Silent Cerebral Infarction Research Articles

Should Magnetic Resonance Angiography Be Used for Screening of Intracranial Aneurysm in Adults with Sickle Cell Disease?

Magnetic resonance imaging (MRI) is used in patients with sickle cell disease (SCD) to detect silent cerebral infarcts. MR angiography (MRA) can identify arterial stenoses and intracranial aneurysms (ICANs) associated with SCD. In this study, we aimed to estimate the prevalence of ICANs in asymptomatic adult patients with SCD referred from the SCD clinic for routine screening by MRI/MRA using a 3T-MRI scanner. Findings were independently reviewed by two neuroradiologists. Between 2016 and 2020, 245 asymptomatic adults with SCD were stratified according to genotype (SS/S-β0thalassemia and SC/Sβ+). ICANs were found in 27 patients (11%; 0.95 CI: 8-16%). ICANs were more frequent in SS/S-β0thalassemia patients (20/118 or 17%; 0.95 CI: 11-25%) than in SC/βb+ patients (7/127 or 6%; 0.95 CI: 2-11%; p = 0.007). Individuals with SCD (particularly SS/S-β0thalassemia) have a higher prevalence of ICANs than the general population. We believe that MRA should be considered in the current American Society of Hematology guidelines, which already contain a recommendation for MRI at least once in adult SCD patients. However, the clinical significance of preventive treatment of unruptured aneurysms remains controversial.

Cerebral hemodynamics during atrial fibrillation: Computational fluid dynamics analysis of lenticulostriate arteries using 7 T high-resolution magnetic resonance imaging.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, inducing irregular and faster heart beating. Aside from disabling symptoms-such as palpitations, chest discomfort, and reduced exercise capacity-there is growing evidence that AF increases the risk of dementia and cognitive decline, even in the absence of clinical strokes. Among the possible mechanisms, the alteration of deep cerebral hemodynamics during AF is one of the most fascinating and least investigated hypotheses. Lenticulostriate arteries (LSAs)-small perforating arteries perpendicularly departing from the anterior and middle cerebral arteries and supplying blood flow to basal ganglia-are especially involved in silent strokes and cerebral small vessel diseases, which are considered among the main vascular drivers of dementia. We propose for the first time a computational fluid dynamics analysis to investigate the AF effects on the LSAs hemodynamics by using 7 T high-resolution magnetic resonance imaging (MRI). We explored different heart rates (HRs)-from 50 to 130 bpm-in sinus rhythm and AF, exploiting MRI data from a healthy young male and internal carotid artery data from validated 0D cardiovascular-cerebral modeling as inflow condition. Our results reveal that AF induces a marked reduction of wall shear stress and flow velocity fields. This study suggests that AF at higher HR leads to a more hazardous hemodynamic scenario by increasing the atheromatosis and thrombogenesis risks in the LSAs region.

Impact on Silent Infarct Incidence of Early Screening of the Extracranial Portion of the Internal Carotid in a Longitudinal Cohort-Study of Children with Sickle Cell Anemia

Background Kaplan-Meier (KM) estimated cumulative incidence of silent cerebral infarcts (SCI) in a SCA-newborn cohort with sickle cell anemia (SCA) early screened by transcranial-color-Doppler-ultrasound (TCD-US) was shown to be high, despite initiation of chronic transfusion (CT), in children detected at risk by TCD, i.e., 28.2% by age 8, 37.4% by age 14, and an incidence of 3.4/100 patient-years (Bernaudin et al Blood 2011). We hypothesized that adding early extracranial Internal Carotid Artery (eICA) assessment would contribute to reducing SCI incidence. Patients and Methods TCD-US was systematically performed since May 1992 in our pediatric sickle cell anemia (SCA) cohort. Cerebral MRI/MRA was assessed every two years after age 5, or earlier in children on CT for abnormal time-averaged mean velocity (TAMV). eICA-color-Doppler-ultrasound and neck-MRA were added since June 2011. The highest TAMV in middle, anterior, posterior, basilar, intra and extracranial internal carotid cerebral arteries were recorded. Abnormal intracranial and eICA TAMV were defined as ≥ 200 cm/s and ≥ 160 cm/s, respectively. Stenosis was defined as a ≥ 25% decrease in the lumen of arteries. SCI was defined as an hyperintensity focus of at least 3 mm diameter, visible in two planes on FLAIR MRI. Genetic markers (alpha and beta genes, G6PD activity) and baseline biological parameters were recorded during the 2nd year of life before intensive therapy, and away from crisis and transfusion. Hospitalizations, annual check-up data, Doppler, MRI/MRA assessments and events (abnormal-TAMV, intra or extracranial stenosis and SCI) were prospectively recorded. CT was systematically applied in children with TAMV ≥ 200 cm/s for any artery and children with normalized TAMV and no stenosis were switched to hydroxyurea (HU) with CT overlap until reaching the maximal tolerated dose. For children with eICA TAMV 160-199 cm/s, neck-MRA was performed, and CT applied in those with eICA-stenosis while the others were given HU. Moreover, HU was initiated in children with frequent crises or baseline hemoglobin < 7g/dL. Stem cell transplantation was performed in children with cerebral vasculopathy and in those with frequent crises despite HU treatment. Cerebral arteriopathy was defined by history of abnormal intracranial or eICA TAMV or of intra or extracranial stenosis. Results We analyzed data updated in 7/2019 from stroke-free SCA children, born between 11/1992 and 8/2015, all assessed with cerebral MRI/MRA, including neck-MRA (n=338). Median (range) age at first and last cerebral MRI was 5.3 (1.8-16.6 yr) and 11.1 (2.8-19.9 yr), respectively, providing 3866 patient-years of MRI follow-up. SCI occurred in 65/388 SCA-children at median age of 6.4 (1.8-17.9 yr). Incidence of SCI was 65/3866 or 1.7/100 patient-years. The KM-estimated cumulative incidence of SCI was 15.1% (95%CI: 10.9-19.3%) by age 8 and 25.7% (95%CI: 19.7-31.7%) by age 14. Intracranial and isolated eICA-arteriopathies were present in 110/338 and 54/338 patients, respectively. SCI were significantly associated with the presence of intra or extracranial arteriopathy (Fisher test, p=0.013) as 41/65 children with SCI had intra or extracranial arteriopathy (20 isolated intra, 15 isolated extra and 6 intra and extracranial), while in the other 24 patients, 5 had history of conditional TAMV, 11 of acute anemia and 8 of recent acute chest syndrome. At first cerebral MRI, the multivariate Cox regression analysis retained as significant and independent predictive risk factors for SCI, baseline high reticulocyte count [HR=1.005 (95%CI: 1.002-1.008); p=0.004] and LDH [HR=1.001 (95%CI :1.001-1.002); p=0.001]. Discussion This long-term longitudinal study shows a reduction of the risk of SCI with time. The addition of eICA-assessment allowed the detection of isolated extracranial arteriopathy in 54 patients, with 15 who had SCI. The earlier HU initiation reducing the risk of ACS, acute anemia and hemolytic rate, along with detection of isolated eICA assessment and the use of transplantation in children with cerebral arteriopathy have most likely contributed to this overall improvement. Nevertheless, we suggest that initiating CT in patients with eICA-TAMV 160-199 cm/s, even in the absence of eICA stenosis, as done for intra- and extracranial-TAMV ≥ 200 cm/s, could further reduce SCI risk. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Headache in Children with Sickle Cell Disease

Children with sickle cell disease (SCD) commonly experience headaches, both acutely and chronically. Although migraine and tension headache are common causes, headaches may also be related to their underlying SCD and associated with acute central nervous system events. The purpose of this study was to determine the frequency, severity, and associated characteristics of headaches in children with SCD. This retrospective study was approved by the Johns Hopkins Institutional Review Board. Subjects were children < 18 years old with SCD identified using Hopkins' clinic rosters and medical records. Patient medical records were searched to determine reports of headaches in inpatient or outpatient encounters. Data were extracted from subjects' charts including, SCD history, headache history, stroke and silent cerebral infarction (SCI) history with additional review of imaging by neurologist (EIL) and radiologist if needed to confirm diagnosis, medications, laboratory values, neurology referrals, and neuroimaging results. Based on patient-reported headache details in the medical record, we determined headache type using the International Classification of Headache Disorders criteria. Headaches were further characterized by frequency and severity. We used descriptive statistics to describe the SCD population with and without headaches. We then compared demographic and clinical characteristics of patients with headaches to those without headaches using parametric and nonparametric statistical tests when appropriate. We included 276 subjects in our data analysis. Fifty three percent of patients had a history of headache. Characteristics of subjects with (N=147) and without (N=129) headache are in Table 1. Sixty-six of the headache subjects were seen by a neurologist/neurodevelopmental physician. The primary reason for referral for 10 subjects was headache, SCI for seven subjects, ADHD for 11 subjects, learning difficulties for 25 subjects, and other for 19 subjects. Compared to those without headaches, subjects with headaches were significantly older at time of chart review (10.52 vs. 6.67, p < 0.0001), had more severe disease (62.2% sickle cell anemia vs. 37.4% compound heterozygous, p<0.001), had more neurological complications (7% stroke & 12% SCI - headache group vs. 3% stroke and 1% SCI - no headache group, p <0.003), had higher median reticulocyte count (8.0% vs. 4.3%, p < 0.003), and lower median hemoglobin F (7.95% vs. 11.7%, p <0.003). In terms of headache characteristics, nine patients reported headaches less than one day per month on average; 13 subjects reported one to 14 days of headache per month on average for more than three months; and four subjects reported greater than 15 days of headache per month on average for more than three months. Five subjects also reported avoidance of their routine due to headaches. Twelve subjects were hospitalized for headache and 30 reported an emergency department visit for headache. Only 10 subjects had enough details about their headache features to determine their headache type (Table 2). Nine of the subjects' headache types were consistent with criteria for migraine headaches and one subject had tension type headache. Headaches are common in children with SCD. Our findings suggest that children with SCD and history of headache are more likely to have SCD-related and neurological complications. Additionally, children with SCD and headache are more likely to have a higher median reticulocyte count which is associated with more severe disease. More studies are needed to classify and understand headaches in children with SCD, which may help guide management and treatment in this patient population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Trials in Progress: Two Randomized, Double-Blind, Multicenter, Placebo-Controlled Trials Investigating the Efficacy of Voxelotor on Cerebral Blood Flow and Neurocognitive Function in Patients with Sickle Cell Disease

Background: Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in the beta chain of hemoglobin (Hb) that results in the formation of sickle hemoglobin, HbS. Polymerization of HbS under conditions of deoxygenation causes red blood cell sickling that can lead to hemolytic anemia and vascular occlusion with subsequent end-organ damage, infarction, and cognitive dysfunction. In patients with SCD, cerebral blood flow (CBF) is elevated throughout the brain, with silent cerebral infarcts (SCIs) occurring mainly in brain regions with the lowest CBF. SCIs, overt strokes, and cognitive impairment are some of the most common complications of SCD, all of which have a substantial impact on the education, employment, and quality of life of patients with SCD. Cognitive impairment in patients with SCD can also manifest in those without SCI or overt stroke, suggesting a potential role of chronic anemia and cerebral hemodynamics in neurocognitive dysfunction. Despite progress in the development of therapies for SCD, little is known about their effect on cognitive function and cerebral hemodynamics. Voxelotor is a HbS polymerization inhibitor approved in the United States for the treatment of SCD in patients aged ≥4 years and in the United Kingdom, European Union, and the United Arab Emirates for patients aged ≥12 years. Objective: To understand the impact of voxelotor on brain function in patients with SCD, 2 post-approval studies of voxelotor are currently recruiting and are described here. Methods: The Neurocognitive Function study (NCT05228834) is a phase 3b, randomized, double-blind, placebo-controlled, multicenter trial investigating the effect of once-daily oral voxelotor (Figure) on neurocognitive function in children and adolescents with SCD. The Cerebral Hemodynamics study (NCT05228821) is a phase 4, randomized, double-blind, placebo-controlled, multicenter trial investigating the impact of once-daily oral voxelotor (Figure) on CBF in adolescents and adults with SCD. An overview of the study population, study design, and key endpoints for both studies is provided in the Table. Results: The primary objective of the Neurocognitive Function study is to assess the effect of voxelotor compared with placebo on the neurocognitive function in children and adolescents with SCD (aged 8 to <18 years), which will be evaluated by measuring the change from baseline at week 12 in the executive abilities composite score, as assessed by the National Institutes of Health Toolbox Cognition Module. The primary objective of the Cerebral Hemodynamics study is to assess the efficacy of voxelotor compared with placebo on CBF in adolescents and adults (aged 12-30 years) with homozygous hemoglobin S (HbSS) or sickle beta zero thalassemia (HbSβ0), which will be evaluated by assessing the change from baseline in CBF measured by magnetic resonance imaging at week 12. Conclusions: Treatments that improve neurocognitive dysfunction represent an important unmet need in the management of SCD. Results from the Neurocognitive Function study and the Cerebral Hemodynamics study (the latter will enroll adult patients) will provide important information on the impact that inhibition of HbS polymerization may have on cognitive function and cerebral hemodynamics by improving anemia and hemolysis in patients with SCD. Funding: Global Blood Therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cognitive Dysfunction Worsens with Age in Patients with Sickle Cell Disease in the Modern Treatment Era

Introduction Patients with sickle cell disease (SCD) suffer from cognitive dysfunction compared to those unaffected by the disease. Such cognitive dysfunction in patients with SCD is further exacerbated by the occurrence of overt stroke or silent cerebral infarcts (SCIs). Fortunately, treatments such as hydroxyurea and red blood cell (RBC) transfusion for patients with SCD have been shown to be neuroprotective. Studies that predate guidelines recommending all patients with HbSS or HbS beta thalassemia null genotypes receive primary disease modification with hydroxyurea report that cognitive dysfunction worsens with age in patients with SCD. However, there is limited investigation into cognitive trajectories across the lifespan during the modern treatment era for patients with SCD. While neuroprotective interventions are widely recommended, we hypothesize that patients with SCD will continue to experience cognitive decline. Methods Patients >5 years of age with any genotype of SCD, excluding those receiving chronic RBC transfusions, were included in these analyses. Cognitive data, as measured by the NIH Toolbox-Cognitive Battery (NIHTB-CB) and the Wechsler Abbreviated Scale Intelligence 2nd edition (WASI-II), were combined from three prospective research studies at a single institution. A subgroup of participants had multiple timepoints of data collected. Multivariate general linear mixed-level models, accounting for multiple timepoints per participant, were used to predict each cognitive subdomain while controlling for the independent variables of age and sex. Age squared (age2) was included in models if necessary to account for a second-order polynomial fit. Significance was defined as α<0.05 and the Benjamini-Hochberg procedure was used to correct for multiple comparison. Results Data was collected from 123 participants with SCD between 2014-2022. The cohort was 45.4% male (56/123 participants). Thirty-four participants had 2 timepoints and 7 participants had 3 timepoints of cognitive data included in the analyses, for 164 total timepoints. First and last-timepoints were separated by 1-4 years for the NIHTB-CB and 1-8 years for the WASI-II tests. The average (SD, range) number of months between the first and last encounters was 31.2 (10.9, 14.2-47.7) for completion of NIHTB-CB testing and 43.9 (22.2, 14.2-89.3) for completion of WASI-II testing. Table 1 describes the cohort. The average (SD, range) hemoglobin at all timepoints was: 9.0 (1.6, 5.6-13.3). The number (percent) of participants taking hydroxyurea and the mean (SD, range) dosage for all timepoints was: 97/164 (59.1%), 380.9mg (649.4, 11.0-2000.0). Using multivariate general linear mixed-level models to predict each cognitive subdomain and composite score provided in the NIHTB-CB and WASI-II, the Flanker Inhibitory Control and Attention (age p=0.0164), Oral Reading (age p=0.0006, age2 p=0.0018), Pattern Comparison Processing Speed (age p=0.0210, age2 p=0.0206, sex p=0.0041), Crystallized Composite (age p=0.0038, age2 p=0.0063) and Total Composite (age p=0.0215, age2 p=0.0219) scores decreased with age while controlling for the effect of sex (Table 1, Figure 1). There was not a significant relationship between age and cognitive outcome measure for the Picture Vocabulary, List Sorting Working Memory, Dimensional Change Card Sorting, Picture Sequence Memory, Fluid Composite, Matrix Reasoning or Full-Scale IQ tests. Conclusion We conclude that cognitive abilities, encompassing executive function abilities (Flanker Inhibitory Control and Attention Test), non-executive function abilities (Oral Reading Test and Crystallized Composite) and processing speed (Pattern Comparison Processing Speed Test), decrease as patients with sickle cell disease age during the modern treatment era. Further analyses are required to determine the impact of age on cognitive outcomes while controlling for the presence of infarction, primary disease modification, hemoglobin and additional biologic covariates. These preliminary analyses support further investigation into the pathophysiology of SCD on both brain development and aging, and consideration of neurocognitive outcomes in the development of new therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment of Individuals with Severe Sickle Cell Disease with OTQ923, an Autologous, Ex Vivo, CRISPR/Cas9-Edited, CD34+ Hematopoietic Stem and Progenitor Cell Product, Leads to Durable Engraftment and Fetal Hemoglobin Induction

Introduction: Increased levels of fetal hemoglobin (HbF; encoded by γ-globin [HBG1/HBG2]) are protective against complications of sickle cell disease (SCD). BCL11A is a transcription factor that binds to HBG1/HBG2 promoters and produces a γ-to-β globin (fetal-to-adult hemoglobin) switch. Inhibiting BCL11A binding to its target can reverse the switch and induce HbF expression in adult red blood cells (RBCs). OTQ923 is an autologous, ex vivo, CRISPR/Cas9-edited, CD34+ cellular product with a targeted disruption of the HBG1/HBG2 promoters on chromosome 11. Targeting this region in preclinical models led to HbF induction, phenotypically recapitulating hereditary persistence of fetal hemoglobin (a naturally occurring condition whose co-inheritance ameliorates SCD severity). This approach is more targeted than complete elimination of BCL11A expression in erythrocyte precursors for treating hemoglobinopathies. Additionally, unlike lentiviral vector gene addition, induction of endogenous γ-globin transcription could concur with reduction of βS-globin expression to avoid α- and β-like globin chain imbalance. Methods: Subjects with severe SCD, defined by a history of stroke, recurrent vaso-occlusive events (VOE), acute chest syndrome (ACS), chronic transfusions, recurrent priapism or red cell alloimmunization, were eligible to participate in the adult cohort (≥18-≤40 years old) of this clinical trial (NCT04443907). OTQ923 was manufactured from cryopreserved, peripheral blood derived CD34+ cells, collected after plerixafor mobilization. Prior to infusion, participants received myeloablative busulfan. Primary endpoints are to evaluate engraftment, long-term safety, and efficacy of HbF expression. Results: As of the data cut-off (July 8, 2022), 2 participants had received OTQ923, with follow-ups of 9 months (mos) and 3 mos, respectively. Here, we present initial clinical data from these 2 participants; additional data will be presented at the meeting. Both participants were homozygous for the sickle mutation. Participant 1 is a 22-year-old male with a history of silent cerebral infarcts, ACS, and priapism. At study entry, he was receiving chronic transfusions. He received 2.8x106 CD34+ cells/kg of OTQ923 (2 combined manufacturing batches). Participant 2 is a 21-year-old male with a history of ACS, and a silent cerebral infarct and was receiving hydroxyurea. He received 5.99x106 CD34+ cells/kg of OTQ923 (3 combined manufacturing batches). Time to neutrophil engraftment (the first of 3 consecutive days of absolute neutrophil count above 500 cells/mL after cell infusion) was 26 and 20 days for Participants 1 and 2, respectively. No OTQ923-related adverse events (AEs) were reported in either participant. All observed AEs were consistent with busulfan conditioning. Participants received RBC transfusions around conditioning and have received none after engraftment. For Participant 1, HbF level increased in the 6 mos after infusion and was stable at data cut-off (22.1% HbF at 9 mos after infusion). Induction of HbF was pancellular, with an F-cell percentage around 91% at 6 mos after infusion (Fig. 1A). Participant 2 had achieved an HbF level of 15.9% at 3 mos after infusion, the latest evaluable timepoint at data cut-off. Neither participant had any SCD-related VOEs after infusion of the cellular product. The proportion of edited alleles in the peripheral blood of Participant 1 was maintained at over 60% until Mo 6, which was the last evaluable timepoint (Fig. 1B). The indels were diverse, except for a predominant, large 5 kb deletion arising from simultaneous double-stranded DNA cleavage at HBG1 and HBG2 on-target sites, similar to previous reports. Conclusion: Preliminary data demonstrate clinically meaningful increases in HbF and evidence of benefit for both Participants 1 and 2 after OTQ923 infusion. Edited alleles were stable and maintained in the peripheral blood for >6 mos. The safety profile of OTQ923 was as expected after myeloablative busulfan and autologous hematopoietic stem cell transplantation. Taken together, these data suggest that this approach is safe and offers a potentially curative option for patients with severe SCD. Using cryopreserved, CD34+ cells as a starting material offers the advantage of centralizing manufacturing, scaling up the process to allow for improved patient access around the globe. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Progressive Silent Cerebral Infarcts Are Prevalent in Adults with Sickle Cell Anemia but Moderate-Severe Cognitive Abnormalities Are Independent of Preexisting Silent Cerebral Infarcts

Progressive Silent Cerebral Infarcts Are Prevalent in Adults with Sickle Cell Anemia but Moderate-Severe Cognitive Abnormalities Are Independent of Preexisting Silent Cerebral Infarcts

Silent Cerebral Infarction during Immune TTP Remission - Prevalence, Predictors and Impact on Cognition

BACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) survivors are at increased risk cardiovascular events including stroke, which is associated with low remission ADAMTS13 activity. In the prospective Neurologic Sequelae of TTP (NeST) study, we evaluated the prevalence of silent cerebral infarction (SCI, ischemic lesions on brain MRI without overt neurodeficits that are a risk factor for future stroke), identified risk factors for SCI, and examined the association of SCI with cognitive impairment, which is prevalent in iTTP survivors. METHODS: We prospectively enrolled adult (age ≥ 18 years) patients with iTTP based on ADAMTS13 activity <10% during an acute episode. All study assessments were performed after achieving hematological remission. Participants undergo annual study visits that include: 1) Brain MRI: SCI is defined as a infarct like lesion (punctate T2 and FLAIR hyperintensity) ≥3 mm in size without corresponding neurodeficits., 2) NIH ToolBox Cognition battery, an extensively-validated tool that tests multiple cognitive domains including executive function (dimensional change card sort test, flanker inhibitory control and attention test), processing speed (pattern comparison test), episodic memory (picture sequence memory test), working memory (list sorting working memory test), language (oral reading recognition, picture vocabulary test). Fully-corrected T scores (normative mean 50, SD 10) adjusted for age, sex, race and educational attainment are computed for individual tests as well as composite scores for fluid cognition, crystallized cognition and total cognition. Mild and major cognitive impairment are defined as a T scores that are 1-2 SD below mean and > 2 SD below mean for any domain, respectively; 3) the Beck depression inventory was also completed since depression is a potential confounder that is common in iTTP and may contribute to impaired cognition. RESULTS: Between September 2020 and July 2022, 39 iTTP patients were enrolled; 32 patients completed MRI (2 excluded due to metal implant/shrapnel, 4 stopped for anxiety/claustrophobia). Median age was 48 years, 71% were female, and 23% had previous stroke (including during acute iTTP). Prevalence and predictors of SCI: MRI showed SCI in 53.1% (Figure 1). Only 47% (8/17) patients with SCI had prior overt stroke. Age [OR 1.07 (95% CI 1.01-1.15, P=0.025) and history of stroke [OR 12.8 (95% CI 1.07-152.9), P=0.044] were associated with SCI in a logistic regression model adjusted for number of iTTP episodes [OR 1.14 (95% CI 0.71-1.86), P=0.570], hypertension [OR 0.77 (95% CI 0.14 - 4.25), P=0.768], and Black race [OR 2.10 (95% CI 0.16-28.20], P=0.574]. SCI is associated with cognitive impairment: Mild and major cognitive impairment were present in 23.1% and 30.8%, respectively. Deficits most commonly involved executive function (flanker inhibitory control and attention test, dimensional change card sort test) and processing speed (pattern comparison test). Compared to patients without SCI, those with SCI had higher rates of cognitive impairment (70.5% vs. 26.7%) including major impairment (52.9% vs. 6.7%) (P=0.014) (Figure 2). In logistic regression models adjusted for age and prior stroke, SCI was associated with major cognitive impairment [OR 18.13 (95% CI 1.3-259.1), P=0.033] as well as mild cognitive impairment [OR 7.76 (95% CI 1.03-58.29]. Patient with SCI had lower composite scores on the NIH ToolBox cognition battery [fluid cognition composite 41 vs. 55, P=0.009, crystallized composite 50 vs. 60, P=0.033, total composite 46 vs, 59, P=0.004), as well as lower scores on tests of executive function (flanker inhibitory control and attention, P=0.020) and processing speed (pattern comparison test, P=0.004), which are most commonly affected in iTTP. Patients with SCI did not have higher mean Beck Depression inventory scores (12.0 ± 7.8 vs. 11.67 ± 11.5, P = 0.659) than those without SCI suggesting that the association with cognitive performance is not due to higher rates of depression in this group. CONCLUSIONS: MRI evidence of brain infarction is common in patients with iTTP with or without a clinical history of stroke. Ongoing follow up with serial MRI continues and will inform whether SCI are progressive in remission and whether low remission ADAMTS13 is a targetable risk factor. The strong association of SCI with impaired cognition suggests that these 'silent infarcts' are neither silent nor innocuous. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Crizanlizumab Use in Recurrent Neurologic Symptoms Attributed to Sickle Cell Disease Induced Moyamoya Syndrome

Sickle cell disease (SCD) is a genetic disorder that affects about 100,000 Americans and carries the risk of significant complications including ischemic stroke. Moyamoya syndrome (MMS), a complication of SCD, is characterized by progressive stenosis of carotid arteries leading to ischemic stroke (Dobson, et al). To reduce these complications, the mainstay of treatment of SCD, until recently, has been transfusion and hydroxyurea. In 2019, the FDA approved the monoclonal antibody crizanlizumab. Crizanlizumab binds and blocks p-selectin to prevent downstream cell to cell interactions, including platelet aggregation, thereby improving blood flow and preventing vaso-occlusion (Ataga, et al). We report a case of a sickle cell patient with recurrent neurological symptoms and MRI findings of MMS that unexpectedly resolved with crizanlizumab treatment. A 26 year old woman with history of vitamin B12 deficiency, HbSS disease complicated by silent cerebral infarct in childhood treated with hydroxyurea and red blood cell (RBC) exchange presented to the hospital with left lower extremity weakness. She reported that her sickle cell crisis typically manifested with left sided weakness rather than pain. Her most recent RBC exchange six days prior had revealed a hemoglobin S level of 11.8%. Her initial workup including MRI brain demonstrated right parietal encephalomalacia and evidence of chronic ischemic change of the right frontal and parietal lobes consistent with previously known silent ischemia of the right middle cerebral artery (MCA). There was no evidence of acute stroke. The patient continued monthly RBC exchange, maintaining a hemoglobin S level less than 36% and continued to experience symptoms of intermittent weakness, typically of the left lower extremity, but also at times involving the bilateral lower extremities and left upper extremity. Repeat MRI brain did not demonstrate any additional acute infarctions. However brain MRA did reveal bilateral stenosis of the MCA arteries and high-grade stenosis of the M1 segment and considered stable from previous MRI, consistent with MMS. Her symptoms continued intermittently and additional evaluation including MRI cervical, thoracic, and lumbar spine was unrevealing. Of note, at one point laboratory evaluation demonstrated a vitamin B12 level of 248 pg/mL, however her symptoms continued in spite of adequate repletion. Approximately 21 months following her initial presentation, the SARS-CoV-2 pandemic began, resulting in limited access to hospital facilities including RBC exchange. Consequently the patient was started on crizanlizumab with intermittent simple transfusion for hemoglobin less than 8 g/dL in an effort to see if this therapeutic measure would alleviate her symptoms. Interestingly, after initiating crizanlizumab, even without continued RBC exchange and a hemoglobin S level of 83%, she had no further episodes of weakness until, due to insurance issues, her crizanlizmab was delayed. Subsequently her symptoms of weakness returned requiring hospital admission. Repeat workup including both MRI and MRA brain were negative for acute ischemia and again consistent with MMS. Resumption of crizanlizumab again alleviated symptoms until infusion was delayed again for insurance reasons. She was readmitted and repeat MRI and MRA of the brain again did not show acute ischemia. Given recurrent issues with insurance and easing of the SARS-CoV-2 pandemic restrictions she was resumed on both red-cell exchange followed by crizanlizumab and continues to do well to this day. SCD carries significant potential neurological morbidity and mortality. SCD patients experience a significantly higher risk of stroke due to repeated vaso-occlusive events leading to cerebral ischemia and the development of MMS. This is the first case we are aware of in which a patient with sickle cell disease and MMS and worsening neurologic symptoms but without acute stroke was successfully was treated with crizanlizumab after failure of RBC exchange. Crizanlizumab targets P-selectin which is implicated in increased platelet aggregation in sickle cell disease. It is possible that crizanlizumab improved the patient's symptoms by reducing the risk of transient cerebral ischemia associated with her underlying abnormal vasculature, which was suspected due to acute cerebral vaso-occlusion secondary to sickle cell disease induced moyamoya syndrome.

A Novel Finding in Cerebral Blood Flow in Patients with Sickle Cell Disease Using Bold Functional MRI

Background: Sickle cell disease (SCD) is an inherited blood disorder which is associated with acute and chronic pain, as well as other vascular complications such as arterial steno-occlusion, stroke, and silent cerebral infarction. Alterations of cerebral blood flow have been found to be associated with different painful stages in SCD, thus cerebral blood flow might be correlated with the disease severity determined by varied pain conditions in SCD. Blood oxygen level dependent (BOLD) imaging is a blood-related contrast technology in functional magnetic resonance imaging (fMRI). We have previously demonstrated the feasibility of using low frequency oscillation (LFO) in BOLD fMRI to track the hemodynamic features of the blood flow with maximum cross-correlation coefficient (MCCC) and the Delay Time (i.e., blood arrival time at different brain regions) (Tong et al., JCBFM. 2017). Positive MCCC value was found between the LFO BOLD signals extracted from the global mean (GMean, averaged signal across the whole brain) and the superior sagittal sinus (SSS) in our previous findings (Tong et al., JCBFM. 2018). In this study, we aim to use LFO BOLD signals to explore the cerebral hemodynamic features with MCCCs and their associations with hematological and disease severity related outcomes in patients with SCD. Methods: Ten subjects with SCD aged 14-43 years old (5 HbSS, 3 HbSC, 1 HbSB+, 1 HbB0) and 10 age- and sex-matched controls from a publicly available dataset Human Connectome Project (HCP) (Essen et al., Neuroimage, 2013) were included for data analysis. T1-weighted and resting-state BOLD fMRI (repetition time (TR)=1.05 sec) were collected using a 3T SIEMENS (Prisma) scanner. A BOLD fMRI dataset with TR of 0.72 sec from healthy subjects was used as control. All the BOLD fMRI data were preprocessed using FSL to correct the motion artifact. The SSS region was identified in the T1-weighted image using FSL. The corresponding SSS mask was then applied in the BOLD fMRI image to extract the BOLD fMRI signals in the SSS region. The GMean BOLD signal was averaged across the whole brain. BOLD fMRI Signals were demeaned and band-pass filtered (0.01-0.1 Hz) to acquire the LFO signals. Cross-correlation between the SSS-LFO signal and GMean-LFO signal was performed to calculate the MCCC and their corresponding Delay Time. Correlations between the MCCCs of the two LFO signals (from SSS and GMean) and each hematological index were further performed. Results: Consistent with the healthy control in our previous findings, half of the patients (3 HbSC, 1 HbSB+, and 1 HbSS) presented positive MCCC values. However, interestingly, negative MCCC values were found from another half of the patients (4 HbSS and 1 HbB0, Figure 1, p < 0.05 for all subjects). Notably, all patients with HbSC presented positive MCCC values that are similar to controls whereas 4 out 5 patients with HbSS (80%) were found to have negative MCCC values. More importantly, higher percentages of HbS and lower total Hgb (HbS(%): r=-0.73, p=0.03; Hgb(GM/dL): r=0.69, p=0.03) were found to be significantly associated with the negative MCCC values. Conclusions: We found a never-before-seen negative MCCC signature between the BOLD fMRI signals in the SSS and the GMean in a subset of patients with SCD compared with healthy controls. This might indicate a significant change in cerebral blood flow in a subset of patients with SS disease compared with SC and controls. Importantly, we further observed that this never-before-seen negative MCCC signature is highly associated with the percentage of the HbS and total Hgb that are known to be correlated with disease severity. This might be due to the microvascular shunting (Juttukonda et al., JCBFM, 2019) that exists in patients who have high percentage of HbS. This study is the first to associate BOLD fMRI derived hemodynamic metrics with disease severity related outcomes in SCD. This never-before-seen anti-correlation MCCC signature may have tremendous promise as a novel biomarker for SCD severity and differentiate pain characteristics in different sickle cell phenotypes, and further investigation in larger number of subjects is needed to understand variations between SCD phenotypes and its relationship to clinical outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effect of Voxelotor on Cerebral Perfusion and Cerebral Oxygen Metabolism in Adult Patients with Sickle Cell Disease; Preliminary Results of the Coverage Study

Background: Sickle cell disease (SCD) is characterized by hemolytic anemia and a hyperdynamic circulation resulting in impaired cerebral hemodynamics and perfusion, culminating in ischemic damage of the brain. SCD is strongly associated with overt strokes or silent cerebral infarctions (SCI) which have been related to elevated flow in the median cerebral artery in children measured by transcranial Doppler. Patients with SCD have an increased cerebral blood flow (CBF) to maintain adequate oxygen delivery (OD). Previously, we and others have demonstrated with special MRI techniques that despite the maintained OD, cerebral metabolic rate of oxygen (CMRO2) is reduced in SCD due to reduced oxygen extraction fraction (OEF), which in turn is strongly related to CBF and hemoglobin (Hb) level. Voxelotor is a small molecule that reversibly binds to Hb and increases its oxygen affinity, thereby decreasing Hb polymerization and sickling. The resulting decreased hemolytic anemia can potentially ameliorate cerebral hemodynamics and perfusion, the increased oxygen affinity may reduce the offloading of oxygen. The aim of our study is to assess the effects of voxelotor on markers of cerebral perfusion and oxygen metabolism. In addition, the effect of voxelotor on the hyperdynamic cardiac function was assessed. Methods: This single-arm, interventional trial is being conducted in a tertiary hospital in Amsterdam, The Netherlands. Adult SCD patients with the severe genotypes of HbSS and HbSβ0-thalassemia were eligible for inclusion. Other major inclusion criteria were: Hb ≤ 10.5 g/dL and in case of hydroxyurea use, a stable dose for at least 90 days. Major exclusion criteria were: regular transfusions or a transfusion within 90 days prior to inclusion, hospitalization for vaso-occlusive crisis ≤ 14 days before inclusion. At baseline and after 3 months of voxelotor treatment (1500 mg pd), MRI scans, echocardiography and laboratory assessments were performed. Time-encoded arterial spin labeling was performed to obtain CBF measurements, gray matter CBF was derived by using white matter and gray matter masks. T2 relaxation under spin tagging was performed in order to calculate OEF. Oxygen delivery and CMRO2 were calculated: formula, CBF x OD, with the OD calculated from OEF and oxygen content. Maximal tricuspid regurgitation velocity (TRVmax) was assessed by trans-thoracic echocardiography as a marker of hyperdynamic circulation. N-Terminal pro-B-type natriuretic peptide (NT-proBNP) was measured as a marker of cardiac stress/dilatation. Parametric data are presented with mean and SD and analyzed by a paired T-test and non-parametric data with median and IQR, and analyzed by a Wilcoxon signed-rank test. Results: Preliminary results of 15 patients (HbSS/HbSβ0-thalassemia, 11/4, mean age 38 years (SD 10), 4 female) who completed their 3 month follow-up are presented here. Upon 3 months of voxelotor treatment, Hb levels significantly increased, 7.6 g/dL, (IQR 6.9 - 8.2) compared to 10.0 g/dL (IQR; p < 0.001), and hemolysis significantly reduced, represented by reticulocyte count, bilirubin and LDH levels (p = < 0.05; Table 1). After 3 months of treatment also a significant increase in oxygen delivery from 6.4 to 8.2 ml O2/100g/min (p = 0.006) was observed, which was primarily due to the increased Hb levels. However, CBF and CMRO2 did not change significantly after 3 months of voxelotor treatment (Table 2) while OEF decreased significantly at 3 months as compared to baseline (from 28.9% to 23.2%, p = 0.002) (Table 2). No significant changes in NT-proBNP levels and TRVmax were observed (Table 1) although a significant decrease was observed in patients with NT-proBNP-levels >160 at baseline (213 (IQR 161 - 254) ng/L vs 152 (IQR 50 -163) ng/L; p = 0.028)). Conclusion: In this preliminary study, no changes in cerebral hemodynamics (CBF) and oxygen metabolic rate (CMRO2) were observed, despite an increased cerebral oxygen delivery due to improvement of Hb levels. CMRO2 remained unchanged as a result of diminished OEF, based on the calibration according to the Li-Bush model, most likely due to the increased oxygen affinity attributed to voxelotor. With respect to the cardiac measures of the circulatory state, no effect on NT-proBNP levels and TRVmax was observed although a significant decrease in NT-proBNP-levels was observed in a post-hoc analysis of patients with elevated NTproBNP levels at baseline. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association of Elevated Tricuspid Regurgitation Velocity with Kidney and Cerebrovascular Disease in Children with Sickle Cell Disease

Introduction: Adult patients with sickle cell disease (SCD) develop progressive end-organ injury leading to multi-organ disease and increased mortality. It is plausible that this multi-organ damage begins in pediatric patients. Tricuspid regurgitation velocity (TRV), measured by echocardiography is a surrogate marker for pulmonary hypertension that is a poor prognostic factor in adults with SCD. The utility of screening echocardiograms as a marker of disease severity is being studied in pediatrics. In this study, we assessed associations between elevated TRV with early development of chronic kidney disease (albuminuria), and cerebrovascular disease (CVD). Methods: We performed an IRB approved cross-sectional study to evaluate the prevalence of elevated TRV ≥ 2.5 m/s and its associations with albuminuria and CVD in patients with SCD ages 1-21 years. We included children with a diagnosis of SCD who had at least one echocardiogram performed during an outpatient clinic visit at steady-state for screening for pulmonary hypertension. We categorized patients as receiving either transfusion therapy (chronic transfusion for >12 months), SCD modifying therapy (hydroxyurea, voxelotor, crizanlizumab, or L-glutamine), or no therapy. Patients on both transfusion and a SCD modifying therapy were defined as being on transfusion therapy. We defined albuminuria as patients with two of three consecutive albumin creatinine ratios ≥30mg/g measured during standard clinic visits. Cerebrovascular disease was defined as having either 1) an overt stroke, 2) silent cerebral stroke defined by MRI, 3) vasculopathy by abnormal magnetic resonance angiography (MRA), 4) transient ischemic event defined by stroke symptoms that resolved within 24 hours, or 5) abnormal TCD (>200 cm/second). We performed bivariate analysis utilizing t-test (or Kruskal-Wallis test) and Cochran-Mantel-Haenszel test for continuous and categorical variables respectively. To determine the association between elevated TRV and albuminuria, and elevated TRV and CVD, logistic regression was fit and adjusted for variables that were significant in the bivariate analysis. Using the TRV <2.5m/sec as the reference group, adjusted odds ratios with their accompanying confidence intervals were calculated for those with albuminuria and those with CVD in separate models. All reported P values were 2-sided. Statistical significance was defined as p<0.05. All analyses were performed using Statistical Analysis Software 9.4, (SAS Institute, Cary, NC). Results: Among 166 children with echocardiography, the prevalence of an elevated TRV was 21%. On bivariate analysis, elevated TRV was significantly associated with persistent albuminuria (OR 2.85 (95% CI: 1.27-6.43) and cerebrovascular disease (OR: 2.46 (95% CI: 1.09-5.53) (Table 1). An elevated TRV was also significantly associated with increased age (15.6 vs 12.9 yrs, p=0.005), lower hemoglobin F% (2.5 vs 4.6%, p=0.01), higher absolute reticulocyte count (0.5 vs 0.4 x 106/ µL p=0.005) and chronic transfusion therapy (p=0.04). After adjusting for age, absolute reticulocyte count, HbF and treatment in a multivariable logistic regression, the associations between elevated TRV with either persistent albuminuria (OR: 1.82 (0.71 - 4.67)) and cerebrovascular disease (OR: 1.15 (0.43-3.10)) were no longer statistically significant (Table 1). Our data suggests that with an odds ratio of 2.9 and a prevalence of elevated TRV of 20%, a prospective study of 166 adolescent patients with SCD would be needed to detect the association between elevated TRV and persistent albuminuria with 80% power and 233 children would be needed to detect this difference with 90% power. Conclusion: This data provides additional evidence that around 20% of pediatric patients have an elevated TRV and those patients may also have an increased risk for developing chronic kidney disease and cerebrovascular disease. A larger, prospective cohort study should be conducted to confirm these findings and determine the role of screening echocardiography in pediatric SCD. At minimum, our data suggests that pediatric patients with known chronic kidney disease or cerebrovascular disease should be screened for cardiac complications. Furthermore, longitudinal studies are needed to evaluate the association between elevated TRV in children with early end-organ complications in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Brain MRI Screening and Abnormal Findings in Sickle Cell Patients, a Single Center Experience

Background Neuropsychiatric effects of Sickle Cell Disease (SCD) are not very well understood. Sickle cells cause vaso-occlusion and ischemic manifestations that can affect various organ systems. The cumulative effect of insults to the brain can be detrimental resulting in potential cognitive delays. Regular blood transfusions and hydroxyurea are established as preventative and therapeutic measures to decrease the risk of cerebrovascular accidents. Strong evidence for timing of screening for brain damage in SCD patients is not available (S C Thust et al). A conditional recommendation from the ASH guideline panel 2020 suggests at least a one-time screening MRI to detect silent cerebral infarcts in adults with SCD (DeBaun MR et al) Objectives 1. To determine rates of obtaining screening MRI for adult SCD patients enrolled in the Sickle Cell Clinic at Henry Ford Hospital 2. To investigate brain parenchymal changes manifested by Brain MRIs and Head CTs and study associated factors Methods: We performed a retrospective chart review on 105 patients enrolled in the sickle cell clinic at Henry Ford Hospital who have been followed from June 2013 - June 2022. Baseline characteristics, laboratory findings and presence of comorbidities along with provided therapies are compared among patients with abnormal MRI findings. Results Out of the 105 patients, 20 (19%) had a Brain MRI done at least once during their lifetime for various reasons. A total of 14/20 MRI reports picked up abnormal findings (70%). Conversely, 44 patients had a CT head done (42%), 17 of which described abnormal findings (39%). Of note, only 4 patients had a transcranial doppler ultrasound, all of which were normal. Dissecting those 14 brain MRI reports, 7 cases had ischemic changes/chronic infarcts, 2 cases had white matter changes and 6 cases had other findings including tonsillar ectopia, cerebral and cerebellar volume loss, aneurysms, and degenerative changes. The baseline characteristics as well as clinical parameters of those patients are described in tables 1 and 2. Looking at the 17 total abnormal head CT reports: 9 cases were described as chronic ischemic changes, 3 hemorrhage cases (one subarachnoid hemorrhage, one subdural and one intracranial hematoma), 2 cases had brain atrophy and 4 cases had other findings including encephalomalacia, punctate hyper-density and trabeculation or lacy appearance of the skull base. Discussion At least 25% of individuals with SCD will have a neurological complication over their lifetime (Lonergan G et al). Despite paucity of literature looking into prevalence of neuroradiological findings, they have been reported in 44-60% of patients with SCD (Silva et al). Looking at our center's experience approximately half of the screened patients had chronic ischemic changes reported, which intuitively corelates with silent infarcts known to happen in SCD patients. Patients with neurological deficits and developmental delays are more likely to be screened. Despite the lack of statistical power to extrapolate further, it seemed that patients with abnormal brain MRI reports were more likely to have Congestive Heart Failure and Deep Vein Thrombosis. They also possibly consumed more alcohol and illicit drugs. Those patients were slightly more likely to be on hydroxyurea and had more frequent blood transfusions, emergency department visits and hospitalizations. Worth mentioning, out of the 14 patients with positive MRI findings, 13 had head CT scans performed concomitantly. 6 of those CT scans reported abnormal findings (46%) and 7 were normal (54%). This infers that there is a high proportion of patients who have normally read head CT scans but have brain parenchymal changes if screened by an MRI. Conclusions Our center presently screened SCD patients by brain MRI in only 19% of cases. The results of this study help to encourage incorporating and reinforcing the implementation of ASH 2020 guidelines. It is likely that patients with more comorbidities have been screened earlier than others. Detection of neurological complications in SCD may potentially reduce ED visits and hospitalizations if picked up and managed early. Our results propose to re-study patient characteristics on a larger scale once more screening is performed and to compare it with our current data, aiming to have more informative conclusions on SCD patients with neuroradiological findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Association between heart and dementia… keep an eye on the left atrium.

Atrial fibrillation is associated with an increased risk of cognitive impairment and dementia. The mechanisms are not well known, but they are probably multifactorial and involve atrial myopathy, cardio-embolism, cerebral hypoperfusion, and comorbidities (systemic vascular sclerosis, disease of the small cerebral vessels, inflammation, etc.). Atrial fibrillation therapy could have a protective effect on dementia through diversified actions: (i) prevention of left atrial remodelling; (ii) prevention of cardio-embolism and silent (and not) cerebral infarcts; (iii) improvement of cardiac output and cerebral perfusion. Randomized trials will be needed to clarify the links between left atrium and dementia and to identify the most appropriate therapeutic strategies.

Abstract 11401: Silent Brain Infarct on MRI Predicts Clinical Stroke/ Transient Ischemic Attack in Mitral Stenosis

Introduction: Mitral stenosis (MS) is associated with a high risk of cardio-embolic events. However, current recommendations for initiating anti-coagulant therapy in patients with MS is limited to patients with atrial fibrillation (AF),atrial thrombi or those with a prior stroke. In patients with moderate to severe MS who are in sinus rhythm there are no firm recommendations for anti-coagulation despite a known higher risk of thromboembolic events. Moreover there is limited data on the prevalence of silent brain infarcts (SBI) in patients with MS. This study evaluated prevalence and predictors of silent and clinical stroke in MS. Methods: A total of 211 patients with moderate to severe MS (mitral valve area ≤ 1.5 cm2) were recruited in the study and were followed up over a7 year period. Patients with existing left atrial clot(s) or prior valvular intervention were excluded from the study. All patients underwent clinical examination, ECG, echocardiogram, and brain MRI on a 1.5T machine. A 24-hour Holter was performed on patients in sinus rhythm. Results: Among 211 patients, 87(41.2%) were male and 140 (66.3%)were in sinus rhythm. Moderate to severe mitral regurgitation and/or aortic regurgitation was present in 31 (14.7%) and 30 (14.2%)patients respectively. SBI was seen in 44 (20.9 %) patients [26 (18.6%)in sinus rhythm and 18(25.4%) in AF]. Female gender (OR 2.3 95% CI 1.01-5.1, p = 0.043), poorer NYHA functional class (Class II OR 16, 95%CI 4.1-62.8, p=0.001; Class III OR 4.1 95%CI 1.2-13.8, p = 0.024),AF (OR 3.8 95%CI 1.6-8.9 p = 0.002) and aortic regurgitation (OR 3.7 95%CI 1.3-10.4 p = 0.011)were associated with increased risk of SBI. Seventeen patients (8%) were lost to follow up. Among 194patients who completed follow up, clinical stroke/TIA occurred in 15 (7.7%) patients. SBI on MRI was associated with a higher risk of clinical stroke/TIA on follow up on multivariate analysis (OR 3.7 95%CI1.26-10.9, p=0.018). Conclusions: Silent brain infarction is present in a significant minority of patients with MS and is predictive of clinical stroke/TIA on follow up.

Abstract 14749: Assessment for Neurocognitive Change After Catheter Ablation for Atrial Fibrillation

Introduction: Several studies have been conducted to evaluate the neurocognitive effects of catheter ablation for atrial fibrillation. However, these studies have found mixed results. Theoretically, silent peri-procedural stroke might yield a worsening of neurocognitive function, though normalization of heart rhythms might yield improvement. The purpose of this study was to prospectively follow patients after catheter-ablation for paroxysmal or persistent atrial fibrillation with serial telephone-based Montreal Cognitive Assessments (t-MoCA) over 6 months to evaluate for changes in neurocognitive function. Hypothesis: No change in t-MoCA scores between baseline and 1-month, 3-months, and 6-months after catheter ablation for atrial fibrillation. Methods: All consenting patients who underwent first time or redo catheter ablation for atrial fibrillation (with either radiofrequency- or cryo-ablation) between January 2021 and May 2022 were enrolled in the study. A t-MoCA was conducted to measure cognitive function at baseline, 1 month, 3 months, and 6 months from the date of catheter ablation. Only patients who completed at least 1 month of follow-up were included for analysis. Paired t-tests and one-way ANOVA were used to assess for significant differences in t-MoCA scores. Results: 42 patients met criteria for analysis. Paired two-tailed t-test values at 1-month, 3-months, and 6-months demonstrated an increase in t-MoCA score by 2.17 (n=42, p = 0.036), 3.08 (n=27, p = 0.005), and 3.06 (n=24, p = 0.006) respectively when compared to baseline. One-way ANOVA testing showed no significant differences between the 1-month, 3-month, and 6-month scores (p = 0.73). Conclusions: Patients undergoing first time or redo catheter ablation for atrial fibrillation had significant improvement in t-MoCA scores at 1-month, 3-months, and 6-months post-ablation. The improvement seen at 1-month was sustained throughout the 6-months of follow-up. Further long-term assessment is needed to determine if this effect persists over a longer period of time and to potentially correlate these findings with post-ablation atrial fibrillation recurrence.

Abstract 11421: Intervention With Cerebral Embolic Protection in Transcatheter Aortic Valve Implantation (INTERCEPTavi): Does Carbon-Dioxide Flushing Reduce Vascular Brain Injury?

Background: Transcatheter Aortic Valve Implantation (TAVI) is associated with 2-3% clinical stroke rate and much higher incidence of silent cerebral infarction. This study investigated the neuroprotective benefits of minimising air emboli in TAVI. It aimed to demonstrate a reduction in vascular brain injury by flushing TAVI valves with CO 2 and saline compared to saline only as per standard practise. Methods: Patients undergoing transfemoral TAVI for aortic stenosis were enrolled. Patients were randomised to CO 2 and saline (TAVI-CO 2 ) versus saline only (TAVI-S) flushing of TAVI valves during preparation. Patients underwent MRI brain following TAVI to identify new cerebral infarcts and any reduction in vascular brain injury by reducing air emboli. Results: Twenty-Two patients were enrolled in the study with a mean age of 79±10 years. Fifteen (68%) were males. Nine patients (41%) had history of hypertension, 5 (23%) had previous cerebrovascular disease and 5 (23%) had diabetes. Two (9%) patients did not have their TAVI valve implanted and hence were excluded. No patients had any procedural related complications. Three (14%) patients required permanent pacemaker insertion post procedure and could not have their MRI. Fifteen patients (68%) had MRI brain post-TAVI, 7 patients in the TAVI-CO 2 group and 8 patients in the TAVI-S group. TAVI-CO 2 group had a total of 41 new cerebral lesions compared to 66 lesions in TAVI-S group. TAVI-CO 2 had on average 6.80 new lesions/patient compared to 8.25 lesions/patients in TAVI-S (p=0.34) Cerebral infarcts were also analysed according to valve type. In self-expanding valves (n=7), TAVI-CO 2 had 8 lesions/patient compared to 10 lesions/patient in TAVI-S (p=0.46). In balloon-expanding valves (n=8), TAVI-CO 2 had 4.25 lesions/patient compared to 6.25 lesions/patient in TAVI-S (p=0.25). Conclusion: There is a trend in the reduction in the number of new cerebral lesions in the TAVI-CO 2 arm compared to the TAVI-S patients. This is the first study that identifies the importance of air emboli in TAVI and the associated potential vascular brain injury. As brain injury remains a significant concern during TAVI, a larger randomised trial is required to further investigate the neuroprotective benefit of flushing TAVI valves with CO 2 .

Brain volume in Tanzanian children with sickle cell anaemia: Aneuroimaging study.

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n=144; aged 5-20 years; 74 male) and sibling controls (n=53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n=37), vasculopathy (n=15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia.