Neuroprotection: further evidence for the early and universal use of hydroxyurea in children with sickle cell disease.

Abstract

The neuroanatomic and neurophysiological complications of sickle cell disease (SCD) are well described and include overt stroke and silent cerebral infarctions, which disproportionately affect areas of the brain involved in executive functioning and attention.1, 2 However, even individuals with SCD without evidence of neuroanatomical changes on imaging score significantly lower on measures of full-scale intelligence (FSIQ) than community-matched peers.3 These changes begin early, often within the first decade of life, and affect academic achievement and later job attainment.4, 5 Nevertheless, to say that the disease itself is the only contributor to neurocognition would be to oversimply a complex process; other biological and socio-environmental factors, including parental education, household income and family cohesion, also play a major role.6, 7 In this issue, Heitzer et al.,8 expand on the work published last year by Partanen et al.,9 specifically describing the results of a cross-sectional analysis of the neurocognitive function of children and young adults aged 8–25 years with all SCD genotypes, treated with and without hydroxyurea. In those with the higher risk genotypes, HbSS and HbSβ0-thalassemia, patients treated with hydroxyurea achieved higher scores on measures of verbal comprehension, perceptual reasoning and FSIQ. In addition, importantly, the age at starting hydroxyurea was significantly associated with FSIQ, with those starting earlier in childhood having improved neurocognitive performance compared to those who began later or not at all. While it is encouraging that the authors determined a significant difference in neurocognitive functioning between treated and untreated children, the average age at starting hydroxyurea in this study was 8 years for those with the HbSS and HbSβ0-thalassemia genotypes; data from the BABY HUG trial showed that neurocognitive decline begins within the first year of life for children with SCD,10 who score significantly lower on measures of kindergarten readiness than matched peers.11 Even as early as primary school, grade repetition rates as high as 20% are seen, significantly higher than regional and national trends.12, 13 The growing body of literature to demonstrate that hydroxyurea can attenuate the progressive neurocognitive decline seen in children with SCD provides further evidence for its universal prescription for all children with HbSS and HbSβ0-thalassemia within the first year of life, regardless of apparent disease severity.14 It is also important to note that another significant contributor to FSIQ (the largest contributor at 6% to the variance in FSIQ seen in those with the HbSS and HbSβ0-thalassemia genotypes) was the social vulnerability index. This finding supports earlier work showing the critical role that parental education and household income play in neurocognitive outcomes in children with SCD.6 Further, it also highlights how individuals with SCD are disproportionately affected by social determinants of health;15 indeed, over 75% of their cohort fell into the highest overall vulnerability ranking, which is consistent with other published cohorts.13 As the authors state, a major limitation of this work is its cross-sectional nature; the recent encouraging data from these small cross-sectional studies lend support to the need for a long-term, longitudinal assessment of neurocognition in individuals with SCD treated with hydroxyurea from early childhood. Definitive evidence for a neuroprotective effect elicited by hydroxyurea should further convince providers to expand their use of this disease-modifying therapy to all children with the more severe genotypes of SCD.