Silent Cerebral Infarction Research Articles

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.

High risk of silent stroke in older bipolar patients with typical-onset age.

Older patients with bipolar disorder (BD) are at a high risk of stroke. Silent stroke could be neglected in BD patients after middle age, particularly in those with illness onset at the young age. Therefore, we investigated the morbidity and related factors for stroke in older BD patients with typical-onset age. Older patients with bipolar I disorder (age > 50 years) and their illness onset prior to the age of 40 years were recruited. After whole-brain magnetic resonance imaging was conducted, the patients were divided into stroke and non-stroke groups. Clinical data were obtained by reviewing all available medical records and directly interviewing the patients along with their reliable family members. We recruited 62 patients with a mean age of 60.4 years and illness onset at the mean age of 28.4 years. Cerebral infarction or old stroke was observed in 24 (38.7%) patients, including 22 without any reported clinical history of stroke. That is, silent stroke (n = 22) was detected in 36.7% of 60 patients without clinical history of stroke. The stroke group had significantly higher mean numbers of lifetime mood episodes (P = 0.006) than the non-stroke one. Logistic regression analysis showed that 10 or more prior mood episodes (odds ratio = 3.43, 95% confidence interval = 1.12-10.47, P < 0·04) was significantly associated with the occurrence of stroke. The two study groups did not exhibit any other differences in demographic and clinical variables, such as age, laboratory or physical measurements during the last acute psychiatric hospitalisation, body mass index, and substance use problems and concurrent medical diseases. High morbidity of stroke, particularly silent stroke, could be found in older bipolar patients with typical-onset age. In addition to traditional risk factors, the number of recurrent mood episodes in a lifetime may increase the risk of stroke in older BD patients.

Abstract 51: Aging and Metabolic Stress Are Associated With Disrupted White Matter Integrity in Children and Young Adults With Sickle Cell Disease

Introduction: Silent cerebral infarcts (SCIs) in sickle cell disease (SCD) begin in early childhood and increase with age, affecting 50% by age 30. SCIs often occur in the watershed area, where cerebral blood flow (CBF) is low, and oxygen extraction fraction (OEF) is high. Diffusion tensor imaging (DTI) measures white matter integrity; lower fractional anisotropy (FA) and higher mean diffusivity (MD) may precede the appearance of SCIs. We hypothesized that age and oxygen metabolic stress, defined by elevated watershed OEF, are associated with disruption of white matter integrity as measured by FA and MD. Methods: Children and young adults with and without SCD were recruited for brain MRI (T1, FLAIR, pseudocontinuous arterial spin label (CBF), asymmetric spin echo (OEF) and DTI). We averaged CBF maps of non-SCD participants and created a watershed region of interest (ROI), defined as CBF &lt;30% of mean gray matter CBF, which was applied to individual maps. All SCIs were outlined and excluded. We evaluated age and SCD as predictors of FA and MD. Within the watershed ROI, we evaluated OEF and age as predictors of FA and MD. Results: Fifty SCD and 53 control participants, age 6-39 years, underwent MRI. Within all normal appearing white matter, FA decreased (p&lt;0.001) and MD increased (p&lt;0.001) with advancing age. MD, but not FA, changed at a faster rate with advancing age in SCD compared to controls (p=0.02). Within the watershed region, OEF significantly predicted FA (p=0.002) and MD (p &lt;0.001), after adjusting for age. Conclusion: Disruption of white matter integrity worsens with early life aging, particularly in SCD. Oxygen metabolic stress within the watershed region, a region at high risk for SCIs, is associated with lower FA and higher MD, suggesting OEF may provide an early tissue marker of ischemic vulnerability in SCD, prior to developing SCIs.

Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease.

Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, with over 300,000 children born with SCD each year.1 Neurologic consequences of SCD include ischemic and hemorrhagic strokes2 and cognitive deficits.3 SCD accounts for almost ¼ of all stroke-related hospitalizations in African-American children.4 Historically, ischemic stroke in SCD has been separated by symptomatology, including “overt stroke,” referring to radiographic ischemia with associated neurologic deficits detectable on a bedside examination, and “silent stroke” referring to radiographic ischemia without focal neurologic deficits, but associated with cognitive deficits. However this dichotomy is likely false, as the two can be radiographically indistinguishable.5 Strokes may have lifelong devastating consequences, including limited educational attainment and decreased quality of life in children.6, 7 Sickle cell anemia refers to the most severe SCD phenotypes, SS and Sβ0 thalassemia, which have the highest stroke incidence. However, other SCD genotypes are also at risk for cerebral ischemia, with up to 13% of HbSC children having silent ischemia on screening MRI.2, 8 Transcranial Doppler (TCD) screening to identify children with SCD at highest stroke risk combined with primary stroke prevention with chronic transfusion therapy (CTT) revolutionized pediatric sickle cell stroke management in the 1990’s. Despite the dramatic reduction of overt strokes through CTT shown in the Stroke Prevention Trial in Sickle Cell Anemia (STOP), children with SCD remain at a high risk of stroke (Figure 1).2, 9–21 Clinical and translational research in the post-STOP era have increased our understanding of the multi-factorial complexity of stroke in children with SCD (Table 1). Recent work has demonstrated how components of the cerebral metabolic rate of oxygen utilization (CMRO2) contribute to ischemia in SCD. CMRO2 is the product of cerebral blood flow (CBF), arterial oxygen content (CaO2) and oxygen extraction fraction (OEF). CBF and CaO2 comprise cerebral oxygen delivery, and OEF quantifies the transfer of available oxygen supply into the brain tissue. Ischemia occurs when CMRO2 does not meet the metabolic demands and falls below the threshold of tissue viability.26 Here, we will review advances in causal pathways of ischemic stroke and therapy options. Open in a separate window Figure 1: Stroke Event Rates as reported in the literature. SCD = Sickle Cell Disease. TCD = Transcranial Doppler CTT = Chronic Transfusion Therapy

Abstract TMP120: Sildenafil Treatment of Vascular Dementia in Aged Rats

Background and Purpose: Vascular Dementia (VaD) caused by silent or mini strokes, affects cognition and memory predominantly in the elderly. Sildenafil, a cGMP-specific phosphodiesterase type 5 inhibitor mediates vasodilation. In this study, we tested the therapeutic effects of Sildenafil on cognitive decline, white matter (WM) damage, autophagy and inflammatory response associated with a model of VaD in aged rats. Methods: Male, 16-18 month old Wistar rats were subjected to a multiple microinfarction (MMI) induced VaD model and were treated daily with or without Sildenafil (2mg/Kg, i.p) starting at 24 hours after MMI for 28 days (n=7/group). A battery of cognitive tests was performed and rats were sacrificed at 28 days after MMI for immunohistochemical evaluation, Western blot and PCR assays. Results: Compared to aged-control, aged-MMI rats exhibit significant (p&lt;0.05): 1) short term memory loss, long term memory deficits and anxiety like behavior, respectively; 2) increased brain inflammatory factor expression such as IL-1β, MCP-1 and thrombin; 3) increased brain WM/axonal damage as well as increased autophagy in the brain. Compared to aged-MMI control rats, Sildenafil treatment in aged-MMI rats significantly (p&lt;0.05): 1) improves short and long term memory as well as decreases anxiety like behavior; 2) improves spatial learning and memory; 3) increases axon and myelin density in the corpus callosum and white matter bundles in the striatum; 4) increases oligodendrocyte and oligodendrocyte progenitor cell number in the corpus callosum, cortex and striatum; 5), increases synaptic protein expression in the cortex and striatum as well as increases water channel protein Aquaporin-4 expression around cerebral blood vessels; 6) decreases inflammatory factors MCP-1, IL-1β and thrombin expression as well as decreases MMI induced autophagy indicated by LC3A and Beclin-1 expression. Conclusions: MMI in aged rats induces significant WM damage, autophagy, and inflammatory responses which lead to decline in cognition and memory. Sildenafil treatment increases white matter remodeling, synaptic plasticity, decreases autophagy and exerts anti-inflammatory effects which in concert may contribute to the improvement in cognition and memory.

Abstract WMP119: An MRI Surveillance Protocol for Pediatric Sickle Cell Anemia

Background: Sickle cell anemia (SCA) is a leading cause of stroke and neurologic disability in children. In the 20 years since the publication of the STOP trial, chronic transfusion therapy and hydroxyurea have shown efficacy as disease-modifying therapies, especially by improvement of transcranial Doppler (TCD) velocities and reduction in the incidence of overt stroke. Despite the publication of the SIT Trial 2014, screening for silent stroke is not universally implemented. Here we report our center’s experience with screening neuroimaging in young children with SCA. Methods: This is a single center, retrospective case series of patients with SCA (HbSS and HbSb 0 -thalassemia) managed in a comprehensive sickle cell center. Patients undergo TCD screening per STOP guidelines beginning at age 24 months. Screening MRI/MRA brain are also recommended at 5, 10, 15, and 20 years of age. Imaging data for the children 5-9 years of age are reported. Results: There were 39 subjects within the defined age range, 37 of whom were receiving disease-modifying therapy (hydroxyurea, N=34; chronic transfusions, N=3). Mean age of initiation of disease-modifying therapy was 4.2 years. MRI/MRA of the brain was obtained according to our screening protocol in only 21 (54%), indicating incomplete screening and opportunity for quality improvement. Indeed, most MRIs were obtained for a clinical concern and/or a non-normal TCD (85%). Abnormal parenchyma and/or vasculature was identified in 11 of 21 (52%) imaged subjects. In patients imaged before starting disease modifying therapy, 2 of 9 had stroke (22%). In patients imaged after starting disease modifying therapy, 7 of 12 had stroke and or arteriopathy (58%). Conclusions: Over half (52%) of young children (5-9 years) with SCA in our center who had an MRI/MRA had abnormal findings, indicating a high yield for potentially actionable results. This may be an under-estimate of CNS disease burden, because 46% of the population did not undergo screening MRI/MRA. Proactive screening for cerebrovascular complications in SCA may allow early intervention that further improves patient outcomes.

Cognitive Impact of Cerebral Small Vessel Disease Changes in Patients With Hypertension.

Hypertension is one of the principal risk factors for cerebral small vessel disease progression and cognitive impairment. We aimed to investigate how changes in cerebral small vessel disease lesions relate to cognitive decline and incident mild cognitive impairment in hypertensive patients. Data were obtained from the ISSYS cohort (Investigating Silent Strokes in Hypertensives: a Magnetic Resonance Imaging Study)-a longitudinal population-based study on hypertensive patients aged 50 to 70 years without dementia and stroke at baseline. Patients underwent a brain magnetic resonance imaging, a cognitive screening test, and cognitive diagnosis (normal aging or mild cognitive impairment) at baseline and follow-up. We evaluated incident lacunar infarcts and cerebral microbleeds. Changes in the periventricular and deep white matter hyperintensities (WMH) were qualitatively defined as none, minor, or marked. We followed up 345 patients (median age, 65 [61-68]; 55.4% men) for 3.95 (3.83-4.34) years. Incident mild cognitive impairment was diagnosed in 9.1% of the sample. Considering the progression of cerebral small vessel disease, the prevalence of incident infarcts was 6.1% and that of incident cerebral microbleeds was 5.5%; progression of periventricular WMH was 22% and that of deep WMH was 48%. Patients with marked progression of periventricular WMH showed a significant decrease in global cognition compared with patients without progression (adjusted mean [SE], -0.519 [0.176] versus 0.057 [0.044], respectively; P value=0.004) and a higher risk of incident mild cognitive impairment (OR, 6.184; 95% CI, 1.506-25.370; P value=0.011). Therefore, our results indicate that hypertensive patients with progression of periventricular WMH have higher odds of cognitive impairment, even in the early stages of cognitive decline.

Invited commentary

Mirza and colleagues present outcomes of upper extremity access (UEA) for complex aortic repair of thoracoabdominal aortic aneurysms (TAAAs).1Mirza A.K. Oderich G.S. Sandri G.A. Tenorio E.R. Davila V.J. Kärkkäinen J.M. et al.Outcomes of upper extremity access during fenestrated-branched endovascular aortic repair.J Vasc Surg. 2019; 69: 635-644Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar To date, this is by far the largest retrospective study on the topic, and the authors are to be congratulated for their results and this important effort to cast some light on a frequently neglected topic. Except for a few reports, UEA for complex aortic repair has rarely been focused on and can be controversially discussed with a diversity of approaches.2Fiorucci B. Kölbel T. Rohlffs F. Heidemann F. Debus S.E. Tsilimparis N. Right brachial access is safe for branched endovascular aneurysm repair in complex aortic disease.J Vasc Surg. 2017; 66: 360-366Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 3Knowles M. Nation D.A. Timaran D.E. Gomez L.F. Baig M.S. Valentine R.J. et al.Upper extremity access for fenestrated endovascular aortic aneurysm repair is not associated with increased morbidity.J Vasc Surg. 2015; 61: 80-87Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The complication rate for UEA in the presented large study from a center of excellence is exceptionally low. However, the majority are strokes, and real-world data would presumably show a significantly higher rate of serious neurologic complications. Operator-reported neurologic outcomes without examination by a neurologist and diffusion-weighted magnetic resonance imaging have a tendency to underestimate the issue. Therefore, reported outcomes, as the authors mention, do not take into account silent brain injury, which is a frequent magnetic resonance finding in thoracic endovascular aortic repair and a growing concern because of induced neurocognitive decline.4Perera A.H. Rudarakanchana N. Monzon L. Bicknell C.D. Modarai B. Kirmi O. et al.Cerebral embolization, silent cerebral infarction and neurocognitive decline after thoracic endovascular aortic repair.Br J Surg. 2018; 105: 366-378Crossref PubMed Scopus (39) Google Scholar The superb illustrations in the article provide excellent visualization of the authors' preferred repair technique for dissected brachial arteries using xenogenic material in one of eight patients with UEA. Whereas the additional time required for UEA closure and patch angioplasty may prolong some of the procedures, reduced catheterization times for the target vessels seem to justify the effort. The absence of secondary procedures needed is an impressive result supporting the group's strategy of open UEA and a low threshold for patch angioplasty. In a significant proportion of complex endovascular repairs, UEA is optional, namely, when solely fenestrations are used to connect target vessels to the main graft (fenestrated endovascular aneurysm repair). Fenestrations can be connected from femoral access, although UEA may provide advantages when target vessels are caudally oriented. Differences in utilization of UEA are mostly due to tradition and surgical teaching. Mirza et al now give us valid information at what cost this frequently used optional step comes in endovascular TAAA repair. For endografts with directional branches (branched endovascular aneurysm repair), such as the t-Branch (Cook Medical, Bloomington, Ind), UEA has been judged unavoidable, and discussions have focused on the preferred side of UEA.1Mirza A.K. Oderich G.S. Sandri G.A. Tenorio E.R. Davila V.J. Kärkkäinen J.M. et al.Outcomes of upper extremity access during fenestrated-branched endovascular aortic repair.J Vasc Surg. 2019; 69: 635-644Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar, 2Fiorucci B. Kölbel T. Rohlffs F. Heidemann F. Debus S.E. Tsilimparis N. Right brachial access is safe for branched endovascular aneurysm repair in complex aortic disease.J Vasc Surg. 2017; 66: 360-366Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar However, recent experience has demonstrated that with the use of steerable sheaths, even four-branched repairs in challenging anatomy of TAAA could be performed from femoral access alone (Fig). Whereas some operators prefer left-sided UEA with the argument of reduced manipulation in the aortic arch and assumed reduced stroke risk, other operators prefer right-sided UEA because of the assumed better workflow and lower radiation dose. The authors conclude that left-sided UEA is associated with a lower stroke rate in their study but acknowledge a significant selection bias and describe a trend in their practice toward right-sided UEA for better workflow and lower radiation dose. Convincing evidence about the better access side is still lacking, and the authors' conclusion should be taken with caution as data do not support a recommendation for left-sided access in general. Outcomes of upper extremity access during fenestrated-branched endovascular aortic repairJournal of Vascular SurgeryVol. 69Issue 3PreviewUpper extremity (UE) access is frequently used during fenestrated-branched endovascular aortic repair (F-BEVAR) to facilitate catheterization of downgoing vessels. Limitations include risk of cerebral embolization and of UE arterial or peripheral nerve injury. The aim of this study was to assess outcomes of F-BEVAR using UE access. Full-Text PDF Open Archive

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.

New Silent Cerebral Infarction in Patients with Acute Non-Cerebral Amyloid Angiopathy Intracerebral Hemorrhage as a Predictor of Recurrent Cerebrovascular Events.

BackgroundThe aim of this study was to investigate the incidence and related risk factors of new silent cerebral infarction in patients with acute non-cerebral amyloid angiopathy (non-CAA) intracerebral hemorrhage (ICH) and to explore clinical cerebrovascular event recurrence within 1 year.Material/MethodsThis prospective study observed 152 patients with non-CAA ICH diagnosed by computed tomography within 3 days after onset. All patients underwent magnetic resonance imaging on day 14 to identify silent cerebral infarction, and their subsequent clinical cerebrovascular events were followed up regularly within 1 year.ResultsOf the 152 patients, 46 (30.26%) had silent cerebral infarctions. Multiple logistic regression analysis revealed that the white blood cell (WBC) count, cerebral microbleeds (CMBs), and leukoaraiosis were silent cerebral infarction risk factors. At 1-year follow-up, 34 (22.37%) had clinical cerebrovascular events, with 8 (23.53%) having vascular-related deaths. Multiple logistic regression analysis showed that silent cerebral infarction was the only independent predictor of future clinical cerebrovascular events.ConclusionsSilent cerebral infarction is common during acute non-CAA ICH and is independently related to WBC counts, CMBs, and leukoaraiosis. The risk of clinical cerebrovascular events in non-CAA ICH patients with silent cerebral infarction increases in the following year; thus, silent cerebral infarction may be a useful predictor of recurrent cerebrovascular events.

Silent cerebral infarction after thoracic endovascular aortic repair: a magnetic resonance imaging study.

Silent cerebral infarction is the most common brain injury incidentally detected on imaging and can be associated with increased risks of future stroke and cognitive decline. However, the incidence and risk factors of silent cerebral infarction after thoracic endovascular aortic repair (TEVAR) for aortic arch pathologies remain unclear. This study aimed to examine silent cerebral infarction following TEVAR using diffusion-weighted (DW) magnetic resonance imaging (MRI). Nineteen patients (16 men, mean age 73.3 years) who underwent elective debranching TEVAR (zone 0/1/2 = 3/8/8) were included. Perioperative brain injury was assessed via cerebral DW-MRI before and after the procedure. The atheroma ratio was calculated from preoperative computed tomography images, and we examined the association between the atheroma ratio and development of new postoperative DW-MRI lesions. Technical success was achieved in all patients, and no patient died within 30 days postoperatively. Postoperative DW-MRI detected a total of 24 new lesions in 5 (26%) patients (1-9 lesions per patient): 4 (21%) patients with silent cerebral infarction and 1 (5%) patient with clinical stroke. The atheroma ratio of the aortic arch (23.8 ± 2.7% vs 18.3 ± 3.9%; P = 0.023), especially at the proximal landing zone (19.5 ± 2.8% vs 14.7 ± 2.7%; P = 0.014), was significantly higher in patients with new postoperative DW-MRI lesions than that in patients without. The incidence of silent cerebral infarction following TEVAR with supra-aortic debranching for aortic arch pathologies was 21%, and the severity of atheromatous change in the aortic arch, especially in the proximal landing zone, was positively associated with the development of silent cerebral infarction.

Silent cerebral infarction and cognitive function following TAVI: an observational two-centre UK comparison of the first-generation CoreValve and second-generation Lotus valve

ObjectiveTo compare the incidence of silent cerebral infarction and impact on cognitive function following transcatheter aortic valve implantation (TAVI) with the first-generation CoreValve (Medtronic, Minneapolis, Minnesota, USA) and second-generation Lotus...

Investigation of Risk Factors in Patients with Silent Posterior Cerebral Artery Infarctions

Investigation of Risk Factors in Patients with Silent Posterior Cerebral Artery Infarctions

Uptake and radiological findings of screening cerebral magnetic resonance scans in patients with hereditary haemorrhagic telangiectasia.

Hereditary haemorrhagic telangiectasia (HHT) results in arteriovenous malformations (AVMs), most commonly in the lungs, liver and brain. Discussion of cerebral vascular malformations is an important element of patient management. The current study objectives were to examine uptake and results of screening cerebral magnetic resonance (MR) scans, excluding symptomatic patients requiring neurological investigations. The remaining non-symptomatic individuals received formal pretest counselling that differed according to family history. For the 603 patients with no neurological symptoms of concern, screening scan uptake was higher after publication of the ARUBA trial. Patients with a family history of cerebral haemorrhage were 4 to 14-fold more likely to have a screening scan than patients with no such family history. For patients without neurological symptoms suggesting cerebral AVMs, none of the 59 screening scans performed at our institution demonstrated a cerebral AVM. Four scans (6.8%) demonstrated small aneurysms. The most common abnormality was cerebral infarction (20/59, 33.9%), predominantly identified in patients with pulmonary AVMs. Of 29 pulmonary AVM patients with no previous history of clinical stroke, 16 (55.2%) had between one and five silent infarcts. For HHT patients with pulmonary AVMs, the most frequently affected sites were the cerebellum (40%) and thalamus (14.3%), and the age-adjusted odds ratio for an infarct was 21.6 (95% confidence intervals 3.7, 126), p = 0.001. We concluded that for cerebral screening programmes in HHT, the findings support informed patient choice incorporating understanding that cerebral AVMs are rare in non-symptomatic HHT patients, but that screening scans commonly detect silent cerebral infarction due to pulmonary AVMs.

Reduced Cerebral Metabolic Rate of Oxygen in Adults with Sickle Cell Disease

Introduction:Cerebral blood flow (CBF) is increased in sickle cell disease (SCD) to compensate for chronic hemolytic anemia. Since the brain is strongly dependent on adequate oxygen levels, severe anemia may result in ischemia and silent cerebral infarctions (SCIs), which are present in the majority of patients with SCD. Besides CBF, the cerebral metabolic rate of oxygen (CMRO2), representing the cerebral oxygen consumption, can be measured using specialized MRI techniques. CMRO2 is dependent on CBF, OEF oxygen extraction fraction (OEF) and the hematocrit in the cerebral circulation. In order to maintain stable CMRO2 the OEF changes to compensate for fluctuations in CBF. Previous studies found either elevated or reduced rather than stable CMRO2 in SCD. To further explore the regulation of cerebral oxygenation in SCD, we measured CMRO2, OEF and CBF using MRI at rest and upon administration of acetazolamide (ACZ), a non-metabolic vasodilator. In addition, we related the CMRO2 to the prevalence and location of SCIs and to laboratory parameters of hemolysis.Methods:Adult SCD patients (HbSS/HbSβ0) without a history of stroke, and healthy age-, sex, and race-matched controls were recruited for this IRB-approved MRI study with ACZ-induced vasodilation and venous blood sampling. MRI images were acquired at 3T (Philips Healthcare, Best, NL). Sequences included 3D FLAIR with 1mm isotropic resolution for lesion evaluation, longitudinal and transverse relaxation times of blood (T1b and T2b) in the cerebral sagittal sinus using a T2 prepared tissue relaxation with inversion recovery sequence (T2-TRIR), and pseudo-continuous arterial spin labeling (ASL) for whole brain CBF measurements. T1b was used to correct ASL-based CBF values. T2b was converted to venous saturation (Yv) using a recently published SCD-specific model, which was calibrated in sickle blood rather than bovine blood. CBF was measured at baseline and 10 min post acetazolamide (ACZ) (16mg/kg intravenous infusion over 3min). Images were co-registered and quantified using the ExploreASL toolbox.CMRO2 was calculated as follows: CMRO2 = CBF * OEF * Ca, where CBF is the whole brain CBF map from ASL, OEF is the arteriovenous oxygen saturation (Y) difference (Ya-Yv/Ya) derived from T2 measurements, and Ca is the oxygen carrying capacity of blood calculated from hematocrit sampled immediately prior to MRI. Blood markers of hemolysis (reticulocyte count and bilirubin) were correlated to MRI hemodynamic markers using bivariate Spearman's rho (ρ). Group comparisons were tested using Student's t-tests. P values <0.05 were considered statistically significant.Results:As expected, CBF was significantly higher in patients with SCD (69 ± 16 mL/100g/min) compared to healthy controls (42 ± 4 mL/100g/min, P <0.001), whereas oxygen carrying capacity (Ca) was significantly lower in patients with SCD vs healthy controls due to lower hematocrit (485 ± 83 vs 794 ± 66 μmol O2/100ml blood, P=0.001). At baseline, mean CMRO2 was lower in patients with SCD compared to healthy controls (88 ± 20 vs 117 ± 18 μmol/100 g/min, P = 0.002), contrary to our hypothesis, indicating a reduced oxygen metabolism in patients with SCD. After acetazolamide, CMRO2 remained the same due to an increase in CBF (P<0.001) and a compensatory reduction in OEF. The reduction in OEF in patients with SCD and healthy controls (20 ± 7 vs 19 ± 6, respectively P= 0.76) indicates that OEF adjusts appropriately according to the increased flow. By mapping CMRO2 and the locations of SCIs, we found that lesions were most prevalent in the regions with the lowest CMRO2 corresponding to the deep white matter and borderzone regions, supporting an ischemic etiology of lesions. High hemolytic rate was associated with higher CMRO2 most likely due to an increased CBF.Conclusion:We observed reduced CMRO2 in patients with SCD compared to healthy controls due to low OEF. A reduced CMRO2 could pose a risk for ischemia, despite high flow rate delivering oxygen, because of low OEF. This is supported by the fact that the silent cerebral infarcts are located in regions with the lowest CMRO2. We postulate that patients with SCD have a reduced capacity to increase the OEF in regions with inadequate CBF resulting in local ischemia and local infarction. The pathogenesis of the reduced OEF remains unclear but could be related to arteriovenous shunting whereby there is insufficient time for oxygen to dissociate. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

Practice Patterns in the Use of MRI/MRA and Chronic Transfusion Therapy for Monitoring and Treatment of Stroke in Pediatric Patients with Sickle Cell Anemia

Introduction: Current stroke prevention guidelines in pediatric sickle cell anemia (SCA) specify the use of transcranial Doppler (TCD) and chronic red cell transfusion therapy (CRCT) for detection and prevention of stroke. Guidance on the use of MRI/MRA in the context of stroke prevention, screening, and monitoring is less clear. While overt stroke is able to be identified clinically, silent stroke can be more difficult to diagnose and screening guidelines have not been developed. The DISPLACE Consortium (Dissemination and Implementation Looking at the Care Environment) is a multi-center study funded to evaluate optimal implementation of stroke prevention guidelines. The purpose of the present study was to provide information on practice patterns across the DISPLACE Consortium as they relate to the use of MRI/MRA and CRCT for monitoring and treating stroke in pediatric patients with SCA.Methods: DISPLACE is a multi-site study in SCA including 28 centers across the United States. A practice patterns survey was sent to the principal investigator (PI) for each DISPLACE site through RedCap. All PIs are specialty care providers in hematology/oncology who provide care to pediatric patients with SCA. The sites were chosen to represent a range of characteristics, including both urban and rural regions, large and small academic institutions, and community-based institutions. The survey was developed by the study investigators and questions were provided predominantly in a multiple choice format. The following types of questions were asked about MRI/MRA: indication for pediatric patients with SCA in general and for those on CRCT for stroke prevention. The following types of questions were asked about CRCT: indication and frequency of CRCT and target hemoglobin S level.Results: All 28 providers completed the survey (100%). About half of providers were female (53.5%). Most providers identified as White (77.8%), followed by Asian (11.1%) and Black or African American (7.4%). Two identified as Hispanic or Latino (7.4%). MRI was used for the following indications: abnormal TCD (85.7%), conditional TCD (46.4%), recurrent headaches (78.6%), and behavior issues (53.6%). A few sites also reported obtaining an MRI if a child has had poor school performance (10.7%) or if there was concern for developmental delay (3.7%). Indications for MRA were similar. Notably, many sites reported the use of a screening or baseline MRI in the absence of other indications (25.0%). The most common indications for initiating CRCT were abnormal TCD (96.4%) and overt stroke (92.9%), followed by silent stroke (53.6%) and abnormal MRA (50.0%). The majority of sites reported scheduling CRCT at a frequency of every 4 weeks (63.0%), though many (37.0%) described other more frequent transfusions intended to either more rapidly reduce hemoglobin S levels or maintain a level under 30%. Most sites used a target of 30% hemoglobin S, though a few sites noted alternatives including 40% (3.7%) and 50% (3.7%). The frequency of MRI for patients receiving CRCT for stroke prevention was as follows: annually (44.4%), every 2 years (14.8%), and every 5 years (3.7%). Several sites reported obtaining MRIs only if there were new changes or concerns (14.8%) or reported alternative practices (14.8%) that depended on patient characteristics. Frequency for MRA was similar for patients on CRCT.Conclusions: The results of the DISPLACE practice patterns survey suggested nearly universal adoption of CRCT for children with abnormal TCD and prior overt stroke across sites. The use of MRI/MRA in detecting potential cerebrovascular abnormalities in the absence of clinical neurologic symptoms and for monitoring patients on CRCT was much more variable, which likely reflects the minimal amount of guidance for the use of MRI/MRA in SCA. Notably, a number of sites were using MRI/MRA to screen pediatric patients for cerebrovascular abnormalities and to monitor patients on CRCT. The variability in responses for MRI/MRA highlights the importance of future studies evaluating best neuroimaging practices for detecting cerebrovascular abnormalities (apart from TCD) and for using MRI/MRA to monitor patients on CRCT. DisclosuresSchlenz:NHLBI: Research Funding. Mueller:NHLBI: Research Funding. Phillips:NHLBI: Research Funding. Melvin:NHLBI: Research Funding. Adams:NHLBI: Research Funding. Kanter:bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Apopharma: Research Funding; Sancilio: Research Funding; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees.

The Role of Hydroxyurea to Prevent Silent Stroke in Sickle Cell Disease: Systematic Review and Meta-Analysis

Chronic blood transfusions are standard of care for stroke prevention in sickle cell disease. We evaluated hydroxyurea's efficacy in preventing silent stroke. We searched for randomized controlled trials (RCTs) and observational studies on Pubmed, CENTRAL, Embase, and Web of Science without using language/time limits. Eligible studies compared hydroxyurea with transfusions or observation to prevent silent stroke. This systematic review adheres to the Cochrane guidelines. Data were pooled using random effects model using STATA to perform meta-analysis. Methodological quality of RCTs was investigated using the Cochrane risk of bias assessment tool, while observational studies were assessed using the Downs & Black Checklist for Study Quality. One RCT enrolling 121 participants was included. There were no strokes, silent strokes, or deaths reported in either arm. There was no difference between hydroxyurea versus chronic blood transfusions (RR 1.52, 95% CI 0.57 to 4.02, P = 0.39) for adverse events. We included 10 observational studies, with 361 participants receiving hydroxyurea. There were no deaths attributed to hydroxyurea. Approximately 1% (I2 = 48.67%, 95% CI 0.0 to 0.05, 314 participants, seven comparisons) of patients receiving hydroxyurea had stroke. Approximately 18% (I2 = 91.37%, 95% CI 0.03 to 0.4, 266 participants, six comparisons) of the hydroxyurea patients had silent stroke. Approximately 24% (I2 = 88.54%, 95% CI 0.02 to 0.57, 91 participants, four comparisons) of the hydroxyurea patients had adverse events attributed to hydroxyurea. Our findings suggest that hydroxyurea is safe and may prevent silent stroke and stroke. More high-quality studies are needed. DisclosuresNo relevant conflicts of interest to declare.

Association of Sickle Cell Trait with Measures of Cognitive Function and Dementia in African Americans

Background: The prevalence of cerebral small vessel disease (CSVD) and its associated complication of cognitive decline is significantly higher amongst African Americans than non-Hispanic Whites. Sickle cell anemia or sickle cell disease has been associated with a 30-45% increased prevalence of CSVD which presents as silent cerebral infarcts and impaired cognitive function. However, the association between sickle cell trait (heterozygosity for the sickle cell mutation) and cognitive decline or dementia has not been reported.Hypothesis: African Americans with SCT will have a significantly higher incidence and prevalence of cognitive impairment and dementia compared to those without SCT.Methods: We studied African Americans participants enrolled in the community-based prospective Atherosclerosis Risk in Communities (ARIC) study. SCT genotype status was determined using Taqman® genotyping from blood samples collected at baseline. Data from cognitive assessments at visits 2, 4 and 5, and an MRI performed at visit 5 were used for analysis. Using linear regression models for visit 2 cognitive measures and visit 5 brain MRI outcomes, a generalized estimating equation (GEE) for cognitive change, and Cox models for the incidence of dementia, we determined whether SCT was associated with a higher risk for cognitive dysfunction, global and regional brain volumes, and dementia.Results: Distribution of traditional risk factors for cognitive decline were not significantly different between participants with SCT (N = 176) and those without SCT (N = 2,532). In multivariable, cross-sectional analyses of 2,708 participants, those participants with SCT compared to those without SCT did not show a statistically significant difference in the global or domain-specific cognitive function scores at baseline. Participants with SCT did not experience a faster 20-year cognitive decline compared to participants without SCT. Also, participants with SCT had larger parietal cortical volume (100.5 cm3 vs. 97.9 cm3, diff. = 2.67 (0.24, 5.11) cm3, p = 0.03), and lower incidence of dementia (HR = 0.63 95% CI = 0.38, 1.05) compared to those without SCT. Participants with a co-inheritance of the apolipoprotein E (APOE) ε4 risk allele and SCT (N = 63) had worse scores on the digit symbol substitution test (DSST) at baseline (z-score = -0.08 (-0.26, 0.09), Pinteraction = 0.05) and over time (z-score = -0.12 (-0.38, 0.14), Pinteraction = 0.04), compared to those with the APOE ε4 risk allele who do not have SCT (N = 113). SCT was associated with 2-fold increased risk of dementia among participants with diabetes mellitus and a 55% reduction in risk of dementia among those without diabetes mellitus (Pinteraction = 0.01).Conclusions: SCT was not an independent risk factor for prevalent or incident cognitive decline, but it could potentially interact with and modify other risk factors for dementia and cognitive dysfunction. DisclosuresKey:UniQure BV: Research Funding.

Validation of Sickle Cell Disease Severity Score in a Cohort of Hemoglobin SC Disease Patients

Introduction: Hemoglobin SC (HbSC) disease is a variant of sickle cell disease (SCD), with a distinct clinical profile from the more common homozygous sickle cell anemia (HbSS) (Nagel RL, et al. 2003). As part of an ongoing study seeking to correlate genome-wide-association data with a clinical phenotypic profile of HbSC; the study attempts to validate the “Sickle Cell Disease Severity Score (SSS) calculator” (Sebastiani et al. 2007) in a longitudinal cohort of HbSC disease patients.Methods: The entire cohort of adult (≥18 years of age) HbSC disease patients enrolled within the ongoing cross-sectional phenotype-genotype correlation study were assessed and scored according to the SSS calculator. Utilizing the Sickle Cell Disease Severity Scores generated from patient data, the study assessed the ability for the calculator to predict patient mortality and morbidity within the cohort. All associated morbidities were defined in accordance to the Cooperative Study of Sickle Cell Disease (CSSSD).Results: A total of 111 adult HbSC disease patients were enrolled. Of the 23 patients with intermediate or high SSS, only 1 died within the study period. A high SSS did not correlate with the presence of SCD clinical outcomes (retinopathy, chronic renal failure, leg ulcers, hearing disorders, cholecystectomy, splenomegaly, splenectomy status, splenic sequestration crisis, osteonecrosis, acute chest syndrome, priapism, painful vaso-occlusive crisis, proteinuria and serum ferritin), when univariate analyses were conducted. In contrast, the study identified association between SSS and cerebral vascular accident (CVA; composite of overt stroke, hemorrhage or silent cerebral infarct) (OR 1.935 for every 0.25 increase in SSS, P = 0.016), as well as tricuspid regurgitant jet velocity (TRJV) > 2.5 m/s (OR 1.944 for every 0.25 increase in SSS, P = 0.022). Elevated TRJV was further analysed after correcting for patient-related factors (weight, hydroxyurea use, regular therapeutic phlebotomy, hemoglobin, hematocrit, red blood cell count, and platelet count) and remained correlative. In addition, SSS was associated with creatinine clearance by a quadratic function (R2 = 16.4%, P = 0.008); which may be indicative of the natural history of declining renal function in HbSC disease patients. SSS was not independently predictive of either the presence or number of SCD morbidities (proteinuria, retinopathy, splenic complications, leg ulcers, cholecystectomy, and hearing disorder) in the cohort after adjusting for patient-related factors.Conclusion: Despite having been derived from a SCD population that was 26% HbSC, the study was unable to validate the SSS within the cohort of HbSC patients. This may reflect the differences in patient population and/or therapeutic intervention between this cohort and the CSSCD cohort used in the construction of the SSS calculator. While SSS was found to correlate with 3 discrete markers of disease morbidity (TRJV, CVA, creatinine clearance), it appears that a new scoring system is required to accurately predict clinical mortality and morbidity in contemporary cohorts of adult HbSC disease patients. DisclosuresNo relevant conflicts of interest to declare.