Hydroxyurea Improves Intelligence Quotient Scores in Children with Sickle Cell Anemia and Elevated Transcranial Doppler Velocity

Introduction: Structural brain abnormalities resulting from sickle cell disease because of strokes, silent cerebral infarcts (SCI) and other biophysical characteristics of parenchymal damage from repeated sickling affect cognitive functioning. Hydroxyurea therapy reduces transcranial Doppler (TCD) velocities and improves SCI and other neurological outcomes in children with sickle cell anaemia. Hence the objectives of EXpanding Treatment for Existing Neurological Disease (EXTEND, NCT02556099), a phase 2 clinical trial, was to determine whether hydroxyurea titrated to maximum tolerated dose was effective in lowering transcranial Doppler (TCD) velocities and improving cognitive function in Jamaican children with sickle cell anemia (SCA) with increased stroke risk.

Methods: Full-Scale Intelligence Quotient (FSIQ), verbal and nonverbal IQ were measured with the Wechsler Abbreviated Scale of Intelligence (WASI-II) at baseline and after 18 months of hydroxyurea treatment in 30 of the 43 enrolled children. Verbal Comprehension Index (VCI) was assessed using the Vocabulary and Similarities subtests. Perceptual Reasoning Index (PRI) was scored with the Block Design and Matrix Reasoning subtests. Members of the team conducting the tests were trained and test results were verified by an experienced member of the Epidemiology Research Unit, Caribbean Institute for Health Research. Participants were enrolled in the EXTEND trial based on a pre-treatment conditional or abnormal TCD velocity. They were assigned to one of three risk categories according to treatment status and stroke history at study enrollment: Group 1 (low stroke risk: no previous stroke, on hydroxyurea treatment n= 12), Group 2 (medium stroke risk: no previous stroke, no hydroxyurea, n=10) and Group 3 (High stroke risk: previous stroke, no hydroxyurea n=8). Anthropometric variables, including height and weight, were recorded as well as oxygen saturation and hematological variables. Differences in post treatment outcome were modelled using mixed linear regression. A p-value of <0.05 was considered statistically significant.

Results: There was no difference in mean anthropometric values or gender distribution at baseline by stroke risk category groups (Table 1). The mean(sd) age in years of participants in Group 1 was 8.2(1.7), while for Group 2 the average age was 7.7(2.1) and for Group 3 it was 10.5(2.8). The mean age of Group 3 was significantly greater than Group 1. After 18 months of hydroxyurea treatment, participants were taking an average dose of 25 mg/kg/d, range 13.7 to 34.9 mg/kg/d. On treatment TCD velocities decreased by mean(sd) of 29.5 cm/sec (31.5). Hemoglobin (Hb) concentration was lowest in Group 3 but all groups showed increases during treatment with the rate of increase in Groups 2 and 3 being greater than Group 1 (p<0.001). Absolute neutrophil counts and absolute reticulocyte counts were not different by group, and both decreased significantly post treatment (p<0.001) (Table 1). At both time points, the VCI, PRI and FSIQ mean scores in Group 3 were low [Overall means(sd); 71(11.7), 71(12.6),69(11.6), respectively] and were significantly lower compared with Group 1 (p<0.001) (Table 1). While there was no significant effect of treatment on VCI and PRI scores, the mean FSIQ score increased on average by 2.9 units (95%CI 0.3, 5.4) post treatment among participants. Adjusting for age at enrollment had no effect on the improvement on FSIQ, however adjusting for changes in hemoglobin resulted in an increase in FSIQ by 3.3 units (95%CI -0.4, 7.0) which approached statistical significance (p=0.079).

Conclusion: Participants treated with hydroxyurea at maximum tolerated dose for 18 months with or without a previous stroke had significant improvement in hematological variables and neuropsychological scores. Children with sickle cell anemia with high risk of stroke may benefit from routine neuropsychological testing, hydroxyurea treatment in addition to educational interventions.