Ultra-Long Transfers for Endovascular Thrombectomy-Mission Impossible?: The Australia-New Zealand Experience.

BACKGROUND: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0-2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. METHODS: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). RESULTS: There were 131 patients; the median age was 64 [53-74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12-22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1-3] versus 3 [1-6] in the patients selected with noncontrast CT+CT angiography, P=0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01-0.19]; P<0.01). CONCLUSIONS: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase.

BACKGROUND: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization. METHODS: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization). RESULTS: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed). CONCLUSIONS: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

A NOTCH3 homozygous nonsense mutation in familial Sneddon syndrome with pediatric stroke.

Sneddon syndrome is a rare disorder affecting small and medium-sized blood vessels that is characterized by the association of livedo reticularis and stroke. We performed whole-exome sequencing (WES) in 2 affected siblings of a consanguineous family with childhood-onset stroke and identified a homozygous nonsense mutation within the epidermal growth factor repeat (EGFr) 19 of NOTCH3, p.(Arg735Ter). WES of 6 additional cases with adult-onset stroke revealed 2 patients carrying heterozygous loss-of-function variants in putative NOTCH3 downstream genes, ANGPTL4, and PALLD. Our findings suggest that impaired NOTCH3 signaling is one underlying disease mechanism and that bi-allelic loss-of-function mutation in NOTCH3 is a cause of familial Sneddon syndrome with pediatric stroke.

Ficolin-1 Levels in Patients Developing Vasospasm and Cerebral Ischemia After Spontaneous Subarachnoid Hemorrhage.

Activation of the inflammatory generating complement system might play a pathogenic role in spontaneous subarachnoid hemorrhage (SAH). We studied whether plasma and cerebrospinal fluid (CSF) levels of complement proteins were associated with angiographic vasospasm and cerebral ischemic lesions after SAH. Ficolin-1 (M-ficolin), ficolin-3 (H-ficolin), mannose-binding lectin (MBL), MBL-associated serine protease 2 (MASP-2), MASP-3, and MAp44 were analyzed in plasma of 45 SAH patients at 24 h after bleeding. Additionally, ficolin-1 levels were measured in cerebrospinal fluid (CSF) samples obtained 24 h after bleeding in 19 patients with external ventricular drainage placement. Angiographic vasospasm was identified using transcranial Doppler or angio-CT and considered symptomatic when new focal deficits or ischemic lesions appeared in follow-up neuroimaging. Functional outcome was assessed using modified Rankin scale (mRS) at 90 days. Higher plasma ficolin-1 levels (ng/ml) at 24 h were associated with poor Hunt and Hess (HH) grade at admission (mean 1158 (SD 360) vs 1654 (871), p = 0.004) and were higher in patients developing angiographic vasospasm (1119.44 (374) vs 1514 (755), p = 0.025) and cerebral ischemia (1067 (325) vs 1610 (766), p = 0.003). In multivariate models adjusted for confounders, higher ficolin-1 remained associated with brain ischemic lesions (OR per 100 ng/ml 1.34, 95 %CI 1.04-1.73, p = 0.026) and vasospasm (OR per 100 ng/ml of increase 1.26, 95 %CI 1.02-1.56, p = 0.031). Patients with angiographic vasospasm and cerebral ischemic lesions had non-significantly lower ficolin-1 concentration in the CSF. Plasma ficolin-1 emerged as a marker of clinical severity and brain ischemia after SAH. Larger studies will be required to establish the therapeutic implications of this finding.

La función de la aurícula izquierda está alterada en algunos pacientes con ictus criptogénico: potenciales implicaciones en su evaluación y tratamiento / Left atrial function is impaired in some patients with stroke of undetermined etiology: potential implications for evaluation and therapy

Introducción y objetivos: El 30% de los casos de ictus sigue siendo de etiología desconocida (criptogénicos). En un 20-28% de los pacientes con ictus inicialmente clasificados como criptogénicos, se detecta posteriormente fibrilación auricular paroxística. El objetivo de este estudio es analizar la función auricular izquierda de pacientes con ictus isquémico para identificar patrones asociados a la etiología cardioembólica y determinar si se puede observar tales patrones en individuos clasificados inicialmente como ictus criptogénicos. Métodos: Se incluyó una cohorte de pacientes hospitalizados por ictus isquémico remitidos a ecocardiografía transtorácica. Los neurólogos al cargo determinaron la etiología del ictus según la clasificación TOAST. Se evaluó la función contráctil de la aurícula izquierda utilizando ecocardiografía bidimensional para determinar su fracción de eyección, y mediante técnicas de deformación miocárdica (speckle tracking o rastreo de marcas) se determinó la onda a del strain rate (tasa de deformación). Se comparó la función de la aurícula izquierda entre los subgrupos etiológicos del ictus así como con un grupo de control de individuos sanos. Resultados: Se incluyó a 97 pacientes (de 67 ± 15 años) con ictus isquémico (el 16,5% aterotrombóticos, el 15,5% lacunares, el 11,3% cardioembólicos, el 5,1% de otra etiología determinada y el 51,1% criptogénicos) y 10 voluntarios sanos (de 63 ± 7 años). Se observó una disminución significativa de la fracción de eyección de la aurícula izquierda solo en los pacientes con ictus cardioembólico y criptogénico respecto al grupo de control (31,5 ± 17,2%, 40,2 ± 17,1% y 59,1 ± 8,4% respectivamente; p = 0,004). El strain-rate de la aurícula izquierda fue significativamente inferior en los pacientes con ictus cardioembólicos, criptogénicos o aterotrombóticos en comparación con el grupo control (-0,86 ± 0,49, -1,31 ± 0,56, -1,5 ± 0,47 y -2,37 ± 1,18 respectivamente; p < 0,001). Conclusiones: Los pacientes con ictus criptogénico que presentan una función auricular izquierda (fracción de eyección y strain) similar a la de los pacientes con ictus cardioembólico podrían estar clasificados de forma incorrecta, por lo que en ellos sería útil una monitorización electrocardiográfica prolongada. El análisis de la función auricular izquierda (fracción de eyección y strain) podría ser útil para identificar a los pacientes con ictus cardioembólico inicialmente mal clasificados como criptogénicos (AU)

Introduction and objectives: Stroke etiology remains undetermined in up to 30% of cases. Paroxysmal atrial fibrillation is found in 20% to 28% of patients with stroke initially classified as being of undetermined etiology. The aim of our study was to analyze left atrial function in ischemic stroke patients to identify patterns associated with cardioembolic etiology and to determine whether the patterns identified can be found in individuals initially classified as having a stroke of undetermined etiology. Methods: We studied a cohort of in-hospital ischemic stroke patients referred for transthoracic echocardiography. Treating neurologists determined stroke etiology based on the TOAST classification. Left atrial contractile function was assessed using 2-dimensional echocardiography to determine their ejection fraction and speckle tracking to measure left atrial strain rate: a-wave. Left atrial function was compared between stroke etiology subgroups and healthy controls. Results: Ninety-seven patients (aged 67 ± 15 years) with ischemic stroke (16.5% large-artery atherosclerosis, 15.5% small-vessel occlusion, 11.3% cardioembolic, 5.1% other determined etiology, 51.1% undetermined etiology) and 10 healthy volunteers (aged 63 ± 7 years) were included. Left atrial ejection fraction was significantly decreased only in patients with stroke of cardioembolic and undetermined etiology compared with the control group (31.5 ± 17.2%, 40.2 ± 17.1%, and 59.1 ± 8.4%, respectively; P = .004). The left atrial strain rate was significantly lower in patients with stroke caused by cardioembolic or undetermined etiology, or large-artery atherosclerosis compared with controls (−0.86 ± 0.49, −1.31 ± 0.56, −1.5 ± 0.47, −2.37 ± 1.18, respectively; P < .001). Conclusions: Patients with stroke of undetermined etiology with left atrial function (ejection fraction and strain) similar to that of cardioembolic stroke patients may be misclassified and could potentially benefit from prolonged electrocardiography monitoring. Left atrial function analysis (ejection fraction and strain) might help to identify potential cardioembolic sources in patients with stroke of undetermined etiology (AU)

Left Atrial Function Is Impaired in Some Patients With Stroke of Undetermined Etiology: Potential Implications for Evaluation and Therapy.

INTRODUCTION AND OBJECTIVES: Stroke etiology remains undetermined in up to 30% of cases. Paroxysmal atrial fibrillation is found in 20% to 28% of patients with stroke initially classified as being of undetermined etiology. The aim of our study was to analyze left atrial function in ischemic stroke patients to identify patterns associated with cardioembolic etiology and to determine whether the patterns identified can be found in individuals initially classified as having a stroke of undetermined etiology. METHODS: We studied a cohort of in-hospital ischemic stroke patients referred for transthoracic echocardiography. Treating neurologists determined stroke etiology based on the TOAST classification. Left atrial contractile function was assessed using 2-dimensional echocardiography to determine their ejection fraction and speckle tracking to measure left atrial strain rate: a-wave. Left atrial function was compared between stroke etiology subgroups and healthy controls. RESULTS: Ninety-seven patients (aged 67±15 years) with ischemic stroke (16.5% large-artery atherosclerosis, 15.5% small-vessel occlusion, 11.3% cardioembolic, 5.1% other determined etiology, 51.1% undetermined etiology) and 10 healthy volunteers (aged 63±7 years) were included. Left atrial ejection fraction was significantly decreased only in patients with stroke of cardioembolic and undetermined etiology compared with the control group (31.5±17.2%, 40.2±17.1%, and 59.1±8.4%, respectively; P=.004). The left atrial strain rate was significantly lower in patients with stroke caused by cardioembolic or undetermined etiology, or large-artery atherosclerosis compared with controls (-0.86±0.49, -1.31±0.56, -1.5±0.47, -2.37±1.18, respectively; P<.001). CONCLUSIONS: Patients with stroke of undetermined etiology with left atrial function (ejection fraction and strain) similar to that of cardioembolic stroke patients may be misclassified and could potentially benefit from prolonged electrocardiography monitoring. Left atrial function analysis (ejection fraction and strain) might help to identify potential cardioembolic sources in patients with stroke of undetermined etiology.

Evolución temporal del tratamiento de los pacientes con fibrilación auricular en un área sanitaria urbana / Temporal evolution of treatment of patients with atrial fibrillation in a urban health care area

Fundamento y objetivo: Evaluar la adecuación del tratamiento de la fibrilación auricular (FA) 6 años después de la instauración de una Unidad coordinada de FA. Pacientes y métodos: Pacientes con FA atendidos durante 14 días consecutivos en los servicios de Urgencias, Medicina Interna, Neurología y Arritmias de un hospital de tercer nivel y en 3 centros de atención primaria de un área sanitaria. Se evaluó: tratamiento y adecuación a las guías clínicas vigentes, pruebas realizadas y conocimiento de la arritmia. Se compararon los resultados con los de una población de 239 pacientes atendidos 6 años antes. Resultados: Se incluyeron 168 pacientes. Mejoró el conocimiento de la arritmia. La adecuación del tratamiento (control de frecuencia, control de ritmo y profilaxis antitrombótica) se mantuvo. La adecuación de la profilaxis antitrombótica se asoció negativamente con la edad avanzada (p < 0,001) y positivamente con el conocimiento de la arritmia (p = 0,026). Conclusión: El tratamiento de la FA en un área sanitaria coordinada se mantiene adecuado 6 años después de la instauración de una Unidad coordinada de FA. Los pacientes de edad avanzada todavía son poco anticoagulados. La educación sanitaria puede mejorar este déficit (AU)

Background and objective: To evaluate the adequacy of atrial fibrillation (AF) management 6 years after the establishment of a coordinated AF Unit. Patients and methods: Patients with AF attended during 14 consecutive days in the Emergency Room, Internal Medicine, Neurology and Arrhythmia departments of a tertiary hospital, and 3 primary health care centers of the same urban health care area were included. Treatment for AF and its adequacy to current clinical guidelines, tests performed and knowledge about the arrhythmia were evaluated. Results were compared with a population of 239 patients treated 6 years earlier. Results: One hundred and sixty-eight patients were included. Knowledge of the arrhythmia improved. The adequacy of treatment (rate control, rhythm control and antithrombotic prophylaxis) remained at the same level as in the previous period in all areas. The adequacy of thromboprophylaxis was negatively associated with advanced age (P < .001) and positively associated with knowledge of arrhythmia (P = .026). Conclusion: Treatment of AF in a coordinated health area remains appropriate 6 years after the establishment of a coordinated AF unit. Elderly patients are still poorly anticoagulated. Health education may improve this deficit (AU)

[Temporal evolution of treatment of patients with atrial fibrillation in a urban health care area]. / Evolución temporal del tratamiento de los pacientes con fibrilación auricular en un área sanitaria urbana.

BACKGROUND AND OBJECTIVE: To evaluate the adequacy of atrial fibrillation (AF) management 6 years after the establishment of a coordinated AF Unit. PATIENTS AND METHODS: Patients with AF attended during 14 consecutive days in the Emergency Room, Internal Medicine, Neurology and Arrhythmia departments of a tertiary hospital, and 3 primary health care centers of the same urban health care area were included. Treatment for AF and its adequacy to current clinical guidelines, tests performed and knowledge about the arrhythmia were evaluated. Results were compared with a population of 239 patients treated 6 years earlier. RESULTS: One hundred and sixty-eight patients were included. Knowledge of the arrhythmia improved. The adequacy of treatment (rate control, rhythm control and antithrombotic prophylaxis) remained at the same level as in the previous period in all areas. The adequacy of thromboprophylaxis was negatively associated with advanced age (P < .001) and positively associated with knowledge of arrhythmia (P = .026). CONCLUSION: Treatment of AF in a coordinated health area remains appropriate 6 years after the establishment of a coordinated AF unit. Elderly patients are still poorly anticoagulated. Health education may improve this deficit.

Mannose-binding lectin promotes local microvascular thrombosis after transient brain ischemia in mice.

BACKGROUND AND PURPOSE: Several lines of evidence support the involvement of mannose-binding lectin (MBL) in stroke brain damage. The lectin pathway of the complement system facilitates thrombin activation and clot formation under certain experimental conditions. In the present study, we examine whether MBL promotes thrombosis after ischemia/reperfusion and influences the course and prognosis of ischemic stroke. METHODS: Middle cerebral artery occlusion/reperfusion was performed in MBL-deficient (n=85) and wild-type (WT; n=83) mice, and the brain lesion was assessed by MRI at days 1 and 7. Relative cerebral blood flow was monitored up to 6 hours after middle cerebral artery occlusion with laser speckle contrast imaging. Fibrin(ogen) was analyzed in the brain vasculature and plasma, and the effects of thrombin inhibitor argatroban were evaluated to assess the role of MBL in thrombin activation. RESULTS: Infarct volumes and neurological deficits were smaller in MBL knockout mice than in WT mice. Relative cerebral blood flow values during middle cerebral artery occlusion and at reperfusion were similar in both groups, but decreased during the next 6 hours in the WT group only. Also, the WT mice showed more fibrin(ogen) in brain vessels and a better outcome after argatroban treatment. In contrast, argatroban did not improve the outcome in MBL knockout mice. CONCLUSIONS: MBL promotes brain damage and functional impairment after brain ischemia/reperfusion in mice. These effects are secondary to intravascular thrombosis and impaired relative cerebral blood flow during reperfusion. Argatroban protects WT mice, but not MBL knockout mice, emphasizing a role of MBL in local thrombus formation in acute ischemia/reperfusion.

Risks and benefits of early antithrombotic therapy after thrombolytic treatment in patients with acute stroke.

BACKGROUND: Current guidelines recommend withholding antithrombotic therapy (ATT) for at least 24 h in patients with acute ischemic stroke treated with thrombolytic therapy. Herein, we report a retrospective analysis of a single-centre experience on the safety and efficacy of antithrombotic therapy (ATT) started before or after 24 h of intravenous thrombolysis in a cohort of acute ischemic stroke patients. METHODS: A total of 139 patients (Rapid ATT group) received antithrombotic therapy before 24 h of thrombolysis, and 33 patients (Standard ATT group) after 24 h. The brain parenchyma and vessel status were assessed using simple CT scan on admission, multimodal CT scan at the end of thrombolysis, and angio-CT/MRI scan at day 3. Functional outcome was scored using the modified Rankin Scale (mRS) at day 90. RESULTS: The two ATT groups had similar demographics, stroke subtypes, baseline NIHSS, thrombolytic strategies, vessel-patency rates at the end of thrombolysis, and incidence of bleeding complications at follow up. At day 3, the Rapid ATT group had a non-significant improved vessel-patency rate than the Standard ATT group. At day 90, a greater proportion of patients in the rapid ATT group had shifted down the mRS, and had improved in the NIHSS score. CONCLUSIONS: ATT initiated before 24 h of intravenous thrombolytic therapy in acute stroke patients disclosed no safety concerns compared with a conventional antithrombotic therapy delay of 24 h and showed better functional outcome at follow up. The value of early initiation of ATT after thrombolysis deserves further assessment in randomized controlled trials.

The outcome of patients with mild stroke improves after treatment with systemic thrombolysis.

INTRODUCTION: In up to one third of patients with mild stroke suitable to receive systemic thrombolysis the treatment is not administered because the treating physicians estimate a good spontaneous recovery. However, it is not settled whether the fate of these patients is equivalent to those who are thrombolysed. METHODS: We analyzed 203 consecutive patients (134 men and 69 women, mean age 69±14 years) without premorbid disability and a NIHSS score ≤5 at admission [median 3 (IQR 2-4)]. Intravenous thrombolysis was administered within 4.5 hours from stroke onset (n = 119), or it was withheld (n = 84) whenever the treating physician predicted a spontaneous recovery. The baseline risk factors, clinical course, infarction volume, bleeding complications, and functional outcome at 3 months were analyzed and declared to a Web-based registry which was accessible to the local Health Authorities. RESULTS: Expectedly, not thrombolysed patients had the mildest strokes at admission [median 2 (IQR 1-3.75)]. At day 2 to 5, the infarct volume on DWI-MRI was similar in both groups. There were no symptomatic cerebral bleedings in the study. An ordinal regression model adjusted for baseline stroke severity showed that thrombolysis was associated with a greater proportion of patients who shifted down on the modified Rankin Scale score at 3 months (OR 2.66; 95% CI 1.49-4.74, p = 0.001). CONCLUSIONS: Intravenous thrombolysis seems to be safe in patients with mild stroke and may be associated with improved outcome compared with untreated patients. These results support the evaluation of the efficacy of intravenous thrombolysis in mild stroke patients in randomized clinical trials.

Single-center experience of cerebral artery thrombectomy using the TREVO device in 60 patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: We sought to explore the safety and efficacy of the new TREVO stent-like retriever in consecutive patients with acute stroke. METHODS: We conducted a prospective, single-center study of 60 patients (mean age, 71.3 years; male 47%) with stroke lasting <8 hours in the anterior circulation (n=54) or <12 hours in the vertebrobasilar circulation (n=6) treated if CT perfusion/CT angiography confirmed a large artery occlusion, ruled out a malignant profile, or showed target mismatch if symptoms >4.5 hours. Successful recanalization (Thrombolysis In Cerebral Infarction 2b-3), good outcome (modified Rankin Scale score 0-2) and mortality at Day 90, device-related complications, and symptomatic hemorrhage (parenchymal hematoma Type 1 or parenchymal hematoma Type 2 and National Institutes of Health Stroke Scale score increment ≥ 4 points) were prospectively assessed. RESULTS: Median (interquartile range) National Institutes of Health Stroke Scale score on admission was 18 (12-22). The median (interquartile range) time from stroke onset to groin puncture was 210 (173-296) minutes. Successful revascularization was obtained in 44 (73.3%) of the cases when only the TREVO device was used and in 52 (86.7%) when other devices or additional intra-arterial tissue-type plasminogen activator were also required. The median time (interquartile range) of the procedure was 80 (45-114) minutes. Good outcome was achieved in 27 (45%) of the patients and the mortality rate was 28.3%. Seven patients (11.7%) presented a symptomatic intracranial hemorrhage. No other major complications were detected. CONCLUSIONS: The TREVO device was reasonably safe and effective in patients with severe stroke. These results support further investigation of the TREVO device in multicentric registries and randomized clinical trials.

Oral anticoagulant-associated intracerebral hemorrhage.

The incidence of oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) is growing due to the increasing use of warfarin and the older age of treated patients. Recent population studies reveal that OAC-ICH currently occurs at a frequency comparable to that of subarachnoid hemorrhage. Most frequently, OAC-ICH are located in deep or lobar regions of the brain, although it may also occur in the brainstem. These hemorrhages are larger than spontaneous hematomas and may be fatal in at least 50% of cases. The primary cause of brain injury in patients with OAC-ICH is the direct mechanical disruption of the brain tissue but secondary damage may occur through the intervention of matrix metalloproteinases, glutamate, cytokines, heme, iron, and the chemical toxicity of products such as thrombin, which are released from the clot. The pathogenesis of OAC-ICH also includes the effects of aging, the level of anticoagulation, genetic factors, and a high prevalence of concurrent cerebrovascular conditions, such as cerebral amyloid angiopathy, leukoaraiosis or previous strokes. The treatment of OAC-ICH is challenging and involves rapid reversal of anticoagulation with hemostatic drug therapies such as vitamin K, fresh frozen plasma, prothrombin complex concentrates or recombinant factor VIIa. These therapies may not always be sufficient to stabilize the patient's clinical condition and lacking randomized controlled trials, the best hematological approach to reverse oral anticoagulation is debated. Other difficult decisions reviewed in this article are whether anticoagulation should be restarted after OAC-ICH, and when anticoagulant treatment should be resumed. The newer oral anticoagulants, which are increasingly being introduced for thromboembolism prevention, may confer a lower risk of intracranial bleeding than warfarin, although they do not have an antidote and their anticoagulant effect is difficult to monitor.

Multimodal CT-assisted thrombolysis in patients with acute stroke: a cohort study.

BACKGROUND AND PURPOSE: The value of multimodal CT to assist thrombolysis has received little attention in stroke. METHODS: We assessed prospectively the impact derived from the routine application of CT perfusion and CTA in patients with acute stroke treated consecutively with alteplase. The safety and efficacy of thrombolytic therapy were compared in 106 patients assisted with CT/CTA/CT perfusion (multimodal CT group) and 262 patients assisted without full multimodal brain imaging (control group) during a 5-year period (2005-2009). RESULTS: Good outcome (modified Rankin scale score ≤2) at 3 months was increased in the multimodal group compared with controls (adjusted OR, 2.88; 95% CI, 1.50-5.52). Multimodal-assisted thrombolysis yielded superior benefits in patients treated beyond 3 hours (adjusted OR, 4.48; 95% CI, 1.68-11.98) than treated within 3 hours (adjusted OR, 1.31; 95% CI, 0.80-2.16; interaction test P=0.043). Mortality (14% and 15%) and symptomatic hemorrhage (5% and 7%) were similar in both groups. CONCLUSIONS: Multimodal CT use in routine clinical practice may heighten the overall efficacy of thrombolytic therapy in acute ischemic stroke. The benefits seem greater in patients treated >3 hours after stroke onset, but further randomized clinical trials are needed to confirm these findings.

Uric acid levels are relevant in patients with stroke treated with thrombolysis.

BACKGROUND AND PURPOSE: Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke. METHODS: A total of 317 consecutive patients treated with thrombolysis were included in a prospective stroke registry. Demographics, laboratory data, neurological course, and infarction volume were prospectively collected. Excellent outcome was defined as achieving a modified Rankin Scale score <2 at 90 days. Binary and ordinal logistic regression models were used to analyze modified Rankin Scale score at 90 days. RESULTS: UA levels were significantly higher in patients with an excellent outcome than in patients with a poor outcome (5.82 [1.39] versus 5.42 [1.81], P=0.029). In multivariate models, increased UA levels (OR, 1.23; 95% CI, 1.03 to 1.49; P=0.025) were associated with an excellent outcome and with an increased risk of shifting to a better category across the modified Rankin Scale (OR, 1.19; 95% CI, 1.04 to 1.38; P=0.014) independently of the effect of confounders. The levels of UA and the volume of final infarction were inversely correlated (r=-0.216, P<0.001) and the inverse correlation remained after adjustment for age, sex, and baseline National Institutes of Health Stroke Scale score (t value=-2.54, P=0.01). Significantly lower UA levels were found in patients with malignant middle cerebral artery infarction and parenchymal hemorrhage post-thrombolysis. CONCLUSIONS: Increased UA serum levels are associated with better outcome in patients with stroke treated with reperfusion therapies. These results support the assessment of the potential neuroprotective role of the exogenous administration of UA in patients with stroke treated with thrombolysis.

Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke.

BACKGROUND: The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans. METHODOLOGY/PRINCIPAL FINDINGS: Focal cerebral ischemia/reperfusion in MBL-null mice induced smaller infarctions, better functional outcome, and diminished C3 deposition and neutrophil infiltration than in wild-type mice. Accordingly, reconstitution of MBL-null mice with recombinant human MBL (rhMBL) enhanced brain damage. In order to investigate the clinical relevance of these experimental observations, a study of MBL2 and MASP-2 gene polymorphism rendering the lectin pathway dysfunctional was performed in 135 stroke patients. In logistic regression adjusted for age, gender and initial stroke severity, unfavourable outcome at 3 months was associated with MBL-sufficient genotype (OR 10.85, p = 0.008) and circulating MBL levels (OR 1.29, p = 0.04). Individuals carrying MBL-low genotypes (17.8%) had lower C3, C4, and CRP levels, and the proinflammatory cytokine profile was attenuated versus MBL-sufficient genotypes. CONCLUSIONS/SIGNIFICANCE: In conclusion, genetically defined MBL-deficiency is associated with a better outcome after acute stroke in mice and humans.

Antithrombotic therapy in cardiac embolism.

Anticoagulation is indicated in most cardioembolic ischemic strokes for secondary prevention. In many cardiac conditions, anticoagulation is also indication for primary stroke prevention, mainly when associated to vascular risk factors. Anticoagulation should be started as soon as possible, as it is safe even in moderate acute strokes. The efficacy of early anticoagulation after cardioembolic stroke in relation to outcome has not been assessed adequately, but there is evidence from animal models and clinical studies that anticoagulation with unfractionated heparin is associated with a better outcome mediated in part by its anti-inflammatory properties.

Course of matrix metalloproteinase-9 isoforms after the administration of uric acid in patients with acute stroke: a proof-of-concept study.

Oxidative stress as well as expression and activity of matrix metalloproteinase 9 (MMP-9) are rapidly enhanced after cerebral ischemia. The magnitude of these effects is related to stroke outcome. In human stroke, the extent of oxidative stress correlates well with increased MMP-9 expression. The aim of this study was to evaluate whether treatment with the antioxidant molecule uric acid (UA) decreased the levels of MMP-9 in stroke patients treated with rtPA. The patients were part of a pilot, double-blind, randomized, vehicle-controlled study of patients with acute stroke treated with rtPA (< 3 h) and randomized to receive an intravenous infusion of UA (n = 16) or vehicle (n = 8). Total matrix metalloproteinase (tMMP)-9 and active (aMMP-9) levels were measured in serum at baseline (< 3 h), at the end of study treatment infusion (< 5.5 h), and at 48 hours. Total MMP-9 and aMMP-9 increased very early after stroke onset in patients allocated vehicle after rtPA therapy. Lower increments of aMMP-9 were associated with better outcome at 3 months. UA treatment was associated with reduced levels of aMMP-9 at T1 (p < 0.02) in multivariate models adjusted for age, NIHSS score, and baseline aMMP-9 levels. The decline of aMMP-9 attained after UA administration supports further clinical assessment of UA therapy in patients with acute stroke.

Monocytes are major players in the prognosis and risk of infection after acute stroke.

BACKGROUND AND PURPOSE: Monocytes participate in adaptive and innate immune responses. Monocyte numbers increase in patients with stroke associated infection (SAI) or severe stroke. Whether changes in monocytes are related to specific effects, or simply mark brain damage, remains unsettled. METHODS: We used flow cytometry in 45 consecutive strokes and 12 healthy controls to assess the time course of monocytes, their phenotype, and the production of cytokines after stimulation. Cortisol, TNF-alpha, IFN-gamma, and IL-10 were measured in serum and metanephrine in plasma. The effects of humoral and cellular parameters on the risk of SAI and poor outcome were tested in multivariate analyses adjusted for confounders (NIHSS score, age, and tube feeding). RESULTS: Surface expression of human leukocyte antigen-DR, Toll-like receptor-2, and production of TNF-alpha in monocytes were independently associated with stroke. Distinct immune mechanisms were related with functional outcome and the risk of SAI; the signature of SAI included an increase of cortisol, metanephrine, and IL-10 in serum, and reduced production of TNF-alpha in monocytes; poor outcome was associated with increased expression of Toll-like receptor-4 in monocytes (OR, 9.61; 95% CI, 1.27-72.47). SAI did not predict poor outcome (OR, 5.63; 95% CI, 0.45-70.42; P=0.18). CONCLUSIONS: In human stroke, poor outcome is associated to innate responses mediated by Toll-like receptor-4 in monocytes. SAI may result from the immunosuppressive and antiinflammatory effects of corticoids, catecholamines, IL-10, and deactivated monocytes. Early treated SAI does not contribute significantly to additional brain damage. These findings encourage the exploration of strategies aimed to inhibit Toll-like receptor-4 signaling in acute stroke.