Hyperacute Phase Of Ischemic Stroke Research Articles

Cortisol as a cerebral cortex neurons apoptosis regulator in acute phase of ischemic stroke (clinical and pathological study)

In response to ischemic stroke (IS) a natural activation of the stress-realizing system occurs. The features of this activation influence the outcome of the acute period and the prognosis of recovery and can be adjusted. At the same time, the role of the stress-realizing system in the pathogenesis of IS is still unexplored.Objective: to investigate the effect of peripheral blood cortisol concentration on the regulation of apoptosis of neurons of the cerebral cortex in the acute phase of IS.Material and methods. A prospective clinical and pathological study was performed. It included 9 patients with IS in the left middle cerebral artery territory who were admitted to hospital and died in the hyperacute phase of IS and had no infectious complications, allergic reactions or oncological diseases and who did not undergo thrombolysis. The cerebral cortex was examined. Neuron-specific enolase (NSE), protein 53 (p53), caspase 3, caspase 8, Fas receptor (CD95), and Fas apoptotic inhibitory molecule 2 (FAIM2) were determined on the slices using an indirect immunoperoxidase immunohistochemical staining method. A total of 567 microscopic fields were analysed for the group of patients with IS and 63 fields for the control group (three people). Before death, the blood concentrations of sFas, sFasL, cortisol, adrenocorticotropic hormone, adrenaline and norepinephrine were determined by enzyme immunoassay (the control group consisted of 28 people).Results. Significant correlation was found between the proportion of casp3-positive neurons and the concentration of cortisol in peripheral blood in zones 2 (r=0.263; p<0.01) and 3 (r=0.383; p<0.01). In the 2nd zone, significant negative correlation was found with the concentrations of sFas (r=-0.177; p<0.05) and sFasL (r=-0.164; p<0.05); in the 3rd zone, significant positive correlation was found with the ratio of the concentrations of sFasL and sFas (r=0.240; p<0.01). The proportion of Fas-positive neurons in the cerebral cortex correlated significantly with the concentration of the soluble form of this molecule (for the 1st zone – r=0.222, for the 2nd zone – r=0.438, for the 3rd zone – r=0.289; p<0.01) and the ratio of the concentrations of sFasL and sFas (respectively: r=0.231, r=0.266 and r=0.281; p<0.01) in the peripheral blood.Conclusion. Peripheral blood cortisol concentration is a factor that determines the regulation of apoptosis of neurons in the cerebral cortex in the acute phase of IS.

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity.

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size. Recovery was evident within hours after initiation of treatment and progressed over the subsequent 12 days. Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172 and accelerated in mGluR5 knock-out mice compared with wild-type mice. After stroke, multisensory stimulation by enriched environments enhanced recovery, a result prevented by VU0360172, implying a role of mGluR5 in enriched environment-mediated recovery. Additionally, MTEP treatment in conjunction with enriched environment housing provided an additive recovery enhancement compared to either MTEP or enriched environment alone. Using optical intrinsic signal imaging, we observed brain-wide disruptions in resting-state functional connectivity after stroke that were prevented by mGluR5 inhibition in distinct areas of contralesional sensorimotor and bilateral visual cortices. The levels of mGluR5 protein in mice and in tissue samples of stroke patients were unchanged after stroke. We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy.

Serum Periostin May Help to Identify Patients with Poor Collaterals in the Hyperacute Phase of Ischemic Stroke.

Background: Periostin is a glycoprotein that mediates cell functions in the extracellular matrix and appears to be a promising biomarker in neurological damage, such as ischemic stroke (IS). We aimed to measure serum periostin levels in the hyperacute phase of ischemic stroke to explore its predictive power in identification of patients with poor collaterals (ASPECT < 6). Methods: We prospectively enrolled 122 patients with acute ischemic stroke within the first 6 h after onset. The early ischemic changes were evaluated by calculating ASPECT score on admission using a native CT scan. An unfavorable outcome was defined as the modified Rankin Scale (mRS) > 2 at 90 days follow-up. Blood samples were collected on admission immediately after CT scan and periostin serum concentrations were determined by ELISA. Results: The admission concentration of serum periostin was significantly higher in patients with unfavorable outcome than in patients with favorable outcome (615 ng/L, IQR: 443–1070 vs. 390 ng/L, 260–563, p < 0.001). In a binary logistic regression model, serum periostin level was a significant predictor for ASPECT < 6 status on admission, within 6 h after stroke onset (OR, 5.911; CI, 0.990–0.999; p = 0.015). Conclusion: Admission periostin levels can help to identify patients who are not suitable for neurointervention, especially if advanced neuroimaging is not available.

Platelet, Plasma, Urinary Tryptophan-Serotonin-Kynurenine Axis Markers in Hyperacute Brain Ischemia Patients: A Prospective Study.

Background and Purpose: Ischemic stroke is one of the most common causes of morbidity and mortality and has numerous clinical mimics. Previous studies have suggested a potential role of the tryptophan-serotonin (5-HT)-kynurenine (TSK) axis in ischemic stroke. Studies assessing this axis in the hyperacute phase of ischemic stroke (<4.5 h) are lacking. This prospective study thus evaluates the TSK axis in transient ischemic attack (TIA) and hyperacute ischemic stroke (AIS) patients.Methods: This study included 28 patients (24 AIS and 4 TIA) and 29 controls. The blood and urine samples of patient were collected within 4.5 h of symptoms onset (day 0, D0), then at 24 h and 3 months. Control blood and urine samples were collected once (D0). The TSK axis markers measured were platelet serotonin transporter (SERT) and 5-HT2A receptor (5-HT2AR) densities and platelet, plasma, and urinary 5-HT, plasma and urinary 5-hydroxyindole acetic acid (5-HIAA), and plasma kynurenine and tryptophan (TRP) levels.Results: At D0, patients exhibited a lower (p = 10−5) platelet SERT density, higher (p < 10−6) platelet 5-HT2AR density, higher (p = 10−5) plasma kynurenine/tryptophan (K/T) ratio, and higher urinary 5-HT (p = 0.011) and 5-HIAA (p = 0.003) levels than controls.Conclusions: We observed, for the first time, a hyperacute dysregulation of the serotonergic axis, and hyperacute and long-lasting activation of the tryptophan-kynurenine pathway in brain ischemia.

EEG spectral parameters correlate with the extent of brain ischemia in hyper-acute ischemic stroke

Brain electrical activity alterations in acute ischemic stroke are related to neurophysiological changes during hypoperfusion as manifestation of neurovascular coupling. EEG could be applicable for bedside functional monitoring in the hyper-acute phase of ischemic stroke. This study aimed to investigate the relation between EEG changes and ischemic core-penumbra CT Perfusion (CTP) volumes, and their association with neurological deficit in the hyper-acute phase of ischemic stroke.

Recombinant tissue plasminogen activator (rTPA) in young adult patient with acute ischemic stroke: a case report

Background: Stroke is one of the highest causes of morbidity and mortality in the world. The incidence rate of ischemic stroke is about 80% of all stroke incidents. The use of recombinant tissue plasminogen activator (rtPA) is recommended under 4.5 hours of stroke onset. Stroke in young adults are reported as being uncommon, compromising 10% -15% of all stroke patients. Many studies were reported the most common risk factor in young adults were obesity and dyslipidemia. This case report will discuss a 33-year-old men with ischemic stroke with obesity and dyslipidemia treated at dr. Kariadi Hospital Semarang.Case presentation: A 33-year old obese man with left-sided hemiparesis and central facial nerve palsy with an onset of 1 hour. On laboratory examination, it was obtained total cholesterol 179mg/dL, LDL level 123mg/dL, and HDL level 39mg/dL. The protocol code stroke was performed in emergency room with alteplase (r-TPA) 0.6 mg/kgBW, after his head MSCT shows there was no sign of blood in the brain parenchym.Conclusion: The increased risk of ischemic stroke in young patients is due to dyslipidemia, hypertension, obesity, physical inactivity, and smoking. Treatment of the hyperacute phase of ischemic stroke with thrombolysis can reduce the outcome of stroke due to the disability.

A Mouse Brain-based Multi-omics Integrative Approach Reveals Potential Blood Biomarkers for Ischemic Stroke

Stroke remains a leading cause of death and disability worldwide. Despite continuous advances, the identification of key molecular signatures in the hyper-acute phase of ischemic stroke is still a primary interest for translational research on stroke diagnosis, prognosis, and treatment. Data integration from high-throughput -omics techniques has become crucial to unraveling key interactions among different molecular elements in complex biological contexts, such as ischemic stroke. Thus, we used advanced data integration methods for a multi-level joint analysis of transcriptomics and proteomics data sets obtained from mouse brains at 2 h after cerebral ischemia. By modeling net-like correlation structures, we identified an integrated network of genes and proteins that are differentially expressed at a very early stage after stroke. We validated 10 of these deregulated elements in acute stroke, and changes in their expression pattern over time after cerebral ischemia were described. Of these, CLDN20, GADD45G, RGS2, BAG5, and CTNND2 were next evaluated as blood biomarkers of cerebral ischemia in mice and human blood samples, which were obtained from stroke patients and patients presenting stroke-mimicking conditions. Our findings indicate that CTNND2 levels in blood might potentially be useful for distinguishing ischemic strokes from stroke-mimicking conditions in the hyper-acute phase of the disease. Furthermore, circulating GADD45G content within the first 6 h after stroke could also play a key role in predicting poor outcomes in stroke patients. For the first time, we have used an integrative biostatistical approach to elucidate key molecules in the initial stages of stroke pathophysiology and highlight new notable molecules that might be further considered as blood biomarkers of ischemic stroke.

Microglial Calcium Waves During the Hyperacute Phase of Ischemic Stroke.

Ischemic injury triggers multiple pathological responses in the brain tissue, including spreading depolarizations across the cerebral cortex (cortical spreading depolarizations [CSD]). Microglia have been recently shown to play a significant role in the propagation of CSD. However, the intracellular responses of myeloid cells during ischemic stroke have not been investigated. We have studied intracellular calcium activity in cortical microglia in the stroke model of the middle cerebral artery occlusion, using the murine Polr2a-based and Cre-dependent GCaMP5 and tdTomato reporter (PC::G5-tdT). High-speed 2-photon microscopy through cranial windows was employed to record signals from genetically encoded indicators of calcium. Inflammatory stimuli and pharmacological inhibition were used to modulate microglial calcium responses in the somatosensory cortex. In vivo imaging revealed periodical calcium activity in microglia during the hyperacute phase of ischemic stroke. This activity was more frequent during the first 6 hours after occlusion, but the amplitudes of calcium transients became larger at later time points. Consistent with CSD nature of these events, we reproducibly triggered comparable calcium transients with microinjections of potassium chloride (KCl) into adjacent cortical areas. Furthermore, lipopolysaccharide-induced peripheral inflammation, mimicking sterile inflammation during ischemic stroke, produced significantly greater microglial calcium transients during CSD. Finally, in vivo pharmacological analysis with CRAC (calcium release-activated channel) inhibitor CM-EX-137 demonstrated that CSD-associated microglial calcium transients after KCl microinjections are mediated at least in part by the CRAC mechanism. Our findings demonstrate that microglia participate in ischemic brain injury via previously undetected mechanisms, which may provide new avenues for therapeutic interventions.

Procarboxypeptidase U (proCPU, TAFI, proCPB2) in cerebrospinal fluid during ischemic stroke is associated with stroke progression, outcome and blood–brain barrier dysfunction

Background Procarboxypeptidase U (proCPU, TAFI, proCPB2), the zymogen of CPU, which is a potent antifibrinolytic enzyme and a modulator of inflammation, has previously been investigated in plasma of stroke patients, but so far, no information on the proCPU levels in cerebrospinal fluid (CSF) during acute ischemic stroke (AIS) is available. Objectives This case-control observational study investigates proCPU in CSF of AIS patients compared with controls with an intact blood-brain barrier (BBB) and evaluates the relationship of CSF/plasma proCPU ratios with stroke parameters. Methods A sensitive HPLC-based enzymatic assay was used to determine proCPU levels in CSF of non-thrombolyzed patients in the hyperacute phase (< 24 h after onset) of AIS (n = 72). Individuals (n = 32) without stroke, an intact BBB and no apparent abnormalities in biochemical and microbiological tests, served as controls. Relations between the CSF/plasma proCPU ratio and (i) stroke severity, (ii) stroke progression/recurrence, (iii) stroke outcome and (iv) BBB dysfunction (CSF/serum albumin ratio) were assessed. Results Mean (SEM) proCPU levels were elevated in the CSF of stroke patients compared with controls (4.36 (0.23) U L-1 vs. 3.50 (0.23) U L-1 ). Higher median [IQR] CSF/plasma proCPU ratios were found in patients with stroke progression ((6.0 [4.2-6.9]) × 10-3 ) and poor outcome ((6.4 [3.9-7.0]) × 10-3 ) after 3 months (modified Rankin Scale; mRS > 3) compared with patients without progression ((3.9 [2.7-5.4]) × 10-3 ) or better outcome ((4.0 [2.8-5.0]) × 10-3 ). In stroke patients with a disrupted BBB, proCPU ratios were higher compared with stroke patients with an intact BBB ((6.4 [5.8-9.0]) × 10-3 vs. (3.7 [2.8-5.0]) × 10-3 ). Conclusions ProCPU is increased in CSF during hyperacute ischemic stroke and is associated with stroke progression and outcome after 3 months, most likely due to BBB dysfunction in the hyperacute phase of ischemic stroke.

Intraarterial transplantation of human umbilical cord blood mononuclear cells in hyperacute stroke improves vascular function

BackgroundHuman umbilical cord blood (hUCB) cell therapy is a promising treatment for ischemic stroke. The effects of hyperacute stem cell transplantation on cerebrovascular function in ischemic stroke are, however, not well understood. This study evaluated the effects of hyperacute intraarterial transplantation of hUCB mononuclear cells (MNCs) on cerebrovascular function in stroke rats using serial magnetic resonance imaging (MRI).MethodsHUCB MNCs or vehicle were administered to stroke rats via the internal carotid artery immediately after reperfusion at 60 min following ischemia onset. Lesion volumes were longitudinally evaluated by MRI on days 0, 2, 14, and 28 after stroke, accompanied by behavioral tests. Cerebral blood flow (CBF) and cerebrovascular reactivity were measured by perfusion MRI and CO2 functional MRI (fMRI) at 28 days post-stroke; corresponding vascular morphological changes were also detected by immunohistology in the same animals.ResultsWe found that CBF to the stroke-affected region at 28 days was improved (normalized CBF value: 1.41 ± 0.30 versus 0.49 ± 0.07) by intraarterial transplantation of hUCB MNCs in the hyperacute stroke phase, compared to vehicle control. Cerebrovascular reactivity within the stroke-affected area, measured by CBF fMRI, was also increased (35.2 ± 3.5% versus 12.8 ± 4.3%), as well as the corresponding cerebrovascular density. Some engrafted cells appeared with microvascular-like morphology and stained positive for von Willebrand Factor (an endothelial cell marker), suggesting they differentiated into endothelial cells. Some engrafted cells also connected to host endothelial cells, suggesting they interacted with the host vasculature. Compared to the vehicle group, infarct volume at 28 days in the stem cell treated group was significantly smaller (160.9 ± 15.7 versus 231.2 ± 16.0 mm3); behavioral deficits were also markedly reduced by stem cell treatment at day 28 (19.5 ± 1.0% versus 30.7 ± 4.7% on the foot fault test; 68.2 ± 4.6% versus 86.6 ± 5.8% on the cylinder test). More tissue within initial perfusion-diffusion mismatch was rescued in the treatment group.ConclusionsIntraarterial hUCB MNC transplantation during the hyperacute phase of ischemic stroke improved cerebrovascular function and reduced behavioral deficits and infarct volume.

Correlation of the L-Arginine Pathway with Thrombo-Inflammation May Contribute to the Outcome of Acute Ischemic Stroke

Immune responses contribute to secondary injury after acute ischemic stroke (AIS), and metabolites of the L-arginine pathway are associated with stroke outcome. Here, we analyzed the relationship of the L-arginine pathway with thrombo-inflammatory biomarkers in AIS and their additive and independent associations to outcome. Serial changes in P-selectin, tPA, MCP-1, sCD40L, IL-6, IL-8, L-arginine, and asymmetric and symmetric dimethylarginine (ADMA, SDMA) were investigated in 55 patients with AIS and without infection within 6 and 72 hours after stroke onset. Outcomes were assessed as National Institutes of Health Stroke Scale (NIHSS) worsening by 24 hours, poststroke infection, and death by 1 month. Serum levels of L-arginine showed negative correlation, whereas ADMA and SDMA showed positive correlation with thrombo-inflammatory biomarkers in the hyperacute phase. Most of these correlations disappeared by 72 poststroke hours. Correlation of MCP-1 with both ADMA and SDMA levels at 6 hours was associated with both NIHSS worsening and poststroke infections, respectively; sCD40L and SDMA correlation at 6 hours was also associated with NIHSS worsening. Negative correlation between P-selectin and L-arginine concentrations in the hyperacute phase was associated with NIHSS worsening. Strong negative correlation was found between IL-6 and L-arginine levels in the hyperacute phase in patients with poststroke infection. Only L-arginine and SDMA at 72 hours were independently associated with poststroke infection respectively. Concentration of L-arginine and ADMA/SDMA differentially correlates with thrombo-inflammation in the hyperacute phase of ischemic stroke. Such correlations are independently associated with poststroke infection but not with other outcomes.

Intravenous thrombolysis, mechanical embolectomy, and intracranial stenting for hyperacute ischemic stroke in a patient with moyamoya disease

The Japanese translation of moyamoya means “puff of smoke” and refers to the angiographic appearance of dilated collateral vessels seen during chronic progressive narrowing of the intracranial supraclinoid portions of the internal carotid arteries. Despite cerebral ischemia being the most common presenting symptom, 20% to 40% of adults suffer a hemorrhagic stroke. Due to the lack of evidence and histopathologic findings, intravenous and endovascular reperfusion therapy is typically avoided. This case study presents a patient with moyamoya disease in the hyperacute phase of ischemic stroke. The patient received full dose (0.9mg/kg) tissue plasminogen activator and subsequently underwent a mechanical clot extraction and Wingspan stent (Stryker, Kalamazoo, MI, USA) placement. The use of these options in the setting of moyamoya disease is novel. This demonstrates that moyamoya disease may not be an absolute contraindication to revascularization in hyperacute ischemic stroke and underscores that many perceived contraindications to thrombolytic and mechanical revascularization therapies are relative.

Systemic amyloidosis as a cause of cerebral thrombo-embolic stroke: A case report

Systemic amyloidosis is a rare clinical disorder and can lead to single organ or fatal multiple organ failure, heart and kidneys are the most affected organs. Currently, there are no relevant guidelines and recommendations about the treatment of systemic amyloidosis. Ischemic stroke is an uncommon complication of systemic amyloidosis and patients with systemic amyloidosis may carry a worse prognosis. We report a case of cerebral thrombo-embolism in a 40-year-old woman due to indicated systemic amyloidosis, she received intravenous rt-PA thrombolytic therapy in hyperacute phase of ischemic stroke and this case proved that intravenous rt-PA thrombolysis therapy may be an effective treatment for acute cerebral thrombo-embolic stroke patients with systemic amyloidosis.

Risk of pneumonia associated with zero-degree head positioning in acute ischemic stroke patients treated with intravenous tissue plasminogen activator.

IntroductionIn the hyperacute phase of ischemic stroke, a 0° position is recommended to increase cerebral perfusion in nonhypoxic patients able to tolerate lying flat. However, use of 0° positioning is not uniformly applied in clinical practice, most likely due to concerns of aspiration pneumonia. We aimed to determine the risk of pneumonia associated with 0° head of bed positioning in acute stroke patients treated with thrombolytic therapy.MethodsA retrospective descriptive study was conducted using prospectively collected, consecutive acute ischemic stroke patients treated with IVtPA whose head of bed was positioned at 0° for the first 24 h. Rates of hospital‐acquired pneumonia were determined using a strict adjudication process to insure accuracy of pneumonia diagnoses. Quantitative characteristics were analyzed in SPSS to compare differences between “true” pneumonia cases and nonpneumonia cases.ResultsTwenty‐four of 333 (7.2%) patients had mention the diagnosis of pneumonia in the registry and/or medical record. Of these cases, only 15 (4.5%) met evidence‐based diagnostic criteria for hospital‐acquired pneumonia. The 15 adjudicated cases had similar median admission NIHSS scores to nonpneumonia cases (10 vs. 9, respectively; P = ns), but were older (74 ± 15 vs. 64 ± 17 years; mean difference 9.889, 95 CI = 1.2–18.6; P = 0.026). A total of eight patients with pneumonia were intubated and mechanically ventilated, and one patient received bilevel positive airway pressure ventilation during the 0° positioning period. Pneumonia cases had significantly longer hospitalizations (14.5 ± 12 vs. 6.6 ± 9 days; mean difference 7.97, 95% CI = 1.1–14.8; P = 0.026) and higher median discharge mRS score (4 vs. 3: P = 0.003).ConclusionsZero‐degree head of bed positioning in the first 24 h following an acute ischemic stroke treated with IV‐tPA was associated with acceptable rates of pneumonia. Rates for pneumonia may be further reduced by eliminating use of a 0° protocol in intubated/mechanically ventilated patients.

Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model.

Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation ([Formula: see text]) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia.

Conundra of the Penumbra and Acute Stroke Imaging

Multimodal imaging of the brain and vasculature during the hyperacute phase of ischemic stroke is perhaps the “mother of all controversies” in stroke's modern era. Opposing views are firmly held and often cleverly defended, as is the case with Drs Lyden and Parsons. Let us highlight the facts: 1 time is brain, every minute counts; and 2 the significance of the ischemic penumbra as a potentially salvageable tissue, if reperfusion is successfully restored in a timely fashion, is undisputed. Now, let us address the following questions regarding the potential benefit (or lack of it) from the additional information gained by MRI with diffusion-weighted imaging, perfusion MRI or CT, or CT angiography, MR angiography, or transcranial Doppler. Is there an added benefit from knowing the vascular anatomy of the patient with stroke who presents within the approved time window for intravenous tissue-type plasminogen activator (tPA)? Knowing the vascular lesion before treatment is certainly helpful but is unlikely to change the management strategy, regardless of the location of the arterial occlusion, during the first 3 to 4.5 hours of stroke onset because there is no evidence to support endovascular intervention as a first-line therapy during this time window, especially when considering the time it takes to get the patient …

A Topographic Study of the Evolution of the MR DWI/PWI Mismatch Pattern and Its Clinical Impact

The ischemic penumbra may be classical, with complete annular configuration around the infarct core, or nonclassical with a more fragmented pattern. We tested the hypotheses that these penumbral patterns may: be associated with specific predictive factors, influence infarct growth and clinical outcome, and influence the effect of tissue plasminogen activator (t-PA). Using the EPITHET/DEFUSE data set, in which patients received alteplase or placebo 3 to 6 hours poststroke, perfusion-weighted imaging and diffusion-weighted imaging images were analyzed. These mismatch patterns were defined as "classical" or "nonclassical." Multivariate analysis was used to identify variables associated with mismatch patterns, the effect of t-PA, as well as the relationship between mismatch patterns, infarct growth, and clinical outcomes. We included 158 patients (median age, 74 years; median National Institute of Health Stroke Scale score, 12). Multivariate analysis indicated that the factors associated with classical mismatch pattern type were large mismatch volume (P<0.001) and cortical infarct location (P=0.036). Infarct growth, clinical outcome, and the efficacy of t-PA were not statistically different between patterns. Coregistered mismatch volume and cortical location of infarction were the important factors associated with presence of the classical mismatch pattern. The lack of effect of the type of mismatch patterns on infarct growth, clinical outcomes, or the benefit of t-PA would suggest that mismatch topography is less important during the hyperacute phase of ischemic stroke than during subacute phase.

Physiologically based model of acute ischemic stroke.

In the treatment of acute ischemic stroke most of the clinical trials have failed, contrasting with promising results in the preclinical stages. This continuing discrepancy suggests some misconceptions in the understanding of acute ischemic stroke. One possible method for identifying the shortcomings of present-day approaches is to integrate all the available knowledge into a single mathematical model and to subject that model to challenges via simulations with available experimental data. As a first stage, then, the authors developed a simplified model, defining the structure and the different parameters that represent the phenomena that occur during the hyperacute phase of ischemic stroke. First, the different critical points of the evolution of ischemic stroke, based on the available evidence on the pathophysiology of stroke, were identified. Those key steps were then related to the quantitative data obtained by magnetic resonance imaging and positron emission tomography scan. These two techniques allow the measurement of diverse key markers of cerebral metabolism: cerebral blood flow (CBF), oxygen extraction factor, cerebral metabolism rate of oxygen, and the apparent diffusion coefficient of water, among others. Those markers were organized together through mathematical equations, and changed over time in order to describe the evolution of an acute ischemic stroke. At each time during the evolution of stroke those parameters are summarized in a parameter called survival delay. This parameter made possible the definition of three different states for tissues-functional, infarcted, salvageable-as end point. Once the model was designed, simulations were performed to explore its internal validity. Simulation results were consistent with the reality of acute ischemic stroke and did not reveal any major drawbacks in the use of the model. The more rapid the decrease in CBF, the larger is the final infarcted area. The model also allowed for the characterization of two types of tissue in the penumbra: tissues with an initial metabolic impairment and tissues altered owing to the closeness of the ischemic area. The results of this experiment were consistent with what is known of acute ischemic stroke. The model integrated different markers of acute ischemic stroke into a single entity in order to mimic acute ischemic stroke, and has been shown to have a reasonable degree of internal validity.