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.)

Context Sickle cell anemia (SCA) is a chronic illness causing progressive deterioration in quality of life. Brain dysfunction may be the most important and least studied problem affecting individuals with this disease. Objective To measure neurocognitive dysfunction in neurologically asymptomatic adults with SCA vs healthy control individuals. Design, Setting, and Participants Cross-sectional study comparing neuropsychological function and neuroimaging findings in neurologically asymptomatic adults with SCA and controls from 12 SCA centers, conducted between December 2004 and May 2008. Participants were patients with SCA (hemoglobin [Hb] SS and hemoglobin level ≤10 mg/dL) aged 19 to 55 years and of African descent (n=149) or community controls (Hb AA and normal hemoglobin level) (n=47). Participants were stratified on age, sex, and education. Main Outcome Measures The primary outcome measure was nonverbal function assessed by the Wechsler Adult Intelligence Scale, third edition (WAIS-III) Performance IQ Index. Secondary exploratory outcomes included performance on neurocognitive tests of executive function, memory, attention, and language and magnetic resonance imaging measurement of total intracranial and hippocampal volume, cortical gray and white matter, and lacunae. Results The mean WAIS-III Performance IQ score of patients with SCA was significantly lower than that of controls (adjusted mean, 86.69 for patients with SCA vs 95.19 for controls [mean difference, −5.50; 95% confidence interval {CI}, −9.55 to −1.44]; P =.008), with 33% performing more than 1 SD (<85) below the population mean. Among secondary measures, differences were observed in adjusted mean values for global cognitive function (full-scale IQ) (90.47 for patients with SCA vs 95.66 for controls [mean difference, −5.19; 95% CI, −9.24 to −1.13]; P =.01), working memory (90.75 vs 95.25 [mean difference, −4.50; 95% CI, −8.55 to −0.45]; P =.03), processing speed (86.50 vs 97.95 [mean difference, −11.46; 95% CI, −15.51 to −7.40]; P <.001), and measures of executive function. Anemia was associated with poorer neurocognitive function in older patients. No differences in total gray matter or hippocampal volume were observed. Lacunae were more frequent in patients with SCA but not independently related to neurocognitive function. Conclusion Compared with healthy controls, adults with SCA had poorer cognitive performance, which was associated with anemia and age.

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 HbS␤°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. IntroductionSilent cerebral infarcts (SCIs) have been recognized by neuroimaging in neurologically normal older adult populations since 1981 1 and were documented in sickle cell anemia (SCA) soon afterward. 2 As with overt stroke, SCIs represent a clinical finding that is common in older adults without SCD, but they appear during early childhood in persons with SCA. SCIs are defined as an MRI signal abnormality visible on 2 views on the T2-weighted images (axial and coronal) that must measure at least 3 mm in one dimension; further, the person deemed to have an SCI must have an absence of focal neurologic deficit compatible with the anatomic location of the brain lesion. 3 SCI is the most common form of neurologic injury among children with SCA, occurring in at least 27% before 6 years of life 4 and 37% by 14 years of life. 5 SCIs in children with SCA are associated with increased risk of future overt strokes and new or progressive SCIs. 6,7 In addition, children with SCA and SCI have been found to have poorer cognitive function The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 3684BLOOD, 19 APRIL 2012 ⅐ VOLUME 119, NUMBER 16For personal use only. on March 28, 2019. by guest www.bloodjournal.org From than children with SCA with normal MRI of the brain 8-10 or sibling controls. 10,11 Clinical and laboratory risk factors for SCI have been evaluated only sparingly. In the most rigorous study to date, the investigators from the Cooperative Study for Sickle Cell Disease (CSSCD) described risk factors associated with SCI in 42 participants, comparing them with 188 controls with ...

Summary Iron‐overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron‐overloaded subjects with Thal (n = 142; 54%M; age 25·8 ± 8·1 years) and transfused sickle‐cell disease (Tx‐SCD; n = 199; 43%M, 24·9 ± 13·2 years) to non‐transfused SCD subjects (non‐Tx‐SCD; n = 64, 50%M, 25·3 ± 11·3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0·001), hypogonadism (40% vs. 4%, P < 0·001), hypothyroidism (10% vs. 2%, P = <0·001) and growth failure (33% vs. 7%, P < 0·001), versus Tx‐SCD. Fifty‐six per cent of Thal had more than one endocrinopathy compared with only 13% of Tx‐SCD (P < 0·001). In contrast, Tx‐SCD was not different from non‐Tx‐SCD. Multivariate analysis indicated that endocrinopathy was more likely in Thal than SCD [Odds Ratio (OR) = 9·4, P < 0·001], with duration of chronic transfusion a significant predictor (OR = 1·4 per 10 years of transfusion, P = 0·04). Despite iron overload, endocrinopathy was not increased in Tx‐SCD versus non‐Tx‐SCD, suggesting that the underlying disease may modulate iron‐related endocrine injury. However, because transfusion duration remained a significant predictor of endocrinopathy, these data should be confirmed in SCD subjects that have been chronically transfused for longer periods of time.