Hydroxyurea Improves Neurocognition in Sickle Cell Disease

Winfred Wang, MD

The first prospective study to apply a battery of cerebrovascular, functional and anatomical MR imaging, and neurocognitive measures to evaluate effects of hydroxyurea on brain function of children with sickle cell disease (SCD) found improved intellectual functioning after 1 year of treatment.

“Hydroxyurea treatment is a standard of care for children with SCA (sickle cell anemia), and yet its effect on brain function has not been carefully examined in prospective longitudinal studies,” observed Winfred Wang, MD, Department of Hematology, St Jude Children’s Research Hospital, Memphis, TN, and colleagues.

“To our knowledge, this approach using fMRI, ASL, MRI, anatomical MRI, TCD, neuropsychologic evaluation and hematologic evaluation has not been previously performed to evaluate the effects of hydroxyurea on brain function,” they indicated.

The investigators noted previous studies which have found neurocognitive deficits in children with SCD, with contributing factors such as low socioeconomic status.They cite other studies that have suggested a beneficial effect of hydroxyurea on neurocognitive performance, although finding most were cross-sectional and retrospective.

Theirs is a prospective, 1-year clinical pilot study with 19 participants with SCD of mean 12.4 years of age (range 7.2-17.8).The absence of a control group was acknowledged by the investigators as a significant limitation.The cohort had a confirmed diagnosis of SCD (HbSS or HbSß0Thalassemia) and had not been previously treated with hydroxyurea; but met clinical criteria to receive it—recurrent vaso-occlusive pain events with ≥3/year requiring medical visits and acute chest syndrome.

The battery of measures taken at baseline and after 1 year of hydroxyurea treatment included brain MRI, transcranial Doppler ultrasound (TCD) and comprehensive neurocognitive testing.MR targets included silent cerebral infarcts (SCI), gray matter cerebral blood flow (GM-CBF), and blood oxygen level dependent (BOLD) signal from visual stimulation.

Standard non-imaging TCD examinations identified time averaged mean maximum velocities (TAMV) of the middle cerebral and internal carotid arteries.These data were stratified into normal (<170cm/sec), conditional (170-199cm/sec) and abnormal (>200cm/sec) risk groups.

The neurocognitive measures were selected for being applicable to the widest study age range, and able to be administered in approximately 2-3 hours.These included the Wechsler Intelligence Scale for Children, Fourth Edition (WISC-IV) to assess intelligence in children 7-17 years of age, and the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) for subjects older than 17 years.In addition to Full-Scale IQ (FSIQ), subtest measures indicated verbal comprehension, perceptual reasoning, working memory, and processing speed.

Academic achievement was assessed with the Woodcock Johnson Tests of Academic Achievement, Third Edition (FSIQ).Selected subtests included Letter-Word Identification, Reading Fluency, Passage Comprehension, Calculation, Math Fluency, and Applied Problems.

Wang and colleagues reported significant increases in FSIQ (+2.8, P = .036) and reading comprehension (+4.8, P = .016), a significant decrease in TCD velocity (-11.4cm/sec, P = .007); but no significant changes in GM-CBF, BOLD, or SCI frequency.In addition, they noted that increased FSIQ was associated with higher hemoglobin F (HbF) and lower GM-CBF, but not with hemoglobin level.

Higher hemoglobin levels were associated with decreased GM-CBF, TCD velocity, and with increased working memory.Higher HbF was associated with increased verbal comprehension, WJ Calculation and Passage Comprehension, in addition to increased FSIQ.

“Taken together, our data indicate that hydroxyurea may provide specific neurocognitive benefits, possibly by increasing both HbF and hemoglobin levels,” Wang and colleagues conclude.“Our data also suggest that increased BOLD signal and decreased CBF may be contributing to the process, because changes with hydroxyurea were in the expected direction, although not statistically significant.”

The investigators call for studies with larger cohorts to confirm the putative benefits of hydroxyurea and to clarify mechanisms involved.

The study, “Effects of Hydroxyurea on Brain Function in Children with Sickle Cell Anemia," was posted as a preprint before peer review on Authorea.