Acute silent cerebral ischemia occurs more frequently than silent cerebral infarction in children with sickle cell anemia

Background: Children with sickle cell anemia (HbSS) are at high risk of overt stroke and clinically silent cerebral infarction (SCI). SCI is an infarct-like lesion visualized on magnetic resonance imaging (MRI) of the brain that produces no corresponding motor or sensory deficits. The prevalence of SCI in HbSS is approximately 20 – 30% by 16 years of age, but less is known about its incidence. The Cooperative Study of Sickle Cell Disease (CSSCD) found the incidence of new or more extensive SCI in children with HbSS to be 7 events per 100 patient-years. Given that SCI is clinically silent, the only way to determine its incidence (the number of new events occurring in a specific time-period) is to screen with two sequential MRIs of the brain. MRI can also detect acute cerebral ischemia in asymptomatic patients using diffusion-weighted imaging (DWI). The incidence of acute silent cerebral ischemic events (ASCIEs) is not known. A clinical trial setting provides a unique opportunity to determine the incidence of ASCIEs and SCI in children with HbSS.Objectives: To determine the incidence rates of (1) ASCIEs in children with HbSS without prior evidence of focal neurological deficits and (2) new, recurrent SCI in children with HbSS who have pre-existing SCI.Methods: We studied a cohort of children with HbSS and sickle-β0-thalassemia who had brain MRIs for the Silent Infarct Transfusion Trial. All participants had no prior history of overt stroke, seizures, or transient ischemic attacks. ASCIE was defined as an infarct-like lesion on brain MRI without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity with restricted diffusion on DWI sequences. SCI was defined an infarct-like lesion without corresponding motor or sensory deficits that appeared as a focus of T2 hyperintensity without restricted diffusion. Given that acute cerebral ischemia appears as a focus of restricted diffusion on DWI for 10 days, we assumed that each MRI scan provided 10 patient-days of observation for detecting ASCIE. Therefore, the incidence of ASCIEs was calculated using a single MRI per patient. The incidence of new or more extensive SCI in children with pre-existing SCI was determined in those who had two MRIs each (screening and pre-randomization). We statistically compared the incidence rates of ASCIEs and SCI obtained by these two different methods. For all ASCIEs and new SCI events, a medical history tool was completed at the local site at the time of MRI of the brain.Results: In total, 972 MRIs were studied (745 screening, 227 pre-randomization). There were 844 MRIs with DWI sequences, providing 23.1 patient-years of observation in 640 children (52% male; mean age 9.7 years). ASCIEs were detected on 1.2% (10 of 844 MRIs), corresponding to an incidence of 43.3 (95% CI: 20.7 – 79.6) events per 100 patient-years. Nine of the 10 ASCIEs were detected incidentally; 1 ASCIE occurred in a participant who was recovering from a recent episode of acute chest syndrome (onset 5 days before MRI) complicated by severe anemia and hypertension. Standard neurological examination was normal in all cases. Two of the 10 participants with ASCIEs had follow-up MRIs of the brain 4 to 10 months later; one had SCI in the same location as the previously detected acute ischemia, but the other had no residual lesion in the same location. Thus, not all ASCIEs produce detectable SCI. A total of 220 participants (55% male; mean age 10.0 years) had both screening and pre-randomization MRIs. The mean interval between the two MRIs was 124.3 days (range: 14 – 645), providing 74.9 patient-years of observation. All screening MRIs showed baseline SCI. New, recurrent SCI was detected on pre-randomization MRI in 8 participants, corresponding to an incidence of 10.7 events per 100 patient-years (95% CI: 4.6 – 21.0). The incidence of ASCIEs was 4-fold higher than recurrent SCI (43.2 vs. 10.7 events per 100 patient-years; P=0.001).Conclusions: The incidence of recurrent SCI was similar to CSSCD findings. However, we show that children with HbSS experience acute cerebral ischemic events far more frequently than previously recognized. These acute ischemic events are mostly clinically silent, potentially reversible radiographically, and not associated with antecedent medical events