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1.  Seizures Following Ischemic Stroke: Frequency of Occurrence and Impact on Outcome in a Long-Term Population-Based Study 
Background & Purpose
Seizures are a known complication of ischemic stroke. This study assesses the long-term incidence and characteristics of post-stroke seizures in a well-defined population.
Methods
Utilizing the Rochester Epidemiology Project medical record linkage system, we identified all incident cases of ischemic stroke (IS) among Rochester, MN residents from 1990-1994, and followed the patients in the comprehensive medical record through March 2014. All patients with post-stroke seizures were identified, and data regarding incident IS, seizures, and status at last follow-up were analyzed.
Results
We identified 489 patients with first IS. Mean follow-up was 6.5 (SD 6.3) years. New onset seizures occurred in 35 patients (7.2%). Patients with post-stroke seizure did not differ from those without in terms of IS etiologic subtype (p=0.44) or IS risk factors (p>0.05). Early seizures (within 14 days of index stroke) developed in 14 patients (40%), the majority within the first 24 hours (n=9; 64.3%). The median time of seizure onset for the remaining 21 patients was 13.8 months. Functional outcome, as measured by modified Rankin scale, was worse following development of post-stroke seizures (mean mRS 2.9 after IS, 3.3 following index seizure; p=0.005), and mortality was higher as well, even after adjusting for IS etiologic subtype (HR 1.52; 95% CI 1.07-2.16; p=0.02).
Conclusion
Development of post-stroke seizures is an infrequent, but significant complication of ischemic stroke, portending a worse short-term functional outcome and a higher long-term mortality rate. Seizure occurrence did not differ based on IS etiologic subtype or stroke risk factors.
doi:10.1016/j.jstrokecerebrovasdis.2015.09.008
PMCID: PMC4957641  PMID: 26454641
stroke; seizure; TOAST; epidemiology
2.  Ambulatory Status Protects Against Venous Thromboembolism in Acute Mild Ischemic Stroke Patients 
Introduction
Ischemic stroke patients are at high risk (up to 18%) for venous thromboembolism. We conducted a retrospective cross-sectional study to understand the predictors of acute post-mild ischemic stroke patient’s ambulatory status and its relationship with venous thromboembolism, hospital length of stay, and in-hospital mortality.
Methods
We identified 522 patients between February 2006 and May 2014 and collected data about patient demographics, admission NIHSS, venous thromboembolism prophylaxis, ambulatory status, diagnosis of venous thromboembolism, and hospital outcomes (length of stay, mortality). Chi-square tests, t-test and Wilcoxon Ranks Sum tests, and binary logistic regression were used for statistical analysis as appropriate.
Results
A total of 61 (11.7%), 48 (9.2%), and 23 (4.4%) mild ischemic stroke patients developed venous thromboembolism, deep venous thrombosis, and pulmonary embolism, respectively. During hospitalization, 281 (53.8%) patients were ambulatory. Independent predictors of in-hospital ambulation were being married (OR 1.64, 95% CI 1.10–2.49), being non-religious (OR 2.19, 95% CI 1.34–3.62), admission NIHSS (per unit decrease in NIHSS; OR 1.62, 95% CI 1.39–1.91), and non-usage of mechanical venous thromboembolism prophylaxis (OR 1.62, 95% CI 1.02–2.61). After adjusting for confounders, ambulatory patients had lower rates of venous thromboembolism (OR 0.47, 95% CI 0.25–0.89), deep venous thrombosis (OR 0.36, 95% CI 0.17–0.73), prolonged length of hospital stay (OR 0.24, 95% CI 0.16–0.37), and mortality (OR 0.43, 95% CI 0.21–0.84).
Conclusions
Our findings suggest that for hospitalized acute mild ischemic stroke patients, ambulatory status is an independent predictor of venous thromboembolism (specifically deep venous thrombosis), hospital length of stay, and in-hospital mortality.
doi:10.1016/j.jstrokecerebrovasdis.2016.06.025
PMCID: PMC5201103  PMID: 27423367
Ischemic stroke; ambulation; ambulatory status; venous thromboembolism; deep vein thrombosis; pulmonary embolism; protection; odds ratio
3.  Racial Differences in Cognitive Function and Risk of Incident Stroke 
Background and Purpose
Cognitive impairment is associated with increased risk of stroke; however, it is not known whether this association varies by race. Our objective was to examine the association of cognitive function with the risk of stroke among non-Hispanic blacks and whites with no history of stroke.
Methods
Participants were from a population-based cohort study of 7,205 older adults (61% black and 59% female) from Chicago’s South Side. A standardized composite cognitive function score based on three components–global cognition (Mini-Mental State Examination), executive function (Symbol Digits Modalities test), and episodic memory (Delayed and Immediate Story Recall tests) – was used to predict risk of stroke (from Medicare hospitalization data) using a Cox model.
Results
During 72,868 person years of follow-up, 16% (N=1,185) developed stroke. After adjusting for vascular risk factors, one standard deviation lower composite cognitive function score was associated with increased risk of stroke in blacks (HR=1.76, 95% CI, 1.66 – 1.88), which was two-fold higher than whites (HR=1.38, 95% CI, 1.26 – 1.55) (Pdifference=0.002). Lower global cognition and executive function were associated with a similarly increased risk of stroke in blacks and whites. Lower episodic memory (composite of recall tests) was associated with increased risk of stroke that was two-fold higher in blacks (HR=1.12, 95% CI, 1.10 – 1.14) than whites (HR=1.06, 95% CI, 1.04 – 1.09).
Conclusions
Lower cognitive function was associated with increased risk of stroke and this association was stronger among blacks than whites. Future studies are needed to determine factors that can explain this finding.
doi:10.1016/j.jstrokecerebrovasdis.2015.08.020
PMCID: PMC4688055  PMID: 26387044
Cognitive Function; Stroke; Epidemiology; Minority Health
4.  Net clinical benefits of guidelines and decision tool recommendations for oral anticoagulant use among patients with atrial fibrillation 
BACKGROUND
The 2012 CHEST, the 2012 European Society of Cardiology (ESC) and the 2014 American Heart Association guidelines and published decision tools by LaHaye and Casciano offer oral anticoagulant (OAC) recommendations for patients with atrial fibrillation (AF). The aim of our study was to compare the net clinical benefit (NCB) of OAC prescribing that was concordant with these decision aids.
METHODS
A cohort study of the 2001–2013 Lifelink claims data was used. NCB of concordance with each decision aid was defined as adverse events (thromboembolic and major bleed events) prevented per 10,000 person-years. Cox proportional hazard models were used to assess the relative risk of AF adverse events associated with concordance with each decision aid adjusted for potential confounders.
FINDINGS
The study included 15,129 AF patients, contributing 33,512 person-years. The NCB of the CHEST guidelines was the highest (NCB=30.07; 95%CI=28.66, 31.49) and the ESC guidelines the lowest (NCB=7.38; 95%CI=5.97, 8.80). Significant unadjusted decreases in the risk of AF adverse events associated with concordant OAC use/non-use were found for the CHEST guidelines (HR=0.825; 95%CI=0.695, 0.979), Casciano tool (HR=0.838; 95%CI=0.706, 0.995), and LaHaye tool (HR=0.841; 95%CI=0.709, 0.999), however none were significant after multivariate adjustment.
CONCLUSION
Concordant OAC use with any of the decision aids except the aggressive LaHaye tool led to a positive NCB. The decision aids based on CHA2DS2VASc algorithm did not consistently improve the NCB compared to CHADS2 based aids. Recommending OAC use when CHA2DS2−VASc=1 resulted in a lower NCB when all other factors guiding recommendations were held constant.
doi:10.1016/j.jstrokecerebrovasdis.2015.08.019
PMCID: PMC4688121  PMID: 26482369
Atrial fibrillation; guideline; decision tool; concordance; Net clinical benefit
5.  Resource Utilization for Patients with Intracerebral Hemorrhage Transferred to a Comprehensive Stroke Center 
Background
As a comprehensive stroke center (CSC), we accept transfer patients with intracerebral hemorrhage (ICH) in our region. CSC guidelines mandate receipt of patients with ICH for higher level of care. We determined resource utilization of patients accepted from outside hospitals compared with patients directly arriving to our center.
Methods
From our stroke registry, we compared patients with primary ICH transferred to those directly arriving to our CSC from March 2011–March 2012. We compared the proportion of patients who utilized at least one of these resources: neurointensive care unit (NICU), neurosurgical intervention, or clinical trial enrollment.
Results
Among the 362 patients, 210 (58%) were transfers. Transferred patients were older, had higher median Glasgow Coma Scale scores, and lower National Institutes of Health Stroke Scale scores than directly admitted patients. Transfers had smaller median ICH volumes (20.5 cc versus 15.2 cc; P = .04) and lower ICH scores (2.1 ± 1.4 versus 1.6 ± 1.3; P < .01). A smaller proportion of transfers utilized CSC-specific resources compared with direct admits (P = .02). Fewer transferred patients required neurosurgical intervention or were enrolled in trials. No significant difference was found in the proportion of patients who used NICU resources, although transferred patients had a significantly lower length of stay in the NICU. Average hospital stay costs were less for transferred patients than for direct admits.
Conclusions
Patients with ICH transferred to our CSC underwent fewer neurosurgical procedures and had a shorter stay in the NICU. These results were reflected in the lower per-patient costs in the transferred group. Our results raise the need to analyze cost–benefits and resource utilization of transferring patients with milder ICH.
doi:10.1016/j.jstrokecerebrovasdis.2015.08.023
PMCID: PMC4688147  PMID: 26460244
Stroke systems; comprehensive stroke center; hemorrhagic stroke; intracerebral hemorrhage
6.  Endothelial Function, Inflammation, Thrombosis, and Basal Ganglia Perivascular Spaces in Patients with Stroke 
Background and Objective
Recent studies suggest perivascular spaces are a marker of small vessel disease, blood–brain barrier permeability, and inflammation, but little is known about their risk factors and associations with peripheral blood markers.
Materials and Methods
In prospectively recruited patients with recent minor ischemic stroke, we investigated the influence of age, sex, hypertension, diabetes, and smoking on the severity of perivascular spaces in the basal ganglia seen on T2-weighted magnetic resonance imaging. We assessed plasma markers of endothelial function (von Willebrand factor, intracellular adhesion molecule-1), inflammation (interleukin-6, tumor necrosis factor-alpha, C-reactive protein), and thrombosis (fibrinogen, prothrombin fragments 1 + 2, thrombin–antithrombin complex, tissue plasminogen activator, D-dimer). We used a validated semi-automated method to measure basal ganglia perivascular spaces count and volume. We tested uni- and multivariable associations between blood markers and basal ganglia perivascular spaces count and volume.
Findings
In 100 patients (median age: 67 years, range: 37-92), on adjusted analysis, basal ganglia perivascular spaces count was associated with age (r = .117, P = .003) and hypertension (r = 2.225, P = .013). On multivariable linear regression, adjusted for age, sex, hypertension, smoking and diabetes, reduced von Willebrand factor was associated with increased basal ganglia perivascular spaces count (r = −.025, P = .032).
Conclusion
The association of increased basal ganglia perivascular spaces count with reduced von Willebrand factor is novel. As von Willebrand factor may promote cerebral endothelial integrity, insufficient von Willebrand factor is consistent with dysfunctional cerebral endothelium and increased basal ganglia perivascular spaces in cerebral small vessel disease. Quantitative perivascular spaces measurement may increase sensitivity to detect cerebral endothelial dysfunction.
doi:10.1016/j.jstrokecerebrovasdis.2016.08.007
PMCID: PMC5176093  PMID: 27576214
Endothelial function; stroke; small vessel disease; perivascular spaces
7.  Accuracy of First Recorded “Last Known Normal” Times of Stroke Code Patients 
Introduction
Given the time-sensitivity of thrombolytic therapy, the accurate documentation of last known normal (LKN) time is crucial to ensure optimal management of stroke patients. This study investigates whether a difference exists between preliminary LKN times (first responders and ED practitioners) and revised LKN times (neurology/stroke practitioners), and what potential impact on emergent management of acute stroke this discrepancy may pose.
Methods
All stroke code patients from UCSD hospitals from 10/2008 to 7/2013 with treatment time data were included and grouped based on the disparity between preliminary LKN time and revised LKN time: preliminary earlier than revised, two times equal, and preliminary later than revised. We compared baseline characteristics, stroke code intervals, rates of rt-PA administration, 90 day mRS score, discharge disposition, and symptomatic intracranial hemorrhage.
Results
73.6% of 261 patients had disparity between preliminary and revised times. 57.5% had later preliminary LKN than revised; 16.1% had earlier preliminary LKN than revised. Baseline characteristics, stroke code speed, 90 day mRS score, rates of rt-PA administration, discharge disposition, or rates of sICH were not significantly different between the groups. Among rt-PA treated stroke patients whose preliminary time was earlier than the revised time, had the preliminary LKN been used, 29.4% would have had rt-PA withheld inappropriately. In those stroke patients excluded from rt-PA treatment for being outside the treatment window, whose preliminary time was later than the revised time, had the preliminary time been used, 69.7% would have been inappropriately treated outside the relevant rt-PA window.
Conclusions
Most patients had disparity between preliminary and revised LKN times. Had the preliminary LKN time been used for acute stroke decision making, 58% of patients would have potentially been treated outside the approved thrombolytic time window, with higher risk of adverse events and 16% may have been inappropriately excluded from thrombolysis. This study highlights the need for training in the determination and refinement of the actual time of stroke onset, especially at hospitals without stroke expertise.
doi:10.1016/j.jstrokecerebrovasdis.2015.04.041
PMCID: PMC4630074  PMID: 26341734
8.  Feasibility and Safety of Using External Counterpulsation (ECP) to Augment Cerebral Blood Flow in Acute Ischemic Stroke – the CUFFS Trial 
Background
External counterpulsation (ECP) increases perfusion to a variety of organs, and may be helpful for acute stroke.
Methods
This was a single-blinded, prospective, randomized controlled feasibility and safety trial of ECP for acute middle cerebral artery (MCA) ischemic stroke, in which 23 patients presenting within 48 hours of symptom onset were randomized into one hour of either 1) ECP at a pressure up to 300mmHg (“full-pressure”), while determining the highest tolerable pressure that would augment MCA mean flow velocity (MFV) by 15%, or 2) ECP at 75mmHg (“sham-pressure”). Transcranial Doppler MCA flow velocities and NIH Stroke Scale (NIHSS) scores were checked before, during, and after ECP, and outcomes were assessed at 30 days after randomization.
Results
While procedures were feasible to implement, there was a frequent inability to augment MFV by 15% despite maximal pressures in full-pressure patients, whereas in sham-pressure patients, MFV frequently increased due to increases in PSV and EDV. In both groups, starting ECP was often associated with contemporaneous improvements in NIHSS stroke scores. There were no between group differences in NIHSS, modified Rankin Scores and Barthel Indices, and no device or treatment-related serious adverse events, deaths, intracerebral hemorrhages, or episodes of acute neuro-worsening.
Conclusions
ECP was safe and feasible to apply in acute ischemic stroke. It was associated with unanticipated effects on flow velocity, and contemporaneous improvements in NIHSS score regardless of pressure used, with a possibility that even very low ECP pressures were physiologically active. Further study is warranted.
doi:10.1016/j.jstrokecerebrovasdis.2015.07.013
PMCID: PMC4630102  PMID: 26347398
external counterpulsation; ischemic stroke; transcranial Doppler; cerebral blood flow velocity
9.  Factors Associated with Nursing Home Admission after Stroke in Older Women 
Objective
We examined the social and economic factors associated with nursing home (NH) admission in older women, overall and post-stroke.
Methods
The Women’s Health Initiative (WHI) included women aged 50–79 years at enrollment (1993–1998). In the WHI Extension Study (2005–2010), participants annually reported any NH admission in the preceding year. Separate multivariate logistic regression models analyzed social and economic factors associated with long-term NH admission, defined as an admission on two or more questionnaires, overall and post-stroke.
Results
Of 103,237 participants, 8,904 (8.6%) reported NH admission (2005–2010); 534 of 2,225 (24.0%) women with incident stroke reported post-stroke NH admission. Decreased likelihoods of NH admission overall were demonstrated for Asian, Black and Hispanic women (versus whites, aORs=0.35–0.44, p<.001) and women with higher income (aOR= 0.75, 95%CI=0.63–0.90); while increased likelihoods of NH admission overall were seen for women with lower social support (aOR=1.34, 95%CI=1.16–1.54) and with incident stroke (aOR=2.59, 95%CI=2.15–3.12). Increased odds of NH admission after stroke were demonstrated for women with moderate disability after stroke (aOR=2.76, 95%CI=1.73–4.42). Further adjustment for stroke severity eliminated the association found for race/ethnicity, income and social support.
Conclusion
The level of care needed after a disabling stroke may overwhelm social and economic structures in place that might otherwise enable avoidance of nursing home admission. We need to identify ways to provide care consistent with patients’ preferences, even after a disabling stroke.
doi:10.1016/j.jstrokecerebrovasdis.2015.06.013
PMCID: PMC4592792  PMID: 26169547
disability; institutionalization; race; ethnicity; social support; long-term care
10.  The Role of Circulating Platelets Microparticles and Platelet Parameters in Acute Ischemic Stroke Patients 
Background
Platelet activation and aggregation are critical in the pathogenesis of acute ischemic stroke (AIS). Circulating platelet microparticles (PMPs) and platelet parameters are biological markers of platelet function in AIS patients, however, their associations with stroke subtypes and infarct volume remain unknown.
Methods
We recruited 112 AIS patients including large artery atherosclerosis (LAA) and small artery occlusion (SAO) subtypes, and 35 controls in this study. Blood samples were collected at admission and after antiplatelet therapy. The levels of circulating PMPs and platelet parameters [mean platelet volume (MPV), platelet count (PC), plateletocrit (PCT) and platelet distribution width (PDW)] were determined by flow cytometry and hematology analysis, respectively. Infarct volume was examined at admission by magnetic resonance imaging.
Results
(1) The levels of circulating PMPs and MPV were significantly elevated in AIS patients when compared with healthy controls; (2) The level of circulating PMPs, but not platelet parameters, was decreased after antiplatelet therapy in AIS patients; (3) The infarct volume in LAA subtype was larger than that in SAO subtype. Notably, circulating PMP level was positively correlated with the infarct volume in LAA subtype. No association with infarct volume in either AIS subtype was observed for platelet parameters; (4) According to the regression analysis, circulating PMPs was an independent risk factor for the infarct volume in pooled AIS patients after adjustments of other impact factors (hypertension and diabetes).
Conclusions
Our results suggest that circulating PMP level is associated with cerebral injury of AIS, which offers a novel evaluation parameter for AIS patients.
doi:10.1016/j.jstrokecerebrovasdis.2015.06.018
PMCID: PMC4592794  PMID: 26169549
Acute ischemic stroke; circulating platelet microparticles; infarct volume; platelet parameters
11.  Persistent Leukocytosis—Is this a Persistent Problem for Patients with Acute Ischemic Stroke? 
Background
In the setting of acute ischemic stroke (AIS), leukocytosis has been shown to be an indicator of inflammatory response. Although leukocytosis on admission has been shown to correlate with initial stroke severity in AIS patients, no work has been done to assess if there are differences in transient or persistent leukocytosis in patients without infection. The objective of this study is to determine the clinical significance of persistent versus transient leukocytosis during the early phase of AIS.
Methods
Patients who presented with AIS to our center within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified by chart review. Patients were included if they had leukocytosis on admission (defined as white blood cell count >11,000/μL based on laboratory reference range values). A logistic regression model was used to evaluate persistent leukocytosis (leukocytosis 48 hours after admission) as a predictor of several outcome measures, including good functional outcome (discharge modified Rankin Scale score of 0-2). Marginal effects were used to estimate the probability of poor functional outcome.
Results
Of the 438 patients screened, 49 had leukocytosis on admission and of those 24 (49%) had persistent leukocytosis. NIHSS score correlated significantly with persistence of leukocytosis (r = .306; P =.0044). More people with transient leukocytosis (leukocytosis lasting <48 hours) had a good functional outcome (44% versus 16%; P = .006). After adjusting for baseline NIHSS score, persistent leukocytosis was not a significant independent predictor of good functional outcome, but showed an association (OR, 2.5; 95% CI, .562-10.7; P = .2322). Persistent leukocytosis after adjusting for age and NIHSS score at admission is associated with a poor functional outcome, but it is not statistically significant (OR, 2.43; 95% CI, .59-9.87; P = .2151). After controlling for age and NIHSS score on admission, for patients with persistent leukocytosis, the probability of having poor functional outcome at discharge was increased by 16 percentage points.
Conclusions
Persistent leukocytosis is associated with higher baseline NIHSS scores. Persistent leukocytosis is tightly linked with baseline stroke severity and is associated with poor patient outcomes. Our study found that patients with persistent leukocytosis are more likely to present with severe strokes and maintain a high NIHSS score at 24 hours after admission, unlike patients without leukocytosis or patients with transient leukocytosis. Furthermore, it appears that persistent leukocytosis outside the setting of an infection negatively impacts the short-term functional outcome of AIS patients. Identifying patients with persistent leukocytosis could help to prognosticate and target patients that may benefit from future anti-inflammatory interventions.
doi:10.1016/j.jstrokecerebrovasdis.2014.02.004
PMCID: PMC5032654  PMID: 24784010
Leukocyte; ischemic stroke; stroke care; inflammation
12.  Leukocytosis in Patients with Neurologic Deterioration after Acute Ischemic Stroke is Associated with Poor Outcomes 
Background
Neurologic deterioration (ND) after acute ischemic stroke (AIS) has been shown to result in poor outcomes. ND is thought to arise from penumbral excitotoxic cell death caused in part by leukocytic infiltration. Elevated admission peripheral leukocyte levels are associated with poor outcomes in stroke patients who suffer ND, but little is known about the dynamic changes that occur in leukocyte counts around the time of ND. We sought to determine if peripheral leukocyte levels in the days surrounding ND are correlated with poor outcomes.
Methods
Patients with AIS who presented to our center within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified by chart review and screened for ND (defined as an increase in National Institutes of Health Stroke Scale score ≥2 within a 24-hour period). Patients were excluded for steroid use during hospitalization or in the month before admission and infection within the 48 hours before or after ND. Demographics, daily leukocyte counts, and poor functional outcome (modified Rankin Scale score 3–6) were investigated.
Results
Ninety-six of the 292 (33%) patients screened had ND. The mean age was 69.5 years; 62.5% were male and 65.6% were black. Patients with a poor functional outcome had significantly higher leukocyte and neutrophil levels 1 day before ND (P =.048 and P =.026, respectively), and on the day of ND (P =.013 and P =.007, respectively), compared to patients with good functional outcome.
Conclusions
Leukocytosis at the time of ND correlates with poor functional outcomes and may represent a marker of greater cerebral damage through increased parenchymal inflammation.
doi:10.1016/j.jstrokecerebrovasdis.2012.08.008
PMCID: PMC5022768  PMID: 23031742
Deterioration; leukocytosis; National Institutes of Health Stroke Scale; outcome; prognosis; stroke
13.  A Model for Predicting Persistent Elevation of Factor VIII among Patients with Acute Ischemic Stroke 
Background and Purpose
Elevated levels of coagulation factor VIII (FVIII) may persist independent of the acute-phase response; however, this relationship has not been investigated relative to acute ischemic stroke (AIS). We examined the frequency and predictors of persistently elevated FVIII in AIS patients.
Methods
AIS patients admitted between July 2008 and May 2014 with elevated baseline FVIII levels and repeat FVIII levels drawn for more than 7 days postdischarge were included. The patients were dichotomized by repeat FVIII level for univariate analysis at 150% and 200% activity thresholds. An adjusted model was developed to predict the likelihood of persistently elevated FVIII levels.
Results
Among 1616 AIS cases, 98 patients with elevated baseline FVIII had repeat FVIII levels. Persistent FVIII elevation was found in more than 75% of patients. At the 150% threshold, the prediction score ranged from 0 to 7 and included black race, female sex, prior stroke, hyperlipidemia, smoking, baseline FVIII > 200%, and baseline von Willebrand factor (vWF) level greater than 200%. At the 200% threshold, the prediction score ranged from 0–5 and included female sex, prior stroke, diabetes mellitus, baseline FVIII level greater 200%, and baseline vWF level greater than 200%. For each 1-point increase in score, the odds of persistent FVIII at both the 150% threshold (odds ratio [OR] = 10.4, 95% confidence interval [CI] 1.63–66.9, P = .0134) and 200% threshold (OR = 10.2, 95% CI 1.82–57.5, P = .0083) increased 10 times.
Conclusion
Because an elevated FVIII level confers increased stroke risk, our model for anticipating a persistently elevated FVIII level may identify patients at high risk for recurrent stroke. FVIII may be a target for secondary stroke prevention.
doi:10.1016/j.jstrokecerebrovasdis.2015.10.015
PMCID: PMC5022778  PMID: 26777556
Ischemic stroke; blood coagulation; biomarker; thrombosis; factor VIII
14.  24/7 Neurocritical Care Nurse Practitioner Coverage Reduced Door-to-Needle Time in Stroke Patients Treated with Tissue Plasminogen Activator 
Background
Stroke centers with limited on-site neurovascular physician coverage may experience delays in acute stroke treatment. We sought to assess the impact of providing 24/7 neurocritical care acute care nurse practitioner (ACNP) “stroke code” first responder coverage on treatment delays in acute stroke patients who received tissue plasminogen activator (tPA).
Methods
Consecutive acute ischemic stroke patients treated with intravenous tPA at a primary stroke center on Oahu between 2009 and 2014 were retrospectively studied. 24/7 ACNP stroke code coverage (intervention) was introduced on July 1, 2011. The tPA utilization, door-to-needle (DTN) time, imaging-to-needle (ITN) time, and independent ambulation at hospital discharge were compared between the preintervention period (24 months) and the postintervention period (33 months).
Results
We studied 166 stroke code patients who were treated with intravenous tPA, 44 of whom were treated during the preintervention period and 122 of whom were treated during the postintervention period. After the intervention, the median DTN time was reduced from 53 minutes (interquartile range [IQR] 45–73) to 45 minutes (IQR 35–58) (P = .001), and the median ITN time was reduced from 36 minutes (IQR 28–64) to 21 minutes (IQR 16–31) (P < .0001). Compliance with the 60-minute target DTN improved from 61.4% (27 of 44 patients) in the preintervention period to 81.2% (99 of 122 patients) in the postintervention period (P = .004). The tPA treatment rates were similar between the preintervention and postintervention periods (P = .60).
Conclusions
Addition of 24/7 on-site neurocritical care ACNP first responder coverage for acute stroke code significantly reduced the DTN time among acute stroke patients treated with tPA.
doi:10.1016/j.jstrokecerebrovasdis.2016.01.033
PMCID: PMC5014379  PMID: 26907680
Stroke; nurse practitioner; thrombolysis; staffing; models; outcomes
15.  Effect of β-adrenergic antagonists on in-hospital mortality after ischemic stroke 
Background
Ischemic stroke accounts for 85–90% of all strokes and currently has very limited therapeutic options. Recent studies of β-adrenergic antagonists suggest they may have neuroprotective effects that lead to improved functional outcomes in rodent models of ischemic stroke, however there is limited data in patients. We aimed to determine whether there was an improvement in mortality rates among patients who were taking β-blockers during the acute phase of their ischemic stroke.
Methods
A retrospective analysis of a prospectively collected database of ischemic stroke patients was performed. Patients who were on β-adrenergic antagonists both at home and during the first three days of hospitalization were compared to patients who were not on β-adrenergic antagonists to determine the association with patient mortality rates.
Results
The study included a patient population of 2804 patients. In univariate analysis, use of β-adrenergic antagonists was associated with older age, atrial fibrillation, hypertension and more severe initial stroke presentation. Despite this, multivariable analysis revealed a reduction in in-hospital mortality among patients who were treated with β-adrenergic antagonists (odds ratio 0.657; 95% confidence interval 0.655–0.658).
Conclusions
The continuation of home β-adrenergic antagonist medication during the first three days of hospitalization after an ischemic stroke is associated with a decrease in patient mortality. This supports the work done in rodent models suggesting neuroprotective effects of β-blockers after ischemic stroke.
doi:10.1016/j.jstrokecerebrovasdis.2015.04.035
PMCID: PMC4564292  PMID: 26163891
16.  Neurochecks as a Biomarker of the Temporal Profile and Clinical Impact of Neurologic Changes after Intracerebral Hemorrhage 
Goals
We sought to determine whether a quantitative neurocheck biomarker could characterize the temporal pattern of early neurologic changes after intracerebral hemorrhage (ICH), and the impact of those changes on long-term functional outcomes.
Methods
We enrolled cases of spontaneous ICH in a prospective observational study. Patients underwent a baseline Glasgow Coma Scale (GCS) assessment, then hourly neurochecks utilizing the GCS in a neuroscience intensive care unit. We identified a period of heightened neurologic instability by analyzing the average hourly rate of GCS change over 5 days from symptom onset. We used a multivariate regression model to test whether those early GCS score changes were independently associated with 3 month outcome measured by the modified Rankin Scale (mRS).
Results
We studied 13,025 hours of monitoring from 132 cases. The average rate of neurologic change declined from 1.0 GCS points per hour initially to a stable baseline of 0.1 GCS points per hour beyond 12 hours from symptom onset (p<0.05 for time intervals before 12 hours). Change in GCS score within the initial 12 hours was an independent predictor of mRS at three months (odds ratio 0.81 [95% confidence interval 0.66–0.99], p=0.043) after adjustment for age, hematoma volume, hematoma location, initial GCS, and intraventricular hemorrhage.
Conclusions
Neurochecks are effective at detecting clinically important neurologic changes in the intensive care unit setting that are relevant to patients’ long-term outcomes. The initial 12 hours is a period of frequent and prognostically important neurologic changes in patients with ICH.
doi:10.1016/j.jstrokecerebrovasdis.2015.04.045
PMCID: PMC4558336  PMID: 26143415
17.  Electrocardiographic and Echocardiographic Left Ventricular Hypertrophy in the Prediction of Stroke in the Elderly 
Introduction
It is unclear whether LVH detected by electrocardiogram (ECG-LVH) is equally predictive of heart failure as LVH detected by echocardiography (echo-LVH).
Methods
This analysis included 4,008 white participants (41% male) aged 65 years or older from the Cardiovascular Health Study (CHS) who were free of stroke and major intraventricular conduction defects at baseline. ECG-LVH was defined by the Cornell criteria from baseline ECG data and echo-LVH was computed from baseline echocardiography measurements. Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association between ECG-LVH and echo-LVH and adjudicated incident stroke events, separately. Harrell’s concordance indices (C-index) were calculated for the Framingham Stroke Risk Score with inclusion of ECG-LVH and echo-LVH, separately.
Results
ECG-LVH was detected in 136 (3.4%) participants and echo-LVH was present in 208 (5.2%) participants. Over a median follow-up of 13 years (interquartile range=7.5, 19.1), a total of 769 (19%; incidence rate=15.4 per 1000 person-years) strokes occurred. In a multivariable Cox regression analysis adjusted for stroke risk factors and potential confounders, ECG-LVH (HR=1.68, 95%CI=1.23, 2.28) and echo-LVH (HR=1.58, 95%CI=1.17, 2.14) were associated with an increased risk of stroke. Similar values were obtained for the C-index when either ECG-LVH (C-index=0.786) or echo-LVH (C-index=0.786) were included in the Framingham Stroke Risk Score.
Conclusion
ECG-LVH and echo-LVH can be used interchangeably in stroke risk scores.
doi:10.1016/j.jstrokecerebrovasdis.2015.04.044
PMCID: PMC4820291  PMID: 26153509
stroke; left ventricular hypertrophy; ECG; echocardiography
18.  COX-2 rs20417 polymorphism is associated with stroke and white matter disease 
Goals
To investigate the effect of COX-2 polymorphism and its product, prostaglandin-E2 (PGE2), on stroke risk in an endemic area for Chagas disease. In a separate cohort, to investigate the effect of COX-2 polymorphisms on the total burden of cerebral white matter disease.
Methods
Cases were outpatients with ischemic stroke; controls were stroke-free subjects from two outpatient clinics (heart failure and caregivers of a movement disorders clinic). We extracted DNA from total blood to investigate the rs20417 COX-2 polymorphism. Serologic tests (ELISA) were performed to confirm T. cruzi infection and to quantify PGE2 levels. In the Boston cohort, white matter hyperintensity volume (WMHv) was quantified on the admission brain MRIs of subjects with ischemic stroke, who also donated DNA for the COX-2 gene region analysis.
Findings
We studied 44 patients with stroke and 96 controls (46 with heart failure and 50 caregivers) in the Brazilian cohort; and 788 stroke patients (302 cardioembolic, 486 non-cardioembolic) in the Boston cohort. In the Brazilian cohort, rs20417 polymorphism was associated with both stroke (p=5x10−6) and decreased PGE2 levels (p=4x10−5); similarly, Chagas was associated with stroke (p=4x10−3) and decreased PGE2 levels (p=7x10−3). In the Boston cohort, rs20417 polymorphism was associated with increased WMHv among non-cardioembolic (p=0.037), but not among cardioembolic stroke patients.
Conclusions
Variation in COX-2 gene is associated with both symptomatic and silent brain cerebrovascular disease. This candidate gene region should be tested in population-based samples.
doi:10.1016/j.jstrokecerebrovasdis.2015.04.018
PMCID: PMC4532599  PMID: 25957909
20.  Surgical Revascularization in North American Adults with Moyamoya Phenomenon: Long Term Angiographic Follow-Up 
Background
North American and Asian forms of moyamoya have distinct clinical characteristics. Asian adults with moyamoya are known to respond better to direct vs. indirect revascularization. It is unclear whether North American adults with moyamoya have a similar long-term angiographic response to direct vs. indirect bypass.
Methods
A retrospective review of surgical revascularization for adult moyamoya phenomenon was performed. Pre-operative and post-operative cerebral angiograms underwent consensus review, with degree of revascularization quantified as extent of new middle cerebral artery (MCA) territory filling.
Results
Late angiographic follow up was available in 15 symptomatic patients who underwent 20 surgical revascularization procedures. In 10 hemispheres treated solely with indirect arterial bypass, 3 had 2/3 revascularization, 4 had 1/3 revascularization, and 3 had no revascularization of the MCA territory. In the 10 hemispheres treated with direct arterial bypass (8 as a stand alone procedure; 2 in combination with an indirect procedure), 2 had complete revascularization, 7 had 2/3 revascularization, and 1 had 1/3 revascularization. Direct bypass provided a higher rate of “good” angiographic outcome (complete or 2/3 revascularization) when compared to indirect techniques (p = 0.0198).
Conclusions
Direct bypass provides a statistically significant, more consistent and complete cerebral revascularization than indirect techniques in this patient population. This is similar to that reported in the Asian literature, which suggests that the manner of presentation (ischemia in North American adults vs. hemorrhage in Asian adults) is likely not a contributor to the extent of revascularization achieved following surgical intervention.
doi:10.1016/j.jstrokecerebrovasdis.2015.03.053
PMCID: PMC4465995  PMID: 25972283
moyamoya; EDAS; EDAMS; STA-MCA; revascularization
21.  Racial Disparities in Post-Stroke Activity Limitations are not due to Differences in Pre-Stroke Activity Limitation 
Introduction
African Americans experience greater post-stroke disability than whites. We explored whether these differences are due to differences in pre-stroke function.
Methods
The Panel Study of Income Dynamics (PSID) is a nationally representative US panel survey of families and their descendants. We included all PSID respondents who reported an incident stroke between 2001 and 2011. Our primary outcome was an index representing the sum of total activities of daily living (ADL) limitations (0–7) and the secondary outcome was an index of instrumental activities of daily living (IADL) limitations (0–6). Survey-weighted descriptive statistics and Poisson regression were used to estimate racial differences in ADL and IADL before, with and after the wave when incident stroke was reported.
Results
A total of 534 incident strokes were identified, 198 (37%) in African-Americans. There were no pre-stroke racial differences in activity limitations (0.7 vs. 0.7, p=0.99). In the wave of the incident stroke (between 0–2 years from incident stroke), African Americans had considerably more ADL limitations than whites (2.2 vs. 1.5, p=0.048). These racial differences persisted after adjusting for age, sex and comorbidities. For IADLs, adjusted models suggested small pre-stroke racial differences and larger post-stroke differences.
Conclusion
Racial disparities in post-stroke ADL limitations are not due to pre-stroke activity limitations. Instead, differences appear largest in the first 2 years after stroke
doi:10.1016/j.jstrokecerebrovasdis.2015.03.058
PMCID: PMC4466013  PMID: 26026217
22.  HIGHER TREADMILL TRAINING INTENSITY TO ADDRESS FUNCTIONAL AEROBIC IMPAIRMENT AFTER STROKE 
Background and Purpose
Peak Aerobic capacity (V02 peak) is severely worsened after disabling stroke, having serious implications for function, metabolism and ongoing cardiovascular risk. Work from our lab and others has previously shown that modest improvements in VO2 peak are possible in stroke participants with aerobic exercise training. The purpose of the current investigation was to test the extent to which greater enhancements in VO2 peak after stroke are possible using a treadmill protocol with far greater emphasis on intensity progression compared to a protocol without such emphasis.
Methods
Using a randomized design we compared stroke survivors engaged in higher intensity treadmill training (HI-TM, 80% Heart Rate Reserve- HRR) with those undergoing lower intensity training (LO-TM, 50% HRR). Measured outcomes were change in VO2 peak, 6-minute walk distance (6MWD), 30-ft walk times (30WT) and 48-hr step counts (48SC). LO-TM participants trained for a longer period of time per session in an effort to approximately match workload/ caloric expenditure. Participants were randomized with stratification according to age and baseline walking capacity.
Results
HI-TM participants (N=18) had significantly greater gains in VO2 peak (+34%) than LO-TM participants (N=16) (+5%) across the 6 month intervention period (p=0.001, group × time interaction). Conversely, there was no statistical difference between groups in the changes observed for 6MWD, 30WT, or 48SC.
Conclusion
HI-TM is far more effective than LO-TM for improving VO2 peak after disabling stroke. The magnitude of relative improvement for HI-TM was double compared to previous reports from our laboratory with probable clinical significance for this population.
doi:10.1016/j.jstrokecerebrovasdis.2015.07.002
PMCID: PMC4908456  PMID: 26303787
stroke recovery; stroke rehabilitation; exercise training; oxygen consumption
23.  Defining Mild Stroke: Outcomes Analysis of Treated and Untreated Mild Stroke Patients 
Introduction
Mild deficit is a relative contraindication to administration of IV rtPA for acute ischemic stroke. However, what constitutes “mild” deficit is vague. Prior studies showed patients with mild strokes have substantial disability rates at hospital discharge and at 90 days. We investigated whether the application of a new definition altered the rates of disability overall, and assessed the effects of thrombolysis.
Methods
This analysis included all adult acute ischemic stroke patients from a prospective registry of consecutive patients (UCSD SPOTRIAS database, 2003-2014) with 90-day mRS score available who were defined as “mild” using either: NIHSS 0-5 or a TREAT Task Force definition (NIHSS 0-5 and non-disabling based on pre-specified syndromes). Dichotomized 90-day mRS were compared between treated and untreated patients using the two definitions.
Results
Of 802 ischemic stroke patients with mRS scores available, 184 had baseline mRS(0) and met TREAT criteria; 45(24.5%) were rtPA-treated. Among treated patients, 35.6% had 90-day mRS(2-6), versus 28.8% in the untreated group, a non-significant difference after adjusting for baseline NIHSS (p=0.47). None of the 45 treated patients had symptomatic hemorrhage. Outcomes were similar using the simpler NIHSS 0-5 definition.
Conclusions
About one-third of mild stroke patients were not functionally independent at 90 days, irrespective of treatment or mild definition applied, calling into question the treatment efficacy of IV rtPA for mild strokes as well as what constitutes an appropriate definition of “mild”. Randomized studies are necessary to determine rtPA treatment efficacy in mild stroke patients.
doi:10.1016/j.jstrokecerebrovasdis.2015.01.037
PMCID: PMC4457618  PMID: 25906938
25.  Left ventricular geometry on transthoracic echocardiogram and prognosis after lacunar stroke: The SPS3 Trial 
BACKGROUND
The spectrum, prevalence, and prognostic implications of abnormal left ventricular geometry (LVG) in patients with lacunar stroke are unknown. We examined the spectrum of LVG and its relationship with vascular risk factors and outcomes after lacunar stroke.
METHODS
LVG was determined with transthoracic echocardiography for 1961 patients with MRI-verified recent lacunar stroke participating in the Secondary Prevention of Small Subcortical Strokes trial. Multivariable logistic regression and Cox proportional hazards models were used to identify characteristics independently associated with LVG and to estimate risk from abnormal LVG for recurrent stroke and death.
RESULTS
Abnormal LVG was present in 77%. Hispanic (OR 1.4, 95% CI 1.1–1.8) or black (OR 2.0, 1.3–2.9) race-ethnicity, diabetes (OR 1.3, 1.0–1.7), hypertension, impaired renal function (OR 1.8, 1.2–2.5), intracranial stenosis (OR 1.5,1.1–2.1), and abnormal left ventricular function (OR 2.0,1.4–3.0) were independently associated with abnormal LVG. Subjects with abnormal LVG also more frequently had advanced manifestations of small vessel disease specifically previous subcortical infarcts and white matter hyperintensities. After adjusting for assigned treatments, clinical risk factors, and advanced manifestations of small vessel disease, subjects with abnormal LVG remained at increased risk of stroke recurrence (HR 1.5, CI 1.0–2.4). There was no interaction between LVG and assigned antiplatelet or blood pressure target. Abnormal LVG was not associated with mortality.
CONCLUSIONS
LVG consistent with chronic hypertensive changes was highly prevalent and correlated with neuroradiological manifestations of small vessel disease in lacunar stroke patients. These results support the constructs that both cerebral small vessel disease and LVG represent end-organ consequences of chronic hypertension.
REGISTRATION
http://www.clinicaltrials.gov/NCT00059306.
doi:10.1016/j.jstrokecerebrovasdis.2015.03.005
PMCID: PMC4457650  PMID: 25840952
lacunar stroke; transthoracic echocardiogram; left ventricular geometry; hypertension; secondary prevention; small vessel disease

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