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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.)

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.)

Purpose: Acute chest syndrome (ACS), defined by the presence of a chest radiographic opacity in sickle cell disease patients experiencing respiratory symptoms is a leading cause of death in these patients. The etiology is ACS is not well understood however pulmonary microvascular occlusion has been postulated to be a major pathophysiologic driver. Our study aims to assess the value of dual-energy CT (DECT) as a marker of pulmonary microvascular occlusion., Materials/methods: A search tool was used to identify CT angiography studies from 1/1/2017 to 9/15/2019 with any variation of the phrases "Acute chest syndrome" and "Sickle cell". These studies were manually reviewed for the use of DECT technique. An age-matched control group was created. DECT pulmonary blood volume (PBV) maps were reviewed semi-quantitatively for the presence of iodine defects and the number of involved bronchopulmonary segments were scored. Other recorded values included type of parenchymal opacities, diameter of main pulmonary artery (MPA) and presence of right ventricular dilatation. Mean values between cases and controls were compared using a two-sample t-test., Results: Nine sickle cell DECT cases with PBV maps and nine age-matched controls were evaluated. Bronchopulmonary segments with iodine defects were significantly higher in cases vs controls (mean: 4.7 vs 0.3, p < 0.003). PBV defects were more extensive than parenchymal findings. MPA diameter was higher in cases (2.9 cm) vs control (2.4 cm), P < 0.03., Conclusions: DECT demonstrates abnormal PBV in sickle cell patients, often the predominant abnormality identified early, and likely reflects the presence of pulmonary microvascular occlusion., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Patients with sickle cell disease (SCD) experience recurrent pain crises, which may mimic appendicitis. A prior study found a significantly lower rate of appendicitis in patients with SCD compared with national averages. We investigate the incidence of appendicitis and number of imaging studies for appendicitis in pediatric patients with SCD., Methods: Using a retrospective study design from a single institution, SCD and control cohorts were created. Inclusion criteria included age 0 to 21years and at least one follow-up appointment within 24 months. Length of observation was calculated from initial presentation to either inpatient admission for appendicitis or last clinic visit. Analysis of an SCD subgroup and a control subset (n = 1,596) was used to compare the number of imaging studies. Incidence rates of appendicitis and number of appendicitis studies were determined. Z-tests, binomial enumeration exact tests, and Fischer's exact tests were used., Results: The SCD cohort included 1,064 patients between January 1, 2001, to December 31, 2014, and the control cohort included 115,109 patients without SCD between January 1, 2011, and December 31, 2011. Incidence rate of appendicitis per 10,000 patient-years was significantly lower in the SCD group compared with controls (2.9 cases versus 10.7 cases per 10,000 patient-years; P = .044). Additionally, the SCD group received significantly more ultrasounds (148 versus 60 per 10,000 patient-years; P< .0001) and CTs (94 versus 27 per 10,000 patient-years; P< .0001) for appendicitis, which remained significant when controlling for race. Patients with SCD also received more false-positive scans., Discussion: Patients with SCD had a significantly lower incidence of appendicitis than controls, yet had a higher number of imaging tests performed for appendicitis. Appendicitis should be viewed as a less common cause of acute abdominal pain in SCD. This consideration should help guide imaging strategy., (Copyright © 2020 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Sickle cell disease (SCD) is an inherited hemoglobinopathy that causes organ dysfunction, including cerebral vasculopathy and neurological complications. Hippocampal segmentation with newer and advanced 7 Tesla (7T) MRI protocols has revealed atrophy in specific subregions in other neurodegenerative and neuroinflammatory diseases, however, there is limited evidence of hippocampal involvement in SCD. Thus, we explored whether SCD may be also associated with abnormalities in hippocampal subregions. We conducted 7T MRI imaging in individuals with SCD, including the HbSS, HbSC and HbS/beta thalassemia genotypes (n = 53), and healthy race and age-matched controls (n = 47), using a customized head coil. Both T1- and T2-weighted images were used for automatic segmentation of the hippocampal subfields. Individuals with SCD had, on average, significantly smaller volume of the region including the Dentate Gyrus and Cornu Ammonis (CA) 2 and 3 as compared to the control group. Other hippocampal subregions also showed a trend towards smaller volumes in the SCD group. These findings support and extend previous reports of reduced volume in the temporal lobe in SCD patients. Further studies are necessary to investigate the mechanisms that lead to structural changes in the hippocampus subfields and their relationship with cognitive performance in SCD patients., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Critical illness-associated cerebral microbleed (CICM) is a relatively rare and newly described condition. It can occur in critically ill ICU patients and can be secondary to many underlying etiologies. CICM is associated with high mortality and permanent neurologic deficits in surviving patients. Distribution of cerebral microhemorrhages in neuroimaging findings is critical for accurate diagnosis of this condition. Here, we present an ICU admitted patient with sickle cell disease crisis and CICM and will discuss their clinically and radiologically distinct phenomenon followed by a review of current literature., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Abnormal placental development is a unifying factor amongst many adverse pregnancy outcomes (APOs) in Sickle Cell Disease (SCD). Our aim was to describe placental histopathologic findings in women with SCD and their relationship with APOs, and to explore the association between antenatal sonographic findings and placental pathology., Methods: Retrospective single-centre case series of all pregnant women with SCD (January 2000-December 2017), pregnancy beyond 20 weeks' gestation, and available placenta histopathology. APOs included intrauterine fetal death, early neonatal death, preterm birth, small for gestational age, and hypertensive disorders of pregnancy. Review of images for mid-pregnancy ultrasound and one proximal to delivery was completed, blinded to clinical outcomes and histopathology results. Gross and histopathologic findings were reviewed and characterized per published classification., Results: Of 72 placentas, abnormalities were present in 69%, with Maternal Vascular Malperfusion (MVM) noted in 40%. APOs were encountered in 61% overall and in 79% of those with MVM. Neither SCD genotype nor severe maternal anemia had an influence on histopathologic placental features. Presence of high-resistance uterine artery waveforms at mid-trimester ultrasound was strongly associated with APOs and with abnormal findings on placental histopathology, most notably MVM. MVM was strongly associated with small for gestational age infants, preterm birth, and stillbirth., Discussion: MVM is the predominant lesion in placentas of women with SCD and is strongly associated with APOs. Mid-trimester ultrasound can identify a subset of women at risk. Future research into advanced imaging modalities to aid in antenatal diagnosis alongside investigations of potentially beneficial therapies is needed., Competing Interests: Declaration of competing interest CD, SK, TP, JK, NS, and ER have no conflict of interest to disclose. AKM has received a speaking honorarium from Alexion for a presentation on atypical hemolytic uremic syndrome in pregnancy, which is unrelated to this publication. RD has received speaking honoraria from Ferring, Canada for presentations related to labour induction and an early career grant from the Canadian Institutes of Health Research for projects related to the use of tranexamic acid in obstetrics, both of which are unrelated to this publication., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: Sickle cell disease is the leading genetic disease in Île-de-France. Stroke is one of its most severe complications. In SS sickle cell children, transcranial Doppler (TDC) is, through the study of average speeds of the skull base arteries, the gold standard for screening and diagnosis of vasculopathy. To our knowledge, in adults with sickle cell disease, no standards have been established for the speed of the arteries at the base of the skull. It therefore seemed useful to us to establish an approach to brain speeds recorded in adults with sickle cell disorders without neurovascular complications., Material and Methods: This was an observational, prospective, monocentric study conducted between February 2017 and June 2017. The main objective of the study was to determine the mean and standard deviation of maximum systolic velocities (MSS) and mean maximum velocities for all arteries recorded during the transcranial Doppler echo. The secondary objectives were to compare the mean maximum systolic velocities in sickle cell adults with those of healthy adults, to compare the mean maximum systolic velocities in sickle cell adults with those of sickle cell children, and to determine whether parameters could influence the speeds recorded at TCD., Results: Forty patients were included between February 1, 2017 and June 30, 2017, with an average age of 39.3 years. The mean maximum velocities recorded were: 78cm/s for the middle cerebral arteries; 59.6cm/s for the internal carotid arteries; 61cm/s for the anterior cerebral arteries; 44cm/s for the posterior cerebral arteries and 55cm/s for the basilar trunk., Discussion: The highest circulatory velocities are found in the middle cerebral arteries. The speeds found in the internal carotid arteries and anterior cerebral arteries are faster than in the vertebrobasilar system. Speeds in sickle cell adults are slower than those described in sickle cell children SS but significantly faster than those found in healthy adults., Conclusion: To our knowledge, this study is the first to evaluate transcranial Doppler circulatory velocities in adult sickle cell patients. This work has limitations due to its small sample size, however, it provides a basis for further studies on transcranial Doppler in sickle cell adults., (Copyright © 2019. Published by Elsevier Masson SAS.)

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts ( P = .148). However, whole-brain OEF was significantly different ( P < .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort ( P = .025 and P = .034 respectively), but higher compared with the CTT cohort ( P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT., (© 2019 by The American Society of Hematology.)

The purpose of this study was to compare the Infinite Cylinder and Forward Field methods of quantifying global venous oxygen saturation (Y v ) in the superior sagittal sinus (SSS) from MRI phase data, and assess their applicability in systemic cerebrovascular disease.15 children with sickle cell disease (SCD) and 10 healthy age-matched controls were imaged on a 3.0 T MRI system. Anatomical and phase data around the superior sagittal sinus were acquired from a clinically available susceptibility weighted imaging sequence and converted to Y v using the Infinite Cylinder and Forward Field methods. Y v was significantly higher when calculated using the Infinite Cylinder method compared to the Forward Field method in both patients (p = 0.003) and controls (p < 0.001). A significant difference in Y v was observed between patients and controls for the Forward Field method only (p = 0.006). While various implementations of Y v quantification can be used in practice, the results can differ significantly. Simplistic models such as the Infinite Cylinder method may be easier to implement, but their dependence on broad assumptions can lead to an overestimation of Y v , and may reduce the sensitivity to pathophysiological changes in Y v ., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: To investigate possible sources of quantification errors in global cerebral blood flow (CBF) measurements by comparing pseudo continuous arterial spin labeling (PCASL) and phase contrast (PC) MRI in anemic, hyperemic subjects., Methods: All studies were performed on a Philips 3T Achieva MRI scanner. PC and PCASL CBF examinations were performed in 10 healthy, young adult subjects and 18 young adults with chronic anemia syndromes including sickle cell disease and thalassemia. CBF estimates from single and two compartment ASL kinetic models were compared. Numerical simulation and flow phantom experiments were used to explore the effects of blood velocity and B1 + on CBF quantification and labeling efficiency., Results: PCASL CBF underestimated PC in both populations using a single compartment model (30.1±9.2% control, 45.2±17.2% anemia). Agreement substantially improved using a two-compartment model (-8.0±6.0% control, 11.7±12.3% anemia). Four of the anemic subjects exhibited venous outflow of ASL signal, suggestive of cerebrovascular shunt, possibly confounding PC-PCASL comparisons. Additionally, sub-study experiments demonstrated that B1 + was diminished at the labeling plane (82.9±5.1%), resulting in suboptimal labeling efficiency. Correcting labeling efficiency for diminished B1 + , PCASL slightly overestimated PC CBF in controls (-15.4±6.8%) and resulted in better matching of CBF estimates in anemic subjects (0.7±10.0% without outflow, 10.5±9.4% with outflow)., Conclusions: This work demonstrates that a two-compartment model is critical for PCASL quantification in hyperemic subjects. Venous outflow and B1 + under-excitation may also contribute to flow underestimation, but further study of these effects is required., (Copyright © 2017. Published by Elsevier Inc.)

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO 2 ). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO 2 , thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA ( P < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels., (© 2018 by The American Society of Hematology.)

Sickle cell anemia (SCA)-related cardiomyopathy is characterized by diastolic dysfunction and hyperdynamic features. Diastolic dysfunction portends early mortality in SCA. Diastolic dysfunction is associated with microscopic myocardial fibrosis in SCA mice, but the cause of diastolic dysfunction in humans with SCA is unknown. We used cardiac magnetic resonance measurements of extracellular volume fraction (ECV) to discover and quantify diffuse myocardial fibrosis in 25 individuals with SCA (mean age, 23 ± 13 years) and determine the association between diffuse myocardial fibrosis and diastolic dysfunction. ECV was calculated from pre- and post-gadolinium T1 measurements of blood and myocardium, and diastolic function was assessed by echocardiography. ECV was markedly increased in all participants compared with controls (0.44 ± 0.08 vs 0.26 ± 0.02, P < .0001), indicating the presence of diffuse myocardial fibrosis. Seventeen patients (71%) had diastolic abnormalities, and 7 patients (29%) met the definition of diastolic dysfunction. Participants with diastolic dysfunction had higher ECV (0.49 ± 0.07 vs 0.37 ± 0.04, P = .01) and N-terminal pro-brain natriuretic peptide (NT-proBNP; 191 ± 261 vs 33 ± 33 pg/mL, P = .04) but lower hemoglobin (8.4 ± 0.3 vs 10.9 ± 1.4 g/dL, P = .004) compared with participants with normal diastolic function. Participants with the highest ECV values (≥0.40) were more likely to have diastolic dysfunction ( P = .003) and increased left atrial volume (57 ± 11 vs 46 ± 12 mL/m 2 , P = .04) compared with those with ECV <0.4. ECV correlated with hemoglobin ( r = -0.46, P = .03) and NT-proBNP ( r = 0.62, P = .001). In conclusion, diffuse myocardial fibrosis, determined by ECV, is a common and previously underappreciated feature of SCA that is associated with diastolic dysfunction, anemia, and high NT-proBNP. Diffuse myocardial fibrosis is a novel mechanism that appears to underlie diastolic dysfunction in SCA., (© 2017 by The American Society of Hematology.)

Sickle cell disease (SCD) is a life-threatening genetic condition. Patients suffer from chronic systemic and cerebral vascular disease that leads to early and cumulative neurological damage. Few studies have quantified the effects of this disease on brain morphometry and even fewer efforts have been devoted to older patients despite the progressive nature of the disease. This study quantifies global and regional brain volumes in adolescent and young adult patients with SCD and racially matched controls with the aim of distinguishing between age related changes associated with normal brain maturation and damage from sickle cell disease. T1 weighted images were acquired on 33 clinically asymptomatic SCD patients (age = 21.3 ± 7.8; F = 18, M = 15) and 32 racially matched control subjects (age = 24.4 ± 7.5; F = 22, M = 10). Exclusion criteria included pregnancy, previous overt stroke, acute chest, or pain crisis hospitalization within one month. All brain volume comparisons were corrected for age and sex. Globally, grey matter volume was not different but white matter volume was 8.1% lower (p = 0.0056) in the right hemisphere and 6.8% (p = 0.0068) in the left hemisphere in SCD patients compared with controls. Multivariate analysis retained hemoglobin (β = 0.33; p = 0.0036), sex (β = 0.35; p = 0.0017) and mean platelet volume (β = 0.27; p = 0.016) as significant factors in the final prediction model for white matter volume for a combined r 2 of 0.37 (p < 0.0001). Lower white matter volume was confined to phylogenetically younger brain regions in the anterior and middle cerebral artery distributions. Our findings suggest that there are diffuse white matter abnormalities in SCD patients, especially in the frontal, parietal and temporal lobes, that are associated with low hemoglobin levels and mean platelet volume. The pattern of brain loss suggests chronic microvascular insufficiency and tissue hypoxia as the causal mechanism. However, longitudinal studies of global and regional brain morphometry can help us give further insights on the pathophysiology of SCD in the brain.

Sickle cell disease (SCD) is a red blood cell disorder that causes many complications including life-long pain. Treatment of pain remains challenging due to a poor understanding of the mechanisms and limitations to characterize and quantify pain. In the present study, we examined simultaneously recording functional MRI (fMRI) and electroencephalogram (EEG) to better understand neural connectivity as a consequence of chronic pain in SCD patients. We performed independent component analysis and seed-based connectivity on fMRI data. Spontaneous power and microstate analysis was performed on EEG-fMRI data. ICA analysis showed that patients lacked activity in the default mode network (DMN) and executive control network compared to controls. EEG-fMRI data revealed that the insula cortex's role in salience increases with age in patients. EEG microstate analysis showed patients had increased activity in pain processing regions. The cerebellum in patients showed a stronger connection to the periaqueductal gray matter (involved in pain inhibition), and negative connections to pain processing areas. These results suggest that patients have reduced activity of DMN and increased activity in pain processing regions during rest. The present findings suggest resting state connectivity differences between patients and controls can be used as novel biomarkers of SCD pain.

Objectives: Cerebrovascular reactivity (CVR) measures the ability of cerebral blood vessels to change their diameter and, hence, their capacity to regulate regional blood flow in the brain. High resolution quantitative maps of CVR can be produced using blood-oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in combination with a carbon dioxide stimulus, and these maps have become a useful tool in the clinical evaluation of cerebrovascular disorders. However, conventional CVR analysis does not fully characterize the BOLD response to a stimulus as certain regions of the brain are slower to react to the stimulus than others, especially in disease. Transfer function analysis (TFA) is an alternative technique that can account for dynamic temporal relations between signals and has recently been adapted for CVR computation. We investigated the application of TFA in data on children with sickle cell disease (SCD) and healthy controls, and compared them to results derived from conventional CVR analysis., Materials and Methods: Data from 62 pediatric patients with SCD and 34 age-matched healthy controls were processed using conventional CVR analysis and TFA. BOLD data were acquired on a 3 Tesla MRI scanner while a carbon dioxide stimulus was quantified by sampling the end-tidal partial pressures of each exhaled breath. In addition, T1 weighted structural imaging was performed to identify grey and white matter regions for analysis. The TFA method generated maps representing both the relative magnitude change of the BOLD signal in response to the stimulus (Gain), as well as the BOLD signal speed of response (Phase) for each subject. These were compared to CVR maps calculated from conventional analysis. The effect of applying TFA on data from SCD patients versus controls was also examined., Results: The Gain measures derived from TFA were significantly higher than CVR values based on conventional analysis in both SCD patients and healthy controls, but the difference was greater in the SCD data. Moreover, while these differences were uniform across the grey and white matter regions of controls, they were greater in white matter than grey matter in the SCD group. Phase was also shown to be significantly correlated with the amount that TFA increases CVR estimates in both the grey and white matter., Conclusions: We demonstrated that conventional CVR analysis underestimates vessel reactivity and this effect is more prominent in patients with SCD. By using TFA, the resulting Gain and Phase measures more accurately characterize the BOLD response as it accounts for the temporal dynamics responsible for the CVR underestimation. We suggest that the additional information offered through TFA can provide insight into the mechanisms underlying CVR compromise in cerebrovascular diseases.

Stroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P< .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 10(9)/L (P< .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion., (© 2016 by The American Society of Hematology.)

Tricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia., (© 2015 by The American Society of Hematology.)

Individuals with sickle cell disease often experience acute and chronic bone pain due to occlusive events within the tissue vasculature that result in ischemia, necrosis, and organ degeneration. Macroscopically, sickle bone is identified in clinical radiographs by its reduced mineral density, widening of the marrow cavity, and thinning of the cortical bone due to the elevated erythroid hyperplasia accompanying the disease. However, the microstructural architecture of sickle bone and its role in mechanical functionality is largely unknown. This study utilized micro-CT and biomechanical testing to determine the relationship between the bone morphology, tissue mineral density, and trabecular and cortical microarchitecture of 10- and 21-week-old femurs from transgenic sickle male mice and littermates with sickle trait, as well as a wild-type control. While bone tissue mineral density did not vary among the genotypes at either age, variation in bone microstructure were observed. At 10 weeks, healthy and trait mice exhibited similar morphology within the cortical and trabecular bone, while sickle mice exhibited highly connected trabeculae. Within older femurs, sickle and trait specimens displayed significantly fewer trabeculae, and the remaining trabeculae had a more deteriorated geometry based on the structure model index. Thinning of the cortical region in sickle femurs contributed to the displayed flexibility with a significantly lower elastic modulus than the controls at both 10- and 21-weeks old. Wild-type and trait femurs generally demonstrated similar mechanical properties; however, trait femurs had a significantly higher modulus than sickle and wild-type control at 21-weeks. Overall, these data indicate that the progressive damage to the microvasculature caused by sickle cell disease, results in deleterious structural changes in the bone tissue׳s microarchitecture and mechanics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Children with sickle cell anemia (SCA), who have mean blood flow velocities <170 cm/s in the terminal internal carotid (tICA) or middle cerebral (MCA) arteries on transcranial Doppler ultrasonography (TCD), are considered to be at low risk of stroke. The prevalence of intracranial stenosis, which raises the risk of stroke, is not known in these children. Here, we estimated the prevalence of stenosis and explored its association with silent cerebral infarcts determined based on Magnetic Resonance (MR) scans., Patients/methods: We studied prospectively a cohort of 67 children with SCA without prior clinically overt stroke or TIA (median age 8.8 years; range limits 2.3-13.1 years; 33 females) and with TCD mean velocity <170 cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries., Results: In 7 children (10.5%, 95% CI: 4.9-20.3%) we found 10 stenoses, including 4 with isolated left tICA stenosis and 3 with multiple stenoses. We found silent infarcts in 26 children (37.7%, 95% CI: 27.2-49.5%). The median number of infarcts in an affected child was 2 (range limits: 1-9), median volume of infarcts was 171 mm(3) (range limits: 7-1060 mm(3)), and median infarct volume in relation to total brain volume was 0.020% (range limits: 0.001-0.101%). The number and volume of infarcts were significantly higher in children with arterial stenosis (both p=0.023)., Conclusions: The prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170 cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts., (Copyright © 2014 Medical University of Bialystok. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)

Objective: To evaluate the intrathyroidal hemodynamic changes and thyroidal volume in sickle cell disease (SCD) patients., Methods: Thirty-two patients with homozygous SCD and 32 control subjects were examined with color Doppler ultrasonography. None of the patients and control subjects had clinical or laboratory evidence of thyroid disease., Results: SCD patients had significantly higher resistance index (RI) and pulsatility index (PI) values and lower thyroid volume compared with control group., Conclusion: Increased intrathyroidal RI and PI and decreased thyroid volume may be due to impaired thyroidal microcirculation. Further and follow-up studies are needed to explain the relationship between Doppler parameters and thyroid functions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Cerebrovascular accidents were until recently responsible for much mortality and morbidity in children with sickle cell disease; the likelihood of a child with HbSS having a stroke was 11% before age 20 years, with a peak incidence of ischemic stroke between 2 and 5 years of age, and of hemorrhagic strokes between 20 and 29 years of age. Vessels occlusion is likely initiated by intimal proliferation and amplified by inflammation, excessive adhesion of cells to activated endothelium, hypercoagulable state, and vascular tone dysregulation. Silent infarcts may occur and are associated with decreased cognitive functions. Transcranial Doppler ultrasonography (TCD) was more recently demonstrated able to achieve early detection of the children at high risk for clinical strokes. A randomized study demonstrated that a first stroke may be prevented by monthly transfusion in children with abnormal TCD, leading to a recommendation for annual TCD screening of children aged between 2 and 16 years and monthly transfusion for those with abnormal results. In children who have had a first stroke, the risk of recurrence is more than 50% and is greatly reduced by chronic transfusion, although not completely abolished. Hematopoietic stem cell transplant is indicated in children with cerebral vasculopathy who have an HLA-identical sibling., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: The status of left ventricle in sickle cell anemia presenting in sickle crisis and follow up has been minimally studied in past. To determine the left ventricular (LV) myocardial performance in these patients, we performed the study to assess two dimensional strains imaging which allowed a rapid and an accurate analysis of global and regional LV myocardial performance in longitudinal, radial, and circumferential directions., Methods: In this prospective study, 2-dimensional echocardiography (2DE) images of the LV were obtained in 52 subjects which included 32 patients (23 ± 8yrs, 16 male) with homozygous sickle cell anemia (SCA) in sickle cell crisis and 20 healthy controls (23 ± 5 yrs, 11 male) using apical 4-chamber and parasternal short-axis at the basal, mid, and apical levels. Of these 32 patients, 2DE was performed again in 18 patients in follow up (8 months ± 5 days). Longitudinal, circumferential and radial strains (LS, CS and RS respectively) were quantified and compared in an 18-segment model using a novel speckle tracking system (2D Cardiac Performance Analysis, TomTec Imaging System, Munich, Germany)., Results: There was no significant difference in LV ejection fraction between both the groups (59.32 ± 12.6 vs. 52.3 ± 7.9; p-value > 0.05). In comparison with normal controls and follow up of sickle cell patients, peak LS was significantly attenuated in the subendocardial and subepicardial regions during sickle cell crisis (p < 0.05). However, a significant reduction in circumferential strain was evident only in subepicardial region (p < 0.001). Also patients in sickle cell crisis showed significantly higher radial strain parameters than controls (p < 0.001)., Conclusion: Patients with SCA presenting in sickle cell crisis have reduced longitudinal shortening. LV myocardial performance remains unaltered due to relatively preserved circumferential shortening and increased radial thickening., (Copyright © 2012 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Silent cerebral infarct (SCI) is the most common form of neurologic disease in children with sickle cell anemia (SCA). SCI is defined as abnormal magnetic resonance imaging (MRI) of the brain in the setting of a normal neurologic examination without a history or physical findings associated with an overt stroke. SCI occurs in 27% of this population before their sixth, and 37% by their 14th birthdays. In adults with SCA, the clinical history of SCI is poorly defined, although recent evidence suggests that they too may have ongoing risk of progressive injury. Risk factors for SCI include male sex, lower baseline hemoglobin concentration, higher baseline systolic blood pressure, and previous seizures. Specific morbidity associated with SCI includes a decrement in general intellectual abilities, poor academic achievement, progression to overt stroke, and progressive SCI. In addition, children with previous stroke continue to have both overt strokes and new SCI despite receiving regular blood transfusion therapy for secondary stroke prevention. Studies that only include overt stroke as a measure of CNS injury significantly underestimate the total cerebral injury burden in this population. In this review, we describe the epidemiology, natural history, morbidity, medical management, and potential therapeutic options for SCI in SCA.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ(0)), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 10(9)/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Sickle cell anemia is the most common hemoglobinopathy worldwide; its musculoskeletal complications consist more often of medullary infarctions involving long bones. Orbital infarction is uncommon. We report on a case of orbital subperiosteal hematoma in a 9-year-old male with a medical history of sickle cell thalassemia., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Stroke is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). This study aimed at defining predictive factors for abnormally high velocities (>/= 2 m/sec) based on the Créteil pediatric sickle cell anemia (SCA) cohort composed of 373 stroke-free SCA children. alpha genes and beta-globin haplotypes were determined. Biologic parameters were obtained at baseline. alpha-thalassemia was present in 155 of 325 and G6PD deficiency in 36 of 325 evaluated patients. TCD was abnormal in 62 of 373 patients. Multivariate logistic regression analysis showed that G6PD deficiency (odds ratio [OR] = 3.36, 95% confidence interval [CI] 1.10-10.33; P = .034), absence of alpha-thalassemia (OR = 6.45, 95% CI 2.21-18.87; P = .001), hemoglobin (OR per g/dL = 0.63, 95% CI 0.41-0.97; P = .038), and lactate dehydrogenase (LDH) levels (OR per IU/L = 1.001, 95% CI 1.000-1.002; P = .047) were independent risk factors for abnormally high velocities. This study confirms the protective effect of alpha-thalassemia and shows for the first time that G6PD deficiency and hemolysis independently increase the risk of cerebral vasculopathy.

Hydroxyurea has hematologic and clinical efficacy in sickle cell anemia (SCA), but its effects on transcranial Doppler (TCD) flow velocities remain undefined. Fifty-nine children initiating hydroxyurea therapy for clinical severity had pretreatment baseline TCD measurements; 37 with increased flow velocities (> or = 140 cm/s) were then enrolled in an institutional review board (IRB)-approved prospective phase 2 trial with TCD velocities measured at maximum tolerated dose (MTD) and one year later. At hydroxyurea MTD (mean +/- 1 SD = 27.9 +/- 2.7 mg/kg per day), significant decreases were observed in the right middle cerebral artery (MCA) (166 +/- 27 cm/s to 135 +/- 27 cm/s, P < .001) and left (MCA) (168 +/- 26 cm/s to 142 +/- 27 cm/s, P < .001) velocities. The magnitude of TCD velocity decline was significantly correlated with the maximal baseline TCD value. At hydroxyurea MTD, 14 of 15 children with conditional baseline TCD values improved, while 5 of 6 with abnormal TCD velocities whose families refused transfusions became less than 200 cm/s. TCD changes were sustained at follow-up. These prospective data indicate that hydroxyurea can significantly decrease elevated TCD flow velocities, often into the normal range. A multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values, and ultimately for primary stroke prevention in children with SCA.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized trial to evaluate whether chronic transfusion could prevent initial stroke in children with sickle-cell anemia at high risk as determined by transcranial Doppler (TCD). The trial demonstrated a large benefit of transfusion and was halted early. After termination of the trial, patients participated in a post-trial follow-up study. More patients in the transfusion group (70%) elected transfusion for primary stroke prevention compared with those on standard care (45%). Six patients with persistently abnormal TCD results developed stroke. A minority with initially abnormal TCD results remained stroke-free without transfusion. Except for lower baseline and follow-up TCD velocities compared with those with stroke, no predictive features of this apparent lower-risk subgroup could be determined. TCD results at last testing in 108 patients that did not have stroke were: normal (44.4%), conditional (26.9%), abnormal (22.2%), and inadequate (6.5%). Patients on transfusion were more likely to have normal TCD results. Transfusion resulted in iron overload and alloimmunization, but no infection. The study provides new information on acceptance rates and long-term effects of transfusion. Persistent TCD elevation signals ongoing stroke risk. Reduction in TCD results over time without transfusion is observed in some patients and requires further study.

Aim: This study was designed to assess the efficacy and the safety of fluoroquinolones in their compassionate use for acute osteomyelitis in children with sickle cell disease in a tropical country., Patients and Methods: This study was non comparative, including twelve children (eight SS, three SC and one SEzerothalassemia) treated for acute osteomyelitis with oral ciprofloxacin or ofloxacin because of the following reasons: financial inability to afford conventional parenteral beta-lactams therapy (nine patients), refusal of hospitalization (two patients), and failure of conventional treatment (one patient)., Results: The mean age of patients was 9.5 +/- 2.6 years. The long bones were the predominantly site. Salmonella species were present in 75% of cases, followed by other enterobacteriaceae (16.7%), and Staphylococcus aureus (8.3%). Successful outcome occurred in all cases after three to four-weeks of treatment and 45 days of plaster immobilization. Transient bilateral Achilles tendon tendinitis was noted in a five-year-old patient., Conclusion: In economically developing countries, oral fluoroquinolones may be a therapeutic alternative for acute osteomyelitis in patients with sickle cell disease particularly in cases of financial hardship or failure with conventional therapy.

Background: Central-nervous-system (CNS) events, including strokes, transient ischaemic attacks, and seizures are common in sickle-cell disease. Stroke can be predicted by high velocities in the internal-carotid or middle-cerebral arteries on transcranial doppler ultrasonography. We tested the hypothesis that nocturnal hypoxaemia can predict CNS events better than clinical or haematological features, or transcranial doppler sonography., Methods: We screened 95 hospital-based patients with sickle-cell disease (median age 7.7 years [range 1.0-23.1]), but without previous stroke, with transcranial doppler and overnight pulse oximetry. Follow-up continued for a median of 6.01 (0.11-8.54) years., Findings: 19 patients had CNS events (six ischaemic and one haemorrhagic stroke, eight transient ischaemic attacks, and four seizures). Mean overnight oxygen saturation ([SaO(2)] hazard ratio 0.82 per 1% increase [95% CI 0.71-0.93]; p=0.003) and higher internal-carotid or middle-cerebral artery velocity (1.02 for every increase of 1 cm/s [1.004-1.03]; p=0.009) were independently associated with time to CNS event. After accounting for mean SaO(2), artery velocity, and haemoglobinopathy, high haemoglobin concentration was also associated with an increased risk of CNS event (1.7 per g/dL, [1.18-2.43]; p=0.004). Dips suggestive of obstructive sleep apnoea did not predict CNS events, and adenotonsillectomy seemed to have no effect, although the CI were wide and clinically important effects cannot be excluded., Interpretation: Screening for, and appropriate management of, nocturnal hypoxaemia might be a safe and effective alternative to prophylactic blood transfusion for primary prevention of CNS events in sickle-cell disease.

Interactions between the endothelium and erythrocytes may contribute to the vascular complications of sickle cell disease (SCD). Endothelium-derived nitric oxide (NO) plays a major role in the regulation of vasomotor tone in response to wall shear stress (WSS) variations and pharmacologic stimuli. However, little is known about endothelial NO production in patients with steady-state SCD. We investigated endothelial NO production in response to flow or vasoactive agonists in 16 homozygous patients with steady-state SCD and 15 controls. Flow-mediated dilation (FMD), arterial diameter changes in response to 100% oxygen inhalation, blood viscosity, and calculated WSS were determined in all patients and controls. At baseline, WSS was higher in SCD patients than in controls, whereas arterial diameter was similar. In patients with SCD, FMD was impaired (1.73% +/- 0.44% vs 3.97% +/- 0.24% in the controls, P <.001) and vasoconstriction in response to 100% oxygen was abolished. Using venous occlusion plethysmography, forearm blood flow (FBF) was evaluated in response to acetylcholine, nitro-monomethyl-L-arginine (L-NMMA), and sodium nitroprusside (SNP) in subgroups of 9 controls and 7 patients with SCD. Acetylcholine induced a significantly greater FBF increase in the patients (9.7 +/- 2.9 mL/min/100 mL of forearm volume vs 2.5 +/- 1.5 mL/min/100 mL in the controls, P <.001), whereas responses to L-NMMA and SNP were similar. These results suggest that endothelial dysfunction may prevent the arterial diameter of patients with SCD from adapting to chronic or acute shear stress elevations. This may contribute to the pathophysiology of vaso-occlusive crisis in patients with SCD.

With the advent of improved therapy, an increasing proportion of individuals suffering from sickle cell disease (SCD) are surviving into adulthood. In contrast to children, little has been documented concerning the typical radiographic findings in adults presenting with sickle cell crises (SCC). We describe the chest radiographic (CXR) manifestations of adults with SCD presenting in SSC, correlated to hemoglobin (Hb) values, and compare them to those of the pediatric sickle cell population. The chest radiographs of 66 consecutive adults presenting to our emergency department complaining of symptoms consistent with acute SCC were retrospectively reviewed over a 12-month period. The radiographic findings were correlated with admission Hb values and compared with those of 50 children with known SCD presenting with SCC. Chi square analysis revealed no significant difference between the cardiovascular and bony findings in the adults and in those of the pediatric controls (p > 0.08-p > 1.0). However, one important difference in the two cohorts was that upper lobe infiltrates occurred exclusively in the pediatric group (p = 0.06). There was a statistically significant (p < 0.05) difference in cardiovascular and skeletal abnormalities between adults with Hb above and below the mean (8.2 g/dL). The radiographic features of adults presenting in acute SCCs are similar to those of children. Although the chest radiograph is often normal, in decreasing frequency, cardiovascular abnormalities, pneumonia sparing the upper lobes, and aseptic osteonecrosis of the shoulders and spine are not uncommon. There is a significant relationship, however, between cardiovascular abnormalities and Hb levels.

The objective of the study was to evaluate the diagnostic utility of contrast enhanced magnetic resonance imaging (MRI) for distinguishing between acute medullary bone infarct and osteomyelitis. There were 11 patients (age 6-34 years) presented to our institution between December 1994 and February 1998 with a clinical differential diagnosis of acute bone infarct versus osteomyelitis and inconclusive radiographs were imaged using MRI. All but one received i.v. gadolinium. Nine of the patients had homozygous Sickle Cell disease (SCD) and two had Systemic Lupus Erythematosus (SLE), the latter requiring chronic methylprednisolone. Osteomyelitis was confirmed either by biopsy alone or by the combination of Gallium(67) scan in conjunction with positive blood cultures and clinical resolution following antibiotics. Infarcts without osteomyelitis were confirmed either by biopsy or resolution of symptoms without antibiotic therapy. All patients had at least six months clinical follow-up. The results found that seven of nine patients with SCD had acute infarct only. One patient with SCD had osteomyelitis only. Three patients (two SLE and one SCD) had both acute-on-chronic infarcts and superimposed osteomyelitis, one with an adjacent soft tissue abscess. Accurate distinction between infarct and osteomyelitis was impossible for one patient with SLE who did not receive contrast. All other cases were correctly diagnosed prospectively based on distinct patterns of MRI contrast enhancement. In all adult patients, acute infarcts demonstrated thin, linear rim enhancement on MRI while osteomyelitis revealed more geographic and irregular marrow enhancement. Two of four cases of osteomyelitis also demonstrated subtle cortical defects with abnormal signal traversing marrow and soft tissue. The single pediatric patient demonstrated elongated, serpiginous central medullary enhancement with periostitis. We concluded that the pattern of MR contrast enhancement may allow accurate distinction between acute infarct and osteomyelitis, or recognition of osteomyelitis superimposed on bone infarction.

Children with sickle cell anemia (SS) have an increased risk for cerebral vasculopathy with stroke (CVA) and cognitive impairment. The present study examines the extent to which adding positron emission tomography (PET) to magnetic resonance imaging (MRI) can improve the detection of cerebral vasculopathy. Whereas MRI has been the prime modality for showing anatomical lesions, PET excels at assessing the functional metabolic state through glucose utilization 2-deoxy-2 [18F] fluoro-D-glucose (FDG) and microvascular blood flow ([15O]H2O). Forty-nine SS children were studied. Among them, 19 had clinically overt CVA, 20 had life-threatening hypoxic episodes or soft neurologic signs, and 10 were normal based on neurological history and examination. For the entire sample of 49 subjects, 30 (61%) had abnormal MRI findings, 36 (73%) had abnormal PET findings, and 44 (90%) showed abnormalities on either the MRI or the PET or both. Of the 19 subjects with overt CVA, 17 had abnormal MRI (89%), 17 had abnormal PET (89%), and 19 (100%) had either abnormal MRI or PET or both. Among the 20 subjects with soft neurologic signs, 10 (50%) had abnormal MRI, 13 (65%) had abnormal PET, and 17 (85%) had abnormal MRI and/or PET. Six (60%) of the 10 neurologically normal subjects had abnormal PET. Among the 30 subjects with no overt CVA, 25 (83%) demonstrated imaging abnormalities based on either MRI or PET or both, thus, silent ischemia. Lower than average full-scale intelligence quotient (FSIQ) was associated with either overt CVA or silent ischemic lesions. Four subjects who received chronic red blood cell transfusion showed improved metabolic and perfusion status on repeat PET scans. In conclusion, (1) the addition of PET to MRI identified a much greater proportion of SS children with neuroimaging abnormalities, particularly in those who had no history of overt neurologic events. (2) PET lesions are more extensive, often bihemispheric, as compared with MRI abnormalities. (3) PET may be useful in management as a tool to evaluate metabolic improvement after therapeutic interventions, and (4) the correlation of PET abnormalities to subsequent stroke or progressive neurologic dysfunction requires further study.

Pulmonary complications are the leading cause of morbidity and mortality in sickle cell disease patients. Acute chest syndrome (ACS), in which chest pain and dyspnea, occurs in combination with a recent chest radiograph abnormality, raises both diagnostic and therapeutic challenges. The pathogenesis of ACS involves alterations in blood rheology, increased coagulability, and, above all, increased adhesion of sickle cells to the vascular endothelium and nitric oxide-mediated dysregulation of vascular reactivity. Sickle cell disease thus impacts all the cells in the vascular environment. Recently gained insights into pathophysiology offer hope that new treatments for preventing and treating acute and chronic pulmonary complications will soon become available.

Background: Orbital complications are an uncommonly reported finding in sickle cell disease., Methods: The authors review the reported orbital manifestations of sickle cell disease and discuss a patient with hemoglobin sickle beta(0) thalassemia in whom rapidly progressive bilateral orbital compression developed., Results: Computed tomography of the orbits in a patient with fever, headache, orbital swelling, and optic nerve dysfunction displayed bilateral superior subperiosteal cystic masses. Surgical exploration showed bilateral liquefied hematomas, which were evacuated. Recovery was complete 13 days after surgery. A mild recurrence 14 months later resolved with conservative treatment. The literature contains 11 reports of 16 young patients with sickle cell disease (15 sickle cell disease [Hb SS] and 1 hemoglobin sickle cell disease [Hb SC]) with rapidly developing findings ranging from frontal headache, fever, and eyelid edema to bilateral complete orbital compression syndrome. Including our patient, 60% had orbital hemorrhage on computed tomography. Ten of 12 patients tested were found to have orbital bone marrow infarctions. Sixteen of 17 patients had complete recovery; 13 were treated conservatively and 4 surgically. Only 2 of 17 had recurrence., Conclusions: Orbital complications in sickle cell disease are unusual manifestations in which a vaso-occlusive process in the marrow space around the orbit results in frontal headache, fever, eyelid edema, and often orbital compression syndrome. Subperiosteal hematomas are common and appear to result from bone marrow infarctions. Appropriate management requires a thorough evaluation to exclude other hemorrhagic, infectious or neoplastic processes, as well as vigilant ophthalmic monitoring. Supportive care is effective, unless optic nerve dysfunction or large hematomas are present, which would indicate that surgical evacuation is warranted to prevent loss of vision and to speed recovery.

The objective of this study was to obtain representative echocardiographic measurements of cardiac size and function in stable patients with sickle cell disease. This prospective, multicenter study utilized central reading of echocardiograms by an investigator blinded to other patient data. Stable outpatients from a balance of inner city and rural settings with SS phenotype and a broad age range were selected, because conflicting results from earlier studies were believed to be due to these patient selection criteria. Right and left ventricular dimensions and wall thickness, left atrial and aortic root dimensions, and systolic time intervals were measured. Body surface area indexed chamber dimensions and septal thickness were significantly increased from normal. Except for the right ventricle, chamber dimensions and wall thickness were inversely correlated with hemoglobin. The relationship between left ventricular dimension and hemoglobin was significantly dependent on age. Systolic time interval ratios were normal though left ventricular ejection time was prolonged. Shortening fraction was normal but velocity of circumferential fiber shortening was abnormally low. Stable patients with sickle cell disease have dilated chambers, septal hypertrophy, and normal contractility. Though left ventricular dilatation was inversely related to hemoglobin, age (duration of illness) was an important factor in that relationship. No specific cardiomyopathy was associated with sickle cell anemia.

Radionuclide ventriculography was performed on 10 normal subjects and 39 patients with sickle cell anemia (10 homozygous and 29 heterozygous sicklers) at rest and after exercise. Their left ventricular (LV) function was assessed in both these situations. The results were then compared within the subgroups. The reduction in ejection fraction (EF) response (47.5 +/- 7 at rest and 46.4 +/- 8 at exercise in homozygous patients, and 52.4 +/- 8 at rest and 54.3 +/- 8 at exercise in heterozygous patients) was significant in both the homozygous and the heterozygous groups but more so in the former group. The diastolic filling was also significantly impaired in the homozygous group (PER 2.64 +/- 0.74, PFR 2.13 +/- 0.42 and PFR/HR 0.014 +/- 0.001). The study statistically demonstrates, that LV filling patterns are altered in the sickle cell patients, even in the absence of clinical symptoms relating to LV dysfunction. This fact may prove to be a marker of sickle cell heart disease. Frequent and significant sickling is probably the cause of more pronounced LV functional abnormalities in homozygous sicklers.

In the absence of evidence for pneumonia or pulmonary embolus, primary pulmonary infarction has been assumed to be the cause of the syndrome of chest pain, fever, and pulmonary infiltrate on chest X-ray that commonly complicates sickle cell anaemia. To find out whether the syndrome might be due to rib infarction, 99mTc-diphosphonate bone scans were done. In the eleven episodes thus investigated (10 patients) the scans showed segmental areas of increased radionuclide uptake in ribs, indicative of bone infarction. A possible sequence of events is that the rib infarcts are primary and cause bone pain, followed by soft tissue reaction, pleuritis, and splinting. The resultant hypoventilation leads to atelectasis and subsequent development of the radiographic changes of the acute chest syndrome. Prevention of hypoventilation and treatment of bone pain are important therapeutic goals.

The cardiac status of 64 children (ages 0.2 to 18 yr) with sickle cell anemia documented by hemoglobin electrophoresis was evaluated by echocardiography. Left atrial, left ventricular and aortic root dimensions were significantly increased in over 60 percent of these children at all ages compared to values for 99 normal black (non-SCA) control subjects. Left ventricular wall thickness was increased in only 20 percent of older children with sickle cell anemia. Estimated LV mass/m2 and left ventricular cardiac index were increased compared to control subjects (p less than 0.001). Left heart abnormalities expressed as a single composite function, derived from multivariate regression analysis, correlated well with severity of anemia expressed as grams of hemoglobin (r = -0.52, p = less than 0.001) and with percentage of hemoglobin S (r = 0.51, p less than 0.001), but not to the same extent with age. Echocardiographically assessed left ventricular function at rest was comparable to that of control subjects. These data suggest that the major cardiac abnormalities in children are related to the volume overload effects of chronic anemia, and that in this age group, there is no evidence for a distinct "sickle cell cardiomyopathy" or cardiac dysfunction.