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1.  Therapeutic Effects of Caloric Stimulation and Optokinetic Stimulation on Hemispatial Neglect 
Hemispatial neglect refers to a cognitive disorder in which patients with unilateral brain injury cannot recognize or respond to stimuli located in the contralesional hemispace. Hemispatial neglect in stroke patients is an important predictor for poor functional outcome. Therefore, there is a need for effective treatment for this condition. A number of interventions for hemispatial neglect have been proposed, although an approach resulting in persistent improvement is not available. Of these interventions, our review is focused on caloric stimulation and optokinetic stimulation. These lateralized or direction-specific stimulations of peripheral sensory systems can temporarily improve hemispatial neglect. According to recent functional MRI and PET studies, this improvement might result from the partial (re)activation of a distributed, multisensory vestibular network in the lesioned hemisphere, which is a part of a system that codes ego-centered space. However, much remain unknown regarding exact signal timing and directional selectivity of the network.
doi:10.3988/jcn.2006.2.1.12
PMCID: PMC2854939  PMID: 20396481
Neglect; Caloric stimulation; Optokinetic stimulation; Vestibular cortex; Ego-centered space
2.  Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects 
Clinical Drug Investigation  2013;34:95-105.
Background and Objectives
Rotigotine is a dopamine receptor agonist with activity across the D1 through to D5 receptors as well as select serotonergic and adrenergic sites; continuous transdermal delivery of rotigotine with replacement of the patch once daily maintains stable plasma concentrations over 24 h. Rotigotine is indicated for the treatment of early and advanced-stage Parkinson’s disease and moderate-to-severe idiopathic restless legs syndrome. The pharmacokinetics and pharmacodynamics of a drug may vary between subjects of different ethnic origin. This study evaluated the pharmacokinetics, safety, and tolerability of single-dose treatment with rotigotine transdermal patch in Japanese and Caucasian subjects.
Methods
In this open-label, parallel-group study, healthy male and female subjects of Japanese or Caucasian ethnic origin were matched by sex, body mass index, and age. A single transdermal patch delivering 2 mg/24 h rotigotine (patch content 4.5 mg) was applied to the ventral/lateral abdomen for 24 h. The main outcome measures were the plasma concentrations of unconjugated and total rotigotine and its desalkyl metabolites and derived pharmacokinetic parameters (area under the concentration–time curve from time zero to last quantifiable concentration [AUClast], maximum plasma concentration [Cmax], and body weight- and dose-normalized values).
Results
The pharmacokinetic analysis included 48 subjects (24 Japanese, 24 Caucasian). The mean apparent dose of rotigotine was 2.0 ± 0.5 mg for Japanese subjects and 2.08 ± 0.58 mg for Caucasians. Plasma concentration–time profiles of unconjugated rotigotine and of the main metabolites were similar for both ethnic groups. Parameters of model-independent pharmacokinetics, Cmax, time to Cmax (tmax), and AUClast, for unconjugated rotigotine showed no statistically significant differences between Japanese and Caucasian subjects. Values of concentration-dependent pharmacokinetic parameters were higher in female subjects; this difference was minimized after correction for body weight. A statistically significant difference between ethnic groups was observed for total rotigotine concentrations (total rotigotine = unconjugated rotigotine + conjugated rotigotine), with slightly lower values in Caucasians after correction for body weight and apparent dose. No relevant differences were observed between males and females. Inter-individual variability was high. The terminal half-life for unconjugated rotigotine was 5.3 h in Japanese subjects and 5.7 h in Caucasians; corresponding values for total rotigotine were 8.6 h and 9.6 h. Less than 0.1 % of the apparent dose was renally excreted as the parent compound. Renal elimination of total rotigotine covers 11.7 % of absorbed dose in Japanese subjects and 10.8 % of the absorbed dose in Caucasians, whereas the renal elimination via total despropyl rotigotine was 8.2 and 7.1 %, respectively. The corresponding values for total desthienylethyl rotigotine were 3.5 % in Japanese subjects and 4.2 % Caucasians. Most adverse events were mild in intensity and typical for dopamine agonists or for transdermal therapeutics.
Conclusion
Administration of a single patch delivering 2 mg/24 h rotigotine resulted in comparable pharmacokinetic profiles in Japanese and Caucasian subjects. The rotigotine transdermal patch was generally well-tolerated. Our findings suggest similar dose requirements for Japanese and Caucasian populations.
doi:10.1007/s40261-013-0150-5
PMCID: PMC3899448  PMID: 24178238
3.  Prism adaptation reverses the local processing bias in patients with right temporo-parietal junction lesions 
Brain  2009;132(6):1669-1677.
Lesions to the right temporo-parietal cortex commonly result in hemispatial neglect. Lesions to the same area are also associated with hyperattention to local details of a scene and difficulty perceiving the global structure. This local processing bias is an important factor contributing to neglect and may contribute to the higher prevalence of the disorder following right compared with left hemisphere strokes. In recent years, visuomotor adaptation to rightward-shifting prisms has been introduced as a promising treatment for hemispatial neglect. Explanations for these improvements have generally described a leftward realignment of attention, however, the present investigation provides evidence that prism adaptation reduces the local processing bias. Five patients with right temporal-parietal junction lesions were asked to identify the global or local levels of hierarchical figures before and after visuomotor adaptation to rightward-shifting prisms. Prior to prism adaptation the patients had difficulty ignoring the local elements when identifying the global component. Following prism adaptation, however, this pattern was reversed, with greater global interference during local level identification. The results suggest that prism adaptation may improve non-spatially lateralized deficits that contribute to the neglect syndrome.
doi:10.1093/brain/awp096
PMCID: PMC2724913  PMID: 19416951
hemispatial neglect; visual attention; prism adaptation; hierarchical processing
4.  Severity of Hypoperfusion in Distinct Brain Regions Predicts Severity of Hemispatial Neglect in Different Reference Frames 
Background and Purpose
Hemispatial neglect is among the most common and disabling consequences of right hemisphere stroke. A variety of variables have been associated with the presence or severity of neglect, but have not evaluated the independent effects of location, severity, and volume of ischemia. Few have determined areas involved in different types of neglect. We identified the contributions of these variables to severity of viewer-centered versus stimulus-centered neglect in acute ischemic right hemisphere stroke.
Methods
We studied 137 patients within 24 hours of stroke onset with MR diffusionand perfusion-weighted imaging and a test of hemispatial neglect that distinguishes between viewer-centered and stimulus-centered neglect. Using multivariable linear regression, we identified the independent contributions of severity of ischemia in specific locations, volume of ischemia, and age in accounting for severity of each neglect type.
Results
Severity of hypoperfusion in angular gyrus was the only variable that significantly and independently contributed to severity of viewer-centered neglect. Volume of dysfunctional tissue and hypoperfusion in posterior frontal cortex also accounted for some variability in severity of viewer-centered neglect. Severity of hypoperfusion of superior temporal cortex was the only variable that independently and significantly contributed to severity of stimulus-centered neglect.
Conclusions/Relevance
Location, severity, and volume of ischemia together determine the type and severity of neglect after right hemisphere stroke. Results also show that perfusion-weighted MRI can be used as a semi-quantitative measure of tissue dysfunction in acute stroke and can account for substantial proportion of the variability in functional deficits in the acute stage.
doi:10.1161/STROKEAHA.109.561969
PMCID: PMC2790042  PMID: 19762699
5.  Effect of Eye Patching in Rehabilitation of Hemispatial Neglect 
Eye patching (EP; monocular or right hemifield) has been proposed to improve visuospatial attention to the ignored field in patients with hemispatial neglect. The aim of this paper is to review the literature on the effects of EP in hemispatial neglect after stroke in order to convey evidence-based recommendations to clinicians in stroke rehabilitation. Thirteen intervention studies were selected from the Medline, EMBASE, Scopus, Cochrane Library, CINAHL, PsychINFO, EBRSR, and Health Star databases. Methodological quality was defined according to the Physiotherapy Evidence Database. Overall, seven studies used monocular EP, five used right hemifield patching, and one compared right monocular with right hemifield patching. Seven studies compared normal viewing to monocular or hemifield patching conditions. Six studies included a period of treatment. As to the monocular EP, four studies reported positive effects of right monocular patching. One study showed an improvement in hemispatial neglect with left monocular patching. Two studies found no superiority of right vs. left monocular patching. One study found no effects of right monocular patching. As to the right hemifield EP, one study showed improvements in neglect after right hemifield patching. Three studies found that right hemifield patching combined with another rehabilitation technique was more effective than that treatment alone. One study found no differences between right hemifield patching combined with another treatment and that treatment alone. One study found the same effect between right hemifield patching alone and another rehabilitation technique. Our results globally tend to support the usefulness of right hemifield EP in clinical practice. In order to define a level of evidence with the standard rehabilitation evidence rating tools, further properly powered randomized controlled trials or meta-analysis are needed.
doi:10.3389/fnhum.2013.00527
PMCID: PMC3759299  PMID: 24032011
hemispatial neglect; rehabilitation; perceptual disorders; treatment; stroke; visual stimulation; superior colliculus; eye patching
6.  Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch 
BMC Neurology  2010;10:86.
Background
Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS).
Methods
Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS.
Results
Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2.
Conclusions
Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy.
Trial registration
NCT00498186
doi:10.1186/1471-2377-10-86
PMCID: PMC2958158  PMID: 20920156
7.  Transdermal rotigotine for the perioperative management of restless legs syndrome 
BMC Neurology  2012;12:106.
Background
Immobilisation, blood loss, sleep deficiency, and (concomitant) medications during perioperative periods might lead to acute exacerbation of symptoms in patients with the restless legs syndrome (RLS). Continuous transdermal delivery of the dopamine agonist rotigotine provides stable plasma levels over 24 h and may provide RLS patients with a feasible treatment option for perioperative situations. To assess the feasibility of use of rotigotine transdermal patch for the perioperative management of moderate to severe RLS, long-term data of an open-label extension of a rotigotine dose-finding study were retrospectively reviewed.
Methods
The data of all 295 patients who had entered the 5-year study were screened independently by two reviewers for the occurrence of surgical interventions during the study period. The following data were included in this post-hoc analysis: patient age, sex, surgical intervention and outcome, duration of hospital stay, rotigotine maintenance dose at the time of surgery, rotigotine dose adjustment, and continuation/discontinuation of rotigotine treatment. All parameters were analysed descriptively. No pre-specified efficacy assessments (e.g. IRLS scores) were available for the perioperative period.
Results
During the study period, 61 surgical interventions were reported for 52 patients (median age, 63 years; 67% female); the majority of patients (85%) had one surgical intervention. The mean rotigotine maintenance dose at time of surgery was 3.1 ± 1.1 mg/24 h. For most interventions (95%), rotigotine dosing regimens were maintained during the perioperative period. Administration was temporarily suspended in one patient and permanently discontinued in another two. The majority (96%) of the patients undergoing surgery remained in the study following the perioperative period and 30 of these patients (61%) completed the 5-year study.
Conclusions
Although the data were obtained from a study which was not designed to assess rotigotine use in the perioperative setting, this post-hoc analysis suggests that treatment with rotigotine transdermal patch can be maintained during the perioperative period in the majority of patients and may allow for uninterrupted alleviation of RLS symptoms.
Trial Registration
The 5-year rotigotine extension study is registered with ClinicalTrials.gov, identifier NCT00498186.
doi:10.1186/1471-2377-12-106
PMCID: PMC3577642  PMID: 23009552
8.  Rotigotine transdermal system: a short review 
Rotigotine (Neupro®) is a new non-ergolinic dopamine agonist transdermal patch that can be applied once daily. To date, it is approved for the treatment of early Parkinson’s disease as monotherapy and has been shown to be effective in the treatment of advanced-stage Parkinson’s disease and restless legs syndrome in several clinical trials. This review gives an overview of physical, chemical, and pharmaceutical characteristics, pharmacokinetics, biotransformation and elimination, drug interactions, and adverse events of rotigotine. Further, the rationale for the treatment of Parkinson’s disease and restless legs syndrome with rotigotine is discussed.
PMCID: PMC2671947  PMID: 19412491
rotigotine; transdermal patch; Parkinson’s disease; restless legs syndrome
9.  The effect of dopamine agonists on cognitive functions in non-demented early-mild Parkinson’s disease patients  
Functional Neurology  2013;28(1): 13 - 18 .
Summary
The effect of dopamine agonists (DAs) on cognition in Parkinson’s disease (PD) is not yet completely established. Previous papers reported a worsening effect on some cognitive functions with some DAs, but not with others, suggesting that DAs may differently affect cognition in PD patients according to their pharmacological characteristics.
We set out to test the effect of rotigotine and cabergoline on cognitive functions in a group of forty non-demented early-mild PD patients (H &Y <2). Subjects were randomly divided into two groups and evaluated in a randomized cross-over study using neuropsychological tests; at the same time, motor function was monitored under three different treatment conditions: DA (rotigotine or cabergoline), L-dopa, and off therapy. Rotigotine and cabergoline were chosen because while they share a mixed D1 and D2 receptor profile, the former is non-ergolinic and the latter ergolinic.
No significant differences were found in cognitive function between the basal condition and the DA treatments. On the basis of the present data, which we compare with previous findings regarding pramipexole IR and pergolide, we hypothesize that combined stimulation of both dopamine receptor families, as occurs with rotigotine, cabergoline, L-dopa and pergolide, may preserve cognitive functions more than pure D2 family stimulation.
PMCID: PMC3812723  PMID: 23731911
cabergoline ;  cognition ;  pharmacokinetic ;  rotigotine
10.  Dropped head sign induced by transdermal application of the dopamine agonist rotigotine in parkinsonian syndrome: a case report 
Introduction
‘Dropped head sign’ relates to a severe disproportionate antecollis in parkinsonism. We present the first report of a rotigotine-induced dropped head sign in a patient with suspected idiopathic Parkinson’s disease, which was later defined as multiple system atrophy. The ‘dropped head sign’ is considered a rare symptom of unknown etiology in parkinsonian disorders, though a disproportionate antecollis is frequently observed in multiple system atrophy. It has also been described as a side effect of dopamine agonist medication with cabergoline and pramipexole. Rotigotine is a transdermally applied, non-ergot dopamine agonist, resulting in a continuous stimulation of dopamine receptors, which is widely used in the treatment of patients with Parkinson’s disease.
Case presentation
We report a case of a 64-year-old Caucasian woman with a rapidly progressive two-and-a-half-year history of a hypokinetic Parkinson’s syndrome with asymmetric development of symptoms and an initially good response to levodopa medication. Due to side effects of other dopamimetic medications the patient was switched to rotigotine medication five weeks before clinical admission. Progressive antecollis without muscle weakness and prominent paraspinal muscle contraction developed within two weeks of treatment and resolved within a week after discontinuation of rotigotine and initiation of levodopa/cabergoline medication.
Conclusion
While the pathophysiology still remains unresolved, this case supports the concept of a dopaminergic imbalance as a cause of certain axial dystonias like disproportionate antecollis including the ‘dropped head sign’. We believe this case is specifically useful for neurologists and general practitioners, as the easily recognizable symptom should prompt a thorough reevaluation of diagnosis and medication in patients with Parkinson’s disease.
doi:10.1186/1752-1947-7-174
PMCID: PMC3708785  PMID: 23829877
11.  Impaired perceptual memory of locations across gaze-shifts in patients with unilateral spatial neglect 
Journal of cognitive neuroscience  2007;19(8):1388-1406.
Summary
Right-hemisphere lesions often lead to severe disorders in spatial awareness and behavior, such as left hemispatial neglect. Neglect involves not only pathological biases in attention and exploration, but also deficits in internal representations of space and spatial working memory. Here we designed a new paradigm to test whether one potential component may involve a failure to maintain an updated representation of visual locations across delays when a gaze-shift intervenes. Right-hemisphere patients with varying severity of left spatial neglect had to encode a single target location and retain it across an interval of 2 or 3 seconds, during which the target was transiently removed, before a subsequent probe appeared for a same/different location judgment. During the delay, gaze could have to shift to either side of the remembered location, or no gaze-shift was required. Patients showed a dramatic loss of memory for target location after shifting gaze to its right (towards their ‘intact’ ipsilesional side), but not after leftward gaze-shifts. Such impairment arose even when the target initially appeared in the right visual field, before being updated leftward due to right gaze; and even when gaze returned to screen center before the memory probe was presented. These findings indicate that location information may be permanently degraded when the target has to be remapped leftward in gaze-centric representations. Across patients, the location-memory deficit induced by rightward gaze-shifts correlated with left neglect severity on several clinical tests. This paradoxical memory deficit, with worse performance following gaze-shifts to the ‘intact’ side of space, may reflect losses in gaze-centric representations of space that normally remap a remembered location dynamically relative to current gaze. Right gaze-shifts may remap remembered locations leftward, into damaged representations; whereas left gaze-shifts will require remapping rightward, into intact representations. Our findings accord with physiological data on normal remapping mechanisms in the primate brain, but demonstrate for the first time their impact on perceptual spatial memory when damaged, while providing new insights into possible components that may contribute to the neglect syndrome.
doi:10.1162/jocn.2007.19.8.1388
PMCID: PMC2601183  PMID: 17651010
spatial neglect; spatial memory; remapping; gaze; awareness
12.  “Left Neglected,” but Only in Far Space: Spatial Biases in Healthy Participants Revealed in a Visually Guided Grasping Task 
Hemispatial neglect is a common outcome of stroke that is characterized by the inability to orient toward, and attend to stimuli in contralesional space. It is established that hemispatial neglect has a perceptual component, however, the presence and severity of motor impairments is controversial. Establishing the nature of space use and spatial biases during visually guided actions amongst healthy individuals is critical to understanding the presence of visuomotor deficits in patients with neglect. Accordingly, three experiments were conducted to investigate the effect of object spatial location on patterns of grasping. Experiment 1 required right-handed participants to reach and grasp for blocks in order to construct 3D models. The blocks were scattered on a tabletop divided into equal size quadrants: left near, left far, right near, and right far. Identical sets of building blocks were available in each quadrant. Space use was dynamic, with participants initially grasping blocks from right near space and tending to “neglect” left far space until the final stages of the task. Experiment 2 repeated the protocol with left-handed participants. Remarkably, left-handed participants displayed a similar pattern of space use to right-handed participants. In Experiment 3 eye movements were examined to investigate whether “neglect” for grasping in left far reachable space had its origins in attentional biases. It was found that patterns of eye movements mirrored patterns of reach-to-grasp movements. We conclude that there are spatial biases during visually guided grasping, specifically, a tendency to neglect left far reachable space, and that this “neglect” is attentional in origin. The results raise the possibility that visuomotor impairments reported among patients with right hemisphere lesions when working in contralesional space may result in part from this inherent tendency to “neglect” left far space irrespective of the presence of unilateral visuospatial neglect.
doi:10.3389/fneur.2014.00004
PMCID: PMC3898521  PMID: 24478751
pseudoneglect; visuospatial neglect; attention; human; peripersonal space; reach-to-grasp; handedness
13.  Dissociation of sensory-attentional from motor-intentional neglect 
OBJECTIVES—Spatial neglect may result from disruption of sensory-attentional systems that spatially allocate perceptual resources and the motor-intentional systems that direct exploration and action. Previous studies have suggested that the line bisection task is more sensitive to sensory-attentional disorders and the cancellation task to motor-intentional disorders. A new technique was developed that allows the dissociation of sensory-attentional and motor-intentional deficits in both tasks and thereby allows comparison of these tasks.
METHODS—Ten patients with right hemispheric injury and hemispatial neglect performed line bisection and cancellation tasks while viewing stimuli on closed circuit TV. Direct view of the exploring hand and the target was precluded; the TV monitor guided performance. The direct condition made the direction of hand movement on the table (workspace) congruent with that on the monitor. Inverting the camera produced the indirect condition wherein the lateral movement in the workspace occurred in the opposite direction on the monitor.
RESULTS—On the cancellation task, five patients marked targets in the right workspace in the direct condition but the left workspace in the indirect condition, indicating sensory-attentional neglect. However, four other patients cancelled targets only in the right workspace in both conditions, failing to explore the left workspace, suggesting motor-intentional neglect. A patient who performed ambiguously may have elements of both types of neglect. Only two out of five patients designated as sensory-attentional in cancellation tasks showed sensory neglect on line bisection. The other three patients, as well as patients defined as motor-intentional by cancellation performance, exhibited motor-intentional neglect on line bisection.
CONCLUSION—The designation of sensory-attentional versus motor-intentional neglect therefore, in part, depends on task specific demands.


PMCID: PMC2170001  PMID: 9527144
14.  Neglect is more common and severe at extreme hemoglobin levels in right-hemispheric stroke 
Background and Purpose
Anemia is one potential mechanism by which the brain receives inadequate oxygenation. The purpose of this study was to determine, in acute stroke patients, if lower hemoglobin values were associated with worse hemispatial neglect.
Methods
In 203 subjects, neglect testing batteries were administered within 24 hours of admission for acute right-hemispheric stroke. We analyzed error rate on each test as well as “any neglect” (Zscore ≥2 on any of 3 selected tests, compared to normal controls), as predicted by hemoglobin level, with adjustment for infarct size, NIH Stroke Scale, age, and sex.
Results
The association between hemoglobin and neglect varied based on hemoglobin level. At lower hemoglobin levels (<12 g/dL), each point higher hemoglobin value was protective (adjusted OR 0.56, 95% CI 0.35–0.89) from having “any neglect”. However, above a hemoglobin of 14 g/dL, each point higher hemoglobin value was associated with higher odds of having neglect (adjusted OR 1.67, 95% CI 1.09–2.57). Similar relationships were found for predicted error rate on the horizontal line bisection, line cancellation, and copy Ogden scene neglect tests. These relationships seemed to be more pronounced in individuals who had a diffusion/ perfusion mismatch.
Conclusions
Lower and higher hemoglobin levels were each associated with increased odds of neglect, and with worse severity of neglect, independent of stroke size and severity. Higher hemoglobin values may represent dehydration or hyperviscosity. The importance of the extremes of hemoglobin in identifying individuals at risk for worse functional consequences of stroke warrants further study.
doi:10.1161/STROKEAHA.110.585265
PMCID: PMC2941527  PMID: 20616320
Neglect; anemia; stroke; cognition
15.  The impact of extended release dopamine agonists on prescribing patterns for therapy of early Parkinson’s disease: an observational study 
Background
Dopamine agonists (DA) are the first-choice drug for treatment of the early stage of Parkinson’s disease (PD) in subjects younger than 70 years. Recently, a number of third generation DA have been marketed, including transdermal patch of rotigotine and extended release oral formulation of ropinirole and pramipexole.
We investigated the impact of third generation DA on management of the early stage of PD in an outpatient service for Movement Disorders in Italy.
Methods
Two 12-month observation periods were selected (January - December, 2007, and January - December, 2011) as representative for prescription of immediate and extended release formulations of DA respectively. Within each period, PD patients were divided into subgroups according to age (<65 years; 65–75 years; >75 years) or functional requirement (high; moderate; low). For each period, the number of subjects receiving monotherapy with DA, monotherapy with levodopa (LD), or combined DA/LD therapy and the relative doses were calculated. The severity of parkinsonian motor symptoms was calculated by means of the Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) score. The frequency and severity of side-effects leading to discontinuation or reduction of DA drugs at each time point were also calculated.
Results
We found a significant reduction of daily LD dose (both as mono- and combined therapy) between the second and the first observation period. There was also a significant increase of monotherapy with DA and corresponding reduction of monotherapy with LD in patients aged 65–75 years, as well as in PD patients with moderate functional requirements. A significant reduction of frequency of side-effects was measured with extended release DA as compared to immediate release formulations. There were no significant differences of the UPDRS-III scores between the 2 observation periods in any subgroup.
Conclusions
Our results suggest that extended release DA might optimize therapeutic management of the early stages of PD even in patients older than 70 years of age.
doi:10.1186/2047-783X-18-60
PMCID: PMC3880455  PMID: 24360350
Dopamine agonists; Extended release; Levodopa; Parkinson’s disease; Pramipexole; Ropinirole; Rotigotine
16.  Dynamic Spatial Coding within the Dorsal Frontoparietal Network during a Visual Search Task 
PLoS ONE  2008;3(9):e3167.
To what extent are the left and right visual hemifields spatially coded in the dorsal frontoparietal attention network? In many experiments with neglect patients, the left hemisphere shows a contralateral hemifield preference, whereas the right hemisphere represents both hemifields. This pattern of spatial coding is often used to explain the right-hemispheric dominance of lesions causing hemispatial neglect. However, pathophysiological mechanisms of hemispatial neglect are controversial because recent experiments on healthy subjects produced conflicting results regarding the spatial coding of visual hemifields. We used an fMRI paradigm that allowed us to distinguish two attentional subprocesses during a visual search task. Either within the left or right hemifield subjects first attended to stationary locations (spatial orienting) and then shifted their attentional focus to search for a target line. Dynamic changes in spatial coding of the left and right hemifields were observed within subregions of the dorsal front-parietal network: During stationary spatial orienting, we found the well-known spatial pattern described above, with a bilateral hemifield representation in the right hemisphere and a contralateral preference in the left hemisphere. However, during search, the right hemisphere had a contralateral preference and the left hemisphere equally represented both hemifields. This finding leads to novel perspectives regarding models of visuospatial attention and hemispatial neglect.
doi:10.1371/journal.pone.0003167
PMCID: PMC2525817  PMID: 18779857
17.  Attention deficits following ADEM ameliorated by guanfacine 
The authors report here the case of a patient with severe deficits in arousal and sustained attention, associated with hemispatial neglect. These impairments were secondary to acute disseminated encephalomyelitis, with bilateral involvement of the medial nuclei and pulvinar of the thalamus. Treatment with the noradrenergic agonist guanfacine, previously used for attention deficits in attention deficit/hyperactivity disorder and stroke, was associated with a significant amelioration of both the spatial and sustained attention impairments in neglect. Guanfacine may prove to be a useful tool in the treatment of disorders of attention associated with neurological conditions.
doi:10.1136/jnnp.2009.195792
PMCID: PMC3090126  PMID: 20562462
Acute disseminated encephalomyelitis; neglect; norepinephrine; sustained attention; thalamus; attention; clinical neurology; neuropharmacology; rehabilitation
18.  Dissociated perceptual-sensory and exploratory-motor neglect. 
A patient with a right sided parietal lobe infarction manifested left sided sensory extinction in the visual, auditory, and tactile modalities but had only mild exploratory-motor neglect. In contrast, another patient with a right frontal haemorrhage demonstrated only left sided exploratory-motor hemispatial neglect. Tasks that combined perceptual and exploratory features elicited varying degrees of neglect in each patient. These two cases with dissociated neglect behaviour lend further evidence for behavioural specialisation within components of a cortical network for directed attention: sensory-representational aspects mediated primarily by the parietal component, motor-exploratory primarily by the frontal component. These cases also highlight the need to include and distinguish among several different measures of neglect in the clinical investigation of patients with hemispatial inattention.
Images
PMCID: PMC489209  PMID: 1527542
19.  Simulating hemispatial neglect with virtual reality 
Background
Hemispatial neglect is a cognitive disorder defined as a lack of attention for stimuli contra-lateral to the brain lesion. The assessment is traditionally done with basic pencil and paper tests and the rehabilitation programs are generally not well adapted. We propose a virtual reality system featuring an eye-tracking device for a better characterization of the neglect that will lead to new rehabilitation techniques.
Methods
This paper presents a comparison of eye-gaze patterns of healthy subjects, patients and healthy simulated patients on a virtual line bisection test. The task was also executed with a reduced visual field condition hoping that fewer stimuli would limit the neglect.
Results
We found that patients and healthy simulated patients had similar eye-gaze patterns. However, while the reduced visual field condition had no effect on the healthy simulated patients, it actually had a negative impact on the patients. We discuss the reasons for these differences and how they relate to the limitations of the neglect simulation.
Conclusion
We argue that with some improvements the technique could be used to determine the potential of new rehabilitation techniques and also help the rehabilitation staff or the patient's relatives to better understand the neglect condition.
doi:10.1186/1743-0003-4-27
PMCID: PMC1965467  PMID: 17640377
20.  Overnight switch from ropinirole to transdermal rotigotine patch in patients with Parkinson disease 
BMC Neurology  2011;11:100.
Background
A recent trial involving predominantly Caucasian subjects with Parkinson Disease (PD) showed switching overnight from an oral dopaminergic agonist to the rotigotine patch was well tolerated without loss of efficacy. However, no such data have been generated for Korean patients.
Methods
This open-label multicenter trial investigated PD patients whose symptoms were not satisfactorily controlled by ropinirole, at a total daily dose of 3 mg to 12 mg, taken as monotherapy or as an adjunct to levodopa. Switching treatment from oral ropinirole to transdermal rotigotine was carried out overnight, with a dosage ratio of 1.5:1. After a 28-day treatment period, the safety and tolerability of switching was evaluated. Due to the exploratory nature of this trial, the effects of rotigotine on motor and nonmotor symptoms of PD were analyzed in a descriptive manner.
Results
Of the 116 subjects who received at least one treatment, 99 (85%) completed the 28-day trial period. Dose adjustments were required for 11 subjects who completed the treatment period. A total of 76 treatment-emergent adverse events (AEs) occurred in 45 subjects. No subject experienced a serious AE. Thirteen subjects discontinued rotigotine prematurely due to AEs. Efficacy results suggested improvements in both motor and nonmotor symptoms and quality of life after switching. Fifty-two subjects (46%) agreed that they preferred using the patch over oral medications, while 31 (28%) disagreed.
Conclusions
Switching treatment overnight from oral ropinirole to transdermal rotigotine patch, using a dosage ratio of 1.5:1, was well tolerated in Korean patients with no loss of efficacy.
Trial registration
This trial is registered with the ClincalTrails.gov Registry (NCT00593606).
doi:10.1186/1471-2377-11-100
PMCID: PMC3166898  PMID: 21831297
21.  Visual hemispatial inattention: stimulus parameters and exploratory strategies. 
Patients with unilateral hemispheric lesions were given visual target cancellation tasks. As expected, marked contralateral and less severe ipsilateral visual inattention were observed in patients with right-sided cerebral lesions whereas those with left-sided lesions showed only mild contralateral neglect. Stimulus material (shapes vs letters) and array (random vs structured) interacted in a complex manner to influence target detection only in patients with right-sided lesions. Furthermore, the search strategy of these patients tended to be erratic, particularly when the stimuli were in an unstructured array. A structured array prompted a more systematic and efficient search. It appears, therefore, that stimulus content and spatial array affect neglect behaviour in patients with right-sided lesions and that a lack of systematic visual exploration within the extrapersonal space is one factor that contributes to visual hemispatial inattention.
PMCID: PMC1032760  PMID: 3221214
22.  Reperfusion of Specific Cortical Areas is Associated with Improvement in Distinct Forms of Hemispatial Neglect 
Objective
To test the hypothesis that restoring blood flow to specific right cortical regions in acute stroke results in improvement in distinct forms of hemispatial neglect distinguished by reference frame: viewer-centered versus stimulus-centered neglect.
Methods
Twenty five patients with acute right stroke were evaluated at Day 1 and Day 3-5 with a battery of neglect tests and diffusion- and perfusion-weighted MRI. Multivariate linear regression analysis revealed Brodmann areas where reperfusion predicted degree of improvement in scores on each type of neglect, independently of reperfusion of other areas, total change in the volume of infarct or hypoperfusion, and age.
Results
Reperfusion of dorsal frontoparietal cortex (including Brodmann areas 40, 46, and 4) independently predicted improvement in viewer-centered neglect, such as detecting stimuli on left in line cancellation and scene copying (r=0.951; p<0.0001). Reperfusion of a more ventral temporo-occipital cortex, including right Brodmann areas 37, 38, 21 and 18, independently contributed to improvement in stimulus-centered neglect, such as detecting left gaps in circles (r=0.926; p<0.0001). Reperfusion of right midfusiform gyrus (temporal occipital cortex), change in total volume of ischemia, change in volume of hypoperfusion and age predicted degree of improvement in reading (reduction in “neglect dyslexic” errors; r=0.915; p<0.0001). Results demonstrate that reperfusing specific cortical regions yields improvement in different types of neglect.
doi:10.1016/j.cortex.2011.01.003
PMCID: PMC3125403  PMID: 21345430
23.  Role of right posterior parietal cortex in maintaining attention to spatial locations over time 
Brain  2009;132(3):645-660.
Recent models of human posterior parietal cortex (PPC) have variously emphasized its role in spatial perception, visuomotor control or directing attention. However, neuroimaging and lesion studies also suggest that the right PPC might play a special role in maintaining an alert state. Previously, assessments of right-hemisphere patients with hemispatial neglect have revealed significant overall deficits on vigilance tasks, but to date there has been no demonstration of a deterioration of performance over time—a vigilance decrement—considered by some to be a key index of a deficit in maintaining attention. Moreover, sustained attention deficits in neglect have not specifically been related to PPC lesions, and it remains unclear whether they interact with spatial impairments in this syndrome. Here we examined the ability of right-hemisphere patients with neglect to maintain attention, comparing them to stroke controls and healthy individuals. We found evidence of an overall deficit in sustaining attention associated with PPC lesions, even for a simple detection task with stimuli presented centrally. In a second experiment, we demonstrated a vigilance decrement in neglect patients specifically only when they were required to maintain attention to spatial locations, but not verbal material. Lesioned voxels in the right PPC spanning a region between the intraparietal sulcus and inferior parietal lobe were significantly associated with this deficit. Finally, we compared performance on a task that required attention to be maintained either to visual patterns or spatial locations, matched for task difficulty. Again, we found a vigilance decrement but only when attention had to be maintained on spatial information. We conclude that sustaining attention to spatial locations is a critical function of the human right PPC which needs to be incorporated into models of normal parietal function as well as those of the clinical syndrome of hemispatial neglect.
doi:10.1093/brain/awn350
PMCID: PMC2664449  PMID: 19158107
sustained attention; vigilance; neglect; attention; spatial memory
24.  Is Persistent Visual Neglect Associated with Poor Survival? 
Background
The association of visual neglect with survival after right hemisphere (RH) stroke has received only limited attention.
Objective
This study explores the relationship of visual neglect and its spontaneous recovery to survival in a homogenous patient group with first-ever RH stroke.
Methods
Fifty-one RH stroke patients who suffered an infarct between 1994 and 1997 were retrospectively followed for survival until August 31, 2009. Acute-phase neurological, neuropsychological and neuroradiological data were studied to identify predictors of survival.
Results
Twenty-eight patients died during the follow-up. Age, education, and poor recovery of visual neglect emerged as significant single predictors of death. The best set of predictors for poor survival in the multivariate model was poor recovery of visual neglect and low education.
Conclusions
Poor recovery of visual neglect is associated with long-term mortality in RH infarct patients. The follow-up of RH patients’ neuropsychological performance gives additional information about the prognosis.
PMCID: PMC3661231  PMID: 23861629
cognition; neglect; stroke; survival
25.  Does vestibular stimulation activate thalamocortical mechanisms that reintegrate impaired cortical regions? 
Caloric stimulation induced a transient reversal of multimodal hemispatial cognitive deficits in an 81-year-old woman with an acute left cerebral hemisphere stroke. The patient had unawareness of her right hand (asomatognosia), right-sided visual unawareness (hemineglect), aphasia and right-sided weakness (hemiplegia) prior to the stimulation. Transient improvements in impaired sensory, motor, linguistic and cognitive function developed within 30 s following application of the caloric stimulus and onset of horizontal nystagmus. The effect persisted for 3 min and ceased completely after 5 min. While several recent reports have described the capacity of caloric stimulation to transiently improve or reverse a wide range of attentional, cognitive and motor impairments, most examples are in right-hemisphere-damaged patients with long-standing brain injury. Typically, patients have been tested several months or years after the onset of the deficit. A possible mechanism for the temporary reintegration of multiple cognitive functions in this patient is discussed.
PMCID: PMC1689689  PMID: 10097398

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