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Objectives: Minor infection can trigger adult arterial ischemic stroke (AIS) and is common in childhood. We tested the hypotheses that infection transiently increases risk of AIS in children, regardless of stroke subtype, while vaccination against infection is protective., Methods: The Vascular Effects of Infection in Pediatric Stroke study is an international case-control study that prospectively enrolled 355 centrally confirmed cases of AIS (29 days-18 years old) and 354 stroke-free controls. To determine prior exposure to infections and vaccines, we conducted parental interviews and chart review., Results: Median (interquartile range) age was 7.6 years for cases and 9.3 for controls (p = 0.44). Infection in the week prior to stroke, or interview date for controls, was reported in 18% of cases, vs 3% of controls, conferring a 6.3-fold increased risk of AIS (p < 0.0001); upper respiratory infections were most common. Prevalence of preceding infection was similar across stroke subtypes: arteriopathic, cardioembolic, and idiopathic. Use of vasoactive cold medications was similarly low in both groups. Children with some/few/no routine vaccinations were at higher stroke risk than those receiving all or most (odds ratio [OR] 7.3, p = 0.0002). In an age-adjusted multivariate logistic regression model, independent risk factors for AIS included infection in the prior week (OR 6.3, p < 0.0001), undervaccination (OR 8.2, p = 0.0004), black race (compared to white; OR 1.9, p = 0.009), and rural residence (compared to urban; OR 3.0, p = 0.0003)., Conclusions: Infection may act as a trigger for childhood AIS, while routine vaccinations appear protective. Hence, efforts to reduce the spread of common infections might help prevent stroke in children., (© 2015 American Academy of Neurology.)

Objective: To estimate the rates and predictors of recurrent stroke among survivors of pediatric cancer who have had a first stroke., Methods: The Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal follow-up that enrolled 14,358 survivors (<21 years old at diagnosis; diagnosed 1970-1986; survived ≥5 years after cancer diagnosis) and followed them prospectively since 1994. We surveyed 443 survivors who reported a first stroke to identify recurrent stroke, and estimated recurrent stroke rates ≥5 years after cancer diagnosis., Results: Among 329 respondents (74% response rate), 271 confirmed a first stroke at a median age of 19 years (range 0-53), and 70 reported a second stroke at a median age of 32 years (range 1-56). In a multivariable Cox proportional hazards model, independent predictors of recurrent stroke included cranial radiation therapy (CRT) dose of ≥50 Gy (vs none, hazard ratio [HR] 4.4; 95% confidence interval [CI] 1.4-13.7), hypertension (HR 1.9; 95% CI 1.0-3.5), and older age at first stroke (HR 6.4; 95% CI 1.8-23; for age ≥40 vs age 0-17 years). The 10-year cumulative incidence of late recurrent stroke was 21% (95% CI 16%-27%) overall, and 33% (95% CI 21%-44%) for those treated with ≥50 Gy of CRT., Conclusion: Survivors of childhood cancer, particularly those previously treated with high-dose cranial radiation, have a high risk of recurrent stroke for decades after a first stroke. Although these strokes are mostly occurring in young adulthood, hypertension, an established atherosclerotic risk factor, independently predicts recurrent stroke in this population., (© 2015 American Academy of Neurology.)

Although transcranial Doppler (TCD) screening assesses the need for stroke prevention efforts among children with sickle cell disease (SCD), screening rates remain low across many parts of the United States. We sought to identify neighborhoods with low TCD screening rates and neighborhood-level factors related to screening to inform the utility of community-level interventions to improve TCD screening. Children ages 2 to 16 years with SCD (HbSS/HbS/β-thalassemia) living in Wayne County, MI, were identified in Michigan Medicaid (2007 to 2011) through newborn screening records. Children were enrolled for ≥ 1 year and could contribute multiple years. We determined receipt of ≥ 1 TCD screening and neighborhood (census tract) each year. The proportion of children receiving TCD in the tract was calculated and investigated for spatial patterns across tracts (Moran's I). Median household income, % unemployment, % black residents, and % less than high school education within each tract were ascertained from the American Community Survey. Logistic regression with generalized estimating equations was used to model associations between TCD screening and neighborhood-level factors. Overall, 329 children contributed 532 person-years and screening rates increased from 7% to 36% from 2007 to 2011. Median screening rate in tracts was 0% (interquartile range = 29%) and there was no spatial pattern of TCD screening across tracts (Moran's I Z-score = -0.94, P-value = 0.35). No associations were found between neighborhood characteristics and receipt of TCD screening in this disadvantaged Michigan county. Additional research is needed to inform interventions to increase TCD screening in this high stroke-risk population.

Objective: We explored factors that may influence physician adherence to transcranial Doppler (TCD) screening guidelines among children with sickle cell disease., Methods: Pediatric hematologists, neurologists, and primary care physicians (n = 706) responded to a mailed survey in May 2012 exploring factors hypothesized to influence physician adherence to TCD screening guidelines: physician (internal) barriers and physician-perceived external barriers. Responses were compared by specialty using chi-square tests., Results: Among 276 physicians (44%), 141 currently treated children with sickle cell disease; 72% recommend screening. Most primary care physicians (66%) did not feel well informed regarding TCD guidelines, in contrast to neurologists (25%) and hematologists (6%, P < .0001). Proportion of correct answers on knowledge questions was low (13%-35%). Distance to a vascular laboratory and low patient adherence were external barriers to receipt of TCD screening., Conclusions: Additional research regarding physicians' lack of self-efficacy and knowledge of recommendations could help clarify their role in recommendation of TCD screening., (© The Author(s) 2014.)

Background and Purpose: A better understanding of the stroke risk factors in children with congenital heart disease (CHD) could inform stroke prevention strategies. We analyzed pediatric stroke associated with CHD in a large community-based case-control study., Methods: From 2.5 million children (aged <20 years) enrolled in a Northern California integrated healthcare plan, we identified children with ischemic and hemorrhagic strokes and randomly selected age- and facility-matched stroke-free controls (3 per case). We determined exposure to CHD (diagnosed before stroke) and used conditional logistic regression to analyze stroke risk factors., Results: CHD was identified in 15 of 412 cases (4%) versus 7 of 1236 controls (0.6%). Cases of childhood stroke (occurring between ages 29 days to 20 years) with CHD had 19-fold (odds ratio, 19; 95% confidence interval 4.2-83) increased stroke risk compared to controls. History of CHD surgery was associated with >30-fold (odds ratio, 31; confidence interval 4-241) increased risk of stroke in children with CHD when compared with controls. After excluding perioperative strokes, the history of CHD surgery still increased the childhood stroke risk (odds ratio, 13; confidence interval 1.5-114). The majority of children with stroke and CHD were outpatients at the time of stroke, and almost half the cases who underwent cardiac surgery had their stroke >5 years after the most recent procedure. An estimated 7% of ischemic and 2% of hemorrhagic childhood strokes in the population were attributable to CHD., Conclusions: CHD is an important childhood stroke risk factor. Children who undergo CHD surgery remain at elevated risk outside the perioperative period and would benefit from optimized long-term stroke prevention strategies., (© 2014 American Heart Association, Inc.)

Objective: To determine what the trends in stroke mortality have been over 2 decades in young adults., Methods: In this cohort study, we analyzed death certificate data for ischemic and hemorrhagic stroke (intracerebral hemorrhage [ICH] and subarachnoid hemorrhage [SAH]) in adults aged 20-44 in the United States for 1989 through 2009, covering approximately 2.2 billion person-years. Poisson regression was used to calculate and compare time trend data between groups and to compare trends in young adults to those in adults over age 45., Results: Mortality from stroke in young adults declined by 35% over the study period, with reductions in all 3 stroke subtypes (ischemic stroke decreased by 15%, ICH by 47%, and SAH by 50%). Black race was a risk factor for all 3 stroke subtypes (relative risk 2.4 for ischemic stroke, 4.0 for ICH, and 2.1 for SAH), but declines in all stroke subtypes were more dramatic in black compared to white participants (p < 0.001 for all stroke subtypes)., Conclusions: Although hospitalizations for stroke in young patients have been increasing, the apparent decrease in mortality rates and in racial disparities suggests that recognition and treatment in this group may be improving., (© 2014 American Academy of Neurology.)

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 (κ=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., (© 2014 American Heart Association, Inc.)

Objective: In a population-based case-control study, we examined whether the timing and number of minor infections increased risk of childhood arterial ischemic stroke (AIS)., Methods: Among 102 children with AIS and 306 age-matched controls identified from a cohort of 2.5 million children in a large integrated health care plan (1993-2007), we abstracted data on all medical visits for minor infection within the 2 years prior to AIS or index date for pairwise age-matched controls. We excluded cases of AIS with severe infection (e.g., sepsis, meningitis). Using conditional logistic regression, we examined the effect of timing and total number of minor infections on stroke risk., Results: After adjusting for known pediatric stroke risk factors, the strongest association between infection and AIS was observed for infectious visits ≤3 days prior to stroke (odds ratio [OR] 12.1, 95% confidence interval [CI] 2.5, 57, p = 0.002). Respiratory infections represented 80% of case infections in that time period. Cases had more infectious visits, but not significantly so, for all time periods ≥4 days prior to the stroke. A greater cumulative number of infectious visits over 2 years did not increase risk of AIS., Conclusions: Minor infections appear to have a strong but short-lived effect on pediatric stroke risk, while cumulative burden of infection had no effect. Proposed mechanisms for the link between minor infection and stroke in adults include an inflammatory-mediated prothrombotic state and chronic endothelial injury. The transient effect of infection in children may suggest a greater role for a prothrombotic mechanism., (© 2014 American Academy of Neurology.)

Unlabelled: OBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes., Methods: The authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010., Results: A total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment., Conclusions: A low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children.

Approximately 15% of all ischemic strokes (IS) occur in young adults and adolescents. To date, only limited prior public health and research efforts have specifically addressed stroke in the young. Early diagnosis remains challenging because of the lack of awareness and the relative infrequency of stroke compared with stroke mimics. Moreover, the causes of IS in the young are heterogeneous and can be relatively uncommon, resulting in uncertainties about diagnostic evaluation and cause-specific management. Emerging data have raised public health concerns about the increasing prevalence of traditional vascular risk factors in young individuals, and their potential role in increasing the risk of IS, stroke recurrence, and poststroke mortality. These issues make it important to formulate and enact strategies to increase both awareness and access to resources for young stroke patients, their caregivers and families, and health care professionals. The American Academy of Neurology recently convened an expert panel to develop a consensus document concerning the recognition, evaluation, and management of IS in young adults and adolescents. The report of the consensus panel is presented herein.

Objective: Trauma and infection have been postulated as "triggers" for hemorrhage from underlying brain vascular lesions (arteriovenous malformations, cavernous malformations, and aneurysms) in pediatric hemorrhagic stroke. We decided to perform an association study examining these environmental risk factors., Methods: In this case-control study nested within the cohort of 2.3 million children enrolled in a Northern California integrated health plan (1993-2004), we identified childhood hemorrhagic stroke cases through electronic searches of diagnostic and radiology databases, confirmed through chart review. Three age- and facility-matched controls per case were randomly selected from the study population. Exposure variables were measured using medical records documented before stroke diagnosis. Main outcome measure was hemorrhagic stroke., Results: Of 132 childhood, non-neonatal hemorrhagic stroke cases, 65 had underlying vascular lesions: 34 arteriovenous malformations, 16 cavernous malformations, and 15 aneurysms. A documented exposure to head and neck trauma in the prior 12 weeks was present in 3 cases (4.6%) with underlying vascular lesions, compared with no controls (p < 0.015). However, all 3 vascular lesions were aneurysms, and traumatic pseudoaneurysms were possible. Recent minor infection (prior 4 weeks) was present in 5 cases (7.7%) and 9 controls (4.6%) (p = 0.34)., Conclusions: Our observed association between trauma and hemorrhagic stroke with a vascular lesion may be explained by traumatic pseudoaneurysms. Neither recent head or neck trauma nor infection appeared to be a "trigger" for pediatric hemorrhagic stroke due to underlying vascular malformations.

Importance: A prior report showed higher stroke mortality in US black children compared with white children (1979-1998), a disparity likely due in part to sickle cell disease, which leads to a high risk of childhood ischemic stroke. We hypothesized that this disparity has diminished since the publication of the Stroke Prevention Trial in Sickle Cell Anemia (STOP trial) in 1998 demonstrating the efficacy of long-term blood transfusions for primary stroke prevention., Objective: To evaluate the demographics and secular trends in mortality from ischemic and hemorrhagic stroke (as a primary cause of death) in US children (<20 years) and determine if there has been a decrease in the disparity between white and black children since the publication of the STOP trial in 1998., Design: We used death certificate data from the National Center for Health Statistics, 1988 through 2007., Setting: United States., Participants: Children who died in 1988 through 2007 in the United States., Intervention: Publication of the STOP trial., Main Outcome Measures: Incidence rate ratios were calculated as the measure of relative risk., Results: Among 1.6 billion person-years of US children (1988-2007), there were 4425 deaths attributed to stroke, yielding an average of 221 deaths per year; 20% were ischemic; 67%, hemorrhagic; and 12%, unspecified. The relative risk of ischemic stroke mortality for black vs white children dropped from 1.74 from 1988 through 1997 to 1.27 from 1998 through 2007. The ethnic disparity in hemorrhagic stroke mortality, however, remained relatively stable between these 2 periods: black vs white relative risk, 1.90 (1988-1997) and 1.97 (1998-2007)., Conclusions and Relevance: The excess risk of death from ischemic, but not hemorrhagic, stroke in US black children has decreased over the past decade. This may be related to the implementation of an effective ischemic stroke prevention strategy for children with sickle cell disease.

Purpose: To test the hypotheses that (1) the increased risk of stroke conferred by childhood cranial radiation therapy (CRT) persists into adulthood; and (2) atherosclerotic risk factors further increase the stroke risk in cancer survivors., Methods and Materials: The Childhood Cancer Survivor Study is a multi-institutional retrospective cohort study of 14,358 5-year survivors of childhood cancer and 4023 randomly selected sibling controls with longitudinal follow-up. Age-adjusted incidence rates of self-reported late-occurring (≥5 years after diagnosis) first stroke were calculated. Multivariable Cox proportional hazards models were used to identify independent stroke predictors., Results: During a mean follow-up of 23.3 years, 292 survivors reported a late-occurring stroke. The age-adjusted stroke rate per 100,000 person-years was 77 (95% confidence interval [CI] 62-96), compared with 9.3 (95% CI 4-23) for siblings. Treatment with CRT increased stroke risk in a dose-dependent manner: hazard ratio 5.9 (95% CI 3.5-9.9) for 30-49 Gy CRT and 11.0 (7.4-17.0) for 50+ Gy CRT. The cumulative stroke incidence in survivors treated with 50+ Gy CRT was 1.1% (95% CI 0.4-1.8%) at 10 years after diagnosis and 12% (95% CI 8.9-15.0%) at 30 years. Hypertension increased stroke hazard by 4-fold (95% CI 2.8-5.5) and in black survivors by 16-fold (95% CI 6.9-36.6)., Conclusion: Young adult pediatric cancer survivors have an increased stroke risk that is associated with CRT in a dose-dependent manner. Atherosclerotic risk factors enhanced this risk and should be treated aggressively., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: To measure intensive care unit (ICU) admission, intubation, decompressive craniotomy, and outcomes at discharge in a large population-based study of children with ischemic and hemorrhagic stroke., Methods: In a retrospective study of all children enrolled in a Northern Californian integrated health care plan (1993-2003), we identified cases of symptomatic childhood stroke (age >28 days through 19 years) from inpatient and outpatient electronic diagnoses and radiology reports, and confirmed them through chart review. Data regarding stroke evaluation, management, and outcomes at discharge were abstracted. Intensive care unit (ICU) admission, intubation, and decompressive neurosurgery rates were measured, and multivariate logistic regression was used to identify predictors of critical care usage and outcomes at discharge., Results: Of 256 cases (132 hemorrhagic and 124 ischemic), 61% were admitted to the ICU, 32% were intubated, and 11% were treated with a decompressive neurosurgery. Rates were particularly high among children with hemorrhagic stroke (73% admitted to the ICU, 42% intubated, and 19% received a decompressive neurosurgery). Altered mental status at presentation was the most robust predictor for all 3 measures of critical care utilization. Neurologic deficits at discharge were documented in 57%, and were less common after hemorrhagic than ischemic stroke: 48% vs 66% (odds ratio 0.5, 95% confidence interval 0.3-0.8). Case fatality was 4% overall, 7% among children admitted to the ICU, and was similar between ischemic and hemorrhagic stroke., Conclusions: ICU admission is frequent after childhood stroke and appears to be justified by high rates of intubation and surgical decompression.

Background and Purpose: PHACE is an acronym for posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Several case reports of arterial ischemic stroke (AIS) in individuals with PHACE have been published, but risk factors for AIS in PHACE have not been clearly defined. The objective of this article is to review all cases of stroke in PHACE in children and describe clinical characteristics that may be associated with an increased risk of AIS., Methods: A literature and registry search was conducted to identify patients with PHACE who had experienced AIS. Data were analyzed to determine age of onset, presenting signs and symptoms, and clinical features among this cohort compared with PHACE without AIS., Results: Twenty-two individuals with PHACE and AIS were identified. Imaging of the arteries of the head and neck was reported in 20 of 22. Narrowing or nonvisualization of at least 1 great cerebral vessel was present in 19 of 20 and of those, 15 had ≥ 2 vessels involved. Aortic arch anomalies were reported in 13 of 22 individuals., Conclusions: Aplasia, hypoplasia, or occlusion of a major cerebral artery appears to be a significant risk factor for AIS in children with PHACE, especially when >1 vessel is involved or if there is coarctation of the aorta.

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 clinician's 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 κ-statistic., Results: In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=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.

Although many underlying diseases have been reported in the setting of childhood arterial ischemic stroke, emerging research demonstrates that non-atherosclerotic intracerebral arteriopathies in otherwise healthy children are prevalent. Minor infections may play a role in arteriopathies that have no other apparent underlying cause. Although stroke in childhood differs in many aspects from adult stroke, few systematic studies specific to pediatrics are available to inform stroke management. Treatment trials of pediatric stroke are required to determine the best strategies for acute treatment and secondary stroke prevention. The high cost of pediatric stroke to children, families, and society demands further study of its risk factors, management, and outcomes. This review focuses on the recent findings in childhood arterial ischemic stroke.

Major infections-sepsis, meningitis, encephalitis-have long been recognized as causes of pediatric arterial ischemic stroke. However, minor infections may also contribute to the pathogenesis of stroke, either by causing a systemic prothrombotic state or direct or indirect vascular injury. A focal cerebral arteriopathy has been identified in a large proportion of otherwise healthy children present with a first ischemic stroke. Both histologic data and small association studies suggest that varicella zoster virus can cause this childhood arteriopathy. Other viruses have been implicated in case reports. New data demonstrate an association between recent upper respiratory infection and this arteriopathy, suggesting a non-specific effect of infection. This manuscript reviews the evidence supporting a role for infection in ischemic stroke of childhood.