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Sickle cell anemia (SCA) is a well-characterized monogenetic disorder with a high prevalence of cerebral vasculopathy, silent cerebral infarcts, and strokes. A significant mechanism for cerebral infarction in SCA is hemodynamic imbalance. To compensate for reduced oxygen-carrying capacity due to anemia, individuals with SCA have chronically elevated cerebral blood flow to maintain viable oxygen delivery to the brain tissue. Often the oxygen extraction fraction (ratio of oxygen consumed to oxygen delivered) is increased in more severely affected individuals. Subsequently, cerebrovascular reserve capacity, the ability of arterioles to dilate and further increase the cerebral blood volume and flow, will be reduced. These hemodynamic profiles have been associated with prior cerebral infarcts and increased evidence of disease severity. These cerebral hemodynamic parameters can be assessed noninvasively with noncontrast magnetic resonance imaging (MRI) of the brain utilizing specific MRI methods. This review focuses on using advanced neuroimaging methods to assess stroke risk in individuals with SCA, and such methods may be utilized before and after bone marrow or hematopoietic stem cell transplant to assess cerebral hemodynamic response. This manuscript is part of the Proceeding of The European Group for Blood and Marrow Transplantation (EBMT) Congress on Sickle Cell Disease, 16th-17 May 2019, Regensburg, Germany.
Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.
OBJECTIVE - To provide a comprehensive quantitative review of neurocognitive function in sickle cell disease (SCD) across multiple domains, cerebral infarct status, and the lifespan.
METHODS - One hundred and ten studies were identified in PubMed, MedLine, and PsycINFO involving 110 studies of 3,600 participants with SCD and 1,127 sibling or health controls.
RESULTS - Meta-analytic findings indicate significant deficits across all neurocognitive domains, age groups, and infarct status. Significant deficits relative to the normative mean ranged from Hedges' g = -.39 to g = -.63 in preschool children, g = -.83 to g = -1.18 in school-aged children and adolescents, and g = -.46 to g = -.86 in adults. Deficits in full scale IQ (FSIQ), verbal reasoning, perceptual reasoning, and executive function increased from preschool to school-aged samples. However, findings also showed that deficits were smaller in adult samples relative to school-aged samples, likely due to sampling bias in adult studies. Findings across infarct status in sickle cell anemia showed that deficits ranged from g = -.54 to g = -.65 in samples without infarcts, g = -.52 to g = -1.03 in samples with silent cerebral infarct, and g = -1.35 to g = -1.82 in samples with stroke. Deficits in each domain increased in magnitude from no infarct or stroke, to silent cerebral infarct, to overt stroke.
CONCLUSION - Individuals with SCD are at risk for cognitive deficits across domains, infarct status, and the lifespan. More research is necessary to determine unbiased effects for cognitive function in adults with SCD.
© The Author(s) 2019. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
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.
BACKGROUND - To improve the quality of care for children with sickle cell anemia in Kano, Nigeria, we initiated a standard care protocol in 2014 to manage children with strokes at Aminu Kano Teaching Hospital.
METHODS - The standard care protocol requires that children with acute strokes be treated with hydroxyurea at a fixed dose of 20 mg/kg/day within two months of the stroke.
RESULTS - Twenty-nine children with sickle cell anemia and initial stroke were identified based on clinical World Health Organization criteria from 2014 to 2017. Follow-up was a median of 1.04 years (interquartile range 0.43 to 1.83 years) to either July 2017 or a second stroke, corresponding to an initial stroke incidence rate of 0.88 per 100 patient-years. Eight children had a recurrent stroke, six of whom were prescribed hydroxyurea 20 mg/kg/day by two months after initial stroke. Two children died. Six of the recurrent strokes occurred within six months of the initial stroke, two before hydroxyurea prescription. The stroke recurrence rate was 17.4 events per 100 patient-years. Adherence was approximately 60%, partly because families had to pay for hydroxyurea. Stroke incidence is probably underestimated because despite formal training for stroke detection during the quality improvement period, no participant had assessment using a standardized pediatric stroke scale and neuroimaging was not available.
CONCLUSIONS - In children with sickle cell anemia, a high rate of initial and recurrent strokes exists in a low-resource setting. Ongoing needs include training to detect strokes with an objective stroke assessment and government-supported free access to hydroxyurea for stroke prevention.
Copyright © 2019 Elsevier Inc. All rights reserved.
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 T -weighted, T -weighted, and T -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.
© 2018 International Society for Magnetic Resonance in Medicine.
Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density ( < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.
© 2018 by The American Society of Hematology.