Table e-1: Definitions of SCI in prior studies (n = 10) with FSIQ in children with SCA and SCIs, with all definitions excluding prior history of overt stroke
Reference Description on T2w MRI Other Details
Armstrong et al. 1996 (CSSCD)
Area of abnormally increased signal intensity;
also visible on intermediate sequence
• Normal neurologic exam
• Classified by size (length; no minimum):
Focal or small (< 0.5 cm), ovoid or medium (0.5 - 1.5 cm), and geographic or large (>
1.5 cm)
• Anatomic location: White matter, basal ganglia, thalamic, cortical
Steen et al. 1998 (CSSCD)
Any “abnormalities” on either T1w or T2w MRI
Abnormalities defined as any of the following:
• T1w: Asymmetric loss of white matter volume, encephalomalacia, or lacunae
• T2w: Lacunae (small, unidentified bright signals) or edema (larger areas of high signal intensity)
Watkins et al.
1998
Unspecified
• Normal neurologic exam
• Classified by size (volume; no minimum):
Small (< 1 cm3), medium (1 - 5 cm3), and large (> 5 cm3)
Bernaudin et al.
2000 (Créteil)
Area of abnormally increased signal intensity;
Classified by size, number, and anatomic location (Group 1: Major vessel and watershed infarction; Group 2: Three or more or bilateral
also visible on proton- density sequence
high-signal areas in the white matter or basal ganglia; Group 3: One or two unilateral high- signal lesions; Group 4: isolated atrophy) Brown et al.
2000
See Armstrong et al. 1996 Normal neurologic exam
Wang et al.
2001 (CSSCD)
See Armstrong et al. 1996 Normal neurologic exam
Thompson et al.
2003 (CSSCD)
See Armstrong et al. 1996 Normal neurologic exam
Kral et al. 2006 (STOP)
Area of abnormally increased signal; also visible on FLAIR sequence
• Normal neurologic exam
• Classified by size (length; no minimum):
Small (< 0.5 cm), medium (0.5 - 1.5 cm), and large (> 1.5 cm)
Hijmans et al.
2011
Unspecified Normal neurologic exam
King et al. 2014 (SITT)
• Infarct-like lesion ≥ 3 mm in length
• Visible in at least two planes (axial and coronal)
• Must be FLAIR sequence
• No focal neurologic deficit consistent with the site of the infarct-like lesion
• Excludes history of seizures
Abbreviations: SCI = silent cerebral infarct; FSIQ = Full-Scale IQ; SCA = sickle cell anemia;
T2w = T2-weighted image on MRI; CSSCD = Cooperative Study of Sickle Cell Disease; T1w = T1-weighted image on MRI; STOP = Stroke Prevention Trial in Sickle Cell Anemia; FLAIR = fluid-attenuated inversion recovery; SITT = Silent Cerebral Infarct Transfusion Trial
Table e-2: Classification and definitions of SCIs in individuals with SCA, with associated prevalence in children randomly allocated in the SIT trial with SCA, SCIs, and normal TCD velocities (N = 196)
Definition of SCI
Size of T2w hyperintensity
Size of T1w hypointensitya
Degree of T1w hypointensityb
Prevalence (%) (N = 196)
1. Pediatric ≥ 3 mm 100.0
2. ≥ 3 mm ≥ 3 mm 49.5
3. ≥ 3 mm ≥ 2 39.8
4. ≥ 3 mm 3 23.5
5. ≥ 3 mm ≥ 3 mm ≥ 2 32.7
6. ≥ 3 mm ≥ 3 mm 3 20.4
7. ≥ 5 mm 75.0
8. ≥ 5 mm ≥ 3 mm 43.4
9. ≥ 5 mm ≥ 2 34.2
10. ≥ 5 mm 3 21.9
11. Adult ≥ 5 mm ≥ 3 mm ≥ 2 29.6
12. ≥ 5 mm ≥ 3 mm 3 19.4
Abbreviations: SCI = silent cerebral infarct; SCA = sickle cell anemia; SIT = Silent Cerebral Infarct Transfusion; TCD = transcranial Doppler; T2w = T2-weighted image on MRI; T1w = T1- weighted image on MRI
aBlank boxes correspond to any length of the corresponding T1w hypointensity
bBlank boxes correspond to any degree of the corresponding T1w hypointensity
Table e-3: Results of multivariable linear regression models for FSIQa in children from the SIT Trial with SCA, with and without SCIs (N = 150); with “presence of silent infarct”
independently substituted by variations of the definition of SCI
Covariateb Bc SE 95% CI P-value
Pediatric definition of SCI
(T2w hyperintensity ≥ 3 mm) -5.21 2.16 -9.48 to -0.93 0.017 T2w hyperintensity ≥ 3 mm and T1w
hypointensity ≥ 3 mm -5.20 2.05 -9.25 to -1.14 0.012 T2w hyperintensity ≥ 3 mm and T1w
hypointensity score ≥ 2 -1.38 2.27 -5.87 to 3.12 0.546 T2w hyperintensity ≥ 3 mm and T1w
hypointensity score = 3
-3.60 2.83 -9.19 to 1.99 0.205
T2w hyperintensity ≥ 3 mm, T1w
hypointensity ≥ 3 mm and score ≥ 2 -3.35 2.39 -8.07 to 1.36 0.162 T2w hyperintensity ≥ 3 mm, T1w
hypointensity ≥ 3 mm and score = 3
-4.42 2.87 -10.10 to 1.25 0.126
T2w hyperintensity ≥ 5 mm -4.36 1.94 -8.19 to -0.52 0.026
T2w hyperintensity ≥ 5 mm and T1w
hypointensity ≥ 3 mm -4.87 2.13 -9.08 to -0.65 0.024 T2w hyperintensity ≥ 5 mm and T1w
hypointensity score ≥ 2 -2.67 2.37 -7.36 to 2.02 0.262
T2w hyperintensity ≥ 5 mm and T1w hypointensity score = 3
-3.60 2.83 -9.19 to 1.99 0.205
Adult definition of SCI (T2w hyperintensity ≥ 5 mm, T1w hypointensity ≥ 3 mm and score ≥ 2)
-3.90 2.45 -8.75 to 0.95 0.114
T2w hyperintensity ≥ 5 mm, T1w hypointensity ≥ 3 mm and score = 3
-4.42 2.87 -10.10 to 1.25 0.126
Abbreviations: FSIQ = Full-Scale IQ; SCA = sickle cell anemia; SCI = silent cerebral infarct;
SE = standard error; T2w = T2-weighted image on MRI; T1w = T1-weighted image on MRI
aWith pre-selected covariates of age in years, percentage hemoglobin oxygen saturation at baseline, education level of the head of household (college versus less than college
education), household income per capita in thousand dollars, and presence of silent infarct (present or absent), based on the original model in King et al. 2014
bEach row corresponds to a model for FSIQ with a variation of the definition of SCI
cUnstandardized regression coefficient; corresponds to amount of change in FSIQ
