Acute Ischemic Stroke Presenting Research Articles

Expediting MRI-Based Proof-of-Concept Stroke Trials Using an Earlier Imaging End Point

Before Phase III trials of acute stroke therapies, proof-of-concept MRI trials are increasingly used to gauge the likelihood of success. Given that animal models use infarct volume as the end point, Phase II trials have aimed to translate the findings using infarct growth. These trials could be expedited if subacute diffusion-weighted imaging lesion volume replaced late T2-weighted lesion volume as the primary end point. In the Echoplanar Imaging Thrombolytic Evaluation Trial, patients with acute ischemic stroke presenting within 3 to 6 hours were randomized to tissue plasminogen activator or placebo. We assessed correlations between acute (Day 1), subacute (Day 3 to 5) as well as late (Day 90) lesion volumes and clinical outcome (National Institutes of Health Stroke Scale). We compared lesion growth between placebo- and tissue plasminogen activator-treated patients. All 3 scans were performed in 72 of 101 patients (32 tissue plasminogen activator, 40 placebo). Median time to subacute imaging was 3 days (interquartile range, 2 to 4) and 90 days (interquartile range, 90 to 95) for the late scan. Increase in lesion volume from acute to subacute scans was smaller in the tissue plasminogen activator group compared with the placebo group (6.77 mL; interquartile range, 2.30 to 49.10; versus 30.00 mL; interquartile range, 7.19 to 85.93; P=0.03). Subsequent shrinkage did not reveal significant treatment effects. Correlation coefficient between acute and late lesion volumes was 0.81 (P<0.01). Subacute and late lesion volumes were strongly correlated (rho=0.94, P<0.01). Correlation coefficient for acute, subacute, and late lesion volume and late National Institutes of Health Stroke Scale score was 0.64 (P<0.01), 0.81 (P<0.01), and 0.77 (P<0.01), respectively. These findings suggest that subacute imaging at Day 3 after thrombolysis is an appropriate imaging end point for proof-of-concept MRI-based stroke treatment trials and can replace later MRI measurements.

A significant temporal and quantitative relationship exists between high-density lipoprotein levels and acute ischemic stroke presentation

Background Reduced serum high-density lipoprotein (HDL-C) is an independent risk factor for ischemic stroke in elderly men. The temporal and quantitative relationships between HDL-C and acute ischemic stroke have not been defined. Methods We identified patients with first ever acute ischemic stroke presenting to our hospital between 2003 and 2006. Patients with serum fasting lipid levels drawn within 24 h of admission and at least one follow-up visit with a neurologist in our hospital were included. Clinical and laboratory data before, immediately after, and several weeks after the index stroke were collected. Results 191 patients were included (47% women, mean age 62 years). The mean time interval between pre-stroke lipid data and index stroke was 5.2 months; 50% of these patients were taking a statin medication. The mean time interval between index stroke and follow-up lipid testing was 2.6 months. Immediately after the index stroke, HDL-C levels decreased by 18% ( p < 0.001) relative to pre-stroke levels. This phenomenon was independent of stroke severity, and was blunted among patients with a prior history of myocardial infarction ( p < 0.01). HDL-C levels increased to pre-stroke levels within 3 months post-stroke. Conclusions HDL-C levels decrease significantly at the time of acute ischemic stroke. Prior history of myocardial infarction diminishes HDL-C depression at the time of stroke. HDL-C may be an acute phase reactant or nascent biomarker of acute stroke susceptibility. Further prospective studies are needed.

Increased leukocyte ROCK activity in patients after acute ischemic stroke

Background Rho-kinase (ROCK) is a downstream effector of Rho GTPase that is known to regulate various pathological processes important to the development of ischemic stroke, such as thrombus formation, inflammation, and vasospasm. Inhibition of ROCK leads to decreased infarct size in animal models of ischemic stroke. This study tests the hypothesis that ROCK activity increases during the acute phase of ischemic stroke. Methods Serial blood samples were drawn from 10 patients with acute ischemic stroke presenting within 24 h of symptom onset and with NIHSS scores ≥ 4. Samples were taken at 24, 48, and 72 h. Leukocyte ROCK activity was determined by immunoblotting leukocyte lysates with antibodies to the phosphorylated form of myosin-binding subunit (P-MBS) of myosin light chain phosphatase (MLCP). MBS and P-MBS contents were normalized to α-tubulin, and ROCK activity was expressed as the ratio of P-MBS to MBS. ROCK activities in these 10 patients were compared to baseline ROCK activities in 10 control subjects without acute illness and matched for sex, age, and number of vascular risk factors using a two-tailed Student's t-test. Results The mean NIHSS score in patients with stroke was 15.4. ROCK activity was significantly increased at 24 and 48 h in patients after acute ischemic stroke when compared to control values, with peak elevations at 48 h after stroke onset. There was no apparent correlation between ROCK activity and stroke severity based on NIHSS. Conclusions Leukocyte ROCK activity is increased in patients after acute ischemic stroke with maximal activity occurring about 48 h after stroke onset. These findings suggest that activation of ROCK may play a role in the pathogenesis of ischemic stroke in humans.

Exploratory study of plasma total homocysteine and its relationship to short-term outcome in acute ischaemic stroke in Nigerians

BackgroundHyperhomocysteinemia is a potentially modifiable risk factor for stroke, and may have a negative impact on the course of ischaemic stroke. The role of hyperhomocysteinemia as it relates to stroke in Africans is still uncertain. The objective of this study was to determine the prevalence and short-term impact of hyperhomocysteinemia in Nigerians with acute ischaemic stroke. We hypothesized that Hcy levels are significantly higher than in normal controls, worsen stroke severity, and increase short-term case fatality rates following acute ischaemic stroke.MethodsThe study employed both a case-control and prospective follow-up design to study hospitalized adults with first – ever acute ischaemic stroke presenting within 48 hours of onset. Clinical histories, neurological evaluation (including National Institutes of Health Stroke Scale (NIHSS) scores on admission) were documented. Total plasma Hcy was determined on fasting samples drawn from controls and stroke cases (within 24 hours of hospitalization). Outcome at 4 weeks was assessed in stroke patients using the Glasgow Outcome Scale (GOS).ResultsWe evaluated 155 persons (69 acute ischaemic stroke and 86 healthy controls). The mean age ± SD of the cases was 58.8 ± 9.8 years, comparable to that of controls which was 58.3 ± 9.9 years (T = 0.32; P = 0.75). The mean duration of stroke (SD) prior to hospitalization was 43.5 ± 38.8 hours, and mean admission NIHSS score was 10.1 ± 7.7. Total fasting Hcy in stroke patients was 10.2 ± 4.6 umol/L and did not differ significantly from controls (10.1 ± 3.6 umol/L; P = 0.88). Hyperhomocysteinemia, defined by plasma Hcy levels > 90th percentile of controls (>14.2 umol/L in women and >14.6 umol/L in men), was present in 7 (10.1%) stroke cases and 11 (12.8%) controls (odds ratio 0.86, 95% confidence interval 0.31 – 2.39; P > 0.05). In multiple regression analysis admission NIHSS score (but not plasma Hcy) was a significant determinant of 4 week outcome measured by GOS score (P < 0.0001).ConclusionThis exploratory study found that homocysteine levels are not significantly elevated in Nigerians with acute ischaemic stroke, and admission Hcy level is not a determinant of short-term (4 week) stroke outcome.

Recommendations and treatment strategies for the management of acute ischemic stroke

Background: Stroke is one of the leading causes of mortality and disability worldwide. From the establishment of the penumbra concept, ischemic stroke has been recognized as a dynamic process and two main therapeutic strategies have been designed: one that tries to reopen the occluded artery and the second aims to protect the penumbra brain tissue until the physiologic mechanisms–or the treatment–stop the ischemia. Objective: To review the most recent, high-quality evidence for acute stroke treatment. Methods: Systematic review of relevant published studies focused in several aspects of acute ischemic stroke management, from neuroprotection to thrombolysis. Conclusions: After the publication of NINDS rt-PA study, the classical nihilistic approach to ischemic stroke started to change and thrombolytic treatment was approved in the treatment of patients with acute ischemic stroke presenting within 3 h from onset of symptoms. Advances in this field are proceeding on several fronts, including the use of next-generation plasminogen activators and glycoprotein IIb/IIIa inhibitors, refined patient selection with advanced magnetic resonance imaging sequences, endovascular approaches to thrombolysis and thrombectomy, and adjuvant use of ultrasound. Abrupt deprivation of oxygen and glucose to neuronal tissues elicits a series of pathologic cascades, leading to the spread of neuronal death. Of the numerous pathways identified, excessive activation of glutamate receptors, accumulation of intracellular Ca2+ cations, abnormal recruitment of inflammatory cells, excessive production of free radicals and initiation of pathologic apoptosis are believed to play critical roles in ischemic damage, especially in the penumbral zone. Several neuroprotective agents designed to block these cascades have been investigated in animal models of cerebral ischemia and numerous agents have been found to reduce infarct size. However, translation of neuroprotective benefits from the laboratory bench to the emergency room has not been successful. Other measures, such as the relevance of body position in the acute phase of stroke, anticoagulant and antiplatelet agents or the effects of statins and antihypertensive therapy, are discussed in this paper, with an overview of the relevance of stroke units.

Comparison of Combined Venous and Arterial Thrombolysis with Primary Arterial Therapy Using Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke

We sought to compare the safety and efficacy of combined intravenous (IV) and intra-arterial (IA) thrombolysis with primary IA therapy using tissue plasminogen activator for acute ischemic stroke presenting within 6 hours of symptom onset. We performed quasirandomization of a single institution's prospectively collected stroke database, comparing IV/IA (0.6 mg/kg IV < or = 60 mg, followed by 0.3 mg/kg IA < or = 30 mg) versus primary IA. Outcome measures include 90-day modified Rankin scale score, mortality, symptomatic intracerebral hemorrhage, and recanalization rates. Statistical analysis was performed using bivariate and propensity score methods. Of 1057 patients, 41 patients were treated with IV/IA, and 55 with IA. There was significant difference in time to treatment (mean of 151 minutes for the combined group and 261 minutes for the IA, P < .0001) and arterial tissue plasminogen activator dose (17.5 mg for IV/IA v 22.8 mg for IA only, P = .05). Propensity score matching yielded 25 patients in each group. Symptomatic intracerebral hemorrhage rate was 12% in each group. Mortality was 20% in the IV/IA group versus 16% in the IA group (relative risk 1.3 [0.4-4.1], P = .7). More patients in IV/IA group had modified Rankin scale score less than or equal to 2 (odds ratio 1.6 [0.5-5.8], P = .3). Recanalization was 64% with IV/IA versus 48% with IA (odds ratio 1.9 [0.5-7.0], P = .3). This study demonstrates that both combined IV/IA and primary IA recombinant tissue plasminogen activator therapy is feasible and safe in the treatment of acute ischemic stroke. Combined IV/IA therapy may be associated with an improvement in clinical outcome without a significant increase in the risk of symptomatic intracerebral hemorrhage and mortality compared with IA therapy.

Hyperglycemia after Acute Ischemic Stroke: Prediction, Significance and Immediate Control with Insulin-Potassium-Saline-Magnesium Infusions

Introduction: It is well known that in the first 24 h after stroke onset, plasma glucose concentrations are elevated in 20–43% of patients, of whom more than half are not known to have diabetes mellitus. Glucose levels >8 mmol/l have been found to be predictive of a poor prognosis in ischemic stroke patients. It is thought that the clinical use of insulin infusions has a beneficial effect on hyperglycemia. Indeed, insulin therapy in critically ill patients, including acute stroke patients, is safe and results in lower mortality and complication rates. Unfortunately, the impact of intensive insulin therapy in non-critically ill patients with hyperglycemia is poorly understood. Objectives: It was the aim of this study to determine the clinical efficacy and safety of early-onset therapy with human recombinant insulin: glycemic control measured by reduction in plasma glucose concentrations, vital activity measured by the Barthel index (no significant disability was defined as ≤50, moderate disability was defined as 51–75, and severe disability was defined as ≧75), and neurological deficit measured by the National Institutes of Health Stroke Scale (NIHSS; values ranging from 0 = normal to 42 = worst case) in non-critically ill ischemic stroke diabetic and non-diabetic patients. Design: We used a randomized prospec- tive open trial of insulin-potassium-saline-magnesium (IPSM) infusions in patients after acute ischemic stroke presenting with mild to moderate hyperglycemia. Acute (<24 h) ischemic stroke patients (n = 128) with hyperglycemia on admission between 7.0 and 16 mmol/l with and without type 2 diabetes mellitus (T2DM) were randomly divided into four groups: (1) hyperglycemia associated with T2DM and treated with IPSM (n = 36), (2) hyperglycemia associated with T2DM without IPSM administration (n = 40), (3) hyperglycemia without confirmed T2DM and treated with IPSM (n = 25), and (4) hyperglycemia without confirmed T2DM and without IPSM administration (n = 27). Results: Treatment with the IPSM regimen permitted to normalize blood glucose levels. The neurological deficit according to the NIHSS in stroke patients with hyperglycemia treated with insulin did not worsen in the first 3 days. Results were expressed as means ± SD of NIHSS scores at admission and at day 30. At the same time, the clinical status of patients not treated with insulin worsened. Three weeks after admission, the neurological deficit improved in treated stroke patients (13.5 ± 1.5 and 8.6 ± 1.1, respectively; p < 0.05) and untreated patients with T2DM (13.2 ± 1.7 and 8.9 ± 1.3; p < 0.05). However, the neurological deficit in stroke patients without T2DM, but with hyperglycemia not treated with insulin did not improve significantly (14.4 ± 1.5 and 10.1 ± 1.0, respectively; p > 0.05). Administration of IPSM led to a significant improvement in the neurological status (14.6 ± 1.5 and 8.9 ± 1.3; p < 0.05). Conclusions: Insulin therapy (IPSM infusion) is a safe and effective approach to normalize blood glucose levels after ischemic stroke. Administration of insulin to patients with hyperglycemia improves functional recovery and vital activity of stroke patients. However, other clinical benefits of the insulin therapy remain to be determined.

Computed tomography angiographic correlates of early computed tomography signs in acute ischemic stroke.

Early computed tomography (CT) signs of stroke signify major arterial occlusion. CT angiogram (CTA) is useful in detecting major arterial occlusion and may help triaging patients for intra-arterial thrombolysis. The correlation between the early signs of stroke and arterial occlusion on CTA was studied. Consecutive patients with suspected acute anterior circulation ischemic stroke presenting within 6 hours of symptom onset underwent noncontrast CT of the head followed by CTA. The scans were later reviewed for evidence of early signs of stroke on CT scan and intracranial arterial occlusion on CTA. Sixteen of 65 patients had arterial occlusion on CTA; 12 (75%) of these showed the early CT signs of stroke. All the early signs except M2 "dot" sign significantly correlated with middle cerebral artery (MCA) occlusion on CTA. Hyperdense MCA sign was the only independent predictor of a MCA occlusion. In a small sample, early CT signs of stroke strongly correlated with arterial occlusion, with hyperdense MCA sign being the most predictive of a MCA occlusion.

Computed Tomography Angiographic Correlates of Early Computed Tomography Signs in Acute Ischemic Stroke

ABSTRACT Background and Purpose. Early computed tomography (CT) signs of stroke signify major arterial occlusion. CT angiogram (CTA) is useful in detecting major arterial occlusion and may help triaging patients for intra‐arterial thrombolysis. The correlation between the early signs of stroke and arterial occlusion on CTA was studied.Methods. Consecutive patients with suspected acute anterior circulation ischemic stroke presenting within 6 hours of symptom onset underwent noncontrast CT of the head followed by CTA. The scans were later reviewed for evidence of early signs of stroke on CT scan and intracranial arterial occlu‐sion on CTA.Results. Sixteen of 65 patients had arterial occlu‐sion on CTA; 12 (75%) of these showed the early CT signs of stroke. All the early signs except M2 “dot” sign significantly cor related with middle cerebral artery (MCA) occlusion on CTA. Hyperdense MCA sign was the only independent predictor of a MCA occlusion.Conclusion. In a small sample, early CT signs of stroke strongly correlated with arterial occlusion, with hyperdense MCA sign being the most predictive of a MCA occlusion.

Candidates for thrombolytic treatment in acute ischaemic stroke--where are our patients in Hong Kong?

OBJECTIVE: Tissue plasminogen activator (t-PA) has been approved by the Food and Drug Administration in the treatment of patients with acute ischaemic stroke presenting within three hours from onset of...

Community Hospitals

Studies have suggested that patients with acute ischemic stroke who present to the hospital during off-hours (weekends and nights) may or may not have worse clinical outcomes compared to patients who present during regular hours.We searched Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Scopus through August 2013, and included any study that evaluated the association between time of patient presentation to a healthcare facility and mortality or modified Rankin Scale in acute ischemic stroke. Quality of studies was assessed with the Newcastle–Ottawa Scale. A random-effect meta-analysis model was applied. Heterogeneity was assessed using the Q statistic and I2. A priori subgroup analyses were used to explain observed heterogeneity.A total of 21 cohort studies (23 cohorts) with fair quality enrolling 1,421,914 patients were included. Off-hour presentation for patients with acute ischemic stroke was associated with significantly higher short-term mortality (OR, 1.11, 95% CI 1.06–1.17). Presenting at accredited stroke centers (OR 1.04, 95% CI 0.98–1.11) and countries in North America (OR 1.05, 95% CI 1.01–1.09) were associated with smaller increase in mortality during off-hours. The results were not significantly different between adjusted (OR, 1.11, 95% CI 1.05–1.16) and unadjusted (OR, 1.13, 95% CI 0.95–1.35) outcomes. The proportion of patients with modified Rankin Scale at discharge ≥ 2–3 was higher in patients presenting during off-hours (OR, 1.14, 95% CI 1.06–1.22).The evidence suggests that patients with acute ischemic stroke presenting during off-hours have higher short-term mortality and greater disability at discharge.