Transcranial Doppler Ultrasound Velocities Research Articles

Transcranial Doppler ultrasound velocities in a population of unstudied African children with sickle cell anemia.

The greatest burden of sickle cell anemia (SCA) globally occurs in sub-Saharan Africa, where significant morbidity and mortality occur secondary to SCA-induced vasculopathy and stroke. Transcranial Doppler ultrasound (TCD) can grade the severity of vasculopathy, with disease modifying therapy resulting in stroke reduction in high-risk children. However, TCD utilization for vasculopathy detection in African children with SCA remains understudied. The objective was to perform a prospective, observational study of TCD findings in a cohort of children with SCA from the Democratic Republic of the Congo, Zambia, and Malawi. A total of 770 children aged 2-17 years without prior stroke underwent screening TCD. A study was scored as low risk when the time-averaged maximum of the mean (TAMMX) in the middle cerebral artery or terminal internal carotid artery was <170cm/s but >50cm/s, conditional risk when 170-200cm/s, and high risk when>200cm/s. Low-risk studies were identified in 604 children (78%), conditional risk in 129 children (17%), and high risk in three children (0.4%). Additionally, 34 (4%) were scored as having an unknown risk study (TAMMX<50cm/s). Over the course of 15 months of follow-up, 17 children (2.2%) developed new neurologic symptoms (six with low-risk studies, seven with conditional risk, and four with unknown risk). African children with SCA in this cohort had a low rate of high-risk TCD screening results, even in those who developed new neurologic symptoms. Stroke in this population may be multifactorial with vasculopathy representing only one determinant. The development of a sensitive stroke prediction bundle incorporating relevant elements may help to guide preventative therapies in high-risk children.

Displace Study Shows Poor Quality of Transcranial Doppler Ultrasound for Sickle Cell Stroke Screening: An Urgent Need for Standardized Reporting

Introduction Children with sickle cell anemia (SCA) are at increased risk of stroke as compared to age-matched peers (Ohene-Frempong et al, Blood, 1998). The Stroke Prevention Trial in SCA (STOP) demonstrated that with use of transcranial Doppler ultrasound (TCD), children at highest risk for stroke could be identified and started on chronic transfusion therapy, reducing stroke risk by &amp;gt; 90% (Adams et al, NEJM, 1998). This led to the adoption of the STOP protocol as standard of care. However, many sites use the transcranial Doppler imaging (TCDi) technique in place of the original non-imaging TCD technique used in STOP. Further, the NHLBI-funded DISPLACE (Dissemination and Implementation of Stroke Prevention in SCD) study demonstrated &amp;lt; 50% of children at participating sites had annual TCD screening (Kanter et al, JPHO, 2021). This sub-study used DISPLACE data to examine TCD report quality. We hypothesized there was high variability in TCD technique, unreliable reporting of variables, inconsistent definitions for diagnosing abnormal scans and that these inconsistencies would be worse with TCDi. Methods An IRB waiver was obtained. This sub-study used data manually extracted from TCD reports in the DISPLACE database. A computer-generated algorithm randomly selected 400 TCD/TCDi reports (200 of each type) from the 12,433 reports collected in DISPLACE for an alpha of 0.05. TCD type, patient age, vessels assessed, velocities measured, and diagnosis made (abnormal/normal) were extracted. Type of TCD was separately extracted from the DISPLACE database. We surveyed study site principal investigators regarding TCD methods used in the study period (2012 - 2016). Results Three hundred and ninety-one TCD/TCDi reports were reviewed from 26 institutions. The median patient age at time of TCD was 5 years (2 - 8 years) and the median year of TCD completion was 2013 (2000 - 2016). On initial review of the TCD/TCDi reports, there was significant variability in how results were classified as “abnormal”, and reports were often inconsistent with STOP definitions of normal/abnormal. Thus, we focused on the quality and completeness of reports. Table 1 details the information included in the reports. Notable findings: • Use of TCDi was not specifically stated in 96% of TCDi reports. • 52% did not clearly identify the time averaged mean maximum velocity (TAMMV) (the key variable required per STOP criteria). • 30% of reports did not assess/did not report assessment of the distal internal carotid artery (dICA). • 14 reports (3.6%) did not include any information about which vessels were assessed. • Only 42% of scans clearly stated that classification of normal vs. abnormal was based on the correct measure (TAMMV). Surveys sent to each site to assess TCD practices from 2012-2016 were evaluated (Table 2). There was substantial variability regarding which vessels were examined for both TCD and TCDi, ranging from 1 - 5 vessels. The type of provider interpreting scans varied and only 8 institutions (35%) had ultrasound technicians who underwent formal STOP training. Conclusion TCD results have critical implications for medical decision-making in SCA, but our study reveals a lack of quality assurance and consistency with sickle cell stroke risk screening using TCD/TCDi. Notably, many reports did not identify which vessels were used to assess stroke risk, did not report on the correct velocity measurement, neglected to measure or report the TAMMV, or made diagnoses based on the wrong measurements or wrong vessels. Additionally, a large percentage of reports did not note whether a TCD or TCDi was performed. Surveys from 23 DISPLACE sites showed significant variation in the method of training for those performing TCDs. With this extreme variation, we recommend creation of a standardized template for TCD reports to be utilized across institutions. We also recommend those interpreting the scans gain expertise in reading and evaluating TCD/TCDi specifically for people with SCA. National quality improvement studies are necessary to implement these recommendations and inform further refinements, especially in the use of TCDi, and assessment of vessels beyond the middle cerebral artery and dICA. This requires engagement of stakeholders, identification of barriers to implementation, and funding. With these interventions, we continue to work towards meeting the recommended screening and interventions instituted by the NHLBI over 25 years ago.

Factors Associated with Elevated Transcranial Doppler Ultrasound Velocities in Children With Sickle Cell Anemia in Mwanza, Tanzania

Background: Stroke occurs in 11% of patients with SCA before 20 years of age. In Northwestern Tanzania, the prevalence of stroke among children living with SCA under the age 15 years is 16.9%, of which might be attributed to the absence of routine screening for the risk of stroke by using Transcranial Doppler Ultrasound (TCD). Screening with TCD allows preventive measures such as chronic blood transfusion to be done which has led to the reduction of stroke by 92%. Methods: This was a prospective analytical cross sectional study which enrolled 267 SCA children aged 2 to 16 years attending Bugando Medical Centre Pediatric Sickle Cell Clinic from July 2019 to June 2020. Assessment of factors associated with elevated TCD included a clinical history of stroke in sibling, death in sibling, temperature, oxygen saturation in room air, blood pressure, hemoglobin level and total white blood cell count. TCD was done by accessing transtemporal window and recording the highest time average mean of maximum velocity (TAMMV) of major vessels mainly, middle cerebral artery (MCA) and distal internal carotid artery (dICA). Results: The median age of enrolled was 6.6 (IQR: 4-9) years. The prevalence of elevated TCD (&gt; 170 cm/s) was found to be 21% (56/267). By multivariate logistic regression, low oxygen saturation in room air, p - value = 0.037, OR 1.08 [95% CI 1.00-1.17] and low hemoglobin level, p - value = 0.001, OR 1.76 [95% CI 1.26-2.45] were statistically significantly associated with elevated TCD among children living with SCA. Conclusion: The high prevalence of elevated TCD velocity, with low hemoglobin and low oxygen saturation in room air as associated factors under multivariate logistic regression, warrants routine TCD screening for children with SCA aged 2 to 16 years.

Managing the Cerebrovascular Complications of Sickle Cell Disease: Current Perspectives.

The importance of protecting brain function for people with sickle cell disease (SCD) cannot be overstated. SCD is associated with multiple cerebrovascular complications that threaten neurocognitive function and life. Without screening and preventive management, 11% of children at 24% of adults with SCD have ischemic or hemorrhagic strokes. Stroke screening in children with SCD is well-established using transcranial Doppler ultrasound (TCD). TCD velocities above 200 cm/s significantly increase the risk of stroke, which can be prevented using chronic red blood cell (RBC) transfusion. RBC transfusion is also the cornerstone of acute stroke management and secondary stroke prevention. Chronic transfusion requires long-term management of complications like iron overload. Hydroxyurea can replace chronic transfusions for primary stroke prevention in a select group of patients or in populations where chronic transfusions are not feasible. Silent cerebral infarction (SCI) is even more common than stroke, affecting 39% of children and more than 50% of adults with SCD; management of SCI is individualized and includes careful neurocognitive evaluation. Hematopoietic stem cell transplant prevents cerebrovascular complications, despite the short- and long-term risks. Newer disease-modifying agents like voxelotor and crizanlizumab, as well as gene therapy, may treat cerebrovascular complications, but these approaches are investigational.

Normalization of cerebral hemodynamics after hematopoietic stem cell transplant in children with sickle cell disease

AbstractChildren with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Abstract TP111: Pterygopalatine Fossa Blockade As Novel, Narcotic-sparing Treatment For Headache In Patients With Spontaneous Subarachnoid Hemorrhage - A Case Series

Background &amp; Purpose: Severe headache is a hallmark of spontaneous subarachnoid hemorrhage (SAH), affecting nearly 90% of patients during index hospitalization. In addition, up to 25% of SAH-survivors experience chronic headaches. Despite its high prevalence, means of management of headaches are limited, largely reliant on opioids, and often ineffective. Urgent efforts to reduce opioid use require innovative treatment strategies for the management of post-SAH headaches. Methods: This is a retrospective cohort comprising 12 adults who received bilateral pterygopalatine fossa (PPF) blockade from 9/2018 to 3/2021 for refractory headaches after spontaneous SAH. We examined pain scores, analgesic requirements and transcranial doppler ultrasound (TCD) parameters before and after the block placement. Descriptive statistics were calculated for all variables. Results: Twelve patients (mean age 54 years, 66% females, nine aneurysmal and three non-aneurysmal SAH) received PPF-block on post-bleed day 2 to 11 (median 6.5) during hospitalization in the neurointensive care unit. Hunt and Hess scores ranged from 1-3. Pain scale scores from 24-hour period before the block (8.8 ±1.4; mean, SD) decreased significantly to a mean of 5.1 (SD ± 3.0) until 20 hours post-block (p = 0.0156). Opioid use also decreased significantly from median (range) oral morphine equivalent dose (mg) administered in the 24h before the block of 22.5 (0-75) vs. 7.5 (0-45) after PPF-block (p=0.0391). Five (41%) patients had radiographic (but not clinical) vasospasm by TCD criteria before PPF-block; in four of these patients, TCD velocities improved on the day after PPF-block, in one patient velocities were increased on the day after PPF-block. The block was well tolerated with no adverse events of bleeding, infection, pain, or numbness at the injection site. Conclusion: These results demonstrate that PPF-blockade might be a promising alternative for managing post-SAH headaches. Further prospective controlled randomized powered to address the safety and efficacy of the PPF-block are warranted.

P118: THE ROLE OF HEMOGLOBIN AND HEMOLYSIS ON TRANSCRANIAL DOPPLER VELOCITIES IN CHILDREN WITH SICKLE CELL DISEASE: DATA FROM A NATURAL HISTORY COHORT

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke, to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments. Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1, 2009, to December 31, 2020 (censoring date). We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Hematological, clinical, and treatment variables were available from the natural history cohort database. Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb. Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1–298.6 months) (interquartile range [IQR]: 36.9–126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1–17.5 years). Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results. We detected an inverse linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064). Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV.

The Role of Hemoglobin and Hemolysis on Transcranial Doppler Velocities in Children with Sickle Cell Disease: Data from a Natural History Cohort

Background: Children with sickle cell disease (SCD) are at increased risk of cerebrovascular events that can impact neurocognitive development and quality of life (Colombatti 2016). Transcranial Doppler ultrasound (TCD) is a validated screening tool to identify pediatric SCD patients with the highest risk of stroke to start on a preventive chronic blood transfusion regimen (Estcourt 2020; Inusa 2019). High TCD velocities are an indication to start disease-modifying treatments or consider disease-curative options in children with SCD (Khemani 2019). However, real-world pediatric data on the correlation between hematological variables and TCD results are scarce (Salama 2020). We aimed to evaluate the distribution of TCD velocities in a pediatric natural history cohort and investigate their correlation with hematological variables and treatments.Methods: We performed a retrospective analysis on data from a prospective pediatric cohort followed from January 1,2009, to December 31, 2020 (censoring date). Standard care includes annual TCD from 2 years of age. We used transcranial Doppler imaging (TCDi) and classified results according to STOP criteria, considering terminal internal carotid artery (TICA) and middle cerebral artery (MCA) time-averaged maximum mean velocities (TAMMVs). Only complete exams with right and left measures available for both vessels were included. Hematological, clinical, and treatment variables were available from the natural history cohort database. Patients were divided according to genotype: HbSS/HbSβ 0 or HbSC/HbSβ +.Two-sample and Welch t-tests for unequal variances were used to compare mean hemoglobin (Hb) values and hemolysis markers in patients with and without abnormal/conditional TCDi results. Fisher and chi-square tests were used to compare categorical variables. Linear regression models were used to assess the effects of MCA and TICA TAMMVs as continuous variables on Hb. Odds ratios (ORs) for neurological events at different Hb levels were estimated using generalized estimated equations (GEE) with a binomial distribution, logistic function, and exchangeable correlation structure, allowing for correlation among repeated observations for the same patient. Multivariable GEE including characteristics and treatment variables were used to evaluate the association between neurological events and Hb.Results: Of the 182 SCD patients in the cohort, 169 had assessments of cerebral vasculopathy, and 155 had evaluable TCDi (583 exams). The median follow-up of the entire cohort was 79.8 months (range: 2.1-298.6 months) (interquartile range [IQR]: 36.9-126.3 months). The median age at the censoring date was 13.4 years (IQR: 9.1-17.5 years); 130 were HbSS/HbSβ 0, and 25 were HbSC/HbSβ +. Basic demographic characteristics of the cohort are in Table 1. The distribution of TCDi results was significantly different between genotypes (P<0.0001): in the HbSC/HbSβ + group (70 exams), 14 were normal (20.0%), and 56 were low (80.0%); in the HbSS/HbSβ 0 group (513 exams), 8 were abnormal (1.6%), 56 were conditional (10.9%), 311 were normal (60.6%), and 138 were low (26.9%). Only 37/138 (26.8%) low TCDi results were confirmed as stenosis at the nearest MRA. Patients with abnormal/conditional TCDi results had lower Hb (8.4 vs 8.9 g/dL, P≤0.0001) and higher reticulocyte counts (317,766 vs 262,750/mm 3, P≤0.0001), lactate dehydrogenase (843 vs 690 U/L, P=0.0012), and aspartate aminotransferase (61 vs 54 U/L, P=0.0007) compared with patients with normal/low results.We detected a linear correlation between TICA/MCA TAMMVs and Hb (Figure 1A and 1B). Univariate analysis showed significant inverse correlation between abnormal/conditional TCDi results and Hb considered as a continuous variable (OR: 0.484, P<0.001). In the multivariate analysis, the correlation between TCDi results and Hb remained significant; moreover, the risk of presenting abnormal/conditional TCDi results decreased with age (OR: 0.833, P<0.0064).Conclusions: This analysis from our natural history cohort shows a significant inverse correlation between Hb and MCA and TICA velocities, supporting the beneficial effect of higher Hb levels in reducing TAMMV. Disease-modifying therapies increasing Hb and reducing hemolysis could be helpful in reducing TAMMV in children with SCD.Funding: This study was supported by Global Blood Therapeutics. [Display omitted] DisclosuresAgodoa: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Beaubrun: Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Biffi: BlueBirdBio: Consultancy, Other: Advisory Board. Colombatti: Global Blood Therapeutics: Research Funding; Addmedica: Consultancy; Forma Therapeutics: Consultancy; Novartis: Consultancy; NovoNordisk: Consultancy; BlueBirdBio: Consultancy; Global Blood Therapeutics: Consultancy; BlueBirdBio: Research Funding.

Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia.

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0-31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5-54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0-15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76-0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2-64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Effects of hydroxyurea on brain function in children with sickle cell anemia.

Sickle cell anemia (SCA) results in numerous adverse effects on the brain, including neurocognitive dysfunction. Hydroxyurea has been utilized extensively for management of SCA, but its effects on brain function have not been established. We examined prospectively the effects of 1year of treatment with hydroxyurea on brain function in children with SCA (HbSS/HbSβ0 -thalassemia) by baseline and exit evaluations, including comprehensive neurocognitive testing, transcranial Doppler ultrasound (TCD), and brain MRI (silent cerebral infarcts [SCI], gray matter cerebral blood flow [GM-CBF], and blood oxygen level-dependent [BOLD] signal from visual stimulation). Nineteen patients with SCA, mean age 12.4years (range 7.2-17.8), were evaluated. At baseline, subjects had these mean values: full-scale IQ (FSIQ) 82.8, TCD velocity 133cm/s, GM-CBF 64.4ml/100g/min, BOLD signal 2.34% increase, and frequency of SCI 47%. After 1year of hydroxyurea, there were increases in FSIQ (+2, p=.059) and reading passage comprehension (+4, p=.033), a significant decrease in TCD velocity (-11cm/s, p=.007), and no significant changes in GM-CBF, BOLD, or SCI frequency. Hemoglobin F (HbF) was associated with passage comprehension, hemoglobin with lower TCD velocity, and lower GM-CBF with greater working memory. Higher BOLD signal was associated with higher processing speed and lower TCD velocity with higher math fluency. Improvements in neurocognition and decreased TCD velocity following 1year of treatment support hydroxyurea use for improving neurocognitive outcomes in SCA. Understanding the mechanisms of benefit, as indicated by relationships of neurocognitive function with HbF, hemoglobin, and CBF, requires further evaluation.

Plasma BDNF Levels Are Associated with Stroke in Children with SCD

Background: Cerebrovascular disease, particularly overt stroke, is one of the most critical clinical complications of sickle cell disease (SCD). Individual stroke risk for patients with SCD is assessed by measuring trans-cranial Doppler ultrasound (TCD) velocity. While TCD screening and resulting use of chronic blood transfusion therapy in patients with abnormal TCDs has reduced stroke incidence in patients with SCD from 11% to 1%, the test has significant limitations. It can only be performed on children old enough to remain still for the assessment, or young enough to have open bony windows; typically 2-16 years of age. Additionally the test has poor positive predictive value, causing patients to be placed on chronic transfusion therapy who would not have gone on to have a stroke. Hydroxyurea (HU) is replacing chronic transfusion therapy in many institutions for primary stroke prevention, but many sites initiate a "cooling off" period of transfusions prior to initiating HU, and transfusion therapy may be indicated for abnormal TCD velocities in patients already on HU. The pathophysiology of stroke in SCD patients is not completely understood, but vascular remodeling, abnormal cerebral blood flow, and vaso-occlusion all play a role. Plasma levels of Brain derived neurotrophic factor (BDNF), myeloperoxidase (MPO), vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) have been shown to be associated with high trans-cranial Doppler ultrasound (TCD) velocity in children with SCD; but there is limited data on their potential association with stroke in this population. BDNF is a neurotropin that is responsive to hypoxia and promotes neurogenesis as well as playing a key role in the regulation of the cell survival pathway; myeloperoxidase (MPO) promotes vascular injury by oxygen radical generation, leukocyte/neutrophil recruitment, and oxidative stress; vascular cell adhesion molecule 1 (VCAM-1) is and endothelial adhesion molecule involved in the pathophysiology of vaso-occlusion in SCD through promoting RBC adhesion; and intercellular adhesion molecule 1 (ICAM-1) is expressed on endothelial and immune system cells and is thought to be a ligand for leukocyte adhesion. We hypothesized that BDNF, MPO, VCAM-1 and ICAM-1 may be involved in stroke in SCD, and may be potential biomarkers to be used to assess an individual with SCD's stroke risk in addition to TCD. Methods: We collected plasma samples from the peripheral blood of fifteen SCD patients (HbSS) at the time of either silent cerebral infarct (SCI) or stroke. Stroke (n=8) or SI was confirmed by MRI using diffusion imaging and T2 FLAIR. The cohort included 6 females and 9 males between the ages of 3 and 20 years. Plasma from fifteen age and gender matched control patients with HbSS but had normal MRIs and TCD velocities less than 170 m/s. We measured plasma levels of BDNF, MPO, VCAM-1 and ICAM-1 using antibody immobilized fluorescent beads (Millipore, Billerica, MA) and Luminex xMAP technology (Bio-Rad, Hercules, CA). Student's t-test was used to analyze the difference in plasma levels between the stroke and control groups. Results and Conclusions: BDNF levels were significantly higher in the stroke group than in the control group; 2978.2 ± 960.3 pg/ml compared to 2200.8 ± 758.4 pg/ml, p=0.005. Difference in MPO levels between the two groups approached significance; 36617.2 ± 14828.9 pg/ml compared to 29521.9 ± 7889.6 pg/ml, p=0.07. Difference in VCAM-1 levels also approached significance; 143997.0 ± 9963.8 pg/ml compared to 138126.9 ± 11902.0 pg/ml, p=0.08, but there was no significant difference in ICAM-1 levels. Only BDNF plasma levels positively correlated with the area and volume of the infarct, p=0.009. These results further support the assertion that BDNF is involved in the pathophysiology of cerebrovascular disease in SCD. It is possible that MPO and VCAM-1 may also play a role, and that a significant difference was not found due to sample size limitations. Plasma BDNF levels, and possibly MPO and VCAM-1 plasma levels, have potential as biomarkers for stroke risk to improve the positive predictive value of TCD velocities in patients with SCD, or to assess risk in patients unable to receive TCDs. Disclosures No relevant conflicts of interest to declare.

Characteristics of Children with Abnormal TCD in the Modern Era: Results from the Displace Consortium

Background: Stroke is one of the most devastating complications of sickle cell anemia (SCA). In 1998, the Stroke Prevention Trial in Sickle Cell Anemia (STOP), demonstrated that a high-risk group of children with SCA could be identified using Transcranial Doppler ultrasound(TCD) and that chronic red cell transfusion therapy (CRCT) could reduce the risk of first ischemic stroke in this group by over 90% (Adams, et al NEJM 1998).At STOP studyenrollment, 9.7% of children with SCA were identified as having an abnormal TCD. Baby HUG, (NCT00006400), an NHLBI supported phase III trial showed that severe anemia in SCA was associated with elevated white blood cell (WBC) and higher TCD velocities (Lebensburger, et al Blood 2010 ). It is unclear if lower hemoglobin (Hb) and/or higher WBC are causative of elevated TCD velocities or correlative biomarkers. As new disease therapies become available, it is important to know the current rate of abnormal TCD and characteristics of those patients. The DISPLACE (Dissemination and Implementation Looking at the Care Environment) project is a multicenter, NHLBI-funded study whose primary purpose is to identify barriers to implementation of stroke screening in SCA and test novel methods for improving outcomes. DISPLACE is a 3-part study: retrospective assessment of current practice, qualitative review of barriers and facilitators to screening and a cluster-randomized intervention implementation project to improve stroke screening. Part 1 of the study showedthat TCD screening rates varied widely among institutions ranging from 30-75.2% (mean 48.4%, median 47%). We are now reporting on the rate of abnormal TCD and the characteristics and outcomes of patients with abnormal TCD. Methods: DISPLACE is a consortium of 28 US centers. Each site performed a rigorous retrospective chart review of children with SCA aged 2-16 years from 2012-2016. To be eligible for inclusion, children must have been seen at their institution at least 2x during the study period and have confirmation of SCA. A custom electronic data capture (EDC) system facilitated entry of de-identified data including demographics, TCD and MRI results, medications, transfusions, and laboratory values. For children with SCA who had TCD or central nervous system imaging prior to 2012, these results were also entered into the EDC. TCD results were recorded in the EDC as normal, conditional or abnormal based on their institutional interpretation. Labs and vitals were entered for each patient in closest proximity to each TCD. Confirmation and adjudication of each abnormal TCD and associated outcomes were performed. Stroke status was also recorded as well as presence or absence of CRCT. Results: In total, 5247 children with SCA are included in the database of whom 5225 should have received a TCD. Of this cohort, 4210 children (80.6%) had at least one TCD recorded in the database. Within this group, 207 (4.9%) of children had an abnormal TCD and 816 (19.4%) had a conditional TCD. For those children who underwent TCD during the study (2012-2016) period, there were 105 (2.9%) abnormal TCD and 501 (13.6%) conditional TCD (Table 1). The mean age of children at the time of abnormal TCD was 6.6 years (range 2-16 yr). The majority of children were &lt;10 yr at first abnormal TCD. Over 30% of patients with an abnormal TCD were identified as receiving hydroxyurea.The mean Hb associated with an abnormal TCD was 7.8 +/- 1.1g/dl (range 5.7-10.6) and the mean WBC was 13 x109/L+/- 3.6 (range 3.9-23.4) (Table 2). Of the 105 patients with abn TCD during the study period, 18% had a stroke. Of the total 5247 patients in the database, 3093 (59%) had been prescribed hydroxyurea (HU) and 999 (19%) were prescribed CRCT. CRCT was prescribed most often for abnormal TCD (37%) or secondary stroke prevention (31%). Discussion: DISPLACE is the largest contemporary cohort of children with SCA. The incidence of abnormal TCD in the DISPLACE cohort is significantly lower than at randomization in the STOP study. The number of children receiving CRCT is higher than expected which may partly account for the decrease in frequency of abnormal TCD. Many patients with abnormal TCD were receiving HU when their TCD was abnormal and were started on CRCT. Additionally, while the outcomes of children with conditional TCD are still being evaluated, many of those children reverted to normal TCD without intervention. These data may also help us redefine the use and interventions needed for abnormal TCD. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; Guidepoint Global: Consultancy; GLG: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy; Cowen: Consultancy; Jeffries: Consultancy; Medscape: Honoraria; Rockpointe: Honoraria; Peerview: Honoraria. Adams:GBT: Consultancy, Other: consultancy to companies GBT and Blueburd Bio; Bluebird: Consultancy.

Middle Cerebral Artery Velocities Are Inversely Related to Hemoglobin Levels and Acutely Drop in Response to RBC Transfusion: Implications for Stroke Screening in SCD

INTRODUCTIONChronic red blood cell (RBC) transfusion therapy can prevent new and progressive stroke in Sickle Cell Disease (SCD), as shown by multiple clinical trials in SCD including the STOP 1&2, SIT, and SWITCH trials. Middle cerebral artery time-averaged mean velocity (MCA velocity), measured by Trans-cranial Doppler Ultrasound (TCD), is a clinical biomarker utilized to initiate chronic RBC transfusion to reduce stroke risk in children with SCD. However, MCA velocity measured by TCD lacks sensitivity and specificity in predicting stroke. Most SCD patients with high MCA velocity do not experience overt stroke, while 10-20% of SCD children will have new strokes on chronic RBC transfusion in spite of normalized MCA velocity.Prior studies showed an association with high MCA velocity and MCA narrowing when TCD and angiography were performed after RBC transfusion to target a hematocrit (HCT) > 30%. HCT adjustments addressed effects of anemia and higher cardiac output (Adams et al, 1992; Stroke PMID 1636180). Nevertheless, HCT adjustments may not always be used for routine TCD. Thus, despite the substantial decrease in strokes with TCD screening, there may be significant lack of specificity that leads to unnecessary RBC transfusion resulting from TCD screening in non-optimal conditions. Due to these concerns, we undertook a detailed study assessing MCA velocity by TCD immediately pre- and post-transfusion in SCD patients.METHODSThe study was approved by the Children's Hospital Los Angeles Institutional Review Board. SCD and thalassemia patients who receive chronic transfusion had pre- and post-transfusion blood laboratory tests and MCA velocity measurements by TCD (GE Vivid I, FE Medical Systems Ultrasound Israel Ltd., Israel). The TCD ultrasound probe was placed on left and right trans-temporal window, landmarks were visualized, and MCA velocity data were collected in 1.7mm depth increments from 65mm to 35mm depth. Magnetic resonance angiography was not done at the time of these measurements. Data was recorded and analyzed in JMP Pro Version 13.0.RESULTSSCD patients (n=24) had a median and interquartile range of 15 years & 14-18 years, with 18 females & 6 males, received 90 transfusions, and 70% of the patients had 3 transfusion events with repeat studies. Seventeen patients received simple RBC transfusion and 7 received red cell exchange. The thalassemia control population received simple transfusion (n=11; 48 transfusion events).Figure 1 shows the relation of MCA velocity compared to HCT in all subjects. There is a highly significant negative correlation showing lower HCT is associated with higher MCA velocity (Dots = TAMV measurements; lines = average TAMV measurements at different TCD depths; R2=0.12, F(1,4270)=556, p<.001). Figure 2 & 3 show that the MCA velocity measurement depends on depth of the TCD measurement. This accounts for a significant part of the variance evident in Figure 1. On average, a rise in HCT from a typical level in SCD of 21% to 31% would result in a 14% drop in TCD velocity. To illustrate the variable impact of acute PRBC transfusion among subjects, we show the MCA velocity response to RBC transfusion in two SCD patients (Figure 2&3: blue ♦=Pre-transfusion, red ♦=Post-transfusion). Patient 1 showed a 37% drop in MCA velocity following RBC transfusion on three occasions (∆HCT=7.5±1.7%; n=3; Figure 2) whereas Patient 2 showed only an 11% drop in MCA velocity following RBC transfusion (∆HCT=6.2±1.3%, n=5, Figure 3).DiscussionThese data show a striking relationship between anemia and TCD velocity, and that RBC transfusion can alter MCA velocity. Even an 11% increase in hemoglobin such as that seen in the low-responder in Figure 3 could change a patient classification from high-risk to conditional TCD. These data also show the significant sensitivity of MCA velocity to the depth of measurement (Figure 2 & 3). The investigators in the STOP study went to extreme ends to standardize these measurements. Nonetheless, TCD measures may not be done with such rigor in clinical settings. It is clear that standard TCD screening has been of tremendous benefit to SCD patients, and many enjoy a good quality of life as a result. Our data suggest that the specificity of TCD screening could be improved if testing was done at an HCT> 30%. Quantifiable blood, patient, and measurement factors can impact TCD MCA velocity and clinical decisions that commit children to years of RBC transfusions. [Display omitted] DisclosuresCoates:ApoPharma: Consultancy, Honoraria; Celgene Corp.: Consultancy; Vifor Pharma: Consultancy; Sangamo: Consultancy, Honoraria.

Relationship between Hemolytic Index Early in Life with Development of Abnormal Transcranial Doppler Velocities in Pediatric Patients with Sickle Cell Anemia

Introduction: Sickle cell disease is a complex disease process highlighted by a high phenotypic variability associated with a myriad of acute and chronic complications. Cerebrovascular disease is a serious complication in SCD associated with a high degree of morbidity and mortality. The utility of transcranial doppler ultrasound (TCD) to measure velocity within major arteries of the brain has been validated as a way to predict those at increased risk for stroke. Unfortunately, despite the availability of TCD, individuals may develop stroke and/or silent stroke prior to obtaining an abnormal study. Hemolysis via a hemolytic index variable has been shown to be associated with other complications associated with SCD. This study aimed to evaluate an association between a hemolytic index variable obtained in the first two years of life and development of abnormal or conditional TCD velocities later in childhood in patients with sickle cell anemia (SCA) with thoughts this may provide an earlier tool to determine those who may be at increased risk for stroke prior to either obtaining a TCD or developing an abnormal TCD.Methods: This study was a single-center, retrospective chart review of patients with SCA receiving their disease related care at our center over a 17 year period. Laboratory values, including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), total bilirubin (TB), absolute reticulocyte count (ARC), and hemoglobin (HB), obtained in the first two years of life were extracted; these values were utilized to calculate a hemolytic index (HI) via principle component analysis to determine if a relationship existed between HI and development of conditional or abnormal TCD. All TCD results obtained from 2-14 years of age were also extracted from the patient's record. Cox proportional hazards models were then used to determine if the hemolytic index was a risk factor for abnormal or conditional TCD results.Results: A total of 193 patients with SCA between ages 2 - 21 years were reviewed with 109 included in the analysis. Laboratory values were averaged from included patients, then principle component analysis was used to find a linear combination of LDH, AST, TB and ARC to calculate a HI. The HI accounted for 49% of the total variation and had a correlation of 0.58 with mean LDH, 0.38 with mean AST, 0.46 with mean TB and 0.56 with mean ARC. Cox regression hazards model utilizing HI revealed a hazard ratio of 1.33 (95% CI 1.04‐1.70, p = 0.025) for developing a conditional or abnormal TCD velocity.HB was then included along with the other four laboratory values for principle component analysis in creation of a hemoglobin HI (HHI); in this case, the index accounts for 44% of the total variance and it has a correlation of 0.52 with mean LDH, 0.33 with mean AST, 0.38 with mean TB, 0.55 with mean ARC and ‐0.42 with mean HB. Cox regression hazards model utilizing HHI revealed a hazard ratio of 1.31 (95% CI 1.04‐1.66, p = 0.024).Conclusions: This retrospective study noted an increased risk for development of an abnormal or conditional TCD with an increased HI. The addition of hemoglobin to the HI to form HHI showed an elevated risk for abnormal or conditional TCD to the same degree as HI itself. These results could offer an additional tool in the evaluation of the pediatric SCA population, although these results would benefit from a prospective look. Further look into a possible association between HI and other SCD related complications such as stroke and acute chest syndrome could provide further information for the treating team for the overall management of this complex disease. [Display omitted] DisclosuresWoods:Global Blood Therapeutics: Research Funding; Pfizer: Research Funding; Guidepoint: Honoraria; Putman: Honoraria; Children's Mercy Hospital: Employment, Membership on an entity's Board of Directors or advisory committees.

Initial Results from a Cohort in a Phase 2a Study (GBT440-007) Evaluating Adolescents with Sickle Cell Disease Treated with Multiple Doses of GBT440, a HbS Polymerization Inhibitor

▪Background: Sickle cell disease (SCD) is a genetic disorder in which deoxygenation produces polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell deformation (sickling), hemolysis, vaso-occlusion and inflammation. Injury from SCD starts in infancy and accumulates over a lifetime causing significant end-organ damage and ischemic tissue injury, leading to fatigue, pain (vaso-occlusive crisis) and other clinical complications that are under-recognized, under-treated, and associated with early death.GBT440 is an oral, once-daily therapy that modulates hemoglobin affinity for oxygen, thereby inhibiting hemoglobin polymerization. GBT440-007 is a Phase 2a study designed to assess the safety, pharmacokinetics (PK) and efficacy of GBT440 in pediatric SCD patients (HbSS or HbSβ0 thalassemia). This abstract reports the first evaluation of multiple doses of GBT440 in adolescents (12 to 17 years) with SCD.Methods: This ongoing study is being conducted in 2 parts, Part A: single dose of GBT440 at 600 mg in pediatric patients (6 to 11 years) and adolescents (12 to 17 years) and Part B: multiple doses of GBT440 at 2 dose levels, 900 mg/d and 1500 mg/d for 24 weeks in adolescents (approximately 12 patients at each dose). Part A PK data in adolescents was previously reported. The primary objective of Part B is to assess the effect of GBT440 on anemia. Secondary objectives include effect on clinical measures of hemolysis, PK (PK parameters determined using population PK analysis), cerebral blood flow as assessed by transcranial Doppler ultrasound (TCD), daily SCD symptoms using a patient-reported outcome (PRO) measure and safety. The PRO Sickle Cell Disease Severity Measure (SCDSM) was developed following FDA guidance as a clinical outcomes assessment.Results: Enrollment in Part B of the 900 mg cohort is complete. As of 21July2017, 13 patients (7 females) have received GBT440 for up to 12 weeks. The median age was 13 years (range 12 to 17 years) and median weight 52 kg (range 30 to 96 kg); 92% were on hydroxyurea (HU); 38% had 2 or more painful crises (range 2 to 8) in the year prior to enrollment.Data for measures of hemolysis and TCD are available for 4 patients who received GBT440 for 12 weeks; all were receiving HU at study entry. Three of the 4 patients achieved hemoglobin (Hb) response of > 1 g/dl increase (Figure 1); one patient had a smaller Hb increase with documented non-adherence with study medication and associated lower GBT440 exposures. Clinical measures of hemolysis improved concordantly; median reduction in reticulocytes and indirect bilirubin were 34% and 27% respectively, consistent with previously reported results of GBT440 in adults with SCD. Preliminary data following multiple doses of GBT440 suggest that the PK in adolescents were similar to those observed in adults with SCD. Baseline TCD velocity ranged from 89 to 150 cm/s in 13 patients. One patient at 12 weeks had a decline in TCD velocity from baseline of 22 cm/s, and 3 patients showed small reductions. Empirical distribution functions of the SCDSM questionnaires indicate total symptom scores (TSS) trended lower post dose in comparison to screening (Figure 2).All treatment-related adverse events (AEs) were Grade 1 or 2 and there were no treatment- related serious adverse events or no drug discontinuations due to AEs. The most common treatment emergent AEs were Grade 1 nausea and diarrhea reported in 2 patients.Data for all 13 patients treated with GBT440 for a minimum of 12 weeks will be presented at the conference.Conclusions: Based on preliminary results, treatment with GBT440 at 900 mg has been well tolerated in all 13 adolescents. Data from 4 adolescents at 12 weeks show a marked improvement in Hb and reduction in clinical measures of hemolysis. Importantly, hematologic improvements are seen in patients already maximally managed with hydroxyurea. TCD and PRO data suggest that TCD velocity (i.e. risk of stroke) and clinical symptoms may improve with GBT440 treatment. Overall, these results are consistent with in vivo inhibition of HbS polymerization by GBT440 and support the ongoing clinical evaluation of GBT440 as a potential disease-modifying therapy for SCD in an ongoing pivotal Phase 3 study. [Display omitted] DisclosuresHoppe:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Inati:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Piccone:Novartis Pharmaceuticals: Honoraria. Fong:Global Blood Therapeutics: Employment, Equity Ownership. Balaratnam:Global Blood Therapeutics: Employment, Equity Ownership. Dixon:Global Blood Therapeutics: Employment, Equity Ownership. Tonda:Global Blood Therapeutics: Employment, Equity Ownership. Washington:Global Blood Therapeutics: Employment, Equity Ownership. Yaron:Global Blood Therapeutics: Employment, Equity Ownership. Lehrer:Global Blood Therapeutics, Inc.: Employment, Equity Ownership.

Haemoglobin oxygen saturation, leucocyte count and lactate dehydrogenase are predictors of elevated cerebral blood flow velocity in Nigerian children with sickle cell anaemia

Background: Transcranial Doppler ultrasound (TCD) scan, which measures blood flow velocity through the time-averaged mean of maximum velocities (TAMMVs) in the internal carotid arteries and middle cerebral arteries, is a useful screening tool for predicting stroke risk in children with sickle cell anaemia (SCA).Aim: To investigate which clinical and laboratory indices predict abnormal TCD velocity in children with SCA.Methods: Fifty-four SCA patients with normal TCD (TAMMV < 170 cm/s), classified as negative TCD (NTCD), and 93 patients with conditional and abnormal TCD velocities (TAMMV ≥ 170 cm/s) classified as positive TCD were recruited. The haemoglobin oxygen saturation, haematological variables, nitric oxide metabolites and lactate dehydrogenase activity of the patients were analysed.Results: The mean (SD) age was 7.16 (3.84) years (range 2–16). The median SpO2 of the patients in the positive TCD group was significantly lower than that of the negative TCD group (p = 0.002). Multivariate logistic regression analysis indicated that the MCV [odds ratio (OR) 1.12, 95% confidence interval (CI) 1.04–1.22, p = 0.01)], MCH (OR 1.34, 95% CI 1.02–1.77, p = 0.04), leucocyte count (OR 1.26, 95% CI 1.07–1.49, p = 0.01) and lactate dehydrogenase (LDH) level (OR 1.00, 95% CI 1.00–1.01, p = 0.01) were independent predictors of high cerebral blood flow velocities.Conclusions: These clinical and laboratory indices are characteristic of chronic hypoxia and severe anaemia and are predictors of abnormal cerebral blood flow velocity. They can be used to predict stroke risk in children with SCA when access to TCD screening is limited.

First Report on Elevated Transcranial Doppler Ultrasound Velocities As First Stroke Risk and Their Association with Hemoglobin F Expression in Saudi Arabian Pediatric Sickle Cell Patients

Introduction: Sickle cell disease (SCD) is one of the most common inherited hemoglobinopathies in Middle East and specifically Saudi Arabia which leads to vaso-occlusive, hematological and infectious crises, including stroke as one of the common complications (1,2). Primary prevention of the first stroke is carried out by risk assessment using transcranial Doppler (TCD) ultrasound and providing blood transfusions to SCD patients with higher than 199 cm/sec TCD velocities (3). Furthermore, althoughhigher HbF expression is also associated with less severity of the SCD, no studies are available about association of HbF with TCD flow velocities and hence risk of stroke in SCD (4). This study has been carried out to identify SCD patients at high risk of stroke based on TCD results, and to determine the association between Hb-F levels and blood velocity using TCD results.Patients and Methods: Cross-sectional study included 56 pediatric SCD patients. TCD ultrasounds were performed at diagnosis for assessment of first stroke risk and then after every 6 months for follow-up studies. Patients with elevated TCD velocities given monthly packed RBCs transfusions to have HbS level around 40% (5,6). Data analysis was performed by "Statistical Package for the Social Sciences (SPSS, Version 17.0)".Results:In our patient population, male to female ratio was 1.33:1 (32 males, 24 females) and mean age was 7.5 ± 3.42 years (range: 2-14 years). Seven (12.5%) patients had TCD velocities higher than or equal to 200 cm/second, with mean age of 4.7±1.4 years and mean HbF 7.5±3.8, which were significantly different from patient group with normal flow velocities (mean age of 7.8±3.4 years; mean HbF 20±15.9). Patients with higher TCD velocities receiving blood transfusion got velocities in normal range within 6-12 months. Most importantly, normal TCD flow velocities were significantly associated with higher HbF expression and vice versa. As protective role of HbF in sickle cell patients is well established (11;13) and inducing the HbF expression in such patients using medications like hydroxyurea (20) or by genetically modifying the silencing of fetal γ-globin gene have been long standing goal in treatment of sickle cell disease (21), our findings about correlation of higher TCD flow velocities with lower HbF expression (and vice versa) and hence higher risk of first stroke in sickle cell patients provides a new direction for assessing the risk for vasculopathy in SCD patients.Discussion/Conclusions:Low prevalence of SCD patients with higher TCD velocities in our study population is in accordance with previous studies (5). Risk of first stroke was clinically manageable by 6-12 months of regular PRBCs transfusions, per established clinical practice (6). Moreover, normal TCD flow velocities and hence lower risk of stroke was significantly associated with the higher hemoglobin F expression and vice versa. As protective role of HbF in sickle cell patients is well established (4) and inducing the HbF expression in such patients have been long standing goal in treatment of sickle cell disease (7), our findings about correlation of higher TCD flow velocities with lower HbF expression (and vice versa) and hence higher risk of first stroke in sickle cell patients provides a new direction for assessing the risk for vasculopathy in SCD patients.

Clinical Development and Implementation of an Institutional Guideline for Prospective EEG Monitoring and Reporting of Delayed Cerebral Ischemia.

Delayed cerebral ischemia (DCI) is the most common and disabling complication among patients admitted to the hospital for subarachnoid hemorrhage (SAH). Clinical and radiographic methods often fail to detect DCI early enough to avert irreversible injury. We assessed the clinical feasibility of implementing a continuous EEG (cEEG) ischemia monitoring service for early DCI detection as part of an institutional guideline. An institutional neuromonitoring guideline was designed by an interdisciplinary team of neurocritical care, clinical neurophysiology, and neurosurgery physicians and nursing staff and cEEG technologists. The interdisciplinary team focused on (1) selection criteria of high-risk patients, (2) minimization of safety concerns related to prolonged monitoring, (3) technical selection of quantitative and qualitative neurophysiologic parameters based on expert consensus and review of the literature, (4) a structured interpretation and reporting methodology, prompting direct patient evaluation and iterative neurocritical care, and (5) a two-layered quality assurance process including structured clinician interviews assessing events of neurologic worsening and an adjudicated consensus review of neuroimaging and medical records. The resulting guideline's clinical feasibility was then prospectively evaluated. The institutional SAH monitoring guideline used transcranial Doppler ultrasound and cEEG monitoring for vasospasm and ischemia monitoring in patients with either Fisher group 3 or Hunt-Hess grade IV or V SAH. Safety criteria focused on prevention of skin breakdown and agitation. Technical components included monitoring of transcranial Doppler ultrasound velocities and cEEG features, including quantitative alpha:delta ratio and percent alpha variability, qualitative evidence of new focal slowing, late-onset epileptiform activity, or overall worsening of background. Structured cEEG reports were introduced including verbal communication for findings concerning neurologic decline. The guideline was successfully implemented over 27 months, during which neurocritical care physicians referred 71 SAH patients for combined transcranial Doppler ultrasound and cEEG monitoring. The quality assurance process determined a DCI rate of 48% among the monitored population, more than 90% of which occurred during the duration of cEEG monitoring (mean 6.9 days) beginning 2.7 days after symptom onset. An institutional guideline implementing cEEG for SAH ischemia monitoring and reporting is feasible to implement and efficiently identify patients at high baseline risk of DCI during the period of monitoring.

Delineating the Role of Cerebral Blood Flow and Hypocapnia on Neuromuscular Function

Neuromuscular fatigue, defined as the inability of a muscle to maintain a given level of force regardless of whether or not a task can be sustained, has been attributed, in part, to central mechanisms. Although reductions in cerebral blood flow (CBF) may be implicated in the development of central fatigue, the contribution from hypocapnic-reductions (i.e., PETCO2) in CBF versus reductions in CBF per se has yet to be isolated. PURPOSE: To examine the hypothesis that hypocapnia, independent of concomitant reductions in CBF, cause impairments in neuromuscular function. METHODS: Neuromuscular function, as indicated by motor evoked potentials (MEP), M-waves and cortical voluntary activation (cVA) of the flexor carpal radialis muscle during isometric wrist flexion, was assessed in 8 males (31±12 y) during 3 separate conditions: 1) cyclooxygenase inhibition using Indomethacin (Indo) to selectively reduce CBF; 2) controlled hyperventilation-induced hypocapnia (Hypocapnia); and 3) isocapnic hyperventilation (Isocapnia). CBF was estimated using transcranial Doppler ultrasound velocity measurements of the middle cerebral artery. Change from baseline and comparison of the 3 conditions was assessed using two-way repeated measures ANOVA. Relationships between variables were assessed using Pearson‘s correlations. RESULTS: The experimental conditions successfully isolated CBF and PETCO2. MEP amplitude (% M-wave amplitude) increased in hypocapnia (14.6±9.5%, p < 0.01) in comparison to Indo (-2.0±2.8%) and Isocapnia (0.6±1.8%); however, no significant changes were observed in M wave (p = 0.666) or cVA (p = 0.117). Correlation analysis revealed that MEP amplitude was inversely associated with PETCO2 (r = -0.54, p < 0.01) and cVA was weakly associated with CBF (r = 0.30, p < 0.05). CONCLUSIONS: Increased motor cortex excitability appears to be exclusive to hypocapnia but not reductions in CBF per se. However, a weak relationship between reductions in CBF and cVA exists, such that further research is required to confirm this finding and explore the potential implications. Supported by NSERC Discovery 227912-2012.

Transcranial Doppler Ultrasound (TCD) Outcomes for Children with Prior Normal TCD: Post-STOP Study Results

Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) study established routine transcranial Doppler ultrasound (TCD) screening with indefinite transfusions for children with abnormal TCD as standard of care. Children with normal TCD studies have the lowest risk of stroke of ~0.5-1% per year (y). Annual TCD screening is usually recommended for these children to detect possible subsequent conversion to high risk. We sought to determine the frequency of TCD screening utilized in “real world” clinical practice and the TCD outcomes for children with prior normal TCD.Subjects and Methods: During STOP and STOP2 (STOP/2), 3,837 children, ages 2 to 16 y with sickle cell disease type SS or S-Beta-0-thalassemia underwent screening TCD. The Post-STOP study was designed to follow-up the outcomes of children who were screened for or participated in one or both of these randomized trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,541 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) on follow-up TCD results and clinical information using standard data collection forms. The rates of TCD re-screening and the proportion of children who converted to abnormal TCD were calculated. Factors associated with conversion to abnormal TCD were assessed.Results: Of the 3,541 subjects, follow-up data were available for 2,838 (80%). The mean age at the last TCD study obtained in STOP/2 was 9.5 y and the mean age at last follow-up in Post-STOP was 19.6 y. The mean duration of follow-up after exiting STOP/2 was 9.2 y. Subjects were classified by their worst TCD in STOP/2: the TCD was normal in 1,814 (64%), conditional in 479 (17%), abnormal in 357 (13%) and inadequate 188 (7%). Among the 1,814 children with only normal studies in STOP/2, follow-up TCD screening was obtained in the Post-STOP era on 842 (46%) at a median rate of 0.28 TCD studies/y (range, 0.05-3.04/y). Among these children, 26 (3.1%) developed an abnormal TCD at a median of 11.5 y (2.2-18.2 y) from the last STOP/2 study, while 77.5% still had normal TCD at a median of 10.7 y (0.7-18.3 y) from last STOP/2 study. The worst follow-up TCD classification for this group with prior normal TCD was conditional in 9.7% and inadequate in 9.6%. Among those that converted from prior normal to abnormal TCD, 12 had an interval conditional study (at median 2.8 y, 0.98-9.2 y) while 14 children converted from normal to abnormal at a median of 4.2 y (1.4-12.7 y) without documented interval conditional study. Children who developed abnormal TCD were younger at STOP/2 study exit (4.9 vs. 7.8 y, p<0.001) and had higher TCD velocity at their last STOP/2 TCD study (154 vs. 136 cm/s, p<0.001) than children whose TCD remained normal. There was no significant difference between the time interval from the last STOP/2 TCD and the first Post-STOP TCD in these 2 groups.Conclusions: In clinical practice, follow-up TCD for children with prior normal TCD was performed less frequently than the generally recommended annual basis. Among children re-screened, the risk of conversion to abnormal TCD was relatively low, but re-screening with TCD identified a subset of at-risk children who could benefit from transfusions to prevent a potentially devastating outcome. Predictors of conversion to abnormal TCD included younger age and prior TCD velocity in the high normal range. DisclosuresAdams:Novartis: Consultancy.