Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia

Abstract

Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0-31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5-54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0-15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76-0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2-64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments.

Trial registration: ClinicalTrials.gov NCT02098863.

Keywords: Stroke; disease-modifying therapy; sickle cell anemia; silent cerebral infarct; vasculopathy; young adult.

Conflict of interest statement

DECLARATION OF CONFLICTING INTERESTS: JSH receives research support from Global Blood Therapeutics and consultancy fees from Global Blood Therapeutics, Vindico Education and bluebird bio. KIA has received research funding from the US Food and Drug Administration and Norvartis, and has served on Advisory Boards for Novartis, Global Blood Therapeutics, Roche, Novo Nordisk, Forma Therapeutics and Agios Pharmaceuticals. JHE receives research support by the ASH Scholar Award, Pfizer, Global Blood Therapeutics, Forma Therapeutics, Eli Lilly and Co, and he serves as a consultant for Daiichi Sankyo, Esperion, Emmaus Life Sciences and Global Blood Therapeutics.

Figures

Figure 1.

CNS disease progression according to baseline status. The risk of MRI (a) and MRA (b) disease progression is significantly higher among those with baseline abnormal exams. PFS: progression free survival. P-values were calculated using exact log rank test. (A color version of this figure is available in the online journal.)