Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease

Sickle cell disease (SCD) is the most common hemoglobinopathy worldwide, with over 300,000 children born with SCD each year.1 Neurologic consequences of SCD include ischemic and hemorrhagic strokes2 and cognitive deficits.3 SCD accounts for almost ¼ of all stroke-related hospitalizations in African-American children.4 Historically, ischemic stroke in SCD has been separated by symptomatology, including “overt stroke,” referring to radiographic ischemia with associated neurologic deficits detectable on a bedside examination, and “silent stroke” referring to radiographic ischemia without focal neurologic deficits, but associated with cognitive deficits. However this dichotomy is likely false, as the two can be radiographically indistinguishable.5 Strokes may have lifelong devastating consequences, including limited educational attainment and decreased quality of life in children.6, 7 Sickle cell anemia refers to the most severe SCD phenotypes, SS and Sβ0 thalassemia, which have the highest stroke incidence. However, other SCD genotypes are also at risk for cerebral ischemia, with up to 13% of HbSC children having silent ischemia on screening MRI.2, 8 Transcranial Doppler (TCD) screening to identify children with SCD at highest stroke risk combined with primary stroke prevention with chronic transfusion therapy (CTT) revolutionized pediatric sickle cell stroke management in the 1990’s. Despite the dramatic reduction of overt strokes through CTT shown in the Stroke Prevention Trial in Sickle Cell Anemia (STOP), children with SCD remain at a high risk of stroke (Figure 1).2, 9–21 Clinical and translational research in the post-STOP era have increased our understanding of the multi-factorial complexity of stroke in children with SCD (Table 1). Recent work has demonstrated how components of the cerebral metabolic rate of oxygen utilization (CMRO2) contribute to ischemia in SCD. CMRO2 is the product of cerebral blood flow (CBF), arterial oxygen content (CaO2) and oxygen extraction fraction (OEF). CBF and CaO2 comprise cerebral oxygen delivery, and OEF quantifies the transfer of available oxygen supply into the brain tissue. Ischemia occurs when CMRO2 does not meet the metabolic demands and falls below the threshold of tissue viability.26 Here, we will review advances in causal pathways of ischemic stroke and therapy options. Open in a separate window Figure 1: Stroke Event Rates as reported in the literature. SCD = Sickle Cell Disease.