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Cerebral arteriopathy can be detected in children with sickle cell disease (SCD) by transcranial Doppler (TCD). Abnormally high velocities are predictive of high stroke risk, which can be reduced by transfusion therapy. We report the results of the screening of 291 SCD children followed in our center, including the clinical and imaging follow-up of 35 children with abnormal TCDs who were placed on transfusion therapy. We postulated that patients with normal MRA findings and abnormal TCD velocities that normalized on a transfusion program could be safely treated with hydroxyurea (HU). We report their outcome (median follow-up of 4.4 years). Of 13 patients with normalized velocities on transfusion, 10 had normal MRAs, and transfusion therapy was stopped and HU begun. Four of these ten patients redeveloped high velocities off transfusion, so currently only six remain transfusion-free. Six other transplanted patients remain transfusion-free. Abnormal TCD velocities detect a high-risk group, justifying the research for suitable transplant donors. Multicenter studies comparing HU therapy to long-term transfusion might help identify which patients can avoid transfusion and its complications while avoiding vasculopathy.

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ0), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 109/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Background Silent infarcts are associated with impaired cognitive functioning and have been shown to be predictors of stroke (Miller ST J Pediatr 2001). Until now, reported risk factors for silent infarcts were low pain event rate, history of seizures, high leukocyte count and Sen bS haplotype (Kinney TR Pediatrics 1999). Here, we seek to define the prevalence and risk factors of silent infarcts in the Créteil SCA pediatric cohort comprising patients assessed at least yearly by transcranial doppler (TCD) since 1992, and by MRI/MRA. Methods This study retrospectively analyzed data from the Créteil cohort stroke-free SS/Sb0 children (280; 134 F, 146 M), according to institutional review board. Time-averaged mean of maximum velocities higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program (TP). A switch to hydroxyurea was proposed to patients with normalized velocities (< 170 cm/sec) and normal MRA on TP, although TP was re-initiated in case of abnormal velocities recurrence. Patients with “conditional” velocities (170–199 cm/sec) were assessed by TCD 4 times yearly. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF, LDH levels; MCV; SpO2) were obtained a minimum of 3 months away from a transfusion, one month from a painful episode, after 12 months of age, before the first TCD, and always before therapy intensification. Results. Patients were followed for a total of 2139 patient-years. Alpha-Thal was present in 114/254 patients (45%) and 27/241 (11.2%) had G6PD deficiency. Beta genotype, available in 240 patients, was BaBa in 102 (42.5%), BeBe in 54 (22.5%), SeSe in 19 (7.9%) and “other” in 65 (27.1%); TCD was abnormal in 52 of 280 patients (18.6%). MRA showed stenoses in 30 of 226 evaluated patients (13.3%) while MRI demonstrated presence of silent infarcts in 81/280 patients (28.9%). Abnormal TCD (p Conclusion We recently showed that G6PD deficiency, absence of alpha-Thal, and hemolysis are independent significant risk factors for abnormal TCD in stroke-free SCA patients (Bernaudin et al, Blood, 2008, in press). Here, we report that an abnormal TCD is the most significant risk factor for stenoses and, expanding previous studies, we demonstrate that stenoses, low Hb and gender are significant independent risk factors for silent infarcts.

Background Predicting the severity of sickle cell anemia (SCA) is important for providing better informed genetic counseling and for better targeting of intensive therapies. Stroke is the most severe complication in children with SCA and is predicted by abnormally high cerebral velocities by transcranial doppler (TCD). We attempted to define the risk factors associated with high velocities. Methods This study concerned the Créteil pediatric SCA cohort, composed of newborn patients, screened and followed at our Center since birth, and of patients secondarily referred to the Center because of the severity of their disease. Time-averaged mean of maximum velocities (TAMMX) higher than 200 cm/sec were considered as abnormal, resulting in initiation of a transfusion program initiated. Cerebral MRI/MRA was done after the age of 5 years or earlier in case of abnormal TCD. Alpha genes and beta-globin haplotypes were determined. Baseline biological parameters (G6PD activity; WBC, PMN, Reticulocytes, Platelets counts; Hemoglobin, Hematocrit, HbF, LDH levels; MCV; SpO2) were obtained a minimum of 3 months away from a transfusion, one month from a painful episode, after 18 months of age and, before intensive therapy. Results SS children (390; 189 F, 201 M) were annually explored by TCD (n=2286) since 1992, and followed for a total of 1962 patient-years. The follow-up before initiation of intensive therapy was 1032 patient-years. Nineteen patients experienced an overt stroke. TCD was abnormal in 65 of 390 patients (17%). MRI (n=850) was performed in 268 patients, was abnormal in 86 cases and showed silent infarcts in 67 of 249 patients (27%). Silent infarcts were seen in 33% of patients with abnormal TCD. Alpha genes study, available in 336 patients, demonstrated alpha-thalassemia in 158 patients (47%): 31 had a deletion of 2 genes (7.9%) and 127 of 1 gene (32.6%). G6PD deficiency was present in 26 of 228 evaluated patients (11%). Beta-globin haplotypes studied in 316 patients were Car/Car in 125 (40%), Ben/Ben in 76 (24%), Sen/Sen in 30 (9%) and, “other” in 85 (27%). Univariate analysis showed that the risk of abnormally high velocities was not related to sex, beta-globin haplotypes, pain and acute chest syndrom rates, WBC, PMN, platelets counts, HbF level and SpO2 but was significantly associated with the absence of alpha-thalassemia (p< 0.001), G6PD deficiency (p=0.012), low Hb and Ht levels (p< 0.001), high reticulocyte count (p=0.008), high MCV (p=0.004) and high LDH level (p 1200 UI/L [OR=4.5, 95% CI (1.5–13.5)], (p=0.007) were independent risk factors of abnormally high velocities. Conclusion This study confirms that the risk of high velocities in patients with SCA is significantly decreased by the presence of alpha-thalassemia. It shows for the first time that hemolysis is a more significant risk factor than the degree of anemia and that absence of alpha-thalassemia, G6PD deficiency and hemolysis are significant independent risk factors of cerebral vasculopathy in patients with SCA.

About 11% of SS patients will have a first stroke by age 18–20 years. Abnormal high velocities are associated with a high risk of stroke, which can be significantly reduced by a long-term transfusion program. The stroke rate in Californian SCD children has declined since the advent of transcranial doppler (TCD), but there are no reports on the outcome of patients screened from birth by TCD. Since 1992, TCD has been systematically performed from the age of 12–18 months in the Creteil cohort. MRI/MRA was performed annually after the age of 5 years, or earlier in case of abnormal TCD. Patients with abn. high velocities (TAMMX >= 200 cm/s) were offered transfusion regimens for stroke prevention, but hydroxyurea was proposed secondarily to patients who had normal MRA findings and whose velocities normalized (< 170 cm/s). TCD was performed every three months in these patients, and a transfusion program was resumed if the findings were again abnormal. We report the cerebrovascular outcome of patients born after 1988 who were regularly followed in our center and screened by TCD. This cohort consisted of 242 SCD patients (178 SS, 9 Sb0, 41 SC, and 14 Sb+). Mean follow-up was 6.2 y (range 0.1–17.8), representing 1498 patient-years overall and 1139 patient-years in the SS/Sb0 population. Alpha gene deletion was present in 41% of patients (71/175). The beta genotype was available in 165 patients, and was homozygous Bantou (n=56, 34%), Senegal (n=9, 5.5%), Benin (n=35, 21.2%), or "other" (n=65, 39.4%). Four deaths occurred, all involving SS patients, at 1.2 y (enteritis in 1995), 1.8 y (trip to Africa in 2003), 1.9 y (pneumo. meningitis in 1997) and 3.7 y (ACS and curare allergy in 1998). The mortality rate was 0.27 per 100 patient-years overall and 0.35 in SS/Sb0 patients. The Kaplan-Meier (KM) estimate of the risk of abn. velocities (> 200 cm/s) was 15.7% at 5 y and 22.7% at 10 y of age in SS/Sb0 patients. No SC/Sb+ patients had abn. velocities. Strokes occurred in only two SS patients: the first patient had abn. high velocities detected at the age of 1.5 years and had a stroke at the age of 1.6 years, just before the TCD control and initiation of the transfusion program. The second patient had normal left-sided velocities but no available temporal window on the right side after the age of 1.4 y; this patient had a stroke at age 4.4 y. These observations prompted us to begin TP after the first abn. TCD and to perform MRI/MRA when no window was available. The rates of stroke were 0.13 per 100 patient-years overall, and and 0.18 per 100 patients-years in SS/Sb0 patients. The KM estimate of the risk of stroke was 1.02% at 5 y and 18 y of age in SS/Sb0 patients. KM estimates of the risk of ischemic lesions at 5 and 10 y were respectively 6.4% and 17.7% in SS/Sb0 patients with normal TCD and 20.9% and 43.5% in patients with a history of abn. TCD (Log Rank test 0.0035). This single-center study shows that a strategy based on early and regular TCD can efficiently prevent stroke in a newborn screened cohort: the rate of stroke and the KM risk of stroke were far lower than recently reported (Quinn CT Blood 2004). However, the risk of ischemic lesions remained high particularly in patients with a history of abn. velocities. Abn. TCD velocities identify a high-risk group who may qualify for matched related donor stem cell transplantation.

Abnormal TCD defined as high mean maximum velocities > 200 cm/sec are highly predictive of stroke risk and justify long term transfusion program. Outcome and risk factors of conditional TCD defined as velocities 170–200 cm/sec remains to be described. Patients and methods Since 1992, 371 pediatric SCD patients (303 SS, 44 SC, 18 Sß+, 6 Sß0) were systematically explored once a year by TCD. The newborn screened cohort (n=174) had the first TCD exploration between 12 and 18 months of age. TCD was performed with a real-time imaging unit, using a 2 MHz sector transducer with color Doppler capabilities. Biological data were assessed at baseline, after the age of 1.5 years and remotely of transfusion or VOC. We report the characteristics and the outcome in patients (n=43) with an history of conditional TCD defined by mean maximum velocities ranging between 170 and 200 cm/s in the ACM, the ACA or the ICA. Results: The mean follow-up of TCD monitoring was 5,5 years (0 – 11,8 y). All patients with an history of conditional doppler were SS/Sb0 (n=43). Mean (SD) age of patients at the time of their first conditional TCD was 4.3 years (2.2) whereas in our series the mean age at abnormal TCD (> 200 cm/sec) occurrence was 6.6 years (3.2). Comparison of basal parameters showed highly significant differences between patients with conditional TCD and those with normal TCD: Hb 7g4 vs 8g5 (p 80 (p=0.04). MRI/MRA was performed in 31/43 patients and showed ischemic lesions in 5 of them at the mean (SD) age of 7.1 y (1.8) (range 4.5–8.9): no significant difference was observed in the occurrence of lesions between the 2 groups. Conclusions This study confirms the importance of age as predictive factor of conditional to abnormal TCD conversion with a risk of 64% when first conditional TCD occured before the age of 3 years. TCD has to be frequently controled during the 5 first years of life.

Abnormal high velocities are predictive of high stroke risk which can be significantly reduced by transfusion program (Adams and al). They are related to stenosis, severe anemia or tissue hypoxia. We hypothesized that high velocities observed in patients with normal MRA and normalized on transfusion program (TP), were anemia related and could be safely decreased with hydroxyurea (HU)-therapy. Patients and Methods: since 1992, 291 pediatric SCD patients (235 SS, 40 SC, 3 Sb0, 11 Sb+) were systematically explored once a year by TCD. The newborn screened cohort (n=149) had the first TCD exploration between 12 and 18 months age. TCD was performed with a real-time imaging unit, using a 2 MHz sector transducer with color Doppler capabilities. When abnormal high velocities (defined as mean maximum velocities > 200 cm/sec in MCA, ACA or ICA) were observed, TCD was controlled and the patient treated with TP and cerebral imaging (MRI/MRA) was performed within 3 months. In patients with severe stenosis, TP was pursued or transplantation performed. In patients with normal MRA and transfusion-normalized velocities, a progressive switch towards HU therapy was applied and TCD controlled once a trimester. Results: among the stroke-free patients (n=281), abn. high velocities were detected in 25 patients (all SS:11% of incidence in SS patients). In the newborn screened population, velocities became abnormal in 10 patients at the median age of 5.7 years (range 1.4 – 12.5 y). The first MRI/MRA (n=24/25) performed in the 3 months following the detection of high velocities showed MRI/silent infarcts in 9/24 (38%): only 1/11 among the newborn screened cohort had silent infarcts in contrast with 8/13 older patients secondary referred in our center. MRA detected severe vascular abnormalities in 10 and mild in 3 patients. Mean velocities (2.69 m/sec) were significantly higher (p=0.002) in the 7 patients with abn. MRI and MRA than in the 10 patients (2.11m/sec) who had normal MRI and MRA. One stroke occurred in a very young 1.6 y old girl just before the second TCD evaluation (first abn. TCD had been observed at 1.5 y) and before the beginning of the TP. Long-term outcome: no stroke was observed following the initiation of the TP. With a median follow-up of 4.4 years (0.5 to 11.4 y.), velocities remained abnormal in 11/25 patients: 7 of them had abnormal MRA and among the 4 patients with normal MRA at first exploration MRA became abnormal in 2 cases showing that abnormal TCD can precede the occurrence of cerebral vasculopathy. TP was maintained in 7 patients and safely stopped in 4 patients transplanted with genoidentical donor. Velocities normalization (defined as < 170 cm/sec) was observed in 13/25 patients in a median delay of 0.75 years (0.25 – 2.3 years). TP was stopped in 10 patients with normal MRA and therapy was switched towards HU in 7 patients with abstention in 3. However, abnormal TCD relapsed in 4 patients who were again placed on TP. Conclusion: abnormal high velocities concerned 11% of SS patients and were predictive of MRA and MRI lesions occurrence. TP was efficient to prevent the stroke risk and normalized velocities in about 50% of patients but relapses were observed in 4/7 patients following TP stop and HU switch. Only few patients with high velocities history did not develop cerebral vasculopathy. Also, early TCD allows a selection of very high risk patients justifying the research of suitable donors.