Effect of nimodipine on final infarct volume after acute ischemic stroke

Placebo-controlled clinical trials with nimodipine in acute ischemic stroke have not fulfilled the early optimistic expectations. Nimodipine has in some experimental studies, when administered either before or up to 90 min after induction of cerebral ischemia, resulted in a reduction of infarct size. No studies on the effects of nimodipine on infarct size in man have been published. We measured the infarct volumes in the admission and control CT examinations 3 weeks to 3 months later in 153 patients who had participated in a multicenter, randomized and placebo-controlled study. No statistically significant differences overall were found within or between the treatment groups. Subgroup analyses revealed in the placebo, but not in the nimodipine arm, an increase in the median infarct volumes if the treatment was started within 24 h of onset, and if the volume in the admission CT was less than median. A beneficial effect of nimodipine in prevention of infarct size increase in these circumstances cannot be excluded.     

Prior therapy with antiplatelet agents is not associated with outcome in patients with acute ischemic stroke/TIA

BACKGROUND AND PURPOSE: It is unclear whether prior therapy with antiplatelet agents (APA) is associated with a better outcome in patients with acute ischemic cerebrovascular events. METHODS: Within a multi-center cross-sectional study, nested in a cohort we analyzed the relation between prior therapy with APA and stroke severity in 1643 patients with acute ischemic stroke or TIA. Clinical severity of the vascular event was evaluated by the National Institutes of Health Stroke Scale on admission (NIHSS1) and after 1 week (NIHSS2). By means of analysis of variance we analyzed a possible association of APA with stroke severity and interactions regarding stroke severity between APA and other clinical measures. RESULTS: 475 patients (29 %) received aspirin prior to the cerebrovascular event, 51 patients (3 %) ticlopidine or clopidogrel and 26 patients (1.6%) aspirin combined with extended release dipyridamole. 66% (1091) of patients did not take any antiplatelet medication. Neither the NIHSS1 nor the NIHSS2 nor the change of stroke severity between these time points (NIHSS1- NIHSS2) was associated with prior APA medication. We did not find significant interactions between APA use and clinical measures regarding stroke severity. CONCLUSIONS: Our results do not indicate that prior therapy with APA is associated with a better outcome in acute ischemic cerebrovascular events. There were no interactions found with other features that were associated with stroke severity.     

尿酸对急性缺血性卒中患者血管再通和梗死体积的影响

目的 探讨急性缺血性卒中患者尿酸（UA）浓度的变化对血管再通和梗死体积的影响.方法 对176例发病24 h内患者应用弥散加权磁共振（DWI）检查,证实为前循环急性缺血性卒中.经改良的NIH卒中（mNIHSS）评分5分以上,随访观察尿酸、尿囊素（尿酸的非酶代谢产物）浓度的变化对血管再通和梗死体积的影响.结果 66例血管再通病人多数接受溶栓治疗,UA浓度在48 h降低,然后逐渐升高呈U行改变,14 d时mNIHSS评分降低,UA和尿囊素浓度变化与DWI梗死体积明显相关.结论 UA是急性缺血性卒中的一种消耗和再生性抗氧化剂,其浓度变化与血管再通和梗死体积有关.     

MAP2 immunostaining in thick sections for early ischemic stroke infarct volume in non-human primate brain

The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick brain sections can accurately identify early ischemia in the entire monkey brain.Using ischemic brains of one rat and three monkeys, a thick-section MAP2 immunostaining protocol was developed to outline the infarct region over the entire non-human primate brain. Comparison of adjacent thick and thin sections in a rat brain indicated complete correspondence between ischemic regions (100.4 mm³ ± 1.2%, n = 7, p = 0.44). Thick sections in monkey brain possessed the increased structural stability necessary for the extensive MAP2 immunostaining procedure permitting quantification of the ischemic region as a percent of total monkey brain, giving infarct volumes of 11.4, 16.3, and 19.0% of total brain. Stacked 2D images of the intact thick brain tissue sections provided a 3D representation for comparison to MRI images. The infarct volume of 16.1 cm³ from the MAP2 sections registered with MRI images agreed well with the volume calculated directly from the stained sections of 16.6 cm³.Thick brain tissue section MAP2 immunostaining provides a new method for determining infarct volume over the entire brain at early time points in a non-human primate model of ischemic stroke.     

Interferon-beta blocks infiltration of inflammatory cells and reduces infarct volume after ischemic stroke in the rat.

The inflammatory response that exacerbates cerebral injury after ischemia is an attractive therapeutic target: it progresses over days and strongly contributes to worsening of the neurologic outcome. The authors show that, after transient ischemic injury to the rat brain, systemic application of interferon-beta (IFN-beta), a cytokine with antiinflammatory properties, attenuated the development of brain infarction. Serial magnetic resonance imaging (MRI) showed that IFN-beta treatment reduced lesion volume on diffusion-weighted MRI by 70% (P < 0.01) at 1 day after stroke. IFN-beta attenuated the leakage of contrast agent through the blood-brain barrier (P < 0.005), indicating a better-preserved blood-brain barrier integrity. Both control and IFN-beta-treated animals showed a similar degree of relative hyperperfusion of the lesioned hemisphere, indicating that neuroprotection by IFN-beta was not mediated by improved cerebral perfusion as assessed 24 hours after stroke onset. IFN-beta treatment resulted in an 85% reduction (P < 0.0001) in infarct volume 3 weeks later, as determined from T2-weighted MRI and confirmed by histology. This effect was achieved even when treatment was started 6 hours after stroke onset. Quantitative immunohistochemistry at 24 hours after stroke onset showed that IFN-beta almost completely prevented the infiltration of neutrophils and monocytes into the brain. Gelatinase zymography showed that this effect was associated with a decrease in matrix metalloproteinase-9 expression. In conclusion, treatment with the antiinflammatory cytokine IFN-beta affords significant neuroprotection against ischemia/reperfusion injury, and within a relatively long treatment window. Because IFN-beta has been approved for clinical use, it may be rapidly tested in a clinical trial for its efficacy against human stroke.     

The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke.

The authors investigated whether the lack of effect of tirilazad on clinical outcome in patients with acute ischemic stroke is explained by failure of tirilazad to reduce infarct volume. Overall, tirilazad had no significant effect on infarct volume. In the subgroups of male patients and of those with a cortical infarct, tirilazad significantly reduced infarct volume. These effects were reduced to nonsignificant trends after adjustment for imbalances in baseline characteristics. In conclusion, early treatment of patients with tirilazad has no effect on infarct volume.     

Relationship between plasma metalloproteinase-9 levels and volume and severity of infarct in patients with acute ischemic stroke

Matrix metalloproteinases (MMP) constitute an endopeptidase family involved in various physiological and pathological processes. It was demonstrated that plasma MMP-9 level was increased in patients with acute ischemic stroke. In this study, it was investigated whether there was a relationship between the levels of plasma MMP-9 and the severity of stroke and infarct volume in patients with acute ischemic stroke. A total of 32 patients with acute ischemic stroke, (16 males and 16 females) and 30 healthy controls were included in the study. Plasma MMP-9 levels were measured using ELISA method. Computed tomography was performed at 48th?hour and infarct volume was calculated using the Cavalieri method. The National Institute of Health Stroke Scale (NIHSS) was checked at baseline, 12, 24, and 48th?hour. Plasma MMP-9 levels of the patient group at baseline, 12, 24, and 48th?hour were found significantly higher compared to the control group (p?<?0.05). An important correlation between MMP-9 levels and the infarct volume was observed at baseline, 12, 24, and 48th?hour (p?<?0.001). Furthermore, a positive correlation was recorded between plasma MMP-9 levels and NIHSS scores at baseline, 12, 24, and 48th?hour (p?<?0.001). Plasma MMP-9 levels of those of suffering medium and heavy damages were found significantly higher when compared to those of having slight damage (p?<?0.05). A significant relationship was also observed between infarct volumes and neurological deficits (p?<?0.05). Plasma MMP-9 levels of the patients at 48th?hour were found to be significantly lower in recovered patients compared to those who did not improved or worsened (p?<?0.05). A positive correlation was recorded between the infarct volume and infarct progression (p?<?0.05). In conclusion, this study showed that plasma MMP-9 level substantially increased during the acute period of ischemic cerebrovascular disease and correlated with the severity of the disease and infarct volume. The definition of the exact role of plasma MMP-9 after ischemic stroke will have important diagnostic implications for stroke and for the development of therapeutic strategies aimed at modulating plasma MMP-9.     

Newly-identified blood biomarkers of neurological damage are correlated with infarct volume in patients with acute ischemic stroke

Our group recently performed a genome-wide informatic analysis that highlighted eight brain-enriched proteins with strong potential to serve as blood biomarkers of neurological injury (GFAP, MBP, β-synuclein, OPALIN, MT-3, SNAP-25, KIF5A, MOBP), including six that have yet to be widely investigated. In this study, our aim was to determine whether the circulating levels of these proteins could be used to approximate the extent of neural tissue damage in ischemic stroke. To address this aim, blood was collected from 43 ischemic stroke patients immediately upon hospital admission. The serum levels of the eight candidate proteins were measured via ELISA, infarct volume was assessed via manual tracing of neuroradiological images, and correlational analysis was performed to examine potential associative relationships. The serum levels of all eight proteins exhibited positive correlations with infarct volume, however the strongest associations were observed in a subset of four proteins known to originate from neurons specifically (MT-3, SNAP-25, KIF5A, β-synuclein). Combining the serum levels of these neuron-originating proteins using principal components analysis produced a single composite value that was more strongly correlated with infarct volume than the levels of any single protein considered in isolation (r = 0.48, p < 0.001). Measures of these proteins could potentially be used to provide a minimally invasive approximation of lesion size when advanced imaging techniques are not available, or when imaging results are inconclusive.