Breakthrough: new guidance for silent cerebral ischemia and infarction in sickle cell disease Charles T. Quinn 1 1 Division of Hematology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH Silent cerebral infarction (SCI) is a highly prevalent and morbid condition in sickle cell disease (SCD). SCI can occur beginning in the first year of life and becomes more common with increasing age. Potentially modifiable risk factors for SCI include anemia and blood pressure. Headache does not appear to be associated with SCI, so neurologically normal children with headache do not necessarily warrant screening MRI for SCI. SCI does affect cognition, but biological determinants of cognition are not more important than socioeconomic factors. The recent identification of acute silent cerebral ischemic events indicates that the total burden of ischemic injury to the brain in SCD is far greater than previously realized. Acute anemic events appear to increase the risk of acute silent cerebral ischemic events and SCI dramatically. The medical management of SCI is not yet defined, but documentation of the presence of SCI may qualify affected individuals for special resources because comprehensive interventions are needed to optimize patients’ academic and vocational outcomes. Learning Objectives ● To summarize the risk factors for SCI in SCD ● To rank by relative frequency the overt and covert neurologic events in SCD ● To explain the joint role of SCI and socioeconomic factors on cognitive outcomes in SCD ● To understand the role of anemia in the genesis of SCI in SCD ● To define and recognize ASCIEs in SCD Background and definition The brain is at constant threat of ischemic injury in sickle cell disease (SCD). The risk of overt stroke for children with SCD is more than 200 times higher than that for the general population, and this burden of overt stroke continues well into adulthood. An even more common form of neurologic injury in SCD is silent cerebral infarction (SCI), which has a prevalence of up to 40%. SCI refers to generally small, permanent brain lesions that are not associated with obvious focal neurologic signs (Figure 1). The term SCI is a misnomer because these strokes, even though they do not produce focal or localizing signs on neurologic examination, are often not “silent.” SCI is a morbid condition associated with neurocognitive impairment, poor academic performance, neurologic soft signs, and increased risk for subsequent overt stroke. Covert cerebral infarc- tion may be a better descriptor, but SCI is the accepted term. The definition of SCI has 2 components: (1) an infarct-like lesion on MRI of the brain and (2) a normal neurologic examination or no abnormality on neurologic examination that can be explained by the location of the infarct-like lesion. Specific definitions of the SCI lesion on MRI vary by study, but the Silent Cerebral Infarct Transfusion (SIT) Trial (www.ClinicalTrials.gov identi- fier #NCT00072761) rigorously defined it to be an MRI signal abnormality (increased signal) of at least 3 mm in 1 dimension that was visible on at least 2 views of T2-fluid-attenuated inversion recovery images of the brain. 1 Because SCI is clini- cally covert, it must be identified by screening MRI of the brain. SCI is therefore almost always identified incidentally as a remote event well after its onset, which makes the study of its causes and frequency quite challenging. The goal of this chapter is to highlight several of the recent advances in our understanding of the frequency, risk factors, correlates, causes, and management of SCI. Prevalence and incidence of SCI SCI is highly prevalent in children and adults with SCD. Like overt stroke, SCI occurs much more frequently (at least twice as frequently) in individuals with sickle cell anemia (HbSS) or sickle- 0 -thalassemia (HbS 0 ) than in those with sickle-hemoglobin C disease or sickle- + - thalassemia. SCI begins to occur in the first year of life. In the Hydroxyurea to Prevent Organ Damage in Children With Sickle Cell Anemia (Baby HUG study; www.ClinicalTrials.gov identifier #NCT00006400), 13% [95% confidence interval (CI), 3-34] of neuro- logically asymptomatic children with HbSS at a mean age of 13.7 months already had SCI detected on screening MRI of the brain. 2 Several additional studies including children of different ages show that the prevalence of SCI increases with age throughout childhood and approaches 40% in adolescents (Figure 2). 2-5 Studies in adults also show a high prevalence of unsuspected brain lesions. Silva et al 6 found a prevalence of 60% of several MRI abnormalities classified as leukoencephalopathy, encephalomalacia, atrophy, and lacunar infarc- tion. Vichinsky et al 7 found that a highly selected population of adults with HbSS (baseline Hb concentration 10 g/dL and no history of stroke, focal neurologic deficits, known brain imaging abnormalities, serious cognitive impairment, or depression) had a 13% prevalence of SCI (lacunar infarction) on screening MRIs. Comparisons of preva- lence across age groups, especially between pediatric and adult groups, are difficult because the studies to date provide cross-sectional esti- mates of prevalence at different ages, which can be biased by several factors (selection bias, survivorship bias, etc) and there are no comprehensive longitudinal data about the prevalence of SCI across the lifespan. The definitions of SCI and the terminology of covert brain lesions also vary across studies. Little has been published about the incidence of SCI, properly defined as new SCI events that occur in a specified time interval SICKLE CELL DISEASE:TREATING PATIENTS WITH BROKEN RED CELLS 438 American Society of Hematology