Transcranial Doppler Screening Research Articles

Limited access to transcranial Doppler screening and stroke prevention for children with sickle cell disease in Europe: Results of a multinational EuroBloodNet survey.

Ensuring equitable access to adequate standard of care for patients with rare hematological disease is one of the aims of the European Reference Network (ERN) EuroBloodNet. Stroke is one of the most devastating complications for children with sickle cell disease (SCD). For effective prevention of stroke risk, annual transcranial Doppler (TCD) according to a defined protocol is recommended for patients aged 2-16years, with red blood cell transfusion therapy for those at risk. There is no information regarding screening for stroke risk and stroke prevention programs in Europe. Seven SCD experts of five healthcare providers (HCPs) of ERN EuroBloodNet developed an online survey to assess the access to TCD screening and stroke prevention programs for children with SCD in Europe. Eighty-one experts in 77 HCPs from 16 European countries responded to 16 online questions. Thirty-two of 77 (51%) HCPs were EuroBloodNet reference centers, and 36% physicians reported not having a dedicated TCD/TCD imaging service for children with SCD. Only 30% of physicians provided estimates that all their patients received annual TCD according to the standard protocol due to lack of trained staff (43%), lack of TCD instruments (11%), refusal of patients due to logistical difficulties (22%), and lack of funds for dedicated staff or equipment (11%). This multinational European survey provides the first comprehensive picture of access to TCD screening and stroke prevention in European countries. Identifying the potential underlying causes of the lack of effective standardized screening, this survey also addresses possible dedicated actions to cover these needs.

Limited access to transcranial Doppler screening and stroke prevention for children with sickle cell disease in Europe: Results of a multinational EuroBloodNet survey.

Ensuring equitable access to adequate standard of care for patients with rare hematological disease is one of the aims of the European Reference Network (ERN) EuroBloodNet. Stroke is one of the most devastating complications for children with sickle cell disease (SCD). For effective prevention of stroke risk, annual transcranial Doppler (TCD) according to a defined protocol is recommended for patients aged 2-16years, with red blood cell transfusion therapy for those at risk. There is no information regarding screening for stroke risk and stroke prevention programs in Europe. Seven SCD experts of five healthcare providers (HCPs) of ERN EuroBloodNet developed an online survey to assess the access to TCD screening and stroke prevention programs for children with SCD in Europe. Eighty-one experts in 77 HCPs from 16 European countries responded to 16 online questions. Thirty-two of 77 (51%) HCPs were EuroBloodNet reference centers, and 36% physicians reported not having a dedicated TCD/TCD imaging service for children with SCD. Only 30% of physicians provided estimates that all their patients received annual TCD according to the standard protocol due to lack of trained staff (43%), lack of TCD instruments (11%), refusal of patients due to logistical difficulties (22%), and lack of funds for dedicated staff or equipment (11%). This multinational European survey provides the first comprehensive picture of access to TCD screening and stroke prevention in European countries. Identifying the potential underlying causes of the lack of effective standardized screening, this survey also addresses possible dedicated actions to cover these needs.

Sustained increase in annual transcranial Doppler screening rates in children with sickle cell disease: A quality improvement project.

Individuals with sickle cell disease (SCD) at increased risk for stroke should undergo annual stroke risk assessment using transcranial Doppler (TCD) screening between the ages of 2 and 16. Though this screening can significantly reduce morbidity associated with SCD, screening rates at Boston Children's Hospital (and nationwide) remain below the recommended 100% screening adherence rates. Three plan-do-study-act (PDSA) cycles were designed and implemented. The Specific, Measurable, Achievable, Relevant, and Time-Bound (SMART) aim of our quality improvement (QI) initiative was to sustainably increase the proportion of eligible patients receiving a TCD within 15months of their last TCD to greater than 95%. An interrupted time series (ITS) analysis was performed, comparing TCD adherence rates from PDSA Cycle 1 to those from PDSA Cycles 2 and 3. Mean TCD adherence increased across all three PDSA cycles, from a baseline of 67% in the first cycle (January 2015 to September 2020) to 92% in the third cycle (May 2021 to March 2023). In the ITS analysis of TCD adherence rates, there was a significant difference in the final TCD adherence rate achieved compared to the rate predicted, with a total estimated increase in adherence of 17.9% being attributable to the interventions from PDSA Cycles 2 and 3. Although other QI initiatives had demonstrated ability to increase adherence to TCD screening for patients with SCD, this is the first QI project to collect data over such a prolonged period of time to demonstrate a sustained increase in screening rates throughout the intervention (an 8-year period).

Association of hydroxyurea adherence with transcranial Doppler screenings in children with sickle cell disease.

National sickle cell disease (SCD) guidelines recommend oral hydroxyurea (HU) starting at 9months of age, and annual transcranial Doppler (TCD) screenings to identify stroke risk in children aged 2-16years. We examined prevalence and proportion of TCD screenings in North Carolina Medicaid enrollees to identify associations with sociodemographic factors and HU adherence over 3years. We conducted a longitudinal study with children ages 2-16years with SCD enrolled in NC Medicaid from years 2016-2019. Prevalence of TCD screening claims was calculated for 3years, and proportion was calculated for 12, 24, and 36months of Medicaid enrollment. Enrollee HU adherence was categorized using HU proportion of days covered. Multivariable Poisson regression assessed for TCD screening rates by HU adherence, controlling for age, sex, and rurality. The prevalence of annual TCD screening was between 39.5% and 40.1%. Of those with 12-month enrollment, 77.8% had no TCD claims, compared to 22.2% who had one or higher TCD claims. Inversely, in children with 36months of enrollment, 36.7% had no TCD claims compared to 63.3% who had one or higher TCD claims. The proportion of children with two or higher TCD claims increased with longer enrollment (10.5% at 12months, 33.7% at 24months, and 52.6% at 36months). Children with good HU adherence were 2.48 (p<.0001) times more likely to have TCD claims than children with poor HU adherence. While overall TCD screening prevalence was low, children with better HU adherence and longer Medicaid enrollment had more TCD screenings. Multilevel interventions are needed to engage healthcare providers and families to improve both evidence-based care and annual TCD screenings in children with SCD.

Barriers and facilitators to a task-shifted stroke prevention program for children with sickle cell anemia in a community hospital: a qualitative study

BackgroundChildren with sickle cell anemia (SCA) are at high risk for stroke. Protocols for stroke prevention including blood transfusions, screening for abnormal non-imaging transcranial Doppler (TCD) measurements, and hydroxyurea therapy are difficult to implement in low-resource environments like Nigeria. This study aimed to examine the contextual factors around TCD screening in a community hospital in Nigeria using qualitative interviews and focus groups.MethodsWe conducted a descriptive qualitative study in a community hospital in Kaduna, Nigeria, using focus groups and interviews. Interview guides and analysis were informed by the Consolidated Framework for Implementation Research (CFIR) framework and the Theory of Planned Behavior. Transcripts were coded and analyzed using an iterative deductive (CFIR)/Inductive (transcribed quotes) qualitative methodology.ResultsWe conducted two focus groups and five interviews with health care workers (nurses and doctors) and hospital administrators, respectively. Themes identified key elements of the inner setting (clinic characteristics, resource availability, implementation climate, and tension for change), characteristics of individuals (normative, control, and behavioral beliefs), and the implementation process (engage, implement, and adopt), as well as factors that were influenced by external context, caregiver needs, team function, and intervention characteristics. Task shifting, which is already being used, was viewed by providers and administrators as a necessary strategy to implement TCD screening in a clinic environment that is overstressed and under-resourced, a community stressed by poverty, and a nation with an underperforming health system.ConclusionTask shifting provides a viable option to improve health care by making more efficient use of already available human resources while rapidly expanding the human resource pool and building capacity for TCD screening of children with SCD that is more sustainable.Trial registrationNCT05434000.

Transcranial Doppler Screening of Children with Sickle Cell Disease for a Large, Multinational Interventional Study: Experience from the Phase 3 HOPE-Kids 2 Trial Investigating the Effect of Voxelotor Treatment on Transcranial Doppler Flow Velocity

Introduction: Transcranial Doppler (TCD) ultrasound is an effective screening tool for identifying children with sickle cell disease (SCD) who are at high risk of stroke. Implementing TCD screening, along with appropriate therapies, for the purpose of primary stroke prevention in resource-constrained settings remains challenging. HOPE-KIDS 2 (NCT04218084) is an ongoing, phase 3, multicenter, double-blind, placebo-controlled trial of voxelotor in children with SCD and elevated arterial cerebral blood flow (measured by time-averaged maximum of the mean velocity [TAMMV]). Our aim is to describe the findings from successful implementation of a standardized TCD screening protocol that was conducted in a multinational setting. Methods: The purpose of HOPE-KIDS 2 is to evaluate the effect of voxelotor treatment on reducing the risk of stroke in participants aged 2 to &amp;lt;15 years with SCD who have conditional TAMMV (170 to &amp;lt;200 cm/s) at baseline. Children aged 2 to &amp;lt;15 years with SCD (HbSS/HbSβ 0) were screened after local sonographers were trained and certified on standardized TCD examination protocol, using the same model of Multi-Dop T digital machine (Compumedics DWL, Germany). TCD assessments were sent for central quality review and interpretation by 2 independent reviewers. STOP criteria were used to classify stroke risk: normal, &amp;lt;170 cm/s; conditional, 170 to &amp;lt;200 cm/s; or abnormal, ≥200 cm/s. Patient baseline characteristics, including clinical measurements of markers of anemia and hemolysis, were measured during study screening. The reasons for patient screen failure were summarized. Results: Between Nov 2020 and Feb 2023, 708 participants consented at 29 sites in Nigeria (n=250; 5 sites), Kenya (n=241; 4 sites), Egypt (n=145; 4 sites), Ghana (n=28; 2 sites), the US (n=17; 8 sites), Italy (n=9; 3 sites), Oman (n=9; 1 site), Saudi Arabia (n=8; 1 site), and the UK (n=1; 1 site). Of these patients, 92.1% (652/708) completed TCD screening examinations (mean [SD] age 7.6 [3.24] years; range 2.0-14.0 years; 50.8% male; 23.0% receiving hydroxyurea). Of the patients who completed TCD screening, the mean (SD) TAMMV was 163.0 (31.26) cm/s, and 47.1% (307/652) had conditional TCD at baseline (29.0% low conditional, 18.1% high conditional). The main reason for screen failure was index TAMMV outside of conditional range (abnormal, n=39 [6.0%]; normal, n=306 [46.9%]). Elevated TAMMV on screening TCD was more common in younger children (2 to ≤8 years vs &amp;gt;8 to &amp;lt;15 years); patients aged 2-8 years comprised 66.8% and 82.1% of the conditional and abnormal TCD categories, respectively. There were 39 assessments that required adjudication, but only 9 were deemed unreadable. Of all patients screened, 36.2% (236/652) fulfilled eligibility criteria for randomization; the characteristics at screening of these patients are summarized (Table). The mean (SD) Hb level and TAMMV at screening for randomly assigned patients was 7.7 (1.06) g/dL and 182.7 (7.53) cm/s, respectively. Conclusions: Clinical sites for the HOPE-KIDS 2 study successfully implemented a standardized, local TCD screening protocol supported by central quality review. For a large interventional trial aimed at reducing the risk of stroke in children with SCD, African and Middle Eastern sites presented relatively few limitations with respect to participant screening.

Prevalence and Proportion of Transcranial Doppler Screenings in a Population Children with Sickle Cell Disease and Association with Hydroxyurea Adherence

Sickle cell disease (SCD) is an inherited or genetic hemoglobinopathy in the United States and approximately 100,000 Americans are affected. The prevalence of stroke in unscreened children with sickle cell anemia (SCA) is 10% and can begin at infancy. National guidelines strongly recommend annual Transcranial Doppler (TCD) screenings as well as hydroxyurea (HU) administration in children with SS and Sβ o thalassemia (SCA) genotypes. The purpose of this project was to examine the prevalence and proportion of TCD screenings in North Carolina (NC) Medicaid enrollees and to identify associations with sociodemographic factors (age, sex, and rurality) and HU adherence. A longitudinal analysis of NC Medicaid claims data (2016-2019) was conducted for children with SCD ages 2-16 years. Prevalence of TCD screening claims was calculated to determine the number of children with TCD claims for each of the three, 12-month enrollment periods. The proportion of TCD screening claims was calculated based on NC Medicaid enrollees who had increasing TCD claims (0, 1, 2, or 3+) for 12, 24, and 36 months of Medicaid enrollment. HU adherence was measured using Proportion of Days Covered (PDC). HU PDC is a measure of HU prescription fills over 365 days within a 12-month period. HU PDC was used to categorize enrollees into good (≥80%), moderate (60-79%), or poor (&amp;lt;60%) adherence categories. Age (years) was declared as the age in years of each participant during each study observation period and was categorized into three groups: preschoolers (2-5 years), school aged (6-11 years), and adolescents (12-16 years). Rurality was identified by converting residential zip codes to rural/urban county codes (RUCC). An adjusted multivariable Poisson regression model was fit to assess the rate of TCD screenings by HU adherence while controlling for age, sex, and rurality. The prevalence of children with annual TCD screening claims ranged from 39.5% to 40.1%. The percentage of children with 2 or more TCD claims increased when they had extended months of NC Medicaid enrollment (10.5% at 12 months, 33.7% at 24 months, and 52.6% at 36 months). Overall, children with Good HU adherence were 2.48 (95% CI 2.00, 3.06) times more likely to have TCD claims than children with poor HU adherence. In conclusion, the prevalence of TCD screenings of children with SCD on NC Medicaid was extremely low. Children with better HU adherence and extended NC Medicaid enrollment time were associated with higher number of TCD screenings.

Sleep Fragmentation and Obstructive Sleep Apnea Are Associated with High Primary Stroke Risk in Children with Sickle Cell Disease

Background Children with sickle cell disease (SCD) are at elevated risk of developing sleep disorders, 1 which may contribute to the sequelae of their disease. One important sequela of SCD exacerbated by sleep disorders is cerebrovascular stroke. Transcranial Doppler (TCD) screening of large intracranial arteries can detect elevated blood velocity and strongly predict stroke in children with SCD. 2 However, the association between stroke risk, as assessed by TCD, and sleep disorders has not been sufficiently investigated. Main Objective To investigate the association between sleep disorders and abnormal TCD examinations in children with SCD. Design/Methods We evaluated associations between sleep disorder severity with TCD examinations in children with SCD. We selected all participants from the Sickle Cell Clinical Research and Intervention Program (SCCRIP), who underwent polysomnography between 2016 - 2020 and had at least one TCD examination. SCCRIP prospectively recruits patients diagnosed with SCD and includes retrospective and longitudinal collection of clinical, neurocognitive, geospatial, psychosocial, and health outcomes data. 3 The severity of sleep apnea was assessed using the apnea/hypopnea index, separated into total and obstructive apnea/hypopnea indices. The number of oxygen desaturation events per hour of sleep as well as the O2 saturation nadir were recorded. Sleep fragmentation was measured by the total arousal index (events per hour of sleep) and sub-categorized into spontaneous and respiratory-related arousal indices. Transcranial Doppler exams were reported as abnormal with timed average mean maximum velocities (TAMMV) of greater than 200 cm/s, high-conditional &amp;gt; 185 cm/s, low-conditional &amp;gt; 170 cm/s, and normal ≤ 170 cm/s. Exact Wilcoxon rank sum test was used to compare sleep outcomes between two groups. The false discovery rate adjusted p-values or q-values were calculated using Benjamini and Hochberg approach to control for multiple comparisons at a level of 0.05. Results Eighty-four patients met inclusion criteria (genotypes SS/SB0 81 (96%), median age 8.3, range 2.2-23.1, 42 male: 42 female). Six patients had abnormal, six high-conditional, 12 low-conditional velocities, while the remainder (60) had normal TCD exams. Patients with abnormal TCD exams exhibited more severe obstructive sleep apnea (mean AHI 25.0 + 9.1 vs. 5.3 + 8.3, p = 0.003), more severe respiratory related arousals (12.7 + 7.9 vs. 3.2 + 4.5, p = 0.008), and higher total arousals (22.9 + 7.7 vs. 12.9 + 5.8, p = 0.01) than those with normal TCD studies at p&amp;lt;0.05.The number of oxygen desaturation events per hour (mean 10.6 + 10.5 vs. 4.5 + 8.0, p = 0.05) was not significantly different among patients with abnormal and normal TCD exams at q&amp;lt;0.05 but the O2 saturation nadir was significantly less in patients with abnormal TCD exams (mean 74.0 + 5.0 vs. 86.8+9.9, p = 0.007) at q&amp;lt;0.05 (Figure 1). Conclusion In pediatric patients with SCD, a link exists between sleep apnea, O2 saturation nadir, sleep fragmentation, and stroke risk. While the findings of this study establish a correlation between sleep disorders and cerebrovascular complications in SCD, further research is still necessary to fully comprehend the exact role of sleep disorders on stroke risk. Nevertheless, this study underscores the importance of addressing sleep apnea and promoting healthy sleep patterns in pediatric patients with SCD to reduce the risk of stroke.

Changing Trends in Sickle Cell Disease-Related Mortality in the United States over Four Decades

Introduction: Sickle cell disease (SCD) causes significant morbidity and early mortality. The Cooperative Study of Sickle Cell Disease estimated median life expectancy for individuals with SCD at 42 years for males and 48 years for females in the early 1990s. However, this calculation was made prior to now standards-of-care in SCD, including routine transcranial doppler screening, pneumococcal prophylaxis, and the introduction of the primary disease-modifying therapy hydroxyurea and the widespread use of chronic blood transfusion. Over the last thirty years, with expanded access to disease modifying therapies, increased evidence exists for the preservation of organ function and less frequent acute vaso-occlusive pain. It remains unclear whether the introduction of these therapies has affected overall SCD-related mortality or the specific causes of death of those with SCD in the United States, particularly in the last decade when the use of hydroxyurea has expanded most significantly. Methods: We used the US mortality statistics for 1979-2020 available publicly through the CDC WONDER database (http://wonder.cdc.gov), which is a compilation of county, state, and national-level mortality statistics derived from death certificates, including age category at death, sex, race, ethnicity, year of death, underlying cause of death, and additional contributing causes using ICD-9 codes for 1979-1998 (282.6 sickle cell anemia- all SCD genotypes were included under one code in ICD-9) and ICD-10 codes for 1999-2020 (D57.0 sickle cell anemia with crisis; D57.1 sickle cell anemia without crisis; D57.2 double heterozygous sickling disorders; D57.8 other sickle cell disorders). We searched the SCD ICD-10 codes listed as underlying cause of death by five-year age groups for Black individuals and all ethnicities, (from Hamideh and Alvarez, Pediatric Blood and Cancer 2013) and compared the crude death rates overall and for each age group to those of 1999-2009. We also searched using the SCD ICD-10 codes included in “the multiple causes of death” to determine the 15 most common ICD categories of death in each 10-year period. Results: For the period 2010-2020, 5272 Black (Hispanic &amp; non-Hispanic) individuals died in the United States with the underlying cause of death listed as one of the ICD-10 SCD codes (see Figure 1A for a map of the crude mortality rate distribution). The crude mortality rate was 1.1 per 100,000 Black individuals, which was significantly lower than the period 1999-2009 (crude rate 1.2 per 100,000, p &amp;lt; 0.0001) (Figure 1B). Of note, similar to prior trends, there is a significant increase in mortality rate in the 15-19 year age group versus 20-24 years (0.9 per 100,000 to 1.4 per 100,000, p &amp;lt; 0.0001) corresponding with the age of transition to adult centers. The mean age at death for all genotypes for 2010-2020 was 43 years (females: 44 years, males: 41 years) versus 39 years for 1999-2009 (females: 40 years, males: 38 years). For the period 2010-2020, 61% of cases listed SCD as the primary cause of death without specificity or proximal cause; for the other 39% of cases when an underlying cause of death was noted, cardiovascular disease was the most common (28%), followed by accidents (7%), cerebrovascular disease (7%), malignancy (6%), septicemia (4.8%), and renal disease (3.8%). The fifteen most common causes of death accounted for 90% of underlying causes of death listed in the SCD population. Conclusion: The sickle cell disease-related mortality rate has significantly declined over the last 40 years, including in the period 1999-2020, corresponding with the introduction of disease modifying therapies, improved SCD care, and decreased infant mortality. This overall improvement, however, provides contrast to the enduring sharp increase in mortality in the young adult years. This demonstrates the critical need to improve the transition process from pediatric to adult care and to emphasize the need for additional support for young adults after they transition to adult SCD care.

A-296G variant of THBS1 gene (rs1478605) is associated with a lower frequency of stroke in a Brazilian population with sickle cell anemia

ObjectivesStroke is a devastating clinical outcome that significantly contributes to the morbidity and mortality of sickle cell anemia (SCA) patients. Despite its advantages in predicting stroke risk, transcranial Doppler screening has limitations that restrict its applicability, highlighting the need for emerging prognostic tools. Thrombospondin-1 plays a crucial role in endothelial injury, platelet adhesion, and nitric oxide metabolism and may be implicated in stroke pathophysiology. Here, we aimed to evaluate the association of THBS1 genetic variations with the occurrence of stroke in SCA patients Materials and methodsBy real-time PCR, 512 SCA patients were fully genotyped for THBS1 A-296G (rs1478605) polymorphism ResultsTHBS1 GG genotype was associated with a lower risk for stroke occurrence [odds ratio (OR): 0.30; 95% confidence interval (CI): 0.11–0.78; P = 0.011], although these findings were not consistent with multivariate logistic regression analysis (OR: 0.73, 95% CI: 0.12 – 4.37; P = 0.736). In agreement, the cumulative incidence of stroke for patients with AG/AA genotypes was higher when compared to the GG genotype (P = 0.018). However, the association was not maintained in the multivariate proportional hazards model (hazard ratio: 0.67, 95% CI: 0.12–3.61; P = 0.643) ConclusionsIn summary, the present study shows that the THBS1 A-296G (rs1478605) polymorphism may be a potential modifier for stroke in SCA.

Socioeconomic Status and Risk of Stroke As Assessed By Transcranial Doppler: A Displace Study Secondary Analysis

Background: Transcranial doppler (TCD) screening (Sickle Stroke Screening) identifies children ages 2-16 years with sickle cell disease (SCD) at an increased risk for stroke. Significant barriers to undergoing annual screening exist for patients with SCD. Previous studies have shown that individuals from households on public insurance with limited neighborhood opportunity have increased barriers to receiving adequate healthcare, including routine screening; however it is unknown whether low socioeconomic status (SES) influences TCD results. Methods: We conducted a secondary analysis of the DISPLACE study, which included a cohort of 3243 TCD-eligible individuals aged 2-16 who had at least one TCD screen performed during their year of study enrollment. We utilized insurance type (Medicaid/CHIP or public versus all other insurances) and overall childhood opportunity index (COI) group (Very Low versus all other COI levels [Low, Medium, High, and Very High]) to proxy household- and neighborhood-level SES. We then examined the association between household- and neighborhood-level SES and conditional and/or abnormal TCD screening results. Baseline characteristics of the overall cohort (Table 1) were described by COI group and insurance type. The primary outcome was TCD result at baseline (i.e. a patient's first TCD in the database); categorized as abnormal, high-conditional, and normal (reference group). Multinomial logistic regression analysis was used to assess whether clinical (age, sex [female vs. male], hemoglobin (Hgb) level, white blood cell [WBC] count, presence of clinical hypertension [yes, no], hydroxyurea (HU) prescription at baseline [yes, no]) or socioeconomic factors (insurance type and COI group) were independently associated with TCD result. The multinomial regression accounted for age, Hgb level, WBC count, HU prescription, COI group, and insurance type. All tests were two-tailed and, an alpha level of &amp;lt;0.05 and &amp;lt;0.1 (to reduce type II error in logistic regression) were used to determine statistical significance. Results: The analytic cohort included 3243 children (Table 1), with 1346 (41.5%) children living in Very Low COI neighborhoods and 2180 (67.2%) of households with public insurance. HU was prescribed to 60.7% of individuals, and this varied by COI level (p=0.021), but not insurance type (p=0.758). WBC count was significantly higher in the Very Low COI group (p=0.004) and public insurance group (p&amp;lt;0.001). Hgb level was noted to be significantly lower in the Very Low COI (p=0.031) and public insurance (p&amp;lt;0.001) groups. Bivariate logistic regression analysis revealed that COI group (OR 1.53, p=0.08) and insurance type (OR=1.76, p=0.056) were significantly associated at p&amp;lt;0.1 with abnormal TCD outcome individually. Lack of HU prescription was significantly associated at p&amp;lt;0.05 with abnormal TCD result (Odds Ratio [OR]=20.36, p&amp;lt;0.001), and WBC count (OR=1.05, p=0.055) was significantly associated at p&amp;lt;0.1 with abnormal TCD result individually. In the multinomial logistic regression model (included variables listed above), only lack of HU prescription remained significantly associated at p&amp;lt;0.05 with abnormal TCD result (OR=19.09, p&amp;lt;0.001). Conclusion: The most robust predictive factor determining abnormal or conditional TCD status in this cohort was lack of HU prescription. Public insurance and COI group as proxies for SES were not independently associated with abnormal or conditional TCD results. As such, the disparities seen by individuals from proxied lower SES are likely mediated by utilization of HU. Notably, HU prescription rates differed by COI group, but not insurance type, suggesting possible neighborhood level factors (such as availability of pharmacies dispensing HU) influencing HU prescription that wouldn't be reflected by insurance type. The limitations of using socioeconomic proxies such as COI group and insurance type must be noted, as these proxies assign group characteristics to an individual based on a snapshot in time, which may not be representative of the dynamic nature of one's SES. Nevertheless, these findings highlight the need to better understand the possible association between SES and HU prescription, as limited HU access and utilization could result in significant health disparities in both treatment and outcomes.

Microemboli on Transcranial Doppler in Patients with Sickle Cell Disease: A Single Center Case Series

Background: Stroke remains a major cause of morbidity in patients with sickle cell disease (SCD). Current guidelines recommend that patients with Hemoglobin SS and Hemoglobin S beta zero thalassemia have annual transcranial doppler (TCD) screening and that patients with abnormal velocities should have regular blood transfusions to maintain a maximum HbS level &amp;lt;30% and maintain a hemoglobin level &amp;gt;9 g/dL for at least one year to decrease risk of stroke (DeBaun et al., 2020). While research has shown that patients with velocities &amp;gt;200cm/sec are at increased risk of cerebral infarct, there is no literature to discuss the follow up and management of patients with microemboli on TCD. In the past microemoli were unable to be detected, however TCD is now able to detect such findings (Wan et al., 2022). Studies have been completed on patients with ischemic stroke without SCD and have shown that the presence of microemboli on TCD is associated with a higher rate of recurrence (Das et al., 2020). The presence of emboli has also been shown to recognize patients with asymptomatic carotid stenosis and increased risk for stroke (Markus et al., 2010). Although noted in the general population, the significance of such a finding on an annual TCD screening in patients with sickle cell disease is unknown. Methods:At the Medical University of South Carolina, we performed a retrospective review of all patients with SCD who have had TCDs from 2017 to February 2023 and were found to have microemboli to evaluate management and outcome. Results: We have had 5 patients with an incidental finding of microemboli on their annual TCD since 2017. Three were male with median age of 3 (range 2 to 15 years). Four individuals are HbSS genotype. Mean hemoglobin at the time of TCD was 8.26 ± 1.4 g/dL. TCD velocity was normal in four patients at the time of the TCD, while the remaining individual had a low conditional TCD. Two have a previous history of conditional or abnormal TCDs. The location of the microemboli was variable among patients (Table 1). At the time of microemboli findings on TCD, discussions were held with family regarding options for treatment including chronic partial exchange transfusions and optimization of other disease modifying therapies. Management of all patients included MRI at the time of microemboli, which was normal in only two patients. Three patients were started on chronic manual exchange transfusions for 10 months to 3 years. One out of the 3 continued home HU while receiving transfusions while the remainder were transitioned to HU once chronic transfusions were complete. One patient was not started on chronic transfusions but monitored closely with TCDs due to family choice. On follow up, 4 have had repeat TCDs and all have normalized without any subsequent episodes of microemboli. One patient was found to have silent infarct on MRI at time of TCD and 1 has had follow up MRI 4 years after original TCD with a new silent infarct. Of note, this patient had inconsistent follow up with chronic transfusions after initial abnormal TCD. Importantly, none of our 5 patients had an acute symptomatic ischemic event since the microemboli were noted. Overall, among these patients, 2 have had concern for silent infarct and 3 of 5 started on chronic transfusions (Table 1). Conclusion: This is the first report within the literature of microemboli on annual TCD screening in patients with SCD. As this is a new phenomenon, the significance within the disease course is not known for those with sickle cell disease. Identifying patients with microemboli has been used to help navigate the need for early intervention to prevent stroke. Given that individuals with SCD are already at an increased risk for cerebrovascular events, these findings of microemboli could indicate further risk in these individuals as well and deserve further investigation. Further research is warranted as the significance of such a finding is unknown and further understanding could impact the standard of care of this patient population.

Sickle Cell Disease Electronic Health Record Population Management Approach to Support Delivery of High-Quality Care: Leaving Paper Lists behind

Children and young adults with sickle cell disease (SCD) require complex health care services to screen for early signs of disease-related complications and to initiate and monitor disease-modifying therapies. Care coordination is challenging as it involves multiple team members across multiple subspecialties. Evidence-based clinical protocols and quality metrics are essential for SCD programs to deliver high-quality care. Systems to track this care delivery are crucial to ensure equitable, accessible care is consistently provided. In 2016, the Comprehensive Sickle Cell Center (CSCC) and the Population Health Innovation Team at Children's Hospital of Philadelphia (CHOP) developed and implemented an electronic health record (EHR)-based system, the SCD patient registry and proactive care outreach tools, to facilitate processes needed to ensure patient service delivery in a timely fashion. We selected Transcranial Doppler (TCD) ultrasounds, hydroxyurea therapy initiation, and annual clinic visits to monitor stroke risk screening, disease-modification therapy, and general chronic illness care. Between January 2015 and June 2023, approximately 1400 patients with SCD were tracked across two CHOP outpatient clinics, the CHOP Philadelphia and CHOP Voorhees campuses. We tracked TCD completion, hydroxyurea prescriptions, and clinic visits per year for age-eligible patients with SS and SB0thal. Prior to implementation of the EHR-based tools and new workflows in October 2016, for age-eligible patients, on average 75% of patients had received annual TCD screening, 55% of patients had received hydroxyurea prescriptions within the prior 6 months, and 85% had attended outpatient hematology clinic at least twice within the year. As of June 2023, on average, completed TCD visits had increased to 91%, patients prescribed hydroxyurea had increased to 78%, and patients attending 2 clinic visits within a year had increased to 89%. These metrics remained consistent and improvement was sustained despite the COVID-19 pandemic. Table 1 describes the drivers influencing these improvements, which included various interventions involving social work, nursing, community health workers, registrars, care coordinators, and physicians. Figure 1 illustrates the changes achieved over time in rates of TCD completion, hydroxyurea prescriptions, and clinic visit attendance. This implementation of an SCD EHR-based population health tool and new care team workflows facilitated more efficient processes for various care team members and improved our ability to consistently provide timely services to children and young adults with SCD. This resulted in sustained improvement in all metrics and high-quality care for our patients.

5616493 MACHINE LEARNING TO IDENTIFY CHILDREN WITH SICKLE CELL DISEASE AT VERY LOW HIGH RISK OF ABNORMAL OR CONDITIONAL TRANSCRANIAL DOPPLER SCREENING.

Background: Annual Transcranial doppler (TCD) screening is an important strategy to mitigate the risk of stroke in children with sickle cell anemia (SCA). While an abnormal TCD is strongly associated with increased chance of stroke, the risk factors for an abnormal doppler study are not well understood. Identifying children at very low risk could help to ensure appropriate focus on screening children at the highest risk. Machine learning presents an opportunity to develop a risk prediction model, incorporating complex interactions between variables. Aim: Identify potential predictive features for normal TCD screens by applying machine learning algorithms to clinical data collected for a multi-site collaboration, Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE).1 Methods: We analyzed clinical data collected for the 28-site DISPLACE study, which included 5116 patients in whom a TCD was indicated.1 For the current study, we included patients, aged 2-16 years, who had both hemoglobin and TCD results reported in the same year between 2012-2016 (N = 2234); after excluding patients who had prior studies with abnormal or conditional results, our analysis dataset included 22 predictive features (maximum missingness: 25.7%) for 1825 children (N = 30 with abnormal, N = 122 with conditional results). We applied traditional logistic regression, logistic regression with LASSO, and tree-based classifiers to 19 features including historical, biometric, vital sign, and laboratory data, to predict the risk of abnormal or conditional TCD. Results: In univariate logistic regression models, all 19 features had a statistically significant relationship with TCD outcome. Eight features (age, hemoglobin, heart rate, systolic blood pressure, oxygen saturation, weight, mean corpuscular volume, and percent reticulocytes) were shown to be of consistently high importance across different machine learning models. Conclusion: Next steps include development of ensemble models to optimize predictive performance and internal validation on our hold-out test set. Machine learning shows promise for identifying low risk children with SCD who may not require annual TCD screening, such that TCD resources can be appropriately directed to higher risk children to mitigate the risk of stroke.Reference 1. Kanter et al, J Pediatr Hematol Oncol 2021; 43:e1062-8

TCD screening and spending among children with sickle cell anemia.

National guidelines recommend that children with sickle cell anemia receive annual transcranial Doppler (TCD) screening to assess stroke risk. Our objectives were to estimate the rate of TCD screening among privately insured children with sickle cell anemia, estimate out-of-pocket spending for TCD screening, and evaluate the association between TCD screening and enrollment in high-deductible health plans (HDHPs). Cross-sectional. Using the 2009-2017 IBM MarketScan Commercial Database, we identified children aged 2 to 15 years who met a validated claims-based definition of sickle cell anemia. We calculated the proportion of children receiving annual TCD screening and out-of-pocket spending per TCD screen. Using logistic regression with generalized estimating equations, we modeled the receipt of annual TCD screening as a function of HDHP enrollment, controlling for demographics and year. The 2519 children in the analysis accounted for 7197 person-years of enrollment; 14% of person-years were from HDHP enrollees. During 2009-2017, the proportion of children receiving TCD screening ranged from 40% to 44%. Median out-of-pocket spending for TCD screening was $20 overall and $65 among HDHP enrollees. Out-of-pocket spending exceeded $100 for 27% of all screens and 42% of screens among HDHP enrollees. HDHP enrollment was not associated with TCD screening (adjusted odds ratio, 0.99; 95% CI, 0.85-1.15). Among privately insured children with sickle cell anemia, fewer than half received annual TCD screening. Out-of-pocket spending exceeded $100 for 27% of TCD screens. Although HDHP enrollment was not associated with TCD screening, additional studies are needed to assess whether cost sharing might deter this screening.

Hydroxyurea with dose escalation for primary stroke risk reduction in children with sickle cell anaemia in Tanzania (SPHERE): an open-label, phase 2 trial

Transcranial Doppler screening with chronic transfusions reduces stroke risk in children with sickle cell anaemia but is not feasible in low-resource settings. Hydroxyurea is an alternative treatment to decrease stroke risk. We aimed to estimate stroke risk in children with sickle cell anaemia in Tanzania and to determine the efficacy of hydroxyurea to decrease and prevent stroke. We did an open-label, phase 2 trial (SPHERE) at Bugando Medical Centre, Mwanza, Tanzania. Children aged 2-16 years with a diagnosis of sickle cell anaemia confirmed by haemoglobin electrophoresis were eligible for enrolment. Participants had transcranial Doppler ultrasound screening by a local examiner. Participants with elevated Doppler velocities, either conditional (170-199 cm/s) or abnormal (≥200 cm/s), received oral hydroxyurea starting at 20 mg/kg once daily and escalated every 8 weeks by 5 mg/kg per day to the maximum tolerated dose. Participants with normal Doppler velocities (<170 cm/s) received usual care from the sickle cell anaemia clinic and were rescreened after 12 months to determine whether they qualified for treatment on trial. The primary endpoint was change in transcranial Doppler velocity from the baseline visit to after 12 months of hydroxyurea treatment, analysed in all patients who had paired baseline and follow-up measurements collected after 12 months of treatment. Safety was analysed in the per-protocol population (all participants who received study treatment). This study is registered with ClinicalTrials.gov, NCT03948867. Between April 24, 2019, and April 9, 2020, 202 children were enrolled and had transcranial Doppler screening. Sickle cell anaemia was confirmed by DNA-based testing in 196 participants (mean age 6·8 years [SD 3·5], 103 [53%] were female, and 93 [47%] were male). At the baseline screening, 47 (24%) of 196 participants had elevated transcranial Doppler velocities (43 [22%] conditional, four [2%] abnormal); 45 initiated hydroxyurea at a mean dose of 20·2 mg/kg per day (SD 1·4) with escalation to a mean dose of 27·4 mg/kg per day (5·1) after 12 months. Treatment response was analysed after 12 months (± 1 month; median 11 months, IQR 11-12) and 24 months (±3 months; median 22 months, 22-22). Transcranial Doppler velocities decreased to a mean of 149 cm/s (SD 27) compared with 182 cm/s (12) at baseline, which was significantly lower than baseline (p<0·0001), with an average decline of 35 cm/s (SD 23) after 12 months of treatment in 42 participants with paired results available at baseline and 12 months. No clinical strokes occurred, and 35 (83%) of 42 participants reverted to normal transcranial Doppler velocities. Clinical adverse events were mild, and dose-limiting toxicities were uncommon. The most common grade 3 adverse events were malaria (12 [29%] episodes in 45 patients) and sepsis (13 [32%] episodes). There were three serious adverse events, none of which were treatment-related, and no treatment-related deaths occurred. Children with sickle cell anaemia in Tanzania have a high baseline stroke risk. Hydroxyurea at the maximum tolerated dose significantly lowers transcranial Doppler velocities and reduces primary stroke risk. Transcranial Doppler screening plus hydroxyurea at the maximum tolerated dose is an effective stroke prevention strategy, supporting wider hydroxyurea access for patients with sickle cell anaemia across sub-Saharan Africa. American Society of Hematology, National Institutes of Health, Cincinnati Children's Research Foundation.

Pediatric Sickle Cell Disease and Stroke: A Literature Review.

Both ischemic and hemorrhagic strokes in children can be a complication of sickle cell disease, which also affects adults. The occurrence is high without any screening or preventative care.This review article found that although transcranial Doppler (TCD) has reduced the prevalence of stroke in pediatric patients, there is still a need for an epidemiological survey to define such screening for adults, the ideal dose of hydroxyurea to reduce the incidence of stroke, and to identify silent cerebral stroke to prevent its complications. Increased hydroxyurea prescription and specific antibiotic and vaccination regimes lowered the occurrence of this condition. In pediatric cases with a time-averaged mean of the maximal velocity greater than 200cm/s, transcranial Doppler screeningand preventive chronic transfusion for at least the first year have lowered the occurrence of stroke by up to 10 times. The ideal dose of hydroxyurea is still debatable, but it seems to reduce the risk of the first stroke to a comparable level in the average population. Adult ischemic and hemorrhagic stroke prevention has not yet received the same attention. Though there are fewer studies, sickle cell disease is also more common than age-matched controls in terms of silent cerebral infarctionon magnetic resonance imaging (MRI),as well as other neurological problems such as cognitive impairment, seizures, and headaches. Currently, there is no evidence-supported way to prevent ischemic stroke in adults at any age. Also, there is no defined ideal dose of hydroxyurea that can be helpful in preventing strokes. Data also lack a way to identify a silent cerebral infarction, so its complications can be prevented. An additional epidemiological survey may help in the prevention of the condition. The primary aim of this article was to emphasize the importance of information on clinical, neuropsychological, and quantitative MRI assessment of sickle cell patients to understand the epidemiology and etiology of stroke in sickle cell patients to prevent stroke and its related morbidity.

Optimizing the Frequency of Transcranial Doppler (TCD) Exams in Children with Sickle Cell Anemia

Background Transcranial Doppler (TCD) screening of the large intracranial arteries can detect elevated blood velocity and is a strong predictor of stroke risk in children with sickle cell anemia (SCA, HbSS and HbSβ0-thalassemia). Initiation of chronic blood transfusion for patients with confirmed abnormal TCD velocities (time-averaged mean velocity, TAMV≥200 cm/sec) is shown to effectively reduce primary stroke. Current guidelines recommend annual TCD screening for children with SCA ages 2-16 years. Screening intervals were developed following evidence from the STOP studies1 (Figure 1). The estimated prevalence of normal TCD velocities is 83%2 and these children will have received 15 TCD exams from ages 2 to 16 if all results remain within normal range. The cumulative incidence of conversion from normal to conditional TCD velocities is dependent on age, whereby the risk is four times lower in children >10 years, compared to those <10 years of age3. Although TCD screening is non-invasive and safe, it consumes time and requires specialized equipment and trained examiners. Identifying sub-populations for whom TCD screening frequency could be safely reduced could lessen time burden on patients and caregivers and could be cost saving. Main objective To estimate the risk of TAMV conversion from normal to conditional or abnormal categories among children with SCA relative to age. Design/Method We included all participants with SCA from the Sickle Cell Clinical Research and Intervention Program, a longitudinal lifetime cohort of patients with SCD with at least one TCD measurement available both before and after age 10 years. We classified participants into two groups based on TCD screening results before 10 years of age; one group with all normal TCDs, and the other group with at least one non-normal TCD. We then compared the time to first non-normal study after ten years of age between the two groups using the log rank test. Time to first conversion was defined as time from age 10, to time of conversion if conversion occurred, or time to last follow up if no conversion occurred. We correlated the number of TCD exams before age 10 with time to first conversion using the Cox proportional regression model. Exposure to chronic transfusion or hydroxyurea before age 10 and age at first TCD measurement were covariates and were correlated with the time to first conversion. Results Of the 614 patients with TCD screening, 297 had SCA and at least 1 screening before and after age 10 (Table 1). Of these, 174 patients had only normal TCD screening before age 10 and the remaining 123 patients had at least 1 non-normal TCD screening before age 10. During the time they were followed,no patients with only normal TCD screenings before age 10, regardless of exposure to hydroxyurea or transfusions, had a conditional or abnormal TCD exam. Conversely, 41.5% of patients with at least one non-normal TCD before age 10 had a conditional or abnormal TCD screening after age 10. Conclusion In a large retrospective cohort study analysis of children with SCA, patients with TCD exams consistently within the normal range under age 10 years were not at risk of conversion to conditional or abnormal TAMV. These results suggest that children with SCA with all normal TCD velocities before age 10 years may not require additional TCD screening exams after age 10. These results translate to 6 fewer TCD exams per each child with SCA over age 10 with all prior normal TCD exams, potentially conserving resources and reducing burden on patients, families, and the health system. De-implementation studies to reduce the use of TCD screening exams in low-risk cases are needed

Improving Rates of Annual Transcranial Doppler Screening in Children with Sickle Cell Disease: A Quality Improvement Project

Background: Transcranial doppler (TCD) screening identifies individuals with sickle cell disease (SCD) at an increased risk for stroke between the ages of 2 and 16. Providers at Boston Children's Hospital recognized an opportunity to improve adherence to the TCD screening guidelines. The Specific, Measurable, Achievable, Relevant, and Time-Bound (SMART) aim of our quality improvement (QI) initiative was to increase the proportion of eligible patients receiving a TCD within 15 months of their last TCD to >95% by July 1st 2022. Methods: This QI project was conducted at an academic pediatric hospital. We used the Model for Improvement as the improvement framework. To understand the current state, a TCD data repository was created in July 2020. We identified patients with SCD eligible for a TCD via our institution's data warehouse. Patients who received their primary hematology care at an alternative institution, and those who received chronic transfusions or definitive curative therapy for SCD were excluded. TCD adherence was defined as receiving a TCD within three months of the TCD being due (12-15 months from the last TCD). Our database was refined with a multidisciplinary group to determine the baseline TCD adherence rate of interest. Multiple plan-do-study-act (PDSA) cycles were performed to identify individuals overdue for screening and test interventions to increase adherence. An electronic notification was sent to providers on overdue patients, initially quarterly, then monthly. This evolved to sending proactive notifications 3 months ahead of when patients would be overdue for a TCD. Monthly adherence rates were tracked, with the data from May 2021 through June 2022 measured via a run chart (Figure 1a). In addition, we used logistic regression to identify variables potentially associated with non-adherence to the recommended TCD screening. Using TCD eligible patients from July 1, 2021 to June 30, 2022 a simple logistic regression model was fit with the following variables: age, gender, poverty, childhood opportunity index (COI) score, distance to the hospital, need for an interpreter, insurance type, and SCD genotype. All tests were two tailed and p<0.05 was considered significant. Using the same variables as input we developed numerous machine learning (ML) models to predict TCD adherence. The top three performing models were chosen for further optimization and were compared using the algorithm's accuracy, area under the receive operator curve, F1 statistic, precision and recall. Confusion matrices were used to summarize model output. Feature importance for the top performing model was determined using Xgboost. All analyses were performed using RStudio version 1.4.1717, Google Colab, and Stata. Results: Our baseline TCD adherence rate was 71%. The average TCD screening rate from June 1, 2021 to June 30, 2022 was 94% (Figure 1a). Using the cohort of patients followed from June 1, 2021-June 30 2022 we identified 127 patients eligible for TCD; 48 patients were overdue for their TCD, a 37.8% "ever-missed TCD screening” rate. In univariate analysis, age, gender, neighborhood poverty level, COI score, distance to the hospital, need for an interpreter, insurance type, and SCD genotype were not predictive of likelihood to be overdue for TCD screening. Using multivariate analysis, there were no statistically significant relationships between sociodemographic variables and likelihood of missed TCD. The need for an interpreter and distance to the hospital trended towards significance with odds ratios of 0.261 (p=0.068) and 1.016 (p=0.06) respectively (Figure 1b). The top performing ML model was a random forest classifier. This model had the following performance metrics: accuracy=0.88, ROC AUC=0.70, F1=0.73, precision=0.80, and recall=0.67. The features that were most predictive of TCD adherence were age, distance from the hospital and COI score. Conclusion: Already high TCD screening rates can be improved with a dedicated QI initiative. Our next intervention will prospectively evaluate our ML algorithm to predict patients at risk of being overdue for their TCD and help us achieve our goal of consistently > 95% TCD adherence. We will provide targeted outreach to these patients to mitigate patient level barriers to obtaining a TCD such as focused education directed towards older patients and their families and transportation vouchers/parking passes for TCD associated visits. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transcranial Doppler Screening for Patent Foramen Ovale Closure in Cryptogenic Strokes in Young: A Single Center Experience from South India.

Cryptogenic strokes are common in young adults. Patent foramen ovale (PFO) is an important cause of cryptogenic ischemic strokes. Transcranial Doppler (TCD) with bubble contrast is a noninvasive bedside tool in screening for PFO and other right to left shunt (R-L shunt). Percutaneous PFO closure in selected patients with a high risk for paradoxical emboli is beneficial. Data on PFO in young cryptogenic strokes from India are limited. To determine the utility of screening for R-L shunt using TCD in young patients with cryptogenic strokes and to identify clinical predictors of an R-L shunt. This was a hospital-based prospective study conducted between January 2013 and December 2019 in a tertiary hospital in South India. All consecutive patients with ischemic stroke and ages between 18 and 45 years were included. TCD with bubble contrast study was performed on all patients. Those who were TCD bubble contrast study positive and had features of an embolic stroke of undetermined source (ESUS) underwent transesophageal echocardiography (TEE) to confirm a PFO and to look for its high-risk features. Selected ESUS patients with PFO and associated high-risk features as identified on TEE underwent percutaneous PFO device closure. All patients were followed up in the stroke and cardiology clinics. During the study period, 6,197 patients with ischemic strokes were screened for eligibility of which 304 (4.9%) were between the age of 18 and 45 years. Of these, 300 patients with ischemic stroke in young underwent the TCD bubble contrast study. R-L shunt was found in 121 (40.3%) patients. Based on an extensive etiological evaluation, 72 patients were identified to have an ESUS and underwent TEE for confirming PFO. Of these, 65 patients had PFO, four were negative, and three were found to have extracardiac shunts. Based on clinical findings, imaging features, and high-risk features on TEE, 29 patients underwent PFO closure. Activity at the time of stroke onset equivalent to a Valsalva maneuver (p ≤ 0.01), isolated cortical infarction (p = 0.027), and posterior circulation involvement (p = 0.0135) were significantly associated with the presence of an R-L shunt. The patients who had a higher modified anatomical-functional risk of paradoxical embolism (AF-RoPE) score, a high-grade shunt on the TCD bubble contrast study had a longer length of the tunnel and had the presence of an interatrial septal aneurysm (p = 0.012) were referred for PFO device closure. R-L shunt is common in cryptogenic ischemic strokes in young. TCD with bubble contrast study is a noninvasive and feasible bedside tool to detect them. Applying the ESUS criteria in these cryptogenic strokes with a positive TCD bubble contrast study can be then used for selecting patients for more invasive tests like TEE. High-risk PFOs picked up with TEE can be then considered for PFO closure for secondary stroke prevention. The history of Valsalva maneuver-like activity (such as lifting heavy weights or straining) at the time of stroke onset can be a clinical predictor for the presence of an R-L shunt. In addition to isolated cortical infarction, the presence of posterior circulation infarct in ESUS can predict the presence of an R-L shunt.