Pediatric Ischemic Stroke: An Infrequent Complication of SARS-CoV-2.

OBJECTIVE: Severe complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include arterial ischemic stroke (AIS) in adults and multisystem inflammatory syndrome in children. Whether stroke is a frequent complication of pediatric SARS-CoV-2 is unknown. This study aimed to determine the proportion of pediatric SARS-CoV-2 cases with ischemic stroke and the proportion of incident pediatric strokes with SARS-CoV-2 in the first 3 months of the pandemic in an international cohort. METHODS: We surveyed 61 international sites with pediatric stroke expertise. Survey questions included: numbers of hospitalized pediatric (≤ 18 years) patients with SARS-CoV-2; numbers of incident neonatal and childhood ischemic strokes; frequency of SARS-CoV-2 testing for pediatric patients with stroke; and numbers of stroke cases positive for SARS-CoV-2 from March 1 to May 31, 2020. RESULTS: Of 42 centers with SARS-CoV-2 hospitalization numbers, 8 of 971 (0.82%) pediatric patients with SARS-CoV-2 had ischemic strokes. Proportions of stroke cases positive for SARS-CoV-2 from March to May 2020 were: 1 of 108 with neonatal AIS (0.9%), 0 of 33 with neonatal cerebral sinovenous thrombosis (CSVT; 0%), 6 of 166 with childhood AIS (3.6%), and 1 of 54 with childhood CSVT (1.9%). However, only 30.5% of neonates and 60% of children with strokes were tested for SARS-CoV-2. Therefore, these proportions represent 2.9, 0, 6.1, and 3.0% of stroke cases tested for SARS-CoV-2. Seven of 8 patients with SARS-CoV-2 had additional established stroke risk factors. INTERPRETATION: As in adults, pediatric stroke is an infrequent complication of SARS-CoV-2, and SARS-CoV-2 was detected in only 4.6% of pediatric patients with ischemic stroke tested for the virus. However, < 50% of strokes were tested. To understand the role of SARS-CoV-2 in pediatric stroke better, SARS-CoV-2 testing should be considered in pediatric patients with stroke as the pandemic continues. ANN NEUROL 2021;89:657-665.

Predicting Recovery and Outcome after Pediatric Stroke: Results from the International Pediatric Stroke Study.

OBJECTIVE: To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke. METHODS: We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with 2-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at 2 years by the Pediatric Stroke Outcome Measure. Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to 2 years as recovery (improved outcome), emerging deficit (worse outcome), or no change. RESULTS: Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates versus 48.8% of children at discharge compared to 8.0% versus 24.7% after 2 years. Predictors of poor outcome included age between 28 days and 1 year (compared to neonates, odds ratio [OR] = 3.58, p < 0.05), underlying chronic disorder (OR = 2.23, p < 0.05), and involvement of both small and large vascular territories (OR = 2.84, p < 0.05). Recovery patterns differed, with emerging deficits more common in children <1 year of age (p < 0.05). INTERPRETATION: Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and 1 year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. ANN NEUROL 2020;87:840-852.

Leukoencephalopathy with calcifications and cysts: Genetic and phenotypic spectrum.

Biallelic mutations in SNORD118, encoding the small nucleolar RNA U8, cause leukoencephalopathy with calcifications and cysts (LCC). Given the difficulty in interpreting the functional consequences of variants in nonprotein encoding genes, and the high allelic polymorphism across SNORD118 in controls, we set out to provide a description of the molecular pathology and clinical spectrum observed in a cohort of patients with LCC. We identified 64 affected individuals from 56 families. Age at presentation varied from 3 weeks to 67 years, with disease onset after age 40 years in eight patients. Ten patients had died. We recorded 44 distinct, likely pathogenic, variants in SNORD118. Fifty two of 56 probands were compound heterozygotes, with parental consanguinity reported in only three families. Forty nine of 56 probands were either heterozygous (46) or homozygous (three) for a mutation involving one of seven nucleotides that facilitate a novel intramolecular interaction between the 5' end and 3' extension of precursor-U8. There was no obvious genotype-phenotype correlation to explain the marked variability in age at onset. Complementing recently published functional analyses in a zebrafish model, these data suggest that LCC most often occurs due to combinatorial severe and milder mutations, with the latter mostly affecting 3' end processing of precursor-U8.

Arteriopathy Influences Pediatric Ischemic Stroke Presentation, but Sickle Cell Disease Influences Stroke Management.

Background and Purpose- Sickle cell disease (SCD) and arteriopathy are pediatric stroke risk factors that are not mutually exclusive. The relative contributions of sickled red blood cells and arteriopathy to stroke risk are unknown, resulting in unclear guidelines for primary and secondary stroke prevention when both risk factors are present. We hypothesized that despite similarities in clinical presentation and radiographic appearance of arteriopathies, stroke evaluation and management differ in children with SCD compared with those without SCD. Methods- We compared presentation and management of children with and without SCD enrolled in the IPSS (International Pediatric Stroke Study) with acute arterial ischemic stroke, according to SCD and arteriopathy status. Regression modeling determined relative contribution of SCD and arteriopathy in variables with significant frequency differences. Results- Among 930 childhood arterial ischemic strokes, there were 98 children with SCD, 67 of whom had arteriopathy, and 466 without SCD, 392 of whom had arteriopathy. Arteriopathy, regardless of SCD status, increased likelihood of hemiparesis (odds ratio [OR], 1.94; 95% CI, 1.46-2.56) and speech abnormalities (OR, 1.67; 95% CI, 1.29-2.19). Arteriopathy also increased likelihood of headache but only among those without SCD (OR, 1.89; 95% CI, 1.40-2.55). Echocardiograms were less frequently obtained in children with SCD (OR, 0.58; 95% CI, 0.37-0.93), but the frequency of identified cardiac abnormalities was similar in both groups ( P=0.57). Children with SCD were less likely to receive antithrombotic therapy, even in the presence of arteriopathy (OR, 0.14; 95% CI, 0.08-0.22). Arteriopathy was associated with a significantly higher likelihood of antithrombotic therapy in children without SCD (OR, 5.36; 95% CI, 3.55-8.09). Conclusions- Arteriopathy, and not SCD status, was most influential of stroke presentation. However, SCD status influenced stroke management because children with SCD were less likely to have echocardiograms or receive antithrombotic therapy. Further work is needed to determine whether management differences are warranted.

Children with sickle cell anemia with normal transcranial Doppler ultrasounds and without silent infarcts have a low incidence of new strokes.

In a prospective cohort study, we tested the hypothesis that children with sickle cell anemia (SCA) with normal transcranial Doppler ultrasound (TCD) velocities and without silent cerebral infarcts (SCIs) would have a lower incidence rate of new neurological events (strokes, seizures or transient ischemic attacks) compared to children with normal TCD measurements and SCIs, not receiving regular blood transfusions. Nonrandomized participants from the silent cerebral infarct transfusion (SIT) Trial who had screening magnetic resonance imaging (MRI) of the brain and normal TCD measurements were included. Follow-up ended at the time of first neurological event (stroke, seizure or transient ischemic attack), start of regular blood transfusion, or loss to follow-up, whichever came first. The primary endpoint was a new neurological event. Of 421 participants included, 68 had suspected SCIs. Mean follow-up was 3.6 years. Incidence rates of new neurological events in nontransfused participants with normal TCD values with SCIs and without SCIs were 1.71 and 0.47 neurological events per 100 patient-years, respectively, P = .065. The absence of SCI(s) at baseline was associated with a decreased risk of a new neurological event (hazard ratio 0.231, 95% CI 0.062-0.858; P = .029). Local pediatric neurologists examined 67 of 68 participants with suspected SCIs and identified 2 with overt strokes classified as SCIs by local hematologists; subsequently one had a seizure and the other an ischemic stroke. Children with SCA, without SCIs, and normal TCD measurements have a significantly lower rate of new neurological events when compared to those with SCIs and normal TCD measurements. Pediatric neurology assessment may assist risk stratification.

Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.

BACKGROUND: Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS: In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS: A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04). CONCLUSIONS: Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Headache and migraine in children with sickle cell disease are associated with lower hemoglobin and higher pain event rates but not silent cerebral infarction.

OBJECTIVE: To identify risk factors for headache and migraine in children with sickle cell disease and test the hypothesis that either or both are independently associated with silent cerebral infarcts. STUDY DESIGN: In this cross-sectional study, we evaluated the health history, laboratory values, and brain magnetic resonance imaging findings of participants with sickle cell disease (hemoglobinSS or hemoglobinSß°-thalassemia) with no history of overt stroke or seizures. Participants characterized headache severity and quality. Migraine was defined by International Headache Society criteria modified for increased sensitivity in children. Neuroradiology and neurology committees adjudicated the presence of silent cerebral infarction by review of magnetic resonance imaging and standardized examination by pediatric neurologists. RESULTS: The cohort included 872 children (51.1% males), ranging in age from 5 to 15 years (mean age, 9.1 years). Of these children, 317 (36.4%) reported recurrent headaches, and 132 (15.1%) reported migraines. In multivariable logistic regression analyses, both were associated with lower steady-state hemoglobin (P = .01 for headaches; P < .01 for migraines) and higher pain rate (P < .01 for headaches; P < .01 for migraines), defined as the number of admissions requiring opioids in the previous 3 years. The presence of silent cerebral infarction was not associated with recurrent headaches or migraines. Only 1.9% (6 of 317) of children with recurrent headaches received medication for headache prophylaxis. CONCLUSION: Recurrent headaches and migraines are common and undertreated in children with sickle cell disease. Low hemoglobin levels and high pain rates are associated with recurrent headaches and migraines; whereas, silent cerebral infarction is not.

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure.

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSß° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

Parent education and biologic factors influence on cognition in sickle cell anemia.

Children with sickle cell anemia have a high prevalence of silent cerebral infarcts (SCIs) that are associated with decreased full-scale intelligence quotient (FSIQ). While the educational attainment of parents is a known strong predictor of the cognitive development of children in general, the role of parental education in sickle cell anemia along with other factors that adversely affect cognitive function (anemia, cerebral infarcts) is not known. We tested the hypothesis that both the presence of SCI and parental education would impact FSIQ in children with sickle cell anemia. A multicenter, cross-sectional study was conducted in 19 US sites of the Silent Infarct Transfusion Trial among children with sickle cell anemia, age 5-15 years. All were screened for SCIs. Participants with and without SCI were administered the Wechsler Abbreviated Scale of Intelligence. A total of 150 participants (107 with and 43 without SCIs) were included in the analysis. In a multivariable linear regression model for FSIQ, the absence of college education for the head of household was associated with a decrease of 6.2 points (P = 0.005); presence of SCI with a 5.2 point decrease (P = 0.017); each $1000 of family income per capita with a 0.33 point increase (P = 0.023); each increase of 1 year in age with a 0.96 point decrease (P = 0.023); and each 1% (absolute) decrease in hemoglobin oxygen saturation with 0.75 point decrease (P = 0.030). In conclusion, FSIQ in children with sickle cell anemia is best accounted for by a multivariate model that includes both biologic and socioenvironmental factors.

Silent cerebral infarction, income, and grade retention among students with sickle cell anemia.

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.

Silent cerebral infarcts occur despite regular blood transfusion therapy after first strokes in children with sickle cell disease.

Children with sickle cell disease (SCD) and strokes receive blood transfusion therapy for secondary stroke prevention; despite this, approximately 20% experience second overt strokes. Given this rate of second overt strokes and the clinical significance of silent cerebral infarcts, we tested the hypothesis that silent cerebral infarcts occur among children with SCD being transfused for secondary stroke prevention. A prospective cohort enrolled children with SCD and overt strokes at 7 academic centers. Magnetic resonance imaging and magnetic resonance angiography of the brain were scheduled approximately every 1 to 2 years; studies were reviewed by a panel of neuroradiologists. Eligibility criteria included regularly scheduled blood transfusion therapy. Forty children were included; mean pretransfusion hemoglobin S concentration was 29%. Progressive cerebral infarcts occurred in 45% (18 of 40 children) while receiving chronic blood transfusion therapy; 7 had second overt strokes and 11 had new silent cerebral infarcts. Worsening cerebral vasculopathy was associated with new cerebral infarction (overt or silent; relative risk = 12.7; 95% confidence interval, 2.65-60.5, P = .001). Children with SCD and overt strokes receiving regular blood transfusion therapy experience silent cerebral infarcts at a higher rate than previously recognized. Additional therapies are needed for secondary stroke prevention in children with SCD.

Newborn brachial plexus palsy: evaluation of severity using quantitative ultrasound of muscle.

INTRODUCTION: We studied ultrasound features of muscle after nerve injury. METHODS: We evaluated ultrasound measurements of muscle thickness and backscatter in injured and contralateral uninjured elbow flexors of 51 children with newborn brachial plexus palsy (NBPP) and compared the results to elbow flexor function (Active Movement Scale), defined as normal, moderate, or severe. RESULTS: Compared with uninjured limbs, muscle in injured arms was 15% thinner with severe impairment, 17% thicker with moderate impairment, and no different with normal function. Relative to uninjured limbs, moderately impaired muscle was thicker than both severely impaired and normal strength muscle. Backscatter was higher in injured than in uninjured limbs regardless of function. In 17 patients with sequential measures, muscle thickness, but not backscatter, increased with function over time. CONCLUSIONS: Muscle thickness differentiates moderate from severe impairment after NBPP and increases with recovery over time. Muscle backscatter identifies prior injury regardless of function.

Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats.

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.

Magnetic resonance angiography-defined intracranial vasculopathy is associated with silent cerebral infarcts and glucose-6-phosphate dehydrogenase mutation in children with sickle cell anaemia.

Silent cerebral infarct (SCI) is the most commonly recognized cause of neurological injury in sickle cell anaemia (SCA). We tested the hypothesis that magnetic resonance angiography (MRA)-defined vasculopathy is associated with SCI. Furthermore, we examined genetic variations in glucose-6-phosphate dehydrogenase (G6PD) and HBA (α-globin) genes to determine their association with intracranial vasculopathy in children with SCA. Magnetic resonance imaging (MRI) of the brain and MRA of the cerebral vasculature were available in 516 paediatric patients with SCA, enrolled in the Silent Infarct Transfusion (SIT) Trial. All patients were screened for G6PD mutations and HBA deletions. SCI were present in 41·5% (214 of 516) of SIT Trial children. The frequency of intracranial vasculopathy with and without SCI was 15·9% and 6·3%, respectively (P < 0·001). Using a multivariable logistic regression model, only the presence of a SCI was associated with increased odds of vasculopathy (P = 0·0007, odds ratio (OR) 2·84; 95% Confidence Interval (CI) = 1·55-5·21). Among male children with SCA, G6PD status was associated with vasculopathy (P = 0·04, OR 2·78; 95% CI = 1·04-7·42), while no significant association was noted for HBA deletions. Intracranial vasculopathy was observed in a minority of children with SCA, and when present, was associated with G6PD status in males and SCI.

Initial Validation of the Weekly Calendar Planning Activity With Adolescents With ABI.

The purpose of this study was to assess the validity of the Weekly Calendar Planning Activity Middle/High School (WCPA) in adolescents with acquired brain injuries (ABI). We recruited neurotypical controls (n = 27) and adolescents with ABI (n = 14) to complete a 90-min battery of cognitive tests. Adolescents with ABI were further divided into mild and severe groups by Glasgow Coma Scale Score and compared with controls. Mann-Whitney U tests revealed significant differences (p = .05) on the WCPA between groups in total time to complete and rules followed. Between the controls and severe group, a significant difference (p = .05) was found for total time spent, errors, rules followed, strategies used, and accurate appointments (p = .01). Moderate correlations were found between the WCPA and neuropsychological tests (ρ = .31-.45). The WCPA is a valid performance-based assessment of functional cognition that can be used to detect deficits in adolescents with severe ABI.

Subdural hemorrhage in a cohort with cerebral sinovenous thrombosis: Application to abusive head trauma.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) is a postulated cause of subdural hemorrhage (SDH) that is hypothesized to mimic abusive head trauma (AHT). Minimal data exists directly investigating this relationship. OBJECTIVES: To evaluate the frequency of SDH in children with CSVT, identify factors associated with CSVT and SDH, and to assess if any association supports the hypothesis that CSVT causes SDH. PARTICIPANTS AND SETTING: The International Pediatric Stroke Study (IPSS) prospectively collects data on subjects birth to 19 years of age with intracranial thrombosis. METHODS: IPSS subjects with CSVT and SDH were compared to those with CSVT and no SDH. For subjects with CSVT and SDH, neuroimaging reports further characterized the findings. In any case with no known risk factors for SDH, neuroimaging studies were reviewed by a pediatric neuroradiologist. RESULTS: Of 216 subjects with CSVT, 20 (9.3%) had SDH. Those with SDH (median age 0.3 years) were younger than those without SDH (median age 4.2 years), p < 0.001. Subjects with CSVT and SDH more frequently had anoxia (OR = 10.8; 95% CI: 1.4, 81.1), head/neck injury (OR = 4.0; 95% CI: 1.3, 12.6), or abnormal consciousness (OR = 3.0; 95% CI: 1.2, 7.6). Of 20 subjects with CSVT and SDH, 19 had known risk factors for SDH. The remaining subject had a chronic SDH identified concomitantly to a newly symptomatic CSVT with accompanying venous infarctions. CONCLUSIONS: SDH in the setting of CSVT is typically identified in children with independent risk factors for SDH. This study does not support the hypothesis that CSVT causes SDH.

Design of the silent cerebral infarct transfusion (SIT) trial.

BACKGROUND: Silent cerebral infarct (SCI) is the most common cause of serious neurological disease in sickle cell anemia (SCA), affecting approximately 22% of children. The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI, and if so, the magnitude of this benefit. PROCEDURE: The Silent Cerebral Infarct Transfusion (SIT) Trial includes 29 clinical sites and 3 subsites, a Clinical Coordinating Center, and a Statistical and Data Coordinating Center, to test the following hypothesis: prophylactic blood transfusion therapy in children with SCI will result in at least an 86% reduction in the rate of subsequent overt strokes or new or progressive cerebral infarcts as defined by magnetic resonance imaging (MRI) of the brain. The intervention is blood transfusion versus observation. Two hundred and four participants (102 in each treatment assignment) will ensure 85% power to detect the effect necessary to recommend transfusion therapy (86% reduction), after accounting for 10% drop out and 19% crossover rates. MRI examination of the brain is done at screening, immediately before randomization and study exit. Each randomly assigned participant receives a cognitive test battery at study entry, 12-18 months later, and study exit and an annual neurological examination. Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA. CONCLUSION: The SIT Trial could lead to a change in standard care practices for children affected with SCA and SCI, with a consequent reduction in neurological morbidity.

Treatment and outcome of childhood cerebral sinovenous thrombosis.

OBJECTIVE: To test our hypothesis that anticoagulation is associated with better neurologic outcomes in childhood cerebral sinovenous thrombosis (CSVT), we analyzed treatment and outcomes in a population of 410 children from the International Pediatric Stroke Study (IPSS). METHODS: We included patients enrolled in the IPSS registry with a diagnosis of CSVT at age >28 days with radiologic confirmation, in isolation or with concomitant arterial ischemic stroke. The primary outcome was the neurologic status at discharge. We defined unfavorable outcome as severe neurologic impairment or death at discharge. The Pediatric Stroke Outcome Measure was used for long-term outcome in those with follow-up. Predictors of anticoagulation use and outcome were analyzed by logistic regression. RESULTS: Most children (95%) had identifiable risk factors, and 82% received anticoagulation. Shift analysis demonstrated better outcomes at discharge in children who were anticoagulated, and this persisted with longer-term outcomes. In multivariable analysis, anticoagulation was significantly associated with favorable outcomes (adjusted odds ratio [aOR] unfavorable 0.32, p = 0.007) whereas infarct was associated with unfavorable outcome (aOR unfavorable 6.71, p < 0.001). The trauma/intracranial surgery was associated with a lower odds of anticoagulation use (aOR 0.14, p < 0.001). CONCLUSIONS: Within the IPSS registry, children with risk factors of trauma or intracranial surgery were less likely to receive anticoagulation for CSVT. Anticoagulation was associated with a lower odds of severe neurologic impairment or death at hospital discharge, but this finding is limited and needs further confirmation in randomized, controlled, prospective studies.

Blood transfusion therapy is feasible in a clinical trial setting in children with sickle cell disease and silent cerebral infarcts.

BACKGROUND: Silent cerebral infarcts are both morbid and progressive in children with sickle cell disease (SCD). While blood transfusion therapy is effective primary and secondary stroke prevention, the efficacy and acceptance of blood transfusion therapy for children with silent cerebral infarcts is unknown. The overall goals of this study were to determine the feasibility and short-term efficacy of blood transfusion therapy for silent cerebral infarcts. PROCEDURE: We conducted a single-arm feasibility intervention study. Children with SCD and silent cerebral infarcts received blood transfusion therapy. Short-term efficacy was defined as no progression of MRI findings on repeat MRI. RESULTS: Ten children enrolled in the study, and nine were evaluable. Five were male. The average age was 10.0 years (range 3.1-16.8). Seven of nine completed the transfusion therapy for over 2 years, with an average duration of therapy of 2.7 years (range 1-6). Twenty infarcts and four cases of Moya Moya were present on the initial MRI. Seven of nine subjects had repeat MRIs. Of these seven, there were a total of 18 infarcts. One infarct increased in size and one case of Moya Moya progressed on repeat MRI. All other lesions were stable or became smaller in diameter while on transfusion therapy during the time of follow up (mean 3.9 years, range 2.1-5.7). CONCLUSIONS: Blood transfusion therapy is a feasible therapy for the prevention of progression of silent cerebral infarcts.