Rehabilitation following hemorrhagic stroke: building the case for stroke-subtype specific recovery therapies

Intracerebral hemorrhage (ICH), a form of brain bleeding and minor subtype of stroke, leads to significant mortality and long-term disability. There are currently no validated approaches to promote functional recovery after ICH. Research in stroke recovery and rehabilitation has largely focused on ischemic stroke, but given the stark differences in the pathophysiology between ischemic and hemorrhagic stroke, it is possible that strategies to rehabilitate the brain in distinct stroke subtypes will be different. Here, we review our current understanding of recovery after primary intracerebral hemorrhage with the intent to provide a framework to promote novel, stroke-subtype specific approaches.

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Abstract WP105: Tissue Plasminogen Activator (tPA) is Essential for Functional Recovery After Stroke by Promoting Axonal Outgrowth

Stroke ◽

10.1161/str.48.suppl_1.wp105 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Shubei Ma

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Plasminogen Activator ◽

Tissue Plasminogen Activator ◽

Functional Recovery ◽

Stroke Recovery ◽

White Matter Integrity ◽

Blue Staining ◽

Tissue Plasminogen

Objectives: Stroke is the leading cause of long term neurological disability with limited therapeutic options. Human recombinant tissue plasminogen activator (tPA) is currently the only FDA approved drug for the thrombolytic treatment of ischemic stroke. Emerging evidence suggests that the effects of tPA in ischemic brain may extend beyond its thrombolytic activity. In this study, we investigated the role of tPA in long term stroke recovery. Methods: Cortical infarct was induced by distal middle cerebral artery occlusion (dMCAO) in tPA knockout (KO) and wild type (WT) mice. Sensorimotor functions were evaluated at 3-35 days after dMCAO. White matter integrity was assessed by luxol fast blue staining, immunohistochemistry for SMI-32, and diffusion tensor imaging (DTI). The neuronal tracer biotinylated dextran amine (BDA) was used to label the corticorubral tract and the corticospinal tract. For rescue experiment, tPA (2mg/kg) was delivered intranasally to tPA KO mice once a day for 14 days starting 6h after dMCAO. Results: Infarct volume was comparable between tPA KO and WT mice after dMCAO. Sensorimotor deficits after dMCAO were exacerbated in tPA KO mice than WT mice. tPA KO mice also showed more severe demyelination in post-stroke white matter and reduced axonal sprouting at 35 days after dMCAO compared to WT mice. DTI studies revealed deteriorated white matter integrity in tPA KO mice, as manifested by decreased fractional anisotropy. Intranasal delivery of tPA after dMCAO rescued the neurological phenotype shown by tPA KO mice. Conclusion: Endogenous tPA promotes white matter integrity and is essential for functional recovery after ischemic stroke. tPA may be a novel neurorestorative therapy for stroke recovery.

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Comparison of Clinical Diagnosis of Stroke with Computed Tomographic Scan of the Brain

Bangladesh Journal of Neuroscience ◽

10.3329/bjn.v28i2.17179 ◽

2013 ◽

Vol 28 (2) ◽

pp. 96-101

Author(s):

Sirajee Shafiqul Islam ◽

Aminur Rahman ◽

Md Manzur Alahi ◽

Md Ahmed Ali ◽

Md Kafiluddin ◽

...

Keyword(s):

Computed Tomography ◽

Ischemic Stroke ◽

Positive Predictive Value ◽

Intracerebral Hemorrhage ◽

Ct Scan ◽

Clinical Diagnosis ◽

Predictive Value ◽

Hemorrhagic Stroke ◽

Sensitivity Specificity ◽

The Brain

Background and purpose: Stroke is a leading cause of mortality and morbidity in both developed as well as developing countries. The clinical presentation of stroke depending on the site and extent of lesions. For the management purpose it is important to know whether we are dealing with a bleed or an infarct. Methodology: Computed Tomography (CT scan) is available most of the tertiary level hospitals in Bangladesh. This study was carried out to compare clinical diagnosis of stroke with Computed tomography (CT) scan findings in ascertaining the type of stroke (hemorrhagic or ischemic). Materials and methods: This cross-sectional comparative study was conducted in the Department of Neurology, Rajshahi Medical College Hospital during the period of January 2010 to December 2010. Total 200 stroke patients were selected by purposive sampling technique on the basis of inclusion and exclusion criteria as the study sample. . CT brain scan was done for all the patients. The clinical diagnosis was compared with the results of CT scan and performance test was done. Results: Clinically 67 patients were diagnosed as hemorrhagic stroke and 133 patients were diagnosed as ischemic stroke. Out of these 67 hemorrhagic patients CT scan revealed that 56 patients had intracerebral hemorrhage, 5 had infarct, 4 had subarachnoid hemorrhage and 2 had space occupying lesions in the brain. Out of these 133 ischemic patients CT scan revealed that 119 patients had infarction, 6 had intracerebral hemorrhage and 8 had space occupying lesions in the brain. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of clinical diagnosis of hemorrhagic stroke were 90.32%, 92.03%, 83.58%, 92.02% and 91.5% respectively. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of clinical diagnosis of ischemic stroke were 95.96%, 81.58%, 89.47%, 92.53% and 90.5% respectively. Conclusion: The diagnosis of stroke in clinically with high accuracy, but perform a CT scan will help to confirm and differentiate to type stroke. Thus CT scan should be done in all cases stroke to specify the diagnosis. DOI: http://dx.doi.org/10.3329/bjn.v28i2.17179 Bangladesh Journal of Neuroscience 2012; Vol. 28 (2): 96-101

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Non-vitamin K oral anticoagulants (NOACs) in patients with stroke and atrial fibrillation

Arhiv za farmaciju ◽

10.5937/arhfarm2005269j ◽

2020 ◽

Vol 70 (5) ◽

pp. 269-283

Author(s):

Dejana Jovanović

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Intracerebral Hemorrhage ◽

Vitamin K ◽

Hemorrhagic Stroke ◽

Small Vessel Disease ◽

Oral Anticoagulants ◽

Stroke Recurrence ◽

Ischemic Attack

Patients with atrial fibrillation who had a previous transient ischemic attack or ischemic stroke had a significantly high risk of stroke recurrence and the introduction of oral anticoagulants should be mandatory. However, the long-term use of oral anticoagulants increases the risk of developing all types of intracranial hemorrhages. The advantages of non-vitamin K oral anticoagulants (NOACs) compared to warfarin are that they have a significantly lower risk for hemorrhagic stroke. They are preferred in elderly patients, those with small vessel disease, or those with previous intracerebral hemorrhage. The time of NOACs introduction after an ischemic stroke depends on its severity and the rule "1-3-6-12" days should be applied. The reintroduction of NOACs in patients with atrial fibrillation and previous intracerebral hemorrhage depends on its etiology and should be after about 4-8 weeks if the cardioembolic risk is high and the risk for intracranial hemorrhage small.

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Mesenchymal Stem Cell Derived Extracellular Vesicles for Repairing the Neurovascular Unit after Ischemic Stroke

Cells ◽

10.3390/cells10040767 ◽

2021 ◽

Vol 10 (4) ◽

pp. 767

Author(s):

Courtney Davis ◽

Sean I. Savitz ◽

Nikunj Satani

Keyword(s):

Ischemic Stroke ◽

Extracellular Vesicles ◽

Neurovascular Unit ◽

Culture Conditions ◽

Therapeutic Effects ◽

Stroke Treatment ◽

Inflammatory Molecules ◽

The Brain

Ischemic stroke is a debilitating disease and one of the leading causes of long-term disability. During the early phase after ischemic stroke, the blood-brain barrier (BBB) exhibits increased permeability and disruption, leading to an influx of immune cells and inflammatory molecules that exacerbate the damage to the brain tissue. Mesenchymal stem cells have been investigated as a promising therapy to improve the recovery after ischemic stroke. The therapeutic effects imparted by MSCs are mostly paracrine. Recently, the role of extracellular vesicles released by these MSCs have been studied as possible carriers of information to the brain. This review focuses on the potential of MSC derived EVs to repair the components of the neurovascular unit (NVU) controlling the BBB, in order to promote overall recovery from stroke. Here, we review the techniques for increasing the effectiveness of MSC-based therapeutics, such as improved homing capabilities, bioengineering protein expression, modified culture conditions, and customizing the contents of EVs. Combining multiple techniques targeting NVU repair may provide the basis for improved future stroke treatment paradigms.

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Cytokine-Laden Extracellular Vesicles Predict Patient Prognosis after Cerebrovascular Accident

International Journal of Molecular Sciences ◽

10.3390/ijms22157847 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7847

Author(s):

Anthony Fringuello ◽

Philip D. Tatman ◽

Tadeusz Wroblewski ◽

John A. Thompson ◽

Xiaoli Yu ◽

...

Keyword(s):

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Hemorrhagic Stroke ◽

Term Outcome ◽

Long Term Outcome ◽

Interleukin 7 ◽

Poor Outcomes ◽

Patient Prognosis ◽

The Brain

Background: A major contributor to disability after hemorrhagic stroke is secondary brain damage induced by the inflammatory response. Following stroke, global increases in numerous cytokines—many associated with worse outcomes—occur within the brain, cerebrospinal fluid, and peripheral blood. Extracellular vesicles (EVs) may traffic inflammatory cytokines from damaged tissue within the brain, as well as peripheral sources, across the blood–brain barrier, and they may be a critical component of post-stroke neuroinflammatory signaling. Methods: We performed a comprehensive analysis of cytokine concentrations bound to plasma EV surfaces and/or sequestered within the vesicles themselves. These concentrations were correlated to patient acute neurological condition by the Glasgow Coma Scale (GCS) and to chronic, long-term outcome via the Glasgow Outcome Scale-Extended (GOS-E). Results: Pro-inflammatory cytokines detected from plasma EVs were correlated to worse outcomes in hemorrhagic stroke patients. Anti-inflammatory cytokines detected within EVs were still correlated to poor outcomes despite their putative neuroprotective properties. Inflammatory cytokines macrophage-derived chemokine (MDC/CCL2), colony stimulating factor 1 (CSF1), interleukin 7 (IL7), and monokine induced by gamma interferon (MIG/CXCL9) were significantly correlated to both negative GCS and GOS-E when bound to plasma EV membranes. Conclusions: These findings correlate plasma-derived EV cytokine content with detrimental outcomes after stroke, highlighting the potential for EVs to provide cytokines with a means of long-range delivery of inflammatory signals that perpetuate neuroinflammation after stroke, thus hindering recovery.

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Abstract MP16: Excessive White Matter Hyperintensity Burden and Functional Outcomes After Acute Ischemic Stroke

Stroke ◽

10.1161/str.52.suppl_1.mp16 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Sungmin Hong ◽

Anne-katrin Giese ◽

Markus D Schirmer ◽

Adrian V Dalca ◽

Anna Bonkhoff ◽

...

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Acute Ischemic Stroke ◽

Functional Outcomes ◽

Life Time ◽

Stroke Recovery ◽

White Matter Hyperintensity ◽

Brain Health ◽

Stroke Outcomes ◽

The Brain

Objective: Ability of the brain to recover after an acute ischemic stroke (AIS) is linked to the pre-stroke burden of white matter hyperintensity (WMH), a radiographic marker of brain health. We sought to determine the excessive WMH burden in an AIS population and investigate its association with 3-month stroke outcomes. Data: We used 2,435 subjects from the MRI-GENIE study. Three-month functional outcomes of 872 subjects among those subjects were measured by 90-day modified Ranking Scale (mRS). Methods: We automatically quantified WMH volume (WMHv) on FLAIR images and adjusted for a brain volume. We modeled a trend using the factor analysis (FA) log-linear regression using age, sex, atrial fibrillation, diabetes, hypertension, coronary artery disease and smoking as input variables. We categorized three WMH burden groups based on the conditional probability given by the model (LOW: lower 33%, MED: middle 34%, and HIGH: upper 33%). The subgroups were compared with respect to mRS (median and dichotomized odds ratio (OR) (good/poor: mRS 0-2/3-6)). Results: Five FA components out of seven with significant relationship to WMHv (p<0.001) were used for the regression modeling (R 2 =0.359). The HIGH group showed higher median (median=2, IQR=2) mRS score than LOW (median=1, IQR=1) and MED (median=1, IQR=1). The odds (OR) of good AIS outcome for LOW and MED were 1.8 (p=0.0001) and 1.6 (p=0.006) times higher than HIGH, respectively. Conclusion: Once accounted for clinical covariates, the excessive WMHv was associated with worse 3-month stroke outcomes. These data suggest that a life-time of injury to the white matter reflected in WMH is an important factor for stroke recovery and an indicator of the brain health.

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Abstract 176: Long Term Mortality in Acute Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation According to Location and Burden of Cerebral Microbleeds

Stroke ◽

10.1161/str.45.suppl_1.176 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Tae-Jin Song ◽

Jinkwon Kim ◽

Dongbeom Song ◽

Yong-Jae Kim ◽

Hyo Suk Nam ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Acute Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Independent Predictor ◽

Stroke Patients ◽

Risk Of Death ◽

Long Term Mortality

Background: Cerebral microbleeds (CMBs) were predictive of mortality in elderly and considered as a putative marker for risk of intracranial hemorrhage. Stroke patients with non valvular atrial fibrillation (NVAF) require anticoagulation, which increases the risk of hemorrhages. We investigated association of CMBs with the long term mortality in acute ischemic stroke patients with NVAF. Methods: During 6 years , consecutive ischemic stroke patients who had NVAF and who had undergone brain MRI with a gradient-recalled echo sequence were enrolled. Long-term mortality and causes of death were identified using data from Korean National Statistical Office. Survival analysis was performed whether the presence, number and location of CMBs were related with all causes, cardiovascular, and cerebrovascular mortality during follow-up. Results: Total 506 patients were enrolled during the study period and were followed up for median 2.5 years. CMBs were found in 30.8% of patients (156/506). Oral anticoagulation with warfarin was prescribed at discharge in 477 (82.7%) patients. During follow up, 177 (35%) patients died and cerebrovascular death was noted in 93 patients (81 ischemic stroke and 12 hemorrhagic stroke). After adjusting age, sex and significant variables in univariate analysis (p<0.1), multiple CMBs (≥5) were the independent predictor for all-cause, cardiovascular and ischemic stroke mortalities. The strictly lobar CMBs were associated with hemorrhagic stroke mortality in multivariate Cox regression analysis (HR 4.776, p=0.032) (Figure 1). Conclusions: Multiple CMBs were the independent predictor for the long term mortality in stroke patients with NVAF. Among them, patients with strictly lobar CMBs had a high risk of death due to hemorrhagic stroke. Our findings suggest that detection of CMBs in stroke patients with NVAF are of clinical relevance for predicting long term outcome and that particular concern is necessary in those with strictly lobar CMBs for their increased risk of death due to hemorrhagic stroke. Figure 1.

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Intranasal Salvinorin A Improves Long-term Neurological Function via Immunomodulation in a Mouse Ischemic Stroke Model

Journal of Neuroimmune Pharmacology ◽

10.1007/s11481-021-10025-4 ◽

2021 ◽

Author(s):

Dilidaer Misilimu ◽

Wei Li ◽

Di Chen ◽

Pengju Wei ◽

Yichen Huang ◽

...

Keyword(s):

Ischemic Stroke ◽

Blood Brain Barrier ◽

Immune Cells ◽

Intranasal Administration ◽

Neurological Function ◽

Salvinorin A ◽

Stroke Model ◽

Peripheral Immune Cells ◽

The Brain

AbstractSalvinorin A (SA), a highly selective kappa opioid receptor agonist, has been shown to reduce brain infarct volume and improve neurological function after ischemic stroke. However, the underlying mechanisms have not been fully understood yet. Therefore, we explored whether SA provides neuroprotective effects by regulating the immune response after ischemic stroke both in the central nervous system (CNS) and peripheral circulation. In this study, adult male mice were subjected to transient Middle Cerebral Artery Occlusion (tMCAO) and then were treated intranasally with SA (50 μg/kg) or with the vehicle dimethyl sulfoxide (DMSO). Multiple behavioral tests were used to evaluate neurofunction. Flow cytometry and immunofluorescence staining were used to evaluate the infiltration of peripheral immune cells into the brain. The tracer cadaverine and endogenous immunoglobulin G (IgG) extravasation were used to detect blood brain barrier leakage. We observed that SA intranasal administration after ischemic stroke decreased the expression of pro-inflammatory factors in the brain. SA promoted the polarization of microglia/macrophages into a transitional phenotype and decreased the pro-inflammatory phenotype in the brain after tMCAO. Interestingly, SA treatment scarcely altered the number of peripheral immune cells but decreased the macrophage and neutrophil infiltration into the brain at 24 h after tMCAO. Furthermore, SA treatment also preserved BBB integrity, reduced long-term brain atrophy and white matter injury, as well as improved the long-term neurofunctional outcome in mice. In this study, intranasal administration of SA improved long-term neurological function via immuno-modulation and by preserving blood–brain barrier integrity in a mouse ischemic stroke model, suggesting that SA could potentially serve as an alternative treatment strategy for ischemic stroke. Graphic Abstract

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BIOELECTRIC ACTIVITY OF THE BRAIN IN PATIENTS WITH ACUTE CEREBROVASCULAR ACCIDENT

Vestnik ◽

10.53065/kaznmu.2021.72.74.006 ◽

2021 ◽

pp. 29-34

Author(s):

Д.А. Митрохин ◽

М.М. Ибрагимов ◽

Б.Р. Нурмухамбетова ◽

Н.Ш. Буйракулова ◽

В.В. Харченко ◽

...

Keyword(s):

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Spectral Power ◽

Spectral Power Density ◽

Cerebral Stroke ◽

Beta Activity ◽

Bioelectric Activity ◽

Early Recovery ◽

Coherence Index ◽

The Brain

Значимость биоэлектрической активности головного мозга в оценке функционального состояния нервной системы при цереброваскулярных заболеваниях широко известна. В настоящей работе показана характеристика биоэлектрической активности головного мозга у больных, перенесших острое нарушение мозгового кровообращения. В данной статье приведены данные о том, что у больных в остром и раннем восстановительном периодах церебрального инсульта биоэлектрическая активность головного мозга характеризовалась, в основном, десинхронным и дезорганизованным типами электроэнцефалограммы. Вместе с тем, отмечались, выраженная дельта и тета активность, а также единичные острые волны, спайки, преимущественно в пораженном полушарии головного мозга, реже в контралатеральном полушарии, межполушарная асимметрия, повышение мощности спектров в сторону преобладания медленных волн. Показатели индекса когерентности по всем отведениям были снижены, что свидетельствует о нарушении функциональных межполушарных взаимосвязей. Более значительное повышение индекса когерентности в дельта и тета диапазонах у пациентов, перенесших геморрагический инсульт, может указывать на более грубые межполушарные нарушения, в сравнении с ишемическим инсультом. Результаты исследования относительной спектральной плотности мощности диапазонов показали, что при геморрагическом инсульте отмечена более высокая дельта и бета активность, а также более значительное снижение мощности альфа ритма, в сравнении с ишемическим инсультом. В тоже время, отмечается повышение интегрального индекса диапазона низкочастотной медленно-волновой активности, особенно выраженное у больных с геморрагическим инсультом р<0,05. The significance of bioelectric activity of the brain in assessing the functional state of the nervous system in cerebrovascular diseases is widely known. In this paper, the characteristics of the bioelectric activity of the brain in patients with acute cerebral circulatory disorders are shown. This article presents data that in patients with acute and early recovery periods of cerebral stroke , the bioelectric activity of the brain was characterized mainly by desynchronous and disorganized types of electroencephalogram. At the, same time, pronounced delta and theta activity was noted , as well as single acute waves, spikes, mainly in the affected hemisphere of the brain, less often in the contralateral hemisphere, interhemispheric asymmetry, increased spectral power in the direction of predominance of slow waves. The coherence index values for all leads were reduced, which indicates a violation of functional interhemispheric relationships. A more significant increase in the coherence index in the delta and theta ranges in patients who have had a hemorrhagic stroke may indicate more severe interhemispheric disorders compared to ischemic stroke. The results of the study of the relative spectral power density of the ranges showed, that in hemorrhagic stroke, there was a higher delta and beta activity, as well as a more significant decrease in the power of the alpha rhythm, in comparison with ischemic stroke. At the same time, there is an increase in the integral index of the range of low-frequency slow-wave activity, especially pronounced in patients with hemorrhagic stroke p < 0.05.

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Abstract WP291: Diabetes Impairs Long-term Functional Recovery in an Embolic Stroke Model in Sex Independent Manner

Stroke ◽

10.1161/str.48.suppl_1.wp291 ◽

2017 ◽

Vol 48 (suppl_1) ◽

Author(s):

Weiguo Li ◽

Sherif Hafez ◽

John Paul Valenzuela ◽

Rebecca Ward ◽

Guangkuo Dong ◽

...

Keyword(s):

Ischemic Stroke ◽

Functional Recovery ◽

Hemorrhagic Transformation ◽

Cognitive Outcome ◽

Embolic Stroke ◽

Neurological Deficits ◽

Independent Manner ◽

Male And Female ◽

The Impact

Ischemic stroke is a leading cause of death and disability. Diabetes not only increases the risk of stroke, it also worsens the outcomes, increases the risk of hemorrhagic transformation (HT) and impairs recovery after stroke. It is well established that young females are more protected and show better outcomes than males after stroke. However, the impact of diabetes on long term recovery after stroke in both sexes was not clear. Accordingly, this study tested the hypothesis that diabetes impairs long term functional recovery after ischemic stroke in a sex independent manner. Methods: Diabetes was induced in male and female Wistar rats using high fat diet and low dose streptozotocin (30 mg/Kg). After 8 weeks of diabetes, animals were subjected to embolic stroke. Male and female Wistar normoglycemic age matched rats were used as controls. Motor (composite score: 14 best outcome and adhesive removal-ART) and cognitive (novel object recognition, NOR) deficits were assessed at day1, 3, 7 and 14. Results: Female control animals had better outcomes compared to the males. Mortality was higher in diabetic animals, especially in males. The neurological deficits were greater in diabetic animals with no difference between males and females. Conclusion: Diabetes impaired functional and cognitive outcome and recovery after ischemic stroke in a sex independent manner.

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