Ipsilateral hand impairment predicts long-term outcome in patients with subacute stroke.

BACKGROUND: Ipsilateral hand (ILH) impairment is documented following motor stroke, but its impact on long-term outcome remains unknown. We assessed ILH impairment in subacute stroke and tested whether ILH impairment predicted long-term outcome. METHODS: We performed a longitudinal study in 209 consecutive patients with unilateral stroke and sensorimotor deficit at admission. ILH impairment was evaluated using the Purdue Pegboard Test (PPT) and handgrip strength and defined as mild (z-score < -1) or moderate (z-score < -1.65). We used logistic regression (LR) to predict outcome assessed 9 (range, 7-12) months post-stroke with the modified Rankin scale (mRS) categorized into good (mRS ≤ 1) and poor outcome (mRS ≥ 2). For internal validation, LR-bootstrapping and cross-validation with LASSO and Random Forest were performed. RESULTS: ILH impairment assessed at 89.04 ± 45.82 days post-stroke was moderate in 10.53% (95% CI 6.7, 14.83) for PPT and 17.22% (95% CI 11.96, 22.49) for grip, and mild in 21.05% (95% CI 15.78, 26.79) for PPT and 35.89 (95% CI 29.67, 42.58) for grip. Good outcome was predicted by ILH-PPT (B = 1.03 [95% CI 0.39, 3.31]), ILH-grip (B = 1.16 [95% CI 0.54, 3.53]), low NIHSS-discharge (B = -1.57 [95% CI -4.0, -1.19]), and no depression (B = -0.62 [95% CI -1.63, -0.43]), accounting for stroke delay (B = -0.011 [95% CI -0.06, 0.01]). Model efficiency was 91.6% (AUC = 0.977; 95% CI 0.959, 0.996). LASSO and Random Forest methods provided similar results, confirming the LR model robustness. CONCLUSIONS: ILH impairment is frequent after motor stroke and predicts long-term outcome. We propose to integrate ILH impairment into rehabilitation programs to improve recovery and serve research interventions such as neuromodulation.

White matter tract disruption is associated with ipsilateral hand impairment in subacute stroke: a diffusion MRI study.

PURPOSE: The ipsilateral hand (ILH) is impaired after unilateral stroke, but the underlying mechanisms remain unresolved. Based on the degeneracy theory of network connectivity that many connectivity patterns are functionally equivalent, we hypothesized that ILH impairment would result from the summation of microstructural white matter (WM) disruption in the motor network, with a task-related profile. We aimed to determine the WM disruption patterns associated with ILH impairment. METHODS: This was a cross-sectional analysis of patients in the ISIS-HERMES Study with ILH and diffusion-MRI data collected 1 month post-stroke. Patients performed three tasks, the Purdue Pegboard Test (PPT), handgrip strength, and movement time. Fractional anisotropy (FA) derived from diffusion MRI was measured in 33 WM regions. We used linear regression models controlling for age, sex, and education to determine WM regions associated with ILH impairment. RESULTS: PPT was impaired in 42%, grip in 59%, and movement time in 24% of 29 included patients (mean age, 51.9 ± 10.5 years; 21 men). PPT was predicted by ipsilesional corticospinal tract (i-CST) (B = 17.95; p = 0.002) and superior longitudinal Fasciculus (i-SLF) (B = 20.52; p = 0.008); handgrip by i-CST (B = 109.58; p = 0.016) and contralesional anterior corona radiata (B = 42.69; p = 0.039); and movement time by the corpus callosum (B = - 1810.03; p = 0.003) i-SLF (B = - 917.45; p = 0.015), contralesional pons-CST (B = 1744.31; p = 0.016), and i-corticoreticulospinal pathway (B = - 380.54; p = 0.037). CONCLUSION: ILH impairment was associated with WM disruption to a combination of ipsilateral and contralesional tracts with a pattern influenced by task-related processes, supporting the degeneracy theory. We propose to integrate ILH assessment in rehabilitation programs and treatment interventions such as neuromodulation.

Solving the Evidence Interpretability Crisis in Health Technology Assessment: A Role for Mechanistic Models?

Health technology assessment (HTA) aims to be a systematic, transparent, unbiased synthesis of clinical efficacy, safety, and value of medical products (MPs) to help policymakers, payers, clinicians, and industry to make informed decisions. The evidence available for HTA has gaps-impeding timely prediction of the individual long-term effect in real clinical practice. Also, appraisal of an MP needs cross-stakeholder communication and engagement. Both aspects may benefit from extended use of modeling and simulation. Modeling is used in HTA for data-synthesis and health-economic projections. In parallel, regulatory consideration of model informed drug development (MIDD) has brought attention to mechanistic modeling techniques that could in fact be relevant for HTA. The ability to extrapolate and generate personalized predictions renders the mechanistic MIDD approaches suitable to support translation between clinical trial data into real-world evidence. In this perspective, we therefore discuss concrete examples of how mechanistic models could address HTA-related questions. We shed light on different stakeholder's contributions and needs in the appraisal phase and suggest how mechanistic modeling strategies and reporting can contribute to this effort. There are still barriers dissecting the HTA space and the clinical development space with regard to modeling: lack of an adapted model validation framework for decision-making process, inconsistent and unclear support by stakeholders, limited generalizable use cases, and absence of appropriate incentives. To address this challenge, we suggest to intensify the collaboration between competent authorities, drug developers and modelers with the aim to implement mechanistic models central in the evidence generation, synthesis, and appraisal of HTA so that the totality of mechanistic and clinical evidence can be leveraged by all relevant stakeholders.

Recovery of balance and gait after stroke is deteriorated by confluent white matter hyperintensities: Cohort study.

BACKGROUND: White matter hyperintensities (WMHs) are well known to affect post-stroke disability, mainly by cognitive impairment. Their impact on post-stroke balance and gait disorders is unclear. OBJECTIVES: We aimed to test the hypothesis that WMHs would independently deteriorate post-stroke balance and gait recovery. METHODS: This study was performed in 210 individuals of the cohort Determinants of Balance Recovery After Stroke (DOBRAS), consecutively enrolled after a first-ever hemisphere stroke. Clinical data were systematically collected on day 30±3 (D30) post-stroke and at discharge from the rehabilitation ward. WMHs were searched on MRI, graded with the Fazekas scale, and dichotomized as no/mild (absence/sparse) or moderate/severe (confluent). The primary endpoint was the recovery of the single limb stance, assessed with the Postural Assessment Scale for Stroke (PASS). The secondary endpoint was the recovery of independent gait, assessed with the modified Fugl-Meyer Gait Assessment (mFMA). The adjusted hazard ratios (aHRs) of achievements of these endpoints by level of WMHs were estimated by using Cox models, accounting for other relevant clinical and imaging factors. RESULTS: Individuals with moderate/severe WMHs (n=86, 41%) had greater balance and gait disorders and were more often fallers than others (n=124, 59%). Overall, they had worse and slower recovery of single limb stance and independent gait (P<0.001). Moderate/severe WMHs was the most detrimental factor for recovery of balance (aHR 0.46, 95% confidence interval [CI] 0.32-0.68, P<0.001) and gait (0.51, 0.35-0.74, P<0.001), along with age, stroke severity, lesion volume and disrupted corticospinal tract. With cerebral infarct, endovascular treatments had an independent positive effect, both on the recovery of balance (aHR 1.65, 95% CI 1.13-2.4, P=0.009) and gait (1.78, 1.24-2.55, P=0.002). CONCLUSIONS: WMHs magnify balance and gait disorders after stroke and worsen their recovery. They should be better accounted for in post-stroke rehabilitation, especially to help establish a prognosis of mobility. CLINICALTRIALS. GOV REGISTRATION: NCT03203109.

Using numerical modeling and simulation to assess the ethical burden in clinical trials and how it relates to the proportion of responders in a trial sample.

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment's efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT's ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial's statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Lateropulsion After Hemispheric Stroke: A Form of Spatial Neglect Involving Graviception.

OBJECTIVE: To test the hypothesis that lateropulsion is an entity expressing an impaired body orientation with respect to gravity in relation to a biased graviception and spatial neglect. METHODS: Data from the DOBRAS cohort (ClinicalTrials.gov: NCT03203109) were collected 30 days after a first hemisphere stroke. Lateral body tilt, pushing, and resistance were assessed with the Scale for Contraversive Pushing. RESULTS: Among 220 individuals, 72% were upright and 28% showed lateropulsion (tilters [14%] less severe than pushers [14%]). The 3 signs had very high factor loadings (>0.90) on a same dimension, demonstrating that lateropulsion was effectively an entity comprising body tilt (cardinal sign), pushing, and resistance. The factorial analyses also showed that lateropulsion was inseparable from the visual vertical (VV), a criterion referring to vertical orientation (graviception). Contralesional VV biases were frequent (44%), with a magnitude related to lateropulsion severity: upright -0.6° (-2.9; 2.4), tilters -2.9° (-7; 0.8), and pushers -12.3° (-15.4; -8.5). Ipsilesional VV biases were less frequent and milder (p < 0.001). They did not deal with graviception, 84% being found in upright individuals. Multivariate, factorial, contingency, and prediction analyses congruently showed strong similarities between lateropulsion and spatial neglect, the latter encompassing the former. CONCLUSIONS: Lateropulsion (pusher syndrome) is a trinity constituted by body tilt, pushing, and resistance. It is a way to adjust the body orientation in the roll plane to a wrong reference of verticality. Referring to straight above, lateropulsion might correspond to a form of spatial neglect (referring to straight ahead), which would advocate for 3D maps in the human brain involving the internal model of verticality.

Balance, Lateropulsion, and Gait Disorders in Subacute Stroke.

OBJECTIVE: To test the hypothesis that impaired body orientation with respect to gravity (lateropulsion) would play a key role in poststroke balance and gait disorders. METHODS: Cohort study of 220 individuals consecutively admitted to a neurorehabilitation ward after a first hemisphere stroke (DOBRAS cohort [Determinants of Balance Recovery After Stroke] 2012-2018, ClinicalTrials.gov: NCT03203109), with clinical data systematically collected at 1 month, then at discharge. Primary outcomes were balance and gait disorders, quantified by the Postural Assessment Scale for Stroke and the modified Fugl-Meyer Gait Assessment, to be explained by all deficits on day 30, including lateropulsion assessed with the Scale for Contraversive Pushing. Statistics comprised linear regression analysis, univariate and multivariate analyses, and receiver operating characteristic curves. RESULTS: Lateropulsion was frequent, especially after right hemisphere stroke (RHS, D30, 48%; discharge 24%), almost always in right-handers. Among all deficits, impaired body orientation (lateropulsion) had the most detrimental effect on balance and gait. After RHS, balance disorders were proportional to lateropulsion severity, which alone explained almost all balance disorders at initial assessment (90%; 95% confidence interval [CI] [86-94], p < 0.001) and at discharge (92%; 95% CI 89-95, p < 0.001) and also the greatest part of gait disorders at initial assessment (66%; 95% CI 56-77, p < 0.001) and at discharge (68%; 95% CI 57-78, p < 0.001). CONCLUSION: Lateropulsion is the primary factor altering poststroke balance and gait at the subacute stage and therefore should be systematically assessed. Poststroke balance and gait rehabilitation should incorporate techniques devoted to misorientation with respect to gravity.

Blood-based biomarkers and stem cell therapy in human stroke: a systematic review.

Stroke is one of the main causes of death and disability worldwide. Cell therapy represents a promising therapeutic approach to improve stroke outcome. Measurement of blood-based biomarkers might serve as a proof-of-concept to monitor the mechanisms undergirding these treatments, and such compounds could be used as surrogate biomarkers to monitor the safety and efficacy of cell therapies in the future. Additionally, the measurement of biomarkers that correlate with circulating stem cells in observational studies might be of interest to improve the understanding of how these cells are spontaneously mobilized and carry out their action after stroke. Thus, a systematic review has been herein performed on blood-based biomarkers assessed in stroke patients treated with cell therapy or in observational studies in which circulating stem cells have been measured after stroke.

Autologous Mesenchymal Stem Cells Improve Motor Recovery in Subacute Ischemic Stroke: a Randomized Clinical Trial.

While preclinical stroke studies have shown that mesenchymal stem cells (MSCs) promote recovery, few randomized controlled trials (RCT) have assessed cell therapy in humans. In this RCT, we assessed the safety, feasibility, and efficacy of intravenous autologous bone marrow-derived MSCs in subacute stroke. ISIS-HERMES was a single-center, open-label RCT, with a 2-year follow-up. We enrolled patients aged 18-70 years less than 2 weeks following moderate-severe ischemic carotid stroke. Patients were randomized 2:1 to receive intravenous MSCs or not. Primary outcomes assessed feasibility and safety. Secondary outcomes assessed global and motor recovery. Passive wrist movement functional MRI (fMRI) activity in primary motor cortex (MI) was employed as a motor recovery biomarker. We compared "treated" and "control" groups using as-treated analyses. Of 31 enrolled patients, 16 patients received MSCs. Treatment feasibility was 80%, and there were 10 and 16 adverse events in treated patients, and 12 and 24 in controls at 6-month and 2-year follow-up, respectively. Using mixed modeling analyses, we observed no treatment effects on the Barthel Index, NIHSS, and modified-Rankin scores, but significant improvements in motor-NIHSS (p = 0.004), motor-Fugl-Meyer scores (p = 0.028), and task-related fMRI activity in MI-4a (p = 0.031) and MI-4p (p = 0.002). Intravenous autologous MSC treatment following stroke was safe and feasible. Motor performance and task-related MI activity results suggest that MSCs improve motor recovery through sensorimotor neuroplasticity. ClinicalTrials.gov Identifier NCT00875654.

Controlled clinical trials of cell therapy in stroke: Meta-analysis at six months after treatment.

Background Cell therapy is promising in experimental studies and has been assessed only in a few studies on humans. Aims To evaluate the effect of cell therapy in humans. Methods We included clinical trials with a control group that reported safety and efficacy six months following treatment. Quality was evaluated and clinical scales data were extracted. Quantitative analysis was based on the standardized means difference (SMD). Among 28 trials published from 1995 to 2016, nine studies (194 patients; 191 controls) were eligible. Publication biases were assessed with the funnel plot and pre-specified explanatory variables were tested with a group analysis and a meta-regression. Results The overall quality was moderate. Cell therapy had a positive effect on the outcome (SMD: 0.57, 95% CI: 0.22-0.92; p = 0.002). The sensitivity analysis showed an upper level of effect size of 0.81 (95% CI: 0.34-1.27; p = 0.001) and a lower level of 0.455 (95% CI: 0.04-0.87; p = 0.03). None of the pre-specified explanatory variable was significantly correlated to outcome: age, ratio infarction/hemorrhage, delay from stroke to treatment, route of administration, cell type, randomization, and blinded outcome assessment. The significant heterogeneity (p = 0.03) was not explained by publication biases (p = 0.09) and was more likely due to methodological and quality differences between the trials. Conclusions This result suggests that cell therapy is beneficial in stroke and is expected to help in the designing of stem cells controlled clinical trials (CCT) in large populations.

Parietal operculum and motor cortex activities predict motor recovery in moderate to severe stroke.

While motor recovery following mild stroke has been extensively studied with neuroimaging, mechanisms of recovery after moderate to severe strokes of the types that are often the focus for novel restorative therapies remain obscure. We used fMRI to: 1) characterize reorganization occurring after moderate to severe subacute stroke, 2) identify brain regions associated with motor recovery and 3) to test whether brain activity associated with passive movement measured in the subacute period could predict motor outcome six months later. Because many patients with large strokes involving sensorimotor regions cannot engage in voluntary movement, we used passive flexion-extension of the paretic wrist to compare 21 patients with subacute ischemic stroke to 24 healthy controls one month after stroke. Clinical motor outcome was assessed with Fugl-Meyer motor scores (motor-FMS) six months later. Multiple regression, with predictors including baseline (one-month) motor-FMS and sensorimotor network regional activity (ROI) measures, was used to determine optimal variable selection for motor outcome prediction. Sensorimotor network ROIs were derived from a meta-analysis of arm voluntary movement tasks. Bootstrapping with 1000 replications was used for internal model validation. During passive movement, both control and patient groups exhibited activity increases in multiple bilateral sensorimotor network regions, including the primary motor (MI), premotor and supplementary motor areas (SMA), cerebellar cortex, putamen, thalamus, insula, Brodmann area (BA) 44 and parietal operculum (OP1-OP4). Compared to controls, patients showed: 1) lower task-related activity in ipsilesional MI, SMA and contralesional cerebellum (lobules V-VI) and 2) higher activity in contralesional MI, superior temporal gyrus and OP1-OP4. Using multiple regression, we found that the combination of baseline motor-FMS, activity in ipsilesional MI (BA4a), putamen and ipsilesional OP1 predicted motor outcome measured 6 months later (adjusted-R2 = 0.85; bootstrap p < 0.001). Baseline motor-FMS alone predicted only 54% of the variance. When baseline motor-FMS was removed, the combination of increased activity in ipsilesional MI-BA4a, ipsilesional thalamus, contralesional mid-cingulum, contralesional OP4 and decreased activity in ipsilesional OP1, predicted better motor outcome (djusted-R2 = 0.96; bootstrap p < 0.001). In subacute stroke, fMRI brain activity related to passive movement measured in a sensorimotor network defined by activity during voluntary movement predicted motor recovery better than baseline motor-FMS alone. Furthermore, fMRI sensorimotor network activity measures considered alone allowed excellent clinical recovery prediction and may provide reliable biomarkers for assessing new therapies in clinical trial contexts. Our findings suggest that neural reorganization related to motor recovery from moderate to severe stroke results from balanced changes in ipsilesional MI (BA4a) and a set of phylogenetically more archaic sensorimotor regions in the ventral sensorimotor trend, in which OP1 and OP4 processes may complement the ipsilesional dorsal motor cortex in achieving compensatory sensorimotor recovery.

How to Measure Recovery? Revisiting Concepts and Methods for Stroke Studies.

In clinical trials, assessing efficacy is based on validated scales, and the primary endpoint is usually based on a single scale. The aim of the review is to revisit the concepts and methods to design and analyze studies focused on restoration, recovery and or compensation. These studies are becoming more frequent with the development of restorative medicine. After discussing the definitions of recovery, we address the concept of recovery as the regain of lost capabilities, when the patient reaches a new equilibrium. Recovery is a dynamic process which assessment includes information from initial and final status, their difference, the difference between the final status of the patient and normality, and the speed of restoration. Finally, recovery can be assessed either for a specific function (focal restoration) or for a more global restoration. A single scale is not able to assess all the facets of a skill or a function, therefore complementary information should be collected and analyzed simultaneously to be tested in a single analysis. We are suggesting that recovery should be considered as a latent variable and therefore cannot be measured in pure form. We are also suggesting to customize the data collection and analysis according to the characteristics of the subjects, the mechanisms of action and consequences of the intervention. Moreover, recovery trials should benefit from latent variable analysis methods. Structural equation modeling is likely the best candidate for this approach applicable in pre-clinical and clinical studies.

Intravenous Injection of Clinical Grade Human MSCs After Experimental Stroke: Functional Benefit and Microvascular Effect.

Stroke is the leading cause of disability in adults. Many current clinical trials use intravenous (IV) administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs). This autologous graft requires a delay for ex vivo expansion of cells. We followed microvascular effects and mechanisms of action involved after an IV injection of human BM-MSCs (hBM-MSCs) at a subacute phase of stroke. Rats underwent a transient middle cerebral artery occlusion (MCAo) or a surgery without occlusion (sham) at day 0 (D0). At D8, rats received an IV injection of 3 million hBM-MSCs or PBS-glutamine. In a longitudinal behavioral follow-up, we showed delayed somatosensory and cognitive benefits 4 to 7 weeks after hBM-MSC injection. In a separate longitudinal in vivo magnetic resonance imaging (MRI) study, we observed an enhanced vascular density in the ischemic area 2 and 3 weeks after hBM-MSC injection. Histology and quantitative polymerase chain reaction (qPCR) revealed an overexpression of angiogenic factors such as Ang1 and transforming growth factor-1 (TGF-1) at D16 in hBM-MSC-treated MCAo rats compared to PBS-treated MCAo rats. Altogether, delayed IV injection of hBM-MSCs provides functional benefits and increases cerebral angiogenesis in the stroke lesion via a release of endogenous angiogenic factors enhancing the stabilization of newborn vessels. Enhanced angiogenesis could therefore be a means of improving functional recovery after stroke.

Positive Predictive Value of French Hospitalization Discharge Codes for Stroke and Transient Ischemic Attack.

BACKGROUND: We aimed at measuring the positive predictive value (PPV) of data in the French Hospital Medical Information Database (FHD). SUMMARY: This retrospective multicenter study included 31 hospitals from where 56 hospital stays were randomly selected among all hospitalizations for the years 2009 and 2010 with at least 1 principal diagnosis of stroke or transient ischemic attack (TIA). Three algorithms were evaluated. Algorithm 1 selected discharge abstracts with at least 1 principal diagnosis identified by one of the relevant International Classification of Diseases, 10th revision codes. Algorithm 2 selected stays with 1 principal diagnosis of the whole stay, but without the dates of the stay. Algorithm 3 took into account the kind of medical wards. The PPV of each algorithm was calculated using medical records as the reference. We found 1,669 discharge abstracts with a diagnosis of stroke among the 1,680 that were randomly selected. The neurologist's review revealed 196 false-positive cases providing a global PPV of 88.26% for algorithm 1, 89.96% for algorithm 2 and 92.74% for algorithm 3. KEY MESSAGES: It was possible to build an algorithm to optimize the FHD for stroke and TIA reporting, with a PPV at 90%. The FHD could be a good tool to measure the burden of stroke in France.

Depression: cognition relations after stroke.

BACKGROUND: Poststroke depression and cognitive dysfunction are common and are independent predictors of poor recovery. AIMS: We assessed whether and how depression and cognition were correlated in the subacute period after stroke. METHOD: We prospectively recruited 207 nondemented patients (Mini Mental State Examination ≥ 23) presenting with a first-ever ischemic stroke (127 males), mean age of 48·5 years (16·4 standard deviation), median 12 days after infarction, as assessed on magnetic resonance imaging. We administered a comprehensive neuropsychological battery involving cognitive domains including instrumental functions, memory, executive functions, and working memory. Depression was quantified with the Beck Depression Inventory. RESULTS: Depression (Beck Depression Inventory > 9) was identified in 30·4% of the patients (95% confidence interval 24·2-37·2%). Median Beck Depression Inventory was 6. Median Mini Mental State Examination was 30. Cognitive dysfunctioning in at least one neuropsychological test was present in 89% (95% confidence interval 84-93%). Each point increase of Beck Depression Inventory was associated with an odd of 1·1 (95% confidence interval 1·04-1·19) of changing to a worse category of cognition. Stroke location was not correlated with depression. All cognitive domains were significantly correlated with depression. In multivariate analysis, the executive functions (P = 0·001) and the working memory (P = 0·009) were the best predictors of depression when adjusted for demographic and stroke characteristics. CONCLUSIONS: The rates of depression and cognitive impairment were in the range of previous stroke studies. Our study suggested a strong relation between depression and cognition characterized by executive functions and working memory dysfunctioning.

Imaging of functional and structural alterations of large arteries after acute ischaemic atherothrombotic stroke or acute coronary syndromes.

BACKGROUND: Non-invasive methods allow the evaluation of structural and functional arterial abnormalities. So far, no study has focused on the comparison of vascular parameters by type of cardiovascular event. METHODS: In this pilot study, cardiovascular risk factors, carotid parameters, carotid-to-femoral pulse wave velocity (PWV), brachial flow-mediated dilation and ambulatory blood pressure were assessed in patients who presented with acute coronary syndromes (ACS) or ischaemic atherothrombotic stroke (IAS). Groups were matched for age and gender. RESULTS: Prevalences of hypertension, diabetes and dyslipidaemia and heredity, smoking and body mass index were similar in the ACS (n=50) and IAS (n=50) groups. Carotid intima-media thickness (IMT) and PWV were significantly higher in the IAS vs. ACS group (769±180 vs. 701±136 µm; P=0.039 and 12.5±3.5 vs. 10.7±2.4 m/s; P=0.006). Carotid distensibility was significantly lower in the IAS vs. ACS group (16.2±3.2 vs. 18.9±7.6 10(-3)/kPa; P=0.02). These differences persisted after adjustment for blood pressure for carotid distensibility but not for PWV. The prevalences of endothelial dysfunction and carotid plaques were not significantly different in the ACS and IAS groups (86% and 74%; 80% and 78%). In a multivariable model, carotid distensibility remained associated with ACS (odds ratio 1.19; 95% confidence interval 1.03-1.38; P=0.016). CONCLUSIONS: Stiffness and carotid wall thickness were higher in IAS than in ACS patients. These differences may support the interest in new therapeutic targets for cardiovascular secondary prevention. NCT NO: NCT00926874.

Upper limb recovery after stroke is associated with ipsilesional primary motor cortical activity: a meta-analysis.

BACKGROUND AND PURPOSE: Although neuroimaging studies have revealed specific patterns of reorganization in the sensorimotor control network after stroke, their role in recovery remains unsettled. To review the existing evidence systematically, we performed activation likelihood estimation meta-analysis of functional neuroimaging studies investigating upper limb movement-related brain activity after stroke. METHODS: Twenty-four studies using sensorimotor tasks in standardized coordinates were included, totaling 255 patients and 145 healthy controls. Across the entire brain, we compared task-related activity patterns in good and poor recovery and assessed the magnitude of spatial shifts in sensorimotor activity in cortical motor areas after stroke. RESULTS: When compared with healthy controls, patients showed higher activation likelihood estimation values in contralesional primary motor soon after stroke that abated with time, but were not related to motor outcome. The observed activity changes were consistent with restoration of typical interhemispheric balance. In contrast, activation likelihood estimation values in ipsilesional medial-premotor and primary motor cortex were associated with good outcome, reorganization that may reflect vicarious processes associated with ventral activity shifts from BA4a to 4p. In the anterior cerebellum, a novel finding was the association of poor recovery with increased vermal activity, possibly reflecting behaviorally inadequate compensatory strategies engaging the fastigio-thalamo-cortical and corticoreticulospinal systems. CONCLUSIONS: Activity in ipsilesional primary motor and medial-premotor cortices in chronic stroke signals good motor recovery, whereas cerebellar vermis activity signals poor recovery. Functional MRI may be useful in identifying recovery biomarkers.

How accurate is the reporting of stroke in hospital discharge data? A pilot validation study using a population-based stroke registry as control.

Population-based stroke registries can provide valid stroke incidence because they ensure exhaustiveness of case ascertainment. However, their results are difficult to extrapolate because they cover a small population. The French Hospital Discharge Database (FHDDB), which routinely collects administrative data, could be a useful tool for providing data on the nationwide burden of stroke. The aim of our pilot study was to assess the validity of stroke diagnosis reported in the FHDDB. All records of patients with a diagnosis of stroke between 2004 and 2008 were retrieved from the FHDDB of Dijon Teaching Hospital. The Dijon Stroke Registry was considered as the gold standard. The sensitivity, positive predictive value (PPV), and weighted kappa were calculated. The Dijon Stroke Registry identified 811 patients with a stroke, among whom 186 were missed by the FHDDB and thus considered false-negatives. The FHDDB identified 903 patients discharged following a stroke including 625 true-positives confirmed by the registry and 278 false-positives. The overall sensitivity and PPV of the FHDDB for the diagnosis of stroke were, respectively, 77.1 % (95 % CI 74.2-80) and 69.2 % (95 % CI 66.1-72.2). For cardioembolic and lacunar strokes, the FHDDB yielded higher PPVs (respectively 86.7 and 84.6 %; p < 0.0001) than those of other stroke subtypes. The PPV but not sensitivity significantly increased over the years (p < 0.0001). Agreement with the stroke registry was moderate (kappa 52.8; 95 % CI 46.8-58.9). The FHDDB-based stroke diagnosis showed moderate validity compared with the Dijon Stroke Registry as the gold standard. However, its accuracy (PPV) increased with time and was higher for some stroke subtypes.

Magnetic resonance imaging and fluorescence labeling of clinical-grade mesenchymal stem cells without impacting their phenotype: study in a rat model of stroke.

Human mesenchymal stem cells (hMSCs) have strong potential for cell therapy after stroke. Tracking stem cells in vivo following a graft can provide insight into many issues regarding optimal route and/or dosing. hMSCs were labeled for magnetic resonance imaging (MRI) and histology with micrometer-sized superparamagnetic iron oxides (M-SPIOs) that contained a fluorophore. We assessed whether M-SPIO labeling obtained without the use of a transfection agent induced any cell damage in clinical-grade hMSCs and whether it may be useful for in vivo MRI studies after stroke. M-SPIOs provided efficient intracellular hMSC labeling and did not modify cell viability, phenotype, or in vitro differentiation capacity. Following grafting in a rat model of stroke, labeled hMSCs could be detected using both in vivo MRI and fluorescent microscopy until 4 weeks following transplantation. However, whereas good label stability and unaffected hMSC viability were observed in vitro, grafted hMSCs may die and release iron particles in vivo.