the patients had been in the constant and continuous care of one and the same experienced epileptologist over the completeobservational period. Seizure control was more than 50% seizure reduction in 46% of the patients and is herewith comparable to that of other newer antiepileptic drugs. In the majority of patients, physicians and parents rated the patients' cognition and vigilance as unchanged during therapy. If changes were reported, these were more likely positive than negative for the patient and most prominent in concentration and vigilance. Parents' ratings were comparable to physicians' view. Results of earlier reports of a favorable cognitive profile of LTG seem to reach relevance in the long-term treatment of childhood epilepsies, as the neutral to beneficial effects of LTG on cognition and vigilance in long-term treatment is confirmed by physicians' and parents' experience. Our qualitative evaluation is supporting LTG as an anticonvulsive drug with a profile suitable for the use in children.

The optimal stimulation site in subthalamic deep brain stimulation (STN-DBS) was evaluated by correlation of the stereotactic position of the stimulation electrode with the electrophysiologically specified dorsal STN border. In a series of 25 electrodes, best clinical results with least energy consumption were found in contacts located in the dorsolateral border zone, whereas contacts within the subthalamic white matter, e.g., zona incerta, were significantly less effective. We suggest that the dorsolateral STN border should be covered by STN-DBS.

Objective : Quantitative tremor analyses using almost identical methods were compared between two independent large normal cohorts, to separate robust measures that may readily be used diagnostically from more critical ones needing lab-specific normalization. Methods : Hand accelerometry and surface EMG from forearm flexors and extensors were recorded with (500 and 1000 g) and without weight loading under postural conditions in 117 and 67 normal volunteers in two different specialty centers for movement disorders in Germany. Results : Tremor amplitude (total power) and frequency fell within a similar range but differed significantly. A significant reduction of tremor frequency under 1000 g weight load (>1 Hz), and a lack of rhythmic EMG activity at the tremor frequency in around 85–90% of the recordings were robust findings in both centers. Conclusions : The differences in frequency and total power indicate that these measures critically depend on the details of the recording conditions being slightly different between the two centers. Thus each lab needs to establish its own normative data. We estimate that at least 25 normal subjects have to be recorded to obtain normal values. The reduction of tremor frequency under load and lacking tremor-related EMG activity were well reproducible allowing a differentiation of physiological from low amplitude pathological tremor. Significance : This study provides a framework for more standardized tremor analyses in clinical neurophysiology.

The function of low-frequency oscillations as correlates of physiological tremor in supplementary motor area (SMA) and M1 remains unclear. In epicortical recordings from M1 and SMA and surface electromyographic (EMG) recordings in an epileptic patient we found reproducibly significant coherence between all three recording sites in the 6- to 15-Hz band. The partial coherence between SMA and muscle, however, was not significant. There was a constant phase shift between SMA and M1 indicating synchronized activity. We conclude that the cortical correlates of physiological tremor may be involved in linking different cortical motor centers and might therefore play a role in cortical motor planning.

Background: The subthalamic nucleus is the preferred target for deep brain stimulation in patients with advanced Parkinson’s disease. The site of permanent stimulation is the subject of ongoing debate, as stimulation both within and adjacent to the subthalamic nucleus may be effective. Objective: To assess the position of active electrode contacts in relation to the dorsal margin of the subthalamic nucleus as determined by intraoperative microrecordings and magnetic resonance imaging (MRI). Methods: In 25 patients suffering from severe levodopa sensitive parkinsonism, deep brain stimulating electrodes (n = 49) were implanted following mapping of the subthalamic nucleus by microrecording and microstimulation along five parallel tracks. Postoperative stereotactic radiography and fusion of pre- and postoperative MRI studies were used to determine the stereotactic position relative to the midcommissural point of the most effective electrode contacts selected for permanent stimulation (n = 49). Intraoperative microrecordings were analysed retrospectively to define the dorsal margin of the subthalamic nucleus. In cases where the dorsal margin could be defined in at least three microrecording tracks (n = 37) it was correlated with the position of the active contact using an algorithm developed for direct three dimensional comparisons. Results: Stimulation of the subthalamic nucleus resulted in marked improvement in levodopa sensitive parkinsonian symptoms and levodopa induced dyskinesias, with significant improvement in UPDRS III scores. In several instances, projection of the electrode artefacts onto the T2 weighted MRI visualised subthalamic nucleus of individual patients suggested that the electrodes had passed through the subthalamic nucleus. When the actual position of active electrode contacts (n = 35) was correlated with the dorsal margin of the subthalamic nucleus as defined neurophysiologically, most contacts were located either in proximity (± 1.0 mm) to the dorsal border of the subthalamic nucleus (32.4%) or further dorsal within the subthalamic region (37.8%). The other active contacts (29.7%) were detected within the dorsal (sensorimotor) subthalamic nucleus. The average position of all active contacts (n = 49) was 12.8 mm (± 1.0) lateral, 1.9 mm (± 1.4) posterior, and 1.6 mm (± 2.1) ventral to the midcommissural point. Conclusions: Subthalamic nucleus stimulation appears to be most effective in the border area between the upper subthalamic nucleus (sensorimotor part) and the subthalamic area containing the zona incerta, fields of Forel, and subthalamic nucleus projections.

Purpose: Spinal meningeal Gd-DTPA enhancement after cranial surgery is a known observation of a not well understood underlying mechanism. This paper demonstrates that this MRI finding is a normal meningeal reaction to subarachnoid hemorrhage, which should not be mistaken for metastatic spread. Material and Methods: Three pediatric patients were examined by MRI for metastatic spread of malignant infratentorial tumors along the spinal canal two to nine days after the removal of the primary cerebral lesion. The findings were compared with a control group that underwent cranial surgery (cyst resection or fenestration of the posterior cranial fossa) without major bleeding into the subarachnoid space. Unenhanced and enhanced sequences were obtained to prove that the high signal within the CSF is caused by an abnormal Gd-DTPA uptake and not by methemoglobin. Results: Meningeal enhancement was observed in all patients with intraoperative bleeding resembling subarachnoid masses on enhanced T 1 -weighted images. This was not present in any patient of the control group. This finding lasts for approximately two weeks. Conclusion: The meningeal enhancement renders immediate postoperative studies inconclusive for the detection of metastatic spread. Consequently, the obligatory tumor staging along the spinal canal should ideally be done prior to the resection of a cerebral tumor.

Introduction: The aim of our study was to assess the influence of cardiovascular complications on the occurrence of late ventricular potentials (LP) in children with diabetes mellitus type 1. Materials and methods: 72 children (36 boys and 36 girls), with average course of diabetes type 1 of 6.5±2.8 years, were included into the study. Standard physical examination, blood pressure measurements, signal-averaged electrocardiogram (SAECG), autonomic test, 24-h Holter monitoring, and Doppler echo investigations were performed. The control group consisted of 55 sex- and age-matched healthy children. We utilised nonlinear logistic regression analysis to assess the effect of disease duration, albuminuria, insulin demand, cardiac autonomic neuropathy (CAN), heart rate variability (HRV) indices, diabetes complication score, metabolic control, systolic and diastolic blood pressure, left ventricular parameters, and ventricular arrhythmias on LP occurrence. Results: LP was discovered in 12 patients with diabetes and in 1 from the control group ( P P P Conclusions: Diabetes type 1 is associated not only with increased occurrence of abnormal SAECG but also with LP presence. The disease duration, posterior wall thickness, and CAN are independent predictors of LP appearance in diabetes type 1 children. The presence of cardiovascular complication has no influence on LP occurrence in diabetic children.

Deep-brain stimulation of the subthalamic nucleus appears to reduce levodopa-induced dyskinesias, but whether this effect is caused by the reduction of the total levodopa ingestion or represents a direct effect on the motor system is unknown. Precision grip force of grasping movements and levodopa-induced dyskinesias was analyzed in 10 parkinsonian patients before and after 3 months of deep-brain stimulation of the subthalamic nucleus. Peak grip force was abnormally increased before surgery in the off-drug state and, particularly, in the on-drug state (sensitization). This grip force upregulation normalized with chronic deep-brain stimulation in both conditions (desensitization). Peak-dose dyskinesias also improved, and off-dystonia was completely abolished. Mean dosage of dopaminergic drugs was reduced, but force overflow and dyskinesias were equally improved in 2 patients without a reduction. Despite the same single levodopa test dose, force excess and levodopa-induced dyskinesias were drastically reduced after 3 months of deep-brain stimulation of the subthalamic nucleus. This indicates that direct effects of deep-brain stimulation of the subthalamic nucleus on levodopa-induced dyskinesias are likely to occur. Grip force overflow is a promising parameter to study the desensitizing effect of chronic deep-brain stimulation on levodopa-induced dyskinesias.

Objective: To investigate the efficacy of a two-week programme of repetitive exercise with cueing and movement strategies upon freezing of gait in people with Parkinson’s disease. Design: Randomized cross-over trial. Setting: Specialist clinic for Parkinson’s disease. Subjects: A total of 22 patients with Parkinson’s disease and freezing while other symptoms had favorably responded to dopaminergic treatment. Intervention: Patients were randomized into a four-week cross-over trial, and received either treatment (Group 1) or no treatment (Group 2) during Period 1, and switched during Period 2. Treatment consisted of a two-week programme during which the patients exercised cueing, and movement strategies together with a physiotherapist. Main measure: The primary outcome measure was a freezing score assessed from blinded and random ratings of video recordings. The secondary outcome measure was a patient-reported freezing questionnaire. Mean differences between the treatment periods (treatment arms) were evaluated for treatment (period) effects. Sums of treatment periods were evaluated for carry-over effects. Results: The programme led to a significant treatment effect in the freezing score of 3.0 improvement (95% confidence interval 0.9–5.0; p < 0.01). No carry-over or period effects were detected. The questionnaire revealed a period effect, so groups were compared after Period 1, where a significant difference was found (15.0 vs. 11.7; p < 0.05). Conclusions: The two-week physiotherapy programme reduced the severity of freezing in patients with Parkinson’s disease.

Dysphagia in patients with Parkinson's disease (PD) significantly reduces quality of life and predicted lifetime. Current screening procedures are insufficiently evaluated. We aimed to develop and validate a patient-reported outcome questionnaire for early diagnosis of dysphagia in patients with PD.The two-phased project comprised the questionnaire, diagnostic scales construction (N = 105), and a validation study (N = 82). Data for the project were gathered from PD patients at a German Movement Disorder Center. For validation purposes, a clinical evaluation focusing on swallowing tests, tests of sensory reflexes, and fiberoptic endoscopic evaluation of swallowing (FEES) was performed that yielded a criteria sum score against which the results of the questionnaire were compared. Specificity and sensitivity were evaluated for the detection of noticeable dysphagia and for the risk of aspiration.The Munich Dysphagia Test - Parkinson's disease (MDT-PD) consists of 26 items that show high internal consistency (α = 0.91). For the validation study, 82 patients, aged 70.9 ± 8.7 (mean ± SD), with a median HoehnYahr stage of 3, were assessed. 73% of patients had dysphagia with noticeable oropharyngeal symptoms (44%) or with penetration/aspiration (29%). The criteria sum score correlated positively with the screening result (r = 0.70, p0.001). The MDT-PD sum score classified not noticeable dysphagia vs. risk of aspiration (noticeable dysphagia) with a sensitivity of 90% (82%) and a specificity of 86% (71%), and yielded similar results in cross-validation, respectively.MDT-PD is a valid screening tool for early diagnosis of swallowing problems and aspiration risk, as well as initial graduation of dysphagia severity in PD patients.

Focal transcranial magnetic stimulation of the hand-associated motor cortex was used to study normal healthy preschool children (n = 7; mean age, 4.6 years) and adults (n = 7; mean age, 29.4 years) under the conditions of standardized tonic voluntary contraction of small hand muscles. Callosally mediated inhibitory as well as corticospinally mediated inhibitory and excitatory motor effects were investigated. Although children had no detectable transcallosal inhibition, their corticospinally mediated postexcitatory silent period was present (mean, 140.8 +/- 30.2 msec). It was significantly shorter than in adults (mean, 192.5 +/- 32.0 msec). The motor thresholds of the cortically elicited muscle responses, measured as the lowest stimulus intensity, were significantly higher in children (mean, 89 +/- 5%) than in adults (mean, 46 +/- 6%). The corticomuscular latency of transcranially elicited motor responses revealed no difference between children and adults. These observations may reflect maturation processes in the motor system. Maturation of at least some direct corticospinal fibers occurs early in life and is followed by that of intracortical excitatory and inhibitory connections. The maturation of functionally competent callosal connections appears to occur after the age of 5 years.

Impairment of gait and freezing are common symptoms in patients with Parkinson's disease (PD). In this paper, a device to improve these symptoms by delivering auditory and somatosensory external stimuli (so-called cues) is presented. The device can be not only used independently but also as actuator of a wearable system to offer situation-dependent cueing during Freezing-episodes. Furthermore, it is possible to individually choose from a variety of settings and wearing-positions. An experiment, where the Multi-Cue Unit (MuCU) was tested and evaluated with six Parkinson-patients was set up and carried out. According to the results of the self-assessment, the MuCU is light weight and also very easy to operate. Moreover, four out of all six patients experienced a shorter FOG - episode with the wearable device and preferred the situation-dependent cueing.

Background and purpose Spastic pes equinovarus is a frequent pathological posture of the lower extremity. Botulinum toxin (BoNT/A) has been successfully applied to treat lower limb spasticity. However, the best time to initiate treatment remains unclear. A beneficial effect of an early treatment has been suggested in previous studies. Methods A single-centre double-blind randomized placebo-controlled trial was performed to investigate the efficacy of BoNT/A to reduce muscle hypertonicity at the ankle. Fifty-two patients with unilateral or bilateral spastic pes equinovarus with a modified Ashworth score (mAS) of at least 1+ after stroke, traumatic brain injury or hypoxic encephalopathy were allocated to receive either BoNT/A or placebo treatment. A second, open injection was optional at week 12. Patients received unilateral or bilateral injections with 230 or 460 U onabotulinumtoxinA, respectively. The course of the mAS was explored during the open study phase. Results Patients who had received BoNT/A treatment had lower mAS compared with placebo at week 12 (P

Botulinum toxin is a powerful and often used agent to treat dynamic rhytides. Focal and reversible neurogenic atrophy is considered to be the relevant mechanism of action.To investigate the loss and regain of muscular volume in relation to clinical wrinkle severity as assessed using standardized scales.The facial procerus and corrugator supercilii muscles were injected in two drug-naïve men with 20 U of onabotulinumtoxinA at five injection points (onA). Two men served as controls (one with the same volume of placebo injection using saline solution, one without any intervention). All subjects underwent 3 Tesla magnetic resonance imaging before and after the injection and 1, 4, 6, 10, and 12 months after the injection. Standardized photographs were taken at each test point.Volumetric muscle analysis revealed a 46% to 48% reduction in procerus muscle volume lasting for 12 months after a single dose of onA; glabellar line severity returned to the drug-naïve status after 6 to 10 months.The gap between long-term focal muscular atrophy and regained function remains to be elucidated. Future studies will be needed to investigate the complex interaction between focal neurogenic atrophy and potential compensatory functional muscle changes.