Background and Purpose— We evaluated the hypothesis that consultation with neurology would be associated with fewer protocol deviations in tissue plasminogen activator-treated patients with stroke.

Methods— A retrospective analysis of consecutive tissue plasminogen activator-treated patients with acute patients was performed. Using ² tests, the proportion of patients with a protocol deviation was calculated and compared between those with evidence of a neurology consultation and those without. Logistic regression was then used to determine the OR for protocol deviation at the same time as controlling for clinical presentation covariates.

Results— Two hundred seventy-three subjects were included. Protocol deviation rates did not significantly differ between those with (44%) and those without (41%) a consultation. The adjusted OR for deviation comparing any consultation versus nonconsultation was 1.25 (95% CI: 0.58 to 2.68). There was no statistically significant difference between symptomatic intracranial hemorrhage and in-hospital mortality rates between the groups. The proportion of patients with pretreatment deviations not related to timing was low in both the consultation (9.7%) and nonconsultation groups (8.1%).

Conclusions— Neurological consultation was not found to be associated with decreased protocol deviations in this cohort, although the high proportion of deviations with and without consultation suggests that quality improvement is needed. Most observed pretreatment deviations were attributable to timing. As acute stroke care becomes more efficient and additional methods in reducing door-to-treatment times are sought, models in which emergency physicians direct the initial phase of treatment may merit further consideration.

Purpose— The aim of this guideline is to present current and comprehensive recommendations for the diagnosis and treatment of acute spontaneous intracerebral hemorrhage.

Methods— A formal literature search of MEDLINE was performed. Data were synthesized with the use of evidence tables. Writing committee members met by teleconference to discuss data-derived recommendations. The American Heart Association Stroke Council’s Levels of Evidence grading algorithm was used to grade each recommendation. Prerelease review of the draft guideline was performed by 6 expert peer reviewers and by the members of the Stroke Council Scientific Statements Oversight Committee and Stroke Council Leadership Committee. It is intended that this guideline be fully updated in 3 years’ time.

Results— Evidence-based guidelines are presented for the care of patients presenting with intracerebral hemorrhage. The focus was subdivided into diagnosis, hemostasis, blood pressure management, inpatient and nursing management, preventing medical comorbidities, surgical treatment, outcome prediction, rehabilitation, prevention of recurrence, and future considerations.

Conclusions— Intracerebral hemorrhage is a serious medical condition for which outcome can be impacted by early, aggressive care. The guidelines offer a framework for goal-directed treatment of the patient with intracerebral hemorrhage.

Background and Purpose— Neurogenesis can arise from neural stem/progenitor cells of the subventricular zone after strokes involving both the cortex and striatum. However, it is controversial whether all types of stroke and strokes of different sizes activate neurogenesis from the subventricular zone niche. In contrast with cortical/striatal strokes, repair and remodeling after mild cortical strokes may involve to a greater extent local cortical stem/progenitor cells and cells from nonneurogenic niches.

Methods— We compared stem/progenitor cell responses after focal cortical strokes produced by distal middle cerebral artery occlusion and cortical/striatal strokes produced by the intraluminal suture model. To label migrating neuroblasts from the subventricular zone, we injected DiI to the lateral ventricle after distal middle cerebral artery occlusion. By immunohistochemistry, we characterized cells expressing stem/progenitor cell markers in the peri-infarct area. We isolated cortical stem/progenitor cells from the peri-infarct area after distal middle cerebral artery occlusion and assayed their self-renewal and differentiation capacity.

Results— In contrast with cortical/striatal strokes, focal cortical strokes did not induce neuroblast migration from the subventricular zone to the infarct zone after distal middle cerebral artery occlusion. By immunohistochemistry, we observed subpopulations of reactive astrocytes in the peri-infarct area that coexpressed radial glial cell markers such as Sox2, Nestin, and RC2. Clonal neural spheres isolated from the peri-infarct area after distal middle cerebral artery occlusion differentiated into neurons, astrocytes, oligodendrocytes, and smooth muscle cells. Notably, neural spheres isolated from the peri-infarct area also expressed RC2 before differentiation.

Conclusions— Mild cortical strokes that do not penetrate the striatum activate local cortical stem/progenitor cells but do not induce neuroblast migration from the subventricular zone niche.

Background and Purpose— Although peripheral artery disease (PAD) has a particularly poor prognosis compared with vascular disease in other territories, little attention is paid to its epidemiology, treatment, and prevention. Despite the high prevalence of PAD in patients with stroke, and of stroke in patients with PAD, PAD is omitted from all guidelines for treatment, prevention, and rehabilitation of stroke, although coronary artery disease risk is considered. Therefore, routine PAD screening is seldom undertaken and so disease is probably often missed.

Summary of Review— This review evaluates epidemiology of PAD in patients with stroke and of stroke in patients with PAD. The role of the ankle–brachial pressure index; imaging and novel markers in risk prediction of PAD in patients with stroke; and treatment and prevention of PAD are reviewed.

Conclusions— In both primary and secondary prevention settings, PAD indicates a high risk of future events. Data on which additional preventive measures are beneficial in this patient group are lacking, but the presence of PAD does have implications for current management in both primary and secondary prevention of stroke.

Background and Purpose— Physician prescribing patterns change slowly despite published randomized trials and consensus guidelines. We measure the effect of Management of Atherothrombosis With Clopidogrel in High-Risk Patients (MATCH) trial on discharge prescribing patterns for patients with stroke and those with transient ischemic attack in the Get With The Guidelines (GWTG)–Stroke Program.

Methods— We analyzed discharge prescribing patterns of antithrombotic medications for patients admitted with ischemic stroke or transient ischemic attack at hospitals participating in GWTG-Stroke between October 2002 to January 2006. Clinical information by quarter was analyzed in relation to publication of the MATCH study. Frequency of discharge prescription of aspirin+clopidogrel post-MATCH publication was compared with the pre-MATCH period after adjusting for patient and hospital characteristics and clustering by hospital.

Results— A total of 107 872 patients at 632 sites were eligible to receive antithrombotic therapy at discharge. Use of aspirin+clopidogrel therapy declined from 22.4% to 15.4% of patients after the publication of MATCH (adjusted OR 0.62, 95% CI 0.56 to 0.70, P<0.0001). Analysis by quarter revealed a rapid and sustained decrease in use of aspirin+clopidogrel therapy for the remainder of the study period.

Conclusions— A rapid and sustained reduction in the frequency of aspirin+clopidogrel use in ischemic stroke and transient ischemic attack was observed after publication of the MATCH trial in the absence of MATCH-specific GWTG-Stroke initiatives and preceding an American Heart Association guideline update.

Background and Purpose— Increased visit-to-visit variability in blood pressure (BP) is a powerful risk factor for stroke, but the mechanism is uncertain. We hypothesized that BP variability might affect the risk of new atrial fibrillation (AF).

Methods— We did a systematic review of large randomized controlled trials reporting new-onset AF by treatment allocation, excluding studies in heart failure and acute myocardial infarction. Estimates of the risk of new AF by treatment allocation were related to effects of treatment on group variability in BP.

Results— Of 94 eligible randomized controlled trials, 14 reported rates of new AF. Although there was considerable heterogeneity between trials in effects of treatment on variance ratio (P<0.0001), lower variance ratio was unrelated to new-onset AF either on meta-analysis (OR=1.02; 95% CI 0.90 to 1.15; 125 878 patients; 13 comparisons) or on metaregression (log OR versus log variance ratio of systolic blood pressure r²=0.109, P=0.270). Angiotensin receptor blockers tended to reduce new-onset AF (OR 0.85; 95% CI 0.71 to 1.01; P=0.067; 4 trials; 47 482 patients) with significant reductions in 2 individual trials but had no consistent reduction on variability in BP.

Conclusions— Effects of randomized treatment on variability in BP are unrelated to risk of new-onset AF, suggesting that other mechanisms account for the link between variability and stroke risk. However, a lower incidence of AF in patients randomized to angiotensin receptor blockers may explain reductions in stroke risk in some trials.

Background and Purpose— Niacin is the most effective medication in current clinical use for increasing high-density lipoprotein cholesterol. We tested the hypothesis that niacin treatment of stroke promotes synaptic plasticity and axon growth in the ischemic brain.

Methods— Male Wistar rats were subjected to 2 hours of middle cerebral artery occlusion and treated with or without Niaspan (a prolonged-release formulation of niacin, 40 mg/kg) daily for 14 days starting 24 hours after middle cerebral artery occlusion. The expression of synaptophysin, Nogo receptor, Bielschowsky silver, brain-derived neurotrophic factor, and its receptor tropomyosin-related kinase B were measured by immunohistostaining and Western blot, respectively, in the ischemic brain. Complementing in vivo studies, primary cultured neurons were used to test the effect of niacin and high-density lipoprotein on neurite outgrowth and brain-derived neurotrophic factor/tropomyosin-related kinase B expression.

Results— Niaspan treatment of stroke significantly increased synaptophysin, Bielschowsky silver, brain-derived neurotrophic factor/tropomyosin-related kinase B expression, and decreased Nogo receptor expression in the ischemic brain compared with middle cerebral artery occlusion control animals (P<0.05, n=8/group). Niacin and high-density lipoprotein treatment significantly increased neurite outgrowth and brain-derived neurotrophic factor/tropomyosin-related kinase B expression in primary cultured neurons. Tropomyosin-related kinase B inhibitor attenuated niacin-induced neurite outgrowth (P<0.05, n=6/group).

Conclusions— Niacin treatment of stroke promotes synaptic plasticity and axon growth, which is mediated, at least partially, by the brain-derived neurotrophic factor/tropomyosin-related kinase B pathways.

Background and Purpose— Carotid intima-media thickness (CIMT) is a noninvasive measure of atherosclerosis, but it is unclear whether it is a stronger risk factor for large vessel disease or small vessel disease.

Methods— One hundred seven volunteers, aged 75 to 81 years, underwent measurements of CIMT and vascular risk factors and brain MRI (structural and diffusion tensor); those with history of stroke were excluded.

Results— In 96 subjects without stroke, there were significant associations between CIMT and markers of large vessel disease (carotid stenosis: =0.28; P=0.01) and intermediary risk factors (systolic blood pressure: =0.34; P=0.001). However, there were no significant associations between CIMT and markers of small vessel disease (white matter lesion load and water diffusion parameters).

Conclusions— CIMT was not associated with neuroimaging biomarkers of small vessel disease in older volunteers without stroke. Any association between CIMT and white matter lesion in previous studies is likely to be mediated via common intermediary risk factors like hypertension.

Background and Purpose— Enhanced vascular permeability attributable to disruption of blood–brain barrier results in the development of cerebral edema after stroke. Using an in vitro model of the brain barrier composed of human brain microvascular endothelial cells and human astrocytes, this study explored whether small GTPase RhoA and its effector protein Rho kinase were involved in permeability changes mediated by oxygen-glucose deprivation (OGD), key pathological phenomena during ischemic stroke.

Methods and Results— OGD increased RhoA and Rho kinase protein expressions in human brain microvascular endothelial cells and human astrocytes while increasing or unaffecting that of endothelial nitric oxide synthase in respective cells. Reperfusion attenuated the expression and activity of RhoA and Rho kinase in both cell types compared to their counterparts exposed to equal periods of OGD alone while selectively increasing human brain microvascular endothelial cells endothelial nitric oxide synthase protein levels. OGD compromised the barrier integrity as confirmed by decreases in transendothelial electric resistance and concomitant increases in flux of permeability markers sodium fluorescein and Evan’s blue albumin across cocultures. Transfection of cells with constitutively active RhoA also increased flux and reduced transendothelial electric resistance, whereas inactivation of RhoA by anti-RhoA Ig electroporation exerted opposite effects. In vitro cerebral barrier dysfunction was accompanied by myosin light chain overphosphorylation and stress fiber formation. Reperfusion and treatments with a Rho kinase inhibitor Y-27632 significantly attenuated barrier breakdown without profoundly altering actin structure.

Conclusions— Increased RhoA/Rho kinase/myosin light chain pathway activity coupled with changes in actin cytoskeleton account for OGD-induced endothelial barrier breakdown.

Background and Purpose— HMGB1 is a nuclear protein and an alarmin that signals cell damage in response to injury. It is believed that after release from injured cells, HMGB1 binds to its receptors to stimulate cross-talk among cells and to drive components of the inflammatory cascade. This study was intended to investigate the role of extracellular HMGB1 in ischemic stroke by examining the response of the zymogen matrix metalloproteinase-9 (MMP-9) to HMGB1 in vivo and in vitro.

Methods— Toll-like receptor 2 (TLR2), TLR4, receptor for advanced glycation endproducts (RAGE), and MMP-9 expression was examined using quantitative RT-PCR in primary cultured neurons, astrocytes, and mouse brain after HMGB1 addition. MMP-9 expression/activity was examined using zymography. Middle cerebral artery occlusion was induced for 60 minutes using a filament model.

Results— TLR4 is constitutively expressed in neurons, astrocytes, and mouse brain. HMGB1 addition to neuronal and glial cell cultures caused MMP-9 upregulation in a dose- and time-dependent manner. Lack of TLR4 function attenuated MMP-9 expression induced by HMGB1 in vitro. After striatal microinjection of HMGB1, MMP-9 was upregulated, and the response was independent of tumor necrosis factor-. Interestingly, MMP-9 upregulation was reduced in TLR4 missense mutant mice after ischemia compared with wild-type controls, as was infarct volume.

Conclusion— Our results suggest that HMGB1 triggers MMP-9 upregulation in neurons and astrocytes predominantly via TLR4 after cerebral ischemia. Hence, targeting HMGB1/TLRs signaling pathway may reduce the acute inflammatory response and reduce tissue damage in cerebral ischemia.

Background and Purpose— Cerebral vasomotor reactivity (VMR) is a capability of cerebral vessels to dilate in response to hypercapnia. Transcranial direct current stimulation (tDCS) effects on cerebral hemodynamics have been poorly studied.

Methods and Results— Ten healthy subjects underwent anodal/cathodal tDCS on the left motor cortex. Before and after tDCS, VMR assessment by transcranial Doppler and an electrocardiogram were performed. Normalized low-frequency band power of heart rate variability and its reactivity from basal to VMR condition (LFN_react) were estimated as relative markers of sympathetic activation. tDCS exerted a polarity-specific effect on both VMR (P=0.0001) and LFN_react (P=0.001). Anodal tDCS decreased VMR by 3.4%/mm Hg CO₂ bilaterally and increased LFN_react, whereas cathodal tDCS increased VMR by 0.8%/mm Hg CO₂ bilaterally and reduced LFN_react.

Conclusions— Cerebral VMR is modified by tDCS. Based on the consensual changes with heart rate variability, we can hypothesize that the sympathetic nervous system could modulate the bihemispheric modification of VMR. Further studies are needed to confirm this hypothesis.

Background and Purpose— Erythropoietin (EPO), a hematopoietic cytokine, exerts neuroprotective effects in experimental stroke. In the present study, we investigated the effect of recombinant human EPO (rhEPO) in combination with tissue plasminogen activator (tPA) on embolic stroke.

Methods— Rats subjected to embolic middle cerebral artery occlusion (MCAO) were treated with rhEPO (5000 U/kg) in combination with tPA (10 mg/kg) at 2 or 6 hours after MCAO. Control groups consisted of ischemic rats treated with rhEPO (5000 U/kg) alone, tPA (10 mg/kg) alone, or saline at 2 or 6 hours after MCAO.

Results— The combination therapy of rhEPO and tPA initiated 6 hours after MCAO did not reduce the ischemic lesion volume and significantly (P<0.05) increased the incidence of brain hemorrhage measured by frequency of gross hemorrhage and a quantitative spectrophotometric hemoglobin assay compared with rats treated with rhEPO alone and tPA alone. However, when the combination therapy was initiated 2 hours after MCAO, the treatment significantly (P<0.05) reduced the lesion volume and did not substantially increase the incidence of hemorrhagic transformation compared with saline-treated rats. Immunostaining analysis revealed that the combination therapy of rhEPO and tPA at 6 hours significantly (P<0.05) increased matrix metalloproteinase-9, NF-B, and interleukin-1 receptor-associated kinase-1 immunoreactive cerebral vessels compared with rats treated with rhEPO alone and saline.

Conclusions— EPO exacerbates tPA-induced brain hemorrhage without reduction of ischemic brain damage when administered 6 hours after stroke in a rat model of embolic MCAO and that matrix metalloproteinase-9, NF-B, and interleukin-1 receptor-associated kinase-1 upregulated by the delayed combination therapy may contribute to augmentation of brain hemorrhage.

Background and Purpose— Mitochondria play a critical role in mediating cell death in both the adult and immature brain. The cyclophilin D mitochondrial membrane permeability transition pore is critical in adult ischemia, whereas in neonatal hypoxic–ischemic (HI) brain injury, mitochondrial permeabilization appears to be primarily Bax-dependent. The aim of this study was to evaluate the neuroprotective effect of a cell-penetrating Bax-inhibiting peptide (BIP) on neonatal mouse HI brain injury.

Methods— BIP (5 µL, 5 mg/mL) or a BIP-negative control (5 µL, 5 mg/mL) was injected intracerebroventricularly immediately before HI in postnatal day 9 mice. Mice were euthanized at different time points after HI for evaluation of brain injury, Bax activation, release of proapoptotic proteins, and caspase activation. The trace fear conditioning and cylinder tests were performed for evaluation of the functional recovery after BIP treatment.

Results— At 5 days after HI, there was a 41.2% reduction of brain injury in BIP-treated mice compared with BIP-negative control treated animals. Myelin basic protein and neurofilament quantification revealed that BIP reduced white matter injury. BIP treatment conferred improvement in both sensorimotor and memory functions at 7 weeks after HI. BIP protection was associated with a reduction of Bax activation, mitochondrial permeabilization, and downstream caspase activation.

Conclusions— Bax inhibition provides neuroprotection and functional improvement in a neonatal mouse model of HI.

Background and Purpose— Intravascular transplantation of neural stem cells represents a minimally invasive therapeutic approach for the treatment of central nervous system diseases. The cellular biodistribution after intravascular injection needs to be analyzed to determine the ideal delivery modality. We studied the biodistribution and efficiency of targeted central nervous system delivery comparing intravenous and intra-arterial (IA) administration of neural stem cells after brain ischemia.

Methods— Mouse neural stem cells were transduced with a firefly luciferase reporter gene for bioluminescence imaging (BLI). Hypoxic–ischemia was induced in adult mice and reporter neural stem cells were transplanted IA or intravenous at 24 hours after brain ischemia. In vivo BLI was used to track transplanted cells up to 2 weeks after transplantation and ex vivo BLI was used to determine single organ biodistribution.

Results— Immediately after transplantation, BLI signal from the brain was 12 times higher in IA versus intravenous injected animals (P<0.0001). After IA injection, 69% of the total luciferase activity arose from the brain early after transplantation and 93% at 1 week. After intravenous injection, 94% of the BLI signal was detected in the lungs (P=0.004) followed by an overall 94% signal loss at 1 week, indicating lack of cell survival outside the brain. Ex vivo single organ analysis showed a significantly higher BLI signal in the brain than in the lungs, liver, and kidneys at 1 week (P<0.0001) and 2 weeks in IA (P=0.007).

Conclusion— IA transplantation results in superior delivery and sustained presence of neural stem cells in the ischemic brain in comparison to intravenous infusion.

Background and Purpose— Reflux esophagitis (RE) is the most common manifestation of gastro-esophageal reflux disease with esophageal injury. To the best of our knowledge, there has been no specific study to evaluate the risk of stroke after diagnosis of RE in young adults. This study aims to evaluate the risk of stroke among RE patients aged 18 to 50 years during a 1-year period after diagnosis of RE compared to a cohort of non-RE patients during the same period.

Methods— This study used the Taiwan Longitudinal Health Insurance Database 2005. A total of 2340 RE patients were included as the study cohort and 11 700 non-RE patients were included as the comparison cohort. Each patient was individually tracked for 1 year from the index ambulatory visit to identify those in whom stroke developed.

Results— Out of the sample of 14 040 patients, 78 patients (0.56%) had strokes develop during the 1-year follow-up period: 22 from the study cohort (0.94% of the RE patients) and 56 from the comparison cohort (0.48% of patients without RE). Patients with RE were 1.68-times more likely to have strokes develop (95% confidence interval, 1.03–2.76) than patients in the comparison cohort during the follow-up period after adjusting for patients’ medical comorbidities, such as hypertension, diabetes, coronary heart disease, renal disease, heart failure, and hyperlipidemia, as well as their demographic differences, such as the level of urbanization of their communities, monthly income, and geographical location.

Conclusions— We conclude that RE is associated with an increased risk of subsequent stroke in young adults.

Background and Purpose— Clinical trials are assessing the efficacy of fibrinolysis in extended time windows for acute ischemic stroke.

Methods— An Internet-based survey was sent to 400 US vascular neurologists affiliated with a university to assess whether there are consensus opinions on how they treat patients beyond 3 hours from symptom onset and which patients they are willing to enroll into clinical trials of fibrinolysis for acute ischemic stroke.

Results— We received 161 responses; 81% were male. Ninety-three percent of respondents treat patients with intravenous tissue plasminogen activator beyond 3 hours. More than 80% were treated beyond 3 hours with intra-arterial therapy (IAT). When asked if IAT improves stroke outcome, >50% selected the choice of "yes for middle cerebral artery and basilar occlusions" and only 2% selected the choice that "IAT does not improve outcome." Over half believe that imaging could be used to approximate the penumbra but with improvements to better identify salvageable tissue. Eighty-seven percent were willing to enroll patients into a placebo-controlled intravenous thrombolysis beyond 3 hours. For IAT trials, >80% would randomize beyond 3 hours with or without prior intravenous treatment.

Conclusions— Vascular neurologists have been treating acute ischemic stroke beyond 3 hours with intravenous tissue plasminogen activator even before the American Heart Association guidelines supported extending the therapeutic window. There is a paradox among the respondents willing to enroll patients into trials involving IAT given that a majority is offering IAT as part of their practice. These results suggest that clinical practice may impair enrollment into trials testing reperfusion therapies for acute ischemic stroke.

Background and Purpose— We compared the test–retest reliability, validity, and responsiveness of the Dynamic Gait Index, the 4-item Dynamic Gait Index, and the Functional Gait Assessment for assessment of walking in patients with stroke.

Methods— Forty-five outpatients participating in the validity and responsiveness study were tested using the 3 walking measures as well as the 10-m walk test, Barthel Index, and Postural Assessment Scale for Stroke Patients. We tested them during the first week, then again after 2 months and 5 months of therapy. Another 48 chronic patients completed the 3 measures twice, 1 week apart, in the test–retest reliability study.

Results— Thirty-five participants completed 3 time-point assessments. The Functional Gait Assessment showed the least floor and ceiling effects, indicating it has the best discriminative ability for patients with stroke with high walking function. We found the 3 measures were highly correlated with each other, indicating excellent concurrent validity, and all measures at the first week of therapy were moderately to highly correlated with the Barthel Index scores at 5 months, indicating good predictive validity. Responsiveness of the 3 measures was moderate during a 5-month period, and all showed good test–retest reliability. The minimal detectable changes between tests indicate acceptable random error.

Conclusions— All 3 measures showed sufficient validity, responsiveness, and reliability for assessment of walking function in patients with stroke undergoing rehabilitation, but the Functional Gait Assessment is recommended for its psychometric properties.