Associations of transcranial doppler velocity, age, and gender with cognitive function in children with sickle cell anemia in Nigeria

Children with sickle cell anemia (SCA) have elevated cerebral blood velocity relative to healthy peers. The primary aim of this study was to evaluate the association between cerebral blood velocity, measured by transcranial Doppler (TCD) ultrasound, age, and gender with cognitive function in children with SCA in Nigeria. Eighty-three children (Mage = 9.10, SD = 1.90 years; 55% female) with SCA in Nigeria completed cognitive assessments and a TCD ultrasound. The association between TCD velocity and measures of perceptual reasoning (Raven's Progressive Matrices), working memory (WISC-IV Digit Span), and executive planning (Tower of London, TOL) were assessed. Results showed that elevated TCD velocity significantly predicted lower scores on TOL Time Violations and Total Problem-Solving Time when controlling for BMI, hemoglobin level, and parent education, suggesting that TCD velocity is related to the efficiency of executive function. Further, age was negatively related to children's performance on the Ravens Matrices and TOL Total Correct, and boys showed greater deficits on the TOL Total Correct relative to girls. Moderation analyses for gender showed that there was a conditional negative association between TCD velocity and Digit Span for boys, but not for girls. Findings suggest that children with SCA in Nigeria with elevated TCD velocity are at risk for deficits in efficiency of executive planning, and boys with elevated TCD velocity are particularly at increased risk for deficits in auditory working memory. Implications of this study are important for interventions to reduce cerebral blood velocity and the use of TCD in this population.</p

World Health Organization’s Growth Reference Overestimates the Prevalence of Severe Malnutrition in Children with Sickle Cell Anemia in Africa

Anthropometric indices are widely used to assess the health and nutritional status of children. We tested the hypothesis that the 2007 World Health Organization (WHO) reference for assessment of malnutrition in children with sickle cell anemia (SCA) overestimates the prevalence of severe malnutrition when compared to a previously constructed SCA-specific reference. We applied the WHO and SCA-specific references to children with SCA aged 5&ndash;12 years living in northern Nigeria (Primary Prevention of Stroke in Children with SCA in sub-Saharan Africa (SPRING) trial) to determine the difference in prevalence of severe malnutrition defined as body mass index (BMI) Z-score &lt;&minus;3 and whether severe malnutrition was associated with lower mean hemoglobin levels or abnormal transcranial Doppler measurements (&gt;200 cm/s). A total of 799 children were included in the final analysis (median age 8.2 years (interquartile range (IQR) 6.4&ndash;10.4)). The application of the WHO reference resulted in lower mean BMI than the SCA-specific reference (&minus;2.3 versus &minus;1.2; p &lt; 0.001, respectively). The use of the WHO reference when compared to the SCA-specific reference population also resulted in a higher prevalence of severe malnutrition (28.6% vs. 6.4%; p &lt; 0.001). The WHO reference significantly overestimates the prevalence of severe malnutrition in children with SCA when compared to an SCA-specific reference. Regardless of the reference population, severe malnutrition was not associated with lower mean hemoglobin levels or abnormal transcranial Doppler (TCD) measurements

Randomized controlled trial of fixed low-vs moderate-dose hydroxyurea for primary stroke prevention in Sub-Saharan Africa: Final results of the Spring Trial

Introduction: In children with sickle cell anemia (SCA) without transcranial Doppler (TCD) screening, the incidence rates of ischemic strokes is approximately the same among children living in low- and high- low-resource settings (Pediatr Neurol. 2019;95:73-78.) with a prevalence of ~ 11%. However, in high-income settings, the standard use of TCD ultrasonography, coupled initially with monthly blood transfusion therapy has dropped the stroke prevalence to &lt; 1%. In a low-income setting, such as Nigeria, where 50% of children in the world with SCA are born (150,000 per year), initial monthly blood transfusion therapy is not practical for most children.In the Stroke Prevention in Nigeria (SPIN) Feasibility Trial (NCT01801423), fixed moderate-dose hydroxyurea was associated with a decreased rate of strokes in children with SCA and abnormal time-averaged mean of the maximum velocity (TAMMV) TCD measurements (≥200cm/sec) when compared to no treatment in the STOP Trial, 0.76 and 10.7 strokes per 100 person-years, repsectively (Am J Hematol. 2020). Based on the success of the SPIN trial, plus the challenges of real-world implementation of a government-supported primary stroke prevention programs for estimated 40,0000 children with SCA in three states in Nigeria, we tested the hypothesis that fixed-moderate dose (~20 mg/kg/day) hydroxyurea therapy for primary stroke prevention results in a 66% relative risk reduction (9 to 3 events per 100 person-years) when compared to fixed low-dose hydroxyurea (~10 mg/kg/day) therapy in a randomized controlled trial (The SPRING Trial; NCT02560935).Methods: In this partial-blind controlled phase III trial, we randomly assigned children between 5 and 12 years of age with SCA and a TCD time-averaged mean of the maximum velocity (TAMMV) ≥ 200 cm/sec measured independently twice or TAMMV ≥220 cm/sec once at study screening to receive fixed low-dose or fixed moderate-dose hydroxyurea. The primary endpoint was a clinical stroke or a transient ischemic attack (TIA). Myelosuppression was assessed with monthly complete blood counts (CBCs). Adherence to hydroxyurea was primarily based on an increase in MCV from baseline and monthly pill count return as a percent of dispensed pills. Hemoglobin F levels were measured at baseline, annually and upon trial exit. To evaluate the safety of hydroxyurea in the trial, children attending the same SCA clinics with TCD (TAMMV) &lt;200 cm/sec at study screening were prospectively followed with biweekly phone calls and annual research visits.Results: A total of 220 children (mean age: 7.5 years, 51.8% female) were randomly assigned to fixed low- (10 mg/kg/day) or moderate- (20 mg/kg/day) dose hydroxyurea, and were followed for a median of 2.4 years (IQR 2.0-2.8). NINDS Clinical Trials leaders stopped the trial early because of futility for the primary outcome. In the fixed low- and moderate-dose hydroxyurea groups, the incidence rates of strokes per 100 person-years were 1.19 and 1.92 respectively, with an incidence rate ratio of 1.60 (95% CI: 0.31-10.34), p = 0.768. The incidence rate ratio of mortality when comparing the children treated with low- and moderate- fixed-dose hydroxyurea to the non-elevated TCD group (no hydroxyurea therapy, n= 211) was 1.97 (95% CI: 0.64-6.02) and 0.47 (95% CI: 0.05-2.38), p = 0.265 and 0.545, respectively. Returned pills during the trial was 5.4% and 4.8% in the fixed low- and moderate-dose groups, respectively, p= 0.144. MCV from baseline to endpoint increased 1.5fl and 7.2 fl in the fixed low- and moderate-dose groups, respectively, p&lt;0.001. Upon exit from the trial 29.4% and 66.7% of the fixed- low and moderate -dose groups, respectively, had either hemoglobin level ≥ 9.0 g/dl, or a fetal hemoglobin level ≥ 20%.Conclusions: For primary stroke prevention in children with SCA, fixed low-dose, when compared to fixed moderate-dose hydroxyurea therapy, demonstrated no difference in the incidence rate of strokes. Both fixed low- and moderate -dose hydroxyurea doses are superior to no treatment for primary stroke prevention with abnormal TCD values. In partnership with Katsina, Kano, and Kaduna health department's leaders in Nigeria, 9 distinct SCA and primary stroke prevention clinics have been established, with the provision of free fixed low-dose hydroxyurea therapy (Bond Chemical, Nigeria; $0.15 per 500 mg) for abnormal TCD values, and biannual CBCs as standard care ,for over 40,000 children with SCA