Higher-than-expected prevalence of silent cerebral infarcts in children with hemoglobin SC disease

To the editor:

Individuals with hemoglobin (Hb) SC disease have fewer vaso-occlusive events and greater life expectancy than those with Hb SS, and they have been excluded from most interventional clinical trials. Although the 10% prevalence of overt stroke and >35% prevalence of silent cerebral infarctions (SCIs) in Hb SS disease is well described, less is known about neurologic complications in children with Hb SC. We sought to determine the prevalence of SCIs in our cohort of 96 children with Hb SC disease. In this cohort, the prevalence of SCIs was 13.5%, much higher than expected based on the Cooperative Study of Sickle Cell Disease (CSSCD).¹ 

We identified all children with Hb SC or Hb SS, ages 6 to 21 years, at our institution between January 2004 and May 2012. In 2006, our institution began screening all children at least 6 years of age with sickle cell disease for SCIs, regardless of neurologic symptoms. Clinical magnetic resonance imaging (MRI) data or magnetic resonance angiograms were available in 96/123 children with Hb SC and 168/181 children with Hb SS. Children ages 6 years and older without an MRI were excluded from analysis. MRIs were performed on 1.5 T or 3 T Siemens MRI scanners, with standard sagittal T1, axial and coronal fluid-attenuated inversion recovery (FLAIR), axial T2 turbo spin echo, susceptibility-weighted and 12-direction diffusion-weighted sequences. Cerebral infarctions were defined as T2- or FLAIR-weighted hyperintensities at least 3 mm in diameter, identified in 2 planes.²  All reports were reviewed, and one investigator (K.P.G.) reviewed all images with possible SCIs noted in the report. Documented absence of neurologic symptoms that correlated with lesion location in the medical record qualified a lesion as an SCI. Lesion characteristics were compared with a Pearson’s χ² or Fisher’s exact test.

SCIs were found in 13/96 (13.5%) children with Hb SC, with a median age of 12.2 years (range, 6.2-19.3 years). No children with Hb SC had overt strokes. In contrast, 72/168 children with Hb SS disease (42.9%) had cerebral infarction: 5/168 (3.0%) had a history of overt strokes without SCIs, 21/168 (12.5%) had overt strokes plus SCIs, and 46 (27.4%) had SCIs only. Infarct lesion location and number were similar between children with Hb SC and Hb SS (Table 1).

In this retrospective cohort of 96 children with Hb SC, SCI prevalence was 13.5%, more than double the 5.8% (7/120) prevalence reported in the CSSCD.¹  Although children with Hb SC typically have fewer disease manifestations than those with Hb SS, this rate of potentially unnoticed brain injury appears to be higher than incidental white matter lesions in children with migraine (6% to 10%)³  or healthy children (1.3%).⁴  In our Hb SS comparison group, the SCI prevalence was comparable to recent cohorts,^2,5  indicating that our center is not biased toward SCI detection. The CSSCD used T1- and T2-weighted sequences on 0.6, 1, or 1.5 T MRI,⁶  as opposed to FLAIR sequences on 1.5 or 3 T MRI currently in clinical use. Therefore, greater SCI prevalence in recent reports^2,5  may be due in part to technological improvements.

The pathophysiology of SCIs is presumed to involve red blood cell (RBC) sickling and vaso-occlusion in small cerebral vessels based on postmortem examinations.⁷  Transient hypoperfusion, hypoxemia, anemia, and cerebral vasculopathy may also contribute,⁸  but the mechanisms of SCIs may differ between children with Hb SC and Hb SS. In people with sickle cell disease, blood viscosity is higher compared with controls, especially at higher hemoglobin concentration; reduced RBC deformability and increased RBC aggregate formation also contribute to vaso-occlusion.⁹  Higher baseline hemoglobin, and thus higher blood viscosity, in Hb SC may contribute to small-vessel occlusion in these children. In Hb SS, both overt strokes and SCIs are associated with more severe anemia, but overt strokes are rare in Hb SC. Perhaps in children with Hb SC, the higher hemoglobin concentration minimizes overt stroke risk but the accompanying viscosity increase predisposes to small-vessel occlusion and SCIs in a subset of patients. Investigations of cerebral blood flow and cerebral oxygen utilization may identify mechanisms of SCIs in children with Hb SC and Hb SS.

SCIs are correlated with decreased intellectual functioning and greater overt stroke risk in children with Hb SS, but their impact is unestablished in Hb SC. Likewise, there is no known treatment of SCIs in Hb SC. Although blood transfusion therapy reduces recurrence of SCIs and overt strokes in children with Hb SS,^2,10  the SCI recurrence risk in Hb SC is unknown. Furthermore, the risk-benefit balance of transfusion therapy in Hb SC is likely different than in Hb SS, given the absence of severe anemia and lower frequency of vaso-occlusive pain and hospitalizations in children with Hb SC. Therefore, transfusion therapy for children with Hb SC and SCIs cannot be advocated currently. Clinical risk factors, consequences, and potential treatments of SCIs in Hb SC should be investigated prospectively.