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Introduction: A significant number of patients who present with mild symptoms following large-vessel occlusion acute ischemic stroke (LVO-AIS) are currently considered ineligible for EVT. However, they frequently experience neurological deterioration during hospitalization. This study aimed to investigate the association between neurological deterioration and hemodynamic impairment by assessing steal phenomenon derived from blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) in this specific patient cohort., Patients and Methods: From the database of our single-center BOLD-CVR observational cohort study (June 2015-October 2023) we retrospectively identified acute ischemic stroke patients with admission NIHSS < 6, a newly detected large vessel occlusion of the anterior circulation and ineligible for EVT. Neurological deterioration during hospitalization as well as outcome at hospital discharge were rated with NIHSS score. We analyzed the association between these two outcomes and BOLD-CVR-derived steal phenomenon volume through regression analysis. Additionally, we investigated the discriminatory accuracy of steal phenomenon volume for predicting neurological deterioration., Results: Forty patients were included in the final analysis. Neurological deterioration occurred in 35% of patients. In the regression analysis, a strong association between steal phenomenon volume and neurological deterioration (OR 4.80, 95% CI 1.32-31.04, p  = 0.04) as well as poorer NIHSS score at hospital discharge (OR 3.73, 95% CI 1.52-10.78, p  = 0.007) was found. The discriminatory accuracy of steal phenomenon for neurological deterioration prediction had an AUC of 0.791 (95% CI 0.653-0.930)., Discussion: Based on our results we may distinguish two groups of patients with minor stroke currently ineligible for EVT, however, showing hemodynamic impairment and exhibiting neurological deterioration during hospitalization: (1) patients exhibiting steal phenomenon on BOLD-CVR imaging as well as hemodynamic impairment on resting perfusion imaging; (2) patients exhibiting steal phenomenon on BOLD-CVR imaging, however, no relevant hemodynamic impairment on resting perfusion imaging., Conclusion: The presence of BOLD-CVR derived steal phenomenon may aid to further study hemodynamic impairment in patients with minor LVO-AIS not eligible for EVT., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: Uncertainty remains regarding antithrombotic treatment in cervical artery dissection. This analysis aimed to explore whether certain patient profiles influence the effects of different types of antithrombotic treatment., Methods: This was a post hoc exploratory analysis based on the per-protocol dataset from TREAT-CAD (NCT02046460), a randomized controlled trial comparing aspirin to anticoagulation in patients with cervical artery dissection. We explored the potential effects of distinct patient profiles on outcomes in participants treated with either aspirin or anticoagulation. Profiles included (1) presenting with ischemia (no/yes), (2) occlusion of the dissected artery (no/yes), (3) early versus delayed treatment start (median), and (4) intracranial extension of the dissection (no/yes). Outcomes included clinical (stroke, major hemorrhage, death) and magnetic resonance imaging outcomes (new ischemic or hemorrhagic brain lesions) and were assessed for each subgroup in separate logistic models without adjustment for multiple testing., Results: All 173 (100%) per-protocol participants were eligible for the analyses. Participants without occlusion had decreased odds of events when treated with anticoagulation (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.07-0.86). This effect was more pronounced in participants presenting with cerebral ischemia (n = 118; OR = 0.16, 95% CI = 0.04-0.55). In the latter, those with early treatment (OR = 0.26, 95% CI = 0.07-0.85) or without intracranial extension of the dissection (OR = 0.34, 95% CI = 0.11-0.97) had decreased odds of events when treated with anticoagulation., Interpretation: Anticoagulation might be preferable in patients with cervical artery dissection presenting with ischemia and no occlusion or no intracranial extension of the dissection. These findings need confirmation. ANN NEUROL 2024;95:886-897., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Bleeding and thromboembolic (TE) complications in neurosurgical diseases have a detrimental impact on clinical outcomes. The aim of this study is to provide a scoping review of the available literature and address challenges and knowledge gaps in the management of coagulation disorders in neurosurgical diseases. Additionally, we introduce a novel research project that seeks to reduce coagulation disorder-associated complications in neurosurgical patients. The risk of bleeding after elective craniotomy is about 3%, and higher (14-33%) in other indications, such as trauma and intracranial hemorrhage. In spinal surgery, the incidence of postoperative clinically relevant bleeding is approximately 0.5-1.4%. The risk for TE complications in intracranial pathologies ranges from 3 to 20%, whereas in spinal surgery it is around 7%. These findings highlight a relevant problem in neurosurgical diseases and current guidelines do not adequately address individual circumstances. The multidisciplinary COagulation MAnagement in Neurosurgical Diseases (COMAND) project has been developed to tackle this challenge by devising an individualized coagulation management strategy for patients with neurosurgical diseases. Importantly, this project is designed to ensure that these management strategies can be readily implemented into healthcare practices of different types and with sustainable integration.

Objectives: Intracranial atherosclerotic disease (ICAD) is a major cause of large vessel occlusion (LVO) in acute ischemic stroke (AIS). Our study aimed to analyze the effect of percutaneous transluminal angioplasty and stenting (PTAS) in patients with ICAD undergoing rescue treatment in terms of functional outcome and mortality rate at 90 days and compare the results to LVO with thromboembolic origins., Materials and Methods: A retrospective review of a mechanical thrombectomy (MT) single center database from 01/2019 to 09/2021 was carried out using chart review and angiogram analysis. From 469 acute stroke patients, 361 patients were enroled in the study, of whom twenty-four (6.6%) were diagnosed with underlying ICAD and treated with angioplasty and stent reconstruction (PTAS) with a standardized medication protocol. Successful reperfusion, peri-procedural complications, and functional independence at 90 days were collected as outcomes., Results: There was no difference in age or admission National Institutes of Health Stroke Scale (NIHSS). Onset to groin puncture (median 460 vs 277 min, P = 0.019) was significantly longer in the ICAD group. The procedure time (median 73 vs 60 min, P = 0.137) did not differ. Successful reperfusion was achieved in 95.8% of ICAD and 91.1% of the remaining patients (P = 0.445). Functional independence (mRS ≤ 2) at 90 days was achieved in 45.8% (11/24) and 42.7% (144/337, (P = 0.767)). The mortality rates (mRS 6) at 90 days were similar (29.2% vs 29.4% (P = 0.983))., Conclusion: Despite significantly longer treatment delays, the outcome and revascularization rates of ICAD patients were similar to the thromboembolic cohort. Our proposed protocol of PTAS and medication protocol in ICAD was effective with a similar safety profile as MT in general., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Purpose: Mechanical thrombectomy is less effective in patients aged 80 years or older. Our goal was to better understand the impact of age in general on recanalization rates and clinical outcome., Methods: We performed a retrospective analysis of our prospective database of adult patients with acute ischemic stroke due to large vessel occlusions, who had undergone mechanical thrombectomy between 2019 and mid-2021. The cohort was categorized into five age groups: 18 - 49, 50 - 59, 60 - 69, 70 - 79 and ≥ 80 years. Our primary outcome measure was clinical outcome at three months after mechanical thrombectomy, measured by the mRS score. Secondary outcomes were procedure times and rates of successful recanalization, defined by mTICI ≥ 2b., Results: Data of 264 patients were analyzed. There were no significant differences in procedure times (p = 0.46) or in rates of successful recanalization (p = 0.49) between age groups. There was a significant association of age and mRS score at three months (p < 0.0001): From youngest to oldest group, odds of functional independence (mRS ≤ 2) decreased (80.0% vs. 21.3%) and odds of death (mRS 6) increased (13.3% vs. 57.3%). Increasing age was significantly associated with lower rates of functional independence (OR 0.93; [95% CI 0.90 - 0.95]), higher rates of care dependency (OR 1.04; [95% CI 1.01 - 1.07]) and higher mortality rates (OR 1.06; [95% CI 1.04 - 1.09])., Conclusion: Higher age had no significant impact on recanalization times or recanalization rates but was strongly associated with worse clinical outcome after mechanical thrombectomy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Despite evolving treatments, functional recovery in patients with large vessel occlusion stroke remains variable and outcome prediction challenging. Can we improve estimation of functional outcome with interpretable deep learning models using clinical and magnetic resonance imaging data?, Methods: In this observational study, we collected data of 222 patients with middle cerebral artery M1 segment occlusion who received mechanical thrombectomy. In a 5-fold cross validation, we evaluated interpretable deep learning models for predicting functional outcome in terms of modified Rankin scale at 3 months using clinical variables, diffusion weighted imaging and perfusion weighted imaging, and a combination thereof. Based on 50 test patients, we compared model performances to those of 5 experienced stroke neurologists. Prediction performance for ordinal (modified Rankin scale score, 0-6) and binary (modified Rankin scale score, 0-2 versus 3-6) functional outcome was assessed using discrimination and calibration measures like area under the receiver operating characteristic curve and accuracy (percentage of correctly classified patients)., Results: In the cross validation, the model based on clinical variables and diffusion weighted imaging achieved the highest binary prediction performance (area under the receiver operating characteristic curve, 0.766 [0.727-0.803]). Performance of models using clinical variables or diffusion weighted imaging only was lower. Adding perfusion weighted imaging did not improve outcome prediction. On the test set of 50 patients, binary prediction performance between model (accuracy, 60% [55.4%-64.4%]) and neurologists (accuracy, 60% [55.8%-64.21%]) was similar when using clinical data. However, models significantly outperformed neurologists when imaging data were provided, alone or in combination with clinical variables (accuracy, 72% [67.8%-76%] versus 64% [59.8%-68.4%] with clinical and imaging data). Prediction performance of neurologists with comparable experience varied strongly., Conclusions: We hypothesize that early prediction of functional outcome in large vessel occlusion stroke patients may be significantly improved if neurologists are supported by interpretable deep learning models., Competing Interests: Disclosures Dr Heldner reports grants from the Bangerter Foundation, the Swiss National Science Foundation, SITEM (Center for Translational Medicine and Biomedical Entrepreneurship) Support Funds, and the Swiss Heart Foundation, all outside the submitted work. Dr Antonenko reports a grant from the Swiss National Science Foundation. Dr Dobrocky reports consultant fees for MicroVention, Inc. Dr Fischer reports grants from Alexion, CSL Behring, Medtronic, Penumbra, Inc, Phenox, Inc, Rapid Medical, Ltd, and Stryker. Dr Gralla reports interests with Medtronic USA, Inc. Dr Arnold reports consultancy fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Pfizer, Boehringer Ingelheim, Covidien, Medtronic, and Novo Nordisk. Dr Luft reports consultancy fees from Amgen and Moleac, Ltd. Susanne Wegener received research funds by the Swiss National Science Foundation, the UZH Clinical research priority program (CRPP) stroke, the Swiss Heart foundation, the Zurich Neuroscience Center (ZNZ), speaker honoraria from Springer, Teva Pharma, and consultancy fees from Bayer and Novartis. The other authors report no conflicts.

Background: Autoregulation of the cerebral vasculature keeps brain perfusion stable over a range of systemic mean arterial pressures to ensure brain functioning, e.g., in different body positions. Verticalization, i.e., transfer from lying (0°) to upright (70°), which causes systemic blood pressure drop, would otherwise dramatically lower cerebral perfusion pressure inducing fainting. Understanding cerebral autoregulation is therefore a prerequisite to safe mobilization of patients in therapy., Aim: We measured the impact of verticalization on cerebral blood flow velocity (CBFV) and systemic blood pressure (BP), heart rate (HR) and oxygen saturation in healthy individuals., Methods: We measured CBFV in the middle cerebral artery (MCA) of the dominant hemisphere in 20 subjects using continuous transcranial doppler ultrasound (TCD). Subjects were verticalized at 0°, -5°, 15°, 30°, 45° and 70° for 3-5 min each, using a standardized Sara Combilizer chair. In addition, blood pressure, heart rate and oxygen saturation were continuously monitored., Results: We show that CBFV progressively decreases in the MCA with increasing degrees of verticalization. Systolic and diastolic BP, as well as HR, show a compensatory increase during verticalization., Conclusion: In healthy adults CBFV changes rapidly with changing levels of verticalization. The changes in the circulatory parameters are similar to results regarding classic orthostasis., Registration: ClinicalTrials.gov, identifier: NCT04573114., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deseoe, Schwarz, Pipping, Lehmann, Veerbeek, Luft, Wegener, Globas and Held.)

Background and Purpose: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms., Methods: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death., Results: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable., Conclusions: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

The ability to learn is assumed to support successful recovery and rehabilitation therapy after stroke. Hence, learning impairments may reduce the recovery potential. Here, the hypothesis is tested that stroke survivors have deficits in feedback-driven implicit learning. Stroke survivors (n=30) and healthy age-matched control subjects (n=21) learned a probabilistic classification task with brain activation measured using functional magnetic resonance imaging in a subset of these individuals (17 stroke and 10 controls). Stroke subjects learned slower than controls to classify cues. After being rewarded with a smiley face, they were less likely to give the same response when the cue was repeated. Stroke subjects showed reduced brain activation in putamen, pallidum, thalamus, frontal and prefrontal cortices and cerebellum when compared with controls. Lesion analysis identified those stroke survivors as learning-impaired who had lesions in frontal areas, putamen, thalamus, caudate and insula. Lesion laterality had no effect on learning efficacy or brain activation. These findings suggest that stroke survivors have deficits in reinforcement learning that may be related to dysfunctional processing of feedback-based decision-making, reward signals and working memory., (Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.)

See Klockgether (doi:10.1093/awv253) for a scientific commentary on this article.The spinocerebellar ataxias types 2 (SCA2) and 3 (SCA3) are autosomal dominantly inherited cerebellar ataxias which are caused by CAG trinucleotide repeat expansions in the coding regions of the disease-specific genes. Although previous post-mortem studies repeatedly revealed a consistent neurodegeneration of the dopaminergic substantia nigra in patients with SCA2 and with SCA3, parkinsonian motor features evolve only rarely. As the pathophysiological mechanism how SCA2 and SCA3 patients do not exhibit parkinsonism is still enigmatic, we performed a positron emission tomography and a post-mortem study of two independent cohorts of SCA2 and SCA3 patients with and without parkinsonian features. Positron emission tomography revealed a significant reduction of dopamine transporter levels in the striatum as well as largely unaffected postsynaptic striatal D2 receptors. In spite of this remarkable pathology in the motor mesostriatal pathway, only 4 of 19 SCA2 and SCA3 patients suffered from parkinsonism. The post-mortem investigation revealed, in addition to an extensive neuronal loss in the dopaminergic substantia nigra of all patients with spinocerebellar ataxia, a consistent affection of the thalamic ventral anterior and ventral lateral nuclei, the pallidum and the cholinergic pedunculopontine nucleus. With the exception of a single patient with SCA3 who suffered from parkinsonian motor features during his lifetime, the subthalamic nucleus underwent severe neuronal loss, which was clearly more severe in its motor territory than in its limbic or associative territories. Our observation that lesions of the motor territory of the subthalamic nucleus were consistently associated with the prevention of parkinsonism in our SCA2 and SCA3 patients matches the clinical experience that selective targeting of the motor territory of the subthalamic nucleus by focal lesions or deep brain stimulation can ameliorate parkinsonian motor features and is likely to counteract the manifestation of parkinsonism in SCA2 and SCA3 despite a severe neurodegeneration of the dopaminergic substantia nigra., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Unlabelled: The aim of this study was to explore the increased risk of stroke survivors to different sustained osteoporotic fractures. We used hospital data and data on functional impairment. We found a higher risk in stroke survivors without functional impairment with the risk higher for lower than for upper extremity fractures., Introduction: Stroke survivors are at high risk of osteoporotic fractures due to frequent falls and an increased risk to develop osteoporosis. Data on their relative risk to sustain other than hip fractures is limited. Furthermore, the role of severe functional impairment on their fracture risk has not been considered yet. The aim of this study was to determine the relative risk of stroke survivors to sustain different osteoporotic fractures with regard to the presence of severe functional impairment., Methods: Data from 2004 to 2009 of more than 1.2 million individuals aged 65 years or older and insured at a large German health insurance company were used for the analyses. Incident stroke and fractures were obtained from hospital diagnoses. Analyses were stratified by gender and information on severe functional impairment. Persons without preceding incident stroke were used as the reference group. Multistate models were used to estimate hazard ratios., Results: Stroke survivors had a higher risk for fractures. However, a strong effect modification by functional impairment was apparent. Stroke survivors with functional impairment had no significantly increased risk for any fractures site compared to the corresponding reference group with functional impairment. In contrast, stroke survivors without functional impairment had a clearly and significantly increased fracture risk for most fracture sites. In these persons, the relative fracture risk for fractures of the lower extremities was higher than for fractures of the upper extremities., Conclusion: To evaluate the relative risk of stroke survivors for osteoporotic fractures, functional status appears to be a relevant parameter.

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence., (Copyright © 2012 S. Karger AG, Basel.)

Learning efficacy depends on its emotional context. The contents learned and the feedback received during training tinges this context. The objective here was to investigate the influence of content and feedback on the efficacy of implicit learning and to explore using functional imaging how these factors are processed in the brain. Twenty-one participants completed 150 trials of a probabilistic classification task (predicting sun or rain based on combinations of playing cards). Smileys or frowneys were presented as feedback. In 10 of these subjects, the task was performed during functional magnetic resonance imaging. Card combinations predicting sun were remembered better than those predicting rain. Similarly, positive feedback fortified learning more than negative feedback. The presentation of smileys recruited bilateral nucleus accumbens, sensorimotor cortex, and posterior cingulum more than negative feedback did. The higher the predictive value of a card combination, the more activation was found in the lateral cerebellum. Both context and feedback influence implicit classification learning. Similar to motor skill acquisition, positive feedback during classification learning is processed in part within the sensorimotor cortex, potentially reflecting the activation of a dopaminergic projection to motor cortex (Hosp et al., 2011). Activation of the lateral cerebellum during learning of combinations with high predictive value may reflect the formation of an internal model., (Copyright © 2012 Wiley Periodicals, Inc.)

Unlabelled: Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominantly inherited neurodegenerative disorder presenting with a variable phenotype including ataxia, dystonia, chorea, and parkinsonism, as well as cognitive impairment. We evaluated morphologic and functional imaging characteristics to elucidate evidence of neurodegeneration in SCA17, even in the presymptomatic stage of the disease., Methods: Nine individuals of 3 large SCA17 pedigrees, including 4 presymptomatic mutation carriers, underwent cranial 3-dimensional MRI volumetry, as well as multitracer PET with (18)F-FDG, (11)C-d-threo-methylphenidate, and (11)C-raclopride. Healthy subjects showing no signs of a neurologic or psychiatric disease served as controls., Results: MRI volumetry revealed atrophy of the cerebellum and caudate nucleus in manifesting patients (P = 0.04 and 0.05, respectively) and in presymptomatic mutation carriers (P = 0.04 and 0.01, respectively). PET demonstrated decreased glucose metabolism in the striatum, as well as in the cuneus, cingulum, and parietal lobe, in all SCA17 patients and presymptomatic mutation carriers. In addition, PET was closely correlated with motor performance as assessed by the Scale for the Assessment and Rating of Ataxia (P = 0.037) and Unified Parkinson Disease Rating Scale (P = 0.05) and with cognitive function as assessed by the Mini-Mental Status Examination (P = 0.037). Furthermore, (11)C-raclopride PET showed impairment of the postsynaptic dopaminergic compartment of the putamen and caudate nucleus not only in manifest SCA17 patients (P = 0.04 and 0.008, respectively) but also in yet-unaffected mutation carriers (P = 0.05 and 0.05, respectively). The degree of postsynaptic dopaminergic dysfunction was associated with impairment of motor performance. In contrast, significant presynaptic dopaminergic deficits assessed with (11)C-d-threo-methylphenidate PET were not detected., Conclusion: MRI volumetry, as well as (11)C-raclopride and (18)F-FDG PET, reveal neuronal dysfunction and neurodegeneration even in the presymptomatic stage and may serve as markers for disease activity in upcoming interventional trials on SCA17.

To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1-3), speech (item 4) and the limb kinetic subscore (items 5-8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose-finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.

Background and Objective: Ambulatory subjects after stroke may benefit from gait-oriented cardiovascular fitness training, but trials to date have not primarily assessed older persons., Methods: Thirty-eight subjects (age >60 years) with residual hemiparetic gait were enrolled >6 months after stroke. Participants were randomized to receive 3 months (3×/week) progressive graded, high-intensity aerobic treadmill exercise (TAEX) or conventional care physiotherapy. Primary outcome measures were peak exercise capacity (Vo(2peak)) and sustained walking capacity in 6-minute walks (6MW). Secondary measures were gait velocity in 10-m walks, Berg Balance Scale, functional leg strength (5 chair-rise), self-rated mobility (Rivermead Mobility Index), and quality of life (SF-12)., Results: Thirty-six participants completed the study (18 TAEX, 18 controls). TAEX but not conventional care improved Vo(2peak) (difference 6.4 mL/kg/min, P < .001) and 6MW (53 m, P < .001). Likewise, maximum walking speed (0.13 m/s, P = .01), balance (P < .05), and the mental subscore of the SF-12 (P < .01) improved more after TAEX. Gains in Vo(2peak) correlated with the degree at which training intensity could be progressed in the individual participant (P < .01). Better walking was related to progression in treadmill velocity and training duration (P < .001). Vo(2peak) and 6MW performances were still higher 1 year after the end of training when compared with the baseline, although endurance walking (6MW) at 1 year was lower than immediately after training (P < .01)., Conclusion: This trial demonstrates that TAEX effectively improves cardiovascular fitness and gait in persons with chronic stroke.

Objective: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits., Methods: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count., Results: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females., Conclusions: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.

Objective: Stroke survivors with motor deficits often have pyramidal tract atrophy caused by degeneration of corticospinal fibers. The authors hypothesized that the degree of atrophy correlates with severity of motor impairment in patients with chronic stroke and predicts the response to rehabilitation training., Methods: They performed a post hoc analysis of 42 hemiparetic patients (>6 months) who had been randomized to either 6 weeks of bilateral arm training with rhythmic auditory cueing (BATRAC) or dose-matched therapeutic exercise (DMTE). Arm function was measured using the Fugl-Meyer (FM) and modified Wolf Motor Function Test (WMFT). Structural MRI and diffusion tensor imaging (DTI) on the pontine level measured corticospinal tract (CST) atrophy by planimetric measurement of the mesencephalon (mesencephalic atrophy ratio) and fractional anisotropy (FA), respectively. Voxel-based lesion symptom mapping (VLSM) was used to determine the lesions associated with highest degrees of atrophy. The predictive value of CST atrophy for impairment and training response was analyzed., Results: CST atrophy predicted baseline motor arm function measured by the FM and WMFT. The authors found only a trend for the correlation with FA. No measure of atrophy predicted response to either BATRAC or DMTE. CST atrophy was higher with larger lesions and those that affected the CST. VLSM identified internal capsule lesions as being associated with highest CST atrophy., Conclusion: Larger lesions, internal capsule lesions, and those overlapping the pyramidal tract are associated with greater CST atrophy. CST atrophy explains in part the variability of baseline deficits but does not seem to predict the response to BATRAC or unilateral arm training on upper-extremity function.

Background: Aerobic treadmill exercise (T-EX) therapy has been shown to benefit walking and cardiorespiratory fitness in stroke survivors with chronic gait impairment even long after their stroke. The response, however, varies between individuals., Objective: The purpose of this post hoc analysis of 2 randomized controlled T-EX trials was to identify predictors for therapy response., Methods: In all, 52 participants received T-EX for 3 (Germany) or 6 (United States) months. Improvements in overground walking velocity (10 m/6-min walk) and fitness (peak VO(2)) were indicators of therapy response. Lesion location and volume were measured on T1-weighted magnetic resonance scans., Results: T-EX significantly improved gait and fitness, with gains in 10-m walk tests ranging between +113% and -25% and peak VO(2) between -12% and 88%. Baseline walking impairments or fitness deficits were not predictive of therapy response; 10-m walk velocity improved more in those with subcortical rather than cortical lesions and in patients with smaller lesions. Improvements in 6-minute walk velocity were greater in those with more recent strokes and left-sided lesions. No variable other than training intensity, which was different between trials, predicted fitness gains., Conclusions: Despite proving overall effectiveness, the response to T-EX varies markedly between individuals. Whereas intensity of aerobic training seems to be an important predictor of gains in cardiovascular fitness, lesion size and location as well as interval between stroke onset and therapy delivery likely affect therapy response. These findings may be used to guide the timing of training and identify subgroups of patients for whom training modalities could be optimized.

To investigate the frequency, details, and consequences of falls in patients with autosomal dominant spinocerebellar ataxias (SCAs) and to derive specific disease-related risk factors that are associated with an increased fall frequency. Two hundred twenty-eight patients with SCA1, SCA2, SCA3, or SCA6, recruited from the EuroSCA natural history study, completed a fall questionnaire that assessed the frequency, consequences, and several details of falls in the previous 12 months. Relevant disease characteristics were retrieved from the EuroSCA registry. The database of the natural history study provided the ataxia severity scores as well as the number and nature of non-ataxia symptoms. Patients (73.6%) reported at least one fall in the preceding 12 months. There was a high rate of fall-related injuries (74%). Factors that were associated with a higher fall frequency included: disease duration, severity of ataxia, the presence of pyramidal symptoms, the total number of non-ataxia symptoms, and the genotype SCA3. Factors associated with a lower fall frequency were: the presence of extrapyramidal symptoms (more specifically dystonia of the lower limbs) and the genotype SCA2. The total number of non-ataxia symptoms and longer disease duration were independently associated with a higher fall frequency in a logistic regression analysis, while the presence of extrapyramidal symptoms was independently associated with a lower fall frequency. Our findings indicate that, in addition to more obvious factors that are associated with frequent falls, such as disease duration and ataxia severity, non-ataxia manifestations in SCA play a major role in the fall etiology of these patients.

Patient-based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ-5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient-reported health status was compromised in patients of all genotypes (EQ-5D visual analogue scale (EQ-VAS) mean 61.45 +/- 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ-VAS variance in the whole sample and might be extrapolated to other SCA genotypes., ((c) 2010 Movement Disorder Society.)

Autonomic dysfunction has been frequently demonstrated in patients with extrapyramidal diseases by cardiovascular autonomic testing. In addition to classical testing, we applied the more detailed baroreflex and spectral analysis on three traditional cardiovascular tests in this study to get additional information on autonomic outflow. We recorded continuously blood pressure, electrocardiogram, and respiration in 35 patients with multiple system atrophy, 32 patients with progressive supranuclear palsy, 46 patients with idiopathic Parkinson's disease and in 27 corresponding healthy subjects during cardiovascular autonomic testing (metronomic breathing, Valsalva manoeuvre, head-up tilt). Baroreflex and spectral analyses were performed by using trigonometric regressive spectral analysis between and during the manoeuvres. Consistent with previous interpretations, our data showed an increase of sympathetic activity in head-up tilt and Valsalva test in healthy controls. This sympathetic activity was significantly decreased in patients with typical and atypical Parkinson syndromes. Significant modulation of baroreflex activity could be observed especially during metronomic breathing; again it was significantly lower in all patient groups. Baroreflex and spectral parameters could not only differentiate between patients and healthy controls, but also differentiate between clinically symptomatic (with autonomic dysfunction as eg. orthostatic hypotension) and asymptomatic patients. In conclusion, our approach allows the evaluation of autonomic variability during short and nonstationary periods of time and may constitute a useful advance in the assessment of autonomic function in both physiological and pathological conditions., ((c) 2009 Movement Disorder Society.)

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

Cardiovascular autonomic dysfunction has frequently been reported in some patients with extrapyramidal syndromes, especially multiple system atrophy (MSA) but also Parkinson's disease (PD). However, there are only few reports on the prevalence of cardiovascular autonomic dysfunction progressive in supranuclear palsy (PSP). Moreover, the relation of detailed cardiovascular testing and easy to assess 24-hour ambulatory blood pressure (BP) is not known. Our study evaluates 24-hour ambulatory BP monitoring in patients with PD, PSP, MSA, and corresponding controls (Con) and relates the findings to the results of comprehensive cardiovascular autonomic testing. Twenty-three patients with PD, 25 patients with PSP, 25 patients with MSA, and 26 corresponding controls were studied by 24-hour ambulatory BP monitoring (ABPM) in comparison to cardiovascular autonomic testing. Patients with PD, PSP, and MSA presented frequently with a pathological nocturnal BP regulation (no decrease or even an increase of nocturnal BP) in comparison to the control group (PD 48%, PSP 40%, MSA 68% vs. Con 8%). In MSA and PD patients, the frequent pathological BP increase during night was closely correlated to orthostatic hypotension. Since loss of nocturnal BP fall is frequent in patients with extrapyramidal syndromes, even if they are free of subjective autonomic dysfunction, we recommend 24-hour ABPM as an easy to perform screening test, especially if detailed autonomic testing is not available. Pathological loss of nocturnal BP fall may account for increased cardiovascular mortality in extrapyramidal syndromes., ((c) 2009 Movement Disorder Society.)

Stroke commonly leads to reduced mobility, which leads to deconditioning and a worsening of vascular risk factors, such as diabetes. The worsened risk profile leads to further strokes and disability--a vicious cycle for the stroke survivor. Exercise (walking) therapy may break this cycle by providing adequate stimuli for improving gait through plastic adaptation in the brain and through increasing fitness. Randomized, controlled data demonstrate the efficacy for gains in fitness and walking speed, the latter being related to lasting changes in activation patterns of the brainstem and cerebellum. Diabetes and muscle inflammation can also be improved by aerobic exercise training. The scope of this review summarizes these data and identifies unresolved issues related to optimization, intensity and maintenance of therapy effects. Exercise should be an integral part of every rehabilitation program.

The valsalva manoeuvre (VM), used as an autonomic function test, can detect sympathetic and/or parasympathetic autonomic dysfunction. This study investigated the value of VM in patients with different Parkinsonian syndromes (PS). We continuously recorded blood pressure, ECG and respiration among 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (PD) and in 27 healthy subjects matched in age and sex (Con). VM was performed in addition to metronomic breathing and tilt-table testing. VM could not be analysed in 26% of the ES patients. Valsalva ratio (VR), as a parameter of cardiovagal function, was pathologically decreased in all patient groups. Valsalva ratio (VR) was not able to discriminate parasympathetic dysfunction between patients and controls as well as E/I ratio of metronomic breathing. As a parameter of sympathetic dysfunction during VM, the physiological increase of blood pressure was more often missing during phase IV than phase II especially in PD and MSA patients. Correlation with orthostatic hypotension during tilt-table testing was only moderate. Although VM can demonstrate sympathetic and parasympathetic autonomic dysfunction, we cannot recommend VM as a first line autonomic test in PS patients. Metronomic breathing and tilt-table test seem more capable as parasympathetic resp. and sympathetic function tests to identify cardiovascular abnormalities in PS patients.

Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two-thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA.

Cardiac autonomic abnormalities have been described in Parkinson's disease and other extrapyramidal syndromes. To investigate baroreflex sensitivity as an important risk marker of cardiovascular mortality in patients with Parkinson's disease and other extrapyramidal syndromes. We recorded continuously blood pressure, ECG and respiration in 35 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 46 patients with idiopathic Parkinson's disease (PD) and in 27 corresponding healthy subjects (Con). Recordings of 2 min at rest were used to calculate baroreflex and spectral analysis of heart rate and systolic blood pressure. Resting baroreflex sensitivity (BRS) was significantly lower in the MSA and the PSP group but not in the PD group in comparison to the Con group. With increasing Hoehn & Yahr stage, BRS significantly decreased in all patient groups. In spectral analysis, all patient groups had a significantly lower relative low frequency (LF)-band power than the healthy controls. Patients with extrapyramidal disorders frequently demonstrate pathologically decreased BRS values and abnormalities of spectral analysis. This may have fundamental impact on the cardiovascular prognosis of patients with extrapyramidal disease.

Objective: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6., Methods: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient., Results: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count., Conclusions: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.

Multiple system atrophy (MSA) can clinically be divided into the cerebellar (MSA-C) and the parkinsonian (MSA-P) variant. However, till now, it is unknown whether autonomic dysfunction in these two entities differs regarding severity and profile. We compared the pattern of autonomic dysfunction in 12 patients with MSA-C and 26 with MSA-P in comparison with 27 age- and sex-matched healthy controls using a standard battery of autonomic function tests and a structured anamnesis of the autonomic nervous system. MSA-P patients complained significantly more often about the symptoms of autonomic dysfunctions than MSA-C patients, especially regarding vasomotor, secretomotor, and gastrointestinal subsystems. However, regarding cardiovascular, sudomotor pupil, urogenital, and sleep subsystems, there were no significant quantitative or qualitative differences as analyzed by autonomic anamnesis and testing. Our results suggest that there are only minor differences in the pattern of autonomic dysfunction between the two clinical MSA phenotypes., ((c) 2007 Movement Disorder Society.)

Objective: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA)., Methods: We assessed three functional measures-8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate-in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial., Results: While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = -0.441 to -0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW., Conclusion: The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.

Objective: To quantify spinal cord atrophy and its impact on clinical disability in spinocerebellar ataxia (SCA) type 3 and 6., Methods: Atrophy of the upper spinal cord was assessed by high resolution T1-weighted MRI of patients with SCA3 (n = 14) and SCA6 (n = 10). Furthermore, two groups of age- and sex-matched healthy control subjects (n = 24,) corresponding to the two SCA groups, were studied. Images were post-processed by a semi-automated volumetry method combining a marker based segmentation and an automatic histogram method facilitating highly reliable quantification and morphometry of the upper cervical cord in vivo., Results: We found a significant reduction of normalized mean crosssectional area of the spinal cord in SCA3 (p < 0.0005), whereas in SCA6 patients normalized mean crosssectional area was in the normal range (p = 0.379). No correlation was found between spinal cord atrophy and disease duration as well as CAG repeat length in both subtypes. In SCA6 a negative dependency between clinical disability, as expressed by the International Cooperative Ataxia Rating Scale as a well established ataxia score, and the mean cross-sectional area was found (p = 0.02). A similar correlation was observed in SCA3 but did not reach statistical significance., Conclusion: Our results quantify for the first time in vivo spinal cord atrophy as a non-cerebellar neurodegenerative process in SCA3. Our results suggest MR volumetry of the upper cervical cord as a marker of functional importance in SCA3 and SCA6.

Spinocerebellar ataxias (SCAs) comprise a clinically and genetically heterogeneous group of autosomal dominantly inherited neurodegenerative disorders affecting the cerebellum and to variable degrees further parts of the nervous system. Electrophysiology is a potent tool to prove impairment of multiple neuronal systems and fibre tracts and even to decipher subclinical affection. Electrooculography, evoked potentials, nerve conduction studies and polysomnography are especially helpful in the setting of SCAs. Severely slowed saccades are a hallmark of SCA2. Vertical nystagmus occurs most frequently in SCA3 and SCA6. Visual potentials recede especially in SCA7. Substantially prolonged central motor conduction times in motor-evoked potentials occur frequently in SCA1 even in patients without clinical signs of pyramidal affection. Thus, electrophysiological analyses may help to predict the SCA genotype and direct molecular genetic diagnostics. Polysomnography is a helpful tool in the analysis of sleep disorders and frequently helps to decipher treatable causes like periodic leg movement in sleep and REM sleep behaviour disorder in SCAs. Nerve conduction studies reveal sensory neuropathy in all common SCA subtypes, but to variable degrees. Age rather than CAG repeat length appears to be the most important determinant for neuropathy and makes sensory nerve action potentials a potential progression marker in SCA.

The most important features that characterize and differentiate progressive supranuclear palsy from other Parkinsonian syndromes are postural instability, supranuclear gaze palsy, pseudobulbar palsy, parkinsonism, and cognitive disturbances. In this article, we demonstrate that progressive supranuclear palsy patients exhibit pathologically decreased pupil diameters after dark adaptation recorded by TV pupillography. A cut off value of 3.99 mm was defined to differentiate progressive supranuclear palsy patients from patients with other extrapyramidal disorders like Parkinson's disease and multiple system atrophy with a specificity of 86.4% and a sensitivity of 70.8%. Other pupil abnormalities could not be described in patients with extrapyramidal syndromes., ((c) 2007 Movement Disorder Society.)

In spinocerebellar ataxias (SCAs), up to 30% of patients complain of restless legs syndrome (RLS). In primary RLS, a putative role of the dopaminergic system has been postulated. To assess dopaminergic function in SCA1, 2, and 3, dopamine D(2) receptor binding potential (BP) was assessed by [(11)C]raclopride positron emission tomography in 10 SCA patients, 4 of whom suffered from RLS as demonstrated by polysomnography. BP was compared to 9 age-matched control subjects. In 2 SCA patients, striatal BP was clearly reduced (<2 SD below the mean of controls). However, there were no significant group differences between SCA and controls, largely owing to a significantly higher variance of striatal BP in SCA. BP was negatively correlated with disease duration. The fit suggests an increased BP in early stages, followed by a moderate decline in all quantified regions (caudate, dorsal putamen, ventral striatum) presumably reflecting a progressive loss of D(2) receptors. RLS in SCA was not accompanied by a significant reduction of D(2) receptor availability in the striatum. This missing correlation may point to an extrastriatal origin of RLS.

Objective: To develop a reliable and valid clinical scale measuring the severity of ataxia., Methods: The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia., Results: The mean time to administer SARA in patients was 14.2 +/- 7.5 minutes (range 5 to 40). Interrater reliability was high, with an intraclass coefficient (ICC) of 0.98. Test-retest reliability was high with an ICC of 0.90. Internal consistency was high as indicated by Cronbach's alpha of 0.94. Factorial analysis revealed that the rating results were determined by a single factor. SARA ratings showed a linear relation to global assessments using a visual analogue scale, suggesting linearity of the scale (p < 0.0001, r(2) = 0.98). SARA score increased with the disease stage (p < 0.001) and was closely correlated with the Barthel Index (r = -0.80, p < 0.001) and part IV (functional assessment) of the Unified Huntington's Disease Rating Scale (UHDRS-IV) (r = -0.89, p < 0.0001), whereas it had only a weak correlation with disease duration (r = 0.34, p < 0.0002)., Conclusions: The Scale for the Assessment and Rating of Ataxia is a reliable and valid measure of ataxia, making it an appropriate primary outcome measure for clinical trials.

To evaluate the efficacy of treatments in spinocerebellar ataxias (SCAs), appropriate clinical scales are required. This study evaluated metric properties of the International Cooperative Ataxia Rating Scale (ICARS) in 156 SCA patients and 8 controls. ICARS was found to be a reliable scale satisfying accepted criteria for interrater reliability, test-retest reliability, and internal consistency. Although validity testing was limited, we found evidence of validity of ICARS when ataxia disease stages and Barthel index were used as external criteria. On the other hand, our study revealed two major problems associated with the use of ICARS. First, the redundant and overlapping nature of several items gave rise to a considerable number of contradictory ratings. Second, a factorial analysis showed that the rating results were determined by four different factors that did not coincide with the ICARS subscales, thus questioning the justification of ICARS subscore analysis in clinical trials., (Copyright (c) 2006 Movement Disorder Society.)

Autosomal dominant cerebellar ataxias (ADCA) are a heterogeneous group of neurological disorders. Point mutations in the gene encoding protein kinase Cgamma (PRKCG) are responsible for spinocerebellar ataxia 14 (SCA14). We screened for mutations in the PRKCG gene, in a large series of 284 ADCA index cases, mostly French (n=204) and German (n=48), in whom CAG repeat expansions in the known SCA genes were previously excluded. Six mutations were found that segregated with the disease and were not detected on 560 control chromosomes, including F643L (exon 18), already reported in another French kindred. Five new missense mutations were identified in exons 4 (C114Y/G123R/G123E), 10 (G360S) and 18 (V692G). All but one (V692G) were located in highly conserved regions of the regulatory or catalytic domains of the protein. All six SCA14 families were French and there was no evidence of reduced penetrance. The phenotype consisted in a very slowly progressive cerebellar ataxia with a mean age at onset of 33.5+/-14.2 years (range 15 to 60 years), occasionally associated with executive dysfunction, myoclonus, myorythmia, tremor or decreased vibration sense. SCA14 represented only 1.5% (7/454) of French ADCA families but none of the German families. It should, however, be considered in patients with slowly progressive ADCA, particularly when myoclonus and cognitive impairment are present.

The authors report a German family with autosomal dominant cerebellar ataxia tightly linked to the spinocerebellar ataxia type 5 (SCA5) locus (multipoint lod score 5.76). The phenotype is characterized by a purely cerebellar syndrome with a downbeat nystagmus occurring prior to the development of other features. Imaging studies demonstrated cortical cerebellar atrophy. Progression is slow even in patients with a disease onset during the second decade. The age at onset varies from 15 to 50 years.

The term idiopathic cerebellar ataxia (IDCA) designates a variety of cerebellar syndromes that may present with a purely cerebellar syndrome (IDCA-C) or with additional extracerebellar features (IDCA-P). Multiple system atrophy is also a sporadic neurodegenerative disorder of unknown origin that may cause prominent cerebellar symptoms (MSA-C). The final neuropathological answer to the question whether IDCA-P and MSA-C represent different varieties of one disease or two distinct entities is still lacking. Three-dimensional MRI-based volumetry allows morphological investigations intra vitam. Volumetric analysis of cerebellum, brainstem and basal ganglia was therefore performed in 46 patients with sporadic cerebellar ataxia and 16 age-matched healthy controls. Patients with dementia were excluded from the study since cognitive impairment is an exclusion criterion for the diagnosis of MSA. Cerebellar patients were clinically divided into two groups: 33 patients with multiple system atrophy with prominent cerebellar symptoms (MSA-C) and 13 patients with extracerebellar features not corresponding to MSA-C (IDCA-P). There was evidence for substantial cerebellar atrophy in both cerebellar groups while additional brainstem atrophy was significantly more pronounced in MSA-C patients. Absolute caudate and putamen atrophy was found to be restricted to single MSA-C individuals while group comparisons of mean volumes did not yield significant differences from controls. Based on the volumetric data, diagnosis could be correctly predicted in 94% of control, 82% of MSA-C and 100% of IDCA-P individuals. The finding of specific imaging characteristics strengthens (i) the value of MRI volumetry in separating MSA-C from other types of sporadic cerebellar ataxia, and (ii) the hypothesis of two independent neurodegenerative disorders in MSA-C and IDCA-P.

The aim of this study was to assess cognitive function in patients with spinocerebellar ataxia type 6 (SCA6), an autosomal-dominantly inherited disease leading to a progressive cerebellar syndrome. In contrast to other SCA types, the pathological changes are mostly restricted to the cerebellum. Cognitive function was studied in 12 patients with genetically confirmed SCA6 (mean duration of disease: 9.2 +/- 11.6 years) and 12 age- and IQ-matched controls using a test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive function. While none of the SCA6 subjects had features of general intellectual impairment, only mild deficits in single subtests especially in fronto-executive tasks were observed, but without reaching statistical significance. Thus the current findings do not demonstrate severe cognitive dysfunction in SCA6.

Cognitive impairment was studied in distinct types of spinocerebellar ataxia (SCA): eleven SCA1, 14 SCA2, and 11 SCA3 individuals and 8 age- and IQ- matched controls. All were submitted to a neuropsychological test battery that comprised tests for IQ, attention, executive function, verbal and visuospatial memory. Executive dysfunction was prominent in SCA1 as compared with controls and all other SCA types. Mild deficits of verbal memory were present in SCA1, SCA2 and SCA3. The neuropathological pattern in different SCA types suggests that these cognitive deficits are not likely to be contingent upon cerebellar degeneration but to result from disruption of a cerebrocerebellar circuitry presumably at the pontine level.

Fourteen patients with spinocerebellar ataxia 1 (SCA1) and 11 controls with similar mean age and IQ estimates were submitted to a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory as well as executive functions. Neuropsychological assessment yielded verbal memory and executive dysfunction while tests of visuospatial memory and attention were not significantly impaired in SCA1 as compared to controls. Test performance was neither related to the repeat length, the age of onset nor the disease duration. The profile of cognitive impairment in SCA1 with prominent executive dysfunction corresponds to the concept of "frontal-subcortical" dementia that is likely to be contingent upon disruption of a cerebrocerebellar circuitry that consists of afferent and efferent connections between the prefrontal cortex and the cerebellum., (Copyright 2001 S. Karger AG, Basel)

This is one of the first studies assessing the pattern of cognitive impairment in spinocerebellar ataxia 2 (SCA2). Cognitive function was studied in 17 patients with genetically confirmed SCA2 and 15 age- and IQ- matched controls using a neuropsychological test battery comprising tests for IQ, attention, verbal and visuospatial memory, as well as executive functions. Twenty-five percent of the SCA2 subjects showed evidence of dementia. Even in non-demented SCA2 subjects, there was evidence of verbal memory and executive dysfunction. Tests of visuospatial memory and attention were not significantly impaired in the non-demented group compared with controls. There was no relationship between test performance and motor disability, repeat length or age of onset, while disease duration was shown to be inversely correlated with two tests reflecting the progression of cognitive deficits during the course of the disease. Intellectual impairment should therefore not be interpreted as a secondary effect of progressive motor disability, but represents an important and independent part of the SCA2 phenotype.