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Background: Postural instability is a major disabling factor in patients with advanced Parkinson’s disease (PD) and often resistant to treatment. Previous studies indicated that imbalance in PD may be reduced by low-intensity noisy galvanic vestibular stimulation (nGVS). Objective: To investigate the potential mode of action of this therapeutic effect. In particular, we examined whether nGVS-induced reductions of body sway in PD are compatible with stochastic resonance (SR), a mechanism by which weak sensory noise stimulation can paradoxically enhance sensory information transfer. Methods: Effects of nGVS of varying intensities (0–0.7 mA) on body sway were examined in 15 patients with PD standing with eye closed on a posturographic force plate. We assumed a bell-shaped response curve with maximal reductions of sway at intermediate nGVS intensities to be indicative of SR. An established SR-curve model was fitted on individual patient outcomes and three experienced human raters had to judge whether responses to nGVS were consistent with the exhibition of SR. Results: nGVS-induced reductions of body sway compatible with SR were found in 10 patients (67%) with optimal improvements of 23±13%. In 7 patients (47%), nGVS-induced sway reductions exceeded the minimally important clinical difference (optimal improvement: 30±10%), indicative of strong SR. This beneficial effect was more likely in patients with advanced PD (R = 0.45; p = 0.045). Conclusions: At least half of the assessed patients showed robust improvements in postural balance compatible with SR when treated with low-intensity nGVS. In particular, patients with more advanced disease stages and imbalance may benefit from the non-invasive and well-tolerated treatment with nGVS.

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.

Mutations in SOX6 have recently been recognized as a new molecular cause of neurodevelopmental disorders characterized by intellectual disability, behavioral changes, and nonspecific facial and digital skeletal abnormalities. To date,25 cases have been reported in the literature.Here we report a new case of SOX6-associated neurodegeneration and expand the phenotype to include ceratoconus. The clinical picture consisted of early onset mildly reduced intellectual function, facial asymmetry, and dystonic tremor of hands and neck, substantially improved by levodopa. Skeletal abnormalities included scoliosis and hypertrophy of the mandibular coronoid process. A heterozygous de novo loss-of-function variant in SOX6 (c.277 CT. p.Arg93*) was molecularly confirmed which leads to truncation of the SOX6 protein in its N-terminus, upstream of any known functional domain.SOX6-associated neurodevelopmental delayis ultrarare with less than 25 cases described in the literature. We report a new case who presented with early-onset mildly reduced intellectual function, facial asymmetry, skeletal abnormalities and dystonic tremor of hands and neck, substantially improved by levodopa. Given the therapeutic implications, SOX6 mutations should be considered in patients with complex dystonia parkinsonism.

Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy movement disorder that can be imaged by the (18)F-labeled tau PET tracer 2-(2-([(18)F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c′]dipyridine ((18)F-PI-2620). The in vivo diagnosis is currently established on clinical grounds and supported by midbrain atrophy estimation in structural MRI. Here, we investigate whether (18)F-PI-2620 tau PET has the potential to improve the imaging diagnosis of PSP. Methods: In this multicenter observational study, dynamic (0–60 min after injection) (18)F-PI-2620 PET and structural MRI data for 36 patients with PSP, 22 with PSP–Richardson syndrome, and 14 with a clinical phenotype other than Richardson syndrome (i.e., variant PSP) were analyzed along with data for 10 age-matched healthy controls (HCs). The PET data underwent kinetic modeling, which resulted in distribution volume ratio (DVR) images. These and the MR images were visually assessed by 3 masked experts for typical PSP signs. Furthermore, established midbrain atrophy parameters were measured in structural MR images, and regional DVRs were measured in typical tau-in-PSP target regions in the PET data. Results: Visual assessments discriminated PSP patients and HCs with an accuracy of 63% for MRI and 80% for the combination of MRI and (18)F-PI-2620 PET. As compared with patients of the PSP–Richardson syndrome subgroup, those of the variant PSP subgroup profited more in terms of sensitivity from the addition of the visual (18)F-PI-2620 PET to the visual MRI information (35% vs. 22%). In quantitative image evaluation, midbrain-to-pons area ratio and globus pallidus DVRs discriminated best between the PSP patients and HCs, with sensitivities and specificities of 83% and 90%, respectively, for MRI and 94% and 100%, respectively, for the combination of MRI and (18)F-PI-2620 PET. The gain of sensitivity by adding (18)F-PI-2620 PET to MRI data was more marked in clinically less affected patients than in more affected patients (37% vs. 19% for visual, and 16% vs. 12% for quantitative image evaluation). Conclusion: These results provide evidence for an improved imaging-based PSP diagnosis by adding (18)F-PI-2620 tau PET to structural MRI. This approach seems to be particularly promising at earlier disease stages and could be of value both for improving early clinical PSP diagnosis and for enriching PSP cohorts for trials of disease-modifying drugs.

Dopamine metabolism, alpha-synuclein pathology, and iron homeostasis have all been implicated as potential contributors to the unique vulnerability of substantia nigra dopaminergic neurons which preferentially decline in Parkinson's disease and some rare neurodegenerative disorders with shared pathological features. However, the mechanisms contributing to disease progression and resulting in dopaminergic neuron loss in the substantia nigra are still not completely understood. Increasing evidence demonstrates that disrupted dopamine, alpha-synuclein, and/or iron pathways, when combined with the unique morphological, physiological, and metabolic features of this neuron population, may culminate in weakened resilience to multiple stressors. This review analyzes the involvement of each of these pathways in dopamine neuron physiology and function, and discusses how disrupted interplay of dopamine, alpha-synuclein, and iron pathways may synergize to promote pathology and drive the unique vulnerability to disease states. We suggest that elucidating the interactions of dopamine with iron and alpha-synuclein, and the role of dopamine metabolism in driving pathogenic phenotypes will be critical for developing therapeutics to prevent progression in diseases that show degeneration of nigral dopamine neurons such as Parkinson's disease and the rare family of disorders known as Neurodegeneration with Brain Iron Accumulation.

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

ZusammenfassungIm späteren Verlauf der Parkinson-Krankheit besteht ein hohes Risiko, neben der charakterisierenden motorischen Symptomatik beeinträchtigende kognitive Funktionsstörungen zu entwickeln. Dieser Störungskomplex kann maßgeblich den klinischen Verlauf bei Patienten in fortgeschrittenen Krankheitsstadien bestimmen. Der Artikel umschreibt knapp das pathophysiologische Konzept kognitiver Beeinträchtigungen bei Parkinson. Er benennt relevante Differenzierungen, die Wege zur Diagnose und aktuelle therapeutische Herangehensweisen.

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.

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.

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.

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.

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.

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.

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.

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.

We studied the clinical impact of neutralizing antibodies to botulinum toxin A that occurred during long-term treatment of children between 1993 and 2001. Antibodies were found in high titers in 35 of 110 (31.8%) samples from individual patients. Antibody formation correlated with secondary nonresponse (p < 0.001). The most significant risk factors for antibody formation were the frequency of treatments (p = 0.0001) and the injection of a higher weight-adapted maximum dose per treatment (p = 0.001).

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.

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.