Cognitive changes associated with cerebral emboli during coronary intervention.

OBJECTIVE: To investigate factors influencing the frequency and type of microembolic signals (MES) detected using transcranial Doppler (TCD) in patients undergoing elective coronary intervention, and to correlate MES with silent stroke detected using magnetic resonance imaging (MRI) and cognitive dysfunction. METHODS: The subset study of a randomized clinical trial was conducted on 70 patients (58 males; mean age 59.9 ± 8.4 years) who underwent bilateral TCD monitoring of middle cerebral arteries (MCAs) during elective coronary interventions. Neurologic examination and brain MRI were performed prior to, and 24 h post­intervention. Cognitive function tests were performed prior to, and on day 30 post­intervention. RESULTS: The incidence of detected MES was 94.3 %. Eighteen (25.7 %) patients had new clinically asymptomatic ischemic lesions on MRI. The number of solid MES negatively correlated with changes in revised Addenbrooke's Cognitive Examination test (ACE-R) and, the number of solid MES and combinations of solid and gaseous MES negatively correlated with changes in Mini Mental­State Examination (MMSE) conducted on day 30 after the intervention (p < 0.05 in all cases). CONCLUSION: Cardiac catheterization was associated with a high risk of cerebral embolism in our patients. A higher number of solid MES and combinations of solid and gaseous MES was associated with the deterioration in cognitive tests (Tab. 5, Fig. 3, Ref. 30).

Safety and Outcomes of Thrombectomy in Ischemic Stroke With vs Without IV Thrombolysis.

OBJECTIVE: To test the hypothesis that IV thrombolysis (IVT) treatment before endovascular thrombectomy (EVT) is associated with better outcomes in patients with anterior circulation large artery occlusion (LAO) stroke, we examined a large real-world database, the Safe Implementation of Treatment in Stroke-International Stroke Thrombectomy Register (SITS-ISTR). METHODS: We identified centers recording ≥10 consecutive patients in the SITS-ISTR, with at least 70% available modified Rankin Scale (mRS) scores at 3 months during 2014 to 2019. We defined LAO as intracranial internal carotid artery, first and second segment of middle cerebral artery, and first segment of anterior cerebral artery. Main outcomes were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial hemorrhage (SICH) per modified SITS-Monitoring Study. We performed propensity score-matched (PSM) and multivariable logistic regression analyses. RESULTS: Of 6,350 patients from 42 centers, 3,944 (62.1%) received IVT. IVT + EVT-treated patients had less frequent atrial fibrillation, ongoing anticoagulation, previous stroke, heart failure, and prestroke disability. PSM analysis showed that IVT + EVT-treated patients had a higher rate of functional independence than patients treated with EVT alone (46.4% vs 40.3%, p < 0.001) and a lower rate of death at 3 months (20.3% vs 23.3%, p = 0.035). SICH rates (3.5% vs 3.0%, p = 0.42) were similar in both groups. Multivariate adjustment yielded results consistent with PSM. CONCLUSION: Pretreatment with IVT was associated with favorable outcomes in EVT-treated LAO stroke in the SITS-ISTR. These findings, while indicative of international routine clinical practice, are limited by observational design, unmeasured confounding, and possible residual confounding by indication. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that IVT before EVT increases the probability of functional independence at 3 months compared to EVT alone.

Safety and Outcome of Intravenous Thrombolysis in Stroke Patients on Prophylactic Doses of Low Molecular Weight Heparins at Stroke Onset.

Background and Purpose- There are limited data on intravenous thrombolysis treatment in patients with ischemic stroke who have received prophylactic doses of low molecular weight heparins (LMWHs). We aimed to evaluate the safety and outcomes of intravenous thrombolysis treatment in stroke patients taking thromboprophylactic doses of LMWH. Methods- We analyzed 109 291patients treated with intravenous thrombolysis, recorded in the Safe Implementation of Treatments in Stroke International Thrombolysis Register between 2003 and 2017 not taking oral anticoagulants or therapeutic doses of heparin at stroke onset. One thousand four hundred eleven patients (1.3%) were on prophylactic LMWH for deep venous thrombosis prevention. Outcome measures were symptomatic intracerebral hemorrhage, parenchymal hematoma, death within 7 days and 3 months, and functional dependency at 3 months. Results- Patients on LMWH were older, had more severe strokes, more prestroke disability, and comorbidities than patients without LMWH. There was no significant increase in adjusted odds ratios (aOR) for symptomatic intracerebral hemorrhage (aOR, 1.02 [95% CI, 0.48-2.17] as per Safe Implementation of Treatments in Stroke -MOST, aOR, 0.95 [0.59-1.53] per ECASS II]), nor for 7-day mortality (aOR, 1.14 [0.82-1.59]), in the prophylactic LMWH group. The LMWH group had a higher aOR for 3-month mortality (aOR, 1.94 [1.49-2.53]) and functional dependency, aOR, 1.44 (1.10-1.90). Propensity score analysis matching patients on baseline characteristics removed differences between groups on all outcomes except 3-month mortality. Conclusions- Intravenous thrombolysis in patients with acute ischemic stroke on treatment with prophylactic doses of LMWH at stroke onset is not associated with an increased risk of symptomatic intracerebral hemorrhage or early death.

Sonolysis in risk reduction of symptomatic and silent brain infarctions during coronary stenting (SONOREDUCE): Randomized, controlled trial.

BACKGROUND: Silent brain infarcts can be detected on magnetic resonance imaging (MRI) in ~22% of patients after coronary angioplasty and stenting (CS). The effect of periprocedural sonolysis on the risk of new brain infarcts during CS was examined. METHODS: Patients undergoing elective CS were allocated randomly to a bilateral sonolysis group (70 patients, 58 men; mean age, 59.9 years) or a control group (74 patients, 45 men; mean age, 65.5 years). Neurologic examination, cognitive function tests, and brain MRI were performed prior to intervention and at 24 h after CS. Neurologic examination and cognitive function tests were repeated at 30 days after CS. RESULTS: No significant differences were observed in the number of patients with new infarcts (25.7 vs. 18.9%, P = 0.423), the number of lesions (1.3 ±â€¯1.0 vs. 2.9 ±â€¯5.3, P = 0.493), lesion volume (0.16 ±â€¯0.34 vs. 0.28 ±â€¯0.60 mL, P = 0.143), and the number of patients with new ischemic lesions in the insonated MCA territories (18.6vs. 17.6%, P = 0.958) between the sonolysis group and the control group. There were no cases of stroke, transient ischemic attack, myocardial infarction, or death in the two groups. Intracranial bleeding was reported only in 1 patient in the control group (0 vs. 1.4%, P = 0.888). Clock-drawing test scores at 30 days were significantly higher in the sonolysis group than in the control group (median 3.0 vs. 2.5, P = 0.031). CONCLUSIONS: Sonolysis does not reduce the risk of new brain infarcts after CS. The effect of sonolysis on number and volume of ischemic lesions and cognitive function should be assessed in further studies.

Interleukin 6 and complement serum level study in Parkinson's disease.

The objective of this study is to assess whether elevation of serum inflammatory markers levels may indicate the progression of clinical impairment in Parkinson's disease (PD) patients. In 47 PD patients, the serum levels of the C3 and C4 part of the complement and Interleukin-6 (IL-6) were measured. The results at baseline and after 2 years were correlated with scales measuring memory, depression, motor symptoms, and quality of life. Patients with higher levels of C3 and C4 at baseline had decreased quality of life, verbal ability, and memory. Patients with higher IL-6 at baseline showed worse depression scores at 2 years. Patients with persistently higher levels of C3 and C4 at 2 years had worse quality of life and memory ability. Uncorrected p values are reported due to the exploratory nature of the study. The results indicate an impact of inflammation on non-motor signs and quality of life in PD. The increase of levels of serum inflammatory biomarkers may indicate the progression of non-motor impairment in PD.

Intravenous thrombolysis for ischemic stroke in the golden hour: propensity-matched analysis from the SITS-EAST registry.

As there are scarce data regarding the outcomes of acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) within 60 min from symptom onset ("golden hour"), we sought to compare outcomes between AIS patients treated within [GH(+)] and outside [GH(-)] the "golden hour" by analyzing propensity score matched data from the SITS-EAST registry. Clinical recovery (CR) at 2 and 24 h was defined as a reduction of ≥10 points on NIHSS-score or a total NIHSS-score of ≤3 at 2 and 24 h, respectively. A relative reduction in NIHSS-score of ≥40% at 2 h was considered predictive of complete recanalization (CREC). Symptomatic intracranial hemorrhage (sICH) was defined using SITS-MOST criteria. Favorable functional outcome (FFO) was defined as a mRS-score of 0-1 at 3 months. Out of 19,077 IVT-treated AIS patients, 71 GH(+) patients were matched to 6882 GH(-) patients, with no differences in baseline characteristics (p > 0.1). GH(+) had higher rates of CR at 2 (31.0 vs. 12.4%; p < 0.001) and 24 h (41 vs. 27%; p = 0.010), CREC at 2 h (39 vs. 21%; p < 0.001) and FFO (46.5 vs. 34.0%; p = 0.028) at 3 months. The rates of sICH and 3-month mortality did not differ (p > 0.2) between the two groups. GH(+) was associated with 2-h CR (OR: 5.34; 95% CI 2.53-11.03) and CREC (OR: 2.38; 95% CI 1.38-4.09), 24-h CR (OR: 1.88; 95% CI 1.08-3.26) and 3-month FFO (OR: 2.02; 95% CI 1.15-3.54) in multivariable logistic regression models adjusting for potential confounders. In conclusion, AIS treated with IVT within the GH seems to have substantially higher odds of early neurological recovery, CREC, 3-month FFO and functional improvement.

Novel missense variant of CACNA1A gene in a Slovak family with episodic ataxia type 2.

INTRODUCTION: Episodic ataxias (EAs) are rare dominantly inherited neurological disorders characterized by recurrent episodes of ataxia lasting minutes to hours. The most common subtype is EA type 2 (EA2) caused by pathogenic variants of calcium voltage-gated channel subunit alpha1 A gene (CACNA1A) on chromosome 19p13. SUBJECTS AND METHODS: We examined a Slovak three-generation family. Genomic DNA of the family members was extracted from peripheral blood and amplified by polymerase chain reaction. CACNA1A variants were screened by Sanger sequencing. RESULTS: We identified four family members with recurrent episodes of ataxia. Complex differential diagnosis was performed. Genetic analysis with direct sequencing revealed a novel heterozygous variant of CACNA1A - c.5264A>G (p.Glu1755Gly) located in the pore loop of domain IV of calcium channel alpha-1A subunit. CONCLUSION: We identified a novel missense variant of a voltage-dependent P/Q-type calcium channel alpha-1A subunit in a Slovak three-generation family with recurrent episodes of ataxia. The heterozygous missense variant resulted in changing a highly conserved glutamic acid within the pore loop of domain IV.

SONOlysis in prevention of Brain InfaRctions During Internal carotid Endarterectomy (SONOBIRDIE) trial - study protocol for a randomized controlled trial.

BACKGROUND: Carotid endarterectomy (CEA) is a beneficial procedure for selected patients with an internal carotid artery (ICA) stenosis. Surgical risk of CEA varies from between 2 and 15%. The aim of the study is to demonstrate the safety and effectiveness of sonolysis (continual transcranial Doppler monitoring, TCD) using a 2-MHz diagnostic probe with maximal diagnostic energy on the reduction of the incidence of stroke, transient ischemic attack (TIA) and brain infarction detected using magnetic resonance imaging (MRI) by the activation of the endogenous fibrinolytic system during CEA. METHODS/DESIGN: Design: a multicenter, randomized, double-blind, sham-controlled trial. SCOPE: international, multicenter trial for patients with at least 70% symptomatic or asymptomatic ICA stenosis undergoing CEA. INCLUSION CRITERIA: patients with symptomatic or asymptomatic ICA stenosis of at least 70% are candidates for CEA; a sufficient temporal bone window for TCD; aged 40-85 years, functionally independent; provision of signed informed consent. Randomization: consecutive patients will be assigned to the sonolysis or control (sham procedure) group by computer-generated 1:1 randomization. Prestudy calculations showed that a minimum of 704 patients in each group is needed to reach a significant difference with an alpha value of 0.05 (two-tailed) and a beta value of 0.8 assuming that 10% would be lost to follow-up or refuse to participate in the study (estimated 39 endpoints). ENDPOINTS: the primary endpoint is the incidence of stroke or TIA during 30 days after CEA and the incidence of new ischemic lesions on brain MRI performed 24 h after CEA in the sonolysis and control groups. Secondary endpoints are occurrence of death, any stroke, or myocardial infarction within 30 days, changes in cognitive functions 1 year post procedure related to pretreatment scores, and number of new lesions and occurrence of new lesions ≥0.5 mL on post-procedural brain MRI. ANALYSIS: descriptive statistics and linear/logistic multiple regression models will be performed. Clinical relevance will be measured as relative risk reduction, absolute risk reduction and the number needed to treat. DISCUSSION: Reduction of the periprocedural complications of CEA using sonolysis as a widely available and cheap method may significantly increase the safety of CEA and extend the indication criteria for CEA. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02398734 . Registered on 20 March 2015.

Plasmin (Human) Administration in Acute Middle Cerebral Artery Ischemic Stroke: Phase 1/2a, Open-Label, Dose-Escalation, Safety Study.

BACKGROUND: This phase 1/2a, open-label, multicenter, dose-escalation, safety study describes the first evaluation of plasmin as an intracranial thrombolytic treatment for acute ischemic stroke in the middle cerebral artery. The rationale for intrathrombus administration is that plasmin would bind fibrin inside the targeted clot, protecting it from circulating inhibitors. METHODS: Plasmin was given in escalating doses within 9 hours of stroke onset, and treatment efficacy was determined in 5 patient cohorts (N = 40): cohort 1 (20 mg, .5 mL/min), cohort 2a (40 mg, .05 mL/min), cohort 2b (40 mg, .33 mL/min), cohort 3a (80 mg, .67 mL/min), and cohort 3b (80 mg, .33 mL/min). RESULTS: Plasmin was generally safe at doses as high as 80 mg. No symptomatic intracranial hemorrhage was observed, and the rate of asymptomatic intracranial hemorrhage (12.5%) was consistent with that expected under supportive care. No relationship was observed between the plasmin dose and the incidence or severity of bleeding events, any particular serious adverse events, nor death. Changes in clinical chemistry, hematology, and coagulation parameters following plasmin treatment were unremarkable and unrelated to the dose. Plasmin administration resulted in successful reperfusion of the occluded vessel in 25% of patients across all cohorts, with no relationship between successful perfusion and total plasmin dose but a potential increase in reperfusion with slower infusion rates. CONCLUSIONS: Plasmin treatment of the occluded middle cerebral artery within 9 hours of stroke onset was well tolerated and did notincrease adverse outcomes; however, successful recanalization was achieved in only a limited number of patients.

RNF213 Rare Variants in Slovakian and Czech Moyamoya Disease Patients.

RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p.R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p.E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.

Detection of occult paroxysmal atrial fibrilation by implantable long-term electrocardiographic monitoring in cryptogenic stroke and transient ischemic attack population: a study protocol for prospective matched cohort study.

BACKGROUND: Cardio-embolic etiology is the most frequently predicted cause of cryptogenic stroke/TIA. Detection of occult paroxysmal atrial fibrillation is crucial for selection of appropriate medication. METHODS: Enrolment of eligible cryptogenic stroke and TIA patients began in 2014 and will continue until 2018. The patients undergo long-term (12 months) ECG monitoring (implantable loop recorder) and testing for PITX2 (chromosome 4q25) and ZFHX3 (chromosome 16q22) gene mutations. There will be an appropriate control group of age- and sex-matched healthy volunteers. To analyse the results descriptive statistics, statistical tests for group differences, and correlation analyses will be used. DISCUSSION: In our study we are focusing on a possible correlation between detection of atrial fibrillation by an implantable ECG recorder, and PITX2 and/or ZFHX3 gene mutations in cryptogenic stroke/TIA patients. A correlation could lead to implementation of this genomic approach to cryptogenic stroke/TIA diagnostics and management. The results will be published in 2018. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02216370 .

Intravenous Thrombolysis for Stroke Recurring Within 3 Months From the Previous Event.

BACKGROUND AND PURPOSE: According to the European license, alteplase can be given no sooner than 3 months after previous stroke. However, it is not known whether past history of stroke influences the effect of treatment. Our aim was to evaluate safety and functional outcome after intravenous thrombolysis administered in everyday practice to patients with previous stroke≤3 months compared with those with first-ever stroke. METHODS: We analyzed consecutive cases treated with alteplase between October 2003 and July 2014 contributed to the Safe Implementation of Thrombolysis for Stroke-Eastern Europe registry from 12 countries. Odds ratios were calculated using unadjusted and adjusted logistic regression. RESULTS: Of 13,007 patients, 11,221 (86%) had no history of stroke and 249 (2%) experienced previous stroke≤3 months before admission. Patients with previous stroke≤3 months had a higher proportion of hypertension and hyperlipidemia. There were no significant differences in outcome, including symptomatic intracerebral hemorrhage according to European Cooperative Acute Stroke Study (unadjusted odds ratio 1.27, 95% confidence interval: 0.74-2.15), and being alive and independent at 3 months (odds ratio 0.81, 95% confidence interval: 0.61-1.09). CONCLUSIONS: Patients currently treated with alteplase, despite a history of previous stroke≤3 months, do not seem to achieve worse outcome than those with first-ever stroke. Although careful patient selection was probably of major importance, our findings provide reassurance that this group of patients may safely benefit from thrombolysis and should not be arbitrarily excluded as a whole. Further studies are needed to identify the shortest safe time lapse from the previous event to treatment with alteplase.

Safety of Statin Pretreatment in Intravenous Thrombolysis for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: A recent meta-analysis investigating the association between statins and early outcomes in acute ischemic stroke (AIS) patients treated with intravenous thrombolysis (IVT) indicated that prestroke statin treatment was associated with increased risk of 90-day mortality and symptomatic intracranial hemorrhage. We investigated the potential association of statin pretreatment with early outcomes in a large, international registry of AIS patients treated with IVT. METHODS: We analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST) registry on consecutive AIS patients treated with IVT during an 8-year period. Early clinical recovery within 24 hours was defined as reduction in baseline National Institutes of Health Stroke Scale score of ≥10 points. Favorable functional outcome at 3 months was defined as modified Rankin Scale scores of 0 to 1. Symptomatic intracranial hemorrhage was diagnosed using National Institute of Neurological Disorders and Stroke, European-Australasian Acute Stroke Study-II and SITS definitions. RESULTS: A total of 1660 AIS patients treated with IVT fulfilled our inclusion criteria. Patients with statin pretreatment (23%) had higher baseline stroke severity compared with cases who had not received any statin at symptom onset. After adjusting for potential confounders, statin pretreatment was not associated with a higher likelihood of symptomatic intracranial hemorrhage defined by any of the 3 definitions. Statin pretreatment was not related to 3-month all-cause mortality (odds ratio, 0.92; 95% confidence interval, 0.57-1.49; P=0.741) or 3-month favorable functional outcome (odds ratio, 0.81; 95% confidence interval, 0.52-1.27; P=0.364). Statin pretreatment was independently associated with a higher odds of early clinical recovery (odds ratio, 1.91; 95% confidence interval, 1.25-2.92; P=0.003). CONCLUSIONS: Statin pretreatment seems not to be associated with adverse outcomes in AIS patients treated with IVT. The effect of statin pretreatment on early functional outcomes in thrombolysed AIS patients deserves further investigation.

Hyperdense cerebral artery computed tomography sign is associated with stroke severity rather than stroke subtype.

BACKGROUND: The hyperdense cerebral artery sign (HCAS) on unenhanced computed tomography (CT) in acute ischemic stroke is a valuable clinical marker, but it remains unclear if HCAS reflects clot composition or stroke etiology. Therefore, variables independently associated with HCAS were identified from a large international data set of patients treated with intravenous thrombolysis. METHODS: All stroke patients undergoing intravenous thrombolysis from the Safe Implementation of Treatments in Stroke-EAST (SITS-EAST) database between February 2003 and December 2011 were analyzed. A general estimating equation model accounting for within-center clustering was used to identify factors independently associated with HCAS. RESULTS: Of all 8878 consecutive patients, 8375 patients (94%) with available information about HCAS were included in our analysis. CT revealed HCAS in 19% of patients. Median baseline National Institutes of Health Stroke Scale (NIHSS) score was 12, mean age was 67 ± 12 years, and 3592 (43%) patients were females. HCAS was independently associated with baseline NIHSS (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.10-1.12), vessel occlusion (OR, 5.02; 95% CI, 3.31-7.63), early ischemic CT changes (OR, 1.63; 95% CI, 1.31-2.04), year (OR, 1.07; 95% CI, 1.02-1.12), and age (10-year increments; OR, .90; 95% CI, .84-.96). Cardioembolic stroke was not associated with HCAS independently of baseline NIHSS. In different centers, HCAS was reported in 0%-50% of patients. CONCLUSIONS: This study illustrates significant variation in detection of HCAS among stroke centers in routine clinical practice. Accounting for within-center data clustering, stroke subtype was not independently associated with HCAS; HCAS was associated with the severity of neurologic deficit.

Role of preexisting disability in patients treated with intravenous thrombolysis for ischemic stroke.

BACKGROUND AND PURPOSE: Little is known about the effect of thrombolysis in patients with preexisting disability. Our aim was to evaluate the impact of different levels of prestroke disability on patients' profile and outcome after intravenous thrombolysis. METHODS: We analyzed the data of all stroke patients admitted between October 2003 and December 2011 that were contributed to the Safe Implementation of Treatments in Stroke-Eastern Europe (SITS-EAST) registry. Patients with no prestroke disability at all (modified Rankin Scale [mRS] score, 0) were used as a reference in multivariable logistic regression. RESULTS: Of 7250 patients, 5995 (82%) had prestroke mRS 0, 791 (11%) had prestroke mRS 1, 293 (4%) had prestroke mRS 2, and 171 (2%) had prestroke mRS≥3. Compared with patients with mRS 0, all other groups were older, had more comorbidities, and more severe neurological deficit on admission. There was no clear association between preexisting disability and the risk of symptomatic intracranial hemorrhage. Prestroke mRS 1, 2, and ≥3 were associated with increased risk of death at 3 months (odds ratio, 1.3, 2.0, and 2.6, respectively) and lower chance of achieving favorable outcome (achieving mRS 0-2 or returning to the prestroke mRS; 0.80, 0.41, 0.59, respectively). Patients with mRS≥3 and 2 had similar vascular profile and favorable outcome (34% versus 29%), despite higher mortality (48% versus 39%). CONCLUSIONS: Prestroke disability does not seem to independently increase the risk of symptomatic intracranial hemorrhage after thrombolysis. Despite higher mortality, 1 in 3 previously disabled patients may return to his/her prestroke mRS. Therefore, they should not be routinely excluded from thrombolytic therapy.

Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial.

BACKGROUND AND PURPOSE: Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients. METHODS: G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging). RESULTS: G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1. CONCLUSIONS: G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Factors influencing in-hospital delay in treatment with intravenous thrombolysis.

BACKGROUND AND PURPOSE: Shortening door-to-needle time (DNT) for the thrombolytic treatment of stroke can improve treatment efficacy by reducing onset-to-treatment time. The goal of our study was to explore the association between DNT and outcome and to identify factors influencing DNT to better understand why some patients are treated late. METHODS: Prospectively collected data from the Safe Implementation of Treatments in Stroke-East registry (SITS-EAST: 9 central and eastern European countries) on all patients treated with thrombolysis between February 2003 and February 2010 were analyzed. Multiple logistic regression analysis was used to identify predictors of DNT ≤ 60 minutes. RESULTS: Altogether, 5563 patients were treated with thrombolysis within 4.5 hours of symptom onset. Of these, 2097 (38%) had DNT ≤ 60 minutes. In different centers, the proportion of patients treated with DNT ≤ 60 minutes ranged from 18% to 84% (P<0.0001). Patients with longer DNT (in 60-minute increments) had less chance of achieving a modified Rankin Scale score of 0 to 1 at 3 months (adjusted OR, 0.86; 95% CI, 0.77-0.97). DNT ≤ 60 minutes was independently predicted by younger age (in 10-year increments; OR, 0.92; 95% CI, 0.87-0.97), National Institutes of Health Stroke Scale score 7 to 24 (OR, 1.44; 95% CI, 1.2-1.7), onset-to-door time (in 10-minute increments; OR, 1.19; 95% CI, 1.17-1.22), treatment center (P<0.001), and country (P<0.001). CONCLUSIONS: Thrombolysis of patients with older age and mild or severe neurological deficit is delayed. The perception that there is sufficient time before the end of the thrombolytic window also delays treatment. It is necessary to improve adherence to guidelines and to treat patients sooner after arrival to hospital.

Is the maximum dose of 90 mg alteplase sufficient for patients with ischemic stroke weighing >100 kg?

BACKGROUND AND PURPOSE: Intravenous alteplase for acute ischemic stroke has a maximum dose limit of 90 mg. Consequently, patients >100 kg body weight receive a lower per-kilogram dose compared with those ≤100 kg. We investigated if the lower per-kilogram dose is associated with poor early neurological improvement and worse outcome after thrombolysis. METHODS: Of 27 910 patients registered in Safe Implementation of Treatment in Stroke-International Stroke Thrombolysis Register (SITS-ISTR; 2002 to 2009), 1190 (4.3%) weighed >100 kg. Major neurological improvement was used to estimate recanalization (National Institutes of Health Stroke Scale improvement ≥8 points or score of 0 at 24 hours). Outcome measures included symptomatic intracerebral hemorrhage (National Institutes of Health Stroke Scale deterioration ≥4 points within 24 hours and Type 2 parenchymal hemorrhage), functional independence (modified Rankin Scale 0 to 2), and mortality at 3 months. RESULTS: Patients >100 kg received a lower per-kilogram alteplase dose (0.82 versus 0.90, P<0.001), were younger (62 versus 70 years, P<0.001), had a lower baseline National Institutes of Health Stroke Scale (10 versus 12, P<0.001), but more frequently had cardiovascular risk factors. Major neurological improvement at 24 hours occurred in 27.7% in both groups. Symptomatic intracerebral hemorrhage occurred in 2.6% versus 1.7% (P=0.03) in >100 kg versus ≤100 kg. Functional independence was 59.7% versus 53.6% (P<0.001) and mortality was 14.4% versus 15.1% (P=0.54). After adjustment for baseline characteristics, there was no significant difference for major neurological improvement or functional independence between >100 kg and ≤100 kg, but >100-kg patients had a higher odds ratio for symptomatic intracerebral hemorrhage (OR, 1.6; 95% CI, 1.06 to 2.41; P=0.02) and mortality (OR, 1.37; 95% CI, 1.08 to 1.74; P=0.01). CONCLUSIONS: Our results support the current upper dose limit. There was a higher incidence of symptomatic intracerebral hemorrhage in patients >100 kg despite the lower per-kilogram recombinant tissue plasminogen activator dose. Major neurological improvement and functional independence were similar.

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.

BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke. METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events. RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events. CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)