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Hydroxycarbamide and white matter integrity in pediatric sickle cell disease

Year: 2019
Type: editorial
Abstract: Hydroxycarbamide, one of the few currently approved disease-modifying therapies for sickle cell disease (SCD), is associated with significantly lower rates of pain episodes, dactylitis, acute chest syndrome, and hospitalization in young children with SCD (Thornburg et al, 2012). Current guidelines recommend offering hydroxycarbamide therapy to children with the most common and severe form of SCD, hemoglobin SS, starting at 9 months of age (Yawn et al, 2014). Still, the efficacy of hydroxycarbamide with regards to neuroprotection in this population is inconclusive. Current studies support the use of hydroxycarbamide to maintain transcranial Doppler (TCD) velocities in children with SCD and a history of abnormal TCD velocities who have received one year of regular blood transfusion therapy, but do not support use for secondary stroke prevention in children with SCD and a history of stroke (Ware, Helms & SWiTCH Investigators, 2012; Ware et al, 2016). A recent meta-analysis of 7 studies documenting TCD measurements before and after hydroxycarbamide therapy in children with HbSS or HbSβ0 thalassemia offers additional support for a neuroprotective effect (DeBaun & Kirkham, 2016). An average decrease in TCD velocity of 25 cm/s was demonstrated after starting hydroxycarbamide therapy; TCD velocity decreases can be seen as soon as 3 months after initiating hydroxycarbamide therapy and are sustained for at least 36 months (DeBaun & Kirkham, 2016; Galadanci et al, 2018). Furthermore, hydroxycarbamide may reduce cerebral metabolic stress in treated patients with SCD in comparison to untreated patients with SCD by reducing cerebral oxygen extraction fraction levels (Fields et al, 2019). In this issue of the British Journal of Hematology, Kapustin et al (2019) showed significant differences in the white matter microstructural integrity of children with SCD treated with hydroxycarbamide in comparison to untreated children with SCD. White matter microstructure was assessed in children with hemoglobin SS ages 10–18 years and age-matched healthy controls with a specialized MRI sequence, diffusion tensor imaging (DTI), that characterizes the diffusion properties of water molecules. Cerebrovascular reactivity (CVR), the ability of cerebral arteries to dilate and increase cerebral blood flow, was assessed with a carbon dioxide challenge and blood-oxygen-level dependent (BOLD) MRI. Analyses utilized mean diffusivity (MD) histograms; MD is a DTI measure which represents the magnitude of water diffusion. Functionally, decreases in MD have been seen in gliosis and axonal injury. Decreased MD is an imaging marker for other neurovascular diseases with associated cognitive impairment (Zhou et al, 2008; Baykara et al, 2016). Differences in specific white matter mean histogram parameters, skew and kurtosis, were seen between the hydroxycarbamide treated group (n = 17) and the untreated SCD group (n = 10), findings suggestive of white matter injury in the untreated group. However, differences were not seen between the hydroxycarbamide treated group and the control group (n = 12). A significant relationship was also found between skew and kurtosis mean diffusivity histogram measures and CVR in healthy controls. This research group has previously shown that CVR was significantly reduced in children with SCD and that lower CVR in this population is associated with lower hematocrit levels and region-specific cortical thinning (Kim et al, 2016; Kosinski et al, 2017). Taken together, these findings suggest that reduced CVR is associated with changes in white matter seen in children with SCD and that the beneficial effects of hydroxycarbamide on anaemia may contribute to improvements in CVR and white matter microstructural integrity. In the setting of anaemia, the cerebral vasculature vasodilates to meet increased cerebral blood flow requirements. In SCD, the cerebral vasculature is chronically vasodilated and thus and has limited ability to vasodilate further in response to carbon dioxide. As hydroxycarbamide increases hemoglobin levels, improved oxygen carry capacity of blood should lessen the need for cerebral vasodilation and should logically improve CVR. Of note, no significant differences were seen in mean CVR between the hydroxycarbamide treated group and the untreated SCD group, though there was a trend towards significance. The authors attribute this lack of significance to statistical and group differences leading to underestimation of CVR, specifically small sample size, and in the group treated with hydroxycarbamide, higher rates of silent cerebral infarction (possibly indicating increased disease severity), and higher numbers of male participants (decreased cerebrovascular dilatory reserve in male patients with SCD, Gladwin et al, 2003). In addition, there is the remaining question of hydroxycarbamide treatment adherence; while the hydroxycarbamide treated group had significantly higher fetal hemoglobin levels and lower neutrophil counts than the untreated SCD group, parental reports or other measures of treatment compliance were not provided. Diffusion Tensor Imaging (DTI) has been applied previously in SCD using more typical methods to assess white matter integrity. Balci et al (2012) noted reduced fractional anisotropy values (attributed to axonal damage) and increased apparent diffusion coefficient values (attributed to loss of myelination) in participants with SCD in comparison to age- and sex-matched healthy control participants, specifically in the frontal, central, peri-ventricular, and gray matter areas of the brain. Sun et al (2012) reported decreased fractional anisotropy and increased diffusivity measures in SCD patients in comparison to normal controls in central areas of the brain, the corpus callosum and centrum semiovale. These white matter changes were seen in patients with SCD and standard clinical neuroimaging with no abnormalities. Most recently, Stotesbury et al (2018) showed correlations between a key measure of cognitive function, processing speed index scores, and various DTI measures, including fractional anisotropy, MD, radial diffusivity, and intracellular volume fraction. While Kapustin et al did not see significant differences in other DTI mean diffusivity parameters in their study (mean, median, other percentiles), their work supports the presence of subtle white matter brain injury in the pediatric SCD, expanding the scope of an advanced imaging technique, DTI, by identifying an association with CVR. With new curative and disease-modifying therapies in the pipeline for SCD, additional imaging techniques to quantify brain injury that correlate with clinical and cognitive measures are necessary to determine if these treatments offer adequate neuroprotection for this high-risk population. This article provides evidence that hydroxycarbamide may protect white matter pathways in children with SCD. While silent cerebral infarcts have been recognized to have salient cognitive effects, more subtle brain injury, particularly DTI abnormalities, have only recently been acknowledged to affect cognition in children with SCD (King et al, 2014; Stotesbury et al, 2018). Future studies with larger sample sizes could explore correlation of CVR and MD measures to cognitive test scores. Research investigating the impact of emerging therapies and treatments on CVR would allow further clarification of this imaging techniques as a measure of neurological function. Additional research using white matter microstructural integrity and CVR measures is needed to further vet these techniques before routine clinical application. Dr. Lance has National Institutes of Health funding, K23HL133455, to study MRI-based imaging methods and blood biomarkers of brain injury in children with sickle cell disease and neurodevelopmental disorders. Dr. Jordan had National Institutes of Health funding, R01NS096127, to study MRI-based novel imaging methods to identify children with sickle cell anaemia at high risk of infarct recurrence.
DOI: 10.1111/bjh.16252
Language: English
Subfield: Genetics
Field: Medicine
Open Access status: green
OpenAlex ID: W2990292475
Cites: 19
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Related to: 10