Timothy J. Bernard

Impact of Thrombophilia on Risk of Arterial Ischemic Stroke or Cerebral Sinovenous Thrombosis in Neonates and Children A Systematic Review and Meta-Analysis of Observational Studies

Background— The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results— A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS), 6.95 (95% CI, 3.67 to 13.14); elevated lipoprotein(a), 6.27 (95% CI, 4.52 to 8.69), and combined thrombophilias, 11.86 (95% CI, 5.93 to 23.73). In the 6 exclusively perinatal AIS studies, summary ORs were as follows: factor V, 3.56 (95% CI, 2.29 to 5.53); and factor II, 2.02 (95% CI, 1.02 to 3.99). Conclusions— The present meta-analysis indicates that thrombophilias serve as risk factors for incident stroke. However, the impact of thrombophilias on outcome and recurrence risk needs to be further investigated.

Predictors of Cerebral Arteriopathy in Children With Arterial Ischemic Stroke Results of the International Pediatric Stroke Study

Background— Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with arterial ischemic stroke. Methods and Results— Between January 2003 and July 2007, 30 centers within the International Pediatric Stroke Study enrolled 667 children (age, 29 days to 19 years) with arterial ischemic stroke and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or postvaricella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56, 20%). Predictors of arteriopathy include early school age (5 to 9 years), recent upper respiratory infections, and sickle cell disease, whereas prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent upper respiratory infection. Conclusions— Arteriopathy is prevalent among children with arterial ischemic stroke, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent upper respiratory infection predicted cerebral arteriopathy and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.

Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study

BACKGROUND For childhood-onset arterial ischaemic stroke (AIS), treatment trials are lacking and practices vary from country to country and centre to centre. We aimed to describe frequencies and predictors of acute treatments and early outcomes in the International Pediatric Stroke Study (IPSS), a large international series of childhood AIS. METHODS The IPSS has 33 centres enrolling children with stroke. Data for children aged 28 days to 19 years with AIS from Jan 1, 2003, to Oct 1, 2007, were collected with standardised case-report forms and analysed to identify factors associated with stroke treatment and early prognosis. FINDINGS Among 661 children with AIS (640 with acute treatment data, 612 with morbidity data, and 643 with mortality data), acute treatments included anticoagulation alone in 171 patients (27%), antiplatelet therapy alone in 177 (28%), antiplatelet and anticoagulation in 103 (16%), and no antithrombotic treatment in 189 (30%). After adjustment for significant covariates, subtypes associated with any use of anticoagulation were dissection (odds ratio 14.09, 95% CI 5.78-37.01; p<0.0001) and cardiac disease (1.87, 1.20-2.92; p=0.01). Factors associated with non-use of anticoagulation included sickle-cell disease subtype (0.12, 0.02-0.95; p=0.04) and the enrolment centre being located in the USA (0.56, 0.39-0.80; p=0.002). By contrast, antiplatelet use was associated with moyamoya (4.88, 2.13-11.12; p=0.0002), whereas non-use was associated with dissection (0.47, 0.22-0.99; p=0.047), low level of consciousness (0.45, 0.31-0.64; p<0.0001), and bilateral ischaemia (0.32, 0.20-0.52; p<0.0001). Outcomes at hospital discharge included neurological deficits in 453 (74%) patients and death in 22 (3%). In multivariate analysis, arteriopathy, bilateral ischaemia, and decreased consciousness at presentation were prognostic of adverse outcome. INTERPRETATION Acute anticoagulation is commonly prescribed in acute childhood-onset AIS although practice varies with AIS subtype and geographical region. Several factors are prognostic of adverse early outcome, and clinical trials are needed to determine the best treatment strategies.

Towards a Consensus-Based Classification of Childhood Arterial Ischemic Stroke

Background and Purpose— The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Methods— Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinicians current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted &kgr;-statistic. Results— In Group 1 (with training), IRR was improved using CASCADE criteria (&kgr;=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (&kgr;=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (&kgr;=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (&kgr;=0.23, 95% CI=[0.03, 0.36]). Conclusions— A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Role of endogenous testosterone concentration in pediatric stroke

Previous studies have indicated a male predominance in pediatric stroke. To elucidate this gender disparity, total testosterone concentration was measured in children with arterial ischemic stroke (AIS; n = 72), children with cerebral sinovenous thrombosis (CSVT; n = 52), and 109 healthy controls. Testosterone levels above the 90th percentile for age and gender were documented in 10 children with AIS (13.9%) and 10 with CSVT (19.2%), totaling 16.7% of patients with cerebral thromboembolism overall, as compared with only 2 of 109 controls (1.8%; p = 0.002). In multivariate analysis with adjustment for total cholesterol level, hematocrit, and pubertal status, elevated testosterone was independently associated with increased disease risk (odds ratio [95% confidence interval]: overall = 3.98 [1.38–11.45]; AIS = 3.88 [1.13–13.35]; CSVT = 5.50 [1.65–18.32]). Further adjusted analyses revealed that, for each 1nmol/l increase in testosterone in boys, the odds of cerebral thromboembolism were increased 1.3‐fold. Ann Neurol 2009;66:754–758

Emergence of the Primary Pediatric Stroke Center Impact of the Thrombolysis in Pediatric Stroke Trial

Background and Purpose— In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. Methods— We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. Results— Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P⩽0.001). Conclusions— Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01591096.

Arteriopathy Diagnosis in Childhood Arterial Ischemic Stroke Results of the Vascular Effects of Infection in Pediatric Stroke Study

Background and Purpose Although arteriopathies are the most common cause of childhood arterial ischemic stroke (AIS), and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with AIS.Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (&kgr;=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Treatment of childhood arterial ischemic stroke.

Traditional risk factors associated with adult arterial ischemic stroke (AIS; ie, hypertension, hyperlipidemia, diabetes, smoking, and atherosclerosis) are relatively rare in children. Childhood AIS is instead associated with a variety of conditions including cerebral arteriopathies, congenital heart disease, infection, head and neck trauma, sickle cell anemia, and prothrombotic abnormalities. Although the pathophysiology and outcomes of adult AIS differ significantly from those in childhood AIS, therapeutic management remains similar, largely because of the paucity of evidence from devoted pediatric observational studies and clinical trials. The purpose of this article is to review the current guidelines and evidence in the treatment of childhood AIS, within the context of that which exists in adult AIS. Medical management of hypoxia, hyperglycemia, fever, blood pressure, and increased intracranial pressure has been insufficiently investigated in childhood stroke, resulting in a lack of guidance in these areas. Although acute antithrombotic management in childhood AIS has received relatively greater attention in published recommendations, it is based almost exclusively on consensus and expert opinion, and differs considerably among existing pediatric guidelines. Rehabilitation therapy in childhood AIS has great potential for meaningful improvements in long‐term outcomes, especially given the plasticity of the young brain; however, little guidance for rehabilitative measures is provided by published recommendations. Ongoing and future multicenter cohort study efforts, and ultimately devoted pediatric clinical trials, will be essential to establish comprehensive evidence‐based guidelines for the treatment of childhood AIS. Ann Neurol 2008

Risk of Recurrent Arterial Ischemic Stroke in Childhood A Prospective International Study

Background and Purpose— Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era. Methods— The Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review. Results— Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0–3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%–10%) at 1 month and 12% (8.5%–15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8–14). The 1-year recurrence rate was 32% (95% confidence interval, 18%–51%) for moyamoya, 25% (12%–48%) for transient cerebral arteriopathy, and 19% (8.5%–40%) for arterial dissection. Conclusions— Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.

Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children

Lipoprotein (a) is a risk factor for adult cardiovascular events, in which the apolipoprotein (a) component is thought to promote atherogenesis and impair fibrinolysis. We investigated whether elevated plasma lipoprotein (a) concentration and small predominant apolipoprotein (a) isoform size (number of kringle-4 domains) are risk factors for childhood arterial ischemic stroke and correlate with plasma fibrinolytic function. Patients who had had an arterial ischemic stroke in childhood (29 days - <21 years at onset; n=43) and healthy controls (n=127) were recruited for plasma sampling and laboratory determinations. Cases were followed for recurrence in a prospective cohort study. The median lipoprotein (a) concentration did not differ between groups [cases: median 18.0 nmol/L (7.5 mg/dL) and observed range 0.9–259 nmol/L (0.38–108.0 mg/dL), controls: 20.4 nmol/L (8.5 mg/dL) and 0.2–282 nmol/L (0.08–117.5 mg/dL); P=0.62]. While odds of incident stroke were not significantly increased, risks of recurrent arterial ischemic stroke were each more than ten-times increased for lipoprotein(a) >90th percentile of race-specific reference values and apolipoprotein (a) <10th percentiles [odds ratio=14.0 (95% confidence interval: 1.0–184), P=0.05 and odds ratio=12.8 (1.61–101), P=0.02]. Statistically significant but weak correlations were observed between euglobulin lysis time and both lipoprotein (a) level (r=0.18, P=0.03) and apolipoprotein (a) size (r= −0.26, P=0.002). In conclusion, elevated lipoprotein (a) and small apolipoprotein (a) potently increase the risk of recurrent arterial ischemic stroke in children, with a mechanism only partially attributable to impaired fibrinolysis. Collaborative studies are warranted to investigate these findings further and, more broadly, to establish key risk factors for incident and recurrent arterial ischemic stroke in children.