Transcranial Doppler Ultrasound Screening Research Articles

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

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

Velocity Curvature Index: a Novel Diagnostic Biomarker for Large Vessel Occlusion

Despite being a conveniently portable technology for stroke assessment, Transcranial Doppler ultrasound (TCD) remains widely underutilized due to complex training requirements necessary to reliably obtain and interpret cerebral blood flow velocity (CBFV) waveforms. The validation of objective TCD metrics for large vessel occlusion (LVO) represents a first critical step toward enabling use by less formally trained personnel. In this work, we assess the diagnostic utility, relative to current standard CT angiography (CTA), of a novel TCD-derived biomarker for detecting LVO. Patients admitted to the hospital with stroke symptoms underwent TCD screening and were grouped into LVO and control groups based on the presence of CTA confirmed occlusion. Velocity curvature index (VCI) was computed from CBFV waveforms recorded at multiple depths from the middle cerebral arteries (MCA) of both cerebral hemispheres. VCI was assessed for 66 patients, 33 of which had occlusions of the MCA or internal carotid artery. Our results show that VCI was more informative when measured from the cerebral hemisphere ipsilateral to the site of occlusion relative to contralateral. Moreover, given any pair of bilateral recordings, VCI separated LVO patients from controls with average area under receiver operating characteristic curve of 92%, which improved to greater than 94% when pairs were selected by maximal velocity. We conclude that VCI is an analytically valid candidate biomarker for LVO diagnosis, possessing comparable accuracy, and several important advantages, relative to current TCD diagnostic methodologies.

Transcranial Doppler screening for stroke risk in children with sickle cell disease: a systematic review.

Background Sickle cell disease (SCD) is one of the most common causes of stroke in children worldwide. Based on the results of the Stroke Prevention Trial in Sickle Cell Anemia (STOP), annual transcranial Doppler ultrasound (TCD) screening for affected children is standard practice. However, the need for TCD surveillance programs could override the accuracy of the screening, affecting the correct stratification of stroke risk and subsequent clinical management of the target population. Aims To shed light on this issue, a systematic review of the literature on TCD screening for children and adolescents with SCD was carried out (CRD42016050549), according to a list of clinically relevant questions, with a particular focus on screening practices in European countries. Quality of the evidence was rated using the grading of recommendations assessment, development and evaluation. Summary of review Thirty-three studies published in English or French were included (5 randomized controlled trials, 8 experimental non-randomized, and 20 observational studies). The quality of the retrieved evidence ranged between low and high, but was rated as moderate or high most of the times. TCD is effective as a screening tool for the primary prevention of stroke in SCD children. There is no high-quality evidence on the effectiveness of alternative screening methods, such as imaging-TCD with or without angle correction or magnetic resonance angiography. No evidence was found on effectiveness of the screening on children on hydroxyurea and with genotypes other than HbSS and HbS/β0. No European data were found on screening rates or adherence of screening practices to the STOP protocol. Conclusions High-quality studies on alternative screening methods that are currently used in real-world practice, and on screening applicability to specific subgroups of patients are urgently needed. Considering the low awareness of the disease in European countries and the lack of data on screening practices and adherence, clinicians need up-to-date guidelines for more uniform and evidence-based surveillance of children with SCD.

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

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

Transcranial Doppler Ultrasound Screening in Urban Pediatric Sickle Cell Center - Better Charting Improves Compliance over Published Rates

Abstract Background: TranscranialDoppler ultrasound (TCD) screening for stroke risk is one of the major advances in pediatric sickle cell disease, since the landmark STOP study. TCD screening is among the measures for quality of pediatric sickle cell care proposed by expert consensus (Wang 2011, NHLBI guidelines 2014). Reeves et al 2016 shows that TCD screening rates are low but still improving (22% in 2006 -44% in 2010). To improve the quality-of-care provided to pediatric sickle cell patients at University of Illinois Hospital, we conducted chart review in 2014 to establish a baseline report of UI Hospitalsadherence to the expert care standards. At that time TCD screening rates were much lower than immunization rates. We then introduced a reminder table in the electronic medical record. 18 months since this change in EMR we re-evaluated our compliance with TCDs. Objectives: To evaluate the improvement atUIHealthpediatric sickle cell clinic compliance with annual TCD. Methods: A manual chart review of these pediatric sickle cell patients was employed to determine adherence to TCD screening standards. All patients ages 2-16yowith SCD-SS and SCD-S/Beta-0-thalassemia that were seen in pediatric sickle cell clinic and adolescent-adult transition clinics two times over 15 months from 2/1/15-5/1/16 were included in study. TCD compliance was determined if patient had TCD between 5/1/2015 through 5/31/16. 5-15 minutes per patient was spent evaluating EMR for TCD compliance Data from the 2014 previous study was also re-evaluated using the same criteria of 2 visits within 15 months of original study date and TCD within 1 year of study. Results: In this work, the charts of 91 pediatric SCD-SS and SCD-S/Beta0 patients were reviewed (ages 2-16 years; M: 34 F 28, 5 ineligible [2 on chronic transfusion, 1 high hemoglobin, 1 yearly MRI, 1 last visit before 2yo]. Lost to follow-up (Seen in clinic since 2014 but not 2 visits from 2/1/15-5/1/16): 24 The rate of TCD screening among these eligible children was 53 out of 62, or 85.5% in 2016. Comparable figures from the 2014 chart review were 17 out of 27, or 63% in 2014. Fishers exact test indicates that this was a significant improvement, p=0.05. Conclusions: We focused our quality-improvement efforts onTranscranialDoppler screening, adding a reminder table in the Electronic Medical Record then re-assessing 18 months later. The rate of TCD screening significantly improved from 63% to 85%. Although less than 100%, these compare favorably to other published TCD rates (Table). The next step is to improve clinic attendance and tracking, to reduce the rate of patients who are "lost to follow-up." To facilitate future chart reviews we have incorporated the key parameters into our "Screening &amp; Management Table" as a component of the electronic medical record. Table Table. Disclosures Hsu: Purdue Pharma: Research Funding; Mast Therapeutics: Research Funding; Eli Lilly: Research Funding; Sancilio: Research Funding; Centers for Medicare and Medicaid Innovation: Research Funding; Pfizer: Consultancy, Research Funding; EMMI Solutions: Consultancy; Gerson Lehman Group: Consultancy; Astra Zeneca: Consultancy, Research Funding; Hilton Publishing: Consultancy, Research Funding.

Stroke in Neonates and Children.

1. Miya E. Bernson-Leung, MD*,§ 2. Michael J. Rivkin, MD*,†,‡,§ 1. Departments of *Neurology, 2. †Radiology, and 3. ‡Psychiatry, Boston Children’s Hospital, Boston, MA 4. §Department of Neurology, Harvard Medical School, Boston, MA 1. Pediatricians should be aware of the appropriate initial evaluation of suspected stroke in children to combat documented delays in diagnosis of greater than 24 hours. (1) 2. Pediatricians should be aware of primary and secondary prevention measures for stroke in at-risk populations, such as transcranial Doppler ultrasonography screening for children with sickle cell disease. 3. Pediatricians must recognize the clinical findings associated with childhood stroke, including ischemic and hemorrhagic stroke, understand the prognosis for each type of stroke, and delineate optimal ongoing management and rehabilitation. After completing this article, readers should be able to: 1. Describe the pathophysiology of stroke in infants, children, and adolescents. 2. Recognize the clinical findings associated with childhood stroke and with arteriovenous malformations and other cerebrovascular abnormalities predisposing to childhood stroke. 3. Delineate the appropriate initial evaluation of suspected stroke in children. Stroke in children is surprisingly common, affecting 1 in 1,600 to 4,000 neonates at birth (2)(3) and 2.3 to 13 per 100,000 older children per year. (4)(5)(6) Strokes can occur in seemingly healthy infants, children, and adolescents. Despite the plasticity of the developing brain, stroke in children carries substantial morbidity. Early recognition of childhood stroke by pediatric clinicians is crucial for the rapid implementation of targeted and neuroprotective therapies. Clinicians should be familiar with risk factors for pediatric stroke and appropriate prevention strategies. Finally, pediatricians are key members of an integrated, multidisciplinary approach to stroke treatment and rehabilitation. This review begins with a discussion of stroke in children older than 28 days, followed by a discussion of perinatal stroke (before 28 days of age) because strokes in these 2 age groups have …

Peak Systolic Velocity Measurements with Transcranial Doppler Ultrasound Is a Predictor of Incident Stroke among the General Population in China.

Background and ObjectiveIt is necessary to develop an effective and low-cost screening tool for identifying Chinese people at high risk of stroke. Transcranial Doppler ultrasound (TCD) is a powerful predictor of stroke in the pediatric sickle cell disease population, as demonstrated in the STOP trial. Our study was conducted to determine the prediction value of peak systolic velocities as measured by TCD on subsequent stroke risk in a prospective cohort of the general population from Beijing, China.MethodsIn 2002, a prospective cohort study was conducted among 1392 residents from 11 villages of the Shijingshan district of Beijing, China. The cohort was scheduled for follow up with regard to incident stroke in 2005, 2007, and 2012 by a study team comprised of epidemiologists, nurses, and physicians. Univariate and multivariate Cox proportional hazard regression models were used to determine the factors associated with incident stroke.ResultsParticipants identified by TCD criteria as having intracranial stenosis had a 3.6-fold greater risk of incident stroke (hazard ratio (HR) 3.57, 95% confidence interval (CI) 1.86–6.83, P<0.01) than those without TCD evidence of intracranial stenosis. The association remained significant in multivariate analysis (HR 2.53, 95% CI 1.31–4.87) after adjusting for other risk factors or confounders. Older age, cigarette smoking, hypertension, and diabetes mellitus remained statistically significant as risk factors after controlling for other factors.ConclusionsThe study confirmed the screening value of TCD among the general population in urban China. Increasing the availability of TCD screening may help identify subjects as higher risk for stroke.

Impact of TCD Screening Protocol on the Incidence of Hemorrhagic Stroke in Children and Young Adults with Sickle Cell Disease

Background: Primary hemorrhagic stroke is a rare complication of sickle cell disease (SCD) that usually occurs in adults. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for patients with abnormal TCD as standard of care. Despite a notable improvement in the incidence of infarctive stroke in children with SCD after the introduction of TCD screening protocols, it is unclear how this protocol will affect the rate of hemorrhagic stroke. Presumably, early TCD screening and subsequent initiation of CRCT in high risk patients will prevent the progression of cerebral vasculopathy, which should decrease the risk of hemorrhagic stroke; however this has not been proven. Using the large multicenter cohort of children who participated in STOP and/or STOP 2 trials, we sought to assess whether the rate of hemorrhagic stroke was impacted by the use of TCD screening and/or CRCT.Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 required at least a single screening TCD for randomization. Patients on STOP 2 also had an observational arm for children started on CRCT who had an abnormal TCD. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both of trials. For all participants the date of their last encounter in STOP/2 was defined as the start of their Post-STOP period. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two separate neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results adjudicated all suspected strokes.Results: Follow-up data were available for 2850 of the 3539 subjects (81%). Twelve children who had a stroke during the STOP study period were further excluded from this analysis resulting 2838 subjects. The mean age at the start of Post-STOP was 10.5 years and mean duration of follow-up after exiting STOP/2 until time of last medical encounter was 9.1 years. A total of 31 patients had a primary hemorrhagic stroke during the Post-STOP observation period (incidence 0.12 per 100 pt years). The mean age at time of stroke was 16.2+5.6 (median 15.3 range (4.8-30.2) years of age. Of those 31 patients, only 52% had a TCD during Post-STOP prior to the event. Seven of those children who underwent screening had documentation of an abnormal TCD prior to the event (5 during STOP era and/or 3 Post-STOP). However, only 1/7 patients (14%) were documented on CRCT at the time of the stroke (4 patients were receiving HU and 2 patients had unknown treatment).Discussion: Although less common than infarctive stroke, patients with SCD are at increased risk for hemorrhagic stroke. There is an increased risk of mortality for patients who suffer from hemorrhagic stroke (up to 26% in some reports in the 2 weeks after the event). It is unclear if TCD screening and subsequent initiation of CRCT will impact the rate of hemorrhagic stroke in the long term. In our results, a similar incidence of primary hemorrhagic stroke was noted although the patients were overall younger than previously reported (16.5+/- 5.5 years versus 20-29 years in Cooperative Study of Sickle Cell Disease). Many patients who had a hemorrhagic stroke (48%) had not undergone TCD screening during the Post-Stop period. Additionally, although a safe stopping point for CRCT has not been established in patients who have had an abnormal TCD, only 1 patient was documented on CRCT at the time of the event (14%). Thus, it is unclear at this time whether TCD screening and subsequent, lifelong continuation of CRCT could have prevented these other events. Clearly, these results demonstrate that improved implementation of STOP protocol is needed as well as further evaluation of the impact of this protocol on the incidence of hemorrhagic stroke. DisclosuresNo relevant conflicts of interest to declare.

Ischemic Stroke in Children and Young Adults with Sickle Cell Disease (SCD) in the Post-STOP Era

Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) screening with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. To identify children at high-risk of stroke, annual TCD screening is recommended from ages 2 to 16 years, with more frequent monitoring if the result is not normal. A reduction in stroke incidence in children with SCD has been reported in several clinical series and analyses utilizing large hospital databases when comparing rates before and after the publication of the STOP study in 1998. We sought to determine the rate of first ischemic stroke in a multicenter cohort of children who had previously participated in the STOP and/or STOP 2 trials and to determine whether these strokes were screening or treatment failures.Subjects and Methods: Between 1995 and 2005, STOP and STOP 2 (STOP/2) were conducted at 26 sites in the US and Canada. These studies included 3,835 children, ages 2 to 16 y with SCD type SS or S-beta-0-thalassemia. Participation in STOP/2 ranged from a single screening TCD to randomization. STOP 2 also had an observational arm for children on CRCT for abnormal TCD whose TCD had not reverted to normal. The Post-STOP study was designed to follow-up the outcomes of children who participated in one or both trials. 19 of the 26 original study sites participated in Post-STOP, contributing a total of 3,539 (92%) of the STOP/2 subjects. After exit from STOP/2, these children received TCD screening and treatment according to local practices. Data abstractors visited each clinical site and obtained retrospective data from STOP/2 study exit to 2012-2014 (depending on site) including follow-up TCD and brain imaging results, clinical information, and laboratory results. Two vascular neurologists, blinded to STOP/2 status and prior TCD and neuroimaging results, reviewed source records to confirm all ischemic strokes, defined as a symptomatic cerebral infarction; discordant opinions were resolved through discussion. For the first Post-STOP ischemic stroke, prior TCD result and treatment history subsequently were analyzed.Results: Of the 3,539 subjects, follow-up data were available for 2,850 (81%). Twelve children who had a stroke during STOP or STOP2 were excluded from these analyses resulting in data on 2,838 subjects. The mean age at the start of Post-STOP was 10.5 y and mean duration of follow-up after exiting STOP/2 was 9.1 y. A total of 69 first ischemic strokes occurred in the Post-STOP observation period (incidence 0.27 per 100 pt years). The mean age at time of stroke was 14.4±6.2 (median 13.8, range 3.5-28.9) y. Twenty-five of the 69 patients (36%) had documented abnormal TCD (STOP/2 or Post-STOP) prior to the stroke; 15 (60%) were receiving CRCT and 9 (36%) were not (treatment data not available for 1 subject). Among the 44 subjects without documented abnormal TCD, 29 (66%) had not had TCD re-screen in the Post-STOP period prior to the event; 7 of these 29 (24%) were 16 y or older at the start of Post-STOP, which is beyond the recommended screening age. Four of the 44 (9%) patients had inadequate TCD in Post-STOP (1 to 10.7 y prior to event). Six (14%) had normal TCD more than a year before the event (1.2 - 4 y); all but one of these children were younger than 16 y at the time of that TCD. Only 5 (11%) had a documented normal TCD less than 1 year prior to the event.Conclusions: In the Post-STOP era, the rate of first ischemic stroke was substantially lower than that reported in the Cooperative Study of Sickle Cell Disease, prior to implementation of TCD screening. Many (39%) of the Post-STOP ischemic strokes were associated with a failure to re-screen according to current guidelines, while only 11% occurred in children who had had recent low-risk TCD. Among those known to be at high risk prior to stroke, treatment refusal or inadequate treatment may have contributed. While TCD screening and treatment are effective at reducing ischemic stroke in clinical practice, significant gaps in screening and treatment, even at sites experienced in the STOP protocol, remain to be addressed. Closing these gaps should provide yet further reduction of ischemic stroke in SCD. DisclosuresNo relevant conflicts of interest to declare.

Abstract 17: Development of High Risk TCD in Sickle Cell Disease

Background: The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) established routine transcranial Doppler ultrasound (TCD) as standard of care. Some information on conversion from low to high risk was derived from the STOP/2 studies but information is needed from “real world” practice to improve TCD screening guidelines. Subjects and Methods: During STOP and STOP2, 3,837 children, ages 2 to 16 y with SCD-SS or SCD-SBeta-0-thalassemia, underwent screening TCD. The POST-STOP study was designed to follow-up all children who participated in one or both of these trials. 19 of the 26 original study sites participated in POST-STOP, contributing a total of 3,541 (92%) of STOP/STOP2 subjects. Data abstractors visited the clinical sites to extract TCD, neuroimaging and neurological outcome information. Results: Of the 3,541 subjects, follow-up data were available for 2834 (80%). The mean age at the last TCD STOP/2study was 9.5 years, the mean age at last follow-up in POST-STOP was 19.6 years and the mean duration of follow-up after exiting STOP/STOP2 was 9.2 years. STOP TCD risk stratification was used: normal &lt; 170 cm/sec; conditional 170-199 cm/sec; abnormal &gt;200 cm/sec. Subjects were classified by their highest risk TCD in STOP/STOP 2. The population was divided on this basis into normal (1813 --64%), conditional (478 --17%), abnormal (357-- 13%) or inadequate (186 --7%). Among the 478 with conditional TCD studies in STOP/STOP2, the mean age at last follow-up in POST-STOP was 19.2 years (range 4.9-33.1) and follow-up TCD was obtained on 252 (53%) from 11 months to 16 years after STOP/2 (median 10.4) . Forty three of these had an abnormal TCD (mean age at abnormal was 8.5 years from 3 months to 8.4 years after STOP/2 (median 1.97 years). Conclusions: 1) We could find evidence of follow up TCD for about of half of these children indicating that more needs to be done to insure regular and consistent surveillance of these children who have some elevated risk. 2) Conversions to abnormal TCD were documented. Treatment decisions as well as stroke outcomes for all the 479 with conditional TCD will be derived from adjudication of the complete data set (in progress).

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

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

Implementation of transcranial Doppler ultrasonography screening and primary stroke prevention in urban and rural sickle cell disease populations.

Transcranial Doppler (TCD) ultrasonography identifies children with sickle cell disease (SCD) at increased risk of stroke. Initiation of chronic transfusions as primary stroke prevention in children with abnormal TCD significantly reduces stroke risk. Here, we report the results describing the implementation of TCD screening and primary stroke prevention in both urban and rural clinical practices. Retrospective chart review identified children ages 2-16 years with Hgb SS or Sß0 -thalassemia and no history of stroke followed in either the local urban or rural SCD clinics at Georgia Regents University. We defined standard of care (SOC) as having one TCD performed annually between January 2010 and December 2012 starting at age 2 years. A total of 195 patients were included in the evaluation of SOC screening, overall 41% achieved SOC. There was no difference in SOC between the two clinics (35% urban and 47.4% rural). The majority of patients with abnormal TCDs are on chronic transfusions (83%), and none have experienced a stroke. Monitoring of effects of transfusion was difficult with 38% and 31% of rural patients lacking documentation of Hgb S% and ferritin levels, respectively, in the past year. We report here data describing primary stroke prophylaxis in rural patients. SOC rates are similar between the two clinical settings. While implementation of primary stroke prevention in rural patients was difficult, rural TCD screening is feasible and can achieve SOC equal to that in an urban setting. This suggests that barriers exist in provided primary stroke prevention to all patients. Pediatr Blood Cancer 2015;62:219-223. © 2014 Wiley Periodicals, Inc.

Sickle cell disease: primary stroke prevention.

Stroke is an important and common complication of sickle cell disease (SCD), affecting children as well as adults. Clinically evident stroke, usually brain infarction, is usually associated with stenosis or occlusion of the intracranial arteries of the Circle of Willis, sometimes with formation of moyamoya (a Japanese word for "hazy" or "like a puff of smoke" that describes the appearance of a abnormal microvasculature on angiography believed secondary to internal carotid artery stenosis or occlusion and the resultant extensive collateralization). Several types of intracranial hemorrhage are observed but usually in older children and adults. Cerebrovascular diseases restricted to small vessels may go unrecognized but is associated with cognitive and learning problems. Prevention of recurrent stroke has been accomplished with chronic blood transfusion. A primary prevention strategy for clinical stroke, based on the Stroke Prevention in Sickle Cell Anemia Trial, has been tested in a randomized clinical trial. Over 2,000 young children with SCD were screened with transcranial Doppler ultrasound (TCD) to detect elevated blood flow velocity indicative of vessel disease and high risk of future stroke. Those randomized to standard care (no transfusion) had a 10%/year risk of stroke, which was reduced >90% with chronic transfusion. This approach is the only primary stroke prevention strategy so far tested in SCD in a randomized controlled trial. Silent lesions on magnetic resonance imaging are associated with an approximately 1.5%/year risk of clinical stroke and a trial is now starting in children with these lesions who do not meet Stroke Prevention in Sickle Cell Anemia Trial criteria for transfusion based on TCD. A controlled trial, based on intervention for nocturnal hypoxemia, is also underway. Hydroxyurea, bone marrow transplantation, antiplatelet, and antithrombotic agents may work but have not been tested in primary prevention in a systematic way. If early and repeated, TCD screening of children, as recommended by National Heart Lung and Blood Institute and the American Stroke Association, were implemented broadly the incidence of new strokes could be greatly reduced in these children.

Hydroxyurea Reduces Conversion From Conditional to Abnormal TCD Velocities In Children with Sickle Cell Anemia (SCA)

AbstractAbstract 270The use of transcranial Doppler ultrasound (TCD), a non-invasive imaging technique, is now clearly established for detecting high risk of stroke in children with sickle cell anemia (SCA). Children with TCD flow velocities ≥200 cm/s have a 10% risk of primary stroke per year. For these children, chronic blood transfusions (CBT) are recommended and have been shown to reduce the risk of primary stroke by up to 90%. The incidence of stroke has decreased to 0.06–0.17 per 100 patient-years since the institution of TCD screening (Fullerton et al. Blood 2004; Enningul-Egham et al., J Pediatr 2010). Although patients with conditional TCDs (flow velocities 170–199 cm/s) have an estimated stroke risk of 2–5% annually, and their rate of conversion from conditional to abnormal is 23% over an 18 month period (Hankins JS et al., BJH 2008), there are no clinical guidelines for primary stroke prevention in this group. We previously conducted a prospective cohort study of hydroxyurea in 37 children with SCA and TCD velocities >140 cm/sec, and demonstrated that TCD velocities decreased significantly after starting hydroxyurea (Zimmerman et al., Blood 2007; NCT00402480). In order to determine if hydroxyurea provided sustained reductions in TCD velocities, we conducted a retrospective review of these 37 children in this original cohort who had elevated TCD velocities and long-term hydroxyurea treatment. The following data were abstracted from the medical record between April 2000 and September 2009: treatment with hydroxyurea and CBT; adherence with treatments; stroke and non-stroke neurological events; and TCD time-averaged mean velocities (TAMV) immediately prior to initiation of hydroxyurea and at the end of extended follow-up. The primary outcome was comparison of pre and post TCD TAMV using a paired t-test. The mean age of enrollment on the original study was 6.8 years (1.8-14.8) and the mean age at follow-up was 12.9 years (5.3-18.5). The mean follow-up was 5.8 years (0.8-8.5) with an overall follow up of 215.1 patient years. Twenty males and 17 females were enrolled. The mean hydroxyurea dose was 25.2 ± 5.6 mg/kg/day, with one patient discontinuing therapy after 15 months. At follow-up, the mean hemoglobin was 8.9 ± 1.2 g/dL and mean HbF was 16 ± 7.2%. Sustained decreases were observed in both the right MCA (164.8 ± 25.5 cm/s to 124.9 ± 35 cm/s, p<0.001) and left MCA (167.9 ± 25.2 cm/s to 126.9 ± 30 cm/s, p<0.001) for all 37 patients. For the 15 patients with conditional TCD velocities at enrollment, 13 had maximal TAMV that reverted to and were sustained in the normal range (185.8 ± 10.0 cm/s to 132.9 ± 14.5 cm/s, p<0.001). Two converted to abnormal TCD velocities at 1.6 years and 4.5 years for a conversion rate of 13%; one was non-adherent but the other was adherent with hemoglobin of 10.8 g/dL and HbF of 23.5%. These two patients were started on CBT and remain stroke free. There were no primary stroke events observed in the 15 subjects with conditional TCD velocities over a total of 78.1 patient years. Of the 5 patients who had abnormal TCD velocities on enrollment and whose parents refused CBT, 1 patient had a stroke after 0.8 years of hydroxyurea therapy. This was the only patient who continued to have abnormal TCD velocities at MTD, 7 months after starting hydroxyurea. The remaining 4 patients continued to have TCD velocities in the normal range off transfusion therapy over 26.3 patient years. Overall, these data illustrate that treatment with hydroxyurea at MTD in children with SCA and elevated TCD velocities resulted in significantly lower and sustained improvements in TCD velocities. Additionally, for children with conditional TCD velocities, hydroxyurea resulted in a lower than expected conversion to abnormal values, thereby sparing many children from CBT without any noted increase risk of stroke. Hydroxyurea did not, however, protect fully against stroke in one patient who had persistently abnormal TCD velocities and therefore CBT remains the standard of care in this population until larger randomized trials are conducted. Further studies are required to evaluate hydroxyurea for primary stroke prevention in children prior to conversion to abnormal TCD and in children who already have abnormal TCD. The currently funded TCD With Transfusions Changing to Hydroxyurea (TWiTCH) clinical trial, which is scheduled to begin enrollment in late 2010, will help answer this important clinical question. Disclosures:Off Label Use: Hydroxyurea is used to reduce complications of sickle cell anemia.

Will submandibular TCD prevent stroke in children with sickle cell anemia?

Stroke is a common and morbid complication of sickle cell disease. Approximately 10% of children with sickle cell anemia (HbSS) will have a stroke by 18 years of age.1 These clinically evident strokes are usually large-vessel and often are associated with the development of obstructive vasculopathy and collaterals (moyamoya).2 As in stroke in other children, intellectual development and ability to function in society are often impaired.3,4 The routine implementation of transcranial Doppler ultrasound (TCD) screening has revolutionized the primary prevention of ischemic stroke in children with HbSS. TCD screening identifies children at a greatly increased risk (∼10%/year) of stroke. Stroke risk in these children with time averaged mean maximal velocity ≥200 cm/s in the middle cerebral artery or distal internal carotid artery (ICA), decreased to about 1%/year with monthly transfusions of sickle-negative blood, a 90% relative risk reduction.5 Thus, …

Stroke prevention in the young child with sickle cell anaemia

Cerebrovascular disease resulting in stroke is a serious and preventable complication of sickle cell anaemia (SCA). Children at high risk of preventable stroke can be identified by transcranial Doppler ultrasound (TCD). Current guidelines in the UK recommend annual TCD screening from 3 years, although studies suggest an earlier peak incidence, between 2 and 5 years. A single centre retrospective review was undertaken to identify the prevalence of stroke and success of TCD screening in young children. We report five episodes of stroke in under 3s and outcome of TCD screening in children under 3, compared to over 3. TCD analysis was as successful in the 2-3-year age group as in the 3-4-year group. We therefore propose that all children with SCA should be offered TCD screening from the age of 2 years. Furthermore, infants with high risk features of SCA should undergo a first attempt at TCD screening even earlier.

The painful face of poverty

The painful face of poverty

Transcranial Doppler (TCD) Ultrasonography in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial.

Introduction: Transcranial Doppler ultrasound (TCD) is used in children with sickle cell anemia (SCA) to detect stroke risk. TCD screening is mostly employed in children between 2–16 yrs of age; its use in infants <2 yr of age is less well established. BABY HUG is an NHLBI-NICHD sponsored Phase III clinical trial in infants with SCA comparing hydroxyurea (HU) to placebo to ascertain efficacy of HU in preventing damage to the spleen and kidney (NCT00006400). As a secondary endpoint in this trial, TCD was done to determine possible effects of HU in babies with SCA. We reviewed the baseline TCD data of infants obtained during eligibility screening in BABY HUG.Methods: All subjects underwent a baseline TCD using the Nicolet Companion (EME) 2-MHz pulsed Doppler. All infants were 7–17 months of age during screening, had no history of stroke and were not receiving chronic blood transfusion. Blood flow velocities were recorded using the Stroke Prevention Trial in Sickle Cell Anemia (STOP) protocol with the exception of reducing the standard sample volume to 4 mm. No sedation was used. The time averaged maximum mean velocity (TAMM) was measured to determine the highest velocity on either side to categorize the study as normal (highest velocity <170 cm/sec), conditional (170 – 199) or abnormal (≥200). Recordings of both middle cerebral (MCA) and internal carotid (ICA) arteries defined an adequate TCD. Eligibility for BABY HUG required at least an attempted TCD. TCD exams were read by blinded reviewers at the Medical College of Georgia and results transmitted to Clinical Trials & Surveys Corp. for statistical analysis.Results: TCD exams were attempted on 204 infants. Six exams were unsuccessful (no data) because of the subjects' lack of cooperation and 11 TCD's were inadequate. Of the remaining (187) TCD exams, 183 were normal and four included at least one conditional velocity. No subjects were found ineligible for the trial due to an abnormal TCD result. The mean velocity of the left MCA was 114.0 cm/sec ± 22.1 and that of the right MCA was 111.7 cm/sec ± 23.1. The top two deciles of the maximum TAMM reading for each child were 149 cm/sec and 141 cm/sec. Both age and total hemoglobin (Hb) were significantly associated (p<0.0001) with the mean MCA velocity in a multiple regression model. Analysis of the maximum TAMM for each child versus age, total Hb, Hb F, reticulocyte count, and Bayley Scales of Infant Devlopment II in a multiple regression model showed that only age (positively, p=0.0001), reticulocyte count (positively, p=0.015), and total Hb (negatively, p=0.0025) were significantly associated with the maximum TAMM.Conclusions: Adequate baseline TCD evaluation was obtained on 187 of 204 (92%) subjects. All but 4 were normal by STOP criteria as compared to approximately 10% abnormal and 18% conditional in STOP screening of older children. Using multivariate analysis, baseline TCD velocities varied inversely with the degree of anemia, as expected, but in addition varied directly with age The lack of significant TCD abnormalities is interesting, given the presence of silent infarcts in 13% of this group of children (Pediatr Blood Canc, 2008). When post-treatment TCD data collection is completed, it may become apparent whether:lower TCD velocities reflect a lack of stenotic vascular disease in infants;infants with TAMMs in the upper deciles will be more likely to have abnormal/conditional velocities as they grow older; andHU will have an impact on TAMM.

A critical assessment of transcranial doppler screening rates in a large pediatric sickle cell center: Opportunities to improve healthcare quality

Transcranial Doppler ultrasound (TCD) has been demonstrated to be a powerful predictor of stroke risk due to sickle cell disease (SCD) in pediatric populations. Little is known about how this healthcare innovation has disseminated into preventive care for SCD. The objective of this study was to determine TCD screening rates and modifiable patient barriers in children with SCD. We retrospectively assessed the screening of 207 children with SCD at the Texas Children's Sickle Cell Center over a 3-year period (2004-2006). Demographics, adherence to comprehensive care visits, severity of disease, and distance from the sickle cell center were obtained from computerized medical record databases. Screenings cancelled or missed by patients were extracted from a computerized order entry system. The average yearly screening rate for eligible patients was 45%. The average yearly cancellation rate by patients was 20%. Patient with private insurance were three times more likely to be compliant with ordered screenings than patients with Medicaid (P = 0.0077). Patients adherent to hematology comprehensive care visits more likely underwent ordered screenings than those who were not (P = 0.0386). When given at least one opportunity per year, providers, on average, ordered TCD screening 74% of the time when it was indicated. Despite evidence that routine screening to assess stroke risk is vital to the preventive care of SCD, implementation of this healthcare technology may be slow to disseminate due to patient and provider related factors.

Preventing Stroke Among Children With Sickle Cell Anemia: An Analysis of Strategies That Involve Transcranial Doppler Testing and Chronic Transfusion

Transcranial Doppler ultrasonography can identify children with sickle cell anemia who are at elevated risk of stroke and may benefit from chronic transfusions. Uncertainty about the risk/benefit trade-offs of chronic transfusion has led some clinicians to decide not to offer transcranial Doppler ultrasonography screening. Our goals were to (1) compare the projected benefits and risks of 6 primary stroke-prevention strategies, (2) estimate the optimal frequency of screening, and (3) identify key assumptions that influence the risk/benefit relationship. We designed a decision model to compare 6 primary stroke-prevention strategies: (1) annual transcranial Doppler ultrasonography screening until age 16 with children at high risk of stroke receiving monthly transfusion for life; (2) annual transcranial Doppler ultrasonography until age 16 with transfusions until age 18; (3) biannual transcranial Doppler ultrasonography until age 16 with transfusions until age 18; (4) annual transcranial Doppler ultrasonography until age 10 with transfusion until age 18; (5) 1-time screening at age 2 with transfusion until age 18; and (6) no intervention. Assumptions were derived from the published literature. For a hypothetical cohort of 2-year-old children, the optimal strategy was transcranial Doppler ultrasonography screening annually until age 10 with children at high risk receiving monthly transfusions until age 18. The optimal strategy would prevent 32% of strokes predicted to occur without intervention. The optimal strategy led to benefits similar to more intensive screening and transfusion strategies but resulted in fewer adverse events. All the intervention strategies resulted in net losses in life expectancy, because the projected mortality averted by stroke prevention was outweighed by the projected increase in mortality from transfusion. Results were sensitive to adherence rates to iron-chelation therapy. The optimal stroke-prevention strategy was projected to be annual transcranial Doppler ultrasonography screening until age 10 with transfusion for children at high risk until age 18. Better adherence to chelation therapy would improve life expectancy in all intervention strategies.