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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.

Sieben Jahre nach der Diagnose einer ParkinsonErkrankung und der weitgehenden Rückbildung der Symptomatik unter einer Dopamin-Ersatztherapie kommt es bei Lehrer Karl Bauer zu Wirkungsschwankungen der Medikamente. Symptome wie Rigor und Bradyhypokinese treten wieder verstärkt auf. Unterstützung erhält er durch eine multimodale Komplextherapie.

Sieben Jahre nach der Diagnose einer Parkinson-Erkrankung und der weitgehenden Rückbildung der Symptomatik unter einer Dopamin-Ersatztherapie kommt es bei Lehrer Karl Bauer zu Wirkungsschwankungen der Medikamente. Symptome wie Rigor und Bradyhypokinese treten wieder verstärkt auf. Unterstützung erhält er durch eine multimodale Komplextherapie.

Spoken language is constantly undergoing change: Speakers within and across social and regional groups influence each other's speech, leading to the emergence and drifts of accents in a language. These processes are driven by mutual unintentional imitation of the phonetic details of others' speech in conversational interactions, suggesting that continuous auditory-motor adaptation takes place in interactive language use and plasticity of auditory-motor representations of speech persists across the lifespan. The brain mechanisms underlying this large-scale social-linguistic behavior are still poorly understood.To investigate the role of cerebellar and basal ganglia dysfunctions in unintended adaptation to the speech rhythm and articulation rate of a second speaker.Twelve patients with spinocerebellar ataxia type 6 (SCA6), 15 patients with Parkinson's disease (PD), and 27 neurologically healthy controls (CTRL) participated in two interactive speech tasks, i.e., sentence repetition and "turn-taking" (i.e., dyadic interaction with sentences produced by a model speaker). Production of scripted sentences was used as a control task. Two types of sentence rhythm were distinguished, i.e., regular and irregular, and model speech rate was manipulated in 12 steps between 2.9 and 4.0 syllables per second. Acoustic analyses of the participants' utterances were performed to determine the extent to which participants adapted their speech rate and rhythm to the model.Neurologically healthy speakers showed significant adaptation of rate in all conditions, and of rhythm in the repetition task and partly also the turn-taking task. Patients with PD showed a stronger propensity to adapt than the controls. In contrast, the patients with cerebellar degeneration were largely insensitive to the model speaker's rate and rhythm. Contrary to expectations, sentences with an irregular speech rhythm exerted a stronger adaptive attraction than regular sentences in the two patient groups.Cerebellar degeneration inhibits the propensity to covertly adapt to others' speech. Striatal dysfunction in Parkinson's disease spares or even promotes the tendency to accommodate to other speakers' speech rate and rhythm.

Introduction Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia. Methods The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource. Results We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone. Conclusions WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.

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

ZusammenfassungAuch im letzten Jahr wurden zahlreiche pharmakotherapeutische Entwicklungen für die Parkinsonkrankheit vorangebracht. Die in den USA kommerziell erfolgreiche retardierte Darreichungsform von Levodopa IPX066 ist in Europa zwar zugelassen, aber nicht am Markt verfügbar. Eine speziell gefaltete Akkordeon Pille verspricht ebenso eine vereinfachte Galenik bei besserer klinischer Wirkung. Levodopa ist als Inhalativum kurz vor Markteintritt und zeigt in den vorgelegten Studien, dass Off-Phasen erfolgreich verkürzt werden können, allerdings nicht schnellere Hilfe leisten als die verfügbaren Stand-by Medikamente. Neu ist auch, dass L-Dopa über die Haut appliziert werden kann. Safinamid und Opicapon sind über Rezept verfügbar. Für letzteres liegen die Ergebnisse der Zulassungsstudien vor. Die neue AmantadinGalenik hat in den USA aufgrund günstiger Studiendaten die Zulassung zur Behandlung von Dyskinesien erhalten. Auch hat sich das Verständnis um Risikofaktoren zur Entwicklung eines Parkinson deutlich weiterentwickelt. Wir stellen neueste Arbeiten zu dem Glucagon-like-Peptid-Analogon Exenatide und dem ß2-Adrenorezeptor vor.

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.

ZusammenfassungDie verschiedenen Parkinson-Syndrome (PS) klinisch einzelnen Krankheitsentitäten zuzuordnen, gilt als schwierig. Es sind viele seltene Parkinson-Syndrome von dem häufigen sporadischen idiopathischen Parkinson-Syndrom (IPS) zu differenzieren. Zum Teil neu aufgelegte Kriterien für das IPS und die atypischen Parkinson-Syndrome wie Demenz vom Lewy-Body-Typ (DLB), Multisystematrophie (MSA), progressiver supranukleärer Blickparese (PSP) und kortikobasales Syndrom (CBS) sollten die diagnostische Einordnung verbessern. Patienten mit vom sporadischen IPS kaum unterscheidbaren monogenetischem PS, z. B. mit LRRK2-Mutationen oder mit einem Risikogen, z. B. Mutationen im GBAGen, können relativ einfach genetisch diagnostiziert werden. Bei jungen PS-Patienten müssen komplexe Krankheiten wie z. B. das häufige Mikrodeletionssyndrom 22q11.2 (Di-George-Syndrom), Morbus Wilson und “Morbus Fahr” sowie die Gruppe der Neurodegenerationen mit Eisenablagerung im Gehirn (NBIAs) berücksichtigt werden.

ZusammenfassungDas idiopathische Parkinson-Syndrom ist nach der Alzheimer Erkrankung die zweithäufigste neurodegenerative Erkrankung und im fortgeschrittenen Stadium durch zahlreiche Besonderheiten gekennzeichnet. Neben nicht-motorischen Symptomen stehen oft motorische Komplikationen im Vordergrund, die mit pulsatilen oralen Therapien nur unzureichend verbessert werden können. Mithilfe der kontinuierlichen dopaminergen Stimulation lassen sich jedoch auch im fortgeschrittenen Stadium Optimierungen vornehmen, die neben der Verbesserung motorischer und nicht-motorischer Symptome auch eine höhere Lebensqualität erzielen können. Etabliert hat sich in diesem Zusammenhang die kontinuierliche subkutane Gabe von Apomorphin mittels Medikamentenpumpe, deren Nutzen, Indikationen, Anwendungsbeschränkungen und praktische Umsetzung in dieser Expertenempfehlung ausführlich dargestellt werden. Besonders hervorzuheben ist das vorteilhafte therapeutische Fenster der Apomorphin-Pumpentherapie, das durch einfache medikamentöse Titration bei einem schnell reversiblen Verfahren optimal ausgenutzt werden kann. Im vorliegenden Artikel werden die Ergebnisse eines Experten-Meetings zur Apomorphin-Therapie vorgestellt, das am 6. Juli 2016 in Frankfurt am Main stattgefunden hat.

Summary Background Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia. Methods For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow. Findings We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism. Interpretation In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations. Funding Else Kroner-Fresenius-Stiftung, Technische Universitat Munchen, Helmholtz Zentrum Munchen, Medizinische Universitat Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency.

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.

Patients with advanced Parkinson’s disease regularly experience unstable motor states. Objective and reliable monitoring of these fluctuations is an unmet need. We used deep learning to classify motion data from a single wrist-worn IMU sensor recording in unscripted environments. For validation purposes, patients were accompanied by a movement disorder expert, and their motor state was passively evaluated every minute. We acquired a dataset of 8,661 minutes of IMU data from 30 patients, with annotations about the motor state (OFF,ON, DYSKINETIC) based on MDS-UPDRS global bradykinesia item and the AIMS upper limb dyskinesia item. Using a 1-minute window size as an input for a convolutional neural network trained on data from a subset of patients, we achieved a three-class balanced accuracy of 0.654 on data from previously unseen subjects. This corresponds to detecting the OFF, ON, or DYSKINETIC motor state at a sensitivity/specificity of 0.64/0.89, 0.67/0.67 and 0.64/0.89, respectively. On average, the model outputs were highly correlated with the annotation on a per subject scale (r = 0.83/0.84; p

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.

Background Dystonia is clinically and genetically heterogeneous. Despite being a first-line testing tool for heterogeneous inherited disorders, whole-exome sequencing has not yet been evaluated in dystonia diagnostics. We set up a pilot study to address the yield of whole-exome sequencing for early-onset generalized dystonia, a disease subtype enriched for monogenic causation. Methods Clinical whole-exome sequencing coupled with bioinformatics analysis and detailed phenotyping of mutation carriers was performed on 16 consecutive cases with genetically undefined early-onset generalized dystonia. Candidate pathogenic variants were validated and tested for cosegregation. The whole-exome approach was complemented by analyzing 2 mutated yet unestablished causative genes in another 590 dystonia cases. Results Whole-exome sequencing detected clinically relevant mutations of known dystonia-related genes in 6 generalized dystonia cases (37.5%), among whom 3 had novel variants. Reflecting locus heterogeneity, identified unique variants were distributed over 5 genes (GCH1, THAP1, TOR1A, ANO3, ADCY5), of which only 1 (ANO3) was mutated recurrently. Three genes (GCH1, THAP1, TOR1A) were associated with isolated generalized dystonia, whereas 2 (ANO3, ADCY5) gave rise to combined dystonia-myoclonus phenotypes. Follow-up screening of ANO3 and ADCY5 revealed a set of distinct variants of interest, the pathogenicity of which was supported by bioinformatics testing and cosegregation work. Conclusions Our study identified whole-exome sequencing as an effective strategy for molecular diagnosis of early-onset generalized dystonia and offers insights into the heterogeneous genetic architecture of this condition. Furthermore, it provides confirmatory evidence for a dystonia-relevant role of ANO3 and ADCY5, both of which likely associate with a broader spectrum of dystonic expressions than previously thought. © 2016 International Parkinson and Movement Disorder Society.

Pozadi: Již schvalene produkty botulotoxinu A vyžaduji rekonstituci. Tekutý abobotulotoxin A je již připraven k přimemu použiti. Cile: Cilem teto studie byl průkaz vyssi efektivity tekute formy abobotulotoxinu A proti placebu a non-inferioritni ucinnost abobotulotoxinu A v tekute formě proti abobotulotoxinu A dodavaneho v praskove formě u cervikalni dystonie. Metody: Jednalo se o fazi 3, multicentrickou, prospektivni, dvojitě zaslepenou, randomizovanou, aktivni a placebem kontrolovanou studii (N=369). Pacient s cervikalni dystonii byli randomizovani (3:3:1) pro abobotulinumtoxin A v tekute formě 500 U, pro abobotulinumtoxin A 500 U dodavaný v praskove formě a pro placebo. Nasledně po dvojitě zaslepene fazi pak nemocni dostavali tekutý abobotulinumtoxin A v otevřene fazi studie a to po dobu 4 cyklů. Primarni cilem byla změna v týdnu 4 hodnocena pomoci TWSTRS (Toronto Western Spasmodic Torticollis Rating Scale) skore. Sekundarni cile byly – změny proti bazalni navstěvě ci zakladně navstěvě cyklu (TWSTRS). Výsledky: V týdnu 4 byly oba hodnocene produkty superiorni proti placebu. Sniženi TWSTRS skore proti placebu - pro tekutou formu -12.5, pro klasickou -14.0 a pro placebo -3.9. Limit noninferiority (3 body dle TWSTRS) nebyl v týdnu 4 dosažen pro tekutou formu, ale byl dosažen ve vsech cyklech extencni faze. Bezpecnostni profil byl stejný u obou hodnocených preparatů – dysfagie a bolesti v mistě aplikace. Zavěr: I když nebylo dosaženo kriteriu non-inferiority, je tekuta preparat podobně ucinný jako klasický preparat, kdy se vytvaři aplikacni forma rozpustěnim suche praskove formy. Nově zkousený tekutý preparat je urcen pro chronickou lecbu a vyznacuje se zlepsenými – vyhovujicimi podminkami při připravě preparatu k aplikaci.

Introduction Deep Brain Stimulation (DBS) is a complex, invasive and cost-intensive therapy that requires a high level of expertise. To date, data on quality of DBS in clinical routine in the German health care system are lacking. Methods The development of evidence-based QIs for DBS in PD patients was performed following a standardized process by a multidisciplinary board between 2014 and 2016. The process was initiated by the German Parkinson Society and followed international recommendations for developing QIs including: a systematic literature search; an appraisal of the published evidence; a consensus-based selection of the QI set; and a pilot study to assess the feasibility in implementing the QIs in clinical routine. Results A set of 28 QIs for determining the quality of DBS in PD was established by the board covering different dimensions of health care quality (structure, process, and outcome) in different treatment phases of DBS care (pre-operative, peri-operative, and post-operative). Implementation in clinical practice was tested in a pilot study comprising three hospitals delivering DBS care. The feasibility of the QI set was evaluated positively by the participating physicians and hospitals. Mean time to document one patient was 25 min. The German-wide implementation of the defined indicator set within a dedicated quality registry (QualiPa) started in June 2016. Conclusion QIs are a necessary requirement to monitor hospital performance in DBS care. The evidence-based approach to develop the proposed indicator set is expected to assure transparency, acceptance and long-term applicability of the QI set in Germany.

Background This phase 2 randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the nicotinic acetylcholine receptor α7 agonist AQW051 in patients with Parkinson's disease and levodopa-induced dyskinesia. Methods Patients with idiopathic Parkinson's disease and moderate to severe levodopa-induced dyskinesia were randomized to AQW051 10 mg (n = 24), AQW051 50 mg (n = 24), or placebo (n = 23) once daily for 28 days. Coprimary end points were change in Modified Abnormal Involuntary Movement Scale and Unified Parkinson's Disease Rating Scale part III scores. Secondary outcomes included pharmacokinetics. Results In total, 67 patients completed the study. AQW051-treated patients experienced no significant improvements in Modified Abnormal Involuntary Movement Scale or Unified Parkinson's Disease Rating Scale part III scores by day 28. AQW051 was well tolerated; the most common adverse events were dyskinesia, fatigue, nausea, and falls. Conclusions AQW051 did not significantly reduce dyskinesia or parkinsonian severity. © 2016 International Parkinson and Movement Disorder Society

ZusammenfassungMotorische Blockaden während des Gehens (engl. freezing of gait) behindern die motorische Selbstständigkeit und sind Ursache für ein gesteigertes Sturzrisiko bei Parkinson-Syndromen. Sie kommen während des Gehens in fünf Situationen vor und kennen drei Schweregrade. Motorische Blockaden sind therapeutisch schwer anzugehen, da sie in vielen Fällen unabhängig von L-Dopa-Gaben auftreten. Für diese als On-Freezing bezeichneten motorischen Blockaden ist das Münchner Anti-Freezing-Training (MAFT) konzipiert. Signifikante Resultate in der Reduktion von Freezing konnten nach zweiwöchigem Training gezeigt werden. MAFT trainiert standardisiert und intensiv die individuell Freezing auslösenden Situationen. Das Training umfasst fünf Komponenten: Motorische FOG-Evaluation, Einsatz von individuell zugeschnittenem Cueing, Schulung von Bewegungsstrategien, hochrepetitives Training von Schrittfolgen und systematische Steigerung der Trainingsanforderung.

ZusammenfassungDie Suche nach besseren symptomatischen Parkinson-Therapeutika hat in den letzten Jahren zahlreiche Neuentwicklungen hervorgebracht. Levodopa ist weiterhin zentraler Therapiebaustein. Die Hersteller suchen nach Wegen, um den Nachteil der kurzen Plasmahalbwertszeit dieser Aminosäure zu kompensieren. In den USA ist eine neue Levodopa-Carbidopa-Galenik mit einer langsameren Wirkstoffreissetzung für fluktuierende Parkinson-Patienten neu auf dem Markt. Hierzu werden eine inhalative und eine subkutane Darreichungsform des Levodopa klinisch geprüft. Der einzige erst jüngst neu zugelassene neue Wirkstoff seit 2007, das Safinamid, beeinflusst die Monoaminooxidase (MAO) sowie den Glutamatstoffwechsel und verspricht mehr dopaminerge Wirkung ohne Auslösung von Dyskinesien. Neue COMT-Inhibitoren sollen ebenso das Levodopa mittels einer Hemmung dieses Abbauweges besser verfügbar machen. Ältere Substanzen wie der NMDA-Inhibitor Amantadin werden neu aufgelegt, um Levodopa induzierte Dyskinesien zu behandeln. Die Gruppe der mGluR5-Antagonisten zielen ebenso auf diese Indikation ab. Mehrere Adenosinantagonisten wurden entwickelt, um über nicht dopaminerge Mechanismen Parkinson-Symptome zu reduzieren. Das Pimavanserin ist ein inverser Serotoninagonist der an psychotischen Parkinson-Patienten erfolgreich geprüft wurde. Eine Studie zu parkinsonassoziierten Schmerzen untersuchte die Kombination Oxycodon und Naloxon bei schweren Schmerzen mit gemischten Ergebnissen. Noch nicht einzuschätzen sind die Möglichkeiten immunotherapeutischer Ansätze, z. B. die „Parkinson-Impfung“ und monoklonale Antikörper, gegen Alphasynuklein, die inzwischen klinisch untersucht werden.

Extensive published evidence supports the use of subcutaneously-administered apomorphine as an effective therapy for Parkinson's disease (PD) but to date no consensus recommendations have been available to guide healthcare professionals in the optimal application of apomorphine therapy in clinical practice. This document outlines best-practice recommendations for selecting appropriate candidates for apomorphine intermittent injection (the pen-injection formulation) or apomorphine continuousinfusion (the pump formulation), for initiating patients onto therapy and for managing their ongoing treatment. Apomorphine is a suitable therapeutic option for PD patients who experience troublesome 'off periods despite optimized treatment with oral PD medications. Due to its speed of onset, apomorphine injection is particularly suited to those patients requiring rapid, reliable relief of both unpredictable and predictable 'off' periods, those who require reliable and fast relief when anticipating an 'off', those with levodopa absorption or gastric emptying problems resulting in delayed or failed 'on', or for rapid relief of early morning dystonia or akinesia. Apomorphine infusionl is suited for patients whose 'off periods can no longer be adequately controlled by standard oral PD treatment or for those in whom rescue doses of apomorphine injection are effective but either needed too frequently (more than 4-6 times per day), or are associated with increasing dyskinesia. In addition to treating motor fluctuations, there is evidence that apomorphine infusion may be effective for the management of specific non-motor symptoms of PD associated with 'off' periods. Apomorphine infusion is less invasive than other non-oral treatment options for advancing disease, intrajejunal levodopa infusion and deep-brain stimulation. (C) 2015 Elsevier Ltd. All rights reserved.

ZusammenfassungApomorphin ist der wohl älteste bekannte Dopaminagonist und wird seit langem in der Parkinsontherapie genutzt. Dabei ist die Bolustherapie mit Injektions-Pen von der kontinuierlichen subkutanen Infusion (csAI) zu unterscheiden. Eine Vielzahl von offenen Studien an mehreren hundert Patienten hat die Vorund Nachteile der csAI herausgearbeitet. Die Patientensicht auf dieses ressourcenintensive Verfahren ist nur selten untersucht. Wir stellen die Ergebnisse einer katamnestischen Befragung an 149 Patienten vor, die zwischen 2005 und 2011 eine Apomorphinpumpe an unserer Klinik erhielten. Die csAI wurde mit einer medianen Schulnote von 2,5 (IQR 2,0; 4,0) bewertet. 70,9% der Patienten würden die Therapie weiterempfehlen. Die Entwicklung von subkutanen Noduli war die häufigste berichtete Nebenwirkung bei 55% der Patienten.

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.

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.

OBJECTIVES: The aim of this study was to investigate the effects of piribedil on vigilance and cognitive performance in patients with Parkinson disease experiencing excessive daytime sleepiness on pramipexole or ropinirole. METHODS: In this 11-week randomized, active-controlled, rater-blinded phase III study, eligible patients were randomly assigned to either receive piribedil or to continue on pramipexole or ropinirole. The primary outcome was the median reaction times during the second 15 minutes of the subtest "vigilance" of the Test battery for Attention Performances (TAP). Secondary outcomes included the Epworth Sleepiness Scale, Unified Parkinson's Disease Rating Scale, neuropsychological testing, and items of the Clinical Global Impression. RESULTS: Forty-four patients received piribedil; 36 continued on either pramipexole or ropinirole. There was no difference in the primary end point reaction time of the TAP subtest vigilance between piribedil and the comparator (996 vs 954 milliseconds, P = 0.68). Piribedil reduced daytime sleepiness with lower Epworth Sleepiness Scale scores at the end of treatment compared with the comparator (-4 vs -2 points; P = 0.01). The median Unified Parkinson's Disease Rating Scale III score at the end of treatment was comparable between the 2 groups. Neuropsychological tests revealed no significant between-treatment differences. A higher therapeutic effect and global improvement were shown by the Clinical Global Impression of piribedil-treated patients. CONCLUSIONS: This study shows that switching from pramipexole or ropinirole to piribedil has no effect on the reaction time of the TAP subtest vigilance but upholds the same therapeutic motor effect and reduces daytime sleepiness to a clinically relevant degree in patients with excessive daytime sleepiness. Language: en

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 An increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts. Methods We screened the entire coding sequence and the 5′-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset. Results In the case cohort, we identified a rare 5′-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%. Conclusions Our study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.

Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA.The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia.This was a phase-3, multicenter, prospective, double-blind, randomized, active, and placebo-controlled study (N = 369). Patients with cervical dystonia were randomized (3:3:1) to abobotulinumtoxinA solution for injection 500 U, abobotulinumtoxinA 500 U, or placebo. Following the double-blind phase, patients received abobotulinumtoxinA solution for injection, open-label, for up to 4 cycles. The primary outcome was change from baseline at week 4 of the Toronto Western Spasmodic Torticollis Rating Scale total score. Secondary measures included change from baseline or cycle baseline in Toronto Western Spasmodic Torticollis Rating Scale scores.At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events.Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA. © 2016 International Parkinson and Movement Disorder Society.

The dopamine agonist rotigotine has shown efficacy and safety for the treatment of early and advanced Parkinson's disease (PD) in controlled clinical trials. This observational study evaluated rotigotine administration in combination with other antiparkinsonian medication in routine clinical practice.Data were collected by 688 German practice-based neurologists, initiating rotigotine treatment in patients with idiopathic Parkinson's disease. Assessments included rotigotine maintenance dose, changes in concomitant PD medication, changes in sleep quality, and rotigotine tolerability over an observation period of 12-16 weeks.The median rotigotine maintenance dose was 6 mg/24 h (n = 969, full analysis set). The proportion of all other prescribed PD medications declined over the observation period; combination therapy decreased by 18.7%. Daily levodopa intake was markedly reduced by 87 mg (18.9%) in 47.6% of the patients with levodopa documentation; 7% no longer required levodopa after 12-16 weeks. Mean overall sleep quality (PD Sleep Scale item 1) improved by 21.4 points, the occurrence of nocturias (PDSS item 8) by 13.4 points, and 'turning in bed' (Unified Parkinson's Disease Rating Scale part II) by 0.6 points. Drug-related adverse events were reported for 7.9% of all patients (n = 1152, safety population). Application site reactions were the most common adverse events (2.2%) resulting in early discontinuation in 1.4% of patients.In routine clinical practice, treatment initiation with rotigotine transdermal patch was associated with a reduction of other prescribed PD medications and with an improvement of self-reported sleep quality.