Progressive loss of brain volume in children with sickle cell anemia and silent cerebral infarct: A report from the silent cerebral infarct transfusion trial
Authors: Deepika S. Darbari, Odianosen Eigbire‐Molen, Maria R. Ponisio, Mikhail V. Milchenko, Mark J. Rodeghier, James F. Casella, Robert C. McKinstry, Michael R. DeBaun
Journal: American Journal of Hematology (2018)

Silent cerebral infarcts (SCIs) in children with sickle cell anemia (SCA) are associated with increased risk of overt stroke,1 new SCI,1 poor academic achievement,2 and lower IQ compared to children with SCA without SCI. Risk factors for a decrease in brain volume3 (also referenced as brain volume percent change) in children with SCA and SCI have not been fully described. In a smaller subset of children from the multicenter Silent Cerebral Infarct Transfusion Trial (SIT) (n = 32) using high-resolution 3D T1-weighted images, Kawadler et al. provided preliminary evidence that there was a negative brain volume percent change in the group randomly allocated to regular blood transfusion or observation of −0.96% and −0.62% per year, respectively. In a larger dataset from the SIT Trial, we tested the hypothesis that the presence of SCI, after adjustment for established risk factors for SCI in the same SIT cohort and observation when compared to regular blood transfusion therapy will be associated with progressive brain volume loss. The SIT Trial is registered at www.clinicaltrials.gov (Unique identifier: NCT00072761). As previously described, 196 children with SCA between 5-15 years with SCI, and no history of strokes, with normal or conditional TCD measurements, were enrolled and followed for a median period of 3 years.1 Data from a subset of the SIT Trial participants (n = 169) with T1-weighted brain MRIs at study entry and exit, were analyzed to determine longitudinal brain volume percent change. We performed a multivariable analysis to identify predictors of brain volume change. Longitudinal brain volume percent change was calculated from T1-weighted structural brain MRIs using the automated image analysis program SIENA, from the FMRIB Software Library (www.fmrib.ox.ac.uk/fsl), which has a reported error of 0.15%.4, 5 SIENA tool estimates volume change between 2 time points based on elastic spatial registration of skull mask at the second time point to the initial time point. This assumes the skull size to be stable over time. Direct segmentation-based volume change measurements may be less accurate (eg, SIENAX that utilizes this strategy has a reported error of 0.5%-1%).5 We elected to use SIENA for more consistent results. The analysis includes 157 SIT Trial participants randomly allocated with paired brain MRIs and complete demographic and clinical information for the multivariable analysis. The clinical characteristics of the participants include 44.6% (70 of 157) having received regular blood transfusion with a goal to keep maximum hemoglobin S percent less than 30% (Supporting Information Tables S1a and b). A significant correlation was identified between the brain volume percent change and age at randomization (P < 0.001) (Figure 1). The average brain volume percent change over a mean follow-up period of 3.4 years was −2.8% (−0.79% per year). To assess the effect of missing data because participants did not have both evaluable entry and exit MRIs, or key missing covariate data, those included and excluded from the analysis were compared on the relevant variables (see Supporting Table S2). No differences were found between the two groups. Variables for the multivariable regression were selected based on previously identified risk factors for SCI or other risk factors that could potentially affect cerebral oxygen delivery: sex, age at study entry, white blood cell count, hemoglobin F percent, reticulocyte count, systolic blood pressure, baseline oxygen saturation, retrospective pain and acute chest syndrome rate. We used actual transfusion status, including crossovers of participants randomly allocated to observation, but receiving regular transfusion or vice versa. Additional models were calculated for the change in white and gray matter using the same set of covariates, plus baseline white or gray matter volume, respectively, and the same model-building methodology (see Supplementary Tables S4 and S5). Analyses were conducted using IBM SPSS Statistics (Version 24, IBM, Armonk, NY), and Stata version 14.2 (Stata Corp., College Station, TX). The primary results of our study revealed progressive brain volume percent loss in children with SCA and SCI. An initial screening multivariable regression model for percent brain volume change revealed that age met criteria for inclusion in a final model, as did sex, baseline oxygen saturation, systolic blood pressure, and transfusion status in the SIT Trial. In the reduced model, with only covariates with a p value <0.2 from the screening model, only age was significantly associated with brain volume percent decrease (−0.46, 95% CI −0.62 to −0.31, P < .001) (Supplementary Tables S3 and S6). In the SIT Trial there was a sequence transition from the standard T1 MRI to a 3D T1 to provide better anatomical information. During the trial 3 different paired combinations of T1-weighted brain MRI sequences were used at study entry and exit: T1 and T1, T1 and 3D T1, and 3D T1 and 3D T1. However, we found no significant difference in the brain volume percent loss between these 3 different paired imaging sequences used in the study (P = 0.378; Supplementary Table S7). Our study is at least 5 times larger than the 2 prior studies, allowing for a multivariable evaluation for interrogation of postulated risk factors associated with brain volume percent loss in SCA. In a study of 28 children with SCA and 28 healthy age-, and sex-matched controls, Chen et al. showed significant age-related decrease in gray matter volume in children with SCA, without SCI status being noted.6 The study by Kawadler et al. evaluated 32 participants in the SIT Trial cohort.3 However, her team used an alternative strategy for measuring brain volume percent change. Further, the analysis was too small to include multivariable regression and the univariate analysis did not demonstrate any benefit in blood transfusion therapy for decrease in brain volume when compared to no transfusion therapy. Limitations of our analysis include lack of comparison group of non-SCI SCA and non-SCA controls. In summary, the current and two prior studies3, 6 provide compelling evidence that children with SCA have progressive brain volume loss with age. Our study is the only 1 of 3 that could assess the impact of regular blood transfusion, and we did not find any evidence that regular blood transfusion therapy prevented brain volume percent loss. A larger longitudinal study is required to address the impact of this decrease in brain volume on cognition, education attainment, and tangible patient-centered outcomes in both children and adults with and without SCA. Supported by grants from the National Institute of Neurological Disorders and Stroke (5U01NS042804, 3U01NS042804 [American Recovery Reinvestment ACT supplementary grant] to Dr. DeBaun) Vanderbilt CTSA. The authors declare that they have no conflicts of interest with the contents of this article. All authors read and approved the final version of the article. Designed the study: DSD, OEM, MRD. Analyzed the data: OEM, MRP, MVM, MJR, RM, MRD. Wrote the article: DSD, OEM, JFC, MJR, MRD, MRP, RM, MVM. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.