Persistent Middle Cerebral Artery Research Articles

Clipping of a persistent middle cerebral artery aneurysm after previous flow diverter placement: An illustrative case and review of the literature.

Flow diverter (FD) is increasingly used in the management of wide necked cerebral aneurysms. Despite a reported lower efficacy in middle cerebral artery (MCA) aneurysms, they are still being utilised. Microsurgery is best considered as an index treatment, but can also be a safe and effective treatment when encountering a persistent MCA aneurysm after prior FD. As there is a paucity in literature and more cases of failed FD are expected to appear, we want to add our experience to the existing literature. The microsurgical management of a persistent MCA bifurcation aneurysm, 3 years after a p48 MW HPC Flow Diverter (phenox GmbH, Bochum Germany) insertion is reported and the relevant literature discussed.

Exogenous Netrin-1 Inhibits Autophagy of Ischemic Brain Tissues and Hypoxic Neurons via PI3K/mTOR Pathway in Ischemic Stroke

Background and Objective: Ischemic stroke is a serious disease that endangers human health. How to reduce the damage of neurons in ischemic regions is an urgent problem to be explored. Autophagy is an important pathophysiological process in cerebral ischemia and Netrin-1 is an effective neuroprotective protein. This study aims to investigate the effect of Netrin-1 on autophagy of ischemic brain tissues and hypoxic neurons. Methods: We constructed rat persistent middle cerebral artery occlusion model in vivo and constructed the Oxygen Glucose-Deprivation model in vitro. Rats and cells were treated with or without Netrin-1. Western blot analysis was performed to detect autophagy related proteins LC3B, P62 and pathway related proteins PI3K, p-PI3K, mTOR, p-mTOR. CCK-8 assay was performed to detect the viability of hypoxic neurons. We also performed western-blot analysis and qRT-PCR test to detect levels of Netrin-1 protein and mRNA. Results: Autophagy enhanced both in ischemic brain tissues and hypoxic neurons. Netrin-1 inhibited autophagy through PI3K/mTOR pathway both in vivo and in vitro. At the same time, we found that exogenous Netrin-1 can promote the secretion of Netrin-1 protein by neurons themselves, which indicated that Netrin-1 can further amplify the neuroprotective effect through the positive feedback mechanism. Conclusions: Exogenous Netrin-1 alleviates damage of ischemic brain tissues and enhances viability of hypoxic neurons by inhibiting autophagy via PI3K/mTOR pathway. This effect can be amplified by positive feedback mechanism.

A stress-related explanation to the increased blood pressure and its course following ischemic stroke

BackgroundA hypertensive response after ischemic stroke is frequent, yet its pathophysiology is unknown. Mechanisms related to local ischemic damage, major vascular occlusion, and psychological stress due to acute illness have been proposed. We assessed the natural course of blood pressure (BP) within the first 24 h in groups of ischemic stroke patients with different characteristics. We hypothesized that a consistent BP reduction, regardless of stroke location, time window from debut to admission and presence of persistent vascular occlusion, would favor a stress-related mechanism as an important cause of the hypertensive response after ischemic stroke.MethodsIschemic stroke patients (n=1067) were prospectively registered, and BP was measured on admission and <3 h, 3–6 h, 6–12 h and 12–24 h after admission. Patients were categorized according to the location of diffusion-weighted imaging (DWI) lesions (cortical, large subcortical, mixed cortico-subcortical, lacunar, cerebellar, brain stem or multiple), time window (admitted within or after 6 h of symptom onset) and presence of persistent proximal middle cerebral artery (MCA) occlusion versus normal findings on magnetic resonance angiography (MRA) at 24 h.ResultsA reduction in systolic BP and diastolic BP from baseline to 12–24 h was found across all DWI locations except for diastolic BP in cerebellar (P=0.072) lesions. Apart from diastolic BP in patients with normal MRA findings at 24 h (P=0.060), a significant fall in systolic BP and diastolic BP at 12–24 h was registered, irrespective of whether patients were admitted within 6 h or after 6 h of stroke onset or had persistent MCA occlusion versus normal MRA findings.ConclusionWe found a relatively consistent decline in BP within 24 h after admission across different stroke locations in patients admitted within or after 6 h of stroke onset and in patients with persistent MCA occlusion. Our findings suggest that a systemic factor such as psychological stress may be an important contributor to the frequently elevated BP on admission in patients with ischemic stroke.

PH gradient difference around ischemic brain tissue can serve as a trigger for delivering polyethylene glycol-conjugated urokinase nanogels

Background and PurposepH-sensitive polyethylene glycol-conjugated urokinase nanogels (PEG-UKs) were previously reported to be a new form of UK nanogels that could release UK at certain pH values. In this study, we evaluated the effect of PEG-UK targeted to ischemic tissue with microcirculation failure in rat model of ischemic stroke and investigated the possible mechanisms of action. MethodsSurgeries were performed to induce persistent middle cerebral artery (MCA) occlusion in adult Sprague–Dawley rats. The pH distribution in the brain was mapped 1h after ischemia using a needle-type pH micro sensor. The release curve of active UK from PEG-UK was also mapped by a continuous measurement of the peripheral blood. The thrombolytic effects of PEG-UK, when it was administrated 1h after occlusion, including dynamic changes in the D-dimer level, neurological deficits and infarction volume, were observed. Next, the possible mechanisms underlying these effects were explored, including the BBB integrity and the extent of apoptosis and neurotoxicity. Additionally, the long-term effects of PEG-UK during the four weeks after treatment were evaluated using the dynamic changes in the body weights and clinical scores and the numbers of deaths and hemorrhagic transformations (HTs). To evaluate the systemic side effects of PEG-UK, the fluctuations of cytokines in the liver and kidney were evaluated. ResultsOn average, MCA occlusion for 1h induced an approximately 0.49 decline in the pH value (from 7.12 to 6.73), and the lowest value was 6.32 in the predominantly affected region around the cortex. PEG suspended the release of UK from PEG-UK into the circulation. When it was administrated 1h after occlusion, PEG-UK treatment clearly reduced the severity of neurological deficits in the acute phase (P=0.001). The relative infarct volume also decreased significantly in PEG-UK rats (P<0.001). As to the integrity of BBB, the EB leakage in the PEG-UK group was reduced (P=0.001). Maintenance of the expression of TIMP-1 (P=0.032) and claudin5 (P<0.001) and inhibition of MMP9 upregulation (P<0.001) were observed through both immunohistochemistry and Western blot in the PEG-UK group. Moreover, the expression of both NMDAR1 (P<0.001) and Caspase9 (P=0.013) in PEG-UK-treated rats was reduced. As to the long-term prognosis, the rats in PEG-UK group recovered faster and better, and the numbers of deaths and HTs were not increased. No significant fluctuation in IL-1β and TNF-α was found in the PEG-UK-treated rats during the four post-treatment weeks. When PEG-UK was administrated 2.5h after occlusion, no clearly better outcomes were observed; however, the number of HTs was not increased. ConclusionsTreatment with PEG-UK decreased the severity of ischemic stroke by improving ischemic brain tissue and protecting the BBB and by inhibiting apoptosis and decreasing neurotoxicity. PEG-UK could further inhibit HT through its BBB protection effect. The administration of PEG-UK also improved the long-term prognosis and had no obvious systemic side effects in rats. Our data provide new insights into the thrombolytic treatment of ischemic stroke.

Abstract 17802: pH Sensitive Polyethylene Glycol-urokinase Nanogels Ameliorates the Severity of Ischemic Stroke in Rats by Effective Thrombolysis and Protection of Blood-brain Barrier

Background: pH sensitive polyethylene glycol-urokinase nanogels(PEG-UK) was reported previously as a new form of UK, which could release UK at certain pH value and has the same thrombolytic effect as naked UK on human clots in vitro. In this study, we evaluated its effect in rat model of ischemic stroke and further investigated possible mechanisms. Methods: Persistent middle cerebral artery occlusion were induced in adult Sprague-Dawley rats. pH distribution in the brain was mapped at 1 hour after ischemia through Needle type pH micro sensor and pH Optica Micro system. Thrombolytic effect of PEG-UK, such as dynamic levels of D-dimer, neurological deficts and infarction volume, were examined respectively. In spite of the overall performances, possible mechanisms were also explored, for example, the permeability of blood-brain barrier(BBB) reflected by Evans Blue(EB) leakage, BBB’s integrity via matrix metalloproteinase 9 (MMP9), tissue inhibitor of metalloproteinase protein-1 (TIMP-1) and Claudin5, and extent of apoptosis and neurotoxicity standed by Caspase9 and N-methyl-D-aspartic acid receptor 1(NMDAR1). Results: In ischemic hemisphere, pH value near cortex was obviously lower than that in deeper white matter. Averagely, occlusion for 1 hour induced the decline of pH value for about 0.49, and the lowest value reached to 6.32. Treatment with PEG-UK brought obvious alleviation of neurological deficts in acute phase( P =0.001). A significant reduction of relative infarction volume was also proved in PEG-UK rats( P &lt;0.001). As to the permeability of BBB, the leakage of EB in PEG-UK group was the least among three groups( P =0.001). What’s more, the sustain of the expression of TIMP-1( P =0.032) and Claudin5( P &lt;0.001) and the inhibition of upregulation of MMP9( P &lt;0.001) were all concluded in PEG-UK group. Besides, both the expression of NMDAR1( P &lt;0.001) and Caspase9( P =0.013) in PEG-UK treated rats were much less. Conclusions: Our findings indicated that treatment with PEG-UK ameliorated the severity of ischemic stroke, accompanied by neuroprotection through keeping the integrity of BBB and inhibiting apoptosis and neurotoxicity. PEG-UK may further inhibit hemorrhagic transformation by its BBB protection effect.

Persistent middle cerebral artery occlusion associated with lower body temperature on admission

BackgroundLow body temperature is considered neuroprotective in ischemic stroke, yet some studies suggest that low body temperature may also inhibit clot lysis and recanalization. We hypothesized that low body temperature was associated with persistent proximal middle cerebral artery (MCA) occlusion in patients with acute ischemic stroke presenting with symptoms of proximal MCA occlusion, suggesting a possible detrimental effect of low body temperature on recanalization.MethodsAll patients with acute ischemic stroke admitted to our Stroke Unit between February 2006 and August 2012 were prospectively registered in a database. Computed tomography (CT) angiography was performed in patients admitted <6 hours after stroke onset. Based on presenting symptoms, patients were classified according to the Oxford Community Stroke Project classification (OCSP). Patients with symptomatic proximal MCA occlusion were compared to patients with total anterior circulation infarct (TACI) without MCA occlusion on CT angiography.ResultsDuring the study period, 384 patients with acute ischemic stroke were examined with CT angiography. A total of 79 patients had proximal MCA occlusion and 31 patients had TACI without MCA occlusion. Median admission body temperatures were lower in patients with MCA occlusion compared to patients without occlusion (36.3°C versus 36.7°C, P = 0.027). Admission body temperature <36.5°C was independently associated with persistent MCA occlusion when adjusted for confounders in multivariate analyses (odds ratio 3.7, P = 0.007).ConclusionOur study showed that low body temperature on admission was associated with persistent proximal MCA occlusion. These results may support a possible detrimental effect of low body temperature on clot lysis and recanalization.

Treatment with tPA Predicts Better Outcome Even if MCA Occlusion Persists

Functional improvement after middle cerebral artery ischaemia seems to depend on recanalization of large-vessel occlusion as early as possible. The only approved medical treatment for acute stroke is early IV tissue plasminogen activator administration. However, while some patients do not benefit from quick recanalization, others recover despite persistent middle cerebral artery occlusion. We wondered whether there are different effects of tissue plasminogen activator treatment on large artery and small artery reopening. We enrolled 55 acute stroke patients who showed persisting middle cerebral artery occlusion evidenced by transcranial colour-coded duplex ultrasonography in follow-up examination within 48 h postonset of middle cerebral artery stroke syndromes (mean 30·8 ± 5·4 h after admission). Twenty-two of 55 had been treated with tissue plasminogen activator and 33/55 had been treated without tissue plasminogen activator. We compared neurological (National Institutes of Health Stroke Scale) and functional (modified Rankin Scale) scores at baseline, after seven-days, and then after two-months. Risk factors, previous stroke prophylaxis, as well as clinical baseline characteristics were analysed to exclude significant differences between both groups. Despite later admission to hospital (tissue plasminogen activator patients 1·6 ± 0·66 h vs. non-tissue plasminogen activator patients 7·4 ± 5·84 h; P < 0·001), there was no significant difference between both groups concerning demographic data, severity of symptoms on admission, risk factors, stroke prophylaxis, as well as basic laboratory values (international normalized ratio, leucocyte count, C-reactive protein) blood pressure and body temperature on admission. Irrespective of Doppler findings demonstrating persistent middle cerebral artery occlusion in all 55 patients, there was a significant neurological and functional improvement in tissue plasminogen activator patients compared to non-tissue plasminogen activator patients. Tissue plasminogen activator patients had a mean improvement on National Institutes of Health Stroke Scale within the first seven-days of 2·8 points, while non-tissue plasminogen activator patients deteriorated by 2·2 points (P < 0·001). Concerning modified Rankin Scale tissue plasminogen activator-treated patients showed a mean improvement within the first seven-days of 0·5 points, while non-tissue plasminogen activator patients deteriorated by 0·3 points (P = 0·019). A favourable overall short-term clinical course (i.e. improvement on National Institutes of Health Stroke Scale >3 points and/or modified Rankin Scale >1 point) was found in 36·4% of tissue plasminogen activator patients and in 6·1% of non-tissue plasminogen activator patients (P = 0·0047). At two-months follow-up, patients still showed a median modified Rankin Scale of 4 points after tissue plasminogen activator treatment and 5 points after non-tissue plasminogen activator treatment (P = 0·023). Although the prognosis of patients with persisting middle cerebral artery occlusion after tissue plasminogen activator administration is known to be poor, patients do better if treated with tissue plasminogen activator vs. those who could not be treated - mainly for late presentation. This may be due to sufficient small vascular territory recanalization despite persistence of large artery occlusion after tissue plasminogen activator treatment.

Insulin Resistance Is Associated With a Poor Response to Intravenous Thrombolysis in Acute Ischemic Stroke

OBJECTIVEInsulin resistance (IR) may not only increase stroke risk, but could also contribute to aggravate stroke prognosis. Mainly through a derangement in endogenous fibrinolysis, IR could affect the response to intravenous thrombolysis, currently the only therapy proved to be efficacious for acute ischemic stroke. We hypothesized that high IR is associated with more persistent arterial occlusions and poorer long-term outcome after stroke thrombolysis.RESEARCH DESIGN AND METHODSWe performed a prospective, observational, longitudinal study in consecutive acute ischemic stroke patients presenting with middle cerebral artery (MCA) occlusion who received intravenous thrombolysis. Patients with acute hyperglycemia (≥155 mg/dL) receiving insulin were excluded. IR was determined during admission by the homeostatic model assessment index (HOMA-IR). Poor long-term outcome, as defined by a day 90 modified Rankin scale score ≥3, was considered the primary outcome variable. Transcranial Duplex-assessed resistance to MCA recanalization and symptomatic hemorrhagic transformation were considered secondary end points.RESULTSA total of 109 thrombolysed MCA ischemic stroke patients were included (43.1% women, mean age 71 years). The HOMA-IR was higher in the group of patients with poor outcome (P = 0.02). The probability of good outcome decreased gradually with increasing HOMA-IR tertiles (80.6%, 1st tertile; 71.4%, 2nd tertile; and 55.3%, upper tertile). A HOMA-IR in the upper tertile was independently associated with poor outcome when compared with the lower tertile (odds ratio [OR] 8.54 [95% CI 1.67–43.55]; P = 0.01) and was associated with more persistent MCA occlusions (OR 8.2 [1.23–54.44]; P = 0.029).CONCLUSIONSHigh IR may be associated with more persistent arterial occlusions and worse long-term outcome after acute ischemic stroke thrombolysis.

Accuracy of the Alberta Stroke Program Early CT Score during the First 3 Hours of Middle Cerebral Artery Stroke: Comparison of Noncontrast CT, CT Angiography Source Images, and CT Perfusion

The Alberta Stroke Program Early CT Score (ASPECTS) is a reliable method of delineating the extent of middle cerebral artery (MCA) stroke. Our aim was to retrospectively compare the accuracy of ASPECTS on noncontrast CT, CT angiography (CTA) source images, and CT perfusion maps of cerebral blood volume (CBV) during the first 3 hours of middle cerebral artery (MCA) stroke. First-time patients with MCA stroke who presented <3 hours from symptom onset and were evaluated by noncontrast CT/CTA/CT perfusion, had confirmed acute nonlacunar MCA infarct on diffusion-weighted MR imaging (DWI) within 7 days, and had follow-up angiography were included. Patients were excluded for persistent MCA occlusion or stenosis. Two raters through consensus assigned an ASPECTS on the noncontrast CT, CTA source images, and the section-selective (2 x 12 mm coverage) CT perfusion CBV maps. ASPECTS on follow-up DWI served as the reference standard. For each CT technique, the detection rates of regional infarction, the mean ASPECTS, and the linear correlation to final ASPECTS were determined and compared. P values <.05 were considered significant. Twenty-eight patients satisfied the criteria with DWI performed at a mean of 50.3 hours (range, 22-125 hours) post-CT imaging. Of 280 ASPECTS regions, 100 were infarcted on DWI. The accuracy of noncontrast CT, CTA source images, and CT perfusion CBV for detecting regional infarct was 80.0%, 84.3%, and 96.8%, respectively (P < .0001). The mean ASPECTSs of noncontrast CT, CTA source images, CT perfusion CBV, and DWI were 8.4 +/- 1.8, 8.0 +/- 1.8, 6.8 +/- 1.9, and 6.5 +/- 1.8, respectively. The mean noncontrast CT and CTA source image ASPECTS was different from that of DWI (P < .05). Correlation of noncontrast CT, CTA source images, and CT perfusion CBV ASPECTS with final ASPECTS was r(2) = 0.34, r(2) = 0.42, and r(2) = 0.91, respectively. In a retrospective cohort of MCA infarcts imaged <3 hours from stroke onset, ASPECTS was most accurately determined on CT perfusion CBV maps.

Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke

This study aimed at an analysis of glial fibrillary acidic protein (GFAP) in acute ischemic stroke, its association with the neurovascular status and its potential value as monitoring parameter. In 53 consecutive patients, serial venous blood samples were taken on admission, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extracranial and transcranial duplex sonography. Neurologic deficits were quantified by the National Institutes of Health stroke scale, and functional outcome was assessed with the modified Rankin Scale. Mean GFAP values were elevated from admission on with highest levels 48 h after stroke onset. GFAP release was highly correlated with severity of neurologic deficits and infarct volume. In patients with persistent middle cerebral artery occlusion, GFAP increased significantly compared with patients with normal sonographic findings (P = 0.019) and recanalization after thrombolysis resulted in a significant reduced increase (P = 0.038). GFAP concentrations were associated with the functional outcome after 3 months. Release kinetics of GFAP are associated with patients clinical deficits and infarct volume, depend on the neurovascular status on admission and on early recanalization after thrombolysis, and may be used as an additional predictor of the early course and functional outcome.

Flow Diversion in Transcranial Doppler Ultrasound Is Associated with Better Improvement in Patients with Acute Middle Cerebral Artery Occlusion

Backgound: Flow diversion (FD) can occur with an acute middle cerebral artery (MCA) occlusion. FD is thought to represent the collateral blood flow to the occluded MCA territory, but it is unclear whether or not FD lessens the stroke severity or leads to improved outcome. Methods: Patients with a proximal MCA occlusion were selected from the CLOTBUST trial data bank. FD to the anterior or posterior cerebral artery was determined using transcranial Doppler ultrasound. Stroke severity and clinical improvement were measured using the National Institutes of Health Stroke Scale (NIHSS) scores. Results: We evaluated 47 patients with an isolated M1 MCA occlusion who received intravenous tissue-type plasminogen activator (t-PA) within 3 h of symptom onset. FD was present in 83% of the patients. Median baseline NIHSS scores were 15.5 in the FD– group and 18 in the FD+ group (n.s.). Complete recanalization rates were 25 and 25.6% (n.s.). In 35 patients with a persistent occlusion, the average NIHSS score reduction was 22% (FD+) and 0.52% (FD–) during 90 min after t-PA bolus (p = 0.017), and 29 versus –25% during the first 24 h after the t-PA bolus, respectively (p = 0.01). Conclusions: In patients with persistent MCA occlusions after thrombolytic treatment, arterial blood flow diversion is associated with earlier and better neurological improvement. FD has protective effects on the ischemic brain tissue with persistent MCA occlusion.

Effects of admission hyperglycemia on stroke outcome in reperfused tissue plasminogen activator--treated patients.

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.