Effects of Hydroxyurea (HU) on Neurocognitive Performance in Children with Sickle Cell Disease: A Prospective Trial
Authors: Wang Winfred , Schreiber Jane , Kang Guolian , Li Chen , Hankins Jane S , Estepp Jeremie H. , Helton Kathleen 
Published: April 2021

Abstract
Background: Sickle cell anemia is associated with progressive compromise of neurocognitive function exacerbated by stroke or silent cerebral infarction. Despite decades of experience with chronic transfusion, hematopoietic stem cell transplantation, and HU, improvement in neurocognitive performance from these interventions has not been clearly demonstrated; only one study has reported improvement in global cognitive index from HU (Puffer, Child Neuropsychology, 2007). As part of a comprehensive prospective evaluation of the effects of HU treatment on the central nervous system, we evaluated neuropsychological performance in school-age children with sickle cell anemia.
Methods: Subjects had HbSS/Sβ0 thalassemia and no history of previous central nervous system (CNS) events and were 7-18 years old. After informed consent, baseline evaluations included the Wechsler Intelligence Scale for Children, 4th edition (WISC-IV) and the Woodcock-Johnson Achievement Test Version III (WJ-III). Treated patients received HU beginning at 20 mg/kg/d with gradual escalation to maximum tolerated dose (MTD) within one year. They were evaluated with the same CNS studies after 12 months. A control group who declined HU treatment was matched by diagnosis and age and was also evaluated at baseline and after one year. Summary statistics of WISC and WJ-III scores were reported for each time point and for their change between two time points in each group and were compared using the Wilcoxon rank sum and Wilcoxon signed rank tests, respectively.
Results: Age and gender distributions in HU-treated (n=21) and untreated control patients (n=11) were comparable. In HU-treated patients, but not in controls, there was significant improvement in mean full scale IQ (FSIQ) after one year (Table 1). In treated subjects, mean WISC subscale scores were all higher after one year, although none were statistically significant. Among controls, FSIQ and all subscales, except working memory, showed a numerical decrease in mean scores, with the greatest decline in perceptual reasoning. Subtest scores from the WJ-III Achievement test in HU-treated patients showed significant improvement in comprehension of word passages. Among controls, WJ-III Achievement subtest scores showed no significant changes. When mean changes in WISC scores from baseline to one-year follow-up were compared (Table 2), treated patients showed greater positive changes than controls, but differences were not significant. Changes in WJ-III scores for treated and control subjects also were not significant.
Conclusions: In children with sickle cell anemia, HU treatment over a one year period was associated with a significant improvement in the Wechsler Full Scale IQ; subscales showed small to medium positive changes although the differences were not statistically significant. By contrast, in the untreated control group, most scores were lower after one year and mean changes in scores from baseline were less positive than those in the HU group. In measures of achievement, the treated group demonstrated improved passage (reading) comprehension, a skill related to executive function. Overall, these results suggest that HU may improve cognitive function or prevent decline. Correlation of standard and functional MR neuroimaging in these subjects with neurocognitive performance is pending. Future trials are needed to examine the impact of other interventions (e.g., memory training, multisensory reading intervention), possibly in conjunction with HU.

Disclosures
No relevant conflicts of interest to declare.