Supplementary Material for: Symptomatic Intracranial Hemorrhage following Intravenous Thrombolysis for Acute Ischemic Stroke: A Critical Review of Case Definitions

<b><i>Background:</i></b> Symptomatic intracranial hemorrhage (SICH) is a devastating complication of intravenous thrombolysis treatment that is associated with high mortality. Clinical trials, stroke registries and cohort studies employ different case definitions to identify stroke patients with SICH following intravenous thrombolysis. We systematically reviewed the reported rates of SICH following intravenous thrombolysis and compared their consistency with mortality outcomes. <b><i>Methods:</i></b> Studies were identified from the PubMed and Embase databases from January 1994 to July 2011 by cross-referencing the following MeSH terms: ‘thrombolysis’, ‘recombinant tissue plasminogen activator’, ‘rtPA’, ‘hemorrhagic stroke’, ‘cerebral hemorrhage’, ‘hematoma’ and ‘ischemic stroke’. Demographic information, baseline National Institute of Health Stroke Scale (NIHSS) scores, time from stroke onset to intravenous thrombolysis, SICH and mortality rates were derived from published data in 7 randomized controlled trials, 7 stroke registries and 10 cohort studies (4 multicenter and 6 single center) with more than 200 consecutively recruited patients. Mortality rates were considered as the percentage of patients treated with intravenous thrombolysis who died within 90 days after stroke. <b><i>Results:</i></b> The mean age of patients included in this analysis was 68.8 years (standard deviation, SD 2.9, range 63–75), of whom 56.3% (SD 4.5, range 45–63) were men. They presented with a mean baseline NIHSS of 12.5 (SD 1.4, range 9–15) and received intravenous thrombolysis 175 min (SD 62, range 120–328) from stroke onset. The overall mean SICH and mortality rates of patients treated with intravenous thrombolysis were 5.6% (SD 2.3) and 14.7% (SD 4.8), respectively. A moderate correlation was observed between the incidence of SICH and mortality in patients treated with intravenous thrombolysis (r = 0.401, p = 0.050). The variation in SICH rates was highest across studies that reported SICH rates using the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria compared with the European Cooperative Acute Stroke Study and National Institute of Neurological Disorders and Stroke (NINDS) criteria. Studies that defined SICH as parenchymal hemorrhage with a neurological decline NIHSS ≥4 occurring within 36 h of intravenous thrombolysis reported a higher consistency between SICH and mortality rates (correlation coefficient 0.631). <b><i>Conclusions:</i></b> SICH rates vary considerably between studies and these differences may relate to the differences in the criteria used to define SICH. Until a case definition with high interrater agreement and good correlation with stroke outcomes becomes available, detailed information on the type of bleeding, the extent of NIHSS deterioration, neuroimaging features and the time from thrombolysis to diagnosis of hemorrhage should be reported to permit a correct interpretation of SICH rates

Supplementary Material for: Asymptomatic Carotid Stenosis: Risk of Progression and Development of Symptoms

<b><i>Background:</i></b> The aim of this study is to evaluate the rate of progression of stenosis and development of symptoms in patients with asymptomatic carotid artery stenosis (aCAS) treated with contemporary medical therapy over a prolonged time interval. <b><i>Methods:</i></b> This study is a retrospective review of consecutive patients diagnosed with moderate or severe aCAS at our institution between 2000 and 2001. Data were gathered from both carotid arteries for each patient excluding vessels operated within 1 year of diagnosis and occlusions. Multivariate analysis was performed to analyze factors associated with ipsilateral transient ischemic attack (TIA)/stroke. <b><i>Results:</i></b> We identified 214 patients (58.8% men; median age 70 years) and collected data on 349 vessels. Degree of stenosis was severe (>70%) upon diagnosis in 92 (26.4%) vessels. Median length of follow-up was 13 years (interquartile range 10-14), and mean number of time points for follow-up imaging were 8.1 ± 3.9. Progression of stenosis was observed in 237 (67.9%) vessels, and 72 (20.6%) patients developed symptoms ipsilateral to the stenosis (TIA in 14.4%, non-disabling stroke in 4%, disabling stroke in 2.2%). Median time to appearance of first symptom was 6 years (range 1-13). On multivariate analysis, degree of baseline stenosis, intracranial stenosis >50%, plaque ulceration, silent infarction and previous history of TIA/stroke were associated with ipsilateral TIA/stroke, but progression of stenosis was not. <b><i>Conclusions:</i></b> There was a substantial rate of progression of stenosis in patients with aCAS over time despite adequate medical therapy, but progression of stenosis did not increase the risk of ipsilateral TIA/stroke. Over long-term follow-up, 1 in 5 patients with aCAS developed ipsilateral TIA/stroke, though most events were either transient or non-disabling

Supplementary Material for: Ultrasound Characteristics of Symptomatic Carotid Plaques: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Ultrasound is the most commonly used imaging modality for assessing carotid artery stenosis. A number of studies have demonstrated that surface irregularities, heterogeneous echotexture and hypoechoic plaques are risk factors for acute ischemic stroke. We performed a systematic review and meta-analysis of the literature to better define the risk of stroke based on the sonographic characteristics of carotid plaques. <b><i>Materials and Methods:</i></b> We performed a comprehensive search for studies reporting imaging findings of symptomatic and asymptomatic carotid plaques on ultrasound using MEDLINE and EMBASE. We included both case-control and cohort studies examining the relationship between complex plaque and acute ischemic stroke or transient ischemic attack. Complex plaque was defined as plaque that had any of the following characteristics: heterogeneous echogenicity, echolucency, neovascularization, surface irregularity, ulceration, and intraplaque motion. Meta-analyses using the random-effects model were performed for complex plaque and each of the individual complex plaque characteristics. p < 0.05 was considered statistically significant. We explored the impact of publication bias by constructing funnel plots and testing their symmetry. We conducted the meta-analysis using Comprehensive Meta-analysis version 2.2, Englewood, N.J., USA. <b><i>Results:</i></b> A total of 1,013 articles were screened and 23 studies with 6,706 carotid plaques were included. Ultrasound plaque characteristics with a higher prevalence in individuals with symptomatic compared to asymptomatic carotid artery stenosis included plaque neovascularity (OR = 19.68, 95% CI = 3.14-123.16), complex plaque (OR = 5.12, 95% CI = 3.42-7.67), plaque ulceration (OR = 3.58, 95% CI = 1.66-7.71), plaque echolucency (OR = 3.99, 95% CI = 3.06-5.19) and intraplaque motion (OR = 1.57, 95% CI = 1.02-2.41). Variables not associated with symptom status included heterogenous echotexture (OR = 2.68, 95% CI = 0.56-12.80) and surface irregularity without ulceration (OR = 2.38, 95% CI = 0.70-8.11). No evidence of publication bias was observed based on Eggers test (p value of 0.05 for complex plaque and 0.53 for plaque echolucency). The remaining plaque features had insufficient data to assess for publication bias. <b><i>Conclusions:</i></b> Our meta-analysis and systematic review of the literature demonstrated that plaques with complex features, particularly those with echolucency, neovascularization, ulceration and intraplaque motion are associated with ischemic symptoms. Assessment of carotid plaque on ultrasound may provide stroke risk information beyond measurement of luminal stenosis. Thus, sonographic evaluation of carotid artery stenosis should focus on the detection of these plaque characteristics in addition to quantifying the degree of stenosis