Acute silent cerebral ischemic events in children with sickle cell anemia.
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ABSTRACT:
SUBMITTER: Quinn CT
PROVIDER: S-EPMC3677221 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
Publications
Acute silent cerebral ischemic events in children with sickle cell anemia.
Quinn Charles T CT McKinstry Robert C RC Dowling Michael M MM Ball William S WS Kraut Michael A MA Casella James F JF Dlamini Nomazulu N Ichord Rebecca N RN Jordan Lori C LC Kirkham Fenella J FJ Noetzel Michael J MJ Roach E Steve ES Strouse John J JJ Kwiatkowski Janet L JL Hirtz Deborah D DeBaun Michael R MR
JAMA neurology 20130101 1
<h4>Background</h4>Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain.<h4>Objective</h4>To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient.<h4>Design</h4>Cross-sectional and cohort study of children with SCA screened by magnetic resona ...[more]
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Project description:Silent cerebral infarction is the most common neurological abnormality in children with sickle cell anemia, affecting 30-40% of 14 year olds. There are no known biomarkers to identify children with silent cerebral infarcts, and the pathological basis is also unknown. We used an unbiased proteomic discovery approach to identify plasma proteins differing in concentration between children with and without silent cerebral infarcts. Clinical parameters and plasma samples were analysed from 51 children (mean age 11.8 years, range 6-18) with sickle cell anemia (HbSS). A total of 19 children had silent cerebral infarcts and 32 normal MRI; the children with silent infarcts had lower HbF levels (8.6 vs 16.1%, P=0.049) and higher systolic blood pressures (115 vs 108.6, P=0.027). Plasma proteomic analysis showed 13 proteins increased more than 1.3 fold in the SCI patients, including proteins involved in hypercoagulability (α2-antiplasmin, fibrinogen-γ chain, thrombospondin-4), inflammation (α2-macroglobulin, complement C1s and C3), and atherosclerosis (apolipoprotein B-100). Higher levels of gelsolin and retinol-binding protein 4 were also found in the population with silent infarcts, both of which have been linked to stroke. We investigated the genetic basis of these differences by studying 359 adults with sickle cell disease (199 with silent cerebral infarcts, 160 normal MRIs), who had previously undergone a genome-wide genotyping array. None of the genes coding for the differentially expressed proteins were significantly associated with silent infarction. Our study suggests that silent cerebral infarcts in sickle cell anemia may be associated with higher systolic blood pressure, lower HbF levels, hypercoagulability, inflammation and atherosclerotic lipoproteins.
| S-EPMC6029528 | biostudies-literature
Project description:OBJECTIVE:To evaluate whether application of the adult definition of silent cerebral infarct (SCI) (T2-weighted hyperintensity ≥5 mm with corresponding T1-weighted hypointensity on MRI) is associated with full-scale IQ (FSIQ) loss in children with sickle cell anemia (SCA), and if so, whether this loss is greater than that of the reference pediatric definition of SCI (T2-weighted hyperintensity ≥3 mm in children on MRI; change in FSIQ -5.2 points; p = 0.017; 95% confidence interval [CI] -9.48 to -0.93). METHODS:Among children with SCA screened for SCI in the Silent Cerebral Infarct Transfusion trial, ages 5-14 years, a total of 150 participants (107 with SCIs and 43 without SCIs) were administered the Wechsler Abbreviated Scale of Intelligence. A multivariable linear regression was used to model FSIQ in this population, with varying definitions of SCI independently substituted for the SCI covariate. RESULTS:The adult definition of SCI applied to 27% of the pediatric participants with SCIs and was not associated with a statistically significant change in FSIQ (unstandardized coefficient -3.9 points; p = 0.114; 95% CI -8.75 to 0.95), with predicted mean FSIQ of 92.1 and 96.0, respectively, for those with and without the adult definition of SCI. CONCLUSIONS:The adult definition of SCI may be too restrictive and was not associated with significant FSIQ decline in children with SCA. Based on these findings, we find no utility in applying the adult definition of SCI to children with SCA and recommend maintaining the current pediatric definition of SCI in this population.
| S-EPMC5772160 | biostudies-literature
Project description:BackgroundSilent 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.MethodsIn 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.ResultsA 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).ConclusionsRegular 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.).
| S-EPMC4195437 | biostudies-literature
Project description: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.
| S-EPMC4261188 | biostudies-literature
Project description:Research in sickle cell anemia (SCA) has used, with limited race-matched control data, binary categorization of patients according to the presence or absence of silent cerebral infarction (SCI). SCI have primarily been identified using low-resolution MRI, with radiological definitions varying in lesion length and the requirement for abnormality on both fluid attenuated inversion recovery (FLAIR) and T1-weighted images. We aimed to assess the effect of published SCI definitions on global, regional, and lobar lesion metrics and their value in predicting cognition. One hundred and six patients with SCA and 48 controls aged 8–30 years underwent 3T MRI with a high-resolution FLAIR sequence and Wechsler cognitive assessment. Prevalence, number, and volume of lesions were calculated using a semi-automated pipeline for SCI defined as: (1) Liberal: any length (L-SCI); (2) Traditional: >3 mm in greatest dimension (T-SCI); (3) Restrictive; >3 mm in greatest dimension with a corresponding T1-weighted hypo-intensity (R-SCI). Globally, as hypothesized, there were large effects of SCI definition on lesion metrics in patients and controls, with prevalence varying from 24–42% in patients, and 4–23% in controls. However, contrary to hypotheses, there was no effect of any global metric on cognition. Regionally, there was a consistent distribution of SCI in frontal and parietal deep and juxta-cortical regions across definitions and metrics in patients, but no consistent distribution in controls. Effects of regional SCI metrics on cognitive performance were of small magnitude; some were paradoxical. These findings expose the challenges associated with the widespread use of SCI presence as a biomarker of white-matter injury and cognitive dysfunction in cross-sectional high-resolution MRI studies in patients with SCA. The findings indicate that with high-resolution MRI: (1) radiological definitions have a large effect on resulting lesion groups, numbers, and volumes; (2) there is a non-negligible prevalence of lesions in young healthy controls; and (3) at the group-level, there is no cross-sectional association between global lesion metrics and general cognitive impairment irrespective of lesion definition and metric. With high-resolution multi-modal MRI, the dichotomy of presence or absence of SCI does not appear to be a sensitive biomarker for the detection of functionally significant pathology; the search for appropriate endpoints for clinical treatment trials should continue.
| S-EPMC9277177 | biostudies-literature
Project description:Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.
| S-EPMC8858025 | biostudies-literature
Project description:Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R 2* and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/-T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R 2* maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R 2* were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = -0.0067 ppm vs. -0.0153 ppm, p < 0.001) and had significantly lower R 2* (16.7 s-1 vs. 19.2 s-1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R 2* , with lesions becoming significantly less diamagnetic and having significantly lower R 2* after the application of a more stringent T1w-based threshold. SCI-NAWM R 2* decrease was significantly greater in patients with SCA compared with controls (-2.84 s-1 vs. -0.64 s-1, p < 0.0001). No significant association was observed between mean SCI-NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R 2* in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI-NAWM R 2* differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R 2* mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls.
| S-EPMC9632444 | biostudies-literature
Project description:Silent cerebral infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA.
| S-EPMC3367871 | biostudies-literature
Project description:ObjectivesTo evaluate the relationship between TGFBR3 rs284875 single nucleotide polymorphism (SNP) state and silent cerebral infarction (SCI) in asymptomatic patients with sickle cell disease (SCD).MethodsA cross-sectional study was conducted on 50 children with SCD above 2 y of age followed up at the hematology outpatient clinic of Alexandria University Children's Hospital in Egypt. Twenty-four healthy children were included as a control group. All patients included in the study were subjected to complete history and clinical examination. Real-time polymerase chain reaction was performed on patients and controls for identification of SNP rs284875 of the TGFBR3 gene. A magnetic resonance imaging (MRI) of the brain were performed only on patients for detection of SCI.ResultsFifty SCD patients were enrolled (26 males and 24 females), with a median age of 10.9 y (2.3-17.8 y), and 24 children as healthy control for the studied SNP. Thirty-five (70%) patients had homozygous SCD, while 30% had sickle β-thalassemia. The brain MRI was normal in all the patients except for 2 patients who had features of SCI. The TGFBR3 rs284875 SNP was detected in 15 (30%) patients in the homozygous state (GG) versus only 1 (4.2%) child from the control group (p = 0.003). The prevalence of SCI was low in the study population and there was no statistically significant relationship between the TGFBR3 rs284875 SNP status and the presence of SCI in the brain MRI (p = 0.621).ConclusionsThis study confirmed a low prevalence of SCI in the SCD patient included in the study. The TGFBR3 rs284875 SNP did not significantly increase SCI among those patients.
| S-EPMC9842542 | biostudies-literature
Project description:BACKGROUND:Blood transfusions are administered to children and adults with sickle cell anemia (SCA) for secondary stroke prevention, or as treatment for recurrent pain crises or acute anemia, but transfusion effects on cerebral hemodynamics and metabolism are not well-characterized. PURPOSE:To compare blood transfusion-induced changes in hemometabolic parameters, including oxygen extraction fraction (OEF) and cerebral blood flow (CBF), within and between adults and children with SCA. STUDY TYPE:Prospective, longitudinal study. SUBJECTS:Adults with SCA (n?=?16) receiving simple (n?=?7) or exchange (n?=?9) transfusions and children with SCA (n?=?11) receiving exchange transfusions were scanned once when hematocrit was near nadir and again within 7 days of transfusion. Adult controls without SCA or sickle trait (n?=?7) were scanned twice on separate days. FIELD STRENGTH/SEQUENCE:3.0T T1 -weighted, T2 -weighted, and T2 -relaxation-under-spin-tagging (TRUST) imaging, and phase contrast angiography. ASSESSMENT:Global OEF was computed as the relative difference between venous oxygenation (from TRUST) and arterial oxygenation (from pulse oximetry). Global CBF was computed as total blood flow to the brain normalized by intracranial tissue volume. STATISTICAL TESTS:Hemometabolic variables were compared using two-sided Wilcoxon signed-rank tests; associations were analyzed using two-sided Spearman's correlation testing. RESULTS:In adults with SCA, posttransfusion OEF?=?0.38?±?0.05 was lower (P?=?0.001) than pretransfusion OEF?=?0.45?±?0.09. A change in OEF was correlated with increases in hematocrit (P?=?0.02; rho?=?-0.62) and with pretransfusion hematocrit (P?=?0.02; rho?=?0.65). OEF changes after transfusion were greater (P?=?0.002) in adults receiving simple versus exchange transfusions. Posttransfusion CBF?=?77.7?±?26.4?ml/100g/min was not different (P?=?0.27) from pretransfusion CBF?=?82.3?±?30.2?ml/100g/min. In children with SCA, both posttransfusion OEF?=?0.28?±?0.04 and CBF?=?76.4?±?26.4 were lower than pretransfusion OEF?=?0.36?±?0.06 (P?=?0.004) and CBF?=?96.4?±?16.5 (P?=?0.004). DATA CONCLUSION:Cerebral OEF reduces following transfusions in adults and children with SCA. CBF reduces following transfusions more often in children compared to adults, indicating that vascular reserve capacity may remain near exhaustion posttransfusion in many adults. LEVEL OF EVIDENCE:2 Technical Efficacy Stage 5 J. Magn. Reson. Imaging 2019;49:466-477.
| S-EPMC6330124 | biostudies-literature