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A patient who had sickle cell disease and had spleen uptake on bone scans is described, and additional causes for that finding are discussed., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Sickle cell disease (SCD)-related neurological effects are particularly devastating. Dilated perivascular spaces (dPVS) are a well-described component of cerebral small vessel disease in older adults without SCD. However, the burden and association of dPVS with neurological complications in children with SCD have not been described. In this study, we used the international consensus criteria to quantify dPVS in the centrum semiovale and basal ganglia in T2-weighted magnetic resonance images (MRI) of children with SCD who were randomized as part of the Silent Cerebral Infarct Transfusion (SIT) trial. We examined the relationship between global and/or regional dPVS burden and presence or area of silent cerebral infarctions, hematological measures, demographic variables, and full-scale intelligence quotient (FSIQ) scores. The study included 156 SIT trial participants who had pre-randomization and study exit MRI. Their median age was 9.6 (5-15) years, 39% were female, and 94 (60%) participants had a high dPVS burden. Participants randomized to the blood transfusion arm and who had a high dPVS burden at baseline had a moderate decline in dPVS score over 36 months compared to no change in the observation group. On multivariable logistic regression, intelligence quotient was not associated with dPVS burden. Children with SCD included in the SIT trial have a high burden of dPVS compared to children without SCD. However, dPVS do not appear to have the same pathophysiology of silent cerebral infarcts. Further study is needed to determine both their etiology and clinical relevance., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Background: Growth failure is commonly encountered in sickle cell disease (SCD). Tissue compartment growth and development are subsequently likely to be altered in such patients., Objective: We aimed to analyze body composition in an Egyptian pediatric SCD cohort using dual-energy x-ray absorptiometry (DEXA), one of the most comprehensive and noninvasive assessment methods available., Methods: Forty children with SCD ≤18 years and 40 healthy youngsters age- and gender-matched were enrolled. Patients' demographic, clinical, and laboratory parameters were obtained from their archived files. All patients and controls were subjected to body composition assessment using a MedixDR-Whole Body DEXA System., Results: In SCD patients; weight and height relative to age Z scores were significantly lower (p < .001), total body lean was significantly higher (p = .006), and total body fat percentage was lower, yet the difference was not statistically significant (p = .09). There were no statistically significant variations in bone mineral density or content, basal metabolic rate, subcutaneous adipose tissue, android/gynoid fat ratio, and visceral adipose tissue. There were no significant gender disparities between SCD patients and controls., Conclusion: Faltering growth in children with SCD should be addressed with a multidisciplinary approach including nutritional support, correction of anemia, and proper medical care. Body composition parameters assessed using DEXA were comparable between cases and controls apart from total body lean. Further clinical studies are needed with multicenter cooperation and a larger sample size to assess the usefulness of DEXA as an assessment tool for body composition in children with SCD., (© 2024 Wiley Periodicals LLC.)

Introduction: Individuals with sickle cell disease (SCD) at increased risk for stroke should undergo annual stroke risk assessment using transcranial Doppler (TCD) screening between the ages of 2 and 16. Though this screening can significantly reduce morbidity associated with SCD, screening rates at Boston Children's Hospital (and nationwide) remain below the recommended 100% screening adherence rates., Methods: Three plan-do-study-act (PDSA) cycles were designed and implemented. The Specific, Measurable, Achievable, Relevant, and Time-Bound (SMART) aim of our quality improvement (QI) initiative was to sustainably increase the proportion of eligible patients receiving a TCD within 15 months of their last TCD to greater than 95%. An interrupted time series (ITS) analysis was performed, comparing TCD adherence rates from PDSA Cycle 1 to those from PDSA Cycles 2 and 3., Results: Mean TCD adherence increased across all three PDSA cycles, from a baseline of 67% in the first cycle (January 2015 to September 2020) to 92% in the third cycle (May 2021 to March 2023). In the ITS analysis of TCD adherence rates, there was a significant difference in the final TCD adherence rate achieved compared to the rate predicted, with a total estimated increase in adherence of 17.9% being attributable to the interventions from PDSA Cycles 2 and 3., Discussion: Although other QI initiatives had demonstrated ability to increase adherence to TCD screening for patients with SCD, this is the first QI project to collect data over such a prolonged period of time to demonstrate a sustained increase in screening rates throughout the intervention (an 8-year period)., (© 2024 Wiley Periodicals LLC.)

Abnormal oxygen extraction fraction (OEF), a putative biomarker of cerebral metabolic stress, may indicate compromised oxygen delivery and ischemic vulnerability in patients with sickle cell disease (SCD). Elevated OEF was observed at the tissue level across the brain using an asymmetric spin echo (ASE) MR method, while variable global OEFs were found from the superior sagittal sinus (SSS) using a T2-relaxation-under-spin-tagging (TRUST) MRI method with different calibration models. In this study, we aimed to compare the average ASE-OEF in the SSS drainage territory and TRUST-OEF in the SSS from the same SCD patients and healthy controls. 74 participants (SCD: N = 49; controls: N = 25) underwent brain MRI. TRUST-OEF was quantified using the Lu-bovine, Bush-HbA and Li-Bush-HbS models. ASE-OEF and TRUST-OEF were significantly associated in healthy controls after controlling for hematocrit using the Lu-bovine or the Bush-HbA model. However, no association was found between ASE-OEF and TRUST-OEF in patients with SCD using either the Bush-HbA or the Li-Bush-HbS model. Plausible explanations include a discordance between spatially volume-averaged oxygenation brain tissue and flow-weighted volume-averaged oxygenation in SSS or sub-optimal calibration in SCD. Further work is needed to refine and validate non-invasive MR OEF measurements in SCD., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Sickle cell disease (SCD) is a hereditary red cell disorder with clinical manifestations secondary to sickling or crescent-shaped distortion of the red blood cells. Musculoskeletal complications of SCD are often the main causes for acute and chronic morbidities in children with manifestations including osteomyelitis, osteoporosis and osteonecrosis. This article aims to familiarise the paediatric radiologist with appendicular skeletal complications of SCD in the paediatric population and their imaging appearance., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Abstract: Children with sickle cell anemia (SCA) are at increased risk of stroke when compared with their age-based counterparts. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) previously demonstrated that with the use of transcranial Doppler ultrasound (TCD; Sickle Stroke Screen) and chronic red cell transfusion, the risk of stroke is reduced by over 90%. The STOP criteria detailed the type and method of measurement required; the time-averaged mean maximum velocity (TAMMV). Unfortunately, it has been difficult to adhere to the appropriate TAMMV measurements. The objectives of this study were to assess the quality of TCD and transcranial Doppler imaging (TCDi) reports to determine the report quality and accuracy. This is a subanalysis of the DISPLACE (Dissemination and Implementation of Stroke Prevention Looking at the Care Environment) study. Over 12 000 TCD/TCDi reports were collected during this study from 28 institutions; 391 TCDs were reviewed for this subanalysis. There were significant variations in the vessels being assessed, the velocities used to define abnormal results, and who was interpreting the scans. In 52% of reports, it was impossible to identify whether the TAMMV was what was measured. Similarly, it was only clear in 42% of reports that the TAMMV was used to interpret the examination as normal/abnormal. Given this inconsistency, we strongly recommend standardization of TCD/TCDi reporting, specialized training for those performing and interpreting the scans in the use of TCD/TCDi in patients with SCA, internal quality assurance, and institutional quality improvement work to ensure appropriate use of this potentially lifesaving technology., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Sickle cell disease (SCD) is the commonest inherited blood disorder leading to complications occurring due to vaso-occlusion including sight-threatening retinopathy. Retinopathy can be managed if diagnosed early and vision loss can be prevented. Since, very less data are available from India, hence, this study was conducted in children (7-18 years) with SCD to diagnose retinopathy by using ocular coherence tomography (OCT) in subclinical stages., Methods: This cross sectional single-center study was performed in 7-18 years age group children with SCD without any visual symptoms. Enrolled participants underwent complete ophthalmological examination including macula and optic disc thickness measurements using Cirrus HD-OCT and results were analyzed., Results: Among 55 participants, none had visual impairment. Significant fundoscopy finding (nonproliferative sickle cell retinopathy/NPSR) was found in three patients (5.4%), thinning of central macula in four patients (7.27%), inner macula thinning in eight patients (14.5%), outer macula thinning in one patient (1.81%), retinal nerve fiber layer thinning in five patients (9%), ganglion cell layer to inner plexiform layer thinning in eight patients (14.54%). Overall NPSR was found in 5.4% patients detected with fundoscopy, whereas retinal layer thinning was found in 14 patients (25.4%) using OCT., Conclusion: Despite of the significant prevalence of SCR, it is still underdiagnosed complication, leading to thinning of the retina from early ages; thus, its early diagnosis by regular screening using newer diagnostic methods can prevent progression to sight-threatening complications and provide better quality of life for these patients., (© 2024 Wiley Periodicals LLC.)

Background: National sickle cell disease (SCD) guidelines recommend oral hydroxyurea (HU) starting at 9 months of age, and annual transcranial Doppler (TCD) screenings to identify stroke risk in children aged 2-16 years. We examined prevalence and proportion of TCD screenings in North Carolina Medicaid enrollees to identify associations with sociodemographic factors and HU adherence over 3 years., Study Design: We conducted a longitudinal study with children ages 2-16 years with SCD enrolled in NC Medicaid from years 2016-2019. Prevalence of TCD screening claims was calculated for 3 years, and proportion was calculated for 12, 24, and 36 months of Medicaid enrollment. Enrollee HU adherence was categorized using HU proportion of days covered. Multivariable Poisson regression assessed for TCD screening rates by HU adherence, controlling for age, sex, and rurality., Results: The prevalence of annual TCD screening was between 39.5% and 40.1%. Of those with 12-month enrollment, 77.8% had no TCD claims, compared to 22.2% who had one or higher TCD claims. Inversely, in children with 36 months of enrollment, 36.7% had no TCD claims compared to 63.3% who had one or higher TCD claims. The proportion of children with two or higher TCD claims increased with longer enrollment (10.5% at 12 months, 33.7% at 24 months, and 52.6% at 36 months). Children with good HU adherence were 2.48 (p < .0001) times more likely to have TCD claims than children with poor HU adherence., Conclusion: While overall TCD screening prevalence was low, children with better HU adherence and longer Medicaid enrollment had more TCD screenings. Multilevel interventions are needed to engage healthcare providers and families to improve both evidence-based care and annual TCD screenings in children with SCD., (© 2024 Wiley Periodicals LLC.)

Background: Sickle cell disease (SCD) is a genetic hematological disorder associated with severe complications, such as vaso-occlusive crises, acute chest syndrome (ACS), and an increased risk of thromboembolic events, including pulmonary embolism (PE). The diagnosis of PE in SCD patients presents challenges due to the overlapping symptoms with other pulmonary conditions. Our previous study revealed that nearly 96% of computed tomography pulmonary angiography (CTPA) scans in SCD patients were negative for PE, highlighting a gap in understanding the significance of CTPA findings when PE is absent., Methods: In this retrospective follow-up study conducted at the Salmaniya Medical Complex in Bahrain, we examined SCD patients with HbSS genotypes who underwent CTPA from January 1, 2018, to December 31, 2021, for suspected PE, but the results were negative. The aim of this study was to identify alternative diagnoses and incidental findings from CTPA scans. Experienced radiologists reviewed the CTPA images and reports to assess potential alternative diagnoses and incidental findings, incorporating an additional analysis of chest X-rays to evaluate the diagnostic value of CTPA. Incidental findings were classified based on their location and clinical significance., Results: Among the 230 evaluated SCD patients (average age 39.7 years; 53% male) who were CTPA negative for PE, 142 (61.7%) had identifiable alternative diagnoses, primarily pneumonia (49.1%). Notably, 88.0% of these alternative diagnoses had been previously suggested by chest radiographs. Furthermore, incidental findings were noted in 164 (71.3%) patients, with 11.0% deemed clinically significant, necessitating immediate action, and 87.8% considered potentially significant, requiring further assessment. Notable incidental findings included thoracic abnormalities such as cardiomegaly (12.2%) and an enlarged pulmonary artery (11.3%), as well as upper abdominal pathologies such as hepatomegaly (19.6%), splenomegaly (20.9%), and gallstones (10.4%)., Conclusion: This study underscores the limited additional diagnostic yield of CTPA for identifying alternative diagnoses to PE in SCD patients, with the majority of diagnoses, such as pneumonia, already suggested by chest radiographs. The frequent incidental findings, most of which necessitate further evaluation, highlight the need for a cautious and tailored approach to using CTPA in the SCD population., (© 2024. The Author(s), under exclusive licence to American Society of Emergency Radiology (ASER).)

Background and Objectives: Previously we demonstrated that 90% of infarcts in children with sickle cell anemia occur in the border zone regions of cerebral blood flow (CBF). We tested the hypothesis that adults with sickle cell disease (SCD) have silent cerebral infarcts (SCIs) in the border zone regions, with a secondary hypothesis that older age and traditional stroke risk factors would be associated with infarct occurrence in regions outside the border zones., Methods: Adults with SCD 18-50 years of age were enrolled in a cross-sectional study at 2 centers and completed a 3T brain MRI. Participants with a history of overt stroke were excluded. Infarct masks were manually delineated on T2-fluid-attenuated inversion-recovery MRI and registered to the Montreal Neurological Institute 152 brain atlas to generate an infarct heatmap. Border zone regions between anterior, middle, and posterior cerebral arteries (ACA, MCA, and PCA) were quantified using the Digital 3D Brain MRI Arterial Territories Atlas, and logistic regression was applied to identify relationships between infarct distribution, demographics, and stroke risk factors., Results: Of 113 participants with SCD (median age 26.1 years, interquartile range [IQR] 21.6-31.4 years, 51% male), 56 (49.6%) had SCIs. Participants had a median of 5.5 infarcts (IQR 3.2-13.8). Analysis of infarct distribution showed that 350 of 644 infarcts (54.3%) were in 4 border zones of CBF and 294 (45.6%) were in non-border zone territories. More than 90% of infarcts were in 3 regions: the non-border zone ACA and MCA territories and the ACA-MCA border zone. Logistic regression showed that older participants have an increased chance of infarcts in the MCA territory (odds ratio [OR] 1.08; 95% CI 1.03-1.13; p = 0.001) and a decreased chance of infarcts in the ACA-MCA border zone (OR 0.94; 95% CI 0.90-0.97; p < 0.001). The presence of at least 1 stroke risk factor did not predict SCI location in any model., Discussion: When compared with children with SCD, in adults with SCD, older age is associated with expanded zones of tissue infarction that stretch beyond the traditional border zones of CBF, with more than 45% of infarcts in non-border zone regions.

Purpose: Acute chest syndrome (ACS) is secondary to occlusion of the pulmonary vasculature and a potentially life-threatening complication of sickle cell disease (SCD). Dual-energy CT (DECT) iodine perfusion map reconstructions can provide a method to visualize and quantify the extent of pulmonary microthrombi., Methods: A total of 102 patients with sickle cell disease who underwent DECT CTPA with perfusion were retrospectively identified. The presence or absence of airspace opacities, segmental perfusion defects, and acute or chronic pulmonary emboli was noted. The number of segmental perfusion defects between patients with and without acute chest syndrome was compared. Sub-analyses were performed to investigate robustness., Results: Of the 102 patients, 68 were clinically determined to not have ACS and 34 were determined to have ACS by clinical criteria. Of the patients with ACS, 82.4% were found to have perfusion defects with a median of 2 perfusion defects per patient. The presence of any or new perfusion defects was significantly associated with the diagnosis of ACS (P = 0.005 and < 0.001, respectively). Excluding patients with pulmonary embolism, 79% of patients with ACS had old or new perfusion defects, and the specificity for new perfusion defects was 87%, higher than consolidation/ground glass opacities (80%)., Conclusion: DECT iodine map has the capability to depict microthrombi as perfusion defects. The presence of segmental perfusion defects on dual-energy CT maps was found to be associated with ACS with potential for improved specificity and reclassification., (© 2024. The Author(s), under exclusive licence to American Society of Emergency Radiology (ASER).)

Cardiopulmonary complications account for approximately 40% of deaths in patients with sickle cell disease (SCD). Diffuse myocardial fibrosis, elevated tricuspid regurgitant jet velocity (TRV) and iron overload are all associated with early mortality. Although HLA-matched sibling hematopoietic cell transplantation (HCT) offers a potential cure, less than 20% of patients have a suitable donor. Haploidentical HCT allows for an increased donor pool and has recently demonstrated improved safety and efficacy. Our group has reported improved cardiac morphology via echocardiography at 1 year after HCT. Here we describe the first use of cardiac magnetic resonance imaging (CMR), the gold standard for measuring volume, mass, and ventricular function, to evaluate changes in cardiac morphology post-HCT in adults with SCD. We analyzed baseline and 1-year data from 12 adults with SCD who underwent nonmyeloablative haploidentical peripheral blood HCT at the National Institutes of Health. Patients underwent noncontrast CMR at 3 T, echocardiography, and laboratory studies. At 1 year after HCT, patients showed marked improvement in cardiac chamber morphology by CMR, including left ventricular (LV) mass (70.2 to 60.1 g/m 2 ; P = .02) and volume (114.5 to 90.6 mL/m 2 ; P = .001). Furthermore, mean TRV normalized by 1 year, suggesting that HCT may offer a survival benefit. Fewer patients had pathologically prolonged native myocardial T1 times, an indirect marker of myocardial fibrosis at 1 year; these data showed a trend toward significance. In this small sample, CMR was very sensitive in detecting cardiac mass and volume changes after HCT and provided complementary information to echocardiography. Notably, post-HCT improvement in cardiac parameters can be attributed only in part to the resolution of anemia; further studies are needed to determine the roles of myocardial fibrosis reversal, improved blood flow, and survival impact after HCT for SCD., (Copyright © 2023. Published by Elsevier Inc.)

Background: Sickle cell anemia (SCA) is a hereditary blood disorder with global prevalence, including in Nigeria. Despite advancements in SCA care management, understanding the long-term impact on organs during steady state has remained inconclusive., Aim: This study aimed to investigate the long-term changes in intra-abdominal organs of SCA children compared with non-SCA children during steady state using two-dimensional ultrasound assessment., Materials and Methods: A total of 116 children (58 SCA and 58 controls) were enrolled between June 2021 and July 2022. Clinico-demographic data were collected through an interviewer-administered questionnaire. Two-dimensional ultrasound was used to measure the liver, spleen, kidneys, and inferior vena cava in all subjects. Age-matched controls had AA or AS genotypes., Results: Of the 58 patients with SCA, 65.5% were males with an overall mean age of 8.1 ± 3.4 years, while among the non-SCA cohort (n = 58), 48.3% were males with an overall mean age of 8.7 ± 3.9 years. There was no statistically significant difference in the age and gender distribution between the SCA and non-SCA cohorts (P = 0.390 and P = 0.091, respectively). SCA subjects had a larger mean hepatic size than non-SCA subjects (12.09 cm ± 2.23 vs. 11.67 cm ± 1.96; P = 0.276) but smaller mean splenic size (8.01 cm ± 1.89 vs. 8.19 cm ± 1.61; P = 0.577) and inferior vena cava diameter (1.16 cm ± 0.29 vs. 1.25 cm ± 0.33; P = 0.100). Left kidney length and breadth were significantly greater in SCA patients (8.91 ± 1.16 vs. 8.27 ± 1.30; P = 0.006 and 4.15 ± 0.92 vs. 3.79 ± 0.48; P = 0.008, respectively)., Conclusion: This study highlights the utility of two-dimensional ultrasound assessment in monitoring intra-abdominal organ changes in SCA children, suggesting its cost-effective benefits in monitoring health outcomes in SCA patients., (Copyright © 2023 Copyright: © 2023 Nigerian Journal of Clinical Practice.)

Background: Acute chest syndrome (ACS) is an important cause of morbidity in sickle cell disease (SCD). A standardized tool for reporting chest radiographs in pediatric SCD patients did not previously exist., Objective: To analyze the interobserver agreement among pediatric radiologists' interpretations for pediatric ACS chest radiographs utilizing a standardized reporting tool. We also explored the association of radiographic findings with ACS complications., Methods: This was a retrospective cohort study of pediatric ACS admissions from a single institution in 2019. ICD-10 codes identified 127 ACS admissions. Two radiologists independently interpreted the chest radiographs utilizing a standardized reporting tool, a third radiologist adjudicated discrepancies, and κ analysis assessed interobserver agreement. Clinical outcomes were correlated with chest radiograph findings utilizing Pearsons' χ 2 , t tests, and Mann-Whitney U tests. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated., Results: Interobserver agreement was moderate to near-perfect across variables, with κ analysis showing near-perfect agreement for opacity reported in the right upper lobe (0.84), substantial agreement for right lower lobe (0.63), and vertebral bony changes (0.72), with moderate agreement for all other reported variables. On the initial chest radiograph, an opacity located in the left lower lobe (LLL) correlated with pediatric intensive care unit transfer (p = .03). Pleural effusion on the initial chest radiograph had a 3.98 OR (95% CI: 1.35-11.74) of requiring blood products and a 10.67 OR (95% CI: 3.62-31.39) for noninvasive ventilation., Conclusion: The standardized reporting tool showed moderate to near-perfect agreement between radiologists. LLL opacity, and pleural effusion were associated with increased risk of ACS complications., (© 2023 Wiley Periodicals LLC.)

Background: Myocardial fibrosis has recently been proposed as one of the contributing factors to the diverse pathogenicity of cardiomyopathy in sickle cell disease., Objective: In this study, cardiac fibrosis and subclinical cardiac changes in children with sickle cell disease were evaluated using cardiac magnetic resonance imaging (MRI), tissue Doppler echocardiography and serum galectin-3., Materials and Methods: The study included 34 children with sickle cell disease who were compared with a similar number of healthy controls. Cardiac MRI was used to evaluate late gadolinium enhancement, native T1 mapping, extracellular volume, and T2* for estimation of iron load. Cardiac function and myocardial performance index (MPI, evaluated by tissue Doppler echocardiography) and serum galectin-3 were compared to controls., Results: The mean age of the included patients was 13.3 ± 3.2 years. Myocardial iron load by T2* was normal. The mean level of extracellular volume (35.41 ± 5.02%) was significantly associated with the frequency of vaso-occlusive crises (P = 0.017) and negatively correlated with hemoglobin levels (P = 0.005). Galectin-3 levels were significantly higher among cases than controls (P = 0.00), at a cutoff value on the receiver operating characteristic curve of 6.5 ng/ml, sensitivity of 82.5% and specificity of 72.8%. The extracellular volume was significantly higher in cases, with a MPI > 0.4., Conclusion: Diffuse interstitial myocardial fibrosis can be detected early in children with sickle cell disease using T1 mapping and is associated with a high frequency of vaso-occlusive crisis. MPI of the left ventricle and serum galectin-3 are recommended screening tools for subclinical cardiac abnormalities., (© 2023. The Author(s).)

Objectives: Sickle cell disease (SCD) can cause osteoporotic changes in the jaw bones. In this study, it was aimed to evaluate possible bone changes using fractal analysis (FA) and morphometric analyses in dental panoramic radiographs of children and adolescents diagnosed with both homozygous and heterozygous forms of SCD., Methods: Sixty-five individuals (33 SCD, 32 controls) aged 6-17 years were included in the study. Four separate areas of interest (ROI) were selected for the right and left sides of all panoramic radiographs, and the FA value of the ROIs was calculated. Mandibular cortical width (MCW), panoramic mandibular index (PMI) and mandibular cortical index (MCI) and were evaluated. Data were statistically analyzed and p < 0.05 was accepted for statistical significance., Results: Fractal values of right and left ROI1 (the center of the mandibular angle.) and ROI4 (the cortical bone), and right ROI2 (the middle of the mandibular ramus) were statistically lower in the case group (p < 0.05). Right ROI2 and ROI4 fractal values of individuals in the case group were lower than those on the left side (p < 0.05). While MCI categories did not differ from the case-control group (p > 0.05), PMI and MCW values were lower in the case group (p < 0.05). All evaluated parameters did not differ according to age and gender (p > 0.05)., Conclusion: The results of this study showed that SCD affects the mandible. FA, MCW and PMI parameters can be used to detect early osteoporotic changes in the disease., (© 2023. The Author(s) under exclusive licence to Japanese Society for Oral and Maxillofacial Radiology.)

Significance: Although the molecular origins of sickle cell disease (SCD) have been extensively studied, the effects of SCD on the vasculature-which can influence blood clotting mechanisms, pain crises, and strokes-are not well understood. Improving this understanding can yield insight into the mechanisms and wide-ranging effects of this devastating disease., Aim: We aim to demonstrate the ability of a label-free 3D quantitative phase imaging technology, called quantitative oblique back-illumination microscopy (qOBM), to provide insight into the effects of SCD on brain vasculature., Approach: Using qOBM, we quantitatively analyze the vasculature of freshly excised, but otherwise unaltered, whole mouse brains. We use Townes sickle transgenic mice, which closely recapitulate the pathophysiology of human SCD, and sickle cell trait mice as controls. Two developmental time points are studied: 6-week-old mice and 20-week-old mice. Quantitative structural and biophysical parameters of the vessels (including the refractive index (RI), which is linearly proportional to dry mass) are extracted from the high-resolution images and analyzed., Results: qOBM reveals structural differences in the brain blood vessel thickness (thinner for SCD in particular brain regions) and the RI of the vessel wall (higher and containing a larger variation throughout the brain for SCD). These changes were only significant in 20-week-old mice. Further, vessel breakages are observed in SCD mice at both time points. The vessel wall RI distribution near these breaks, up to 350    μ m away from the breaking point, shows an erratic behavior characterized by wide RI variations. Vessel diameter, tortuosity, texture within the vessel, and structural fractal patterns are found to not be statistically different. As with vessel breaks, we also observe blood vessel blockages only in mice brains with SCD., Conclusions: qOBM provides insight into the biophysical and structural composition of brain blood vessels in mice with SCD. Data suggest that the RI may be an indirect indicator of vessel rigidity, vessel strength, and/or tensions, which change with SCD. Future ex vivo and in vivo studies with qOBM could improve our understanding of SCD., (© 2023 The Authors.)

Background: Silent cerebral infarcts (SCI) in sickle cell anemia (SCA) are associated with future strokes and cognitive impairment, warranting early diagnosis and treatment. Detection of SCI, however, is limited by their small size, especially when neuroradiologists are unavailable. We hypothesized that deep learning may permit automated SCI detection in children and young adults with SCA as a tool to identify the presence and extent of SCI in clinical and research settings., Methods: We utilized UNet-a deep learning model-for fully automated SCI segmentation. We trained and optimized UNet using brain magnetic resonance imaging from the SIT trial (Silent Infarct Transfusion). Neuroradiologists provided the ground truth for SCI diagnosis, while a vascular neurologist manually delineated SCI on fluid-attenuated inversion recovery and provided the ground truth for SCI segmentation. UNet was optimized for the highest spatial overlap between automatic and manual delineation (dice similarity coefficient). The optimized UNet was externally validated using an independent single-center prospective cohort of SCA participants. Model performance was evaluated through sensitivity and accuracy (%correct cases) for SCI diagnosis, dice similarity coefficient, intraclass correlation coefficient (metric of volumetric agreement), and Spearman correlation., Results: The SIT trial (n=926; 31% with SCI; median age, 8.9 years) and external validation (n=80; 50% with SCI; age, 11.5 years) cohorts had small median lesion volumes of 0.40 and 0.25 mL, respectively. Compared with the neuroradiology diagnosis, UNet predicted SCI presence with 100% sensitivity and 74% accuracy. In magnetic resonance imaging with SCI, UNet reached a moderate spatial agreement (dice similarity coefficient, 0.48) and high volumetric agreement (intraclass correlation coefficient, 0.76; ρ=0.72; P <0.001) between automatic and manual segmentations., Conclusions: UNet, trained using a large pediatric SCA magnetic resonance imaging data set, sensitively detected small SCI in children and young adults with SCA. While additional training is needed, UNet may be integrated into the clinical workflow as a screening tool, aiding in SCI diagnosis., Competing Interests: Disclosures Dr Fields reports salary support in Global Blood Therapeutics, Inc, Monteore Medical Center, and Proclara Biosciences and from Washington University in St. Louis. H. An reports compensation from Pfizer, Inc, for consultant services and grants from the National Institutes of Health. Dr Binkley reports consultant services from CNS Consultants LLC and OpenCell Technologies. Dr Lee reports consultant services from Biogen. Dr McKinstry reports consultant services from NOUS Imaging, Inc, Philips, and Siemens. Dr Jordan reports compensation for expert witness and salary support from the National Institutes of Health and Vanderbilt University. Dr DeBaun reports consultant services from Forma Therapeutics, Global Blood Therapeutics, Graphite Bio, Novartis, and salary support Vanderbilt University. The other authors report no conflicts.

Sickle cell disease (SCD) is an autosomal recessive haemoglobinopathy, which manifests as multisystem ischaemia and infarction, as well as haemolytic anaemia. The morphological changes of red blood cells (RBCs) that promote ischaemia/infarction as the main multi-systemic manifestation, with associated vasculopathy, may also lead to haemorrhage and fat embolisation. Bone infarctions, whether of the skull or spine, are relatively common with subsequent increased infectious susceptibility. We present a broad spectrum of brain and spine imaging findings of SCD from a level III paediatric hospital in Lisbon, between 2010 and 2022. Our aim is to highlight brain and spine imaging findings from a serial review of multiple patients with SCD and respective neuroimaging characterisation., (Copyright © 2023. Published by Elsevier Ltd.)

Symptomatic avascular necrosis (AVN) imposes a higher risk for acute care consumption in adults living with SCD. Symptomatic AVN, have higher rates of visits to the emergency department, higher rates of admissions, and longer lengths of stay in hospitals. Properly timed diagnosis and early interventions can reduce morbidity and enhance the quality of life in these patients. Vaso-occlusion secondary to sickling leads to osteonecrosis of the joint/bone (AVN, dactylitis) and invites infection (osteomyelitis and septic arthritis). Understanding and awareness of the imaging features related to this major morbidity complication are essential for early diagnosis and prompt management. In about half of the patients with SCD, AVN can lead to chronic pain, particularly in the head of the femur and humerus. Humeral and femoral head AVN tend to be linked with each other.  Vertebral bone compression and collapse secondary to AVN have also been reported.  The diagnosis of AVN must be accurate, as the condition is complex requiring specific treatment according to the grade of bone and joint involvement. There are several classifications or staging systems used for grading bone and joint involvement. Knowledge of the image patterns and grade of affection in different joints and bones and the degree of progression of AVN lesions can markedly improve management decisions on AVN-specific surgical versus non-surgical interventions and improve patient outcomes. The aim of this report is to summarize the different imaging techniques and their role in the proper/early diagnosis and follow up of patients with AVN with detailed examples of the common sites involved.

Background: Acute chest syndrome (ACS) is a leading cause of death in patients with sickle cell disease. Lung ultrasound (LUS) is emerging as a point-of-care method to diagnose ACS, allowing for more rapid diagnosis in the ED setting and sparing patients from ionizing radiation exposure., Research Question: What is the diagnostic accuracy of LUS for ACS diagnosis, using the current reference standard of chest radiography?, Study Design and Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed for this systematic review and meta-analysis. Embase, MEDLINE, Web of Science, and Google Scholar were used to compile all relevant studies. Two reviewers screened the studies for inclusion in this review. Cases of discrepancy were resolved by a third reviewer. Meta-analyses were conducted using both metadta and midas STATA software packages to retrieve summary receiver operating characteristic curves, sensitivities, and specificities. Three reviewers scored the studies with QUADAS-2 for risk of bias assessment., Results: From a total of 713 unique studies retrieved, six studies were included in the final quantitative synthesis. Of these, five studies were in pediatric EDs. Two studies were conference abstracts and not published manuscripts. Data were available for 625 possible ACS cases (97% of cases in patients aged ≤ 21 years) and 95 confirmed ACS diagnoses (pretest probability of 15.2%). The summary sensitivity was 0.92 (95% CI, 0.68-0.98) and the summary specificity was 0.89 (95% CI, 0.69-0.97) with an area under the curve of the summary receiver operating characteristic curve of 0.96 (95% CI, 0.94-0.97)., Interpretation: LUS has excellent sensitivity and very good specificity for ACS diagnosis and may serve as an initial point-of-care test to facilitate rapid treatment of ACS and spare pediatric patients from ionizing radiation; however, further research is warranted to improve the generalizability to the adult sickle cell disease population., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary complications are common in sickle cell disease (SCD) and can mimic pulmonary embolisms (PEs), leading to potential overuse of computed tomography pulmonary angiography (CTPA). Maximizing the quality of CTPA is essential for its diagnostic accuracy. However, little is known about the positive rate and quality of CTPA in SCD., Methods: This retrospective case‒control study aimed to determine the positive rate and quality of CTPA studies performed to rule out PE in SCD (HbSS genotype) patients compared to a control group. Logistic regression analysis was used to identify independent factors associated with suboptimal CTPA studies, defined as a mean enhancement of < 210 HU in the pulmonary artery., Results: The study included 480 patients, consisting of 240 SCD patients and 240 controls. The positive rate of PE was 4.0%, with a similar rate in both SCD patients and the control group (4.2% vs. 3.8%, p = 0.08). However, SCD patients had significantly lower contrast enhancement of the pulmonary artery than the control group (266.1 ± 90.5 HU vs. 342.2 ± 116.1 HU, p < 0.01). Notably, 25.4% of SCD patients had suboptimal scans. The logistic regression model demonstrated that SCD was significantly associated with suboptimal pulmonary arterial contrast enhancement compared to the control group (OR = 4.4; 95% CI: 2.4-8.3)., Conclusions: This study revealed a relatively low positive rate of CTPA in both SCD patients and the control group. However, SCD was significantly associated with suboptimal image quality due to inadequate contrast enhancement of the pulmonary artery. Further research is needed to identify measures that can enhance the quality of CTPA studies in SCD patients and to establish a specific imaging protocol for this patient population., (© 2023. The Author(s), under exclusive licence to American Society of Emergency Radiology (ASER).)

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5-20 years; 74 male) and sibling controls (n = 53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: The authors declare no conflict of interest.

Aim: To evaluate bone marrow fat fraction using the Dixon technique (FFDix) of magnetic resonance imaging (MRI) as a potential biomarker of haemolysis and clinical severity in the overall assessment and follow-up of sickle cell disease (SCD) patients., Material and Methods: The present study was a cross-sectional study in which healthy individuals and SCD patients (matched for age, sex, and weight) were subjected to MRI of the lumbar spine and pelvis to quantify FFDix in the bone marrow using the Dixon technique. SCD severity was analysed by clinical and laboratory data, and an online calculator. A high degree of haemolysis was defined using the cut-off values haemoglobin (Hb) ≤10 g/dl, lactate dehydrogenase (LDH) ≥325 U/l, reticulocytes ≥3% and total bilirubin (TB) ≥1.2 mg/dl. Pearson's correlation, receiver operating characteristic (ROC) curve and binary logistic regression analysis were performed., Results: Forty-eight SCD patients (26 homozygous: HbSS and 22 compound heterozygous: HbSC) and 48 healthy individuals participated in the study. FFDix was lower in SCD patients than in the control group, showing even lower values in the HbSS subtype and patients with a higher degree of haemolysis. HbSC patients with a higher degree of haemolysis using hydroxyurea (medium dosage 9.8 mg/kg/day) had lower FFDix. ROC curves and odds ratios for detecting patients with a higher degree of haemolysis at the different FFDix measurement sites demonstrated excellent performance: iliac bones (cut-off ≤16.75%, AUC = 0.824, p<0.001), femoral heads (cut-off ≤46.7%, AUC = 0.775, p=0.001), lumbar vertebrae (cut-off ≤7.8%, AUC = 0.755, p=0.002)., Conclusion: Decreased FFDix is indicative of higher degree of haemolysis and SCD severity with great potential as a non-invasive biomarker contributing to the overall assessment and follow-up of SCD patients., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The aim of this multicenter study was to prospectively assess the predictive value of multiparametric cardiac magnetic resonance (CMR) for cardiovascular complications in sickle cell disease (SCD) patients. Among all patients with hemoglobinopathies consecutively enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) Network, we selected 102 SCD patients (34.38 ± 12.67 years, 49 females). Myocardial iron overload (MIO) was measured by the multislice multiecho T2* technique. Atrial dimensions and biventricular function parameters were quantified by cine images. Late gadolinium enhancement (LGE) images were acquired to detect focal myocardial fibrosis. At baseline CMR, only two patients had significant MIO (global heart T2* < 20 ms). During a mean follow-up of 63.01 ± 24.95 months, 11 cardiovascular events (10.8%) were registered: 3 pulmonary hypertension, 2 supraventricular arrhythmias, 1 heart failure, 1 death for heart failure, 1 pulmonary embolism, 1 peripheral vascular disease, 1 transient ischemic attack, and 1 death after acute chest syndrome. In the multivariate analysis, the independent CMR predictors of cardiovascular events were left ventricular (LV) ejection fraction (hazard ratio-HR = 0.88; p = 0.025) and right ventricular (RV) mass index (HR = 1.09; p = 0.047). According to the receiver-operating characteristic curve analysis for adverse events, an LV ejection fraction < 58.9% and an RV mass index > 31 g/m 2 were optimal cut-off values. Reduced left ventricular ejection fraction and increased right ventricular mass index showed a significant prognostic value in patients with SCD. Our data seem to suggest that CMR may be added as a screening tool for identifying SCD patients at high risk for cardiopulmonary and vascular diseases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To provide ultrasound baselines for spleen length in homozygous sickle cell disease (HbSS) and in normal controls with a HbAA genotype., Methods: The Jamaican cohort study identified 311 babies with HbSS and 246 matched HbAA controls during the screening of 100,000 consecutive deliveries in Kingston, Jamaica from 1973 to 1981. Ultrasonography commenced in 1988 when the youngest patients were aged 6 years at which time deaths, emigrations and default had reduced the numbers to 206 HbSS and 89 controls. It continued annually until 2000., Results: The spleen was visualized in all HbAA controls but in only 1103/2138 (52%) scans in HbSS. Where available, mean splenic lengths were significantly lower in HbSS (77-103 mm in males, 70-83 mm in females) compared to normal controls (89-101 mm in males, 86-95 mm in females). Assessed by statistical modelling after adjusting for body height, the splenic ratio (splenic length/body height) declined over the age range 12-20 years in HbSS, consistent with progressive splenic fibrosis. Genetic factors known to inhibit sickling, α thalassemia and fetal hemoglobin level (HbF) significantly reduced the decline in splenic ratio. Clinical splenomegaly was an insensitive measure of splenic enlargement as only 50% of patients aged 18 years and above with spleens measuring ≥150 mm on ultrasonography had palpable spleens., Conclusions: An age-related decline in splenic length occurred in HbSS and occurred more slowly with genetic factors known to inhibit sickling. The standards provided may be of value in assessing minor degrees of subclinical acute splenic sequestration., Advances in Knowledge: These are the first standards available for splenic length in HbSS. They may be useful in detecting red cell sequestration, not apparent from clinical splenomegaly and also provide a model for identifying factors inhibiting vaso-occlusion.

Sickle cell disease (SCD) is complicated by neurologic complications including vasculopathy, hemorrhagic or ischemic overt stroke, silent cerebral infarcts and cognitive dysfunction. Patients with SCD, even in the absence of vasculopathy or stroke, have experience cognitive dysfunction that progresses with age. Transcranial Doppler ultrasound and structural brain MRI are currently used for primary and secondary stroke prevention, but laboratory or imaging biomarkers do not currently exist that are specific to the risk of cognitive dysfunction in patients with SCD. Recent investigations have used advanced MR sequences assessing cerebral hemodynamics, white matter microstructure and functional connectivity to better understand the pathophysiology of cognitive decline in SCD, with the long-term goal of developing neuroimaging biomarkers to be used in risk prediction algorithms and to assess the efficacy of treatment options for patients with SCD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Transcranial doppler (TCD) ultrasonography can be used to identify stroke risk in children with sickle cell anemia. Previous studies have reported mixed findings on neurocognitive outcomes in children with elevated TCD. This study examined associations between TCD velocity and neurocognitive outcomes in children and adolescents without prior history of stroke., Procedure: Participants were selected from the Sickle Cell Clinical Research Intervention Program cohort. The highest recorded mean maximum TCD velocity was selected for analysis, along with participant's most recent data from serial neurocognitive surveillance., Results: A total of 200 children with sickle cell anemia completed neurocognitive testing (109 males, 91 females; mean age 12.7 years [SD = 3.56]). Most participants were prescribed hydroxyurea (72%) at the time of neurocognitive testing and nearly 16% had a history of chronic transfusions prior to neurocognitive evaluation. Mean age at time of highest TCD value was 6.6 years (SD = 2.5) and 13.5% of screenings were abnormal (≥200 cm/s). Mean interval between TCD and most recent neurocognitive evaluation was 6.1 years (±3.5). There were no significant differences in the interval between TCD and neurocognitive testing across normal, conditional, and abnormal groups. Maximum TCD velocity was not significantly associated with neurocognitive outcomes in multivariate models., Conclusions: History of elevated TCD in the absence of overt stroke should not be considered a risk factor for poor neurocognitive outcomes in children and adolescents with sickle cell anemia on modern disease-modifying therapy., (© 2022 Wiley Periodicals LLC.)

A 61-year-old woman was admitted to the hospital for management of a painful vaso-occlusive crisis. She had a history of sickle cell beta-thalassaemia and end-stage renal disease managed with intermittent haemodialysis. While hospitalised, she became lethargic and unresponsive and developed acute chest syndrome. Initial MR scan of brain, cerebrospinal fluid examination and continuous electroencephalogram were unremarkable, but subsequent MR scan of brain identified a right transverse venous sinus thrombosis and extensive supratentorial and infratentorial microhaemorrhages consistent with fat emboli. We; therefore, discuss a case of non-traumatic fat embolism syndrome, a rare complication of sickle cell disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

To quantitatively determine testicular tissue stiffness values using shear wave elastography (SWE) in males that have sickle cell anemia (SCA) and to evaluate the relationship between elastography results and semen analysis parameters and hormone levels. Fifty patients diagnosed with SCA and followed up in the hematology outpatient clinic were evaluated in the urology outpatient clinic as the study group. In addition, there were 88 patients without any SCA-related complaints in the control group. We compared these groups with respect to their values, spermiogram parameters, testicular volume, and SWE values. Among patients in the SCA group, 28% had impaired sperm parameters. When testicular elastography was assessed, the testicular volumes were materially lower in the SCA group in comparison to the control group [right testicular volume: 14.76 (12.77-18.12) and 19.68 (15.12-24.18), respectively, p < 0.001; left testicular volume: 14.11 (11.06-17.32) and 16.59 (13.38-20.13), respectively, p = 0.015]. Additionally, the left testis central stiffness and the left testis inferior stiffness were significantly higher in the SCA group (p < 0.001 and p = 0.014, respectively). The age and hydroxyurea use had a worse effect on sperm parameters in patients with SCA (odds ratio: -0.161 and -1.914, standard deviation: 0.071 and 0.921, and p = 0.024 and p = 0.038, respectively). We consider that the technique utilized in this study for SWE values is fast and can be adopted as a reliable diagnostic tool and follow-up practice in routine clinical practice to evaluate the acuteness of damage to the testicles in patients having SCA., (© 2022 Wiley-VCH GmbH.)

Background: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function., Methods: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics., Results: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P =0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P =0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P =0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P =0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P =0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P =0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P =0.053) and correlated with SCI volume (ρ=0.49, P =0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia., Conclusions: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

Background: Venous blood oxygenation (Yv), which can be derived from venous blood T 2 (T 2 b), combined with oxygen-extraction fraction (OEF) and cerebral metabolic rate of oxygen, is considered indicative for tissue viability and brain functioning and frequently assessed in patients with sickle cell disease. Recently, T 2 -Prepared-Blood-Relaxation-Imaging-with-Inversion-Recovery (T 2 -TRIR) was introduced allowing for simultaneous measurements of blood T 2 and T 1 (T 1 b), potentially improving Yv estimation by overcoming the need to estimate hematocrit., Purpose: To optimize and compare T 2 -TRIR with T 2 -relaxation-under-spin-tagging (TRUST) sequence., Study Type: Prospective., Population: A total of 12 healthy volunteers (six female, 27 ± 3 years old) and 7 patients with sickle cell disease (five female, 32 ± 12 years old)., Field Strength/sequence: 3 T; turbo field echo planar imaging (TFEPI), echo planar imaging (EPI), and fast field echo (FFE)., Assessment: T 2 b, Yv, and OEF from TRUST and T 2 -TRIR were compared and T 2 -TRIR-derived T 1 b was assessed. Within- and between-session repeatability was quantified in the controls, whereas sensitivity to hemodynamic changes after acetazolamide (ACZ) administration was assessed in the patients., Statistical Tests: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, mixed linear model, Bland-Altman analysis and correlation analysis. Sidak multiple-comparison correction was performed. Significance level was 0.05., Results: In controls, T 2 b from T 2 -TRIR (70 ± 11 msec) was higher compared to TRUST (60 ± 8 msec). In patients, T 2 b values were lower pre- compared to post-ACZ administration (TRUST: 80 ± 15 msec and 106 ± 23 msec and T 2 -TRIR: 95 ± 21 msec and 125 ± 36 msec). Consequently, Yv and OEF were lower and higher pre- compared to post-ACZ administration (TRUST Yv: 68% ± 7% and 77% ± 8%, T 2 -TRIR Yv: 74% ± 8% and 80% ± 6%, TRUST OEF: 30% ± 7% and 21% ± 8%, and T 2 -TRIR OEF: 25% ± 8% and 18% ± 6%)., Data Conclusion: TRUST and T 2 -TRIR are reproducible, but T 2 -TRIR-derived T 2 b values are significantly higher compared to TRUST, resulting in higher Yv and lower OEF estimates. This bias might be considered when evaluating cerebral oxygen homeostasis., Evidence Level: 2 TECHNICAL EFFICACY: Stage 2., (© 2022 International Society for Magnetic Resonance in Medicine.)

Background: Cerebral arteriopathy in patients with sickle cell anemia mainly affects the intracranial anterior circulation. However, the extracranial internal carotid artery (eICA) can also be stenosed and responsible for ischemic lesions. In children with sickle cell anemia, we perform routine annual Doppler ultrasound assessment of the eICA and magnetic resonance imaging with 3-dimensional time-of-flight magnetic resonance angiography of the Willis circle and neck arteries in those with abnormal velocity. Our aim was to report the evolution of eICA stenoses from 2011 to the present as a function of therapy in a retrospective case-series study. We hypothesized that chronic transfusion (CTT) would be more effective than hydroxyurea and simple observation on the evolution of eICA stenosis., Methods: Eligibility criteria were a history of eICA velocity ≥160 cm/s with a minimum Doppler and magnetic resonance imaging follow-up of 1 year. eICAs were graded for stenosis according to NASCET (The North American Symptomatic Carotid Endarterectomy Trial). Magnetic resonance imaging was investigated for ischemic lesions. Treatment with hydroxyurea and CTT were obtained from the chart review., Results: Fifty-four patients were included. Eight patients had a stroke history. The median (range) follow-up was 4.7 years (1.1-9.2 years). On the first neck magnetic resonance angiography, stenosis was present in 48/54 (89%) patients. Kinking was found in 39/54 (72%) patients. On the last neck magnetic resonance angiography, the proportion of patients with eICA stenosis decreased to 39/54 (72%). ICA occlusion occurred in 5 patients despite CTT. Three patients had carotid webs without intracranial stenosis. The proportion of patients with improvement in stenosis score was 8% with no treatment intensification, 20% with hydroxyurea, and 48% with CTT ( P =0.016). The mean (SD) change per year in stenosis score was 0.40 (0.60) without intensification, 0.20 (0.53) with hydroxyurea, and -0.18 (0.55) with CTT ( P =0.006). Ischemic lesions were present initially in 46% of patients, and the incidence of progressive ischemic lesions was 2.5 events/100 patient-years. Cox regression analysis showed that the initial score for eICA stenosis was a significant predictive factor for the risk of new silent cerebral infarct events., Conclusions: Our study reinforces the need to assess cervical arteries for better prevention of cerebral ischemia and encourage initiation of CTT in sickle cell anemia children with eICA stenosis.

Sickle cell disorder (SCD) refers to a spectrum of hematologic disorders that cause a characteristic clinical syndrome affecting the entire body. It is the most prevalent monogenetic hemoglobinopathy worldwide, with a wide range of focal and systemic expressions. Hemoglobin gene mutation leads to the formation of abnormal sickle-shaped red blood cells, which cause vascular occlusion and result in tissue and organ ischemia and infarction. Recurrent episodes of acute illness lead to progressive multisystem organ damage and dysfunction. Vaso-occlusion, hemolysis, and infection as a result of functional asplenia are at the core of the disease manifestations. Imaging plays an essential role in the diagnosis and management of SCD-related complications in the abdomen and pelvis. A thorough understanding of the key imaging findings of SCD complications involving hepatobiliary, gastrointestinal, genitourinary, and musculoskeletal systems is crucial to timely recognition and accurate diagnosis. The authors aim to familiarize the radiologist with the SCD spectrum, focusing on the detection and evaluation of manifestations that may appear at imaging of the abdomen and pelvis. The topics the authors address include (a) the pathophysiology of the disease, (b) the placement of SCD among hemoglobinopathies, (c) the clinical presentation of SCD, (d) the role of imaging in the evaluation and diagnosis of patients with SCD who present with abdominal and pelvic manifestations in addition to extraperitoneal manifestations detectable at abdominal or pelvic imaging, (e) imaging features associated with common and uncommon sequelae of SCD in abdominal and pelvic imaging studies, and (f) a brief overview of management and treatment of patients with SCD. Online supplemental material is available for this article. © RSNA, 2022.

Background: Sickle cell anemia (SCA) is the leading cause of childhood stroke. We aimed to evaluate whether altered cerebral flow velocities, as measured by transcranial Doppler (TCD), are associated with vaso-occlusive complications in addition to stroke in pediatric SCA patients., Methods: We evaluated 37 children aged between 2 and 16 years with SCA who underwent screening for TCD between January 2012 and October 2018. Genotypic profiles and demographic data were collected, TCD examinations were performed during follow-up, and the presence of sickling crises was compared. Survival analyses were performed using simple frailty models, in which each predictor variable was analyzed separately in relation to the occurrence of a sickling crisis., Results: The variables related to sickle cell crises in the univariate analysis were peak systolic velocity (PSV) in the middle cerebral artery (MCA), hazard ratio (HR) 1.01 (1.00-1.02) p = 0.04; end-diastolic velocity (EDV) in the MCA, HR 1.02 (1.01-1.04) p = 0.01; time average mean maximum velocity (TAMMV) in the basilar artery (BA), HR 1.02 (1.00-1.04) p = 0.04; hemoglobin, HR 0.49 (0.38-0.65) p < 0.001; hematocrit, HR 0.78 (0.71-0.85) p < 0.001; leukocyte counts, HR 1.1 (1.05-1.15) p < 0.001; platelets counts, HR 0.997 (0.994-0.999) p = 0.02; and reticulocyte numbers, HR 1.14 (1.06-1.23) p < 0.001., Conclusions: Our results indicate PSV and EDV in the MCA and TAMMV in the BA as markers of risk for the occurrence of sickling crises in SCA., (© 2022. The Author(s).)

Background Children with sickle cell anemia (SCA) are predisposed to developing leg ulcers in early adolescence; however, the underlying physiologic mechanisms are not well understood, which hinders the development of prophylactic antiulcer interventions. Purpose To determine if occlusive arterial disease or abnormal hemodynamics exist in the lower limb peripheral arteries of children with SCA. Materials and Methods This was a prospective cross-sectional study conducted between July 2020 and May 2021. Two groups of participants were enrolled: children with SCA and healthy controls. Each child had their anthropometric measurements taken, followed by B-mode, color Doppler, and spectral Doppler US evaluation of the distal anterior and posterior tibial arteries. Ankle-brachial index evaluation was also performed. Hemodynamic values were compared between children with SCA and healthy controls, with statistical significance set at the P < .05 level. Results Forty-five children with SCA (mean age, 9.5 years ± 3.7 [SD]; 26 boys) and 45 healthy controls (mean age, 9.3 years ± 3.8; 25 boys) were evaluated. Children with SCA had higher peak systolic velocities, end-diastolic velocities, and blood volume flow in their distal anterior and posterior tibial arteries compared with the healthy participants ( P < .001 across all 12 measurements). Children with SCA also had lower resistive index and pulsatility index values compared with healthy controls in at least one of the anterior and posterior tibial arteries bilaterally. Monophasic spectral patterns were exclusively observed in participants with SCA. The ankle-brachial index values for the participants with SCA (mean, 1.09 ± 0.08) and healthy participants (mean, 1.06 ± 0.02) were within normal range. Conclusion Abnormal peripheral hemodynamic characteristics were found in the lower limbs of children with sickle cell anemia. No evidence of occlusive peripheral artery disease was present. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Prior studies have described high venous signal qualitatively using arterial spin labelling (ASL) in patients with sickle cell anemia (SCA), consistent with arteriovenous shunting. We aimed to quantify the effect and explored cross-sectional associations with arterial oxygen content (CaO 2 ), disease-modifying treatments, silent cerebral infarction (SCI), and cognitive performance. 94 patients with SCA and 42 controls underwent cognitive assessment and MRI with single- and multi- inflow time (TI) ASL sequences. Cerebral blood flow (CBF) and bolus arrival time (BAT) were examined across gray and white matter and high-signal regions of the sagittal sinus. Across gray and white matter, increases in CBF and reductions in BAT were observed in association with reduced CaO 2 in patients, irrespective of sequence. Across high-signal sagittal sinus regions, CBF was also increased in association with reduced CaO 2 using both sequences. However, BAT was increased rather than reduced in patients across these regions, with no association with CaO 2 . Using the multiTI sequence in patients, increases in CBF across white matter and high-signal sagittal sinus regions were associated with poorer cognitive performance. These novel findings highlight the utility of multiTI ASL in illuminating, and identifying objectively quantifiable and functionally significant markers of, regional hemodynamic stress in patients with SCA.

Rationale and Objectives: To compare bone marrow fat quantification using magnetic resonance spectroscopy (MRS) and six-point DIXON (6PD) techniques in patients with sickle cell disease (SCD) and healthy subjects., Materials and Methods: Prospective study, with 43 SCD patients (24 homozygous [SS], 19 double heterozygous [SC), and 41 healthy subjects paired by age, weight and sex with SCD patients. All participants underwent magnetic resonance imaging with 6PD and single voxel MRS in the L3 vertebral body. Pearson's correlation, ROC curve, and bland-altman analysis were performed, p-values ​​≤0.05 were considered statistically significant for all tests., Results: Significant linear correlation was found between fat fraction (FF) by 6PD and Total Lipids (TL) (r = 0.932; p < 0.001) and Saturated Lipids (SL) (r = 0.934; p < 0.001), in all subjects. Strong correlations were also identified considering subjects of the SS/SC subgroups. Despite high correlations, no significant difference was observed only between FF and SL in the SS subgroup (Bland-Altman analysis), indicating excellent agreement between the fat estimations in this specific situation. Significant differences were observed in all variables (FF, TL, SL) comparing the SCD and healthy subjects. The ROC curve between SCD and healthy subjects showed the following areas under the curve: FF(0.924) > TL(0.883) > SL(0.892)., Conclusions: The comparison between fat quantification by the 6PD with MRS demonstrated an excellent correlation in SCD patients, especially in the SS subgroup, which usually has a higher degree of hemolysis. The diagnostic performance of 6PD and MRS is similar, with advantages of shorter imaging processing time and larger studied area with the 6PD., (Copyright © 2021 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Blood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized., Purpose: To examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive magnetic resonance imaging technique. We hypothesized that SCD participants will have increased BBB permeability., Study Type: Prospective cross-sectional., Population: Twenty-six pediatric participants (10 ± 1 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients., Field Strength/sequence: 3 T. Water extraction with phase-contrast arterial spin tagging with echo-planer imaging, phase-contrast and T 1 -weighted magnetization-prepared rapid acquisition of gradient echo., Assessment: Water extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow, hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). Regions of interest were drawn by Z.L. (6 years of experience)., Statistical Tests: Wilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures, and neuropsychological scores. A two-tailed P value of 0.05 or less was considered statistically significant., Results: Compared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0 ± 33.3 mL/100 g/minute, SCT: 171.2 ± 27.2 mL/100 g/minute). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3 ± 31.7 mL/100 g/minute, mild: 193.3 ± 31.8 mL/100 g/minute). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (β = -8.84, 95% confidence interval [CI] [-14.69, -3.00]), lower hematocrits (β = -2.96, 95% CI [-4.84, -1.08]), and higher hemoglobin S fraction (β = 0.77, 95% CI [0.014, 1.53])., Data Conclusion: These findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 2., (© 2021 International Society for Magnetic Resonance in Medicine.)

Objective: Children with sickle cell anaemia (SCA) are highly susceptible to cerebrovascular injury. We performed brain magnetic resonance imaging and angiography (MRI-MRA) in Ugandan children with SCA to identify structural cerebrovascular abnormalities and examine their relationship to standardized clinical assessments., Methods: A sub-sample (n=81) was selected from a cross-sectional study of children attending SCA clinic, including 52 (64.2%) with and 29 (35.8%) without clinically detected abnormalities. Clinical evaluation included assessment for prior stroke, cognitive testing and cerebral arterial transcranial doppler (TCD) flow velocity. MRI-MRA scans were interpreted by at least two neuroradiologists., Results: Mean age was 6.5±2.7 years, with 39 (48.1%) female. Mean haemoglobin was 7.3±0.9 g/dl. Overall, 13 (16.0%) were malnourished. Infarcts and/or stenoses were detected in 55 (67.9%) participants, with stenoses primarily in the anterior circulation. Infarcts were seen in those with normal 17/29 (58.6%) or abnormal 34/52 (65.4%) clinical testing (p=0.181). Neither abnormal MRI nor MRA was associated with age, sex, haemoglobin, or malnutrition. Abnormal MRA was highly associated with infarcts (p<0.0001). Participants with abnormal imaging had two-fold higher proportion of stroke on exam and/or impaired cognition. Stroke on exam was strongly associated with an imaging abnormality after adjusting for age, sex, malnutrition, and haemoglobin (OR 11.8, 95%CI 1.87-74.2)., Conclusion: Over half of these SCA children had cerebrovascular infarcts and/or arterial stenoses. Cerebrovascular disease was frequently undetectable by clinical assessments. While rarely available in under-resourced settings, MRI-MRA brain imaging is an important tool for defining SCA cerebrovascular disease and for assessing impact of clinical intervention trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The funding agency had no role in study design, the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the paper for publication., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Developmental difficulties in many cognitive domains are common in children with sickle cell anaemia (SCA). Children with stroke are most affected but delayed or atypical cognitive function has been reported in children with SCA and silent infarcts (SCI), vasculopathy, and normal brain MRI. However, very few studies of cognition have been conducted in Africa, a continent with 75% of the SCA burden. We therefore investigated cognitive profiles in Tanzanian children with SCA and examined the impact of age, SCI, vasculopathy, and haemoglobin concentration (Hb)., Methods: Children aged 6-16 years with and without SCA were eligible for this cross-sectional study. Cognitive assessment was performed using Raven's Matrices, assessing fluid, non-verbal intelligence and subtests from the Wechsler Intelligence Scales for Children (WISC-IV), assessing processing speed (PS), perceptual reasoning (PR), and working memory (WM) as these tests are less culture-bound. Magnetic resonance imaging (MRI) and angiography (MRA) were also completed to assess the presence of SCI and vasculopathy. Hb was collected in both SCA children and their non-SCA siblings., Results: Seventy-three children with SCA and 71 healthy siblings (Mean ages 11.9, SD = 2.8 and 11.1, SD = 2.9 years respectively) were recruited. Compared with healthy siblings, children with SCA had lower PS (Mean diff 7.35 points; p = .002). Older children had higher performance scores on all tests in relation to their ages. Lowest cognitive scores were observed on the PS subtest, where patients with SCI (SCI+) had lowest mean values as compared to children with no SCI (SCI-) and healthy siblings (i.e., SCI+ < SCI- < healthy siblings, p = .028). On post-hoc analysis the difference was between SCI+ and healthy siblings SCI+ < non-SCA siblings (p = .015); there was no difference between SCI+ and SCI- patient groups. PS was significantly lower in SCA patients with no vasculopathy as compared to healthy siblings. The mean difference from healthy siblings was -8.352 and -0.752 points for VASC- and VASC + respectively (p = .004). There was a significant positive effect of Hb on PSI (p = .001) in both patients and controls and a trend level significant positive effect of Hb on PR (p = .050) and WM (p = .051)., Conclusion: In this Tanzanian study, cognitive performance was reduced in children with SCA with or without SCI on MRI or vasculopathy. Cognitive performance improved with increasing age. Lower Hb was associated with lower cognitive performance in both patients with SCA and their non-SCA siblings. SCI and vasculopathy do not appear to have an impact on cognitive function., (Copyright © 2022. Published by Elsevier Ltd.)

Purpose: To determine the relationship between macular microvascular abnormalities on optical coherence tomography angiography and silent cerebral infarctions (SCIs) on cerebral magnetic resonance imaging in sickle cell disease., Methods: Patients (age <18 years old) from our previous pediatric sickle cell disease study cohort who had prior optical coherence tomography angiography and brain magnetic resonance imaging were identified. Brain magnetic resonance imaging images were compared with macular optical coherence tomography angiography scans to identify macular vascular density differences between patients with SCI and without SCI., Results: Sixty-eight eyes from 34 patients who underwent optical coherence tomography angiography were evaluated, of whom 28 eyes from 14 patients met the inclusion criteria for this study. Eight patients (57%) with SCI and 6 patients (43%) without SCI were identified. The mean age (17 years in SCI and 16.3 years in non-SCI) was comparable between groups. There was no statistically significant difference in systemic complications. Deep capillary plexus vessel density was lower in the temporal quadrant in patients with SCI (49.3% vs. 53.7%, P = 0.014)., Conclusion: Patients with SCI were found to have lower vessel density in the deep capillary plexus compared with those without SCI. This finding suggests that deep capillary plexus vessel density may have utility as an imaging biomarker to predict the presence of SCI.

Pain is the most common symptom experienced by patients with sickle cell disease (SCD) and is associated with poor quality of life. We investigated the association between grey matter volume (GMV) and the frequency of pain crises in the preceding 12 months and SCD-specific quality of life (QOL) assessed by the PedsQL TM SCD module in 38 pediatric patients with SCD. Using voxel-based morphometry methodology, high-resolution T1 structural scans were preprocessed using SPM and further analyzed in SPSS. The whole brain multiple regression analysis identified that perigenual anterior cingulate cortex (ACC) GMV was negatively associated with the frequency of pain crises (r = -0.656, P = 0.003). A two-group t-test analysis showed that the subgroup having pain crisis/crises in the past year also showed significantly lower GMV at left supratemporal gyrus than the group without any pain crisis (p=0.024). The further 21 pain-related regions of interest (ROI) analyses identified a negative correlation between pregenual ACC (r = -0.551, P = 0.001), subgenual ACC (r = -0.540, P = 0.001) and the frequency of pain crises. Additionally, the subgroup with poorer QOL displayed significantly reduced GMV in the parahippocampus (left: P = 0.047; right: P = 0.024). The correlations between the cerebral structural alterations and the accentuated pain experience and QOL suggests a possible role of central mechanisms in SCD pain., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

We present a case of a 65 years-old male with sickle cell mutation and beta-thalassemia (Hb S/β-Thal), who had whole-body bone scan evaluation for osteomyelitis. The examination revealed high radiopharmaceutical uptake in the left abdomen. Further evaluation with hybrid single photon emission computed tomography/computed tomography (SPECT/CT) showed calcification of approximately the entire spleen, in the context of sickle cell anemia. This report highlights the role of SPECT/CT in such cases.