Abnormal expression of some matrix metalloproteinases (MMP) has shown to play a deleterious role in brain injury in experimental models of cerebral ischemia. We aimed to investigate MMP-2 (gelatinase ...A) and MMP-9 (gelatinase B) in brain parenchyma in both ischemic and hemorrhagic strokes.
Postmortem fresh brain tissue from 6 ischemic and 8 hemorrhagic stroke patients was obtained within the first 6 hours after death. Finally, 78 brain tissue samples from different areas (infarct, peri-infarct, perihematoma and contralateral hemisphere) were studied. To quantify gelatinase content we performed gelatin zymograms that were confirmed by Western Blot Analysis, immunohistochemistry to localize MMP source, and in situ zymography to detect gelatinase activity.
Among ischemic cases, gelatin zymography showed increased MMP-9 content in infarct core although peri-infarct tissue presented also higher levels than contralateral hemisphere (P<0.0001 and P=0.042, respectively). Within infarct core, MMP-9 was mainly located around blood vessels, associated to neutrophil infiltration and activated microglial cells. In peri-infarct areas the major source of MMP-9 were microglial cells. Tissue around intracranial hemorrhage also displayed higher MMP-9 levels than contralateral hemisphere (P=0.008) in close relationship with glial cells. MMP-2 was constitutively expressed and remained invariable in different brain areas.
Our results demonstrate in situ higher levels of MMP-9 in human brain tissue after ischemic and hemorrhagic stroke, suggesting a contribution of MMP-9 to ischemic brain injury and perihematoma edema.
Although tandem internal carotid artery/middle cerebral artery (MCA; TIM) occlusion has been associated with low recanalization rate after IV tissue plasminogen activator (tPA), its independent ...contribution on stroke outcome remains unknown. Moreover, whether the relative resistance to thrombolysis in tandem lesions varies depending on the location of MCA clot remains uncertain.
Two hundred and twenty-one consecutive stroke patients with an acute MCA occlusion treated with IV tPA were studied. Emergent carotid artery ultrasound and transcranial Doppler (TCD) examinations were performed in all patients before treatment. Recanalization was assessed on TCD at 2 hours of tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and after 24 hours. Modifed Rankin Scale score was used to assess outcome at 3 months.
Median prebolus NIHSS score was 16 points. On TCD, 156 (71.6%) patients had a proximal and 65 (29.4%) a distal MCA occlusion. TIM occlusion was identified in 44 (19.9%) patients. Eighteen (41.9%) patients with and 123 (69.5%) without TIM lesions achieved an MCA recanalization (P=0.01). In a logistic regression model, hyperglycemia >140 mg/dL (odds ratio OR 3.3, 95% CI, 1.6 to 6.8) and the presence of TIM occlusion (OR 2.8, 95% CI, 1.1 to 6.9) emerged as independent predictors of absence of recanalization. However, the independent contribution of TIM lesions on poor response to thrombolysis varied depending on the location of MCA occlusion. TIM occlusion independently predicted resistance to thrombolysis in patients with proximal (OR 4.63, 95% CI, 1.79 to 11.96), but not in those with distal MCA occlusion. Patients with TIM occlusion had worse short- (P<0.0001) and long-term (P<0.0001) clinical outcome.
TIM occlusion independently predicts poor outcome after IV thrombolysis. However, its impact varies depending on the location of MCA clot. Therefore, emergent carotid ultrasound plus TCD examinations may improve the selection of patients for more aggressive reperfusion strategies.
Matrix metalloproteinase (MMP) expression is related to blood brain barrier disruption after cerebral ischemia. Moreover, MMP inhibitors reduce hemorrhagic transformation (HT) after embolic ischemia ...in tissue plasminogen activator (t-PA)-treated animals. We aimed to correlate plasmatic MMP levels with the appearance of intracranial bleeding complications in stroke patients treated with t-PA.
Serial MMP-2 and MMP-9 determinations were performed (ELISA, ng/mL) in 41 strokes involving the middle cerebral artery territory in patients who received t-PA within 3 hours of stroke onset. Blood samples were obtained at baseline (pretreatment) and at 12 and 24 hours after symptom onset. Hemorrhagic events were classified according to CT criteria (petechial hemorrhagic infarctions HI, 1 to 2 and large parenchymal hemorrhages PH, 1 to 2). Brain CT scan was obtained at 48 hours or when a neurological worsening occurred. HT was present in 36.5% of the patients (24.4% HI and 12.1% PH). MMP-2 values were unrelated to any subtype of HT. The highest baseline MMP-9 level (normal range <97 ng/mL) corresponded to patients who later developed a PH (PH: 270.2+/-87.8, non-HT: 126.3+/-127.5, HI: 94.6+/-88.7; P=0.047). A graded response was found between mean baseline MMP-9 levels and the degree of bleeding (HI-1=37.4; HI-2=111.0; PH-1=202.5; PH-2=337.8). Baseline MMP-9 was the most powerful predictor of PH appearance in the multiple logistic regression model (OR= 9.62; CI 1.31 to 70.26; P=0.025).
Baseline MMP-9 level predicts PH appearance after t-PA treatment. Therefore, we suggest that MMP determination may increase the safety profile for thrombolysis and, in the future, anti-MMP drugs might be combined with t-PA to prevent hemorrhagic complications.
We aimed to determine clinical and hemodynamic predictors of early reocclusion (RO) in stroke patients treated with intravenous tissue plasminogen activator (tPA).
We studied 142 consecutive stroke ...patients with a documented middle cerebral artery (MCA) occlusion treated with intravenous tPA. All patients underwent carotid ultrasound and transcranial Doppler (TCD) examination before tPA bolus. National Institutes of Health Stroke Scale (NIHSS) scores were performed at baseline and serially for <24 hours. TCD monitoring of MCA recanalization (RE) and RO was performed during the first 2 hours after tPA bolus and repeated when clinical deterioration occurred <24 hours after documented RE in absence of intracranial hemorrhage.
After 1 hour of tPA administration, RE occurred in 84 (61%) patients (53 partial, 31 complete). Of these, 21 (25%) patients worsened after an initial improvement and 17 (12%) of them showed RO on TCD. RO was identified at a mean time of 65+/-55 minutes after documented RE. RO was associated (P=0.034) with a lower degree of 24-hour NIHSS score improvement than sustained RE, and a higher modified Rankin scale score at 3 months (P=0.002). Age older than 75 years (P=0.012), previous antiplatelet treatment (P=0.048), baseline NIHSS score >16 points (P=0.009), higher leukocytes count (P=0.042), beginning of RE <60 minutes after tPA bolus (P=0.039), and ipsilateral severe carotid stenosis/occlusion (P=0.001) were significantly associated with RO. In a logistic regression model, NIHSS score >16 at baseline (odds ratio OR, 7.1; 95% CI, 1.3 to 32) and severe ipsilateral carotid disease (OR, 13.3; 95% CI, 3.2 to 54) remained as independent predictors of RO.
Stroke severity and ipsilateral severe carotid artery disease independently predict RO after tPA-induced MCA RE.
Matrix Metalloproteinases (MMPs) play an important role in brain injury after ischemic stroke. In the present study, we aimed to assess the global expression of MMP-Family proteins in the human brain ...after stroke by using a combination of Searchlight Protein Array and Laser Microdissection to determine their cellular origin. This study demonstrated that MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-13, and TIMP-1 were upregulated in the infarcted tissue compared to healthy control areas. Using laser microdissection we obtained specific neuronal and vascular populations from both infarcted and control areas. From these fractions, we showed that MMP-9 and TIMP-2 were highly produced in brain microvessels while MMP-10 was notably increased in neurons of the ischemic brain but not in healthy areas. These findings demonstrate a selective cell-dependent MMP secretion, opening the possibility of selectively targeting specific MMPs for neuroprotection or vasculoprotection following stroke.
We sought to investigate the impact of hyperglycemia before reperfusion on long-term outcome in patients treated with intravenous tissue plasminogen activator (tPA).
Of 268 consecutive patients with ...a nonlacunar middle cerebral artery (MCA) stroke evaluated at <3 hours after onset, 73 (27.2%) received intravenous tPA. Serum glucose was determined at baseline before tPA administration. Hyperglycemia was defined as a glucose level >140 mg/dL. National Institutes of Health Stroke Scale (NIHSS) scores were obtained at baseline and 24 hours. Transcranial Doppler monitoring of recanalization and reocclusion was conducted during the first 24 hours. Total infarct volume was measured on CT at day 5 to 7. Modified Rankin Scale was used to assess outcome at 3 months.
Median NIHSS score was 17. At baseline, 31 patients (42.5%) were hyperglycemic and 42 (57.5%) normoglycemic. Early reperfusion (<6 hours) occurred in 43 patients (58.9%). Admission blood glucose correlated negatively with the degree of neurological improvement at 24 hours in reperfused (r=-0.43; P=0.019) but not in nonreperfused (r=-0.20; P=0.21) tPA-treated patients. Increased age (P=0.014), history of diabetes mellitus (P=0.043), admission glucose >140 mg/dL (P=0.002), and early reocclusion (P=0.004) were factors associated with poor outcome among reperfused patients. A logistic regression modeling revealed that only admission glucose value >140 mg/dL (odds ratio, 8.4; 95% CI, 1.76 to 40.02; P=0.005) emerged as an independent predictor of poor outcome despite tPA-induced recanalization. In patients with 6-hour persistent MCA occlusion, baseline NIHSS score >15 points (P=0.011) and proximal MCA occlusion (P=0.039) were variables associated with poor outcome on univariate analysis. In a logistic regression model, only NIHSS score >15 points (odds ratio, 11.9; 95% CI, 1.48 to 97.1; P=0.032) remained as an independent predictor of poor outcome and functional dependence at 3 months in nonreperfused tPA-treated patients.
Hyperglycemia before reperfusion may in part counterbalance the beneficial effect of early restoration of blood flow, which translates into a worse outcome in hyperglycemic patients despite tPA-induced recanalization.
Summary
Obstructive sleep apnea syndrome is very prevalent in hypertensive subjects. Moreover, obstructive sleep apnea syndrome activates multiple processes that might be associated with silent ...cerebral infarct independently of established risk factors. Our aim is to estimate the frequency of obstructive sleep apnea syndrome in hypertensive patients with and without silent cerebral infarct, and to determine whether obstructive sleep apnea syndrome is an independent risk factor of silent cerebral infarct and/or lacunar silent cerebral infarct in patients with hypertension. In this matched cross‐sectional study performed in hypertensive subjects, each patient with silent cerebral infarct detected by magnetic resonance imaging was matched with two patients without silent cerebral infarct. Polysomnographic studies were performed, and the apnea–hypopnea index was calculated. Severe obstructive sleep apnea syndrome was considered in those with apnea–hypopnea index >30. One‐hundred and eighty‐three patients, 61 with silent cerebral infarct and 122 without silent cerebral infarct, were evaluated. The mean age was 64.1 ± 4.5 years, and 72.1% were men. The frequency of severe obstructive sleep apnea syndrome was 44.3% in patients with silent cerebral infarct and 38.5% in the control group. An adjusted conditional logistic regression model did not show a significant increased risk of silent cerebral infarct in patients with severe obstructive sleep apnea syndrome (odds ratio 1.362; 95% confidence interval: 0.659–2.813; P = 0.404). Forty‐three patients (70.5%) of the silent cerebral infarct were lacunar. The presence of severe obstructive sleep apnea syndrome was significantly higher in lacunar silent cerebral infarct when compared with patients without lacunar infarcts (55.8% versus 35.7%, P = 0.019), being independently associated on an adjusted logistic regression model (odds ratio 2.177; 95% confidence interval: 1.058–4.479; P = 0.035). In conclusion, severe obstructive sleep apnea syndrome is highly prevalent among hypertensive subjects, and is independently associated with lacunar silent cerebral infarct.
Background Citicoline is a drug approved for the treatment of acute ischemic stroke. Although evidence of its efficacy has been reported, recently published results of a large placebo-controlled ...clinical trial did not show differences. This study aims to assess whether starting citicoline treatment within 14 days after stroke onset improves the outcome in patients with acute ischemic stroke, as compared with placebo. Methods A systematic search was performed to identify all published, unconfounded, randomized, double-blind, and placebo-controlled clinical trials of citicoline in acute ischemic stroke. Results Ten randomized clinical trials met our inclusion criteria. The administration of citicoline was associated with a significant higher rate of independence, independently of the method of evaluation used (odds ratio OR 1.56, 95% confidence interval CI = 1.12-2.16 under random effects; OR 1.20, 95% CI = 1.06-1.36 under fixed effects). After studying the cumulative meta-analysis, and with the results obtained with the subgroup of patients who were not treated with recombinant tissue plasminogen activator (rtPA) (OR 1.63, 95% CI = 1.18-2.24 under random effects; OR 1.42, 95% CI = 1.22-1.66 under fixed effects), our hypothesis of dilution of the effect of citicoline was confirmed. When we analyzed the effect of citicoline in patients who were not treated with rtPA and were receiving the highest dose of citicoline started in the first 24 hours after onset, based on more recent trials, there was no heterogeneity, and the size of the effect has an OR of 1.27 (95% CI = 1.05-1.53). Conclusions This systematic review supports some benefits of citicoline in the treatment of acute ischemic stroke. But, on top of the best treatment available (rtPA), citicoline offers a limited benefit.
Advances in acute stroke therapy resulting from thrombolytic treatment, endovascular procedures, and stroke units have improved significantly stroke survival and prognosis; however, for the large ...majority of patients lacking access to advanced therapies stroke mortality and residual morbidity remain high and many patients become incapacitated by motor and cognitive deficits, with loss of independence in activities of daily living. Therefore, over the past several years, research has been directed to limit the brain lesions produced by acute ischemia (neuroprotection) and to increase the recovery, plasticity and neuroregenerative processes that complement rehabilitation and enhance the possibility of recovery and return to normal functions (neurorepair). Citicoline has therapeutic effects at several stages of the ischemic cascade in acute ischemic stroke and has demonstrated efficiency in a multiplicity of animal models of acute stroke. Long-term treatment with citicoline is safe and effective, improving post-stroke cognitive decline and enhancing patients' functional recovery. Prolonged citicoline administration at optimal doses has been demonstrated to be remarkably well tolerated and to enhance endogenous mechanisms of neurogenesis and neurorepair contributing to physical therapy and rehabilitation.
Statins may exert some neuroprotection, because use before stroke onset has been related to better outcome and reduced mortality. The purpose of this study was to evaluate whether patients who ...receive tissue plasminogen activator have better outcome when statins were taken before stroke.
We evaluated 145 patients with a stroke involving the middle cerebral artery (who received tissue plasminogen activator treatment (<3 hours).
Fifty-eight patients (40%) became functionally independent at 3 months. Factors associated with good outcome were age (68 versus 74.4 years, P<0.001), baseline National Institutes of Health Stroke Scale score (13 versus 18, P<0.001), and proximal middle cerebral artery occlusion (56.1% versus 84.3%, P<0.001). Statins were the only drug taken before stroke that conditioned neurologic outcome. In fact, among patients who were functionally independent, 27.3% were under statins at the time of the index stroke as compared with 13.6% among the group of patients who were dependent or dead by the end of the study period (P=0.046). A logistic regression model identified baseline National Institutes of Health Stroke Scale score <15 (OR: 5.8, 95% CI: 2.05 to 16.36, P=0.001), age <70 years (OR: 2.93, 95% CI: 1.13 to 7.59, P=0.027), and previous treatment with statins (OR: 5.26, 95% CI: 1.48 to 18.72, P=0.027) as independent predictors of good functional outcome.
Patients under statins at the moment of stroke who received thrombolytics had an improved neurologic outcome.
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