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© 2022 European Academy of Neurology, Background and purpose: Rare diseases affect up to 29 million people in the European Union, and almost 50% of them affect the nervous system or muscles. Delays in diagnosis and treatment onset and insufficient treatment choices are common. Clinical practice guidelines (CPGs) may improve the diagnosis and treatment of patients and optimize care pathways, delivering the best scientific evidence to all clinicians treating these patients. Recommendations are set for developing and reporting high-quality CPGs on rare neurological diseases (RNDs) within the European Academy of Neurology (EAN), through a consensus procedure. Methods: A group of 27 experts generated an initial list of items that were evaluated through a two-step Delphi consensus procedure and a face-to-face meeting. The final list of items was reviewed by an external review group of 58 members. Results: The consensus procedure yielded 63 final items. Items are listed according to the domains of the AGREE instruments and concern scope and purpose, stakeholder involvement, rigour of development, and applicability. Additional items consider reporting and ethical issues. Recommendations are supported by practical examples derived from published guidelines and are presented in two tables: (1) items specific to RND CPGs, and general guideline items of special importance for RNDs, or often neglected; (2) items for guideline development within the EAN. Conclusions: This guidance aims to provide solutions to the issues specific to RNDs. This consensus document, produced by many experts in various fields, is considered to serve as a starting point for further harmonization and for increasing the quality of CPGs in the field of RNDs.

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of-3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (+/- SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (+/- 674) and levodopa dose by 273 mg (+/- 515).Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson’s disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.

ObjectiveParkinson’s disease is characterised neuropathologically by α-synuclein aggregation. Currently, there is no blood test to predict the underlying pathology or distinguish Parkinson’s from atypical parkinsonian syndromes. We assessed the clinical utility of serum neuronal exosomes as biomarkers across the spectrum of Parkinson’s disease, multiple system atrophy and other proteinopathies.MethodsWe performed a cross-sectional study of 664 serum samples from the Oxford, Kiel and Brescia cohorts consisting of individuals with rapid eye movement sleep behavioural disorder, Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, corticobasal syndrome and controls. Longitudinal samples were analysed from Parkinson’s and control individuals. We developed poly(carboxybetaine-methacrylate) coated beads to isolate L1 cell adhesion molecule (L1CAM)-positive extracellular vesicles with characteristics of exosomes and used mass spectrometry or multiplexed electrochemiluminescence to measure exosomal proteins.ResultsMean neuron-derived exosomal α-synuclein was increased by twofold in prodromal and clinical Parkinson’s disease when compared with multiple system atrophy, controls or other neurodegenerative diseases. With 314 subjects in the training group and 105 in the validation group, exosomal α-synuclein exhibited a consistent performance (AUC=0.86) in separating clinical Parkinson’s disease from controls across populations. Exosomal clusterin was elevated in subjects with non-α-synuclein proteinopathies. Combined neuron-derived exosomal α-synuclein and clusterin measurement predicted Parkinson’s disease from other proteinopathies with AUC=0.98 and from multiple system atrophy with AUC=0.94. Longitudinal sample analysis showed that exosomal α-synuclein remains stably elevated with Parkinson’s disease progression.ConclusionsIncreased α-synuclein egress in serum neuronal exosomes precedes the diagnosis of Parkinson’s disease, persists with disease progression and in combination with clusterin predicts and differentiates Parkinson’s disease from atypical parkinsonism.

Despite over 30 years of clinical experience, high-quality studies on the efficacy of bilateral versus unilateral deep brain stimulation (DBS) of the ventral intermediate (VIM) nucleus of the thalamus for medically refractory essential tremor (ET) remain limited.To compare benefits and risks of bilateral versus unilateral VIM DBS using the largest ET DBS clinical trial dataset available to date.Participants from the US St. Jude/Abbott pivotal ET DBS trial who underwent staged-bilateral VIM implantation constituted the primary cohort in this sub-analysis. Their assessments "on" DBS at six months after second-side VIM DBS implantation were compared to the assessments six months after unilateral implantation. Two control cohorts of participants with unilateral implantation only were also used for between-group comparisons.The primary cohort consisted of n = 38 ET patients (22M/16F; age of 65.3 ± 9.5 years). The second side VIM-DBS resulted in a 29.6% additional improvement in the total motor CRST score (In the largest ET DBS study to date, staged-bilateral VIM DBS was a highly effective treatment for ET with bilateral implantation resulting in greater reduction in total motor tremor scores when compared to unilateral stimulation alone.

Although deep brain stimulation (DBS) of the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has become an established treatment for Parkinson’s disease (PD), a recent meta-analysis of outcomes is lacking. To address this gap, we performed a meta-analysis of bilateral STN- and GPi-DBS studies published from 1990-08/2019. Studies with ≥10 subjects reporting Unified Parkinson’s Disease Rating Scale (UPDRS) III motor scores at baseline and 6–12 months follow-up were included. Several outcome variables were analyzed and adverse events (AE) were summarized. 39 STN studies (2035 subjects) and 5 GPi studies (292 subjects) were eligible. UPDRS-II score after surgery in the stimulation-ON/medication-OFF state compared to preoperative medication-OFF state improved by 47% with STN-DBS and 18.5% with GPi-DBS. UPDRS-III score improved by 50.5% with STN-DBS and 29.8% with GPi-DBS. STN-DBS improved dyskinesia by 64%, daily OFF time by 69.1%, and quality of life measured by PDQ-39 by 22.2%, while Levodopa Equivalent Daily Dose (LEDD) was reduced by 50.0%. For GPi-DBS information regarding dyskinesia, OFF time, PDQ-39 and LEDD was insufficient for further analysis. Correlation analysis showed that preoperative L-dopa responsiveness was highly predictive of the STN-DBS motor outcome across all studies. Most common surgery-related AE were infection (5.1%) and intracranial hemorrhage (3.1%). Despite a series of technological advances, outcomes of modern surgery are still comparable with those of the early days of DBS. Recent changes in target selection with a preference of GPi in elderly patients with cognitive deficits and more psychiatric comorbidities require more published data for validation.

Objective To examine the aetiology of parkinsonian camptocormia, a non-fixed pathological forward bending of the trunk, by measuring trunk muscle activation and force regulation in Parkinson patients with (PD + CC) and without (PD) camptocormia matched for disease severity, and in age- and sex-matched healthy controls (HC). Methods The isometric forces of trunk extension and flexion were measured in PD + CC, PD and HC. Neuromuscular efficiency (increase of extension force per increase of paravertebral muscle surface electromyography signal) and the ability to maintain a constant submaximal trunk extension force were examined. Results Peak trunk extension force was significantly lower in PD + CC and PD than in HC, with PD + CC non-significantly weaker than PD. Compared with HC and with PD, the neuromuscular efficiency of trunk extension was significantly reduced in PD + CC. The variability of the force output (coefficient of variation) was significantly larger for PD + CC than for HC or PD. Conclusion The reduced neuromuscular efficiency of trunk extension separates PD + CC from PD. Moreover, control of the trunk extensor force is impaired in PD + CC. Significance There is weakness and a force control deficit in parkinsonian camptocormia suggesting a disturbed sensory-motor integration, which may contribute to myopathic changes in the trunk extensor muscles.

Background We previously showed that the protein pattern of lenses removed in cataract surgery differs between patients with Parkinson's disease and age-matched controls. In this study, we identified the protein reduced in abundance in the 34- to 37-kDa gel band. Methods During cataract surgery (phacoemulsification), we collected the rinsing fluid and lens particles from the eyes of PD patients and controls. Residual lens fragments in the supernatant of 3 PD patients and aged-matched controls were studied for protein profiles using liquid chromatography-mass spectrometry and Western blots. Results We identified glyceraldehyde-3-phosphate dehydrogenase by mass spectrometry as the protein reduced in abundance and verified this finding in Western blots. Conclusions Glyceraldehyde-3-phosphate dehydrogenase has been implicated in PD development. The reduction of glyceraldehyde-3-phosphate dehydrogenase in the lenses of PD patients may be a new biomarker for PD and might also indicate an important role for this protein in PD development. © 2016 International Parkinson and Movement Disorder Society

Background We aimed at critically appraising the clinimetric properties of existing pain scales or questionnaires and to give recommendations for their use in Parkinson's disease (PD). Methods Clinimetric properties of pain scales used in PD were systematically evaluated. A scale was classified as ‘recommended’ if was used in PD, showed adequate clinimetric properties, and had been used by investigators other than the original developers; as ‘suggested’ if it was used in PD and fulfilled only one other criterion; and as ‘listed’ if it was used in PD but did not meet the other criteria. Only scales rating pain intensity or for syndromic classification were assessed. Results Eleven of the 34 scales initially considered fulfilled inclusion criteria. Among the scales rating pain intensity, the “Brief Pain Inventory short form,” “McGill Pain Questionnaire short and long forms,” “Neuropathic Pain Symptoms Inventory,” “11-point Numeric Rating Scale,” “10-cm Visual Analog Scale,” and “Pain-O-Meter” were “recommended with caution” because of lack of clinimetric data in PD, whereas the “King's PD Pain Scale” was “recommended.” Among scales for pain syndromic classification, the “DN4” was “recommended with caution” because of lack of clinimetric data in PD; the “Leeds Assessment of Neuropathic Symptoms and Signs,” “Pain-DETECT,” and the “King's PD Pain Scale” were “suggested.” Conclusions King's PD pain scale can be recommended for the assessment of pain intensity in PD. Syndromic classification of pain in PD may be achieved by the DN4, but clinimetric data in PD are needed for this scale.

Das Kompetenznetz Parkinson (KNP) stellt eine Forschungsinfrastruktur fur krankheitsorientierte und klinische Forschung auf dem Gebiet der Parkinson-Syndrome (PS) dar. Es wurde von 1999 bis 2008 vom Bundesministerium fur Bildung und Forschung (BMBF) gefordert. Das KNP erstellte eine hoch frequentierte Webseite mit Informationen uber PS fur die Offentlichkeit und fur Wissenschaftler und Kliniker. Das KNP entwarf, programmierte und implementierte eines der ersten elektronischen internetbasierten Dateneingabesysteme (secuTrial®) – gemas den rechtlichen Vorgaben von Datenschutz und -sicherheit –, grundete eine Materialbank fur genetische Forschung uber die Parkinson-Krankheit (PK) und testete neue diagnostische Verfahren fur die Fruhdiagnose der PK und verwandter atypischer PS – wie z. B. die In-vivo-Dopamintransporter-Darstellung (DAT SPECT). Zudem baute das KNP die German Parkinson Study Group (GPS-Pharma) mit 40 zertifizierten klinischen Studienzentren fur pharmakotherapeutische Studien und die German Interdisciplinary Parkinson Study Group (Neurologie und Neurochirurgie) fur Tiefenhirnstimulation (GPS-DBS) auf und fuhrte mehrere versorgungs- und pharmakookonomische Untersuchungen uber die PK in Deutschland durch. Die Nachhaltigkeit wichtiger Teile der Infrastruktur des KNP wurde in Form der GPS-Pharma und der GPS-DBS sowie der Deutschen RBD-Studiengruppe zur Erforschung der REM-Schlaf-Verhaltensstorung (RBD), einer prodomalen Phase der PK, erzielt. Teile der im KNP geforderten Projekte wie die genetische Forschung und die Erforschung von Kohorten von ausgewahlten Parkinson-Patienten wurden in das Deutsche Zentrum fur neurodegenerative Erkrankungen (DZNE) integriert. Daruber hinaus werden einige Themen des KNP, wie z. B. die Versorgungsforschung, innerhalb von europaischen Forschungsprogrammen gefordert. Der Artikel beschreibt Probleme, die beim Aufbau eines Kompetenznetzwerkes – ohne dass Vorbilder existieren – auftreten, und enthalt Empfehlungen, wie diese in Zukunft zu vermeiden sind.

This document presents the Movement Disorder Society Clinical Diagnostic Criteria for Parkinson's disease (PD). The Movement Disorder Society PD Criteria are intended for use in clinical research but also may be used to guide clinical diagnosis. The benchmark for these criteria is expert clinical diagnosis; the criteria aim to systematize the diagnostic process, to make it reproducible across centers and applicable by clinicians with less expertise in PD diagnosis. Although motor abnormalities remain central, increasing recognition has been given to nonmotor manifestations; these are incorporated into both the current criteria and particularly into separate criteria for prodromal PD. Similar to previous criteria, the Movement Disorder Society PD Criteria retain motor parkinsonism as the core feature of the disease, defined as bradykinesia plus rest tremor or rigidity. Explicit instructions for defining these cardinal features are included. After documentation of parkinsonism, determination of PD as the cause of parkinsonism relies on three categories of diagnostic features: absolute exclusion criteria (which rule out PD), red flags (which must be counterbalanced by additional supportive criteria to allow diagnosis of PD), and supportive criteria (positive features that increase confidence of the PD diagnosis). Two levels of certainty are delineated: clinically established PD (maximizing specificity at the expense of reduced sensitivity) and probable PD (which balances sensitivity and specificity). The Movement Disorder Society criteria retain elements proven valuable in previous criteria and omit aspects that are no longer justified, thereby encapsulating diagnosis according to current knowledge. As understanding of PD expands, the Movement Disorder Society criteria will need continuous revision to accommodate these advances.

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.

Consensus criteria for classifying tremor disorders were published by the International Parkinson and Movement Disorder Society in 1998. Subsequent advances with regard to essential tremor, tremor associated with dystonia, and other monosymptomatic and indeterminate tremors make a significant revision necessary.Convene an international panel of experienced investigators to review the definition and classification of tremor.Computerized MEDLINE searches in January 2013 and 2015 were conducted using a combination of text words and MeSH terms: "tremor", "tremor disorders", "essential tremor", "dystonic tremor", and "classification" limited to human studies. Agreement was obtained using consensus development methodology during four in-person meetings, two teleconferences, and numerous manuscript reviews.Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part and is classified along two axes: Axis 1-clinical characteristics, including historical features (age at onset, family history, and temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurological), and laboratory tests (electrophysiology, imaging); and Axis 2-etiology (acquired, genetic, or idiopathic). Tremor syndromes, consisting of either isolated tremor or tremor combined with other clinical features, are defined within Axis 1. This classification scheme retains the currently accepted tremor syndromes, including essential tremor, and provides a framework for defining new syndromes.This approach should be particularly useful in elucidating isolated tremor syndromes and syndromes consisting of tremor and other signs of uncertain significance. Consistently defined Axis 1 syndromes are needed to facilitate the elucidation of specific etiologies in Axis 2. © 2017 International Parkinson and Movement Disorder Society.

Die Tiefe Hirnstimulation (THS) stellt eine effektive und evidenzbasierte Therapieoption in der Behandlung der Parkinsonerkrankung dar. Studien haben belegt, dass die THS gute und langanhaltende Effekte auf die Motorik und die Lebensqualitat der Patienten in einem fortgeschrittenen Krankheitsstadium hat und einer rein medikamentosen Therapie uberlegen ist. Erst kurzlich konnte nun auch eine positive Wirkung der THS in einem fruheren Stadium der Erkrankung nachgewiesen werden. Dem stehen die Risiken und Nebenwirkungen des Verfahrens gegenuber, die sich als prozedural-assoziierte Komplikationen, wie Blutungen und Infek­tionen, aber auch als Therapie-assoziierte Phanomene, wie etwa neuropsychiatrische Storungen und motorische Nebenwirkungen, manifestieren konnen. Dieser Ubersichtsartikel fasst die Ergebnisse randomisierter, kontrollierter Studien zusammen. Danach ist die THS der besten medikamentosen Behandlung schon fruher im Krankheitsverlauf, namlich beim ersten Auftreten von Wirkfluktuationen oder Dyskinesien, uberlegen und kann somit schon zu diesem Zeitpunkt als Therapieoption in Erwagung gezogen werden. Die strenge Indikationsstellung ist ebenso wie der Ausschluss von Kontraindikationen fur den Erfolg der Intervention entscheidend. Die Wahl des Zielpunktes sollte sich an der individuellen Symptomauspragung des Patienten ausrichten, wobei sich der Nucleus subthalamicus (STN) als Standardziel etabliert hat. In jedem Fall mussen eine individuelle Abwagung von Chancen und Risiken erfolgen und mit dem Patienten eine realistische Zielsetzung sowie angemessene Erwartungen formuliert werden.

Die tiefe Hirnstimulation (THS) stellt eine effektive und evidenzbasierte Therapieoption in der Behandlung der Parkinson-Erkrankung dar. Studien haben belegt, dass die THS gute und langanhaltende Effekte auf die Motorik und die Lebensqualitat der Patienten in einem fortgeschrittenen Krankheitsstadium hat und einer rein medikamentosen Therapie uberlegen ist. Erst kurzlich konnte nun auch eine positive Wirkung der THS in einem fruheren Stadium der Erkrankung nachgewiesen werden. Dem stehen die Risiken und Nebenwirkungen des Verfahrens gegenuber, die sich als prozedural-assoziierte Komplikationen, wie Blutungen und Infektionen, aber auch als therapieassoziierte Phanomene, wie etwa neuropsychiatrische Storungen und motorische Nebenwirkungen, manifestieren konnen. Trotz der guten Wirksamkeit der THS bleiben weiterhin wichtige klinische Fragen offen, denen sich diese Ubersichtsarbeit unter Berucksichtigung neuer randomisierter, kontrollierter Studien widmet. Nach diesen Studien ist die THS der besten medikamentosen Behandlung schon fruher im Krankheitsverlauf, namlich beim ersten Auftreten von Wirkfluktuationen oder Dyskinesien, uberlegen und kann somit schon zu diesem Zeitpunkt als Therapieoption in Erwagung gezogen werden. Die strenge Indikationsstellung ist ebenso wie der Ausschluss von Kontraindikationen fur den Erfolg der Intervention entscheidend. Die Wahl des Zielpunktes sollte sich an der individuellen Symptomauspragung des Patienten ausrichten, wobei sich der Nucleus subthalamicus (STN) als Standardziel etabliert hat. In jedem Fall mussen eine individuelle Abwagung von Chancen und Risiken erfolgen und mit dem Patienten eine realistische Zielsetzung sowie angemessene Erwartungen formuliert werden.

The Competence Network Parkinson (CNP) is a research infrastructure for disease-oriented translational and clinical research in the field of Parkinson syndromes (PS). It was initiated in 1999 and funded until 2008 by the German Ministry for Education and Research (BMBF). The CNP created a highly frequented website with information on PS for the general public and for experts. The CNP designed and established one of the first electronic internet-based data entry systems (secuTrial®) - fulfilling the legal standards of data safety and security - a material bank for genetic research on Parkinson's disease (PD), implemented and investigated new methods for early diagnosis of PD and related atypical PS including in vivo dopamine transporter imaging (DAT SPECT), established the German Parkinson Study Group (GPS-Pharma) with 40 certified trial centres for pharmacotherapeutical trials and the German interdisciplinary Parkinson Study Group (neurology and neurosurgery) for deep brain stimulation (GPS-DBS), and carried out several pharmacoeconomic and health care studies on PD in Germany. Sustainability of the infrastructure CNP has in part been achieved in form of the GPS-Pharma and the GPS-DBS, as well as in the German Study Group on REM Sleep Behaviour Disorder (RBD), a prodromal phase of PD. Part of the CNP activities, such as genetic research and research on cohorts of PD patients, have been incorporated into the German Center for Neurodegenerative Disorders (DZNE). Furthermore, topics such as health care research are funded within projects of the EU research program. The article describes problems in setting up a competence network from scratch and contains recommendations how to avoid them in the future.

Objective Patients with hereditary spastic paraplegia (HSP) show pathological findings when transcranial magnetic stimulation (TMS) is used to test corticospinal projections to the lower limbs. However, TMS studies on the pathways to the upper limbs revealed inconsistent results. Standard clinical TMS procedures are not well suited for testing axonal integrity, which is thought to be affected in HSP. More appropriate measures can be achieved by testing corticospinal projections with the triple stimulation technique (TST). Methods TST was used to test axonal integrity of corticospinal projections to the upper limbs in 15 patients with pure HSP (13 of whom were tested positive for SPG 4) and 15 healthy control subjects. Results TST measurements revealed normal values for corticospinal transmission in all 15 patients with pure HSP, as well as in all healthy control subjects. No differences between groups could be found. Conclusions Axonal integrity of projections to the upper limbs is unimpaired in patients with pure HSP. The pathological mechanisms leading to spasticity and motor disability seem to be restricted to those fibres of the corticospinal pathways projecting to the lower limbs. Significance Abnormal corticospinal function to the upper limbs seems to be incompatible with pure HSP.

Objective Tremor in Multiple Sclerosis is an important cause for disability. As medical treatment often does not provide a sufficient reduction of tremor amplitude, deep brain stimulation is an important option in these patients. Because in previous studies often unilateral stimulation of the VIM was performed, the aim of our retrospective analysis was to evaluate the effect of bilateral stimulation on tremor amplitude, activities of daily living, and due to an additional effect on axial tremor, improvement of global disability (EDSS) and mobility. Methods Data from 22 Patients (12 male an 10 female) were included in our analysis. Surgery was performed at the mean age of 37,7 (range 22–54). The present evaluation included Extended Disability Status Scale (EDSS) preoperatively and 3–6 month after surgery. The clinical tremor rating (Fahn Tolosa Marin Tremor Rating Scale A–C) was scored preoperatively, 3–6 month, 1–2 years, 3–5 years and >5 years postoperatively. Results After surgery the clinical tremor rating showed a significant improvement of tremor amplitude in the Stim-ON condition compared to baseline parameters before surgery 3–6 month (n = 16; Fahn A p = 0.005; Fahn B p = 0.003) and 1–2 years (n = 12; Fahn A p = 0.013; Fahn B p = 0.068) but no significant improvement 3–5 and >5 years after surgery. Concerning the activities of daily living (Fahn C) no significant change could be observed during the whole period. Two patients, who were dependent on a wheelchair because of severe tremor of the lower extremities, could walk with assistance during a postoperative period of 6 respectively 24 month. Expectedly no significant change of the EDSS score could be observed (mean 6.3; range 3–8) compared to preoperative values (mean 6.1; range 3.5–8.0). 3–6 month after surgery 6.3). Conclusion Global disability was not changed under treatment with bilateral stimulation of the VIM. A significant improvement of mobility was observed in only two of 22 patients, whereby impaired mobility in only 5 cases was caused by tremor and ataxia. An important problem are the tremor scales which do not appropriately reflect the changes in these most severely handicapped patients. Deep brain stimulation in Patients with Multiple Sclerosis can improve tremor amplitude, but the benefit beyond 2 years is limited. These limitations should be considered in shared decision making with the patient.

While the use of deep brain stimulation (DBS) for the treatment of neurological disorders has risen substantially over the last decade, it is often difficult to compare the results from different studies due to the lack of consistent reporting of key study parameters. We present guidelines to standardize the reporting of clinical studies of DBS for Parkinson's disease (PD). These guidelines provide a minimal set of required data elements to facilitate the interpretation and comparison of results across published clinical studies. The guidelines, summarized in the format of a checklist, may also have utility in the planning of clinical studies of DBS for PD as well as other neurological and psychiatric disorders.

The diagnosis of nonconvulsive status epilepticus (NCSE) can be a diagnostic challenge in emergency situations. A quick diagnosis and a consequent antiepileptic pharmacotherapy is necessary in order to achieve good outcome. However, NCSE is often initially not recognized since EEG is not always available in the emergency situation. Non-contrast enhanced cerebral computed tomography (CT) on the other hand is an established tool in the diagnosis of patients with acute stroke. It can be complemented by CT-angiography (CTA) and CT-perfusion (CTP) in many hospitals in emergency situations even outside of regular working hours. Here we report the case of an 82-year-old female patient who presented to our emergency room with right-sided hemiparesis, forced eye deviation towards the right and deep somnolence. CT with CTA did not show signs of acute cerebral ischemia or vascular occlusion, but CTP demonstrated cerebral hyperperfusion in the left parieto-occipital region. The patient received intravenous benzodiazepines because of clinically and morphologically suspected NCSE, which led to fast improvement of vigilance and neurological function. EEG on the following day showed regional slowing and epileptiform activity in the left parieto-occipital region. After one week of antiepileptic pharmacotherapy neither hyperperfusion nor epileptiform discharges were detectable. CTP is quickly accomplished, broadly available and rapidly evaluated. Our case report shows that CTP can help to establish a quick diagnosis of NCSE with subsequent therapy in the emergency situation. In order to shorten the latency until diagnosis is made, CTP should be considered as a diagnostic tool in patients with suspected NCSE.

Deep brain stimulation (DBS) in the nucleus ventralis intermedius thalami (VIM) is a common procedure to treat disabling tremor in multiple sclerosis which is refractory to pharmacological treatment. The sparse studies on DBS in multiple sclerosis tremor remain controversial regarding the clinical effect on postural and action tremor of hands, trunk and head. Furthermore, it remains unclear whether DBS in multiple sclerosis tremor is superior to thalamotomy and whether patients show an overall improvement in quality of life and activities of daily living. Therefore, the consensus recommendations of the German Deep Brain Stimulation Study Group rely primarily on expert opinion and include (1) extensive preoperative characterisation oftremor, ataxia with accompanying disabilities, status ofthe multiple sclerosis, co-morbidities and burden of disease, (2) careful intraoperative testing of effects and side effects and (3) intensive postoperative testing and programming as well as regular re-evaluation of the therapeutic effect.

Die tiefe Hirnstimulation (THS) im Nucleus ventralis intermedius des Thalamus (VIM) ist in Deutschland zur Behandlung eines pharmakotherapeutisch nicht beherrschbaren essenziellen Tremors zugelassen. Insbesondere ein alltagshinderlicher Handtremor lasst sich bessern, wahrend ein Kopf-, Zungen- oder Stimmtremor schlechter anspricht. Die Uberlegenheit der THS gegenuber einer Thalamotomie als lasionellem Verfahren in Bezug auf eine grosere funktionelle Verbesserung und geringere unerwunschte Wirkungen wurde nachgewiesen. Die hier vorgelegten Konsensusempfehlungen der Arbeitsgemeinschaft Tiefe Hirnstimulation fassen die Ein- und Ausschlusskriterien sowie Hinweise zum peri-, intra- und postoperativen neurologischen Management der THS bei essenziellem Tremor zusammen.

Deep brain stimulation (DBS) has been shown to be effective for levodopa-responsive symptoms and tremor in Parkinson’s disease (PD). The subthalamic nucleus (STN) is the preferred target for most patients suffering from late stage motor complications of the disorder. STN DBS is superior to best medical treatment concerning the control of motor fluctuations and the increase of on-time without dyskinesias. In contrast to DBS of the internal pallidum (GPi), STN stimulation also permits a reduction of the dopaminergic medication. Long-term data demonstrated sustained effectiveness of STN DBS despite progressive disease. DBS of the thalamic ventral intermediate nucleus (VIM) is an alternative target in older PD patients with severe PD tremor refractory to medication. In order to minimize potential risks and side effects, the use of DBS needs careful adherence to inclusion and exclusion criteria for eligible PD patients. This paper summarizes the current consensus recommendations of the German Deep Brain Stimulation Association for DBS in PD.

OFF-period dyskinesias have been reported as a consequence of fetal nigral transplantation for Parkinson's disease. This type of dyskinesias may appear in patients even in the prolonged absence of antiparkinson medication and be aggravated by levodopa. Therefore, pharmacological therapeutic approaches in these patients are limited. Here we report two patients with bilateral fetal nigral grafts in the caudate and putamen subjected to deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN). Clinical assessment was performed according to UPDRS and the clinical dyskinesia rating scale. In both patients, we found significant improvement in OFF-period symptoms as well as levodopa-induced dyskinesias. However, only GPi-DBS led to a significant reduction of OFF-period dyskinesias whereas STN-DBS did not influence dyskinesias unrelated to external dopaminergic application. These findings, based on two case reports, highlight the pivotal role of the GPi in mediating dyskinesia-related neural activity within the basal ganglia loop.

We report the case of a 57-year old female patient who presented with a gait disorder and sensory disturbances a few years after gastrectomy. In the neurological examination, clinical findings were similar to those observed in vitamin B 12 deficiency. T2-weighted images in the MRI of the spine showed an increased T2-signal involving the dorsal cervical cord. After exclusion of a vitamin B 12 deficiency, a copper deficiency was diagnosed causing the clinical symptoms and MRI findings. Copper deficiency as a cause of myelopathy is underrecognized. The clinical picture bears striking similarities to vitamin B12 deficiency and should be considered as a differential diagnosis.

Using coherence analysis (which is an extensively used method to study the correlations in frequency domain, between two simultaneously measured signals) we estimate the time delay between two signals. This method is suitable for time delay estimation of narrow band coherence signals for which the conventional methods cannot be reliably applied. We show by analysing coupled R\"ossler attractors with a known delay, that the method yields satisfactory results. Then, we apply this method to human pathologic tremor. The delay between simultaneously measured traces of Electroencephalogram (EEG) and Electromyogram (EMG) data of subjects with essential hand tremor is calculated. We find that there is a delay of 11-27 milli-seconds ($ms$) between the tremor correlated parts (cortex) of the brain (EEG) and the trembling hand (EMG) which is in agreement with the experimentally observed delay value of 15 $ms$ for the cortico-muscular conduction time. By surrogate analysis we calculate error-bars of the estimated delay., Comment: 21 pages, 8 figures, elstart.cls file included. Accepted for publication in Physica A

During the last few years, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as a promising therapy, alleviating major motor symptoms of Parkinson’s disease (PD). However, in times of growing budgetary limitations, medical decisions are no longer merely based on clinical efficacy, but also on cost-effectiveness. Here we assess treatment costs (i. e. costs for conservative pharmacological treatment and all in-patient admissions) of 46 PD patients for one year before and two years after STN-DBS. The present data show that total treatment costs were increased by 32 % for the first year and decreased by 54 % for the second year of STN-DBS in comparison with preoperative values while the Unified Parkinon’s Disease Rating Scale (UPDRS III) was significantly improved. The increase for the first year after surgery was mainly due to the implantation of the STN electrodes and the stimulation device. Taken together, STNDBS pays off from the second year of stimulation while motor symptoms are significantly improved. The present study provides first data of an important number of patients on clinical effectiveness and expenses in relation to STNDBS.

Die tiefe Hirnstimulation stellt eine wirkungsvolle Erweiterung der medikamentosen Behandlung von behindernden motorischen Symptomen bei neurologischen Bewegungsstorungen dar. Die Vorteile gegenuber ablativen stereotaktischen Verfahren liegen in der nur geringen Gewebsschadigung durch das Einbringen der Stimulationselektroden und der damit prinzipiell gegebenen Reversibilitat von unerwunschten Therapieeffekten. Weiterhin kann die Therapie durch Anderung der Stimulationsparameter an den Verlauf der Erkrankung angepast werden, so das uber Jahre hinaus die Moglichkeit der Therapieoptimierung gegeben ist. Die Hochfrequenzstimulation des Nucleus subthalamicus (STN) und Globus pallidus internus (GPi) bei M. Parkinson, des Nucleus ventralis intermedius thalami (VIM) bei essenziellem Tremor und des GPi bei Dystonien gelten als etablierte Therapieverfahren und fuhren zu einer messbaren Verbesserung der motorischen Symptome der betroffenen Patienten. Studien zur Erfassung der Einflusse auf die Lebensqualitat sind dringend erforderlich und werden aktuell fur M. Parkinson und Dystonien durchgefuhrt.

OBJECTIVES—Botulinum toxin injections have become a first line therapeutic approach in cervical dystonia. Nevertheless, published dosing schedules, responder rates, and frequency of adverse events vary widely. The present prospective multicentre placebo controlled double blind dose ranging study was performed in a homogenous group of previously untreated patients with rotational torticollis to obtain objective data on dose-response relations. METHODS—Seventy five patients were randomly assigned to receive treatment with placebo or total doses of 250, 500, and 1000 Dysport® units divided between one splenius capitis (0, 175, 350, 700 units) and the contralateral sternocleidomastoid (0, 75, 150, 300 units) muscle. Assessments were obtained at baseline and weeks 2, 4,and 8 after treatment and comprised a modified Tsui scale, a four point pain scale, a checklist of adverse events, global assessment of improvement, and a global rating taking into account efficacy and adverse events. At week 8 the need for retreatment was assessed and then the code was unblinded. For those still responding, there was an open follow up until retreatment to assess the duration of effect. RESULTS—seventy nine per cent reported subjective improvement at one or more follow up visits. Decreases in the modified Tsui score were significant at week 4 for the 500 and 1000 unit groups versus placebo (p

Sirs: Sporadic spastic paraplegia (SSP) and hereditary spastic paraplegia (HSP) are heterogeneous neurodegenerative disorders. On physical examination spasticity of the lower limbs is often predominant, whereas paraparesis may be mild [1, 2]. The gait disorder of SSP/HSP patients which is the cardinal source of disability in these patients has been recently characterized [3]. The treatment of spastic paraplegia is symptomatic and limited to oral antispastic drugs and physiotherapy. In 1984 Penn [4] showed that intrathecal baclofen (ITB) could alleviate spinal cord spasticity. The efficacy of ITB on spasticity has been proven in several studies [5, 6]. In these studies ITB was used as a symptomatic treatment to reduce painful spasm and muscle contractions in mostly wheelchair bound patients. However, SSP/HSP patients are often able to walk even in advanced stages of their disease. Therefore, ITB therapy in SSP/HSP has the special requirement of reducing spasticity but preserving gait function. So far most clinical trials on spasticity rely on rating scales such as the modified “Ashworth Scale of Spasticity” (ASH), which may not adequately reflect the functional benefit in gait in SSP/HSP patients. In the particular case of ITB therapy for SSP/HSP the indication for an ITB pump implantation should moreover be based on the global clinical impression of gait improvement after an ITB test injection. Unfortunately, there are no scientific operational data to test the functional benefit of ITB in SSP/HSP. Here we describe the clinical effect of ITB in 10 patients, who were all treated with oral antispastic drugs and ongoing physiotherapy. Additionally we tested the usefulness of a three-dimensional movement analysis system for the selection of candidates for an ITB pump implantation. The gait of 10 SSP/HSP patients before and after a testing dose of 25 or 50 μg ITB was examined with this method, which is described elsewhere in detail [7]. In cooperation with the responsible physiotherapists we clinically distinguished responders (group 1; n = 5) from non responders (group 2; n = 5) based on the global clinical impression of gait improvement after ITB. Group 1 was recommended for an ITB pump implantation, whereas group 2 was not. With respect to spastic tone SSP/HSP patients showed a significant reduction of the ASH after ITB (p = 0.014). These result are comparable to the study of Penn et al. who analysed the effect of ITB via an implanted pump system [6]. We found an increased gait velocity accompanied by larger step length and a reduced step width after ITB in all patients, but no significant change in other kinematic gait parameters at a self chosen comfortable speed. Additionally, gait analysis was also performed with a fixed velocity of 1 km/h to eliminate the variable influence of speed. Under this condition group 1 presented an increased range of motion (ROM) of the ankle angle. Furthermore group 1 showed a reduction of the minimum knee angle as shown in a patient in Fig. 1. Gait parameters alone, however, did not allow us to separate clinical responders and non responders. An ITB pump implantation was performed in three of the five screened patients of group 1. Two patients did not opt for ITB owing to subjective unsteadiness and weakness in the lower extremities. We were able to collect follow up gait analysis data of two patients under chronic ITB. Both patients showed an effect of chronic ITB (mean dosage 60 μg/day), which was equivalent to the effect of the test bolus (Fig. 2). In conclusion, our findings show that ITB is a potential treatment option in SSP/HSP. However, only 50 % of our patients were recommended for a pump implantation. Therefore it can be assumed that all patients showed a variable effect of ITB that was probably too strong and a formerly existing weakness was unmasked by the ITB in some patients. In the quantitative gait analysis an improvement of gait was documented in the gait velocity and the step length. However, gait analysis alone was not able to discriminate between clinical responders and non-responders. This may be due to the relatively small number of investigated patients. If so, in the individual patient the clinical examination of gait before and after bolus injection of ITB in a multidisciplinary assessment by a neurologist and physiotherapists experienced with gait disorders is decisive and cannot be replaced by a technical assessment alone.

The purpose of this review is to explain a practical clinical approach to the diagnosis and management of tremor.A number of rare but important causes of tremor have been delineated, which means that attention to detail in clinical assessment of patients with tremor is even more important.Tremors are best divided into those occurring mainly at rest, mainly on posture, and mainly during action. This basic division leads directly to differential diagnosis and effective treatment.

Summary Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.