Presence Of Silent Cerebral Infarction Research Articles

5612627 MORTALITY, CHRONIC MORBIDITY AND INTENSITY OF TREATMENTS IN A NATURAL HISTORY COHORT OF SICKLE CELL DISEASE

Background: While many advances have been made in the understanding of Sickle Cell Disease (SCD) in the past decades, the natural history of the disease is often elusive due to lack of long-term prospective data collection (1). The SCD Natural History Study is a longitudinal follow-up study. During the 15 years of the study, the Italian Association of Pediatric Hematology Oncology (AIEOP) guidelines were used to standardize treatment with Hydroxyurea (HU), red blood cell transfusion and Hematopoietic Stem Cell Transplantation (HSCT) as well as management of acute and chronic complications (2). Aims: To describe mortality, chronic morbidity and intensity of treatments in a pediatric natural history cohort. Methods: Since 2007 all pediatric patients with SCD followed in the Pediatric SCD Reference Center of Padua were enrolled. Data on physical examination, acute/chronic complications and laboratory parameters were prospectively recorded at every outpatient and inpatient visit since diagnosis. Results: 197 children and adolescents with SCD were enrolled and 182 patients had clinical, hematological and organ damage monitoring information as of 31/12/2020. The mean follow-up is 79.8 months (range 2.1-298.6) (IQR 36.9-126.3). Females were 51%, mean age at diagnosis was 39.0 months (range 0-228.4), with only 31% diagnosed before the first year of life and 18% before the 2nd year, due to the lack of national universal newborn screening. 83% were HbSS/SB°, 14.8% SC, 2.2% SB +; 83% came from Sub-Saharan Africa, 9.3% from Europe. 44.5% had chronic comorbidities, the most frequent being: neurological manifestations, asthma and wheezing, gallbladder stones. As of 12/31/2020, 117 were in follow-up and treatment, 57 had transferred abroad or to other national centers, 4 had been lost to follow-up and 4 deceased (3 due to Pneumococcus septic shocks, 1 for a trauma accident). 67% of children required disease-modifying therapies in various combinations (44% HU, 2.2% transfusion regimen, 10% HU and transfusions, 10.8% HSCT after having performed HU and/or transfusion regimen) showing the need for intensive treatments to control the symptoms of the disease (mainly recurrent Vaso-Occlusive Crisis or Acute Chest Syndrome, Anemia or Cerebral Vasculopathy); 16/182 required enrollment in clinical trials with new drugs due to lack of persistent response to HU or chronic transfusion. The treatment with HU, although prescribed according to the national guidelines only to children with clinical manifestations (for anemia, VOC or ACS), was effective in increasing Hemoglobin (9 vs 8.3 g/ dl, p <0, 0001), reducing hemolysis indices and lowering the incidence of neurological complications overall (abnormal/conditional TCD or presence of silent cerebral infarcts on MRI or stenosis on MRA) with EFS 89.1 (95% CI 81.2-93.8) in those who performed HU within 5 years of diagnosis vs 65.6 (95% CI 51.2-76.6) in those who did not (p<0,0001) (Figure 1).However, 11% of the children still present significant neurological complications 5 years after diagnosis in spite of undergoing HU, thereby in need of more intensive treatment to reduce the cerebrovascular complications which in our cohort appear to develop early. Conclusion: Long-term data collection in our setting indicates that, in spite of being offered highly specialized monitoring and treatment options, a subgroup of children still displays significant organ damage and would require intensified treatment in early age.

Quantifying Dilated Perivascular Spaces in Children with Sickle Cell Disease

Introduction: The neurological complications of sickle cell disease (SCD) are particularly devastating and range from "overt stroke" to cerebral small vessel disease (CSVD), including silent cerebral infarction (SCI) and cognitive deficits despite the absence of magnetic resonance imaging (MR)-detectable evidence of cerebral injury. This suggests the possibility of additional, possibly covert, mechanisms of injury. Perivascular (Virchow-Robin) spaces (PVS) are fluid filled spaces that surround cerebral vessels penetrating or leaving the brain parenchyma and become visible when enlarged (dilated), due to inflammation or hypertension. The presence of dilated PVS (dPVS) in the basal ganglia (BG) and centrum semiovale (CO) are rare in children and have been associated with multiple neurodegenerative and neuroinflammatory disorders in aging populations. dPVS in the BG specifically are associated with CSVD, while those in the CO are associated with neuroinflammation. However, until now, the presence of dPVS has not been studied in either adults or children with SCD. Our overall objectives were to use MR images from children who were screened and/or participated in the Silent Cerebral Infarct Treatment in SCD (SIT) trial to 1) determine the burden of dPVS in children with SCD, specifically within the basal ganglia and centrum semiovale, and 2) correlate these findings with other markers of CSVD, specifically silent cerebral infarctions. Methods: The SIT trial was a multicenter, randomized clinical trial that evaluated the effect of monthly chronic transfusions to prevent the development of new SCI in children with SCD. As part of the enrollment process, all children underwent an initial MRI. We used both the Wardlaw (currently used as part of the international consensus criteria for evaluating CSVD) and Rotterdam criteria to quantify dPVS burden on T2-weighted screening MR images for 340 participants from the SIT trial. Briefly, both rating scales evaluate dPVS in the BG, CO, and midbrain (MB); the Rotterdam criteria also includes the hippocampus. The Wardlaw criteria categorize dPVS on an ordinal scale from 0 (none) to 4 (> 40) in the BG and CO and 0 or 1 point (absent or present) for the MB, with a total score of 9 as the maximum dPVS burden from all 3 brain regions. The Rotterdam criteria uses a semi-continuous scale and specifies counting dPVS to a total of 20 for each region for a maximum combined dPVD burden score of 80. Additional variables in our analysis were participant's age, hemoglobin, total white blood cell (WBC) count, and presence of SCI at baseline. We categorized dPVS burden score from the Wardlaw rating scale into low (0-2), medium (3-4), and high ( 5) and performed an ordinal multivariate logistic regression with age, sex, presence of SCI, hemoglobin, and total WBC count as independent variables. Results: We completed the two dPVS rating scales on 340 initial (screening) MR images from 340 children screened for the SIT trial, with a median age of 8.3 years (range 5 - 15 years). Eighty-eight (26%) had evidence of at least one SCI. The mean hemoglobin was 8 ± 1.1 g/dL and total WBC count was 12,000 ± 4200 cells/ml. The mean dPVS burden score from the Wardlaw criteria was 3.7 ± 1.7, while for the Rotterdam criteria, the mean was 32 ± 14 (Table). Global and regional dPVS scores from the two rating scales were well correlated (p < 0.001, r = 0.72 - 0.8). dPVS score in the BG and CSO was moderately correlated (p < 0.001, r = 0.45). There was no significant sex difference in dPVS burden (mean Wardlaw rating: males = 3.9 versus females = 3.6, p = 0.08). Multivariate analysis show that increasing age was associated with dPVS burden (p = 0.005), as was increasing hemoglobin, which showed a trend towards association (p = 0.06), potentially due to increased pressure within microvasculature, resulting in extravasation of fluid into the surrounding space. Surprisingly, presence or size of SCI were not associated with dPVS burden. Conclusions: Children with SCD have evidence of more than expected dilated perivascular spaces compared to not only healthy children but also adults, which increase with age. Although likely involved in neurological injury, dilated PVS in children with SCD do not appear to be associated with the presence of CSVD phenotypes such as SCI. We reasoned that in SCD, dPVS may be sequelae of underlying neuroinflammation. Future studies are needed to examine correlation of dPVS with biomarkers of neuroinflammation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Does TGFBR3 Polymorphism Increase the Risk of Silent Cerebral Infarction in Egyptian Children with Sickle Cell Disease?

ObjectivesTo evaluate the relationship between TGFBR3 rs284875 single nucleotide polymorphism (SNP) state and silent cerebral infarction (SCI) in asymptomatic patients with sickle cell disease (SCD).MethodsA cross-sectional study was conducted on 50 children with SCD above 2 y of age followed up at the hematology outpatient clinic of Alexandria University Children's Hospital in Egypt. Twenty-four healthy children were included as a control group. All patients included in the study were subjected to complete history and clinical examination. Real-time polymerase chain reaction was performed on patients and controls for identification of SNP rs284875 of the TGFBR3 gene. A magnetic resonance imaging (MRI) of the brain were performed only on patients for detection of SCI.ResultsFifty SCD patients were enrolled (26 males and 24 females), with a median age of 10.9 y (2.3–17.8 y), and 24 children as healthy control for the studied SNP. Thirty-five (70%) patients had homozygous SCD, while 30% had sickle β-thalassemia. The brain MRI was normal in all the patients except for 2 patients who had features of SCI. The TGFBR3 rs284875 SNP was detected in 15 (30%) patients in the homozygous state (GG) versus only 1 (4.2%) child from the control group (p = 0.003). The prevalence of SCI was low in the study population and there was no statistically significant relationship between the TGFBR3 rs284875 SNP status and the presence of SCI in the brain MRI (p = 0.621).ConclusionsThis study confirmed a low prevalence of SCI in the SCD patient included in the study. The TGFBR3 rs284875 SNP did not significantly increase SCI among those patients.

Stroke Recurrence in First-Ever Symptomatic Carotid Web: A Cohort Study.

Background and Purpose Carotid web (CaW) is an intimal variant of fibromuscular dysplasia responsible for ipsilateral cerebral ischemic events (CIE). Symptomatic CaW likely has a high risk of recurrent CIE, but no salient prospective data are available. We aimed to assess recurrence rate and its predictors after a first-ever CIE. Methods Consecutive Afro-Caribbean patients who had cryptogenic first-ever CIEs (ischemic stroke [IS] or transient ischemic attack [TIA]) associated with ipsilateral CaW were included in this multicenter observational cohort study. The follow-up (January 2008 to March 2019) focused on CIE recurrences. Kaplan-Meier method assessed rates of recurrences and Cox proportional hazards regression analyzed risk factors. Results Ninety-two patients (79 first-ever ISs and 13 TIAs; mean age±standard deviation, 49.8±9.9 years; 52 [56.5%] women) were included. During a mean follow-up of 50.5±29.6 months, 19 (20.7%) patients experienced recurrent ipsilateral CIEs (16 ISs and three TIAs). Of 23 patients receiving surgery/stenting treatment, no recurrence occurred after the intervention (median follow-up, 39.8 months [interquartile range, 27.6 to 72.4]). Under medical treatment alone, the annual recurrent CIE rate was 6.9%, and the cumulative rate was 4.4% at 30-day, 10.8% at 1-year, 19.8% at 2-year, 23.2% at 3-year, and 27.3% at 5-year. Presence of silent cerebral infarctions was the only independent risk factor of CIE recurrences (hazard ratio, 6.99; 95% confidence interval, 2.4 to 20.4; P=0.004). Conclusions Under medical treatment alone, symptomatic CaW was associated with a high rate of recurrence that reached 27.3% at 5-year. Surgery/stenting seems to be efficient, and randomized control trials are required to confirm the benefit of these interventions.

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.

Silent Cerebral Infarcts in Sickle Cell Disease: A Systematic Review

Introduction The most common neurological finding in children and adults with sickle cell disease (SCD) is the presence of silent cerebral infarcts (SCIs). SCIs are, by definition, undetectable by neurologic examination and are recognized on magnetic resonance imaging (MRI) as increased signal intensity in multiple T2-weighted images (1). SCIs are associated with a decline in full-scale IQ (2, 3) and increased risk for future strokes (4). In this paper, we provide an overview of studies that have used magnetic resonance imaging (MRI) to detect SCIs in patients with SCD. We systematically review evidence on SCI prevalence, incidence and associated risk factors. Methods A comprehensive systematic search was performed of Embase, MEDLINE, Cochrane, Web of Science and Google Scholar. Publications through June 1st, 2019 were included. Search terms included synonyms for 'SCIs' and 'SCD' in various combinations. All references listed in identified papers, or noted in footnotes of data tables, were reviewed for additional articles missed by computerized database search. After removal of duplicates, 651 studies were screened on potential eligibility. Studies were included if they concerned patients of all ages with either homozygous or compound heterozygous SCD and assessed for and specifically reported MRI-detected SCIs (Figure 1). We present a weighted prevalence by study size. When multiple articles reported on a single or overlapping population sample, prevalence estimates were obtained from the article with the largest sample size to prevent duplications. Results We included 61 original papers describing results in a total of 3740 individual SCD patients. Most studies were performed in HbSS or HbSβ0thal SCD patients (n=2122). However, five studies separately reported SCI prevalence in other SCD genotypes i.e. HbSC, HbSβ+thal (n=254) and healthy controls (n=52). The pooled prevalence of SCI among all included patients with SCD (n=3740) was 28.4% (95% CI: 4.0;32.9). Data from included studies showed a statistically significant correlation (P&lt;0.001) between mean SCI prevalence % and increasing mean patient sample age (Figure 2). SCIs were more common in patients with HbSS/HbSβ0thal compared to other SCD genotypes (p&lt;0.001) and healthy controls (P&lt;0.001) (Figure 3). Studies focusing on incidence rates were sparse, with only four identified studies providing estimates ranging from 3.1% to 13.6% per year. The majority of included studies analyzed possible risk- or protective factors for SCI in SCD patients, i.e. hematological parameters, α-thalassemia presence and cerebral blood flow velocity (Table 1). Conflicting results are noted for most risk- and protective factors, with equal numbers of similar studies finding significant versus non-significant associations. Conclusions SCIs are common in patients with SCD with a weighted prevalence of 28.4%. Despite advancing neuroimaging technologies and therefore potentially enhanced detection of SCIs, there has been no apparent rise in SCI prevalence over the years. SCIs occur much more frequently in individuals with HbSS or HbSβ0thal than in other SCD genotypes. Analyses of risk- and protective factors showing varying results. The absence of robust findings is probably due to a combination of small sample sizes and weak associations. We believe SCIs are a poorly understood entity in patients with SCD. Despite substantial research efforts into risk- and protective factors, too little attention has been given to underlying pathophysiological mechanisms. Further research should focus on both SCI etiology in SCD as well as on clinical management of patients with evidence of these MRI lesions. Disclosures Cnossen: Pfizer: Other: Travel Grants, Research Funding; Bayer: Other: Travel Grants, Research Funding; Novo Nordisk: Research Funding; Nordic Pharma: Research Funding; CSL Behring: Other: Travel Grants, Research Funding; Sobi: Research Funding; Baxter: Other: Travel Grants, Research Funding; Shire: Other: Travel Grants, Research Funding; Takeda: Other: Travel Grants, Research Funding; Roche: Other: Travel Grants; NWO: Other: Governmental grants , ZonMW, Innovation fund and Nationale Wetenschapsagenda 2018.

Silent Cerebral Infarcts Following Left-Sided Accessory Pathway Ablation in Wolff-Parkinson-White (WPW) Syndrome: A Preliminary Report

BackgroundCatheter ablation is a routine procedure in patients with WPW syndrome. Silent cerebral infarcts (SCI) detected in magnetic resonance imaging may be a complication of the ablation procedure, but it is well documented only in atrial fibrillation ablation. Ablation of left-sided accessory pathways (L-AP) has a similar target area, but WPW patients differ from those with atrial fibrillation, due to lower initial risk of cerebral embolic events. The aim of this study was to determine whether the ablation of left-sided accessory pathways carries the risk of SCI.Material/MethodsTwenty consecutive patients with overt L-AP referred for RF ablation in our center were included in the study. An irrigated ablation catheter was used in 8 patients, and a non-irrigated ablation catheter was used in 12 patients. Diffusion-weighted magnetic resonance imaging was performed pre-procedurally and on the next day after the ablation in all patients.ResultsAblation procedures were completed without complications and there were no neurological symptoms following the procedure, although in 2 patients (10%), post-procedural diffusion-weighted magnetic resonance revealed new acute silent cerebral infarcts. Both patients with new cerebral lesions were female, and a non-irrigated catheter was used in both cases.ConclusionsThis is the first study documenting the presence of silent cerebral infarcts after WPW ablation. Further investigations are needed to evaluate the risk of silent cerebral infarcts associated with L-AP ablation.

Neuroimaging findings in midlife and risk of late-life dementia over 20 years of follow-up.

To examine the association between neuroimaging features in a predominantly middle-aged cohort and risk of late-life dementia. Cerebral MRI was performed on 1,881 individuals with no history of stroke from the Atherosclerosis Risk in Communities Study cohort in 1993 to 1995. White matter hyperintensities (WMH), ventricular size, and sulcal size were graded on a semiquantitative scale, and presence of silent cerebral infarcts was identified. In 2011 to 2013, dementia was determined from neuropsychological testing, informant interview, hospital ICD-9 codes, and death certificate dementia codes. Cox regression was used to evaluate associations between MRI findings and dementia. Over 20 years of follow-up, dementia developed in 279 participants (14.8%). High-grade WMH and high-grade ventricular size were independently associated with increased dementia risk (hazard ratio [HR] for WMH 1.62, 95% confidence interval [CI] 1.14-2.30; HR for ventricular size 1.46, 95% CI 1.06-2.03). There was an increased risk of dementia for diabetic participants with silent infarcts (HR 2.56, 95% CI 1.23-5.31) but not among nondiabetic participants (HR 0.87, 95% CI 0.56-1.37). Each 1-unit increase in the total number of high-grade cerebral abnormalities at baseline (count values range 0-4) showed increased dementia risk, with a considerably higher risk among diabetic participants (HR for diabetes mellitus 1.97, 95% CI 1.44-2.69; HR for no diabetes mellitus 1.20, 95% CI 1.03-1.39). In adults without evidence of clinical stroke, MRI-detected WMH and ventricular enlargement in midlife may represent markers of brain injury that increase risk for later-life cognitive impairment. The presence of diabetes mellitus may modify the association between silent infarcts and dementia.

Cerebral Infarcts and Cerebrovascular Disease in Neurologically Intact Tanzanian Children with Sickle Cell Anaemia

Introduction:Children and adolescents with sickle cell anemia (SCA) without history of neurological manifestations remain at risk of stroke and require cost effective screening as evidence-based stroke prevention interventions are developed. Although there are data on the prevalence of Transcranial Doppler (TCD) abnormality, there are relatively few studies on the prevalence of silent cerebral infarction (SCI) on magnetic resonance imaging (MRI) and vasculopathy on MR angiography (MRA), paricularly in Africa, where the burden of disease is greatest. In this study in Africa, we determined the prevalence of SCI on MRI and cerebral vasculopathy on MRA, and explored associations with age, sex, internal carotid/middle cerebral artery (ICA/MCA) and basilar cerebral blood flow velocities (CBFV) on TCD, and hematological variables.Patients and methods:We prospectively studied children with homozygous SCA (HbSS) without prior clinically overt stroke or TIA or seizures. Clinical information and blood for full blood count was collected for all patients. All were offered TCD using non-imaging equipment (Compumedics) and MRI and MRA of intracranial arteries on a Philips 1.5 Tesla scanner. MRA was graded as 1 Turbulence, 2 Stenosis, 3 Occlusion, 4 Occlusion with collaterals (moyamoya). Imaging was reviewed by 2 neuroradiologists (MJ and DS) and consensus was reached.Results:Within a period of 12 months, 395 children with SCA were recruited. Mean age was 12.7+/-4 (range 5-19 years); 199 (50.4%) were male. Mean hemoglobin was 7.6±1.1 (range 4.1-13.5) g/dl. 381 had TCD, of whom 227 (57%) have had brain MRI and MRA so far.Only 14/395 (3.5%) of patients had abnormal CBFV, 8 (2%) with maximum CBFV <50 cm/sec, 3 with CBFV 150-169 cm/sec, 1 with conditional (170-199 cm/sec) and 2 (0.5%) with abnormal CBFV (>200cm/sec).Prevalence of silent cerebral infarction was 29% (65/227) and was similar in males (30%; 34/114) and females (28%; 31/110) but was lower in children aged <9 years (20%; 10/51) than in those aged 10-14 years (33%; 27/83) or those aged 15-19 years (32%; 28/89); this was not significant (p=0.2).The prevalence of cerebral vasculopathy on MRA, defined as stenosis (Grade 2), occlusion (Grade 3) or occlusion with collaterals (moyamoya; Grade 4), was 9% (20/227). The internal carotid and/or middle cerebral artery was affected in all 20 and the anterior cerebral artery was affected in 7 patients. Vasculopathy was not observed on MRA in the posterior cerebral artery and no patients had moyamoya. An additional 9 (4%) patients had turbulence (Grade 1) in at least one artery on MRA.SCI were more common in those with MRA vasculopathy Grades 2-3 (12/64; 19%) and in those with Grade 1 Turbulence (2/9; 22%) than in those with normal MRA (8/165; 5%) (p<0.05). Patients with Grade 1 Turbulence had higher ICA/MCA CBFv (mean 122+/-36 cm/sec) than those with normal MRA (mean 101+/-25 cm/sec) or Grades 2-3 (mean 109+/-21 cm/sec) vasculopathy. The difference in those with Grade 1 turbulence compared with those with normal MRA was significant (mean difference 20 cm/sec, 95% confidence intervals 1, 39 cm/sec; p=0.037). Basilar velocity was also significantly higher in those with Grade 1 turbulence (87+/-21 cm/sec) than in those with normal MRA (76+/-14 cm/sec) and those with Grade 2-3 vasculopathy (80+/-11 cm/sec)(mean difference 11.5 cm/sec, 95% confidence intervals 0.3, 22.6 cm/sec; p=0.043). Basilar velocity weakly correlated with hemoglobin (r=-0.18) but the relationships between hemoglobin and ICA/MCA CBFV or either presence of SCI or MRA abnormality were not significant.Conclusions:The prevalence of SCI on MRI is high in children with SCA without neurological history living in Africa even when TCD CBFV is normal. Children and adolescents with all grades of vasculopathy on MRA are at higher risk of brain parenchymal injury. The lack of association between SCI and hemoglobin may be related to the relatively severe anemia in our African study. As MRA contrast depends on velocity of blood flowing in vessels, it is not surprising that Grade 1 turbulence on MRA appears to reflect high CBFV on TCD. Importantly, high TCD velocity and Grade 1 turbulence may reflect the potentially reversible early stages in the development of SCA vasculopathy when cerebral blood flow is high before stenosis and occlusion supervene. TCD is operator dependent and there may be a case for MRI and MRA screening if follow-up shows that these measures predict stroke. DisclosuresNo relevant conflicts of interest to declare.

Silent infarct is a risk factor for infarct recurrence in adults with sickle cell anemia.

Because of the high prevalence of silent cerebral infarcts (SCIs) in adults with sickle cell anemia (SCA) and lack of information to guide treatment strategies, we evaluated the risk of recurrent SCIs and overt stroke in adults with SCA with preexisting SCI. This observational study included adults with SCA (HbSS or Sβ0 thalassemia) aged 18 to 40 years. Participants received 3-tesla brain MRI and a detailed neurologic examination. Time-to-event analysis assessed those with or without baseline SCI and with new or progressive infarcts. The incidence rate of new events was compared by log-rank test. Univariable Cox regression assessed the association of SCI with infarct progression. Among adults with SCA with 2 MRIs and at least 6 months between MRIs (n = 54, mean interval = 2.5 years), 43% had SCI at baseline. Of participants with baseline SCI, 30% had new or progressive SCI over 2.5 years compared to 6% with no SCI at baseline; no participant had an overt stroke. New SCIs at follow-up were present in 12.9 per 100 patient-years with existing SCI compared with 2.4 per 100 patient-years without prior SCI (log-rank test, p = 0.021). No statistically significant differences were seen among those with or without baseline SCI in use of hydroxyurea therapy, hydroxyurea dose, or other stroke risk factors. The presence of SCI was associated with increased hazard of a new or progressive infarct (hazard ratio 5.27, 95% confidence interval 1.09-25.51, p = 0.039). Silent infarcts in adults with SCA are common and are a significant risk factor for future silent infarcts.

A role of insomnia in the development of silent cerebral infarctions

To investigate the relationship between insomnia, hemostatic abnormalities and silent cerebral infarctions. A complex study of 76 male patients, aged 40-85, with vascular risk factors was carried out. Magnetic resonance imaging (MRI) data was used to verify presence of silent cerebral infarctions; the presence and severity of insomnia were determined using questionnaires and polysomnography. Laboratory diagnosis included a complete assessment of hemostatic system with thrombodynamics test. Patients were divided into 2 groups according the MRI data. The 1st group included 20 men with less than 4 silent cerebral infarctions, the 2nd group 56 men with multiple silent cerebral infarctions - from 5 to 25. Chronic insomnia was diagnosed in 35 (46%) of patients, more frequently in the second group (25% and 54% respectively, p<0.05). The group of patients with multiple silent infarctions demonstrated a loss of sleep efficiency and hypercoagulation with an increased rate of clot growth in thrombodynamics test. Correlation analysis confirmed the dependence between sleep efficiency and quantity of vascular sites, sleep efficiency and clot growth rate. The more severe plasma haemostasis disorder in patients with multiple silent infarctions and relation between insomnia severity and plasma haemostasis activation suggest that insomnia can be an additional risk factor of arteriole thrombosis.

Targeting on Morning Blood Pressure Surge

Morning blood pressure surge (MBPS) is an independent predictor of cardiovascular events. The most common definition of MBPS was a pre waking surge (mean blood pressure for 2 hours after wakeup minus mean blood pressure for 2 hours before wake-up). The sympathetic nervous system plays a major role in the regulation of BP variability. Asleep blood pressure has been shown to better reflect cardiovascular risk than awake BP in hypertensive patients. A possible link was found between disturbed sleep and MBPS. Exaggerated MBPS and increased low-grade inflammation independently increase the risk of stroke, while the relationship between exaggerated MBPS and the presence of silent cerebral infarct is slightly affected by low-grade inflammation. Furthermore, type 2 diabetes mellitus was an independent risk factor for increased MBPS. Serum uric acid, low density lipoprotein-cholesterol, anxiety disorder and so on may also involve in MBPS. Telmisartan was shown to normalize the circadian blood pressure pattern to a dipper profile in a larger proportion of patients than ramipril, and reduce early-morning systolic blood pressure surge in high-risk patients. Telmisartan alone or with HCTZ improved morning high blood pressure control and maintained a smooth high blood pressure profile throughout the day in a real-life setting. Furthermore, once-daily dosing of valsartan results in equally effective 24-hour blood pressure efficacy, regardless of dosing time. In total, future studies specifically designed to evaluate the real impact of MBPS on outcomes, as well as to define its optimal cutoff value, are required.

Correlation Between Cerebral Blood Flow Velocities Measured By Magnetic Resonance and Transcranial Doppler Ultrasound in Children with Sickle Cell Anemia

BackgroundTranscranial Doppler (TCD) ultrasonography is the standard stroke screening test for children with sickle cell anemia (SCA). However, approximately 10% of children have inadequate ultrasonographic windows for a successful TCD study, and some clinical sites may lack the equipment or personnel to perform TCDs in children. Magnetic resonance imaging (MRI) techniques can also measure blood flow velocities and could substitute for TCD in these clinical scenarios. We tested the hypothesis that MRI-derived middle cerebral artery (MCA) blood flow velocities would correlate with TCD-derived MCA blood flow velocities in children with SCA.MethodsChildren age 6 years and up with SCA at their baseline state of health underwent TCD and MRI as part of a prospective clinical study. Imaging TCD of the bilateral MCAs to determine time-average mean of maximum blood flow velocities (TCD-CBFV) were performed using clinical ultrasound equipment. MRIs were performed at 3T without sedation. MRI cerebral time-averaged mean blood flow velocities (MR-CBFV) were measured in the MCAs using phase contrast sequences without cardiac cycle gating to shorten acquisition time and reduce ghosting artifacts. TCD- and MR-CBFV of each hemisphere were compared. Silent cerebral infarctions (SCIs) were categorized as present or absent in each hemisphere. Non-parametric tests were used with a level of significance of <0.05. Statistics were performed in SPSS version 21.ResultsTwenty hemispheres from 15 children had both TCD-CBFV and MR-CBFV measurements. Median age was 9 years (IQR 6.25-10). In these children, two hemispheres had unobtainable TCDs due to skull thickness, and eight hemispheres had MR-CBFV excluded due to patient motion or poor positioning. The median TCD-CBFV was 116 cm/sec (IQR 90.25-124) and none of the included hemispheres had arterial stenosis or TCD-CBFV in the conditional or abnormal range. Eight included hemispheres were from children receiving chronic blood transfusion therapy for primary or secondary stroke prevention. There was a linear relationship between TCD-CBFV and MR-CBFV (Spearman correlation, ρ=0.781, p<0.001, Figure) although MR-CBFV values were lower than TCD-CBFV values (median difference 32.6%, IQR 26.7-42.8). When evaluating only the children not receiving chronic transfusion therapy, MR-CBFV was significantly higher in 8 hemispheres without SCIs (median 80 cm/sec, IQR 77.8-87.8) than in 4 hemispheres with SCIs (median 60 cm/sec, IQR 44.6-72.3, p=0.004). In a multivariate model adjusting for age, MR-CBFV continued to be associated with presence of SCIs (p=0.036). There was no significant difference in TCD-CBFV when analyzed by SCI status (p=0.2), consistent with published studies of TCD-CBFV and SCIs.ConclusionsIn this small cohort of children with SCA, MR-CBFV correlated significantly with TCD-CBFV, but MR-CBFV values were approximately 30% lower than TCD-CBFV. This may be due to the method of acquiring MR-CBFV via non-gated methodology, which is known to produce lower blood flow velocity estimates. Further work is needed to determine a threshold for high-risk MR-CBFV values before this modality could be used as a substitute for TCD screening. Lower MR-CBFV was associated with SCIs, suggesting a potential role for MR-CBFV in predicting SCI risk. The relationship between MR-CBFV and SCIs should be explored further. [Display omitted] DisclosuresHulbert:Pfizer, Inc.: Other: spouse employment. Fields:NeuroPhage Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

High incidence of silent cerebral infarcts in adult patients with beta thalassemia major

ObjectivesSurvival of beta thalassemia major (TM) patients has improved significantly over the past few decades. Consequently, less commonly reported complications are now being recognized. An incidence as high as 60% of silent cerebral infarcts (SCI) has been demonstrated by brain Magnetic Resonance Imaging (MRI) studies in beta thalassemia intermedia (TI). The aim of this study was to determine whether regularly transfused TM adult patients experience less SCI, as compared to the incidence described in TI. MethodsIn this observational study, 28 transfusion dependent TM patients, >18years of age underwent brain MRI studies. ResultsFocal bright foci in the cerebral white matter were demonstrated in 17 (60.7%) patients; most of them had multiple lesions. Elevated serum ferritin (SF), primarily 5years Area Under the Curve, was found to have a significant association with the presence of SCI (p<0.031). Similar results were found when 4 patients with intact spleen and 2 patients with splenules were excluded (p=0.027). There was no significant association between number of SCI and clinical or other laboratory parameter evaluated. ConclusionsThe present study demonstrates a high rate of SCI in regularly transfused TM adult patients. Effective continuous iron chelation, preventive low dose aspirin and routine periodical brain MRI are recommended.

Mild cognitive impairment of vascular origin: Proposal for an empirical approach in primary care

The incidence of mild cognitive impairment of vascular origin is increasing continuously among individuals with cardiovascular risk factors. The etiology of this kind of impairment is related to cerebrovascular pathologies, with the presence of silent cerebral infarctions the most relevant etiology. The incidence of cognitive impairment affects around 22% of patients at 3 months after an ischemic stroke, and this incidence is maintained or increased even 5 years after the stroke. Silent infarction should be considered the first clinical suspicion in patients with cardiovascular risk factors (such as hypertension, diabetes and dyslipidemia) who are attending a consultation for cognitive complaints, not only memory complaints. There are various tools for detecting such cognitive problems during the examination, such as brief cognitive tests and neuropsychological evaluations (for example, MMSE, SPMSQ or MoCA), and to assess its development. For a patient with cardiovascular risk factors and cognitive complaints it should be possible to carry out an empirical treatment and assess the development of the cognitive deficits before referring the patient to the specialist. This review outlines various attitudes and therapeutic possibilities that might be useful in the scope of Primary Care.

Increased whole blood viscosity is associated with silent cerebral infarction

The presence of silent cerebral infarction (SCI) increases the risk of transient ischemia attack, symptomatic stroke, cardiovascular disease and dementia. Increased viscosity is associated with aging, obesity, carotid intima-media thickness, metabolic syndrome, hypertension, diabetes, ischemic heart disease, and stroke. The purpose of the study was to assess the hemorheological parameters levels in SCI patients. A cross-sectional study was conducted to evaluate the association between hemorheological parameters and SCI in 1487 subjects (868 men and 619 women) undergoing medical check-up. The participants with SCI had higher whole blood viscosity (WBV) levels at low shear rate than those without SCI (10.34 ± 1.77 mPa.s vs. 8.98 ± 0.88 mPa.s; P < 0.001). Moreover, the subjects with a high WBV had a higher prevalence of SCI. Logistic regression analysis revealed that a significant association of WBV levels with the risk of SCI after adjustment for confounding factors (OR: 2.025; 95% CI: 1.750-2.343; P < 0.001). Whole blood viscosity at low shear rate is a novel indicator for SCI regardless of classical cardiovascular risk factors. Early measurement of whole blood viscosity may be helpful to assess the risk of stroke.

Elevated mean platelet volume is associated with silent cerebral infarction.

The presence of silent cerebral infarction (SCI) increases the risk of transient ischaemia attack, symptomatic stroke, cardiovascular disease and dementia. Mean platelet volume (MPV) is a surrogate marker of activated platelets and is considered a link between inflammation and thrombosis. In addition, MPV is a risk predictor for cardiovascular disease, stroke and overall vascular mortality. The purpose of the study was to assess the MPV levels in SCI patients. A cross-sectional study was conducted to evaluate the association between MPV and SCI in 2215 subjects (1385 men and 830 women). The participants with SCI had higher MPV levels than those without SCI (10.4 ± 1.3 fL vs. 9.2 ± 1.2 fL; P < 0.001). Moreover, the subjects with a high MPV had a higher prevalence of SCI. Multivariate logistic regression analyses revealed that the odds ratios and 95% confidence intervals for SCI according to MPV quartiles were 1.000, 2.131 (1.319-3.444), 3.015 (1.896-4.794), 7.822 (4.874-12.554) respectively (P < 0.001). MPV is a novel index for SCI regardless of classical cardiovascular risk factors.

Headache and Migraine in Children with Sickle Cell Disease Are Associated with Lower Hemoglobin and Higher Pain Event Rates But Not Silent Cerebral Infarction

To 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. In this cross-sectional study, we evaluated the health history, laboratory values, and brain magnetic resonance imaging findings of participants with sickle cell disease (hemoglobinSS or hemoglobinSβ°-thalassemia) with no history of overt stroke or seizures. Participants characterized headache severity and quality. Migraine was defined by International Headache Society criteria modified for increased sensitivity in children. Neuroradiology and neurology committees adjudicated the presence of silent cerebral infarction by review of magnetic resonance imaging and standardized examination by pediatric neurologists. The cohort included 872 children (51.1% males), ranging in age from 5 to 15 years (mean age, 9.1 years). Of these children, 317 (36.4%) reported recurrent headaches, and 132 (15.1%) reported migraines. In multivariable logistic regression analyses, both were associated with lower steady-state hemoglobin (P = .01 for headaches; P < .01 for migraines) and higher pain rate (P < .01 for headaches; P < .01 for migraines), defined as the number of admissions requiring opioids in the previous 3 years. The presence of silent cerebral infarction was not associated with recurrent headaches or migraines. Only 1.9% (6 of 317) of children with recurrent headaches received medication for headache prophylaxis. Recurrent headaches and migraines are common and undertreated in children with sickle cell disease. Low hemoglobin levels and high pain rates are associated with recurrent headaches and migraines; whereas, silent cerebral infarction is not.

Parent education and biologic factors influence on cognition in sickle cell anemia

Children with sickle cell anemia have a high prevalence of silent cerebral infarcts (SCIs) that are associated with decreased full-scale intelligence quotient (FSIQ). While the educational attainment of parents is a known strong predictor of the cognitive development of children in general, the role of parental education in sickle cell anemia along with other factors that adversely affect cognitive function (anemia, cerebral infarcts) is not known. We tested the hypothesis that both the presence of SCI and parental education would impact FSIQ in children with sickle cell anemia. A multicenter, cross-sectional study was conducted in 19 US sites of the Silent Infarct Transfusion Trial among children with sickle cell anemia, age 5-15 years. All were screened for SCIs. Participants with and without SCI were administered the Wechsler Abbreviated Scale of Intelligence. A total of 150 participants (107 with and 43 without SCIs) were included in the analysis. In a multivariable linear regression model for FSIQ, the absence of college education for the head of household was associated with a decrease of 6.2 points (P = 0.005); presence of SCI with a 5.2 point decrease (P = 0.017); each $1000 of family income per capita with a 0.33 point increase (P = 0.023); each increase of 1 year in age with a 0.96 point decrease (P = 0.023); and each 1% (absolute) decrease in hemoglobin oxygen saturation with 0.75 point decrease (P = 0.030). In conclusion, FSIQ in children with sickle cell anemia is best accounted for by a multivariate model that includes both biologic and socioenvironmental factors.