Susan L. Benedict

Arterial ischemic stroke risk factors: The international pediatric stroke study

To describe presumptive risk factors (RFs) for childhood arterial ischemic stroke (AIS) and explore their relationship with presentation, age, geography, and infarct characteristics.

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.

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.

Cerebral Sinovenous Thrombosis in Children: Another Reason to Treat Iron Deficiency Anemia

Iron deficiency anemia is a rare cause of cerebral sinovenous thrombosis in children. We report three cases of cerebral sinovenous thrombosis and iron deficiency anemia treated at Primary Childrens Medical Center in Salt Lake City, Utah, between 1998 and 2001. The children were 9, 19, and 27 months old at the time of admission. Hemoglobin levels ranged from 6.6 to 7.0 g/dL, mean corpuscular volume levels from 45 to 56 fL, and platelet counts from 248,000 to 586,000/μL. Magnetic resonance imaging and magnetic resonance venography revealed thrombosis of the straight sinus and internal cerebral veins in all three children, with the addition of the vein of Galen, left transverse and sigmoid sinuses, and upper left internal jugular vein in one child. Recovery ranged from excellent to poor in 3 months to 3 years of follow-up. Four additional cases, ages 6 to 22 months, were found in the English-language literature. Evaluation for prothrombotic disorders was negative in all children, including the current cases. Treatments have included thrombectomy, corticosteroids, mannitol, heparin, low-molecular-weight heparin, warfarin, aspirin, blood transfusion, and iron supplementation, but there is no consensus regarding therapy, other than to correct the anemia and treat iron deficiency. Iron deficiency anemia, a preventable cause of cerebral sinovenous thrombosis, deserves consideration when cerebral sinovenous thrombosis is detected in young children. (J Child Neurol 2004;19:526—531).

Intra-arterial thrombolysis in a 2-year-old with cardioembolic stroke.

Recombinant tissue plasminogen activator, although the standard of care for the management of acute ischemic stroke in adults, is used infrequently in children. The authors describe the use of intra-arterial recombinant tissue plasminogen activator in a young child with embolic stroke. Thrombolysis restored flow to the affected middle cerebral artery and appeared to limit the extent of the infarction and the severity of the subsequent neurologic deficits.

Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study

Objectives We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). Methods Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. Results Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9–12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. Conclusions Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted.

Methylenetetrahydrofolate reductase gene polymorphism and childhood stroke.

Genotyping for the methylenetetrahydrofolate reductase gene (MTHFR) has been recommended for part of the evaluation for underlying prothrombotic state in childhood stroke; however, studies are inconclusive regarding the role of this gene and also the role of hyperhomocysteinemia, which is the putative mechanism by which MTHFR polymorphism is related to stroke. The prevalence of MTHFR polymorphism in childhood arterial ischemic stroke and cerebral sinovenous thrombosis was compared with that of a reference population, and prevalence of hyperhomocysteinemia was reviewed. In arterial ischemic stroke, the prevalence of at-risk methylenetetrahydrofolate reductase genotypes was 27%, and in cerebral sinovenous thrombosis it was 13%; the population prevalence was 26%. The odds ratio for at-risk genotype in childhood arterial ischemic stroke was 1.06 (95% confidence interval, 0.22-4.0); in cerebral sinovenous thrombosis, it was 0.42 (95% confidence interval, 0.01-3.6). No tested cases had hyperhomocysteinemia. MTHFR polymorphism and hyperhomocysteinemia were not risk factors in childhood arterial ischemic stroke or cerebral sinovenous thrombosis in the Intermountain West region.

Failure to impact prevalence of arterial ischemic stroke in pediatric cardiac patients over three decades.

INTRODUCTION Over the past three decades, significant advances in treatment have improved the mortality of children with cardiac disease. The effect of these advances on the prevalence of arterial ischemic stroke (AIS) is unknown. We describe AIS in children with cardiac disease in the modern era. DESIGN The prospectively enrolled Intermountain Pediatric Stroke Database (including Utah, Wyoming, Idaho, and Nevada) was queried for all patients less than 18 years old with new-onset AIS between January 1, 2003 and August 31, 2009. Medical records of patients with AIS and cardiac disease were reviewed for cardiac diagnosis, age at AIS, anticoagulant therapy, diuretics, hematocrit, bolus fluids, and ongoing morbidity. Data were analyzed using chi-square test and a mixed-effects Poisson regression growth curve model. RESULTS AIS incidence in our catchment area was 0.01% (10.7/100,000; N = 97). The incidence of AIS in patients with cardiac disease was higher compared with AIS in the total population (incidence 0.13% [132/100,000], odds ratio [OR] 16.1, 95% confidence interval [CI; 9.7--25.9], P < 0.001). Of the 97 patients with AIS, 24 had cardiac disease (25%). The most common cardiac diagnosis was single ventricle (SV; 8/24, 33%). The incidence of AIS in patients with SV cardiac disease was higher compared with those with other cardiac diagnoses (incidence 1.38% [1380/100,000], OR 15.3, 95% CI [5.7--38.2], P < 0.001). Modeling the prevalence estimates reported since 1978, the prevalence of cardiac disease in AIS patients has remained unchanged across time (prevalence increase per each additional year, 0.5%, 95% CI [--2.1%, 3.1%], P = 0.71). CONCLUSION Children with cardiac disease (particularly those with SV) have increased risk for AIS. The prevalence is unchanged from reports over previous decades. AIS occurred in SV patients despite compliance with current anticoagulation recommendations. Future efforts should focus on best practices to prevent AIS in cardiac patients.

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence.

Background and Purpose— Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. Methods— In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-&agr;. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. Results— Median age at index stroke was 8.2 years (interquartile range, 3.6–14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3–10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. Conclusions— Among children with AIS, specific inflammatory biomarkers correlate with cause and—in the arteriopathy group—risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS.In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS.Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies.Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.