Delayed cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) remain severe complications after subarachnoid hemorrhage (SAH). Although focal changes in cerebral metabolism indicating ischemia are detectable by microdialysis, routinely used biomarkers are missing. We therefore sought to evaluate a panel of possible global markers in serum and cerebrospinal fluid (CSF) of patients after SAH. CSF and serum of SAH patients were analyzed retrospectively. In CSF, levels of inhibitory, excitatory, and structural amino acids were detected by high-performance liquid chromatography (HPLC). In serum, neuron-specific enolase (NSE) and S100B level were measured and examined in conjunction with CVS and DCI. CVS was detected by arteriography, and ischemic lesions were assessed by computed tomography (CT) scans. All CSF amino acids were altered after SAH. CSF glutamate, glutamine, glycine, and histidine were significantly correlated with arteriographic CVS. CSF glutamate and serum S100B were significantly correlated with ischemic events after SAH; however, NSE did not correlate neither with ischemia nor with vasospasm. Glutamate, glutamine, glycine, and histidine might be used in CSF as markers for CVS. Glutamate also indicates ischemia. Serum S100B, but not NSE, is a suitable marker for ischemia. These results need to be validated in larger prospective cohorts.

Despite the importance of regaining independent ambulation after stroke, the amount of daily walking completed during in-patient rehabilitation is low. The purpose of this study is to determine if (1) walking-related heart rate responses reached the minimum intensity necessary for therapeutic aerobic exercise (40%–60% heart rate reserve) or (2) heart rate responses during bouts of walking revealed excessive workload that may limit walking (>80% heart rate reserve). Eight individuals with subacute stroke attending in-patient rehabilitation were recruited. Participants wore heart rate monitors and accelerometers during a typical rehabilitation day. Walking-related changes in heart rate and walking bout duration were determined. Patients did not meet the minimum cumulative requirements of walking intensity (>40% heart rate reserve) and duration (>10 minutes continuously) necessary for cardiorespiratory benefit. Only one patient exceeded 80% heart rate reserve. The absence of significant increases in heart rate associated with walking reveals that patients chose to walk at speeds well below a level that has meaningful cardiorespiratory health benefits. Additionally, cardiorespiratory workload is unlikely to limit participation in walking. Measurement of heart rate and walking during in-patient rehabilitation may be a useful approach to encourage patients to increase the overall physical activity and to help facilitate recovery.

NADPH oxidase is a major source of superoxide anion following stroke and reperfusion. This study evaluated the effects of apocynin, a known antioxidant and inhibitor of Nox2 NADPH, on neuronal injury and cell-specific responses to stroke induced in the conscious rat. Apocynin treatment (50 mg/kg i.p.) commencing 1 hour prior to stroke and 24 and 48 hours after stroke significantly reduced infarct volume in the cortex by ~ 60%, but had no effect on striatal damage or neurological deficits. In situ detection of reactive oxygen species (ROS) using dihydroethidium fluorescence revealed that increased ROS detected in OX-42 positive cells following ischemia was reduced in apocynin-treated rats by ~ 51%, but surprisingly increased in surrounding NeuN positive cells of the same rats by ~ 27%, in comparison to the contralateral hemisphere. Reduced ROS from activated microglia/macrophages treated with apocynin was associated with reduced Nox2 immunoreactivity without change to the number of cells. These findings confirm the protective effects of apocynin and indicate a novel mechanism via reduced Nox2 expression. We also reveal compensatory changes in neuronal ROS generation as a result of Nox2 inhibition and highlight the need to assess long term individual cell responses to inhibitors of oxidative stress.

The field of neuroprotection generated consistent preclinical findings of mechanisms of cell death but these failed to be translated into clinics. The approaches that combine the modulation of the inhibitory environment together with the promotion of intrinsic axonal outgrowth needs further work before combined therapeutic strategies will be transferable to clinic trials. It is likely that only when some answers have been found to these issues will our therapeutic efforts meet our expectations. Stroke is a clinically heterogeneous disease and combinatorial treatments require much greater work in pharmacological and toxicological testing. Advances in genetics and results of the Whole Human Genome Project (HGP) provided new unknown information in relation to stroke. Genetic factors are not the only determinants of responses to some diseases. It was recognized early on that “epigenetic” factors were major players in the aetiology and progression of many diseases like stroke. The major players are microRNAs that represent the best-characterized subclass of noncoding RNAs. Epigenetic mechanisms convert environmental conditions and physiological stresses into long-term changes in gene expression and translation. Epigenetics in stroke are in their infancy but offer great promise for better understanding of stroke pathology and the potential viability of new strategies for its treatment.

Transcranial direct current stimulation (tDCS) is a noninvasive technique that is emerging as a prospective therapy for different neurologic disorders. Previous studies have demonstrated that anodal and cathodal stimulation can improve motor performance in terms of dexterity and manual force. The objective of this study was to determine whether different electrodes' setups (anodal, cathodal, and simultaneous bilateral tDCS) provide different motor performance and which montage was more effective. As secondary outcome, we have asked to the patients about their satisfaction, and to determine if the bilateral tDCS was more uncomfortable than unilateral tDCS. Nine patients with stroke in subacute phase were enrolled in this study and randomly divided in three groups. Our results showed that tDCS was an effective treatment if compared to Sham stimulation (P = 0.022). In particular, anodal stimulation provided the higher improvement in terms of manual dexterity. Cathodal stimulation seemed to have a little effect in terms of force improvement, not observed with other setups. Bipolar stimulation seemed to be the less effective. No significant differences have been noted for the different set-ups for patients' judgment. These results highlight the potential efficacy of tDCS for patients with stroke in subacute phase.

The Stroke Therapy Academic Industry Roundtable (STAIR) provided initial (in 1999) and updated (in 2009) recommendations with the goal of improving preclinical stroke therapy assessment and to increase the translational potential of experimental stroke treatments. It is important for preclinical stroke researchers to frequently consider and revisit these concepts, especially since promising experimental stroke treatments continue to fail in human clinical trials. Therefore, this paper will focus on considerations for several key aspects of preclinical stroke studies including the selection and execution of the animal stroke model, drug/experimental treatment administration, and outcome measures to improve experimental validity and translation potential. Specific points of interest discussed include the incorporation of human comorbid conditions and drugs, the benefits of defining a proposed mechanism of action, replication of results using multiple methods, using clinically relevant routes of administration and treatment time windows, and performing and reporting good experimental methods to reduce bias such as, as suggested by the updated STAIR recommendations, sample size calculations, randomization, allocation concealment, blinding, and appropriate inclusion/exclusion criteria. It is our hope that reviewing and revisiting these considerations will benefit researchers in their investigations of stroke therapies and increase the likelihood of translational success in the battle against stroke.

Stroke and diabetes mellitus are two separate conditions which share multiple common threads. Both are increasing in prevalence, both are diseases which affect blood vessels, and both are associated with other vascular risk factors, such as hypertension and dyslipidemia. Abnormal glucose regulation, of which diabetes is one manifestation, is seen in up to two-thirds of people suffering from an acute stroke. Surprisingly, aggressive management of glucose after an acute stroke has not been shown to improve outcome or reduce the incidence of further strokes. More encouragingly, active management of other cardiovascular risk factors has been demonstrated to prevent stroke disease and improve outcome following a stroke in the diabetic person. Hypertension should be treated with a target of 140/80 mmHg, as a maximum. The drug of choice would be an ACE inhibitor, although the priority is blood pressure reduction regardless of the medication chosen. Lipids should be treated with a statin whatever the starting cholesterol. Antiplatelet treatment is also essential but there are no specific recommendations for the diabetic person. As these conditions become more prevalent it is imperative that the right treatment is offered for both primary and secondary prevention in diabetic people, in order to prevent disease and minimize disability.

Background. No strongly clinical evidence about the use of hand robot-assisted therapy in stroke patients was demonstrated. This preliminary observer study was aimed at evaluating the efficacy of intensive robot-assisted therapy in hand function recovery, in the early phase after a stroke onset. Methods. Seven acute ischemic stroke patients at their first-ever stroke were enrolled. Treatment was performed using Amadeo robotic system (Tyromotion GmbH Graz, Austria). Each participant received, in addition to inpatients standard rehabilitative treatment, 20 sessions of robotic treatment for 4 consecutive weeks (5 days/week). Each session lasted for 40 minutes. The exercises were carried out as follows: passive modality (5 minutes), passive/plus modality (5 minutes), assisted therapy (10 minutes), and balloon (10 minutes). The following impairment and functional evaluations, Fugl-Meyer Scale (FM), Medical Research Council Scale for Muscle Strength (hand flexor and extensor muscles) (MRC), Motricity Index (MI), and modified Ashworth Scale for wrist and hand muscles (AS), were performed at the beginning (T0), after 10 sessions (T1), and at the end of the treatment (T2). The strength hand flexion and extension performed by Robot were assessed at T0 and T2. The Barthel Index and COMP (performance and satisfaction subscale) were assessed at T0 and T2. Results. Clinical improvements were found in all patients. No dropouts were recorded during the treatment and all subjects fulfilled the protocol. Evidence of a significant improvement was demonstrated by the Friedman test for the MRC (P < 0.0123). Evidence of an improvement was demonstrated for AS, FM, and MI. Conclusions. This original rehabilitation treatment could contribute to increase the hand motor recovery in acute stroke patients. The simplicity of the treatment, the lack of side effects, and the first positive results in acute stroke patients support the recommendations to extend the clinical trial of this treatment, in association with physiotherapy and/or occupational therapy.

Foot drop is a quite common problem in nervous system disorders. Neuromuscular electrical stimulation (NMES) has showed to be an alternative approach to correct foot drop improving walking ability in patients with stroke. In this study, twenty patients with stroke in subacute phase were enrolled and randomly divided in two groups: one group performing the NMES (i.e. Walkaide Group, WG) and the Control Group (CG) performing conventional neuromotor rehabilitation. Both groups underwent the same amount of treatment time. Significant improvements of walking speed were recorded for WG (168 ± 39%) than for CG (129 ± 29%, P = 0.032) as well as in terms of locomotion (Functional Ambulation Classification score: P = 0.023). In terms of mobility and force, ameliorations were recorded, even if not significant (Rivermead Mobility Index: P = 0.057; Manual Muscle Test: P = 0.059). Similar changes between groups were observed for independence in activities of daily living, neurological assessments, and spasticity reduction. These results highlight the potential efficacy for patients affected by a droop foot of a walking training performed with a neurostimulator in subacute phase.

Aims. Homonymous hemianopia (HH), a severe visual consequence of stroke, causes difficulties in detecting obstacles on the nonseeing (blind) side. We conducted a pilot study to evaluate the effects of oblique peripheral prisms, a novel development in optical treatments for HH, on detection of unexpected hazards when driving. Methods. Twelve people with complete HH (median 49 years, range 29–68) completed road tests with sham oblique prism glasses (SP) and real oblique prism glasses (RP). A masked evaluator rated driving performance along the 25 km routes on busy streets in Ghent, Belgium. Results. The proportion of satisfactory responses to unexpected hazards on the blind side was higher in the RP than the SP drive (80% versus 30%; P = 0.001), but similar for unexpected hazards on the seeing side. Conclusions. These pilot data suggest that oblique peripheral prisms may improve responses of people with HH to blindside hazards when driving and provide the basis for a future, larger-sample clinical trial. Testing responses to unexpected hazards in areas of heavy vehicle and pedestrian traffic appears promising as a real-world outcome measure for future evaluations of HH rehabilitation interventions aimed at improving detection when driving.

Stroke is the leading cause of long-term disability for adults in industrialized societies. Rehabilitation's efforts are tended to avoid long-term impairments, but, actually, the rehabilitative outcomes are still poor. Novel tools based on new technologies have been developed to improve the motor recovery. In this paper, we have taken into account seven promising technologies that can improve rehabilitation of patients with stroke in the early future: (1) robotic devices for lower and upper limb recovery, (2) brain computer interfaces, (3) noninvasive brain stimulators, (4) neuroprostheses, (5) wearable devices for quantitative human movement analysis, (6) virtual reality, and (7) tablet-pc used for neurorehabilitation.

Healthy cerebrovascular myocytes express members of several different ion channel families which regulate resting membrane potential, vascular diameter, and vascular tone and are involved in cerebral autoregulation. In animal models, in response to subarachnoid blood, a dynamic transition of ion channel expression and function is initiated, with acute and long-term effects differing from each other. Initial hypoperfusion after exposure of cerebral vessels to oxyhemoglobin correlates with a suppression of voltage-gated potassium channel activity, whereas delayed cerebral vasospasm involves changes in other potassium channel and voltage-gated calcium channels expression and function. Furthermore, expression patterns and function of ion channels appear to differ between main and small peripheral vessels, which may be key in understanding mechanisms behind subarachnoid hemorrhage-induced vasospasm. Here, changes in calcium and potassium channel expression and function in animal models of subarachnoid hemorrhage and transient global ischemia are systematically reviewed and their clinical significance discussed.

Introduction. In stroke rehabilitation, bilateral upper limb training is gaining ground. As a result, a growing number of mechanical and robotic bilateral upper limb training devices have been proposed. Objective. To provide an overview and qualitative evaluation of the clinical applicability of bilateral upper limb training devices. Methods. Potentially relevant literature was searched in the PubMed, Web of Science, and Google Scholar databases from 1990 onwards. Devices were categorized as mechanical or robotic (according to the PubMed MeSH term of robotics). Results. In total, 6 mechanical and 14 robotic bilateral upper limb training devices were evaluated in terms of mechanical and electromechanical characteristics, supported movement patterns, targeted part and active involvement of the upper limb, training protocols, outcomes of clinical trials, and commercial availability. Conclusion. Initial clinical results are not yet of such caliber that the devices in question and the concepts on which they are based are firmly established. However, the clinical outcomes do not rule out the possibility that the concept of bilateral training and the accompanied devices may provide a useful extension of currently available forms of therapy. To actually demonstrate their (surplus) value, more research with adequate experimental, dose-matched designs, and sufficient statistical power are required.

Background. There are no evidence-based strategies that have been shown to be superior in maintaining motor function for months to years after the stroke. The LAST study therefore intends to assess the effect of a long-term follow-up program for stroke patients compared to standard care on function, disability and health. Design. This is a prospective, multi-site randomised controlled trial, with blinded assessment 18 months after inclusion. A total of 390 patients will be recruited and randomised to a control group, receiving usual care, or to an intervention group 10 to 16 weeks after onset of stroke. Patients will be stratified according to stroke severity, age above 80, and recruitment site. The intervention group will receive monthly coaching on physical activity by a physiotherapist for 18 consecutive months after inclusion. Outcomes. The primary outcome is motor function (Motor Assessment Scale) 18 months after inclusion. Secondary outcomes are: dependency, balance, endurance, health-related quality of life, fatigue, anxiety and depression, cognitive function, burden on caregivers, and health costs. Adverse events and compliance to the intervention will be registered consecutively during follow-up.

The aim of this pilot study was to analyze the effect of a strength training program on indicators of trait and state anxiety in patients with ischemic stroke. The subjects were divided into two groups: experimental group (EG) consisting of 11 subjects aged 51.7 ± 8.0 years and a control group (CG) with 13 subjects aged 52.5 ± 7.7 years. EG underwent 12 weeks of strength training, with a frequency of three times a week. For data collection, a State-Trait Anxiety Inventory (STAI) was used. Significant differences were found between pre- and posttest in EG for trait anxiety (43.2 ± 12.5 pretest 39.9 ± 7.3 posttest) and state anxiety (46.9 ± 7.6 pretest 44.9 ± 7.7 posttest) with no differences in CG for trait anxiety (42.9 ± 12.2 pretest 42.6 ± 12.1 posttest) and state anxiety (47.4 ± 8.1 pretest 47.5 ± 8.0 posttest). In the evaluation between the groups, significant differences were found for all indicators of trait anxiety (39.9 ± 7.3 EG; 42.6 ± 12.1 CG) and state anxiety (44.9 ± 7.7 EG; 47.5 ± 8.0 CG). This pilot study indicates that strength training may provide an improvement in trait and state anxiety more than one year after stroke.

In adult life, many of the social determinants of health are connected to working life. Yet, our knowledge of the role of work-related factors for the risk of stroke is fairly limited. In contemporary occupational health research, the Demand-Control Model (DCM) is frequently used to measure work stress. Previous literature reviews of the association of work stress and cardiovascular disease (CVD) do not include stroke as a specific outcome. Results regarding work stress and the risk of CVD are less evident in working women. With the focus on working women, the purpose of the present paper was to review the current research into the DCM in relation to stroke and to scrutinize potential gender differences. A literature search was performed and eight studies from three countries were identified. Based on the reviewed studies, there is some evidence that high psychological demands, low job control, and job strain are associated with increased stroke risk in women as well as in men. Any major reduction in deaths and disability from stroke is likely to come from decreasing social inequalities in health, and reducing work stress has a potential to contribute to a reduced risk of stroke in working populations.

Obstructive sleep apnoea (OSA) carries an increased risk of ischaemic stroke, but the underlying mechanism is not clear. As right-to-left shunting can occur through a patent foramen ovale (PFO) during periods of apnoea, we investigated nocturnal changes in fibrinolytic activity and platelet function in subjects who had OSA with or without PFO and in controls. We determined plasminogen activator inhibitor 1 (PAI-1) activity and antigen and platelet activation parameters. The severity of OSA was verified by polygraphy and PFO was detected by ear oximetry. We found a higher PAI-1 activity and antigen and a lower ratio of 2,3-dinor-PGF1α to 2,3-dinor-TXB2 in the subjects with OSA than in the controls. Linear regression analysis showed the apnoea-hypopnoea index (β-coefficient, 0.499; P = 0.032) and PFO (β-coefficient, 0.594; P = 0.015) to be associated independently with PAI-1 activity in the morning, while the increment in PAI-1:Ag from evening to morning was significantly associated with the presence of PFO (rs = 0.563, P = 0.002). Both OSA and PFO reduce fibrinolytic activity during nocturnal sleep. We hypothesize that subjects having both OSA and PFO may develop a more severe prothrombotic state during sleep than those having either OSA or PFO alone.

Prevention plays a crucial role in counteracting morbidity and mortality related to ischemic stroke. It has been estimated that 50% of stroke are preventable through control of modifiable risk factors and lifestyle changes. Antihypertensive treatment is recommended for both prevention of recurrent stroke and other vascular events. The use of antiplatelets and statins has been shown to reduce the risk of recurrent stroke and other vascular events. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are indicated in stroke prevention because they also promote vascular health. Effective secondary-prevention strategies for selected patients include carotid revascularization for high-grade carotid stenosis and vitamin K antagonist treatment for atrial fibrillation. The results of recent clinical trials investigating new anticoagulants (factor Xa inhibitors and direct thrombin inhibitors) clearly indicate alternative strategies in stroke prevention for patients with atrial fibrillation. This paper describes the current landscape and developments in stroke prevention with special reference to medical treatment in secondary prevention of ischemic stroke.

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown. Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included. Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited. Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

The purpose of this study was to test the validity of the SenseWear Pro Armband (SWA) for the measurement of energy expenditure (EE) and step count against a criterion in persons with stroke. Twelve participants with chronic stroke (mean age 64.2 ± 10.4 years; mean gait speed 0.67 ± 0.25 m/sec) completed two trials of a six-minute walk test, while wearing a SenseWear Armband (SWA) on each arm and being continuously monitored using a portable metabolic cart. Agreement between estimates of energy expenditure from the SWA and the metabolic cart was fair for the armband on the hemiplegic arm (intraclass correlation cefficient (ICC) = 0.586) and good for the armband on the unaffected arm (ICC = 0.702). Agreement between the SWA estimate of step count, and step count as measured by the Step Activity Monitor was poor (ICC < 0.352), with significant underestimation by the SWA. Our results show that, for these moderately impaired persons with stroke, the SWA should be used with caution for the measurement of energy expenditure and should not be used to measure step count.

Repetitive transcranial magnetic stimulation and transcranial direct current stimulation are noninvasive brain stimulation (NIBS) techniques that can alter excitability of the human cortex. Considering the interhemispheric competition occurring after stroke, improvement in motor deficits can be achieved by increasing the excitability of the affected hemisphere or decreasing the excitability of the unaffected hemisphere. Many reports have shown that NIBS application improves motor function in stroke patients by using their physiological peculiarity. For continuous motor improvement, it is important to impart additional motor training while NIBS modulates the neural network between both hemispheres and remodels the disturbed network in the affected hemisphere. NIBS can be an adjuvant therapy for developed neurorehabilitation strategies for stroke patients. Moreover, recent studies have reported that bilateral NIBS can more effectively facilitate neural plasticity and induce motor recovery after stroke. However, the best NIBS pattern has not been established, and clinicians should select the type of NIBS by considering the NIBS mechanism. Here, we review the underlying mechanisms and future views of NIBS therapy and propose rehabilitation approaches for appropriate cortical reorganization.

Studies from a single laboratory have shown that in rodent models of permanent stroke, administration of the sulfonylurea glibenclamide (Glib) is highly effective in reducing edema, mortality, and lesion volume. The Stroke Therapy Academic Industry Roundtable (STAIR) recommends that new acute treatments for ischemic stroke to be replicated across different laboratories. Accordingly, we examined the effect of low-dose Glib in a permanent suture occlusion model of stroke. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (pMCAO) followed by an initial intraperitoneal injection of Glib (10 μg/kg) and the start of a constant infusion (200 ng/h) via miniosmotic pump at the onset of ischemia. Functional deficits were assessed by Neurological Severity Score (NSS) and grip-strength meter at 24 and 48 h after pMCAO. Glib-treated rats showed a significant reduction in infarct volume, lower NSS, and less hemispheric swelling compared to vehicle. Grip strength was decreased significantly in pMCAO rats compared to shams and significantly improved by treatment with Glib. Taken together, these data indicate that Glib has strong neuroprotective effects following ischemic stroke and may warrant further testing in future clinical trials for human stroke.

Background and Purpose. Training in the virtual environment in post stroke rehab is being established as a new approach for neurorehabilitation, specifically, ReoTherapy (REO) a robot-assisted virtual training device. Trunk stabilization strapping has been part of the concept with this device, and literature is lacking to support this for long-term functional changes with individuals after stroke. The purpose of this case series was to measure the feasibility of auditory trunk sensor feedback during REO therapy, in moderate to severely impaired individuals after stroke. Case Description. Using an open label crossover comparison design, 3 chronic stroke subjects were trained for 12 sessions over six weeks on either the REO or the control condition of task related training (TRT); after a washout period of 4 weeks; the alternative therapy was given. Outcomes. With both interventions, clinically relevant improvements were found for measures of body function and structure, as well as for activity, for two participants. Providing auditory feedback during REO training for trunk control was found to be feasible. Discussion. The degree of changes evident varied per protocol and may be due to the appropriateness of the technique chosen, as well as based on patients impaired arm motor control.