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Stroke is the most common cause of disability. Brain repair mechanisms are often insufficient to allow a full recovery. Stroke damage involve all brain cell type and extracellular matrix which represent the crucial "glio-neurovascular niche" useful for brain plasticity. Regenerative medicine including cell therapies hold great promise to decrease post-stroke disability of many patients, by promoting both neuroprotection and neural repair through direct effects on brain lesion and/or systemic effects such as immunomodulation. Mechanisms of action vary according to each grafted cell type: "peripheral" stem cells, such as mesenchymal stem cells (MSC), can provide paracrine trophic support, and neural stem/progenitor cells (NSC) or neurons can act as direct cells' replacements. Optimal time window, route, and doses are still debated, and may depend on the chosen medicinal product and its expected mechanism such as neuroprotection, delayed brain repair, systemic effects, or graft survival and integration in host network. MSC, mononuclear cells (MNC), umbilical cord stem cells and NSC are the most investigated. Innovative approaches are implemented concerning combinatorial approaches with growth factors and biomaterials such as injectable hydrogels which could protect a cell graft and/or deliver drugs into the post-stroke cavity at chronic stages. Through main publications of the last two decades, we provide in this review concepts and suggestions to improve future translational researches and larger clinical trials of cell therapy in stroke., (Copyright © 2023 IBRO. Published by Elsevier Inc. All rights reserved.)

Background: Lateropulsion is a deficit in body orientation with respect to gravity, frequent after stroke. Although it is a primary factor affecting mobility, the impact of its attenuation on balance and gait recovery has never been investigated. Moreover, most studies on the lateropulsion time-course focus on severe forms suspected to have a poor recovery, which is not proven., Objectives: To investigate lateropulsion attenuation and test 2 hypotheses: 1) lateropulsion attenuation greatly contributes to balance and gait recovery and 2) severe forms of lateropulsion recover slower than moderate forms., Methods: This longitudinal study involved individuals included in the Determinants of Balance Recovery After Stroke (DOBRAS) cohort, after a first-ever hemispheric stroke, with data collected on day 30 (D30), D60 and D90 post-stroke. Body orientation with respect to gravity was assessed using the Scale for Contraversive Pushing (both scores and severity grouping), in parallel with balance (Postural Assessment Scale for Stroke) and gait (modified Fugl-Meyer Gait Assessment)., Results: Among the 106 eligible individuals (mean age 66.5 [SD 9.7] years), on D30, 43 (41%) were considered upright and 63 (59%) showed lateropulsion: 30 (28%) moderate and 33 (31%) severe. Most individuals with lateropulsion (73%) improved their body orientation, progressing from severe to moderate lateropulsion, or becoming upright. However, half were still not upright on D90. The improvement in body orientation had a large impact on mobility, especially in individuals with severe lateropulsion, in whom it explained about 50% of balance and gait recovery between D30 and D60, then 20% (D60-D90). For moderate lateropulsion, its attenuation explained about 20% of balance and gait recovery until D90. Lateropulsion attenuation was not slower in individuals with severe forms., Conclusions: Lateropulsion attenuation enhances balance and gait recovery in individuals after stroke suggesting that specific rehabilitation of body orientation with respect to gravity might help to recover mobility., Registration: NCT03203109., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023. Published by Elsevier Masson SAS.)

Introduction: Elderly patients are a growing population in stroke units, characterized by higher frailty, but underrepresented in clinical trials about acute care. We investigated efficacy of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) in elderlies in current practice., Methods: We assessed consecutive patients with acute ischemic stroke (AIS) hospitalized in the four stroke units of the French Northern Alps Emergency Network between 2015 and 2020. We compared baseline characteristics, early neurological evolution and outcome of patients aged 80-89 and≥90years old (yo)., Results: Among 8367 patients, 2744 (32.8%) were 80-89 yo and 541 (6.5%) were≥90 yo. IVT and/or MT were performed in 787 patients≥80 yo (632 patients aged 80-89, 155 patients aged>90). Early neurological improvement was more frequent in patients≥80 yo treated by IVT and/or MT compared to untreated patients (45.6% versus 38.4%, P=0.002). After adjustment, reperfusion treatments improved likelihood of good outcome at discharge (OR=2.0 [1.6-2.7]) and reduced in-hospital mortality (OR=0.5 [0.4-0.7]). Age and initial NIHSS score were independent factors of poor functional outcome at discharge and in-hospital mortality. The rate of successful recanalization was comparable between octogenarians and nonagenarians (87% versus 85.2%, P=0.8). Octogenarians had better functional outcome at discharge compared to nonagenarians [modified Rankin scale (mRS) 0-2: 36% versus 25.7%, P=0.02], whatever IVT or MT strategy. In-hospital mortality was lower for octogenarians compared to nonagenarians (19.5% versus 27.1%, P=0.04)., Discussion: IVT and MT improve early neurological recovery and functional outcome at discharge of both octogenarians and nonagenarians in current practice. Despite a poorer outcome for nonagenarians than octogenarians, these reperfusion treatments should not be withheld on the basis of age only., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background and Purpose: The best management of acute ischemic stroke patients with a minor stroke and large vessel occlusion is still uncertain. Specific clinical and radiological data may help to select patients who would benefit from endovascular therapy (EVT). We aimed to evaluate the relevance of National Institutes of Health Stroke Scale (NIHSS) subitems for predicting the potential benefit of providing EVT after intravenous thrombolysis (IVT; "bridging treatment") versus IVT alone., Methods: We extracted demographic, clinical, risk factor, radiological, revascularization and outcome data of consecutive patients with M1 or proximal M2 middle cerebral artery occlusion and admission NIHSS scores of 0-5 points, treated with IVT ± EVT between May 2005 and March 2021, from nine prospectively constructed stroke registries at seven French and two Swiss comprehensive stroke centers. Adjusted interaction analyses were performed between admission NIHSS subitems and revascularization modality for two primary outcomes at 3 months: non-excellent functional outcome (modified Rankin Scale score 2-6) and difference in NIHSS score between 3 months and admission., Results: Of the 533 patients included (median age 68.2 years, 46% women, median admission NIHSS score 3), 136 (25.5%) initially received bridging therapy and 397 (74.5%) received IVT alone. Adjusted interaction analysis revealed that only facial palsy on admission was more frequently associated with excellent outcome in patients treated by IVT alone versus bridging therapy (odds ratio 0.47, 95% confidence interval 0.24-0.91; p = 0.013). Regarding NIHSS difference at 3 months, no single NIHSS subitem interacted with type of revascularization., Conclusions: This retrospective multicenter analysis found that NIHSS subitems at admission had little value in predicting patients who might benefit from bridging therapy as opposed to IVT alone. Further research is needed to identify better markers for selecting EVT responders with minor strokes., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Sleep-wake disorders (SWD) are acknowledged risk factors for both ischemic stroke and poor cardiovascular and functional outcome after stroke. SWD are frequent following stroke, with sleep apnea (SA) being the most frequent SWD affecting more than half of stroke survivors. While sleep disturbances and SWD are frequently reported in the acute phase, they may persist in the chronic phase after an ischemic stroke. Despite the frequency and risk associated with SWD following stroke, screening for SWD remains rare in the clinical setting, due to challenges in the assessment of post-stroke SWD, uncertainty regarding the optimal timing for their diagnosis, and a lack of clear treatment guidelines (i.e., when to treat and the optimal treatment strategy). However, little evidence support the feasibility of SWD treatment even in the acute phase of stroke and its favorable effect on long-term cardiovascular and functional outcomes. Thus, sleep health recommendations and SWD treatment should be systematically embedded in secondary stroke prevention strategy. We therefore propose that the management of SWD associated with stroke should rely on a multidisciplinary approach, with an integrated diagnostic, treatment, and follow-up strategy. The challenges in the field are to improve post-stroke SWD diagnosis, prognosis and treatment, through a better appraisal of their pathophysiology and temporal evolution., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Purpose: Efficacy of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) is strongly time dependent in acute stroke management. We investigated the impact of a direct magnetic resonance imaging (MRI) room admission protocol in order to reduce in-hospital delays., Methods: We implemented a protocol of direct MRI room admission, bypassing the Emergency Department. We compared in-hospital delays, clinical and functional outcomes using National Institute of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores, between patients hospitalized via this protocol and those admitted via the standard workflow and treated by IVT and/or MT. The primary endpoint was the proportion of patients with door-to-needle time (DTN) ≤ 60minutes., Results: Among 308 consecutive patients included, 62 underwent direct MRI room admission. The proportion of patients with DTN ≤ 60minutes was higher in the intervention group compared to the control group (82.5% vs. 17.8%, P<0.001), and median DTN was lower (45min vs. 75min, P<0.001). Despite a functional benefit at discharge on dichotomized mRS (mRS [0-2, as independence]: 66.1% vs. 51.2%, P=0.003), the difference was no longer statistically significant at six months (68.4% vs. 57.4%, P=0.10)., Conclusion: Direct MRI room admission of stroke alerts is associated with an important reduction of treatment times and improves functional outcomes., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Whether bridging therapy (intravenous thrombolysis [IVT] followed by mechanical thrombectomy) is superior to IVT alone in minor stroke with large vessel occlusion is unknown. Perfusion imaging may identify subsets of large vessel occlusion-related minor stroke patients with distinct response to bridging therapy., Methods: We conducted a multicenter international observational study of consecutive IVT-treated patients with minor stroke (National Institutes of Health Stroke Scale score ≤5) who had an anterior circulation large vessel occlusion and perfusion imaging performed before IVT, with a subset undergoing immediate thrombectomy. Propensity score with inverse probability of treatment weighting was used to account for baseline between-groups differences. The primary outcome was 3-month modified Rankin Scale score 0 to 1. We searched for an interaction between treatment group and mismatch volume (critical hypoperfusion-core volume)., Results: Overall, 569 patients were included (172 and 397 in the bridging therapy and IVT groups, respectively). After propensity-score weighting, the distribution of baseline variables was similar across the 2 groups. In the entire population, bridging was associated with lower odds of achieving modified Rankin Scale score 0 to 1: odds ratio, 0.73 [95% CI, 0.55-0.96]; P =0.03. However, mismatch volume modified the effect of bridging on clinical outcome ( P interaction =0.04 for continuous mismatch volume); bridging was associated with worse outcome in patients with, but not in those without, mismatch volume <40 mL (odds ratio, [95% CI] for modified Rankin Scale score 0-1: 0.48 [0.33-0.71] versus 1.14 [0.76-1.71], respectively). Bridging was associated with higher incidence of symptomatic intracranial hemorrhage in the entire population, but this effect was present in the small mismatch subset only ( P interaction =0.002)., Conclusions: In our population of large vessel occlusion-related minor stroke patients, bridging therapy was associated with lower rates of good outcome as compared with IVT alone. However, mismatch volume was a strong modifier of the effect of bridging therapy over IVT alone, notably with worse outcome with bridging therapy in patients with mismatch volume ≤40 mL. Randomized trials should consider adding perfusion imaging for patient selection.

Rationale: Sleep-disordered breathing (SDB) is highly prevalent after stroke. The clinical and ventilatory chemosensitivity characteristics of SDB, namely obstructive, central and coexisting obstructive and central sleep apnoea (coexisting sleep apnoea) following stroke are poorly described., Objective: To determine the respective clinical and ventilatory chemosensitivity characteristics of SDB at least 3 months after a first ischaemic stroke., Methods: Cross-sectional analysis of a prospective, monocentric cohort conducted in a university hospital. 380 consecutive stroke or transient ischaemic attack patients were screened between December 2016 and December 2019., Measurements and Main Results: Full-night polysomnography, and hypercapnic ventilatory response were performed at a median (Q1; Q3) time from stroke onset of 134.5 (97.0; 227.3) days. 185 first-time stroke patients were included in the analysis. 94 (50.8%) patients presented no or mild SDB (Apnoea-Hypopnoea Index <15 events/hour of sleep) and 91 (49.2%) moderate to severe SDB, of which 52 (57.1%) presented obstructive sleep apnoea and 39 (42.9%) coexisting or central sleep apnoea. Obstructive sleep apnoea patients significantly differed regarding their clinical presentation from patients with no or mild SDB, whereas there was no difference with coexisting and central sleep apnoea patients. The latter presented a higher frequency of cerebellar lesions along with a heightened hypercapnic ventilatory response compared with no or mild SDB patients., Conclusion: SDB in first-time stroke patients differ in their presentation by their respective clinical traits and ventilatory chemosensitivity characteristics. The heightened hypercapnic ventilatory response in coexisting and central sleep apnoea stroke patients may orientate them to specific ventilatory support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., (© 2022 European Academy of Neurology.)

Sleep apnoea, one of the most common chronic diseases, is a risk factor for ischaemic stroke, stroke recurrence, and poor functional recovery after stroke. More than half of stroke survivors present with sleep apnoea during the acute phase after stroke, with obstructive sleep apnoea being the most common subtype. Following a stroke, sleep apnoea frequency and severity might decrease over time, but moderate to severe sleep apnoea is nevertheless present in up to a third of patients in the chronic phase after an ischaemic stroke. Over the past few decades evidence suggests that treatment for sleep apnoea is feasible during the acute phase of stroke and might favourably affect recovery and long-term outcomes. Nevertheless, sleep apnoea still remains underdiagnosed and untreated in many cases, due to challenges in the detection and prediction of post-stroke sleep apnoea, uncertainty as to the optimal timing for its diagnosis, and a scarcity of clear treatment guidelines (ie, uncertainty on when to treat and the optimal treatment strategy). Moreover, the pathophysiology of sleep apnoea associated with stroke, the proportion of stroke survivors with obstructive and central sleep apnoea, and the temporal evolution of sleep apnoea subtypes following stroke remain to be clarified. To address these shortcomings, the management of sleep apnoea associated with stroke should be integrated into a multidisciplinary diagnostic, treatment, and follow-up strategy., Competing Interests: Declaration of interests SB has received travel grants from AGIRàDom, outside the submitted work. MHS has received grants from Interfaculty Research Cooperation and Innosuisse (30664.1IP-LS), paid directly to the institution, outside the submitted work. J-LP declares consulting fees from Jazz Pharmaceutical, Resmed, and Philips; has received travel grants from AGIRàDom, AstraZeneca, Boehringer Ingelheim, Nightbalance, and Sefam; has received grants from Vitalaire, Resmed, Air Liquide Foundation, AGIRàDom, AstraZeneca, Fisher and Paykel, Mutualia, and Philips, paid directly to their institution, all outside the submitted work. RT declares honoraria from Fondation Périmètres and Jazz Pharmaceutical, and travel grants from AGIRàDom; and has received grants from Resmed, Inspire, BioProjet, “Fond de la recherche médicale”, “Direction de la recherche Clinique du CHU Grenoble Alpes”, and “Fond de dotation Agir pour les maladies chroniques” paid directly to their institution, all outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background and Purpose: The efficacy of patent foramen ovale (PFO) closure to reduce the frequency of migraine attacks remains controversial., Methods: This was a planned sub-study in migraine patients enrolled in a randomized, clinical trial designed to assess the superiority of PFO closure plus antiplatelet therapy over antiplatelet therapy alone to prevent stroke recurrence in patients younger than 60 years with a PFO-associated cryptogenic ischaemic stroke. The main outcome was the mean annual number of migraine attacks in migraine patients with aura and in those without aura, as recorded at each follow-up visit by study neurologists., Results: Of 473 patients randomized to PFO closure or antiplatelet therapy, 145 (mean age 41.9 years; women 58.6%) had migraine (75 with aura and 70 without aura). Sixty-seven patients were randomized to PFO closure and 78 to antiplatelet therapy. During a mean follow-up of about 5 years, there were no differences between antiplatelet-only and PFO closure groups in the mean annual number of migraine attacks, both in migraine patients with aura (9.2 [11.9] vs. 12.0 [19.1], p = 0.81) and in those without aura (12.1 [16.1] vs. 11.8 [18.4], p > 0.999). There were no differences between treatment groups regarding cessation of migraine attacks, migraine-related disability at 2 years and use of migraine-preventive drugs during follow-up., Conclusions: In young and middle-aged adults with PFO-associated cryptogenic stroke and migraine, PFO closure plus antiplatelet therapy did not reduce the mean annual number of migraine attacks compared to antiplatelet therapy alone, in migraine patients both with and without aura., (© 2021 European Academy of Neurology.)

Motor hand deficits impact autonomy in everyday life, and neuroplasticity processes of motor recovery can be explored using functional MRI (fMRI). However, few studies have used fMRI to explore the mechanisms underlying hand recovery following stroke. Based on the dual visuomotor model positing that two segregated dorsomedial and dorsolateral cerebral networks control reach and grasp movements, we explored the relationship between motor task-related activity in the sensorimotor network and hand recovery following stroke. Behavioral recovery was explored with a handgrip force task assessing simple grasp, and a visuomotor reaching and precise grasping task, the Purdue Pegboard Test (PPT). We used a passive wrist flexion-extension task to measure fMRI activity in 36 sensorimotor brain areas. Behavioral and fMRI measurements were performed in 27 patients (53.2 ± 9.5 years) 1-month following stroke, and then 6-month and 24-month later. The effects of sensorimotor activity on hand recovery were analyzed using correlations and linear mixed models (LMMs). PPT and handgrip force correlated with fMRI activity measures in the sensorimotor and parietal areas. PPT recovery was modeled by fMRI measures in the ipsilesional primary motor cortex (MI-4p), superior parietal lobule (SPL-7M) and parietal operculum OP1, and lesion side. Handgrip force was modeled by ipsilesional MI-4a, OP1, and contralesional inferior parietal lobule (IPL-PFt). Moreover, the relationship between fMRI activity and hand recovery was time-dependent, occurring in the early recovery period in SPL-BA-7M, and later in MI. These results suggest that areas of both dorsolateral and dorsomedial networks participate to visuomotor reach and grasp tasks (PPT), while dorsolateral network areas may control recovery of simple grasp (handgrip force), suggesting that the type of movement modulates network recruitment. We also found functional dissociations between MI-4p related to PPT that required independent finger movements and MI-4a related to simple grasp without independent finger movements. These findings need to be replicated in further studies., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Purpose- Hypertension is the most frequent comorbidity in stroke.The purpose of this study was to evaluate whether hypertension alters the response to treatment with adipose tissue-derived mesenchymal stem cells (ADMSCs) after an ischemic stroke in rats. Methods- Ischemic stroke was induced in male normotensive or hypertensive rats. Either vehicle or 1×10 6 ADMSC was intravenously administered at 48 hours poststroke. Functional outcome, lesion size and volume, and markers of brain repair (GFAP [glial fibrillary acidic protein], doublecortin, CD-31, α-smooth muscle actin) were evaluated. Results- Hypertensive rats had larger lesions, higher apparent diffusion coefficients (ADC) and worse functional outcomes than normotensive rats. Hypertension increased GFAP and vascular markers (CD-31 and α-smooth muscle actin). The hypertensive rats treated with ADMSC did not show any significant improvement in functional recovery, lesion size, ADC values, or histological markers compared with those which received the vehicle. Conclusions- ADMSC did not reverse the hypertension-induced increase in lesion severity or functional impairment. Gliosis, neurogenesis, or vascular markers were not affected by ADMSC in hypertensive rats. Hypertension has a negative impact on the therapeutic effect of ADMSC after an ischemic stroke.

Background: Bradykinin-mediated angioedema (AE) is a complication associated with thrombolysis for acute ischemic stroke. Risk factors are unknown and management is discussed., Objectives: To clarify risk factors associated with bradykinin-mediated AE after thrombolysis for acute ischemic stroke., Methods: In a case-control study conducted at a French reference centre for bradykinin angiœdema, patients with thrombolysis for acute ischemic stroke and a diagnosis of bradykinin-mediated angiœdema, were compared to controls treated with thrombolysis treatment without angiœdema., Results: Fifty-three thrombolysis-related AE were matched to 106 control subjects. The sites of attacks following thrombolysis for ischemic stroke mainly included tongue (34/53, 64%) and lips (26/53, 49%). The upper airways were involved in 37 (70%) cases. Three patients required mechanical ventilation. Patients with bradykinin-mediated angiœdema were more frequently women [33 (62%) vs. 44 (42%); P = 0.01], had higher frequency of prior ischemic stroke [12 (23%) vs. 9 (8%); P = 0.01], hypertension [46 (87%) vs. 70 (66%); P = 0.005], were more frequently treated with angiotensin-converting enzyme inhibitor [37 (70%) vs. 28 (26%); P < 0.001] and were more frequently hospitalized in intensive care medicine [ICU; 11 (21%) vs. 5 (5%); P = 0.004]. In multivariate analysis, factors associated with thrombolysis-related AE were female sex [odds ratio (OR), 3.04; 95% confident interval (CI), 1.32-7.01; P = 0.009] and treatment with angiotensin-converting enzyme inhibitors [(OR), 6.08; 95% (CI), 2.17-17.07; P < 0.001]., Conclusions: This case-control study points out angiotensin-converting enzyme inhibitors and female sex as risk factors of bradykinin AE associated with thrombolysis for ischemic stroke., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Background: Over 50% of acute stroke patients have hyperglycemia, which is associated with a poorer prognosis and outcome. Our aim was to investigate the impact of hyperglycemia on behavioral recovery and brain repair of delivered human adipose tissue-derived mesenchymal stem cells (hAD-MSCs) in a rat model of permanent middle cerebral artery occlusion (pMCAO)., Methods: Hyperglycemia was induced in rats by the administration of nicotinamide and streptozotocin. The rats were then subjected to stroke by a pMCAO model. At 48 h post-stroke, 1 × 10 6 hAD-MSCs or saline were intravenously administered. We evaluated behavioral outcome, infarct size by MRI, and brain plasticity markers by immunohistochemistry (glial fibrillary acidic protein [GFAP], Iba-1, synaptophysin, doublecortin, CD-31, collagen-IV, and α-smooth muscle actin [α-SMA])., Results: The hyperglycemic group exhibited more severe neurological deficits; lesion size and diffusion coefficient were larger compared with the non-hyperglycemic rats. GFAP, Iba-1, and α-SMA were increased in the hyperglycemic group. The hyperglycemic rats administered hAD-MSCs at 48 h after pMCAO had improved neurological impairment. Although T2-MRI did not show differences in lesion size between groups, the rADC values were lower in the treated group. Finally, the levels of GFAP, Iba-1, and arterial wall thickness were lower in the treated hyperglycemic group than in the nontreated hyperglycemic group at 6 weeks post-stroke., Conclusions: Our data suggest that rats with hyperglycemic ischemic stroke exhibit increased lesion size and impaired brain repair processes, which lead to impairments in behavioral recovery after pMCAO. More importantly, hAD-MSC administration induced better anatomical tissue preservation, associated with a good behavioral outcome.

In the future, stroke patients may receive stem cell therapy as this has the potential to restore lost functions. However, the development of clinically deliverable therapy has been slower and more challenging than expected. Despite recommendations by STAIR and STEPS consortiums, there remain flaws in experimental studies such as lack of animals with comorbidities, inconsistent approaches to experimental design, and concurrent rehabilitation that might lead to a bias towards positive results. Clinical studies have typically been small, lacking control groups as well as often without clear biological hypotheses to guide patient selection. Furthermore, they have used a wide range of cell types, doses, and delivery methods, and outcome measures. Although some ongoing and recent trial programs offer hints that these obstacles are now being tackled, the Horizon2020 funded RESSTORE trial will be given as an example of inconsistent regulatory requirements and challenges in harmonized cell production, logistic, and clinical criteria in an international multicenter study. The PISCES trials highlight the complex issues around intracerebral cell transplantation. Therefore, a better understanding of translational challenges is expected to pave the way to more successful help for stroke patients.

Background: Setting up a follow-up secondary prevention program after stroke is difficult due to motor and cognitive impairment, but necessary to prevent recurrence and improve patients' quality of life. To involve a referent nurse and a caregiver from the patient's social circle in nurse-led multimodal and long-term management of risk factors after stroke could be an advantage due to their easier access to the patient and family. The aim of this study is to compare the benefit of optimized follow up by nursing personnel from the vascular neurology department including therapeutic follow up, and an interventional program directed to the patient and a caregiving member of their social circle, as compared with typical follow up in order to develop a specific follow-up program of secondary prevention of stroke., Methods/design: The design is a randomized, controlled, clinical trial conducted in the French Stroke Unit of the Strokavenir network. In total, 410 patients will be recruited and randomized in optimized follow up or usual follow up for 2 years. In both group, patients will be seen by a neurologist at 6, 12 and 24 months. The optimized follow up will include follow up by a nurse from the vascular neurology department, including therapeutic follow up, and a training program on secondary prevention directed to the patient and a caregiving member of their social circle. After discharge, a monthly telephone interview, in the first year and every 3 months in the second year, will be performed by the nurse. At 6, 12 and 24 month, the nurse will give the patient and caregiver another training session. Usual follow up is only done by the patient's general practitioner, after classical information on secondary prevention of risk factors during hospitalization. The primary outcome measure is blood pressure measured after the first year of follow up. Blood pressure will be measured by nursing personnel who do not know the group into which the patient has been randomized. Secondary endpoints are associated mortality, morbidity, recurrence, drug side-effects and medico-economic analysis., Discussion: The result of this trial is expected to provide the benefit of a nurse-led optimized multimodal and long-term interventional program for management of risk factors after stroke, personalizing the role of the nurse and including the patient's caregiver., Trial Registration: ClinicalTrials.gov, NCT 02132364. Registered on 7 May 2014. EUDRACT, A 00473-40.

Regenerative cell therapy is a promising therapeutic strategy in neurology, most notably to improve stroke recovery. Although tolerability and feasibility have apparently been validated, many questions remain as to what is the best type of cells to use, the best route and the post-stroke delay for administration. Two main strategies have currently emerged: intravenous injection of mesenchymal stem cells with systemic trophic support; and intracerebral grafting of neural stem cells with brain repair effects at the lesion site. Multicenter clinical trials have just begun and are starting to assess the efficacy of these treatments on functional recovery. However, experimental studies also need to be conducted in parallel to precisely identify the mechanisms of action regarding the pathophysiology of brain plasticity, notably when stroke occurs with comorbidities. Such studies should also evaluate the potential of cell grafting combined with injectable biomaterials., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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.

Background: Trials of patent foramen ovale (PFO) closure to prevent recurrent stroke have been inconclusive. We investigated whether patients with cryptogenic stroke and echocardiographic features representing risk of stroke would benefit from PFO closure or anticoagulation, as compared with antiplatelet therapy., Methods: In a multicenter, randomized, open-label trial, we assigned, in a 1:1:1 ratio, patients 16 to 60 years of age who had had a recent stroke attributed to PFO, with an associated atrial septal aneurysm or large interatrial shunt, to transcatheter PFO closure plus long-term antiplatelet therapy (PFO closure group), antiplatelet therapy alone (antiplatelet-only group), or oral anticoagulation (anticoagulation group) (randomization group 1). Patients with contraindications to anticoagulants or to PFO closure were randomly assigned to the alternative noncontraindicated treatment or to antiplatelet therapy (randomization groups 2 and 3). The primary outcome was occurrence of stroke. The comparison of PFO closure plus antiplatelet therapy with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 2, and the comparison of oral anticoagulation with antiplatelet therapy alone was performed with combined data from randomization groups 1 and 3., Results: A total of 663 patients underwent randomization and were followed for a mean (±SD) of 5.3±2.0 years. In the analysis of randomization groups 1 and 2, no stroke occurred among the 238 patients in the PFO closure group, whereas stroke occurred in 14 of the 235 patients in the antiplatelet-only group (hazard ratio, 0.03; 95% confidence interval, 0 to 0.26; P<0.001). Procedural complications from PFO closure occurred in 14 patients (5.9%). The rate of atrial fibrillation was higher in the PFO closure group than in the antiplatelet-only group (4.6% vs. 0.9%, P=0.02). The number of serious adverse events did not differ significantly between the treatment groups (P=0.56). In the analysis of randomization groups 1 and 3, stroke occurred in 3 of 187 patients assigned to oral anticoagulants and in 7 of 174 patients assigned to antiplatelet therapy alone., Conclusions: Among patients who had had a recent cryptogenic stroke attributed to PFO with an associated atrial septal aneurysm or large interatrial shunt, the rate of stroke recurrence was lower among those assigned to PFO closure combined with antiplatelet therapy than among those assigned to antiplatelet therapy alone. PFO closure was associated with an increased risk of atrial fibrillation. (Funded by the French Ministry of Health; CLOSE ClinicalTrials.gov number, NCT00562289 .).

Stroke is the leading cause of disability in adults. After the very narrow time frame during which treatment by thrombolysis and mechanical thrombectomy is possible, cell therapy has huge potential for enhancing stroke recovery. Accurate analysis of the response to new therapy using imaging biomarkers is needed to assess therapeutic efficacy. The aim of this study was to compare 2 analysis techniques: the parametric response map (PRM), a voxel-based technique, and the standard whole-lesion approach. These 2 analyses were performed on data collected at 4 time points in a transient middle cerebral artery occlusion (MCAo) model, which was treated with human mesenchymal stem cells (hMSCs). The apparent diffusion coefficient (ADC), cerebral blood volume (CBV), and vessel size index (VSI) were mapped using magnetic resonance imaging (MRI). Two groups of rats received an intravenous injection of either 1 mL phosphate-buffered saline (PBS)-glutamine (MCAo-PBS, n = 10) or 3 million hMSCs (MCAo-hMSC, n = 10). One sham group was given PBS-glutamine (sham, n = 12). Each MRI parameter was analyzed by both the PRM and the whole-lesion approach. At day 9, 1 d after grafting, PRM revealed that hMSCs had reduced the fraction of decreased ADC (PRM ADC - : MCAo-PBS 6.7% ± 1.7% vs. MCAo-hMSC 3.3% ± 2.4%), abolished the fraction of increased CBV (PRM CBV+ : MCAo-PBS 16.1% ± 3.7% vs. MCAo-hMSC 6.4% ± 2.6%), and delayed the fraction of increased VSI (PRM VSI+ : MCAo-PBS 17.5% ± 6.3% vs. MCAo-hMSC 5.4% ± 2.6%). The whole-lesion approach was, however, insensitive to these early modifications. PRM thus appears to be a promising technique for the detection of early brain changes following treatments such as cell therapy.

Recent advances in MRI methodology, such as microvascular and brain oxygenation (StO 2 ) imaging, may prove useful in obtaining information about the severity of the acute stroke. We assessed the potential of StO 2 to detect the ischaemic core in the acute phase compared to apparent diffusion coefficient and to predict the final necrosis. Sprague-Dawley rats (n = 38) were imaged during acute stroke (D0) and 21 days after (D21). A multiparametric MRI protocol was performed at 4.7T to characterize brain damage within three region of interest: 'LesionD0' (diffusion), 'Mismatch' representing penumbra (perfusion/diffusion) and 'Hypoxia' (voxels < 40% of StO 2 within the region of interest LesionD0). Voxel-based analysis of stroke revealed heterogeneity of the region of interest LesionD0, which included voxels with different degrees of oxygenation decrease. This finding was supported by a dramatic decrease of vascular and perfusion parameters within the region of interest hypoxia. This zone presented the lowest values of almost all parameters analysed, indicating a higher severity. Our study demonstrates the potential of StO 2 magnetic resonance imaging to more accurately detect the ischaemic core without the inclusion of any reversible ischaemic damage. Our follow-up study indicates that apparent diffusion coefficient imaging overestimated the final necrosis while StO 2 imaging did not.

Background: Since 2015, the emergence of mechanical thrombectomy as standard care in acute stroke has involved organizational changes not only for stroke centers, but also for entire emergency regional networks. The aim of our study was to assess the proportion of ischemic stroke patients, admitted to stroke units in the Northern French Alps within the first 6h of onset, eligible for thrombectomy., Methods: This study retrospectively analyzed the clinical and radiological data of all acute stroke patients hospitalized at three stroke units of the Northern French Alps Emergency Network (RENAU) in 2014. Eligible patients had proximal arterial occlusions of the anterior and posterior cerebral circulation, as confirmed by brain imaging, which could be treated by thrombectomy within 6h of symptom onset., Results: Of the 435 cases of acute ischemic stroke, 152 patients were treated by intravenous thrombolysis (IV rtPA). Of these patients, 83 (55%) had intracranial occlusions and were eligible for combined thrombectomy. Of the 283 patients not treatable by IV rtPA, 32 patients (11%) were eligible for primary thrombectomy., Conclusion: Thrombectomy could be performed in 26% of our acute ischemic stroke patients (n=115/435), and a large increase in endovascular procedures is expected over the next few years that will require close collaboration among all partners in the emergency networks. Using our RENAU stroke database, it will be possible to compare various factors contributing to effective activity., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

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-R 2  = 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-R 2  = 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.

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.

Objective: To determine whether the ratio single chain (sc)/(sc + 2 chain [tc]) recombinant tissue plasminogen activator (rtPA) influences outcomes in patients with cerebral ischemia., Methods: We prospectively included consecutive patients treated with IV rtPA for cerebral ischemia in 13 stroke centers and determined the sc/(sc + tc) ratio in the treatment administered to each patient. We evaluated the outcome with the modified Rankin Scale (mRS) at 3 months (prespecified analysis) and occurrence of epileptic seizures (post hoc analysis). We registered Outcome of Patients Treated by IV Rt-PA for Cerebral Ischaemia According to the Ratio Sc-tPA/Tc-tPA (OPHELIE) under ClinicalTrials.gov identifier no. NCT01614080., Results: We recruited 1,004 patients (515 men, median age 75 years, median onset-to-needle time 170 minutes, median NIH Stroke Scale score 10). We found no statistical association between sc/(sc + tc) ratios and handicap (mRS > 1), dependency (mRS > 2), or death at 3 months. Patients with symptomatic intracerebral hemorrhages had lower ratios (median 69% vs 72%, adjusted p = 0.003). The sc/(sc + tc) rtPA ratio did not differ between patients with and without seizures, but patients with early seizures were more likely to have received a sc/(sc + tc) rtPA ratio >80.5% (odds ratio 3.61; 95% confidence interval 1.26-10.34)., Conclusions: The sc/(sc + tc) rtPA ratio does not influence outcomes in patients with cerebral ischemia. The capacity of rtPA to modulate NMDA receptor signaling might be associated with early seizures, but we observed this effect only in patients with a ratio of sc/(sc + tc) rtPA >80.5% in a post hoc analysis., (© 2016 American Academy of Neurology.)

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.

Background: Stroke, as the third cause of death in developed countries, is a public health issue. Atrial fibrillation is an important cause of ischemic stroke and its prevention is efficient with oral anticoagulation. However, oral anticoagulation can be contraindicated because of hemorrhagic risk related to these treatments. Percutaneous left atrial appendage occlusion is a new alternative of oral anticoagulation for patients with atrial fibrillation and high risk of cardio-embolic stroke but contraindicated for oral anticoagulation., Methods: We describe in this paper the procedure of left atrial appendage occlusion with the Amplatzer cardiac plug device, used in our center in Grenoble university hospital, for the first three patients who have been treated with this device. These three patients (one man and two women) have all atrial fibrillation with neurological complication of this arrhythmia, as ischemic stroke. Oral anticoagulation is indicated to prevent another ischemic stroke. However, they all have a high risk of cerebral bleeding for different reasons (cavernomatosis, history of intracerebral hemorrhage and aneurysm of the polygon of Willis). Consequently, they have a high risk of cardio-embolic complication but contraindication for oral anticoagulation. They have been treated by left atrial appendage occlusion with Amplatzer cardiac plug device by percutaneous and trans-septal access. Then, they have been followed by neurologist and cardiologist, with clinical and paraclinical evaluation by echocardiography., Results: Our three first patients have been successfully implanted, without periprocedural complication. No latest adverse event was observed, and particularly no cardiac or neurologic adverse event., Conclusion: The technique of left atrial appendage occlusion is a very interesting and promising technique for ischemic stroke prevention in patient with high risk of cardio-embolic complication because of atrial fibrillation, but high risk of bleeding and contraindication for oral anticoagulation. Because of frequency of both atrial fibrillation and contraindication for oral anticoagulation, occlusion of the left atrial appendage should become an interesting alternative for many patients. However, it remains an invasive procedure and efficacy and indications need to be evaluated in further clinical trials. Risk/benefit ratio must be carefully assessed and compared to that of the new anticoagulant drugs., (Copyright © 2015. Published by Elsevier Masson SAS.)

Stroke is the second leading cause of death worldwide and the most common cause of severe disability. Neuroprotection and repair mechanisms supporting endogenous brain plasticity are often insufficient to allow complete recovery. While numerous neuroprotective drugs trials have failed to demonstrate benefits for patients, they have provided interesting translational research lessons related to neurorestorative therapy mechanisms in stroke. Stroke damage is not limited to neurons but involve all brain cell type including the extracellular matrix in a "glio-neurovascular niche". Targeting a range of host brain cells, biotherapies such as growth factors and therapeutic cells, currently hold great promise as a regenerative medical strategy for stroke. These techniques can promote both neuroprotection and delayed neural repair through neuro-synaptogenesis, angiogenesis, oligodendrogliogenesis, axonal sprouting and immunomodulatory effects. Their complex mechanisms of action are interdependent and vary according to the particular growth factor or grafted cell type. For example, while "peripheral" stem or stromal cells can provide paracrine trophic support, neural stem/progenitor cells (NSC) or mature neurons can act as more direct neural replacements. With a wide therapeutic time window after stroke, biotherapies could be used to treat many patients. However, guidelines for selecting the optimal time window, and the best delivery routes and doses are still debated and the answers may depend on the chosen product and its expected mechanism including early neuroprotection, delayed neural repair, trophic systemic transient effects or graft survival and integration. Currently, the great variety of growth factors, cell sources and cell therapy products form a therapeutic arsenal that is available for stroke treatment. Their effective clinical use will require prior careful considerations regarding safety (e.g. tumorgenicity, immunogenicity), potential efficacy, cell characterization, delivery route and in vivo biodistribution. Bone marrow-derived cell populations such as mesenchymal stromal/stem cells (MSC) or mononuclear cells (MNC), umbilical cord stem cells and NSC are most investigated notably in clinical trials. Finally, we discuss perspectives concerning potential novel biotherapies such as combinatorial approaches (growth factor combined with cell therapy, in vitro optimization of cell products, or co-transplantation) and the development of biomaterials, which could be used as injectable hydrogel scaffold matrices that could protect a cell graft or selectively deliver drugs and growth factors into the post-stroke cavity at chronic stages. Considering the remaining questions about the best procedure and the safety cautions, we can hope that future translational research about biotherapies will bring more efficient treatments that will decrease post-stroke disability for many patients., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

A quantitative estimate of cerebral blood oxygen saturation is of critical importance in the investigation of cerebrovascular disease. While positron emission tomography can map in vivo the oxygen level in blood, it has limited availability and requires ionizing radiation. Magnetic resonance imaging (MRI) offers an alternative through the blood oxygen level-dependent contrast. Here, we describe an in vivo and non-invasive approach to map brain tissue oxygen saturation (StO2) with high spatial resolution. StO2 obtained with MRI correlated well with results from blood gas analyses for various oxygen and hematocrit challenges. In a stroke model, the hypoxic areas delineated in vivo by MRI spatially matched those observed ex vivo by pimonidazole staining. In a model of diffuse traumatic brain injury, MRI was able to detect even a reduction in StO2 that was too small to be detected by histology. In a F98 glioma model, MRI was able to map oxygenation heterogeneity. Thus, the MRI technique may improve our understanding of the pathophysiology of several brain diseases involving impaired oxygenation.

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., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

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.

Background: Microvasculature plays a key role in stroke pathophysiology both during initial damage and extended neural repair. Moreover, angiogenesis processes seem to be a promising target for future neurorestorative therapies. However, dynamic changes of microvessels after stroke still remain unclear, and MRI follow-up could be interesting as an in vivo biomarker of these., Methods: The aim of this study is to characterize the microvascular plasticity 25 days after ischemic stroke using both in vivo microvascular 7T-MRI (vascular permeability, cerebral blood volume (CBV), vessel size index (VSI), vascular density) and quantification of angiogenic factor expressions by RT-qPCR in a transient middle cerebral artery occlusion rat model. CBV and VSI (perfused vessel caliber) imaging was performed using a steady-state approach with a multi gradient-echo spin-echo sequence before and 2 min after intravenous (IV) injection of ultrasmall superparamagnetic iron particles. Vascular density (per mm2) was derived from the ratio [ΔR₂/(ΔR₂*)²/³]. Blood brain barrier leakage was assessed using T₁W images before and after IV injection of Gd-DOTA. Additionally, microvessel immunohistology was done., Results: 3 successive stages were observed: 1) 'Acute stage' from day 1 to day 3 post-stroke (D1-D3) characterized by high levels of angiopoietin-2 (Ang2), vascular endothelial growth factor receptor-2 (VEGFR-2) and endothelial NO synthase (eNOS) that may be associated with deleterious vascular permeability and vasodilation; 2) 'Transition stage' (D3-D7) that involves transforming the growth factors β1 (TGFβ1), Ang1, and tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1), stromal-derived factor-1 (SDF-1), chemokine receptor type 4 (CXCR-4); and 3) 'Subacute stage' (D7-D25) with high levels of Ang1, Ang2, VEGF, VEGFR-1 and TGFβ1 leading to favorable stabilization and maturation of microvessels. In vivo MRI appeared in line with the angiogenic factors changes with a delay of at least 1 day. All MRI parameters varied over time, revealing the different aspects of the post-stroke microvascular plasticity. At D25, despite a normal CBV, MRI revealed a limited microvessel density, which is insufficient to support a good neural repair., Conclusions: Microvasculature MRI can provide imaging of different states of functional (perfused) microvessels after stroke. These results highlight that multiparametric MRI is useful to assess post-stroke angiogenesis, and could be used as a biomarker notably for neurorestorative therapy studies. Additionally, we identified that endogenous vessel maturation and stabilization occur during the 'subacute stage'. Thus, pro-angiogenic treatments, such as cell-based therapy, would be relevant during this subacute phase of stroke.

Objective: This pilot study aimed to compare metabolic disturbances, particularly insulin resistance (IR) and cardiovascular risk factors (CRFs), following two types of acute vascular atherothrombotic disease events: ischaemic atherothrombotic stroke (AS); and acute coronary syndrome (ACS)., Design and Methods: A total of 110 non-diabetic patients presenting with either AS (n=55) or ACS (n=55) were included in our prospective comparative study, and matched for age and gender. IR was determined using the homoeostasis model assessment of insulin resistance (HOMA-IR) method, and each patient's personal and family history were also recorded., Results: IR was significantly higher in the ACS vs AS group (HOMA-IR index 2.17±1.90 vs 1.50±0.81, respectively; P=0.03). The AS group had a significantly higher prevalence of personal history of hypertension (51% vs 31%; P=0.03), while current smoking was more prevalent in the ACS group (30% vs 18%; P=0.04). There were no significant differences between the two groups as regards any other CRFs., Conclusion: The distribution of CRFs varied depending on the vascular event, and metabolic disturbances differed according to the atherothrombotic disease. IR was greater after ACS than AS., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Stroke, the leading cause of disability, lacks treatment beyond thrombolysis. The acute injection of human mesenchymal stem cells (hMSCs) provides a benefit which could be mediated by an enhancement of angiogenesis. A clinical autologous graft requires an hMSC culture delay incompatible with an acute administration. This study evaluates the cerebral microvascular changes after a delayed injection of hMSCs. At day 8 after middle cerebral artery occlusion (MCAo), two groups of rats received an intracerebral injection in the damaged brain of either 10 μL of cell suspension medium (MCAo-PBS, n = 4) or 4 × 10⁵ hMSCs (MCAo-hMSC, n = 5). Two control groups of healthy rats underwent the same injection procedures in the right hemisphere (control-PBS, n = 6; control-hMSC, n = 5). The effect of hMSCs on the microvasculature was assessed by MRI using three parameters: apparent diffusion coefficient (ADC), cerebral blood volume (CBV) and vessel size index (VSI). At day 9, eight additional rats were euthanised for a histological study of the microvascular parameters (CBV, VSI and vascular fraction). No ADC difference was observed between MCAo groups. One day after intracerebral injection, hMSCs abolished the CBV increase observed in the lesion (MCAo-hMSC: 1.7 ± 0.1% versus MCAo-PBS: 2.2 ± 0.2%) and delayed the VSI increase (vasodilation) secondary to cerebral ischaemia. Histological analysis at day 9 confirmed that hMSCs modified the microvascular parameters (CBV, VSI and vascular fraction) in the lesion. No ADC, CBV or VSI differences were observed between control groups. At the stroke post-acute phase, hMSC intracerebral injection rapidly and transiently modifies the cerebral microvasculature. This microvascular effect can be monitored in vivo by MRI., (Copyright © 2012 John Wiley & Sons, Ltd.)

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.

Background: For individuals with lateral postural imbalance after stroke, the decision to adopt a cane for walking often is not based on objective findings., Objective: The authors investigated the explanatory value of 2 posturographic criteria for lateral postural imbalance on the walking abilities of poststroke subjects., Methods: Indices of postural asymmetry (percentage of body weight on the less loaded lower limb) and instability (mediolateral variance of center-of-pressure displacements) were measured in 40 healthy individuals and 52 patients (mean 94.2 days after first hemispheric stroke), who stood still on a double force platform. Cut-off values (mean ± 2 standard deviations) were calculated and compared. The predictive value of both postural indices on walking abilities with or without a cane was analyzed., Results: Of the patients, 34.6% were unstable along the mediolateral axis (variance >7 mm(2)), and 44.2% were asymmetrical (body weight <40%); 30% needed a technical aid and 35% walked without a cane. The probability of being able to walk without a cane was less than 5% if the paretic lower limb was not loaded more than 40%. The postural instability index was less informative., Conclusions: This study suggests that patients who do not load more than 40% of their body weight on their paretic lower limb may benefit from the prescription of a cane.

One out of four ischemic strokes in France occurs in adults under 65 years old. About a third of them remain unexplained even after an extensive etiological assessment. A large part of these unexplained strokes could be linked to illegal drug abuse, and 10 % are estimated to be directly linked to illegal drugs in some international studies. The most frequently incriminated recreational drug remains cocaine, via several mechanisms. However, several other illegal drugs, some very commonly used such as cannabis, are suspected to have an important role in neurovascular diseases. In this article, we reviewed the epidemiological, pathophysiological and clinical studies, published in the international literature over the past 30 years. The drug-caused stroke epidemiology needs to be more precisely studied, as well as the underlying mechanisms depending on each drug. This is a public health issue that affects an economically active population, as stroke is the first cause of acquired handicap in adults., (Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Human mesenchymal stem cells (hMSC) are a promising source for cell therapy after stroke. To deliver these cells, an IV injection appears safer than a local graft. We aimed to assess the whole-body biodistribution of IV-injected (99m)Tc-HMPAO-labeled hMSC in normal rats (n = 9) and following a right middle cerebral artery occlusion (MCAo, n = 9). Whole-body nuclear imaging, isolated organ counting (at 2 and 20 h after injection) and histology were performed. A higher activity was observed in the right damaged hemisphere of the MCAo group [6.5 +/- 0.9 x 10(-3) % of injected dose (ID)/g] than in the control group (3.6 +/- 1.2 x 10(-3) %ID/g), 20 h after injection. In MCAo rats, right hemisphere activity was higher than that observed in the contralateral hemisphere at 2 h after injection (11.6 +/- 2.8 vs. 9.8 +/- 1.7 x 10(-3) %ID/g). Following an initial hMSC lung accumulation, there was a decrease in pulmonary activity from 2 to 20 h after injection in both groups. The spleen was the only organ in which activity increased between 2 and 20 h. The presence of hMSC was documented in the spleen, liver, lung, and brain following histology. IV-injected hMSC are transiently trapped in the lungs, can be sequestered in the spleen, and are predominantly eliminated by kidneys. After 20 h, more hMSC are found in the ischemic lesion than into the undamaged cerebral tissue. IV delivery of hMSC could be the initial route for a clinical trial of tolerance.