Background and Purpose
We hypothesized that patients with intracranial stenosis with lacunar stroke presentations would face lower risks of recurrent stroke than those with index non-lacunar strokes, and that their recurrent strokes would predominantly be lacunar.
We analyzed subjects enrolled with an index stroke into the Warfarin Aspirin Symptomatic Intracranial Disease (WASID) trial. The index stroke was classified as lacunar or non-lacunar. The primary endpoint was recurrent ischemic stroke. Cox proportional hazard models were generated with stratification for severity of stenosis.
347 subjects were enrolled after an index stroke, 38 were lacunar and 309 were non-lacunar. Over a mean follow-up of 1.8 years there was no significant difference in stroke recurrence between patients whose index stroke was lacunar (7/38; 18%) vs. non-lacunar (69/309; 22%) (HR 0.79, 95%CI:0.36–1.71). Further, no significant differences were found when groups were stratified by 50–69% stenosis (HR 0.50, 95%CI:0.12–2.1) and ≥70% stenosis (HR 0.87, 95%CI:0.34–2.2). Of the 7 recurrent strokes in patients whose index stroke was lacunar, all 7 were non-lacunar and 3 were in the territory of the stenotic artery.
In patients with symptomatic intracranial stenosis, the risk of recurrent stroke was similar in patients who presented with lacunar and non-lacunar strokes, and recurrent strokes in patients presenting with lacunar stroke were typically non-lacunar. These findings suggest that the pathophysiology of these strokes is related to the stenosis rather than small vessel disease. Patients presenting with lacunar strokes should be included in trials investigating secondary prevention for symptomatic intracranial stenosis.
Introduction: Given the high morbidity and mortality associated with intracerebral hemorrhage (ICH), family members, and healthcare providers base early supportive management decisions, at least in part, on expected prognosis. In the comatose patient with ICH, this short-term prognosis is most overtly characterized by regaining of consciousness.
Design: A retrospective consecutive cohort of 51 patients admitted to a neuroICU with ICH and admission Glasgow Coma Scale score ≤8 was identified. Logistic regression was performed to assess the association of baseline characteristics and treatment parameters associated with awakening.
Results: Awakening from coma was observed in 53% of ICH patients: 83% with an initial GCS score of 7–8, 43% with an initial score of 5–6, and 20% with an initial score of 3–4. Awakening from coma in the cohort of 27 patients who regained consciousness occurred in 59% of patients by day 2, 89% by day 7, and 96% by day 9. In multivariable analysis, only higher admission GCS score was associated with a greater likelihood of awakening from coma [OR 4.9 (95% CI 1.9–13) per two-point category, p = 0.001]. DNR status during the first 24 h was not associated with awakening but was at later time points.
Conclusion: GCS score is the predominant initial predictor of early awakening in patients who present in coma after ICH. Patients who regained consciousness typically did so within the first 9 days of hospital admission.
intracerebral hemorrhage; intracranial hemorrhage; ICH; prognosis; coma
Inflammation contributes to secondary injury and neuronal loss after intracerebral hemorrhage, but the role of individual immune populations in these processes is unclear. In a mouse model, the injection of autologous blood into the striatum was associated with an intense inflammatory cell infiltrate composed of neutrophils, monocytes, and dendritic cells. Selective depletion of neutrophils resulted in decreased infiltration of monocytes and improved functional outcomes at day 3 post-hemorrhage. These findings indicate that neutrophil infiltration into the site of hemorrhage contributes to brain injury either by direct cellular damage or the recruitment of monocytes.
Intracerebral hemorrhage; Inflammation; Neutrophils; Monocytes
Intracerebral hemorrhage (ICH) is a devastating stroke subtype in which perihematomal inflammation contributes to neuronal injury and functional disability. Histologically, the region becomes infiltrated with neutrophils and activated microglia followed by neuronal loss but little is known about the immune signals that coordinate these events. This study aimed to determine the role of Toll-like receptor 4 (TLR4) in the innate immune response after ICH and its impact on neurobehavioral outcome.
Transgenic mice incapable of TLR4 signaling and wild-type controls were subjected to striatal blood injection to model ICH. The perihematomal inflammatory response was then quantified by immunohistochemistry, whole brain flow cytometry, and PCR. The critical location of TLR4 signaling was determined by blood transfer experiments between genotypes. Functional outcomes were quantified in all cohorts using the cylinder and open field tests.
TLR4-deficient mice had markedly decreased perihematomal inflammation, associated with reduced recruitment of neutrophils and monocytes, fewer microglia, and improved functional outcome by day 3 after ICH. Moreover, blood transfer experiments revealed that TLR4 on leukocytes or platelets within the hemorrhage contributes to perihematomal leukocyte infiltration and the neurological deficit.
Together, these data identify a critical role for TLR4 signaling in perihematomal inflammation and injury and indicate this pathway may be a target for therapeutic intervention.
Successful implementation of a randomized clinical trial (RCT) for neuro-vascular emergencies such as cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage is extraordinarily challenging. Besides establishing an accurate, hyper-expedited diagnosis among many mimics in a person with acute neurological deficits, informed consent must be obtained from this vulnerable group of patients who may be unable to convey their own wishes, grasp the gravity of their situation, or give a complete history or examination. We review the influences, barriers, and factors investigators encounter when providing established and putative stroke therapies, and focus on informed consent, the most important research protector of human subjects, as the rate-limiting step for enrollment into acute stroke RCTs. The informed consent process has received relatively little attention in the stroke literature, but is especially important for stroke victims with acute cognitive, aural, lingual, motor, or visual impairments. Consent by a surrogate may not accurately reflect the patient’s wishes. Further, confusion about trial methodology, negative opinions of placebo-controlled studies, and therapeutic misconception by patients or surrogates may impede trial enrollment and requires further study. Exception from informed consent offers an opportunity that is rarely if ever utilized for stroke RCTs. Ultimately, advancing the knowledge base and treatment paradigms for acute stroke is essential but autonomy, beneficence (non-malfeasance), and justice must also be carefully interwoven into any well-designed RCT.
informed consent; acute stroke; cerebral infarction; clinical trial
Background and Purpose
The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult NIH Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records.
Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores.
Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was “excellent” (intraclass correlation coefficient of 0.95, 95% confidence interval 0.94–0.97). Interrater reliability for individual test items was “substantial” or “excellent” for 14 of 15 items.
The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.
arterial ischemic stroke; pediatric; NIH stroke scale
Background: Antiphospholipid antibodies (aPLs) have been associated with thrombosis in the antiphospholipid antibody syndrome (APS) and with atherosclerotic vascular events in patients without APS. We examined the significance of aPLs in transient ischemic attack (TIA). Patients/methods: Patients with TIA <48 h from symptom onset were prospectively enrolled. Traditional aPLs, including anticardiolipin and β2-glycoprotein-I (β2GPI), and newer aPLs, including anti-phosphatidylserine/prothrombin (aPS/PT), β2GPI Domain 4/5 and β2GPI Domain 1 were measured. Primary outcome was a composite of stroke or death within 90 days or identification of a high risk stroke mechanism. Secondary outcomes were stroke or death and the presence of clinical/sub-clinical atherosclerosis. Results: Over 4.5 years, 167 patients were enrolled. Forty one patients (25%) had the composite endpoint. Antibodies were measured in 158 subjects. aPS/PT IgG antibodies were significantly associated with stroke/death (OR 16.3, 95% CI 2.3–116.7, p = 0.005) and were non-significantly associated with the composite endpoint (OR 4.7, 95% CI 0.8–29.2, p = 0.10). In multivariate analysis adjusting for ABCD2 risk score, aPS/PT IgG remained associated with stroke/death (OR 15.7, 95% CI 2.0–125.6, p = 0.009). Other aPLs were not associated with clinical outcome and no association between APLs and atherosclerosis was identified. Conclusion: In contrast to other aPLs, aPS/PT IgG antibodies are independently associated with stroke or death in patients with TIA.
anticardiolipin; antiphospholipid; biomarker; infarction; thrombosis; transient ischemic attack; aPS/PT antibodies
The purpose of this study was to systematically compare clinical outcomes of patients treated with thrombolysis with those without treatment in a multi-year, multicenter cohort of strokes after cardiac catheterization.
Ischemic strokes after cardiac catheterization procedures, although uncommon, lead to the morbidity and mortality of thousands of patients each year. Despite the availability of Food and Drug Administration–approved thrombolytic therapy for acute ischemic stroke since 1996, thrombolysis remains unestablished in the setting of cardiac catheterization, owing to unique concerns regarding safety and efficacy.
Consecutive cases of ischemic stroke after cardiac catheterization were abstracted retrospectively and reviewed by clinicians at 7 major North American academic centers with acute stroke teams. Safety and efficacy outcome measures were pre-defined.
A total of 66 cases of ischemic strokes after cardiac catheterization were identified over 3 to 4 years; 12 (18%) were treated with thrombolysis, consisting of 7 intravenous and 5 intra-arterial recombinant tissue plasminogen activator cases. Improvement in stroke symptoms, as measured by the primary efficacy measure of median change in National Institutes of Health Stroke Scale score from baseline to 24 h, was greater in treated versus nontreated cases (p < 0.001). Additional secondary measures of efficacy also showed better outcomes in the treated group. There were no significant differences in bleeding events, defined as symptomatic intracerebral hemorrhage, hemopericardium, or other systemic bleeding resulting in hemodynamic instability or blood tranfusions. Mortality rates were also similar.
Thrombolysis might improve early outcomes after post-catheterization strokes and seems safe in this context. Emergent cerebral revascularization should be a routine consideration.
The initial therapeutic approach to acute ischemic stroke consists of thrombolytic therapy and early initiation of supportive care, usually commenced prior to the determination of the underlying stroke etiology. Varying stroke mechanisms may call for specific, etiology-based treatment. The majority of strokes result from cardioembolism, large-vessel atherothromboembolism, and small-vessel occlusive disease. There are scant data to support the use of acute anticoagulation therapy over anti-platelet therapy in cardioembolic stroke and large-vessel atherosclerosis, although it may be reasonable in a certain subset of patients. However, augmentation of blood flow with early surgery, stenting, or induced hypertension, may play a role in patients with large artery stenosis. The less commonly identified stroke mechanisms may warrant special consideration in treatment. Controversy remains regarding the optimal anti-thrombotic treatment of arterial dissection. Reversible cerebral vasoconstriction syndrome may benefit from therapy with calcium channel blockers, high-dose steroids, or magnesium, although spontaneous recovery may occur. Inflammatory vasculopathies, such as isolated angiitis of the central nervous system and temporal arteritis, require prompt diagnosis as the mainstay of therapy is immunosuppression. Cerebral venous thrombosis is a rare cause of stroke, but one that needs early identification and treatment with anticoagulation. Rapid determination of stroke mechanism is essential for making these critical early treatment decisions.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0041-5) contains supplementary material, which is available to authorized users.
Nonthrombolytic stroke therapy; Cardioembolic stroke; Large-artery atherosclerosis; Arterial dissection; Inflammatory cerebral vasculopathy; Cerebral venous thrombosis
Background and Purpose
To describe the occurrence of hemorrhagic transformation (HT) among children with arterial ischemic stroke (AIS) within 30 days after symptom onset and to describe clinical factors associated with HT.
Sixty-three children age 1 month to 18 years with AIS between January 2005 and November 2008 were identified from a single center prospective pediatric stroke registry. All neuroimaging studies within 30 days of stroke were reviewed by a study neuroradiologist. Hemorrhage was classified according to the European Cooperative Acute Stroke Study-1 definitions. Association of HT with clinical factors, systemic anticoagulation, stroke volume, and outcome was analyzed.
HT occurred in 19 of 63 children (30%; 95%CI 19–43%), only 2 (3%) of whom were symptomatic. Hemorrhage classification was HI1 in 14, HI2 in 2, PH1 in 2, and PH2 in 1. HT was less common in children with vasculopathy (RR 0.27; 95%CI 0.07–1.06; p=0.04) than in those with other stroke mechanisms. HT was not significantly associated with anticoagulation versus antiplatelet therapy (RR 0.6; 95%CI 0.2–1.5; p=0.26) but was associated with larger infarct volumes (p=0.0084). In multivariable analysis, worse PSOM scores were associated with infarct volume ≥5% of total supratentorial brain volume (OR 4.0; 95%CI 1.1–15; p=0.04), and a trend existed toward association of worse PSOM scores with HT (OR 4.0; 95%CI 0.9–18; p=0.07).
HT occurred in 30% of children with AIS within 30 days. Most hemorrhages were petechial and asymptomatic. Infarct volume was associated with HT and worse outcome.
hemorrhagic transformation; arterial ischemic stroke; anticoagulation; pediatric
Background and Purpose
To describe features of children with intracerebral hemorrhage (ICH) and to determine predictors of short-term outcome in a single-center prospective cohort study.
Single-center prospective consecutive cohort study of spontaneous ICH in children age 1-18 years from January 2006 to June 2008. Exclusion criteria were inciting trauma; intracranial tumor; isolated epidural, subdural, intraventricular, or subarachnoid hemorrhage; hemorrhagic transformation of ischemic stroke; and cerebral sinovenous thrombosis. Hospitalization records were abstracted. Follow-up assessments included outcome scores using the Pediatric Stroke Outcome Measure (PSOM) and King's Outcome Scale for Childhood Head Injury (KOSCHI). ICH volumes and total brain volumes (TBV) were measured by manual tracing.
Twenty-two patients, median age of 10.3 years (range 4.2-16.6 years), had presenting symptoms of headache in 77%, focal deficits 50%, altered mental status 50%, and seizures 41%. Vascular malformations caused hemorrhage in 91%. Surgical treatment (hematoma evacuation, lesion embolization or excision) was performed during acute hospitalization in 50%. One patient died acutely. At median follow-up of 3.5 months (range 0.3-7.5 months), 71% of survivors had neurological deficits; 55% had clinically significant disability. Outcome based on PSOM and KOSCHI scores was worse in patients with ICH volume >2% of TBV (p=0.023) and altered mental status at presentation (p = 0.005).
Spontaneous childhood ICH was due mostly to vascular malformations. Acute surgical intervention was commonly performed. Although death was rare, 71% of survivors had persisting neurological deficits. Larger ICH volume and altered mental status predicted clinically significant disability.
intracerebral hemorrhage; outcome; childhood; vascular malformation
Background. Cervicocephalic arterial dissection (CCAD) is rare in the postpartum period. To our knowledge this is the first reported case of postpartum angiopathy (PPA) presenting with ischemic stroke due to intracranial arterial dissection. Case. A 41-year-old woman presented with blurred vision, headache, and generalized seizures 5 days after delivering twins. She was treated with magnesium for eclampsia. MRI identified multiple posterior circulation infarcts. Angiography identified a complex dissection extending from both intradural vertebral arteries, through the basilar artery, and into both posterior cerebral arteries. Multiple segments of arterial dilatation and narrowing consistent with PPA were present. Xenon enhanced CT (Xe-CT) showed reduced regional cerebral blood flow that is improved with elevation in blood pressure. Conclusion. Intracranial vertebrobasilar dissection causing stroke is a rare complication of pregnancy. Eclampsia and PPA may play a role in its pathogenesis. Blood pressure management may be tailored using quantitative blood flow studies, such as Xe-CT.
“Diffuse correlation spectroscopy” (DCS) is a technology for non-invasive transcranial measurement of cerebral blood flow (CBF) that can be hybridized with “near-infrared spectroscopy” (NIRS). Taken together these methods hold potential for monitoring hemodynamics in stroke patients. We explore the utility of DCS and NIRS to measure effects of head-of-bed (HOB) positioning at 30°, 15°, 0°, −5° and 0° angles in patients with acute ischemic stroke affecting frontal cortex and in controls. HOB positioning significantly altered CBF, oxy-hemoglobin (HbO2) and total-hemoglobin (THC) concentrations. Moreover, the presence of an ipsilateral infarct was a significant effect for all parameters. Results are consistent with the notion of impaired CBF autoregulation in the infarcted hemisphere.
Cerebrovascular thrombosis is a major source of morbidity and mortality after surgery, but thromboprophylaxis in this setting is limited because of the formidable risk of perioperative bleeding. Thrombolytics (eg, tissue-type plasminogen activator [tPA]) cannot be used prophylactically in this high-risk setting because of their short duration of action and risk of causing hemorrhage and central nervous system damage. We found that coupling tPA to carrier red blood cells (RBCs) prolongs and localizes tPA activity within the bloodstream and converts it into a thromboprophylactic agent, RBC/tPA. To evaluate the utility of this new approach for preventing cerebrovascular thrombosis, we examined the effect of RBC/tPA in animal models of cerebrovascular thromboembolism and ischemia.
Methods and Results
Preformed fibrin microemboli were injected into the middle carotid artery of mice, occluding downstream perfusion and causing severe infarction and 50% mortality within 48 hours. Preinjected RBC/tPA rapidly lysed nascent cerebral thromboemboli, providing rapid, durable reperfusion and reducing morbidity and mortality. These beneficial effects were not achieved by preinjection of tPA, even at a 10-fold higher dose, which increased mortality from 50% to 90% by 10 hours after embolization. RBC/tPA injected 10 minutes after tail amputation to simulate postsurgical hemostasis did not cause bleeding from the wound, whereas soluble tPA caused profuse bleeding. RBC/tPA neither aggravated brain damage caused by focal ischemia in a filament model of middle carotid artery occlusion nor caused postthrombotic hemorrhage in hypertensive rats.
These results suggest a potential RBC/tPA utility as thromboprophylaxis in patients who are at risk for acute cerebrovascular thromboembolism.
erythrocytes; fibrinolysis; plasminogen activators; stroke
Background and Purpose
Echocardiography is often performed in stroke patients, even when alterative stroke etiologies are identified. We evaluated the utility of echocardiography in patients with TIA or stroke due to stenosis of a major intracranial artery.
The Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial was an NIH-funded randomized, double-blinded, multicenter clinical trial in which 569 patients with TIA or ischemic stroke attributed to angiographically-proven 50–99% stenosis of a major intracranial artery were randomly assigned to warfarin or aspirin. Patients with unequivocal cardiac sources of embolism were excluded. The risk of ischemic stroke, myocardial infarction (MI), and vascular death was compared among patients who had or did not have echocardiography performed prior to enrollment, and Cox proportional hazards models were employed to determine whether echocardiographic abnormalities present in >5% of subjects were associated with these outcomes.
264 of 569 patients in WASID had echocardiograms; 37% were transesophageal. Of these 264 patients, 69 suffered subsequent ischemic stroke, MI, or vascular death. Patients who underwent echocardiography had similar event rates to those who did not (p=0.18). Common abnormalities identified on echocardiography were not associated with subsequent risk in this population.
Among patients with TIA or stroke due to intracranial arterial stenosis, echocardiography appears to offer limited diagnostic and prognostic value.
To examine whether frontal lobe abnormalities on magnetic resonance spectroscopy (MRS) in amyotrophic lateral sclerosis (ALS) correlate with poor letter fluency (LF).
Twenty-five patients with ALS (20 with definite, probable, or possible ALS and 5 with progressive muscular atrophy) performed an LF task, involving F word generation in 1 minute, and underwent MRS. Comparisons were made between patients with ALS with impaired LF and unimpaired LF based on an empirically derived cutoff score. A Spearman correlation was performed between the patient's N-acetyl acetate/creatinine-phosphocreatinine ratio (NAA/Cr) and the number of F words generated.
LF was impaired in 50% of patients with ALS. Patients with impaired LF had reduced NAA/Cr in the DLPFC compared with those with unimpaired LF (p = 0.007). There was a significant correlation between LF and NAA/Cr in the DLPFC (r = 0.51, p = 0.0009). The ALS Functional Rating Scale score, clinical region of motor onset, and disease category had no effect on LF or NAA/Cr in the DLPFC.
A reduced NAA/Cr in the DLPFC of patients with ALS is a marker of neuronal dysfunction and correlates with impaired performance on a clinical measure of executive function.
Over one third of ischemic strokes occur in the posterior circulation, a leading cause of which is atherosclerotic vertebrobasilar disease (VBD). Symptomatic VBD carries a high annual recurrent stroke risk, averaging 10–15% per year. Endovascular angioplasty and stenting are increasingly employed, but carry risks, and the benefit remains unproven. Determining stroke predictors in this population is critical to identifying high risk patients for future trials of intervention. Preliminary studies indicate that stroke risk in VBD is strongly related to hemodynamic compromise, which can be measured noninvasively using quantitative magnetic resonance angiography (QMRA).
The VERiTAS Study, a prospective multi-center NIH funded observational study of symptomatic vertebrobasilar stenosis (≥ 50%) or occlusion, is designed to test the hypothesis that patients demonstrating compromised blood flow as assessed by QMRA are at higher stroke risk. The study will recruit 80 patients at 6 sites in North America over four years. Upon enrollment, subjects will undergo hemodynamic assessment with blinded QMRA to assess large vessel flow in the vertebrobasilar territory, and be prospectively designated as compromised or normal flow. Patients will be reimaged with QMRA at 6, 12 and 24 months, and followed for 12 to 24 months for the primary endpoint of stroke in the vertebrobasilar territory.
VERiTAS is the first prospective study of hemodynamics and stroke risk in the posterior circulation. The results may impact the selection criteria for interventional candidates and also define a low risk population in whom the risks of invasive interventions would be unnecessary.
stroke; vertebrobasilar ischemia; magnetic resonance imaging; quantitative magnetic resonance angiography; blood flow