Cognitive Function in Sickle Cell Disease Across Domains, Cerebral Infarct Status, and the Lifespan: A Meta-Analysis

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.

Silent cerebral infarct definitions and full-scale IQ loss in children with sickle cell anemia

ObjectiveTo 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).MethodsAmong 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.ResultsThe 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.ConclusionsThe 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.

Parvovirus B19 Infection Associated with Silent Cerebral Infarcts: A Secondary Analysis of the Silent Cerebral Infarct Trial Cohort

Introduction: Silent cerebral infarcts (SCI) are the major cause of neurological injury occurring in almost 40% of the population in children with sickle cell anemia (SCA); and are associated with a Full-Scale IQ decrease of approximately 5 points. Acute anemic events, defined as hemoglobin< 6.0 g/dl, is associated with an increase odds ratio (OR) of SCI (OR 2.72; 95% CI, 1.13-6.54; P = .025; Bernaudin et al. Blood. 2015 Mar 5; 125(10):1653-61). Infection with parvovirus B19 (B19V) causes a transient reticulocytopenia and an acute drop in hemoglobin levels in children with SCA. We tested the hypothesis that a history of B19V infection was associated with increased odds ratio of SCIs. Methods: In this retrospective cross-sectional study design, we performed a secondary analysis on the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial). Children with SCA between 5 and 15 years of age, with no history of overt strokes or seizures, were screened for SCIs with MRIs of the brain. Research personnel reviewed medical records to determine a history of B19V infection. Based on prior evidence from the SIT Trial cohort demonstrating that lower hemoglobin levels divided into tertiles are associated with an increase odds of SCI (DeBaun et al. Blood. 2012 Apr 19;119(16):3684-90), three analyses were performed. We stratified by hemoglobin levels into tertiles (<7.6g/dL, ³7.6 and ²8.4 g/dL, and >8.4 g/dL), to determine an association between SCI status and history of B19V infection. Chi squared statistic was used as the measure of association. As a secondary analysis of the original SIT trial cohort, the level of strong significance associated with an increased odds ratio of SCI was determined to be <0.01, with values <0.05 considered moderate significance. Results: A total of 814 of the SIT Trial participants had their SCI status adjudicated (present or absent) and a recorded history of B19V status (yes or no). In the cohort, 30% had a SCI and 17% had a history of B19V infection. Prior B19V infection with baseline hemoglobin levels <7.6 g/dL were associated with increase OR of SCI (OR 2.20; 95% CI, 1.22 to 3.97; p=0.008). Prior B19V infection with a baseline hemoglobin levels in the middle (³7.6 to²8.4 g/dL) and upper tertiles (> 8.4 g/dl) were not associated with an increased OR of SCI (OR 0.88; 95% CI, 0.47 to 1.66; p=0.695; and ³8.5 g/dL OR 1.39; 95% CI, 0.72 to 2.69; p=0.328; respectively). Conclusion: Children with SCA, a history of B19V and a low baseline hemoglobin level <7.6 g/dL have an increased OR of SCIs. Future efforts in developing a vaccine for B19V may provide an opportunity for decreasing the incidence of SCIs in children with SCA. Disclosures No relevant conflicts of interest to declare.