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ObjectivePediatric brain arteriovenous malformations (AVMs) are the leading cause of spontaneous intracranial hemorrhage (SICH) in children. Although the incidence of SICH is low in pediatric populations, such events cause substantial morbidity. The recently created Ruptured Arteriovenous Malformation Grading Scale (RAGS) is proposed as a reliable and novel grading system to specifically serve as a predictor of clinical outcomes in patients following AVM rupture, similar to the Hunt and Hess (HH) grade for ruptured aneurysms. While these data are promising, pediatric patients were notably absent from the original study validating the RAGS. Therefore, correlation of the RAGS score with clinical outcomes following AVM rupture in individuals younger than 18 years of age using the RAGS score is needed. The objective of this study was to validate the RAGS in a cohort of pediatric patients with AVMs who presented with hemorrhage, thereby demonstrating the score's generalizability, and expanding its external validity.MethodsA cohort of children with ruptured AVMs were retrospectively reviewed. Using disability, measured by the modified Rankin Scale (mRS), as the response variable, the area under the receiver operating characteristic curve (AUROC) was calculated for patients based on their RAGS scores for three time periods. The AUROC values were then compared with those generated by two commonly used clinical grading systems, the HH classification and Glasgow Coma Scale.ResultsA total of 81 children who presented with ruptured AVMs were included in the study, with a mean follow-up duration of 4 years. The RAGS score outperformed other clinical grading scales in predicting mRS scores, with AUROC values of 0.81, 0.82, and 0.81 at three distinct follow-up periods.ConclusionsThe RAGS score correlated well with the clinical outcome after AVM rupture in pediatric patients. Additional validation studies across multiple treatment centers are needed to further demonstrate the generalizability of the scoring system.

BackgroundNeurocognitive deficits in pediatric cancer survivors occur frequently; however, individual outcomes are unpredictable. We investigate clinical, genetic, and imaging predictors of neurocognition in pediatric cancer survivors, with a focus on survivors of central nervous system (CNS) tumors exposed to radiation.MethodsOne hundred eighteen patients with benign or malignant cancers (median diagnosis age: 7; 32% embryonal CNS tumors) were selected from an existing multi-institutional cohort (RadART Pro) if they had: 1) neurocognitive evaluation; 2) available DNA; 3) standard imaging. Utilizing RadART Pro, we collected clinical history, genomic sequencing, CNS imaging, and neurocognitive outcomes. We performed single nucleotide polymorphism (SNP) genotyping for candidate genes associated with neurocognition: COMT, BDNF, KIBRA, APOE, KLOTHO. Longitudinal neurocognitive testing were performed using validated computer-based CogState batteries. The imaging cohort was made of patients with available iron-sensitive (n = 28) and/or T2 FLAIR (n = 41) sequences. Cerebral microbleeds (CMB) were identified using a semi-automated algorithm. Volume of T2 FLAIR white matter lesions (WML) was measured using an automated method based on a convolutional neural network. Summary statistics were performed for patient characteristics, neurocognitive assessments, and imaging. Linear mixed effects and hierarchical models assessed patient characteristics and SNP relationship with neurocognition over time. Nested case-control analysis was performed to compare candidate gene carriers to non-carriers.ResultsCMB presence at baseline correlated with worse performance in 3 of 7 domains, including executive function. Higher baseline WML volumes correlated with worse performance in executive function and verbal learning. No candidate gene reliably predicted neurocognitive outcomes; however, APOE ϵ4 carriers trended toward worse neurocognitive function over time compared to other candidate genes and carried the highest odds of low neurocognitive performance across all domains (odds ratio 2.85, P=0.002). Hydrocephalus and seizures at diagnosis were the clinical characteristics most frequently associated with worse performance in neurocognitive domains (5 of 7 domains). Overall, executive function and verbal learning were the most frequently negatively impacted neurocognitive domains.ConclusionPresence of CMB, APOE ϵ4 carrier status, hydrocephalus, and seizures correlate with worse neurocognitive outcomes in pediatric cancer survivors, enriched with CNS tumors exposed to radiation. Ongoing research is underway to verify trends in larger cohorts.

BACKGROUNDThe authors recently reported a series of children with vertebral artery (VA) compression during head turning who presented with recurrent posterior circulation stroke. Whether VA compression occurs during head positioning for cranial surgery is unknown.OBSERVATIONSThe authors report a case of a child with incidental rotational occlusion of the VA observed during surgical head positioning for treatment of an intracranial arteriovenous fistula. Intraoperative angiography showed dynamic V3 occlusion at the level of C2 with distal reconstitution via a muscular branch “jump” collateral, supplying reduced flow to the V4 segment. She had no clinical history or imaging suggesting acute or prior stroke. Sequential postoperative magnetic resonance imaging scans demonstrated signal abnormality of the left rectus capitus muscle, suggesting ischemic edema.LESSONSThis report demonstrates that rotational VA compression during neurosurgical head positioning can occur in children but may be asymptomatic due to the presence of muscular VA–VA “jump” collaterals and contralateral VA flow. Although unilateral VA compression may be tolerated by children with codominant VAs, diligence when rotating the head away from a dominant VA is prudent during patient positioning to avoid posterior circulation ischemia or thromboembolism.

Background and purposeDo children have an increased risk for brain arteriovenous malformation (AVM) recurrence compared with adults and does this risk vary depending on initial presentation with AVM rupture?MethodsWe retrospectively studied 115 patients initially presenting with brain AVM under age 25 years who underwent complete surgical resection of the AVM as documented by digital subtraction angiography (DSA) and had delayed follow-up DSA to evaluate for AVM recurrence after apparent initial cure.ResultsThe mean time from baseline DSA to follow-up DSA was 2.3 years, ranging from 0 to 15 years. Twelve patients (10.4% of the 115 patient cohort and 16.7% of 72 patients with hemorrhage at initial presentation) demonstrated AVM recurrence on follow-up DSA. All patients with recurrence initially presented with intracranial hemorrhage, and intracranial hemorrhage was a significant predictor of recurrence (log rank P=0.037). Among patients with initial hemorrhage, the 5-year recurrence rate was 17.8% (95% CI, 8.3%-35.7%). All recurrences occurred in patients who were children at the time of their initial presentation; the oldest was 15 years of age at the time of initial AVM surgery. The 5-year recurrence rate for children (0-18 years of age) with an initial presentation of hemorrhage was 21.4% (95% CI, 10.1%-41.9%). Using Cox regression, we found the risk of AVM recurrence decreased by 14% per each year increase in age at the time of initial surgical resection (hazard ratio=0.86 [95% CI, 0.75-0.99]; P=0.031).ConclusionsThere is a high rate of recurrence of apparently cured brain AVMs in children who initially present with AVM rupture. Imaging follow-up is warranted to prevent re-rupture.

ObjectiveTo describe a pediatric stroke syndrome with chronic focal vertebral arteriopathy adjacent to cervical abnormalities.MethodsAt a single pediatric stroke center, we identified consecutive children with stroke and vertebral arteriopathy of the V3 segment with adjacent cervical bony or soft tissue abnormalities. We abstracted clinical presentation, treatment, and follow-up data from medical charts.ResultsFrom 2005 to 2019, 10 children (all boys, ages 6-16 years) presented with posterior circulation strokes and vertebral arteriopathy with adjacent cervical pathology. Two children had bony abnormalities: one had a congenital arcuate foramen and one had os odontoideum with cervical instability. In children without bony pathology, vertebral artery narrowing during contralateral head rotation was visualized by digital subtraction angiography. Eight boys had recurrent ischemic events despite anti-thrombotic treatment (including 5 with multiple recurrences) and were treated surgically to prevent additional stroke. Procedures included vertebral artery decompression (n = 6), endovascular stent and spinal fusion (n = 1), and vertebral artery endovascular occlusion (n = 1). In boys treated with decompression, cervical soft tissue abnormalities (ruptured atlantoaxial bursa, ruptured joint capsule, or connective tissue scarring) were directly visualized during open surgery. No other etiology for stroke or dissection was found in any of the cases. Two boys without recurrent stroke were treated with activity restriction and antithrombotics. At a median follow-up of 51 months (range 17-84), there have been no additional recurrences.ConclusionsChildren with V3 segmental vertebral arteriopathy frequently have stroke recurrence despite antithrombotics. Cervical bone imaging and angiography with neck rotation can identify underlying pathology.

Moyamoya is a progressive cerebrovascular arteriopathy that affects children of any age. The goal of this study was to determine imaging and clinical outcomes as well as complication rates in a pediatric cohort undergoing either a combined direct/indirect or indirect-only revascularization approach. Patients with moyamoya disease or syndrome ≤ 18 years of age at the time of initial surgery were identified, and clinical data were collected retrospectively. Over a 12-year period, 26 patients underwent revascularization procedures on 49 hemispheres with a median follow-up of 2.6 years from surgery. Median age at surgery was 7.3 years (range 1.4-18.0 years). Thirty-three hemispheres (67.3%) underwent combined revascularization with a direct bypass and encephalomyosynangiosis, and sixteen hemispheres (32.7%) underwent indirect-only revascularization. The rate of 30-day perioperative complication was 10.2%, and the rate of postoperative clinical stroke by end of follow-up was 10.2% by hemisphere. There was a 5.7% rate of intraoperative bypass failure requiring conversion to an indirect revascularization approach. On follow-up imaging, 96.9% of direct bypasses remained patent. On multivariate analysis, higher preoperative Pediatric Stroke Outcome Measure (PSOM) scores were associated with lower rates of good clinical outcome on follow-up (unit OR 0.03; p = 0.03). Patients with age

ObjectiveTo determine that children with arterial ischemic stroke (AIS) due to an identifiable arteriopathy are distinct from those without arteriopathy and that each arteriopathy subtype has unique and recognizable clinical features.MethodsWe report a large, observational, multicenter cohort of children with AIS, age 1 month to 18 years, enrolled in the International Pediatric Stroke Study from 2003 to 2014. Clinical and demographic differences were compared by use of the Fisher exact test, with linear step-up permutation min-p adjustment for multiple comparisons. Exploratory analyses were conducted to evaluate differences between cases of AIS with and without arteriopathy and between arteriopathy subtypes.ResultsOf 2,127 children with AIS, 725 (34%) had arteriopathy (median age 7.45 years). Arteriopathy subtypes included dissection (27%), moyamoya (24.5%), focal cerebral arteriopathy-inflammatory subtype (FCA-i; 15%), diffuse cerebral vasculitis (15%), and nonspecific arteriopathy (18.5%). Children with arteriopathic AIS were more likely to present between 6 and 9 years of age (odds ratio [OR] 1.93, p = 0.029) with headache (OR 1.55, p = 0.023), multiple infarctions (OR 2.05, p < 0.001), sickle cell anemia (OR 2.9, p = 0.007), and head/neck trauma (OR 1.93, p = 0.018). Antithrombotic use and stroke recurrence were higher in children with arteriopathy. Among arteriopathy subtypes, dissection was associated with male sex, older age, headache, and anticoagulant use; FCA-i was associated with hemiparesis and single infarcts; moyamoya was associated with seizures and recurrent strokes; and vasculitis was associated with bilateral infarctions.ConclusionSpecific clinical profiles are associated with cerebral arteriopathies in children with AIS. These observations may be helpful indicators in guiding early diagnosis and defining subgroups who may benefit most from future therapeutic trials.

Children can have a variety of intracranial vascular anomalies ranging from small and incidental with no clinical consequences to complex lesions that can cause substantial neurologic deficits, heart failure, or profoundly affect development. In contrast to high-flow lesions with direct arterial-to-venous shunts, low-flow lesions such as cavernous malformations are associated with a lower likelihood of substantial hemorrhage, and a more benign course. Management of vascular anomalies in children has to incorporate an understanding of how treatment strategies may affect the normal development of the central nervous system. In this review, we discuss the etiologies, epidemiology, natural history, and genetic risk factors of three high-flow vascular malformations seen in children: brain arteriovenous malformations, intracranial dural arteriovenous fistulas, and vein of Galen malformations.

Hemorrhagic strokes account for half of all strokes seen in children, and the etiologies of these hemorrhagic strokes differ greatly from those seen in adult patients. This review gives an overview about incidence and etiologies as well as presentation of children with intracerebral hemorrhage and with differential diagnoses in the emergency department. Most importantly it describes how neuroimaging of children with intracerebral hemorrhage should be tailored to specific situations and clinical contexts and recommends specific imaging protocols for acute and repeat imaging. In this context it is important to keep in mind the high prevalence of underlying vascular lesions and adapt the imaging protocol accordingly, meaning that vascular imaging plays a key role regardless of modality. Magnetic resonance imaging (MRI), including advanced sequences, should be favored whenever possible at the acute phase.

OBJECTIVE:Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs. METHODS:A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram. RESULTS:The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I-III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year). CONCLUSIONS:Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs.

BackgroundPoor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).MethodsThe CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.ResultsAmong 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).ConclusionsStroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.

BACKGROUND:Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders. METHODS:We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability. RESULTS:Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design. CONCLUSIONS:Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules.

Purpose- Much has transpired since the last scientific statement on pediatric stroke was published 10 years ago. Although stroke has long been recognized as an adult health problem causing substantial morbidity and mortality, it is also an important cause of acquired brain injury in young patients, occurring most commonly in the neonate and throughout childhood. This scientific statement represents a synthesis of data and a consensus of the leading experts in childhood cardiovascular disease and stroke. Methods- Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee and were chosen to reflect the expertise of the subject matter. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. This scientific statement is based on expert consensus considerations for clinical practice. Results- Annualized pediatric stroke incidence rates, including both neonatal and later childhood stroke and both ischemic and hemorrhagic stroke, range from 3 to 25 per 100 000 children in developed countries. Newborns have the highest risk ratio: 1 in 4000 live births. Stroke is a clinical syndrome. Delays in diagnosis are common in both perinatal and childhood stroke but for different reasons. To develop new strategies for prevention and treatment, disease processes and risk factors that lead to pediatric stroke are discussed here to aid the clinician in rapid diagnosis and treatment. The many important differences that affect the pathophysiology and treatment of childhood stroke are discussed in each section. Conclusions- Here we provide updates on perinatal and childhood stroke with a focus on the subtypes, including arterial ischemic, venous thrombotic, and hemorrhagic stroke, and updates in regard to areas of childhood stroke that have not received close attention such as sickle cell disease. Each section is highlighted with considerations for clinical practice, attendant controversies, and knowledge gaps. This statement provides the practicing provider with much-needed updated information in this field.

Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.

ObjectiveTo determine whether lower socioeconomic status (SES) is associated with worse 1-year neurologic outcomes and reduced access to rehabilitation services in children with arterial ischemic stroke (AIS).MethodsFrom 2010 to 2014, the Vascular effects of Infection in Pediatric Stroke (VIPS) observational study prospectively enrolled and confirmed 355 children (age 29 days-18 years) with AIS at 37 international centers. SES markers measured via parental interview included annual household income (US dollars) at the time of enrollment, maternal education level, and rural/suburban/urban residence. Receipt of rehabilitation services was measured by parental report. Pediatric Stroke Outcome Measure scores were categorized as 0 to 1, 1.5 to 3, 3.5 to 6, and 6.5 to 10. Univariate and multivariable ordinal logistic regression models examined potential predictors of outcome.ResultsAt 12 ± 3 months after stroke, 320 children had documented outcome measurements, including 15 who had died. In univariate analysis, very low income (p = 0.004). In multivariable analysis, including adjustment for stroke etiology, this association persisted (OR 3.17, 95% CI 1.18-8.47, p = 0.02). Income did not correlate with receiving rehabilitation services at 1 year after stroke; however, quality and quantity of services were not assessed.ConclusionsIn a large, multinational, prospective cohort of children with AIS, low income was associated with worse neurologic outcomes compared to higher income levels. This difference was not explained by stroke type, neurologic comorbidities, or reported use of rehabilitation services. The root causes of this disparity are not clear and warrant further investigation.

ObjectiveTo quantify the incidence, timing, and risk of ischemic stroke after trauma in a population-based young cohort.MethodsWe electronically identified trauma patients (

Background and purposeCase-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag-polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases.MethodsThe multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens.ResultsPathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries.ConclusionsUsing MassTag-polymerase chain reaction, we detected parvovirus B19-a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis.

In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 (74%) of the 3,840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1,896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1,090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. Am. J. Hematol. 91:1191-1194, 2016. © 2016 Wiley Periodicals, Inc.

BackgroundA specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors.MethodsIn a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age

OBJECTIVE Intracranial dural arteriovenous fistulas (DAVFs) are rare in children. This study sought to better characterize DAVF presentation, angioarchitecture, and treatment outcomes. METHODS Children with intracranial DAVFs between 1986 and 2013 were retrospectively identified from the neurointerventional database at the authors' institution. Demographics, clinical presentation, lesion angioarchitecture, treatment approaches, angiographic outcomes, and clinical outcomes were assessed. RESULTS DAVFs constituted 5.7% (22/423) of pediatric intracranial arteriovenous shunting lesions. Twelve boys and 10 girls presented between 1 day and 18 years of age; boys presented at a median of 1.3 years and girls presented at a median of 4.9 years. Four of 8 patients ≤ 1 year of age presented with congestive heart failure compared with 0/14 patients > 1 year of age (p = 0.01). Five of 8 patients ≤ 1 year old presented with respiratory distress compared with 0/14 patients > 1 year old (p = 0.0021). Ten of 14 patients > 1 year old presented with focal neurological deficits compared with 0/8 patients ≤ 1 year old (p = 0.0017). At initial angiography, 16 patients harbored a single intracranial DAVF and 6 patients had 2-6 DAVFs. Eight patients (38%) experienced DAVF obliteration by the end of treatment. Good clinical outcome (modified Rankin Scale score 0-2) was documented in 77% of patients > 1 year old at presentation compared with 57% of patients ≤ 1 year old at presentation. Six patients (27%) died. CONCLUSIONS Young children with DAVFs presented predominantly with cardiopulmonary symptoms, while older children presented with focal neurological deficits. Compared with other pediatric vascular shunts, DAVFs had lower rates of angiographic obliteration and poorer clinical outcomes.

Transcranial Doppler (TCD) screening rates remain low among children with sickle cell disease (SCD). We assessed TCD screening rates and missed opportunities for TCD screening. Children 2 to 16 years old with SCD enrolled in Michigan Medicaid for ≥1 year (2007-2011) were identified through newborn screening. Receipt of TCD screening and presence of a missed opportunity (≥1 SCD-related outpatient visit, no TCD screening) were identified through administrative claims. Potential correlates of missed opportunities included SCD-related health services, comorbidities, and demographics. Logistic regression with generalized estimating equations modeled associations between a missed opportunity and correlates. Overall, 353 children contributed 1066 person-years. TCD screening was low yearly (10%-32%); missed opportunities occurred in 73% of the person-years. Increasing age (odds ratio [OR] = 1.11; confidence interval CI = 1.07, 1.15), previous TCD screening (OR = 0.26; CI = 0.16, 0.41), and 4 to 5 (OR = 0.48; CI = 0.26, 0.87) or ≥6 outpatient visits (OR = 0.26; CI = 0.14, 0.49) were associated with a missed opportunity. Reduction of missed opportunities is a potential strategy to increase TCD screening rates.

Background and purposeThere are limited data about the reliability of subtype classification in childhood arterial ischemic stroke, an issue that prompted the IPSS (International Pediatric Stroke Study) to develop the CASCADE criteria (Childhood AIS Standardized Classification and Diagnostic Evaluation). Our purpose was to determine the CASCADE criteria's reliability in a population of children with stroke.MethodsEight raters from the IPSS reviewed neuroimaging and clinical records of 64 cases (16 cases each) randomly selected from a prospectively collected cohort of 113 children with arterial ischemic stroke and classified them using the CASCADE criteria. Clinical data abstracted included history of present illness, risk factors, and acute imaging. Agreement among raters was measured by unweighted κ statistic.ResultsThe CASCADE criteria demonstrated a moderate inter-rater reliability, with an overall κ statistic of 0.53 (95% confidence interval [CI]=0.39-0.67). Cardioembolic and bilateral cerebral arteriopathy subtypes had much higher agreement (κ=0.84; 95% CI=0.70-0.99; and κ=0.90; 95% CI=0.71-1.00, respectively) than cases of aortic/cervical arteriopathy (κ=0.36; 95% CI=0.01-0.71), unilateral focal cerebral arteriopathy of childhood (FCA; κ=0.49; 95% CI=0.23-0.76), and small vessel arteriopathy of childhood (κ=-0.012; 95% CI=-0.04 to 0.01).ConclusionsThe CASCADE criteria have moderate reliability when used by trained and experienced raters, which suggests that it can be used for classification in multicenter pediatric stroke studies. However, the moderate reliability of the arteriopathic subtypes suggests that further refinement is needed for defining subtypes. Such revisions may reduce the variability in the literature describing risk factors, recurrence, and outcomes associated with childhood arteriopathy.

Background and purposeAmong 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.MethodsIn 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.ResultsMedian 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.ConclusionsAmong 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.

ObjectivesTo determine incidence rates and risk factors of remote seizure after perinatal arterial ischemic stroke.MethodsWe retrospectively identified a population-based cohort of children with perinatal arterial ischemic stroke (presenting acutely or in a delayed fashion) from a large Northern Californian integrated health care system. We determined incidence and predictors of a remote seizure (unprovoked seizure after neonatal period, defined as 28 days of life) by survival analyses, and measured epilepsy severity in those with active epilepsy (≥1 remote seizure and maintenance anticonvulsant treatment) at last follow-up.ResultsAmong 87 children with perinatal stroke, 40 (46%) had a seizure in the neonatal period. During a median follow-up of 7.1 years (interquartile range 3.2-10.5), 37 children had ≥1 remote seizure. Remote seizure risk was highest during the first year of life, with a 20% (95% confidence interval [CI] 13%-30%) cumulative incidence by 1 year of age, 46% (CI 35%-58%) by 5 years, and 54% (CI 41%-67%) by 10 years. Neonatal seizures increased the risk of a remote seizure (hazard ratio 2.8, CI 1.3-5.8). Children with neonatal seizures had a 69% (CI 48%-87%) cumulative incidence of remote seizure by age 10 years. Among the 24 children with active epilepsy at last follow-up, 8 (33%) were having monthly seizures despite an anticonvulsant and 7 (29%) were on more than one anticonvulsant.ConclusionsRemote seizures and epilepsy, including medically refractory epilepsy, are common after perinatal stroke. Neonatal seizures are associated with nearly 3-fold increased remote seizure risk.

Background and purposeArteriopathy is the leading cause of childhood arterial ischemic stroke. Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy. We aimed to quantify cerebral arterial tortuosity in childhood arterial ischemic stroke, hypothesizing increased tortuosity in dissection.MethodsChildren (1 month to 18 years) with arterial ischemic stroke were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated the mean arterial tortuosity of the major cerebral arteries using 3-dimensional time-of-flight magnetic resonance angiographic source images. Tortuosity of unaffected vessels was compared between children with dissection, transient cerebral arteriopathy, meningitis, moyamoya, cardioembolic strokes, and controls (ANOVA and post hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student t test).ResultsOne hundred fifteen children were studied (median, 6.8 years; 43% women). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074; n=15) was comparable with moyamoya (1.324±0.038; n=15; P=0.998), meningitis (1.348±0.052; n=11; P=0.989), and cardioembolic (1.379±0.056; n=27; P=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084; n=22; P=0.021) and transient cerebral arteriopathy (1.390±0.040; n=27; P=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissections (P=0.70).ConclusionsIn children with dissection and transient cerebral arteriopathy, cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.

Background and purposeArteriopathy is the leading cause of childhood arterial ischemic stroke. Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy. We aimed to quantify cerebral arterial tortuosity in childhood arterial ischemic stroke, hypothesizing increased tortuosity in dissection.MethodsChildren (1 month to 18 years) with arterial ischemic stroke were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated the mean arterial tortuosity of the major cerebral arteries using 3-dimensional time-of-flight magnetic resonance angiographic source images. Tortuosity of unaffected vessels was compared between children with dissection, transient cerebral arteriopathy, meningitis, moyamoya, cardioembolic strokes, and controls (ANOVA and post hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student t test).ResultsOne hundred fifteen children were studied (median, 6.8 years; 43% women). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074; n=15) was comparable with moyamoya (1.324±0.038; n=15; P=0.998), meningitis (1.348±0.052; n=11; P=0.989), and cardioembolic (1.379±0.056; n=27; P=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084; n=22; P=0.021) and transient cerebral arteriopathy (1.390±0.040; n=27; P=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissections (P=0.70).ConclusionsIn children with dissection and transient cerebral arteriopathy, cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.

BackgroundEpidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS.Methods and resultsWe enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (≤3 weeks after stroke/trauma); cases had convalescent samples (7-28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1-14.3) years for cases and 10.7 (6.9-13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2-4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic.ConclusionsHerpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.

Background and purposePublished 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.MethodsThe 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.ResultsOf 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.ConclusionsChildren 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.

Abstract Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures. Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed. Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event. Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. Disclosures No relevant conflicts of interest to declare.

ImportanceOur understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk.ObjectiveIn this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC).Design, setting, and participantsChildren ages 2-17 years who were members of KPNC for ≥6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache.Main outcome measuresMain outcome measures included stroke incidence rates and incidence rate ratios (IR).ResultsAmong the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8-5.2). A post-hoc analysis of adolescents (12-17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2-9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2-2.0).ConclusionsThere was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs.

ObjectivesMinor 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.MethodsThe 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.ResultsMedian (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).ConclusionsInfection 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.

ObjectiveTo estimate the rates and predictors of recurrent stroke among survivors of pediatric cancer who have had a first stroke.MethodsThe Childhood Cancer Survivor Study is a retrospective cohort study with longitudinal follow-up that enrolled 14,358 survivors (

BackgroundVein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized.ObjectiveTo examine the clinical and radiological features of VOGMs and the predictors of outcome in patients.MethodsWe retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by χ(2) analyses.ResultsForty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at