Cerebral Infarction 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.

Current Treatment Results of Intracranial Carotid Artery Dissection Causing Cerebral Ischemia: A Japanese Nationwide Survey.

Intracranial carotid artery dissection causing cerebral ischemia is a rare but important cause of cerebral infarction in children and adolescents. Although endovascular therapy has been reported to be effective, questions regarding the indications for intervention are yet to be addressed. Therefore, this study aimed to evaluate factors related to clinical outcomes through a nationwide survey. Overall, 35 neurosurgical centers reported patients within 2 weeks after ischemic onset due to intracranial carotid artery dissection causing cerebral ischemia treated between January 2015 and December 2020. Data on clinical and radiological findings were statistically analyzed. Twenty-eight patients met the inclusion criteria. The median age was 36 years (range, 7-59 years), without sex differences. Headache at onset was documented in 60.7% of the patients. Dissection findings were categorized into stenosis (71.4%) or occlusion (28.6%). Initial treatments, including various antithrombotic agent combinations in 23 (82.1%) patients, effectively improved or prevented aggravation in half of the patients. The patients with stenotic dissection were significantly more likely to experience aggravation during the initial treatment than did those with occlusive dissection (P = 0.03). In addition, the patients with moderate to severe neurological deficits on admission had poorer outcomes at discharge more frequently than did those with mild neurological deficits on admission. Eight patients undergoing endovascular therapy had no procedural complications or further aggravation after intervention. In conclusion, patients with intracranial carotid dissection causing cerebral ischemia who had a stenotic dissection were at risk of further aggravation, and endovascular therapy effectively improved or prevented aggravation.

Incidence of Stroke and Other Brain Imaging Findings in Adult Patients with Sickle Cell Disease: A Retrospective Study

Background: Vaso-occlusion and hemolytic anemia are the main features of sickle cell disease. Central Nervous system complications of sickle cell disease (SCD) can include silent cerebral infarcts (SCI), hemorrhagic or ischemic strokes, seizures and Moyamoya syndrome. SCI is the most common neurological complications in SCD. SCI patients have abnormal Magnetic Resonance Imaging (MRI) of the brain with normal neurological examination and no history of stroke. More precisely, Casella et al in the Silent Cerebral Infarct Multi-Center Clinical trial (SIT) defined infarct as MRI signal abnormality that was at least 3 mm in one dimension and that was visible in two planes on fluid-attenuated inversion recovery T2 -weighted images, as determined by agreement of two of the three study neuroradiologists. SCI in children is associated with lower Intelligence Quotient and increased risk of stroke.Methods: In this retrospective study we reviewed 100 adult patients at our Comprehensive Sickle Cell Center. We looked at the incidence of documented stroke and other neurological complications in SCD patients. We reviewed the hospital records of SCD patients for any incidental brain imaging (MRI brain or Computed Tomography(CT) brain) findings, done as inpatient or in the emergency room as part of hospital visits.Results: Out of the 100 patients, 14 patients had documented stroke. On the review of other 86 patients, 10 patients had MRI brain, 23 patients had CT brain, and 53 patients had no brain imaging record. Out of the 10 patients with MRI brain, 7 patient had significant findings- 3 patients had small vessel ischemic changes, 1 patient with chronic petechial hemorrhage of cerebellar vermis, 1 patient with ischemic changes and Chiari malformation type 1 (CTM 1), 1 patient with CTM 1 and non-specific white matter changes and 1 patient with CTM 1 alone. Out of the 22 CT of the brain and 1 CT angiogram of brain, 2 imaging showed ischemic changes and the angiogram showed large cerebral vessel narrowing. Therefore, on our review, 19 patients out of 100 were found to have stroke and 24 out of 100 had significant neurological findings. However, only 14 out of 19 patients had documented stroke. 7 out the 10 patients with MRI brain had significant incidental neurological findings. The number of adult SCD patients with neurological findings in our cohort could have been higher, if we had brain imaging record for the 53 other patients.Conclusion: This study shows that there is a heavy burden of neurological complications in SCD patients and SCI is under-diagnosed. MRI brain is superior to CT brain in detecting neurological complications in SCD patients. SIT showed that regular blood-transfusion significantly reduced the recurrence of cerebral infarct in children with SCI. Finding of SCI in adults also warrants consideration for follow up brain imaging, neurology referral and discussion of treatment modalities including chronic blood transfusion and hydroxyurea therapy. CTM 1 can also be associated with SCD. In CTM 1, tonsil herniates 5 millimeter or below foramen magnum. SCD may cause increased thickness of calvarium from extramedullary hematopoiesis in skull, which can result in cranio-cephalic disproportion with cerebellar ectopia and subsequent CTM 1. Because of high incidence of neurological complications in SCD patients, routine screening with MRI brain should be considered in adult SCD patients. DisclosuresIdowu: Forma Therapeutics, Inc.: Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ironwood: Research Funding.

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.

Study on the relationship between post-circulatory lesions and cerebral infarction in children with ischemic moyamoya disease

Objective To explore the relationship between post-circulatory lesions and cerebral infarction in children with ischemic moyamoya disease (MMD). Methods A total of 44 children with ischemic MMD who were admitted to Department of Neurosurgery, Tianjin Medical University General Hospital from January 2010 to December 2018 were retrospectively enrolled into this study. All of them were divided into cerebral infarction group (15 cases) and non-cerebral infarction group (29 cases) according to whether they had cerebral infarction or not. Three cases were treated with encephalo-myosynangiosis (EMS), 5 cases with superficial temporal artery-middle cerebral artery anastomosis bypass (STA-MCA bypass) and 36 cases with EMS+ STA-MCA. All children were followed up by outpatient visits or telephone and were asked about the improvement of clinical symptoms and whether there were any cerebral infarction events. The outcome was assessed by the modified Rankin scale score (mRS). The clinical efficacy was compared between the 2 groups of children. The clinical factors affecting the children with cerebral infarction were further analyzed by single factor and multiple factor logistic regression. Results All 44 patients underwent successful operation. Postoperative complications occurred in 12 cases (27.3%, 12/44). There was no statistically significant difference in the incidence of complications between 2 groups [40.0% (6/15) vs. 28.7% (6/29), P=0.615]. The follow-up duration of 44 cases was 7.2±1.5 months (6-12 months). During the follow-up period, none of the children had cerebral infarction. Among the 44 cases, 35 (79.5%) had good outcomes and 9 (20.5%) had poor outcomes. There was no statistically significant difference in the favorable prognosis rate between the 2 groups [66.7% (10/15) vs. 86.3% (25/29), P=0.130]. Single factor analysis showed that MCA stenosis, PCA (posterior cerebral artery) stenosis and transient ischemic attack before operation were the influencing factors of cerebral infarction in children (all P < 0.05). Further multiple factor analysis showed that PCA stenosis was an independent risk factor for cerebral infarction in children (OR=5.465, 95% CI: 1.224-24.400, P=0.026). Conclusion In children with ischemic MMD, PCA stenosis is an independent risk factors for cerebral infarction, and whether there is cerebral infarction has no significant effect on the prognosis of those children. Key words: Moyamoya disease; Child; Factor analysis, statistical; Post-circulatory lesions; Cerebral infarction

Clinical and imaging features of cerebral infarction in children

To summarize and analyze the etiology, clinical manifestations and imaging features of children with cerebral infarction. A retrospective analysis was performed for the clinical data of 54 children with cerebral infarction, including etiology, clinical manifestations, distribution of infarcts, type of infarcts and clinical outcome. Of the 54 children, 93% had a clear cause, among whom 46% had the coexistence of multiple factors, and the top three causes were infection (54%), vascular disease (40%) and trauma (26%). Major clinical manifestations included limb paralysis (85%), pyrexia (20%), disturbance of consciousness (19%) and convulsion (17%). As for the location of infarcts, 80% of the infarcts were located in the cerebral cortex and 52% in the basal ganglia. Major types of infarcts were small-area infarcts (74%) and multifocal infarcts (56%). Viral encephalitis was the most common cause of cerebral infarction caused by infection, with the cerebral cortex as the most common location of infarcts (21/23, 91%) and multiple infarcts as the most common type of infarcts (13/23, 57%). Among the 12 children with cerebral infarction caused by nonspecific endarteritis, 10 (83%) had infarcts located in the basal ganglia and only one child had multiple infarcts. Among the five children with cerebral infarction caused by moyamoya disease, four children (80%) had infarcts located in the cerebral cortex, and large-area infarction (4/5, 80%) and multifocal infarction (4/5, 80%) were the major types of infarcts. Among the children with traumatic cerebral infarcts, 92% had infarcts located in the basal ganglia, and small-area infarcts (92%) and single infarcts (85%) were the major types of infarcts. Among the 46 children with limb paralysis, 34 (74%) had infarcts located in the basal ganglia; 50% of the children with disturbance of consciousness had infarcts located in the basal ganglia. Subcortical infarcts were observed in all six children with epilepsy. Seventy-five percent of the infarcts located in the cerebral cortex and 87% of the infarcts located in the basal ganglia had a good prognosis. Among the two children with cerebral infarcts located in the brainstem, one had the sequela of hemiplegia and the other had the sequela of cognitive impairment. Eighty-eight percent of the children with cerebral infarction caused by infection and 82% of the children with traumatic cerebral infarction tended to have a good prognosis, and 83% of the children with cerebral infarction caused by nonspecific endarteritis had good prognosis. Recurrence was observed in all three children with cerebral infarction caused by vascular malformations. Of the five children with cerebral infarction caused by moyamoya disease, one child died and four children survived with the sequela of localized brain atrophy, among whom one child also had the sequela of epilepsy. Infection, vascular disease and trauma are the most common causes of cerebral infarction in children, and limb paralysis is the most common clinical manifestation. Cerebral cortex is the most common infarct site, and small-area infarcts and multifocal infarcts are the most common types of infarcts, which tend to have a better prognosis.

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

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

Different response to antiepileptic drugs according to the type of epileptic events in a neonatal ischemia-reperfusion model

Perinatal arterial stroke is the most frequent form of cerebral infarction in children. Neonatal seizures are the most frequent symptom during the neonatal period. The current management of perinatal stroke is based on supportive care. It is currently unknown if treatment of the seizures modifies the outcome, and no clinical studies have focused on seizures during neonatal stroke. We studied the effect of phenobarbital and levetiracetam on an ischemic-reperfusion stroke model in P7 rats using prolonged electroencephalographic recordings and a histologic analysis of the brain (24h after injury). The following two types of epileptic events were observed: 1) bursts of high amplitude spikes during ischemia and the first hours of reperfusion and 2) organized seizures consisting in discharges of a 1–2Hz spike-and-wave. Both phenobarbital and levetiracetam decreased the total duration of the bursts of high amplitude spikes. Phenobarbital also delayed the start of seizures without changing the total duration of epileptic discharges. The markedly limited efficacy of the antiepileptic drugs studied in our neonatal stroke rat model is frequently observed in human neonatal seizures. Both drugs did not modify the stroke volume, which suggests that the modification of the quantity of bursts of high amplitude spikes does not influence the infarct size. In the absence of a reduction in seizure burden by the antiepileptic drugs, we increased the seizure burden and stroke volume by combining our neonatal stroke model with a lithium-pilocarpine-induced status epilepticus. Our data suggest that the reduction of burst of spikes did not influence the stroke volume. The presence of organized seizure with a pattern close to what is observed in human newborns seems related to the presence of the infarct. Further research is required to determine the relationship between seizure burden and infarct volume.

Factors Affect on development and clinical course of ischemic stroke in children

Child strokes cause persistent neurologic impairment affecting on quality of life. Prophylaxis cerebral infarction in children promoted by Identification of factors influencing on development of ischemic stroke. 47 children with arterial ischemic stroke confirmed by MRI or CT was enrolled in cohort study. All children has focal neurological symptomatic which was assessed by pedNIHSS, PSOM, British muscular strength scale. General cerebral symptoms precede focal neurologic impairments in 67% cases. Fact of head trauma was documented in 55% observed children. Seizures occurs in 24% cases in acute period ischemic stroke. As major part of children had lacunar infarction in middle cerebral artery origin, so motor dysfunctions was admitted in clinical curse of general cases. By neuroimaging data we defined lacunar infarctions mainly in basal ganglia, thalamus and internal capsule. In the rest 5 cases - in cortex, white matter, frontal, parietal and occipital lobes, cerebellum and brain stem. In 10 children during observation over time the secondary haemorrhage at ischaemic site was detected. Besides post-ischemic alterations additional structural features was assessed in neuroimaging study. Calcification in white mater of brain was reviled in one third children with ischemic stroke (33,4%). Overwhelming majority calcifications in white mater of brain was diagnosed in lenticular-striatal arteries infarctions. Latent factors structure influenced on severity neurologic outcomes was received by partial least square method (PLS). Acquired data emphasize importance of mind depression, vertigo, dysphagia as poor outcome predictors.

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.

Silent Cerebral Infarcts and Cerebral Aneurysms Are Prevalent in Adults with Sickle Cell Disease

Introduction: Neurologic complications are a major cause of morbidity in sickle cell disease (SCD). The cumulative cerebral risk for neurological complications in sickle cell anemia has been estimated around 50% by age 14 (Bernaudin et. al, 2011;Blood 4:1130-40). Silent cerebral infarcts (SCI), is the most commonly recognized cause of neurological injury, associated with cognitive difficulties (King et al, Am J Hematol 2014;89:162-7) found in 20-40% of children with SCD, more common in genotype SS or Sβ0 thalassemia. The prevalence of SCI has not been well studied in adults. The prevalence of intracranial saccular aneurysms by radiographic and autopsy series is estimated to be 3.2% in a population without comorbidity, a mean age of 50 years, and a 1:1 gender ratio. (Valk et al, Lancet Neurol 2011; 10: 626–36) while other investigators found a 1.8% prevalence and no increased incidence with age (Vernooij et al NEJM 2007;357:1821-8). The goal of this study was to assess the prevalence of neurologic morbidity, including SCI, overt stroke, and cerebral aneurysm, in a large cohort of adults with SCD. We hypothesized the SCI would be more prevalent in adults compared to children with SCD.Methods: Due to the high prevalence of cerebral infarcts in children with SCD, we elected to obtain as part of routine clinical practice, a MRI and magnetic resonance angiography (MRA) of the brain in adultswith SCD in our Hematology clinic. As standard care if SCIs are seen, neurocognitive testing is recommended, and based on this testing and MRI results, appropriate patients are referred for vocational rehabilitation service. All MRIs and MRAs were reviewed by 2 board certified neuroradiologists and consensus findings were recorded including presence of cerebral infarcts, intracerebral hemorrhage, aneurysms and cerebralvasculopathy. All adults with SCD were followed by a single hematologist and were asked about neurological symptoms. Medical records were reviewed to see if stroke like symptoms had been reported. If no symptoms were reported and no abnormalities were documented on neurological examination, then infarcts were judged to be silent.Results: The study population included 94 adults with SCD (80% HbSS or Hb Sβ0 thalassemia; 11% HbSC, and 9% other), 51% males, median age 26 years, interquartile range (22-36 years) who had MRI of the brain and 88 had MRA of the brain. Of these, 91 MRIs were of sufficient quality to assess for the presence or absence of infarcts. Infarcts were present in 58% (53 individuals) with multiple infarcts in 40% (37 patients); infarcts were overt/symptomatic in 13% (12) and silent in 45% (41). Hemorrhages were present in 8 patients (9%) and of these, 7 of 8 also had infarcts present on MRI. MRI and MRA of the brain were felt of adequate quality to assess for vascular disease or aneurysm in 79 patients. Of these 7.5% (6 of 79 patients) had moyamoya vasculopathy and 7.5% (6 of 79 patients) had saccular aneurysms with no overlap between groups. All of the adults with moyamoya vasculopathy had overt strokes. The aneurysms were incidental findings and all were <5mm in size. Patients were referred to Neurosurgery for evaluation of aneurysmal lesions. Amongst the 12 adults with a history of overt stroke, 67% were on therapy (50% on hydroxyurea therapy; 17% on chronic blood transfusion therapy), 42% (5 of 12) received aspirin for stroke and 1 patient was already on warfarin for history of systemic thrombosis at the time of stroke.Conclusions: Silent cerebral infarctions are common in adults with SCD. Silent cerebral infarcts were present in 45% and over strokes had occurred in 13% of adults with SCD. Our aneurysm prevalence of 7.5% in a younger cohort (median age 26 years) suggests that adults with SCD may have a higher prevalence of cerebral aneurysms than the general population. Further study is warranted to assess whether SCD should be considered a comorbidity that confers a higher risk of cerebral aneurysm in adults. The optimal strategies for primary and secondary stroke prevention and to mitigate against the progressive cerebral vasculopathy in adults with SCD are still being debated. DisclosuresNo relevant conflicts of interest to declare.

Controlled Trial of Transfusions for Silent Cerebral Infarcts in Sickle Cell Anemia

BackgroundSilent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.MethodsIn this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.ResultsA total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).ConclusionsRegular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.)

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