Epidemiology of Silent and Overt Strokes in Sickle Cell Disease

Sickle Cell Disease (SCD) is a rare disease occurring in an estimated 100,000 children and
adults, often poor and underserved, in the United States. Silent strokes and overt strokes
contribute significantly to morbidity in adults with SCD, resulting in functional impairment,
challenges with school and job performance, and premature death. Five NIH-funded randomized
controlled trials (RCT) have identified therapies to prevent silent and overt strokes in
children with SCD, including monthly blood transfusion therapy (for preventing initial and
recurrent strokes) and hydroxyurea (for preventing initial strokes). Despite the observation
that at least 99% of children with SCD in high-income countries reach adulthood, and
approximately 60% of adults will experience one or more strokes (~50% with silent strokes and
~10% with overt strokes), no stroke trials have established therapeutic approaches for adults
with SCD. For adults with SCD, inadequate evidence-based guidelines exist for secondary
stroke prevention strategies. Applying stroke prevention strategies in children may not be
effective for stroke prevention in adults with SCD, particularly given the high rate of
co-morbidities. Identifying subgroups of adults with SCD and higher incidence coupled with
the contribution of established stroke risk factors in the general population (smoking,
diabetes, obesity, renal disease) will provide the requisite data required for the first ever
phase III clinical trials focused on secondary stroke prevention in adults. In three adult
sickle cell disease centers, we will conduct a prospective cohort study to test the primary
hypothesis that the incidence of infarct recurrence (stroke or silent stroke) or new strokes
in adults with silent strokes treated with hydroxyurea will be greater than in those without
strokes treated with hydroxyurea. We will test two secondary hypotheses: 1) adults with SCD
and silent strokes have cognitive morbidity when compared to adults with SCD without silent
strokes; and 2) adults with SCD and strokes receiving regular blood transfusion will have a
higher incidence of infarct recurrence than those with SCD without strokes. The aims include
Aim 1: Compare the incidence of new overt and silent strokes in adults with SCD and silent
strokes to a comparison group of adults without silent strokes or overt strokes. Aim 2:
Compare the cognitive morbidity of those with silent strokes and overt strokes to those
without strokes. Aim 3: Compare the incidence of new overt and silent stroke in adults with
SCD and overt strokes receiving transfusion to adults with SCD without silent or overt
strokes treated with hydroxyurea. All clinical information and neuroimaging will be centrally
adjudicated with masked and experienced neurology and neuroradiology committees. Data
generated after completion of this proposal are critical for developing the first ever phase
III trials for secondary stroke prevention therapies in adults with SCD.