Sally Sultan

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.

Circle of Willis configuration as a determinant of intracranial dolichoectasia.

Background: Circle of Willis (COW) variants might influence arterial caliber in the brain. We hypothesized that these variants would be associated with the prevalence of intracranial dolichoectasia (DE). Methods: We examined COW variants and DE in a sample of stroke-free participants (n = 436) undergoing magnetic resonance angiography (MRA) as part of a population-based study. Large intracranial arterial diameters were obtained when available; if not, the artery was defined as hypoplastic or absent according to its visibility on MRA. Subscores for the anterior and the posterior circulations were created. DE was defined as arterial diameters ≥2 SD above the population mean for that artery, adjusting for intracranial volume. Generalized linear models with a Poisson distribution were used to evaluate predictors of both absent and hypoplastic vessels, and logistic regression was used to assess the odds ratio (OR) and 95% confidence interval (95% CI) of DE depending on COW variants. Results: Only 44% of the sample had all 14 arteries present, 32% lacked 1 artery, 18% lacked 2 and 6% lacked 3 or more. DE of at least 1 artery was not associated with the total number of hypoplastic or absent arteries, but DE in a posterior circulation artery was weakly associated with the number of absent arteries in the posterior circulation (β coefficient = 0.36, p = 0.06). DE of at least 1 artery was more frequent in those with 1 or more absent arteries (OR 1.27, 95% CI 1.03-1.57). Posterior circulation DE was more frequent in participants with at least 1 or more absent arteries at any location (OR 1.35, 95% CI 1.02-1.78). Participants with an incomplete posterior COW were more likely to have DE in the anterior circulation (OR 1.52, 95% CI 1.01-2.33). Having an absent left anterior cerebral artery (ACA) A1 segment was associated with right ACA DE (OR 34.1, 95% CI 3.16-368.2); an absent right ACA was associated with left ACA DE (OR 14.1, 95% CI 1.69-118.28). Absence of 1 (OR 1.9, 95% CI 1.1-3.4) or 2 (OR 3.0, 95% CI 1.4-6.6) of the 2 arteries connecting the anterior to the posterior circulation was associated with basilar artery DE. Conclusion: The COW is a pleomorphic structure that allows collateral flow to compensate for an insufficient or absent arterial component at the base of the skull. By presumed flow diversion, arteries might undergo outward remodeling. Whether this compensatory arterial dilatation is beneficial or not remains unknown.

Stroke in young adults On the rise

Stroke has traditionally been considered a disease of the elderly, its incidence doubling with each decade after age 50. Given the aging of the population of the developed world, prevalent stroke is projected to increase by 24.9% over the next 20 years.1 In this light, decreasing overall stroke incidence rates in the 21st century are welcome news. The Framingham Heart Study reported a decline in age-adjusted stroke incidence per 1,000 person-years from 1950 to 2004 …

Review of Lipid and Lipoprotein(a) Abnormalities in Childhood Arterial Ischemic Stroke

National organizations recommend cholesterol screening in children to prevent vascular disease in adulthood. There are currently no recommendations for cholesterol and lipoprotein (a) testing in children who experience an arterial ischemic stroke. While dyslipidemia and elevated lipoprotein (a) are associated with ischemic stroke in adults, the role of atherosclerotic risk factors in childhood arterial ischemic stroke is not known. A review of the literature was performed from 1966 to April 2012 to evaluate the association between childhood arterial ischemic stroke and dyslipidemia or elevated lipoprotein (a). Of 239 citations, there were 16 original observational studies in children (with or without neonates) with imaging-confirmed arterial ischemic stroke and data on cholesterol or lipoprotein (a) values. Three pairs of studies reported overlapping subjects, and two were eliminated. Among 14 studies, there were data on cholesterol in 7 and lipoprotein (a) in 10. After stroke, testing was performed at >three-months in nine studies, at ≤three-months in four studies, and not specified in one study. There were five case-control studies: four compared elevated lipoprotein (a) and one compared abnormal cholesterol in children with arterial ischemic stroke to controls. A consistent positive association between elevated lipoprotein (a) and stroke was found [Mantel-Haenszel OR 4.24 (2.94–6.11)]. There was no association in one study on total cholesterol, and a positive association in one study on triglycerides. The literature suggests that elevated lipoprotein (a) may be more likely in children with arterial ischemic stroke than in control children. The absence of confirmatory study on dyslipidemia should be addressed with future research.

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.

Orbital Hemangioma with Intracranial Vascular Anomalies and Hemangiomas: A New Presentation of PHACE Syndrome?

We present two cases of infants with a similar constellation of clinical findings: retro‐orbital infantile hemangioma (IH), internal carotid artery (ICA) arteriopathy, and intracranial IH. In both cases, intracranial vascular anomalies and hemangiomas were found incidentally during evaluation of unilateral proptosis. Neither infant had evidence of cutaneous segmental IH of the face or neck, which might have provided a clue to the diagnosis of PHACE syndrome or of intracranial hemangiomas. In one case, intracranial involvement was particularly extensive and function threatening, with mass effect on the brain parenchyma. These cases serve to highlight the fact that clinical findings of proptosis, globe deviation, and strabismus should prompt immediate imaging to confirm the presence of orbital IHs and to exclude other diagnoses. Moreover, based on our cases and the embryologic origin of the orbit as a unique developmental unit, patients with confirmed retro‐orbital IHs should undergo evaluation for anomalies associated with PHACE syndrome. Patients with orbital IHs and an additional major criterion for PHACE syndrome should be considered to have definite, and not just possible, PHACE syndrome.

Predictive validity of severity grading for cerebral steno‐occlusive arteriopathy in recurrent childhood ischemic stroke

Background Cerebral arteriopathy is a risk factor for incident and recurrent childhood AIS. There are no standardized criteria to quantify arteriopathy severity. Aims To evaluate a method of scoring severity of steno-occlusive arteriopathy in childhood arterial ischemic stroke (AIS) and its association with recurrence. Methods In a single-center prospectively enrolled cohort of 49 children with first AIS and arteriopathy, a composite cerebrovascular stenosis score (CVSS) was measured by two independent raters as the sum of stenosis scores in each of 18 intracranial large and medium arteries, where 0 = none; 1 = low-grade, 1–50%; 2 = high-grade, >50–99%; 3 = occlusion, 100%. Cox proportional-hazards models were used to determine the association of CVSS with recurrence. The analysis was stratified by presence or absence of moyamoya arteriopathy (syndrome or disease). Results At a median follow-up period of 2·5 years (range: 0·8–9), 18/49 children (37%) experienced a recurrence. Median time to recurrence was 0·2 (range: 0·02–2·8) years. Interrater agreement was good, with an intraclass correlation coefficient of 0·77 [95% confidence interval (CI) 0·63–0·87, P < 0·001). Higher CVSS was associated with higher recurrence rate [hazard ratio (HR) per point 1·09, 95% CI 1·04–1·16, P = 0·001]. Among those with moyamoya arteriopathy, CVSS was associated with recurrence (HR per point of CVSS 1·11, 95% CI 1·03–1·19, P = 0·004), but there was no association in those without moyamoya arteriopathy (HR per point of CVSS 0·91, 95% CI 0·75–1·09, P = 0·32). Conclusions The CVSS is a reliable measure of severity of steno-occlusive arteriopathy in childhood stroke. This preliminary study suggests that higher CVSS is associated with stroke recurrence in children with moyamoya arteriopathy.

Predictors of Cholesterol and Lipoprotein(a) Testing in Children with Arterial Ischemic Stroke

BACKGROUND Professional societies recommend screening lipids in healthy children. Dyslipidemia and elevated lipoprotein(a) are risk factors for adult cardiovascular disease and stroke. Their role in childhood arterial ischemic stroke is unexplored. Inconsistencies in testing limit analysis of existing lipid data. The objective of this study is to identify predictors and modifiable barriers to lipid testing in pediatric stroke. METHODS In this cross-sectional analysis, children (28 days-18 years) with arterial ischemic stroke were identified from the International Pediatric Stroke Study registry (January 2003-April 2012). Analyzed predictors of recorded lipid or lipoprotein a (Lp(a)) testing were age, sex, race, ethnicity, body mass index (BMI) category, other stroke risk factors, country, US region, and recurrent thrombosis. RESULTS Among 1652 participants (median, 6 years [interquartile range, 1.7-12.7]; 59.0% male; 40.8% white; 7.0% black), at least 1 lipid parameter or Lp (a) was available for 461 (27.9%). Compared with infants, testing was incrementally higher for older age categories. Compared with whites, testing was lower in blacks (adjusted odds ratio [OR], .5; 95% confidence interval [CI], .4-.5; P < .0001). Hispanic ethnicity only predicted testing within the United States (OR, 2.2; 95% CI, 1.4-3.4; P = .001]. Testing was lower in the United States and Australia and higher in Chile. Any thrombotic recurrence and recurrent symptomatic arterial ischemic stroke were associated with testing, unlike male sex, BMI, other stroke risk factors, and region in the United States. CONCLUSIONS Only a quarter of children with stroke had recorded lipid testing. Older age, white race, and recurrence predicted testing. In future study adjusting for these predictors may be necessary. Standardized lipid testing in children with arterial ischemic stroke may further our understanding of this potential risk factor.