Silent Cerebral Infarcts In Children Research Articles

Rapid, Low-Cost Measurement of Carotid Artery Distensibility in Children with Sickle Cell Disease Using Compact Point-of-Care Ultrasound

Introduction: Silent cerebral infarction (SCI) is common in children with sickle cell disease and is linked to cognitive decline, poor academic performance, and overt stroke (DeBaun, 2014). Currently, the only clinical approach to identify patients at risk of SCI involves MRI screening for school-age children (DeBaun, 2020). However, this method is costly, not easily accessible, and often requires sedation, making implementation difficult. Moreover, prophylactic therapies, such as chronic blood transfusion, have shown minimal success in preventing SCI progression. Arterial stiffening is tightly linked with the development of stroke and SCIs in heart disease and elderly populations (Mattace-Raso, 2006). However, prior work in sickle cell disease on central arterial stiffening is inconclusive and arterial stiffness of the cerebrovascular is largely unknown, especially in children (Pikilidou, 2015). Therefore, the goal of this work was to determine the feasibility of compact, point of care ultrasound in the assessment of arterial stiffening of the carotid arteries and establish normative values in children with sickle cell disease. Methods: All studies were performed with IRB approval and with informed consent. The study population included 16 pediatric patients (14.75 ± 4.54 years, 11 Male, hemoglobin 9.72± 1.78 g/dL) recruited from the Blood and Cancer Center at Dell Children's Hospital in Austin, TX. All participants had their vitals taken and their right common carotid artery imaged in supine position following at least 10 minutes rest. Imaging was performed by an experienced imaging professional (AB, 10 years experience) using a Butterfly IQ + ultrasound probe (Burlington, MA) and an Apple smartphone (Cupertino, CA) in the B-mode vascular setting. Three to ten second recordings of the carotid artery were recorded at a rate of approximately 20 frames per second. In house MATLAB scripts were developed for semiautomated cross sectional area segmentation across the cardiac cycle to calculate vessel lumen area (Figure 1). Strain was calculated using the ratio of change in systolic and diastolic area over diastolic area, and distensibility (1/stiffness) was calculated as strain/ln[SBP/DBP] (Godia, 2007). Univariate and stepwise multiple analysis was performed to determine the correlates of arterial distensibility. Results: We measured an average distensibility of 0.23 ± 0.10 (a.u) across patients. A statistically significant inverse relationship between systolic pressure and distensibility (p=0.039, R 2=0.53) was measured. Upon multivariate analysis, systolic blood pressure was the only predictor of carotid distensibility. All other factors (sex, age, height, weight, hemoglobin concentration, and diastolic blood pressure) showed a statistically insignificant relationship (p>0.05). Further Applications: Our study shows it is possible to rapidly and inexpensively measure a metric of cerebral arterial stiffness in children with sickle cell disease and that arterial stiffness is linked with systolic blood pressure. Silent cerebral infarcts in children are known to be linked with systolic blood pressure, male gender and increase with age during adolescence (DeBaun, 2012). Whether arterial stiffening predicts the prevalence and progression of SCI and the role of point of care ultrasound is an ongoing area of research.

Localization of Silent Cerebral Infarcts in Children with Sickle Cell Disease Impacts Structural Disconnection

Silent cerebral infarcts (SCIs) occur in 40% of children with sickle cell disease (SCD) by 18 years of age and are associated with cognitive dysfunction. SCIs localize to the border zone of the brain, but the significance of this localization is unclear. In adults with stroke, an infarct's disruption of white matter (WM) tracts, or structural disconnection, is more strongly associated with the functional impact of the infarct than the size of the lesion. We aim to define the WM tracts disconnected by SCIs and the relationship between structural disconnection and functional connectivity (FC) in SCD. Simulated and real-world data were used to test the hypothesis that specific WM tracts are vulnerable to disconnection if an infarct occurs in the region at highest risk for SCIs, and that FC will decrease with increased structural disconnection in SCD. Utilizing data from the Silent Infarct Transfusion (SITT) trial, the regions at greatest risk for SCIs were defined (risk region, PMID 30061156). A simulated dataset comprised of 1000 infarcts within the risk region and 1000 infarcts within the white matter outside of the risk region was created. The real-world dataset was comprised of 44 participants with SCD and SCIs (median age 13.0 [11.0, 15.8] years, 29 female/15 male). The Human Connectome Project (HCP) 842 atlas contains thousands of streamlines comprising 28 WM tracts (excluding brainstem and cerebellar tracts). The Lesion Connectivity Toolbox defined streamlines within the HCP 842 atlas that intersected with each individual lesion, permitting quantification of two measures of structural disconnection: tract-wise disconnection (the percentage of streamlines within each tract that intersect a lesion) and global disconnection (the average percentage of streamlines connecting each pair of gray matter (GM) parcels in the FC parcellation (PMID 25316338)). Tract density images (TDi) illustrate the number of streamlines impacted by a lesion within each voxel of the brain permitting computation of total lesion impact as the volume of the TDi image associated with each lesion. Resting state functional connectivity MRI was obtained in 27 of the real-world participants for computation of whole brain modularity as a metric of global FC. The WM tracts with the highest mean tract-wise disconnection due to lesions within the risk region were the posterior and mid-anterior corpus callosum, superior longitudinal fasciculus, frontal aslant tract, and middle longitudinal fasciculus while the inferior frontal occipital fasciclus, anterior commissure, inferior longitudinal fasciculus, posterior corpus callosum, and arculate fasciculus were most impacted by lesions outside of the risk region. Numerous tracts showed a significant difference in tract-wise disconnection resulting from lesions in the risk region vs. lesions outside the risk region. The tracts impacted due to real-world lesions were similar to tracts impacted from lesions within the risk region (Table 1). Despite lesioned volume being equivalent (p = 0.31) for simulated data within and outside the risk region, the average volume of lesion impact as measured by volume of the TDi image was significantly larger for lesions occurring inside the risk region (p < 0.001; Fig 1). In the real-world dataset, whole brain modularity, a metric of global FC, decreased as global structural disconnection increased (r = -0.49, p =0.009) Using simulated data that was validated with a real-world dataset, specific WM tracts vulnerable to SCIs were identified. Previous work on cerebral hemodynamics in SCD elucidated the mechanism of injury in the border zone, and these results demonstrate the significance of the localization of this injury to the border zone. SCIs have a far-reaching effect as lesions in the risk region within the border zone were associated with a greater volume of structural disconnection compared to lesions of the same size distributed outside the risk region. These results suggest that the regions in which the SCIs localize represent “high impact” areas of the brain, where a lesion of a given volume may intersect a large number of streamlines. Further, given the correlation between global structural disconnection and whole brain modularity, these data link structural disconnection with function of the brain, suggesting these “high impact” regions may also play a key role in mediating communication between functionally connected GM regions.

Toward Automated Detection of Silent Cerebral Infarcts in Children and Young Adults With Sickle Cell Anemia.

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. 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. 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. 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.

Nocturnal hypertension associated with stroke and silent cerebral infarcts in children with sickle cell disease.

Strokes and silent cerebral infarcts (SCIs) lead to significant morbidity and mortality in children with sickle cell disease (SCD). Higher systolic blood pressures increase risk for stroke and SCIs; however, patients with SCD often have lower clinic blood pressures than the general population. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) allows for more robust examination of blood pressures. This study evaluated associations between abnormal ABPM measurements with stroke and SCIs. A cross-sectional study was performed. Children with SCD completed 24-hour ABPMs. Children with a documented magnetic resonance imaging (MRI) brain within a year of the ABPM were included in the analysis. Bivariate analyses were performed to identify associations between ABPM parameters with cerebrovascular outcomes. Forty-two children with a median age of 13years (10, 17) were included in the analysis. Seven (17%) had history of stroke and seven (17%) had SCIs. Nocturnal hypertension, elucidated via 24-hour ABPM, was noted in 25% of subjects. The presence of nocturnal hypertension was significantly higher in the SCI/stroke group (55% vs 12%, P=.01). Sensitivity analyses were performed during which stroke patients were removed from analysis. Nocturnal hypertension remained significantly associated with the presence of SCIs (P=.006). This study reveals an association between nocturnal hypertension and a higher prevalence of SCI and stroke in children with SCD. Larger, prospective studies are needed to confirm these findings and evaluate the contributory nature of blood pressure abnormalities to cerebrovascular events in children with SCD.

Nocturnal Hypertension Associated with Stroke and Silent Cerebral Infarcts in Children with Sickle Cell Disease

Background: Strokes and silent cerebral infarcts (SCIs) lead to significant morbidity and mortality in children with sickle cell disease (SCD). Discovering modifiable risk factors is paramount to decreasing the incidence and progression of these devastating cerebrovascular outcomes. Higher systolic blood pressures have previously been shown to increase risk for stroke and SCIs however patients with SCD often have lower clinic blood pressures than the general population. 24 hour ambulatory blood pressure monitoring (ABPM) allows for more robust examination of blood pressure values. Previous studies have investigated associations with abnormal ABPM parameters and end-organ dysfunction, mainly SCD nephropathy. Associations with cerebrovascular events have not yet been investigated. This study aimed to determine if there is an association between blood pressure abnormalities on ABPM with stroke and silent cerebral infarcts. Methods: A cross-sectional study was performed. Children with SCD were enrolled and completed a 24-hour ABPM. Of this cohort, children with HbSS or HbSβ0 with a documented MRI brain within a year of the ABPM were included in the analysis. SCIs were defined as discrete, infarct-like T2 hyperintense lesions measuring at least 3mm in diameter on two orthogonal imaging sequences. Bivariate analyses were performed to identify the association between ambulatory blood pressure parameters with cerebrovascular outcomes specifically SCI or history of stroke. Results: A final cohort of 42 children with a median age of 13 years (10, 17) was included in the analysis. Seven (17%) had a history of stroke, 7 (17%) had documented SCIs, and the remaining 28 (67%) had no history of stroke or SCIs. Masked hypertension was seen in 5% of subjects and nocturnal hypertension was seen in 25%. Abnormal overnight dipping noted in 85% of subjects. The presence of nocturnal hypertension was significantly higher in the SCI/stroke group (55% vs 12%, p = 0.01). Sensitivity analyses were performed to determine if blood pressure abnormalities continued to show an association with cerebrovascular findings when stroke patients were removed. Nocturnal hypertension remained significantly associated with the presence of SCIs (p = 0.006). The median systolic load (percentage of blood pressures above the 95th percentile on ABPM), while below the cutoff for hypertension in both cohorts, was higher in the stroke/SCI group (18.6) compared to the group without SCIs or stroke (6.1), but did not meet statistical significance (p = 0.07). Conclusions: This study reveals an association between nocturnal hypertension and a higher prevalence of SCI and stroke in children with SCD. Our findings also confirm the high prevalence of nocturnal hypertension and impairment of nocturnal dipping seen in this population. Adequately powered, prospective cohorts of ABPM in SCD patients are needed to further evaluate causation between nocturnal hypertension and cerebrovascular outcomes. Disclosures No relevant conflicts of interest to declare.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Interventions for preventing silent cerebral infarcts in people with sickle cell disease.

Elevated Plasma Thrombospondin-1 (TSP1) Levels Are Correlated with Oxidative Stress and Worse Cognitive Function in Sickle Cell Disease

IntroductionCognitive impairment (CI) is a serious complication of sickle cell disease (SCD) with a prevalence of more than 40% (Vichinsky, JAMA 2010). It is responsible for functional limitations in schooling in children and in occupation and compliance with therapy in adults, and is therefore recognized as both a medical and social devastation of SCD. While the pathophysiology of SCD-related cognitive impairment is not fully elucidated, SCD patients are exposed to high levels of chronic inflammation and oxidative stress, which are responsible for cognitive impairment in other vascular diseases, suggesting that these factors may also play a role in SCD. Thrombospondin-1 (TSP1) is a secreted protein that stands at the crossroads of multiple inflammatory and oxidative pathways crucial to the SCD pathology (Isenberg, PNAS 2005, JBC 2006, Blood 2008, Csanyi, ATVB 2012; Yao, JASN 2014). Importantly, TSP1 levels are elevated in patients with SCD and correlate with an increased risk of vaso-occlusive complications in adults (Novelli, AJH 2012) and a higher burden of silent cerebral infarcts in children (Faulcon, BJH 2013). Herein, we explored the association between TSP1, oxidative stress and cognitive function in a cohort of patients with SCD.MethodsThirty-four SCD patients (HbSS, HbSC and HbS/β-thalassemia) >18 years and in steady state were recruited from the UPMC Adult Sickle Cell Program outpatient clinic (Pittsburgh, PA). Upon obtaining informed consent, patients underwent a blood draw and the Hopkins Verbal Learning Test - Revised (HVLT-R), a test of episodic memory whose scores are associated with cerebral small vessel disease in SCD patients (Novelli, PRN 2015). Platelet-poor plasma was collected and stored for analysis by ELISA of TSP1 and the oxidized derivative of deoxyguanosine, 8-hydroxy-2-deoxy guanosine (8-OH2dG), a marker of oxidative stress. Statistical analyses were completed using SAS 9.3.ResultsSCD patients had a mean age of 35 (22-65), were 65% female, 66% had greater than high school education, and 65% had HbSS disease, 30% had HbSC disease, and 5% had S/β-thalassemia. Elevated plasma TSP1 levels correlated inversely with HVLT-R retention score (standardized b=-0.457, p=0.007). Conversely, elevated plasma TSP1 levels positively correlated with increased levels of plasma 8-OH2dG (standardized b=0.361, p<0.001). The association between TSP1 and HVLT-R was potentiated after adjustment for 8-OH2dG (standardized b=-0.762, p<0.001). Moreover, the association between 8-OH2dG and cognitive function was also significant after adjusting for TSP1 (standardized b=-0.633, p=0.015).DiscussionElevated plasma TSP1 levels are associated with poorer episodic memory in SCD patients. This is the first evidence of a link between a plasma protein associated with vascular disease and cognitive function in adults with SCD. TSP1 levels were also positively correlated with 8-OH2dG, and adding 8-OH2dG to the model of TSP1 and HVTL-R retention appeared to increase the detrimental effect of TSP1. These results suggest that the effect of 8-OH2dG on cognitive function becomes evident only in the presence of higher TSP1 levels and implicate oxidative stress as intermediary to the effect of TSP1 on cognitive function in SCD. [Display omitted] DisclosuresIsenberg:RCTI, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313; Vasculox, Inc.: Equity Ownership, Patents & Royalties: US Patent No. 8236313.

Headache does not equal stroke in sickle cell

Headache is a common complaint in children with sickle cell disease. Dowling et al conducted a planned secondary analysis from the Silent Infarct Transfusion Trial to determine whether recurrent headache or, more specifically, migraine were predictive of silent cerebral infarction in children with sickle cell disease. In a cross-sectional study of 872 children, about one-third had headaches and 15% had migraines. Asymptomatic cerebral infarcts were not more likely in patients with recurrent headaches or migraine. As a take-home point, the authors note that neuroimaging may not be needed for children with sickle cell disease who have recurrent headache without additional risk factors or neurologic findings. Interestingly, recurrent headaches and migraine were associated in patients with sickle cell disease with a higher rate of overall painful events requiring hospitalization.Article page 1175▶ Headache is a common complaint in children with sickle cell disease. Dowling et al conducted a planned secondary analysis from the Silent Infarct Transfusion Trial to determine whether recurrent headache or, more specifically, migraine were predictive of silent cerebral infarction in children with sickle cell disease. In a cross-sectional study of 872 children, about one-third had headaches and 15% had migraines. Asymptomatic cerebral infarcts were not more likely in patients with recurrent headaches or migraine. As a take-home point, the authors note that neuroimaging may not be needed for children with sickle cell disease who have recurrent headache without additional risk factors or neurologic findings. Interestingly, recurrent headaches and migraine were associated in patients with sickle cell disease with a higher rate of overall painful events requiring hospitalization. Article page 1175▶ Headache and Migraine in Children with Sickle Cell Disease Are Associated with Lower Hemoglobin and Higher Pain Event Rates But Not Silent Cerebral InfarctionThe Journal of PediatricsVol. 164Issue 5PreviewTo identify risk factors for headache and migraine in children with sickle cell disease and test the hypothesis that either or both are independently associated with silent cerebral infarcts. Full-Text PDF

Sickle cell anemia: Intracranial stenosis and silent cerebral infarcts in children with low risk of stroke

Purpose:Children with sickle cell anemia (SCA), who have mean blood flow velocities <170cm/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/methodsWe 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 <170cm/s. They underwent MR imaging of the brain and MR angiography of intracranial arteries. ResultsIn 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 171mm3 (range limits: 7–1060mm3), 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). ConclusionsThe prevalence of intracranial arterial stenosis in children with SCA classified as at low risk of stroke by TCD mean velocity <170cm/s is high. Children with stenosis are at higher risk of brain parenchymal injury as they have more silent cerebral infarcts.

Abstract W MP111: Prevalence and Risk Factors of Silent Cerebral Infarcts in Children with Hemoglobin SC Disease

Background: Hemoglobin (Hb) SC disease comprises 22% of all sickle hemoglobinopathies and is the second most common form of sickle cell disease. Silent cerebral infarcts (SCI) are common in Hb SS disease and are associated with male sex, higher systolic blood pressure (SBP), and lower baseline Hb concentration among children with Hb SS. However, SCI prevalence and risk factors are less well characterized in Hb SC disease. We tested the hypothesis that risk factors for SCI in Hb SC and Hb SS are similar. Methods: Retrospective chart review of children with Hb SC seen at St. Louis Children’s Hospital (SLCH) Sickle Cell Clinic 2004-2012 who had brain magnetic resonance imaging (MRI) available. At SLCH, all children with sickle cell disease undergo screening brain MRI after their 6 th birthday; additional MRIs are obtained for concerning symptoms. Cerebral infarctions were identified as T2- or FLAIR-weighted hyperintensities identified in at least 2 planes or decreased diffusion; silent infarcts were diagnosed when the patient had no neurological symptoms that correlated with the infarct lesions. Hb concentrations and SBP were obtained from clinic well visits within a year before and after MRI. Human Studies Committee approval and waiver of consent were granted for this study. Results: Thirteen of 96 patients with Hb SC disease had SCI on MRI. The prevalence of SCI was 13.5%. Twelve (92%) subjects had subcortical lesions; 11 (85%) had SCI in the frontal lobe; and 10 (77%) subjects had bilateral infarctions. Seven (50%) of subjects with SCI were male. The mean age at identification of SCI was 11.9 years (range, 6.2-19.3 years). Ten children with SCIs had repeat MRI (range 0.1-6.4 years) following the SCI diagnosis. No child had progression or additional SCI on repeat imaging. Sex, SBP, and Hb concentration were not significantly different between children with and without SCIs (p=0.4). Conclusion: Our cohort of children with Hb SC had a SCI prevalence of 13.5%. The majority of children had bilateral subcortical lesions. SCIs had frontal lobe predominance. Unlike children with Hb SS, gender, elevated SBP or lower baseline Hb were not risk factors for SCIs in this cohort.

Prevalence of Intracranial Stenosis and Silent Cerebral Infarcts in Children with Sickle Cell Anemia and Low Risk of Stroke

Prevalence of Intracranial Stenosis and Silent Cerebral Infarcts in Children with Sickle Cell Anemia and Low Risk of Stroke

Silent Cerebral Infarcts in Children With Sickle Cell Anemia

Source: Debaun MR, Sarnaik SA, Rodeghier MJ, et al. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin and relative high systolic blood pressure. Blood. Epub 2011 Nov 17; doi: 10.1182/blood-2011-05-349621Investigators from 29 clinical sites in the United States conducted the Silent Cerebral Infarct Transfusion (SIT) Trial to assess the risk factors for silent cerebral infarcts (SCI). In this cross-sectional study, children with sickle cell anemia (SCA) between the ages of 5 and 15 years with no history of overt stroke or seizures were evaluated with magnetic resonance imaging (MRI) of the brain to screen for SCI. SCI was radiographically defined as MRI signal abnormality measuring at least 3 mm on the T-2 weighted images judged by two of three neuroradiologists on a central review committee. SCI was determined to be truly silent by a central neurology committee’s review of the local neurologist’s examination and the patient’s MRI findings. Clinical history and baseline laboratory values were examined to determine potential risk factors for SCI.Study data were analyzed on 814 participants; the mean age of enrolled children was 9.1 years and 50.7% were male. SCIs were diagnosed in 30.8% (n=251) of study patients. In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P<.001), higher baseline systolic blood pressure (SBP) (P=.013), and male gender (P=.026) were all associated with a significantly increased risk of a SCI. The odds ratio for SCIs for patients with a hemoglobin less than 7.6 g/dl or SBP greater than 112 mm/Hg were 2.12 and 1.73, respectively. Those individuals who had both a hemoglobin less than 7.6 and SBP greater than 104 had the highest odds of a SCI. In addition, 83% (5 of 6) of patients who carried a diagnosis of hypertension had a higher rate of SCIs than the other study participants (P=.012).The investigators conclude that lower hemoglobin concentration and higher SBP are risk factors for SCI in children with SCA. Further research is needed to determine if interventions targeting these risk factors, such as hydroxyurea, blood transfusion therapy, or antihypertensive medications, can be effective in preventing SCIs.Dr Villella has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Although previous investigators have also identified SCIs in approximately one third of patients with SCA, this study is the first to identify a lower baseline hemoglobin and higher SBP as risk factors for SCI in a large multicenter setting.1–3 SCIs may be silent, but they are not benign. SCIs in children with SCA are associated with an increased risk of overt stroke as well as progressive SCIs.4 Additionally, SCIs are associated with poorer cognitive function and school performance as compared to children with SCA without SCIs as well as sibling controls.5–6 Even more concerning is the finding that cognitive function appears to worsen over time in children with SCA and SCIs.7 As children mature and develop into young adults, they may be silently losing IQ points. Indeed, a recent study showed that asymptomatic adults with SCA have significantly lower performance IQs as compared to matched controls.8These findings have important implications for all pediatric practitioners. Many children do not live in close proximity to a sickle cell center and therefore the responsibility of providing health maintenance for these children can fall onto the shoulders of the primary care giver. The American Academy of Pediatrics recommends that all children with SCA receive a thorough assessment of school attendance and performance with consideration for formal neurocognitive testing.9 MRI of the brain should also be considered for children struggling in school, although this remains controversial since a proven intervention to prevent or limit SCIs is lacking. Neurocognitive testing, however, can be extremely helpful in identifying cognitive deficiencies and helping the family and school to optimize the child’s learning environment.There is strong evidence that SCIs in children with SCA are common and associated with significant morbidity. Studies evaluating potential interventions are desperately needed. By identifying risk factors for SCI in this study, the investigators have uncovered potential therapeutic targets which may respond to interventions to decrease the proportion of sickle cells and thereby increase cerebral blood flow, such as hydroxyurea and chronic blood transfusion therapy, or decrease blood pressure through the use of antihypertensive medications. Thankfully, the investigators of the SIT trial are addressing this as well. Patients enrolled into SIT are randomized to receive chronic blood transfusion therapy or standard observation. Follow-up imaging and neurocognitive testing is then performed to ascertain whether chronic blood transfusion therapy can prevent progression of SCIs and stabilize cognitive function. We anxiously await the results.

Do Transfusions Prevent Recurrent Strokes in Children with Sickle Cell Disease

Overt strokes and silent cerebral infarcts in children with sickle cell disease (SCD) result in considerable physical and cognitive disability. Chronic transfusion therapy (TT) reduces the risk for recurrent overt strokes, but whether it also lowers the frequency of silent brain infarcts is unclear. To investigate this issue, a consortium of researchers from seven academic SCD centers conducted prospective magnetic resonance imaging (MRI) studies of the brain in 40 children …

Acute Silent Cerebral Ischemia Occurs More Frequently Than Silent Cerebral Infarction In Children with Sickle Cell Anemia

AbstractAbstract 268 Background:Children with sickle cell anemia (HbSS) are at high risk of overt stroke and clinically silent cerebral infarction (SCI). SCI is an infarct-like lesion visualized on magnetic resonance imaging (MRI) of the brain that produces no corresponding motor or sensory deficits. The prevalence of SCI in HbSS is approximately 20 – 30% by 16 years of age, but less is known about its incidence. The Cooperative Study of Sickle Cell Disease (CSSCD) found the incidence of new or more extensive SCI in children with HbSS to be 7 events per 100 patient-years. Given that SCI is clinically silent, the only way to determine its incidence (the number of new events occurring in a specific time-period) is to screen with two sequential MRIs of the brain. MRI can also detect acute cerebral ischemia in asymptomatic patients using diffusion-weighted imaging (DWI). The incidence of acute silent cerebral ischemic events (ASCIEs) is not known. A clinical trial setting provides a unique opportunity to determine the incidence of ASCIEs and SCI in children with HbSS. Objectives:To determine the incidence rates of (1) ASCIEs in children with HbSS without prior evidence of focal neurological deficits and (2) new, recurrent SCI in children with HbSS who have pre-existing SCI. Methods:We studied a cohort of children with HbSS and sickle-β0-thalassemia who had brain MRIs for the Silent Infarct Transfusion Trial. All participants had no prior history of overt stroke, seizures, or transient ischemic attacks. ASCIE was defined as an infarct-like lesion on brain MRI without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity with restricted diffusion on DWI sequences. SCI was defined an infarct-like lesion without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity without restricted diffusion. Given that acute cerebral ischemia appears as a focus of restricted diffusion on DWI for 10 days, we assumed that each MRI scan provided 10 patient-days of observation for detecting ASCIE. Therefore, the incidence of ASCIEs was calculated using a single MRI per patient. The incidence of new or more extensive SCI in children with pre-existing SCI was determined in those who had two MRIs each (screening and pre-randomization). We statistically compared the incidence rates of ASCIEs and SCI obtained by these two different methods. For all ASCIEs and new SCI events, a medical history tool was completed at the local site at the time of MRI of the brain. Results:In total, 972 MRIs were studied (745 screening, 227 pre-randomization). There were 844 MRIs with DWI sequences, providing 23.1 patient-years of observation in 640 children (52% male; mean age 9.7 years). ASCIEs were detected on 1.2% (10 of 844 MRIs), corresponding to an incidence of 43.3 (95% CI: 20.7 – 79.6) events per 100 patient-years. Nine of the 10 ASCIEs were detected incidentally; 1 ASCIE occurred in a participant who was recovering from a recent episode of acute chest syndrome (onset 5 days before MRI) complicated by severe anemia and hypertension. Standard neurological examination was normal in all cases. Two of the 10 participants with ASCIEs had follow-up MRIs of the brain 4 to 10 months later; one had SCI in the same location as the previously detected acute ischemia, but the other had no residual lesion in the same location. Thus, not all ASCIEs produce detectable SCI. A total of 220 participants (55% male; mean age 10.0 years) had both screening and pre-randomization MRIs. The mean interval between the two MRIs was 124.3 days (range: 14 – 645), providing 74.9 patient-years of observation. All screening MRIs showed baseline SCI. New, recurrent SCI was detected on pre-randomization MRI in 8 participants, corresponding to an incidence of 10.7 events per 100 patient-years (95% CI: 4.6 – 21.0). The incidence of ASCIEs was 4-fold higher than recurrent SCI (43.2 vs. 10.7 events per 100 patient-years; P=0.001). Conclusions:The incidence of recurrent SCI was similar to CSSCD findings. However, we show that children with HbSS experience acute cerebral ischemic events far more frequently than previously recognized. These acute ischemic events are mostly clinically silent, potentially reversible radiographically, and not associated with antecedent medical events. Disclosures:No relevant conflicts of interest to declare.

Low Levels of Apolipoprotein A1 Are Associated with Silent Cerebral Infarcts in Children with Sickle Cell Disease.

Abstract 259 Background:Cerebral infarct is a frequent complication in children and adults with sickle cell disease (SCD). About 10% of children with sickle cell anemia (HbSS) will have an overt stroke by 18 years of age and another 22% will have “silent” cerebral infarcts by 14 years of age. There is a second peak in the incidence of overt ischemic stroke in adults with SCD. Both silent and overt stroke can be accompanied by cognitive impairment and thereby increased risk of academic failure. Several laboratory parameters have been associated with these complications, including low hematocrit or hemoglobin, high white blood cell count (WBC), and high platelet count, while lactate dehydrogenase (LDH) and apolipoprotein A1 have been associated with pulmonary vasculopathy in adults with SCD. Elevated C-reactive protein (CRP) and the ratio of apolipoprotein B/A1 are associated with increased stroke risk in the general population. We hypothesized that these and other biomarkers might also be important in children with silent cerebral infarction. Methods:We prospectively measured potential biomarkers, including complete blood count, reticulocytes, fetal hemoglobin (HbF), LDH, CRP, and apolipoprotein A1 and B in 73 children with HbSS and 3 with sickle-β0-thalassemia (HbSβ0), in addition to performing brain magnetic resonance imaging (MRI), in a single center ancillary study of the Silent Infarct Transfusion Trial. MRIs were interpreted for the presence or absence of silent cerebral infarcts (FLAIR hyperintensities ≥3 mm in diameter seen in at least two imaging planes without corresponding symptoms or signs of stroke). Groups were compared by Student's t-test or Wilcoxon rank-sum test and associations evaluated by univariate and multivariate logistic regression. Results:Twenty-seven participants (35.5%, 1 with HbSβ0) had silent cerebral infarcts (age 8.9 ± 2.4 years, 59% male) and 49 (65.2%) had normal brain MRIs (age 8.7 ± 2.1, 53% male). The group with SCD and silent cerebral infarcts had significantly lower hemoglobin concentration and apolipoprotein A1 (P=0.01 for both) than children with SCD without silent cerebral infarcts. Apolipoprotein B and the ratio of apolipoprotein B to A1 were similar between groups. By univariate logistic regression, both apolipoprotein A1 [Odds ratio (OR) 0.95 per mg/dl increase, P<0.05] and hemoglobin (OR 0.52 per g/L increase, P<0.05) were associated with silent cerebral infarct; however, in a multivariate model, apolipoprotein A1 (OR 0.96 per mg/dl, P<0.05), but not hemoglobin (OR 0.78 per g/L, P=0.5), was significantly associated with silent cerebral infarct. Discussion and Conclusions:These data suggest a role of apolipoprotein A1 in the pathogenesis of silent cerebral infarct in children with SCD. Apolipoprotein A1 is a plausible marker or risk factor for cerebrovascular disease in SCD, given the association of lower levels with pulmonary hypertension in SCD and increased risk for cererbrovascular and cardiac disease in the general population. This marker should be studied in a larger longitudinal cohort of children at risk for cerebral infarcts.Table:Potential Biomarkers by Group [Mean ± Standard Deviation Compared by T-Test or Median (IQR) by Rank-Sum Test]MarkerSCD: InfarctSCD: No InfarctP-ValueHemoglobin (g/dl)7.7±1.08.3±1.00.01Hemoglobin F (%)8.4 (5.5, 11.5)10.6 (5.1, 16.5)0.18WBC (per ul)12,514±346912,076±35990.60Reticulocytes (%)12.6±6.511.6±4.80.46CRP (mg/L)2.2 (1.6, 5)2 (1.2, 4.3)0.5Apo A1 (mg/dl)114±16124±190.01Apo B (mg/dl)57±1560±200.72Apo B/Apo A10.50±0.130.49±0.180.49LDH (U/L)573±140631±1780.21Apo indicates apolipoprotein [Display omitted] Disclosures:Strouse:General Electric: Equity Ownership. Casella:Boehringer Ingelheim: Honoraria; Cytrex: Research Funding; Ikaria: Research Funding.

Elevated Systolic Blood Pressure and Low Fetal Hemoglobin Are Risk Factors for Silent Cerebral Infarcts in Children with Sickle Cell Anemia.

Abstract 262 Introduction:The most common cause of neurological injury in sickle cell anemia is silent cerebral infarcts (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial (SIT Trial) cohort, we sought to identify risk factors associated with SCI. Patients and Methods:In this cross-sectional study, we evaluated the clinical history, baseline laboratory values and performed magnetic resonance imaging of the brain. For those children with SCI-like lesions, a pediatric neurologist examined the child and neuroradiology and neurology committees adjudicated the presence of SCI. Children between the ages of 5 and 15 years with hemoglobin SS or S-beta° thalassemia and no history of overt strokes or seizure were evaluated. Results:A total of 542 children were evaluated; 173 (31.9%) had SCI. The mean age of the children was 9.3 years, with 280 males (51.7%). In a multivariate logistic analysis, two covariates were significant: a single systolic blood pressure (SBP) obtained during a baseline well-visit, p = 0.015 and hemoglobin F (Hgb F) level obtained after three years of age, p = 0.038. Higher values of SBP and lower values of Hgb F increased the odds of SCI; Figure. Baseline values of white blood cell count, hemoglobin level, oxygen saturation, reticulocytes, pain, or ACS event rates were not associated with SCI. [Display omitted] Conclusion:SBP and Hgb F level are two previously unidentified risk factors for SCI in children with sickle cell disease. Modulation of SBP and Hgb F levels might decrease the risk of SCI. Disclosures:No relevant conflicts of interest to declare.

Acute silent cerebral infarction in children with sickle cell anemia

Silent cerebral infarctions (SCI) occur in up to 35% of children with sickle cell anemia (HbSS) but are rarely recognized during the initial 10-14 days when diffusion weighted magnetic resonance imaging (MRI) can differentiate acute infarctions from remote events. We report acute SCI in seven children with HbSS who had areas of restricted diffusion on MRI without persistent focal neurologic deficits. Four had acute SCI identified following acute anemic events. Our observations suggest that SCI are detectible in the acute phase, present with subtle neurologic symptoms, result in permanent neurologic injury, and may be caused by acute anemic events.

Cognitive Screening for Silent Cerebral Infarction in Children With Sickle Cell Disease

Silent cerebral infarctions have been shown to cause major morbidity in children with sickle cell disease, suggesting that silent infarctions are not as "silent" as once thought. The current definition of silent infarction includes signal changes on magnetic resonance imaging, the absence of overt abnormalities on neurologic examination, and no history of focal neurologic event. Using a decision tree algorithm, we identified a cognitive profile distinguishing children with (n=16) and without (n=49) silent infarctions. The best model combined learning slope from the California Verbal Learning Test-Children's Version and Block Design from the Wechsler Abbreviated Scale of Intelligence. Accuracy was 75%, with 75% sensitivity and 76% specificity. Administration of a brief cognitive battery may be the most feasible approach to screen for silent infarctions in children with sickle cell disease.

Silent brain infarcts are rare in Kuwaiti children with sickle cell disease and high Hb F.

Overt stroke is rare among sickle cell disease (SCD) patients in Kuwait. However, there are no previous studies of silent cerebral infarcts, which have been described in up to 20% of American children with Hb SS. We have carried out a prospective brain MRI study among otherwise normal SCD patients, who were consecutive patients seen in a 1-year period to document the prevalence of silent cerebral infarcts in children with sickle cell disease in Kuwait. Any patient with a previous seizure or other neurological abnormality was excluded. MRI was done with a 1.5 Tesla unit with super-conducting magnet. T1- and T2-weighted sagittal and axial sections and proton density axial images were obtained in 5-mm thick sections. The study group consisted of 30 (23 SS and 7 Sbeta(0)Thal) patients-19 males and 11 females-whose ages ranged from 6 to 17 (mean of 9.8 +/- 3.5) years. Hb F ranged from 11% to 35% with a mean of 22.8% +/- 5.7%. Only one patient, a 10-and-a-half-year-old boy with Hb SS, showed hyperintense signals in the parietal white matter, consistent with small infarcts, thus giving a prevalence of 3.3%. Silent brain infarcts are uncommon in our patients, and the protective factors remain to be fully elucidated.