Transcranial Doppler ultrasound (TCD) screening for primary stroke prevention in children with sickle cell anemia (SCA) was established in higher-resource regions, targeting interventions for highest velocity ("abnormal"). We sought to identify additional stroke risk factors in Uganda.

We conducted a 30-month open-label single-arm Ugandan hydroxyurea trial, dose-escalated to maximum-tolerated dose, aimed to test brain protection for children aged 3-9 years with SCA. Study procedures included history, clinical stroke examination, and prospective TCD and laboratory assessments.

Overall, 264 children received study HU, mean age 5.6 ± 1.7, hemoglobin 7.8 ± 1.2 g/dL, fetal hemoglobin (HbF) 11.9% ± 8.1%, enrolment TCD mean TAMV 148.4 ± 29.3 cm/sec; 15 (5.7%) had abnormal TCD. The mean TAMV at trial completion was 131.9 ± SD 25.7 cm/sec. Four participants without abnormal enrolment TCD developed acute stroke within the initial 16 months (incidence 0.62 per 100 person-years): two had enrolment HbF ≤3.1%, two had low oxygen saturation (90%), and one had recurring severe anemia necessitating multiple transfusions. Apparent stroke precipitants were severe malaria, acute chest syndrome, recent pain crisis, or uncertain cause. At trial completion, eight additional participants had a higher risk TCD category than at enrolment.

The effectiveness of TCD screening for stroke prevention may vary by region, as no participant with an incident stroke was at the highest risk. Antecedent and/or ongoing SCA-related risks of anemia, low HbF, hypoxemia, infections, and/or disease complications likely contributed to stroke despite trial HU. Results suggest that TCD alone may not fully identify the highest stroke risk in the region, and there is a need for primary stroke prevention from early childhood and continuous hydroxyurea therapy.

Children with sickle cell anemia (SCA) frequently develop progressive neurocognitive impairment. We aimed to determine effects of hydroxyurea therapy on neurocognitive function in Ugandan children with SCA by comparing levels at enrollment to a planned 18-month interim assessment. Ugandan children (N = 264) aged 3 to 9 years attending SCA clinic were enrolled and treated in a 30-month, single-arm, open-label trial with escalation to maximum tolerated dose. Sibling controls (N = 110) without SCA underwent parallel neurocognitive testing to establish age-normalized z scores for comparison. At enrollment, mean participant age was 5.6 ± 1.2 years, with comparable socioeconomic status and caregiver education vs. controls. Month 18 mean daily hydroxyurea dose was 25.4 mg/kg. We found significantly improved participant z scores vs. baseline in all 3 neurocognitive domains tested: cognition: -0.54 ± 1.10 vs. -0.07 ± 1.16, P < .001; attention: -0.07 ± 1.01 vs. 0.27 ± 0.84, P < .001; and executive function: -0.06 ± 0.62 vs. 0.08 ± 0.72, P = .010. No month-18 measures differed from controls. Participants with SCA and cognitive impairment declined from 8.7% at enrollment to 4.0%, vs. 1.6% of controls; with decreased mean TCD velocity. Improved neurocognitive treatment z-scores were associated with higher baseline scores and socioeconomic status, hydroxyurea-associated lower TCD velocity, and hematological-induced effects, eg higher hemoglobin. Despite improvement, unadjusted neurocognitive scores remained negatively associated with age. Hydroxyurea therapy improved SCA neurocognitive function in sub-Saharan children, potentially aided by practice effects. Early treatment is needed for optimal impact. Our ongoing trial will assess impact from longer-term hydroxyurea therapy. This trial was registered at www.ClinicalTrials.gov as #NCT04750707.

Children with sickle cell disease (SCD) may develop large vessel narrowing, but studies suggest vessels may also be enlarged, possibly related to increased cerebral blood flow (CBF). We used MRI to investigate whether the cross-sectional total inflow vessel luminal area (TIVLA) proximal to the circle of Willis (carotid arteries + basilar artery) would be increased in SCD compared to age- and sex-matched peers after adjusting for CBF. Across 36 children with SCD (19 female, median age 10.7 [8.0-14.5] years and 43 controls (26 female, median age 12.7 [9.2-18.2] years) matched by age (p = 0.13) and sex (p = 0.50), the median TIVLA in the SCD group (35.9 mm2 [30.7, 39.5]) was larger than controls (30.5 mm2 [27.8, 35.4], p = 0.002). In a mixed model including age, sex, hemoglobin, CBF, SCD status, and an interaction between hemoglobin and SCD status, CBF (β = 0.11, CI 0.02-0.20, p = 0.02), SCD (β = 28.02, CI 5.62-50.42, p = 0.015), and the interaction between SCD and hemoglobin (β = -2.48, CI -4.49 to -0.47, p = 0.018) were all significantly associated with increased TIVLA. Notably, TIVLA as a measure of arterial lumens is larger in children with SCD, even after adjusting for CBF in the mixed model. This implies disease-specific normative values may be needed to detect early vasculopathy.

Globally, sickle cell disease (SCD) is the most common inherited haemoglobinopathy. The highest burden of SCD is encountered in low- and middle-income countries (LMICs), most of which lack the resources to contend with the disease. There is a marked divide between care for individuals with SCD in high-income countries (HICs) versus LMICs, whereby the few disease-modifying therapies and curative regimens are only accessible to those in HICs. As such, blood transfusion remains central to the emergent treatment and prevention of complications of SCD. However, there are a myriad of related challenges in LMICs, which have impeded efforts to treat patients with SCD effectively. In addition to blood safety and availability, examples that impact SCD specifically include capabilities to detect and/or manage red blood cell alloimmunization, capacity for automated red cell exchange, limited immunohematology, suboptimal quality oversight with a lack of safeguards to prevent transfusion of incompatible blood and limited or absent post-transfusion surveillance to detect and/or manage transfusion-associated adverse events. Consequently, clinical practices that are otherwise regarded as standard of care in HICs remain the exception in LMICs, highlighting disparities in care. A multifaceted approach that prioritizes transfusion support in LMICs is needed to improve care for patients with SCD.

Sickle cell disease (SCD) is a genetic disorder characterized by sickle red blood cells (RBCs). Sickle RBCs cause cerebral vasculopathies including vaso-occlusive events, leading to ischemia-reperfusion injury and hypoxic tissue environment. To date, the physiological blood flow velocities in cerebral vessels of preclinical SCD models has not been evaluated under hypoxic-reoxygenation. In our study, we used transcranial ultrasound techniques to measure abnormal blood flow velocities in the internal carotid (ICA) and middle cerebral arteries (MCA) of transgenic sickle cell mice (SS) challenged with hypoxia-reoxygenation. Our study showed that SS mice that underwent hypoxic stress exhibited lower relative mean velocities in the MCA compared to wildtype mice (AA) (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Comparison of the Lindegaard ratio between normoxia and hypoxia in SS mice suggested that the MCA underwent vasodilation (0.67 ± 0.18 vs. 0.95 ± 0.15; p < 0.05). Bilirubin, a potential biomarker for cerebral vasculopathies in SCD, was higher in SS than AA mice (0.56  ±   0.28 vs. 0.05  ±   0.07 mg/dL; p < 0.05). Correlation analyses revealed a significant association between bilirubin levels and blood velocities of MCA (r = -0.9377, p = 0.0002) and ICA (r = 0.8203, p = 0.0068), especially in hypoxic conditions of SS mice. We propose that the reactivity of cerebral vessels in SS mice is correlated with the elevated plasma bilirubin level.

Sickle cell anemia (SCA) is associated with increased morbidity and mortality and impacts resource-limited settings with limited capacity for diagnosis and treatment. This review provides context for the magnitude of the problem, describes screening methods to prevent stroke, and factors that impact outcomes.

A narrative review was conducted. Topics included background information on SCA, its clinical characteristics, complications including primary stroke, and available treatment options. Social, economic, and political factors in East and Central Africa were described.

A total of 37 publications were categorized into four themes: morbidity and mortality of SCA in sub-Saharan Africa; TCD screening for risk of primary stroke in children; treatment of children with SCA in resource-limited settings; and approaches to capacity gaps.

SCA represents a public health problem in sub-Saharan Africa. TCD screening with hydroxyurea treatment can improve outcomes and prevent primary stroke. Multiple barriers exist, including limited diagnostic screening, inconsistent availability of and access to hydroxyurea, and knowledge gaps. These barriers are influenced by social, economic and policy factors that can be addressed to build capacity and improve outcomes.

Sickle cell disease (SCD) is a rare group of inherited red blood cell disorders that affect hemoglobin, resulting in serious multi-system complications. The limited number of patients available to participate in research studies can inhibit investigating sophisticated relationships. Secondary analysis is a research method that involves using existing data to answer new research questions. Data harmonization enables secondary analysis by combining data across studies, especially helpful for rare disease research where individual studies may be small. The National Heart, Lung, and Blood Institute Cure Sickle Cell Initiative (CureSCi) Metadata Catalog is a web-based tool to identify SCD study datasets for conducting data harmonization and secondary analysis. We present a proof-of-concept secondary analysis to explore factors associated with discontinuation of hydroxyurea, a safe and effective first line SCD therapy, to illustrate the utility of the CureSCi Metadata Catalog to expedite and enable more robust SCD research.

We performed secondary analysis of SCD studies using a multi-step workflow: develop research questions, identify study datasets, identify variables of interest, harmonize variables, and establish an analysis method. A harmonized dataset consisting of eight predictor variables across five studies was created. Secondary analysis employed a generalized linear model to identify factors that significantly impact hydroxyurea discontinuation.

The CureSCi Metadata Catalog provided a platform to efficiently find relevant studies and design a harmonization strategy to prepare data for secondary analysis. Multivariate analysis of the harmonized data identified that patients who were female, had a history of blood transfusion therapy, experiencing pain, and had the SC sickle cell genotype are more likely to stop hydroxyurea treatment.

This secondary analysis provides a template for how the CureSCi Metadata Catalog expedites dataset discovery of sickle cell studies for identifying relationships between variables or validating existing findings.

Sickle cell anemia (SCA) is recognized globally, but little is known about affected Hispanic populations. In partnership with the Dominican Republic, a Hispanic Caribbean island with a large SCA population, a transcranial Doppler (TCD) screening program provided hydroxyurea to children with conditional velocities. Building local capacity, 10 Dominican medical graduates were certified in TCD examinations and trained in hydroxyurea management. The Stroke Avoidance for Children in REpública Dominicana (SACRED) trial enrolled 283 children with average age of 8.7 ± 3.4 years and 130 (46%) females. At initial screening, treatment-naïve children with conditional velocities (170-199 cm/s) were younger (6.6 ± 2.7 vs 8.9 ± 3.4 years; P = .0002) and more anemic (hemoglobin, 7.4 ± 0.8 vs 8.0 ± 1.2 g/dL; P = .0046) than children with normal screening velocities (<170 cm/s). Among 57 treatment-naïve children receiving 6 months of fixed-dose hydroxyurea at 20 mg/kg per day, average TCD velocities decreased by 20 cm/s, and 61% became normal. Compared with fixed-dose hydroxyurea, dose escalation to maximum tolerated dose (MTD) led to fewer sickle-related events with incidence rate ratio 0.59, 95% confidence intervals 0.36 to 0.98, P = .0420. At MTD, TCD benefits were sustained over 5 years, with 81% reverting to normal and an average TCD velocity decrease of 27 cm/s. Brain magnetic resonance imaging documented substantial baseline parenchymal disease; during treatment, 10% developed new vasculopathy, plus 1 stroke and 1 death. The SACRED trial documents a high burden of cerebrovascular disease among Hispanic children with SCA and demonstrates the feasibility of partnership to establish TCD screening programs, the utility of hydroxyurea to reduce TCD velocities and reduce stroke risk, and sustained benefits of hydroxyurea dose escalation. This trial was registered at www.clinicaltrials.gov as #NCT02769845.

Sickle cell disease results in vaso-occlusion and hemolysis, leading to ophthalmic and systemic complications. In the eye, these processes initiate retinal ischemia and neovascularization resulting in sickle cell retinopathy (SCR). Hydroxyurea therapy increases fetal hemoglobin (reducing ischemia), and chronic blood transfusions (CTXN) reduce strokes in children with abnormally high intracranial vessel velocities. It is not known if these treatments reduce retinopathy. Our hypothesis is that hydroxyurea and CTXN lower the risk of the development and slow the progression of retinopathy.

Using a large longitudinal cohort study, we determined the prevalence of SCR among pediatric and adolescent patients with sickle cell disease and the effects of disease-modifying therapy on reducing the prevalence and severity of sickle cell retinopathy.

We included all eye examinations of participants (age 10-18 at time of initial eye exam) at a single site from the Sickle Cell Research and Intervention Program cohort between October 2010 and September 2022. Patients without a dilated eye exam were excluded.

At 10 years of age, yearly ophthalmologic assessments began for patients with hemoglobin SC disease and every other year for other sickle cell genotypes. Two ophthalmologists reviewed all 2237 eye examination results.

We obtained patient age, sex, sickle genotype, treatment received for sickle cell retinopathy, duration of exposure to sickle cell disease-modifying therapy, and hematologic indices (fetal hemoglobin and hemoglobin concentration) and abstracted data regarding SCR, severity grading, and treatment.

We observed that pediatric and adolescent patients with sickle cell disease receiving hydroxyurea therapy were 29% less likely to demonstrate SCR. Of those receiving hydroxyurea, 107 of 351 patients (30%) had SCR as compared with the 118 of 279 patients (42%) not receiving hydroxyurea (P = 0.0028). Patients receiving CTXN were 68% less likely to develop SCR. Of those, 20 of 121 patients (17%) had retinopathy as compared with the 205 of 509 patients (40%) not receiving CTXN (P < 0.001).

Our data from one of the largest cohorts of pediatric and adolescent patients with sickle cell disease support widespread use of hydroxyurea, CTXN, or both. We found that these therapies are associated with a smaller number of patients demonstrating SCR.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Sickle cell disease (SCD) is the most common hemoglobinopathy in North America. The life expectancy of SCD has extended into adulthood with screenings, preventative care, and hydroxyurea. However, comorbidities arise as adults with SCD age, leading to early mortality.

We conducted a retrospective chart review of the Georgia Comprehensive Sickle Cell Center at Grady Health System, analyzing records of deceased SCD patients from 2013 to 2020.

Amongst the 72 patients analysed, majority had severe complications from SCD and at least 1 cardiovascular comorbidity. The median age of death was 44 (STD = 15.5) for all genotypes with the median age of death at 39 (STD = 14.26) for SS and Sβ0 genotypes (n = 51). There was no difference in the median age of death for patients who maintained regular clinic visits (a visit in the last 6 months prior to death) compared to those who did not. Despite hydroxyurea's known benefits in reducing SCD morbidity and mortality, less than 50% of patients had a prescription.

As new therapies are approved, their impact on SCD-related morbidity and mortality must be evaluated. Improving access to, and education about, disease-modifying therapies like hydroxyurea for both patients and clinicians is essential to improving outcomes.

Transcranial Doppler (TCD) screening is essential for stroke prevention in children with sickle cell disease (SCD), but screening rates are low nationally. We use Medicaid administrative claims to assess TCD completion rates before and after a 12-month QI initiative to improve rates in the Pacific Sickle Cell Regional Collaborative (PSCRC). We found an increase in TCD screening rates for QI participant sites (52.4% to 58.6%), but not for the nonparticipant SCD population (48.3% to 38.3%). The increase in QI participant sites was not sustained 1 year after the initiative. Local clinic-level QI initiatives may need to be supplemented with health system partnerships to sustain higher TCD screening rates, thereby improving SCD outcomes.

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n = 12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity (CVR) in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Cerebral vasculopathy is a frequent and serious complication of major sickle cell disease syndromes. Transcerebral Doppler (TCD) can detect stenosis of the main arteries at the base of the skull before stroke occurs, and initiate therapy to avoid complications. The objective of the study is to evaluate and compare the hemodynamic profile of the middle cerebral artery using TCD in children with sickle cell disease compared to children without sickle cell disease.

Prospective analytical study extended over a 6-month period from July 04, 2023 to December 28, 2023. The study population consisted of subjects followed for homozygous sickle cell disease SS and non-sickle cell subjects received at the above-mentioned centers, of all sexes, aged 2 to 16 years at most.

We recruited 182 children (52.2% male and 47.8% female) divided into 70 children with sickle cell disease and 112 children without sickle cell disease. The mean of Maximum systolic velocity (MSV) on the left was 85.0 ± 49.5 cm/s in sickle cell patients and 84.5 ± 17.8 cm/s in non-sickle cell patients. The mean of telediastolic velocity (TDV) was 40.9 ± 31.2 cm/s in sickle cell patients and 44.0 ± 15.8 cm/s in non-sickle cell patients. The mean maximum velocity (MMV) was 53.22 ± 39.0 cm/s in sickle cell patients and 57.5 ± 16.3 cm/s in non-sickle cell patients.

The mean velocity of children with sickle cell disease was lower than that of non-sickle cell patients, and the peak systolic velocity of children with sickle cell disease was slightly higher than those of children without sickle cell disease.

Sickle cell disease (SCD) is an inherited disorder of hemoglobin that affects tens of millions of individuals worldwide. Without preventive and disease-modifying therapy, SCD results in many acute and chronic complications impacting both quality and length of life. We are currently in a new generation of SCD care in high resource settings due to recent advancements in care. Universal newborn screening (NBS) for SCD with associated parental education and preventive care significantly improved mortality rates. Beginning in the 1990s, hydroxyurea emerged as a promising pharmacologic treatment for SCD due to its ability to increase the amount of fetal hemoglobin. It is now the mainstay of treatment, with strong recommendations to begin as early as the first year of life with the goal of reducing most short- and long-term complications and allowing for a normalized quality of life. More recently, gene therapy has come to the forefront in SCD and brings the hope of a cure for many patients. In 2023, the FDA approved two cell-based gene therapies for patients with SCD. The future is bright for patients with SCD, and the current generation of affected children will expectantly be able to grow up free of suffering and severe, frequent pain.

Red blood cell (RBC) utilization in patients with sickle cell disease (SCD) in Canada is poorly defined. This study describes RBC utilization in an SCD cohort at a single Canadian center.

All adults with SCD who received care at the Ottawa Hospital between January 2006 and May 2019 were included, and followed until December 2021. Data on hospital encounters and RBC transfusions were obtained from hospital databases.

Overall, 273 patients were included (median age: 25 years; 53.8% female; median follow-up: 8.1 years). During the study period, there were 23,127 hospital encounters (median: 45 [interquartile range (IQR) 18, 100] per patient), with 165 patients (60.4% of cohort) receiving 22,538 RBC units. Most RBC units (86.5%) were transfused in the outpatient setting. Although only 2.9% of patients had O-negative blood type, O-negative RBC units accounted for 29.1% of units transfused. One hundred forty-seven patients received 2205 RBC units (9.8% of total) as simple transfusions (median: 5 [IQR 3, 13] per patient), and 88 patients received 20,333 RBC units (90.2% of total) during 2702 red cell exchange (RCE) sessions (median: 14.5 (IQR 1, 47.5) RCE per transfused patient). A median of 7 RBC units (IQR 6, 9) were transfused per RCE session, with a median of 30 days (IQR 28, 40) between sessions.

Patients with SCD at our center frequently received O-negative units, and large RBC volumes were used for RCE. These results provide a utilization baseline for future education and quality improvement initiatives to optimize RBC stewardship.

Red cell exchange (RCE) is an important treatment for sickle cell disease (SCD). It is a resource-intensive intervention requiring large volumes of red blood cells (RBC), which are frequently antigen-matched. Efforts to reduce the volume of units transfused, while maintaining treatment efficacy is an important need. This study evaluates the impact of a change to isovolemic hemodilution (IHD)-RCE on RBC utilization in SCD patients at a Canadian center.

Adult SCD patients receiving chronic automated RCE at the Ottawa Hospital were approached for study inclusion. To safely attain a meaningful reduction in transfused RBCs, RCE parameters were individualized for each patient. IHD-RCE was performed only if an estimated reduction in RBC volume of at least 200 mL was expected, with hematocrit not allowed to decrease below 20%. Data were compared in the 6-months before and after the protocol change.

Twenty-two adult patients met the criteria for inclusion. There was a net reduction of 107 RBC units after the transition from standard RCE to IHD-RCE (1035 vs. 928 units; -10.3%). The mean number of RBC units transfused per patient decreased by 4.8 (47.0 vs. 42.2 units; p = .01). No difference in target post-RCE hemoglobin S levels was observed.

In this study IHD-RCE reduced RBC utilization without impacting efficacy or safety, conserving 107 RBC units (an annualized savings of $95,444 CAD). No adverse events due to saline replacement were observed. Increased awareness of the benefits of IHD-RCE through knowledge translation could promote greater uptake.

Background: Hereditary hemoglobin disorders are the most common globally distributed monogenic red cell diseases. The rights of women with thalassemia or sickle cell disease (SCD) to motherhood need to be protected by creating a roadmap to guide her, and her family network, along all the phases of the event. In fact, pregnancy in these vulnerable patients requires special attention and guidelines from the counseling stage (giving information about the special requirement and risks posed by their pregnancy with respect to the general population) the pre-conception stage, the early and mid-late pregnancy stage, to labor and lactation. The biocomplexity of these diseases requires a multidisciplinary team synergizing with gynecologists and obstetricians. In addition, the presence of a multicultural scenario requires healthcare workers to overcome stereotypes and adopt appropriate anthropological tools that might help them integrate the different cultural models of disease and motherhood. Methods: The Management Committee of the Society for Thalassemia and Hemoglobinopathies (SITE) selected and brought together a multidisciplinary and multiprofessional group made up of experts in hemoglobinopathies and experts in anthropology, flanked along with by experts with methodological and organizational expertise in order to create recommendations based on the integration of available scientific evidence together with expert opinion. Results: The panelists critically analyzed the literature, combining in a single document practices developed over several years of managing young women with hemoglobinopathies in a sensitive phase of their lives. Conclusions: This good practice document is the result of a collegial effort by Italian experts on hemoglobinopathies who are members of SITE. (SITE).

Pediatric point-of-care ultrasonography (POCUS) has grown in utilization and is now an integral part of pediatric acute care. Applications within the pediatric critical care, neonatology and pediatric emergency were once limited to evaluation of undifferentiated shock states, abdominal free fluid assessments in trauma resuscitation and procedural guidance. The body of pediatric POCUS literature is ever expanding and recently published international consensus guidelines are available to guide implementation into clinical practice. The authors present a review of emerging applications and controversies within thoracic, hemodynamic, neurologic, and ocular POCUS in pediatric acute care medicine.

Transcranial doppler ultrasound (TCD) screening for primary stroke prevention in children with sickle cell anemia (SCA) was established in higher-resource regions, targeting interventions for highest velocity ("abnormal"). We sought to identify additional stroke risk factors in Uganda.

We conducted a 30-month open-label single-arm Ugandan hydroxyurea trial, dose-escalated to maximum tolerated dose, aimed to test brain protection for children aged 3-9 years with SCA. Study procedures included history, clinical stroke examination and prospective TCD and laboratory assessments.

Overall, 264 children received study HU, mean age 5.6±1.7, hemoglobin 7.8±1.2g/dL, fetal hemoglobin (HbF) 11.9±8.1%, enrolment TCD maximum velocity 148.4±29.3cm/second; 15 (5.7%) had abnormal TCD. Mean TAMV at trial completion was131.9±SD25.7 cm/sec. Four participants without abnormal enrolment TCD developed acute stroke within the initial 16 months (incidence 0.62 per 100 person years); Two had enrolment HbF ≤3.1%, 2 had low oxygen saturation (90%), 1 had recurring severe anemia necessitating multiple transfusions. Apparent stroke precipitants were severe malaria, acute chest syndrome, recent pain crisis or uncertain cause. At trial completion, 8 additional participants had a higher risk TCD category than at enrolment.

Effectiveness of TCD screening for stroke prevention may vary by region, as no participant with incident stroke was at highest risk. Antecedent and/or ongoing SCA-related risks of anemia, low HbF, hypoxemia, infections and/or disease complications likely contributed to stroke despite trial HU. Results suggest that TCD alone may not fully identify highest stroke risk in the region, and need for primary stroke prevention from early and continuous hydroxyurea therapy.

Patients with sickle cell disease (SCD) are at elevated risk of silent cerebral infarcts and strokes; however, they frequently lack established stroke risk factors (eg, macrovascular arterial steno-occlusion) and the mechanisms underlying such events are incompletely characterized. This study evaluated cerebral hemometabolism with respect to imaging markers of vascular shunting in 143 participants with SCD, including 73 pediatric (aged 6-17 years) and 70 adult (aged 18-40 years) participants using 3-Tesla brain magnetic resonance imaging (MRI). Vascular shunting was assessed in each patient using a previously published ordinal venous hyperintensity score (VHS) of 0, 1, or 2 on cerebral blood flow-weighted MRI. Participants with VHS of 2, indicative of the most rapid arteriovenous transit, had significantly reduced blood oxygen content (CaO2; 10.90 ± 1.69 mL O2/100 mL blood), oxygen extraction fraction (OEF; 33.52% ± 5.54%), and cerebral metabolic rate of oxygen consumption (CMRO2; 2.91 ± 0.69 mL O2/100 g tissue per minute) compared with their counterparts with VHS = 0 (CaO2 = 12.42 ± 1.58 mL O2/100 mL blood; OEF = 39.03% ± 3.80%; CMRO2 = 3.77 ± 0.84 mL O2/100 g tissue per minute) or VHS = 1 (CaO2 = 11.86 ± 1.73 mL O2/100 mL blood; OEF = 36.37% ± 5.11%; CMRO2 = 3.59 ± 0.78 mL O2/100 g tissue per minute). Both pediatric and adult patients with SCD presenting with greater imaging evidence of vascular shunting had mildly reduced OEF and CMRO2. These findings highlight that imaging markers of vascular shunting are associated with significant, albeit mild, evidence of reduced OEF and CMRO2 in patients with SCD.

The ability of transcranial Doppler (TCD) to detect asymptomatic cerebrovascular disease among childhood brain tumor survivors following exposure to cranial radiation therapy has not been established.

Survivors of childhood brain tumors, more than 3 years since diagnosis and exposed to greater than 30 Gy cranial radiation, underwent a history and physical exam, laboratory biomarkers of cerebrovascular disease (cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), high-sensitivity CRP, hemoglobin A1C, apoprotein A, and apoprotein B), and a TCD evaluation of their cerebral arteries.

In all 165 cerebral arteries from 13 patients (medulloblastoma = 10; germ cell tumor = 3; females = 5; mean age at diagnosis = 8.0 years; mean age at time of study = 20.9 years) were examined. Twenty-eight of 165 (17%) were considered abnormal by pre-specified criteria. Total 114 cerebral arteries from 13 patients were assessed for greater than 50% stenosis velocities. Arteries most likely to be considered abnormal included the distal bilateral vertebral arteries (right 38%, left 30%), basilar artery 30%, bilateral siphon internal carotid arteries (right 30%, left 23%), bilateral middle cerebral arteries (23% bilaterally), and bilateral anterior cerebral arteries (7% bilaterally). Two vessels had mean flow velocities consistent with ≥ $ \ge $ 50% stenosis (1.8%). No vessels were found to have greater than 80% stenosis.

TCD may be a useful and practical tool to examine asymptomatic cerebrovascular disease among childhood brain tumor survivors after exposure to cranial radiation therapy. Posterior circulation vessels appear to have the highest burden of disease in this group of brain tumor survivors, a majority of whom had medulloblastoma.

Children with sickle cell disease (SCD) have increased stroke risk, identifiable by elevated velocities on transcranial Doppler (TCD). This review assessed the impact of TCD screening on stroke, mortality, quality of life and morbidity in children with SCD.

A systematic search of MEDLINE, PubMed, Cochrane libraries, and trial registries was conducted from inception to 28th February 2023. Randomised controlled trials (RCTs) and non-randomised studies (NRS) were included. A meta-analysis and narrative synthesis were performed.

Nine studies were included in the review. In one RCT, initiating chronic blood transfusion in children with abnormal TCD velocities reduced stroke risk by 92 %, while no deaths were reported. Pooled results from three NRS indicated TCD screening leads to four fewer strokes per 1000 patients annually. No studies analysing morbidity nor quality of life were identified.

TCD screening may decrease the risk of stroke in patients with SCD.

Neurovascular complications, including strokes and transient ischemic attacks (TIAs), are common and cause significant morbidity in individuals with sickle cell disease (SCD). The Stroke Prevention Trial in Sickle Cell Anemia (STOP) (1998) established chronic transfusions as the standard of care for children with SCD at high risk for stroke. Using statewide data from the California Department of Health Care Access and Innovation (1991-2019), we determined the cumulative incidence (CMI) and rates of primary and recurrent strokes/TIAs in people with SCD pre- and post-STOP trial. For the 7636 patients included in our SCD cohort, the cumulative incidence of the first ischemic stroke was 2.1% by the age of 20 years and 13.5% by the age of 60 years. The CMI of the first intracranial hemorrhage (ICH) was 0.5% and 6.8% by the age of 20 and 60 years, respectively. Ischemic stroke rates increased in children (age <18 years; 234.9 vs 165.1 per 100 000 patient years [PY]; P = .012) and adults (age 31-50 years; 431.1 vs 303.2 per 100 000 PY; P = .031) in 2010 to 2019 when compared with the preceding decade. There was an increase in the rates of ICH in those aged 18 to 30 years and TIA in children <18 years from 2010 to 2019 when compared with the previous decade. Risk factors for strokes included increasing age, hypertension, and hyperlipidemia. These findings underscore the need for stroke prevention in adults with SCD, suggesting an emphasis on management of modifiable cerebrovascular risk factors that have been proven to be effective in the general population.

The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke.

A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed.

Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

Critically ill children are at risk of neurologic dysfunction and acquiring primary and secondary brain injury. Close monitoring of cerebral function is crucial to prevent, detect, and treat these complications.

A variety of neuromonitoring modalities are currently used in pediatric and neonatal ICUs. These include noninvasive modalities, such as electroencephalography, transcranial Doppler, and near-infrared spectroscopy, as well as invasive methods including intracranial pressure monitoring, brain tissue oxygen measurement, and cerebral microdialysis. Each modality offers unique insights into neurologic function, cerebral circulation, or metabolism to support individualized neurologic care based on a patient's own physiology. Utilization of these modalities in ICUs results in reduced neurologic injury and mortality and improved neurodevelopmental outcomes.

Monitoring of neurologic function can significantly improve care of critically ill children. Additional research is needed to establish normative values in pediatric patients and to standardize the use of these modalities.

Children with sickle cell anemia (SCA) in Sub-Saharan Africa are at high risk of sickle cerebrovascular injury (SCVI). Hydroxyurea, a commonly used disease-modifying therapy, may reduce SCVI resulting in potential impact on reducing stroke and cognitive dysfunction. We aim to test the impact of daily hydroxyurea therapy on these outcomes in Ugandan children with SCA. We hypothesized that hydroxyurea therapy over 36 months will prevent, stabilize or improve these complications of SCA.

The BRAIN SAFE II study is an open label, single arm trial of daily hydroxyurea in 270 children with SCA (HbSS) in Uganda, ages 3-9 years. Following baseline assessments, participants began hydroxyurea therapy and are followed according to local guidelines. Standard hydroxyurea dose is escalated to maximum tolerated dose (MTD). SCVI is assessed by cerebral arterial velocity using Doppler ultrasound, with cognitive function determined by formal neurocognitive testing (primary outcomes). Structural SCVI is assessed by magnetic resonance imaging (MRI) and angiography (MRA) in a sub-sample of 90 participants ages >5 years. At trial midpoint (18 months) and completion (36 months), outcomes of age-specific assessments will be compared to baseline, as well as biomarkers of anemia, inflammation and malnutrition (secondary outcomes) to determine their relationships to primary outcomes.

This trial will examine the impact of hydroxyurea on preventing or ameliorating SCA SCVI in children, assessed by reducing incident stroke, stroke risk and neurocognitive dysfunction. Trial results will provide critical insight into the role of hydroxyurea therapy on critical manifestations of SCVI in children with SCA.

https://clinicaltrials.gov/ct2/show/NCT04750707 (registered 11 February 2021).

BRAIN SAFE II Protocol Version 3.0, Mar 02, 2022.

Many children with sickle cell disease (SCD) who suffer a stroke receive chronic transfusion therapy (CTT) indefinitely; however, their adulthood neurologic outcomes have not been reported. Understanding these outcomes is critical to inform decisions regarding curative therapy in childhood.

In this retrospective study, we described a cohort of adults with SCD and a history of childhood stroke who received care at a single center and compared their outcomes with matched subjects without childhood stroke using chi2 and Mann-Whitney U tests.

Of 42 subjects with childhood stroke, all received CTT for secondary stroke prophylaxis. Five (11%) developed recurrent stroke. The rate of stroke was similar in subjects with and without childhood stroke (0.7 vs. 1.1 per 100 person·years, p = .63). Both cohorts exhibited evidence of iron overload (median ferritin 2227 vs. 1409 ng/dL, p = .10) and alloimmunization (45% vs. 45%, p = 1.0), despite receiving care in a comprehensive SCD program.

For adults with SCD who had a childhood stroke, our results suggest CTT returns the risk of stroke to that of age-matched stroke naïve patients with SCD.

Stroke is a devastating complication of Sickle Cell Disease (SCD) with significant mortality and substantial morbidity. The burden of prevalent stroke in SCD is highest in sub-Saharan Africa and estimated at 4.2 % to 6.4 % in the era where evidence-based prevention strategies such as use of hydroxyurea therapy and transcranial doppler ultrasound were not routine care.

To assess the contemporary frequency and factors associated with prevalent stroke across the lifespan in an SCD registry at the tertiary medical center in Ghana.

This is a cross-sectional study conducted at the Komfo Anokye Teaching Hospital, a tertiary medical center in the middle belt of Ghana. The center has comprehensive Sickle Cell Clinics for children, adolescents, and adults with a patient registry established as part of the Sickle Pan-African Research Consortium (SPARCo)-Ghana study from 2017 to date. Data captured in the registry and analyzed for the present study include demographics, stroke status using the WHO criteria supplemented by the Questionnaire for Verifying Stroke Free Status (QVSFS), use of hydroxyurea, and complete blood count. Logistic regression modeling was utilized to assess factors associated with stroke.

Among a registry cohort of 4115 individuals with confirmed SCD, 35 (0.85 %, 95 % CI: 0.59-1.18 %) had overt or clinically confirmed stroke. The frequency of stroke differed significantly across the lifespan being 0.38 % (95 % CI: 0.12-0.64 %) among children <10 years, 1.23 % (95 % CI: 0.73-1.94 %) among adolescents aged 10 to 17 years, and 1.44 % (95 % CI: 0.66-2.71 %) among adults 18 years or more, p = 0.007. In adjusted analysis, each 10-year increase in age was associated with odds ratio, OR (95 % CI) of 1.90 (1.42-2.54) and hydroxyurea use, OR of 6.09 (2.65-13.99). The association between hydroxyurea and stroke observed in this cross-sectional study is not causal.

Approximately 1 in 120 SCD patients in this large Ghanaian cohort had clinically overt stroke. The gradual uptake of hydroxyurea therapy into routine care for SCD in this resource-limited setting, may partly explain the lower frequency of stroke.

Hemorrhagic stroke (HS) in childhood accounts for almost 50% of childhood strokes, is among the top ten causes of deaths, or determines lifelong disability. These facts form significant socio-economic and demographic problems. The purpose of this review is to analyze current knowledge about HS in children. The data on HS terminology are presented, taking into account the International Classification of Diseases 11 edition. Attention is paid to the epidemiology of HS in children, including the results of individual local studies. The risk factors of HS in children were studied with an analysis of the causal, pathophysiological mechanisms of HS of various etiologies. The ideas about the clinical manifestations of HS in children are described. The analysis of HS treatment in children was carried out with an emphasis on achievements in neurointensive therapy of the acute period of HS. This review also includes information on the outcomes of HS in children.

Sickle cell anemia (SCA) is an autosomal recessive inherited hemoglobinopathy that results in a high risk of stroke. SCA primarily affects an underserved minority population of children who are frequently not receiving effective, multi-disciplinary, preventative care. This article reviews primary and secondary stroke prevention and treatment for children with SCA for the general adult and pediatric neurologist, who may play an important role in providing critical neurologic evaluation and care to these children.

Primary stroke prevention is efficacious at reducing ischemic stroke risk, but it is not consistently implemented into clinical practice in the United States, resulting in these children remaining at high risk. Acute symptomatic stroke management requires neurology involvement and emergent transfusion to limit ischemia. Furthermore, while chronic transfusion therapy is a proven secondary preventative modality for those with prior symptomatic or silent cerebral infarcts, it carries significant burden. Newer therapies (e.g., stem cell therapies and voxelotor) deserve further study as they may hold promise in reducing stroke risk and treatment burden. Effective primary and secondary stroke prevention and treatment remain a challenge. Informing and engaging neurology providers to recognize and provide critical neurologic evaluation and treatment has potential to close care gaps.

Stroke is one of the most devastating complications of sickle cell disease (SCD). Transcranial Doppler Imaging (TCDI) is the least invasive screening method to predict patients at risk for developing stroke in the disease. After a 10-year follow-up, we longitudinally assessed the TCDI in children with SCD without neurological symptoms.

25 out of 43 pediatric patients with SCD studied 10-year previously were recruited. The remaining 18 patient were not available for follow-up, but their initial data are presented for comparison. TCDI scanning was carried out using a phased-array transducer of 1-3 MHz through the trans-temporal window. Peak systolic velocity (PSV), end-diastolic velocity (EDV), time-averaged mean of the maximum velocity (TAMMV), resistive index (RI), and pulsatility index (PI) were obtained in the anterior and posterior Circle of Willis vessels.

The highest initial and follow-up TAMMV (mean ± SD) were: 77.3 ± 20.9 and 71.6 ± 9.9 in the t-ICA, 94.3 ± 25.8 and 82 ± 18.2 in the MCA, 76.6 ± 25.6 and 70.6 ± 10.7 in the ACA, and 59.1 ± 15.8 and 63.9 ± 8.5 in the PCA, respectively. There was no statistically significant difference between initial and follow-up SCD data for all vascular parameters in all vessels on each side (P > 0.05) except for RI and PI (P < 0.05). There was significant correlation between TAMMV, PSV, and EDV (P = 0.001).

There are no absolute Doppler velocity changes between the initial and follow-up period over the years. There is a possibility that PSV and EDV could be used in parallel with TAMMV Subclinical vascular degeneration is not suggested by these vascular measures.

Cerebrovascular imaging assessments are particularly challenging in adolescent cohorts, where not all modalities are appropriate, and rapid brain maturation alters hemodynamics at both macro- and microvascular scales. In a preliminary sample of healthy adolescents (n=12, 8-25 years), we investigated relationships between 4D flow MRI-derived blood velocity and blood flow in bilateral anterior, middle, and posterior cerebral arteries and BOLD cerebrovascular reactivity in associated vascular territories. As hypothesized, higher velocities in large arteries are associated with an earlier response to a vasodilatory stimulus (cerebrovascular reactivity delay) in the downstream territory. Higher blood flow through these arteries is associated with a larger BOLD response to a vasodilatory stimulus (cerebrovascular reactivity amplitude) in the associated territory. These trends are consistent in a case study of adult moyamoya disease. In our small adolescent cohort, macrovascular-microvascular relationships for velocity/delay and flow/CVR change with age, though underlying mechanisms are unclear. Our work emphasizes the need to better characterize this key stage of human brain development, when cerebrovascular hemodynamics are changing, and standard imaging methods offer limited insight into these processes. We provide important normative data for future comparisons in pathology, where combining macro- and microvascular assessments may better help us prevent, stratify, and treat cerebrovascular disease.

Sickle cell disease (SCD) is among the most frequent hereditary disorders globally and its prevalence in Europe is increasing due to migration movements.

The basic pathophysiological event of SCD is polymerization of deoxygenated sickle hemoglobin, resulting in hemolysis, vasoocclusion, and multiorgan damage. While the pathophysiological cascade offers numerous targets for treatment, currently only two disease-modifying drugs have been approved in Europe and transfusion remains a mainstay of both preventing and treating severe complications of SCD. Allogeneic stem cell transplantation and gene therapy offer a curative option but are restricted to few patients due to costs and limited availability of donors.

Further efforts are needed to grant patients access to approved treatments, to explore drug combinations and to establish new treatment options.