Silent Cerebral Infarct Pathophysiology Study in Sickle Cell Anemia Children By a Multimodal Approach

Context and objectives:

Infra clinical cerebral infarcts have emerged as a central problem in sickle cell anemia (SCA) since the effective reduction of clinical cerebral infarcts following systematic vasculopathy screening and prevention. They are found in up to 37% of SCA children at 14 years old, and correlate with neurocognitive deficit. The tendency of silent infarcts to occur in the border zone areas of the brain, mainly the deep subcortical white matter, highly suggests that they could be due to hypoperfusion or hypoxic events but no clear pathophysiological process has been demonstrated. The aim of this study was to better decipher the mechanisms involved in infra clinical cerebral injury by analyzing the determinants of cerebral oxygenation and perfusion at the microcirculatory level in children with SCA and without cerebral or cervical vasculopathy. We conducted a multimodal prospective pilot study combining conventional brain exploration and laboratory biomarkers as well as novel brain investigational tools such as Arterial Spin Labeling (ASL) perfusion Magnetic Resonance imaging (MRI) and brain Near Infra-Red Spectroscopy (NIRS).

Patients and Methods:

Following parental approval, children with SCA aged 5-17 years, with no past history of abnormal or conditional transcranial Doppler (TCD), at steady state (> 3 months from any vaso occlusive event, transfusion or infection) were enrolled in two investigating centers in Ile de France. Relevant medical history and biological parameters were recorded and all investigation was performed during an out-patient visit.

Results:

Fifty-nine SCA patients (11.4± 3.9 yrs) at steady state were included between February 2015 and August 2016. Eight (13%) children had infra clinical lesions on MRI (3-5 mm: n= 6; 5-15 mm: n=4; > 15mm: n=0), predominating in the middle cerebral artery border zone in five children. The two groups of patients with lesions (MRI⁺) and without lesions (MRI^-) were comparable in terms of age, hydroxycarbamide (HC) treatment, G6PD or alpha thalassemia status. Conversely, the MRI⁺ group had a lower annual VOC rate (0.2 ± 0.2 vs 0.7 ± 0.6/year, p< 0.05) and lower mean arterial pressure (76 ± 8 vs 83 ± 9mmHg, p< 0.05), hematocrit (23.0 ± 3.0 vs 25.3 ± 3.2 %, p < 0.05), RBC deformability (Elongation index: 0.44 ± 0.07 vs 0.50 ± 0.08, p < 0.05) but higher P selectin level (73.5 ± 21.7 vs 57.1 ± 20.7ng/mL, p < 0.05) and RBC aggregate strength (491 ± 236 vs 358 ± 190 s^-1, p < 0.05), when compared to the MRI- group.

ASL perfusion in all cerebral territories showed no major asymmetry. High ASL perfusion was significantly inversely correlated with Hb level, RBC deformability, cerebral oximetry, HbF level and blood viscosity. High ASL perfusion correlated positively with vasomotion, hemolysis markers (AST, LDH, absolute reticulocyte count), platelets, P-and E- selectin levels, RBC aggregate strength, neutrophil count. Furthermore and importantly, silent lesions in the right anterior border zone were associated with high ASL perfusion (p<0.05).

Discussion and conclusion:

Among this cohort of highly selected SCA children with no vasculopathy, we found a prevalence of infra clinical cerebral injury of 13.5%. Our results altogether suggest that marked hemolysis, anemia and hypoxia result in an increased compensatory cerebral perfusion, as well as endothelial lesions as evidenced by elevated E and P selectins. Our results comfort the hypothesis that infra clinical cerebral lesions in the border zone territories occur when the compensatory perfusion of the brain, which is increased at steady state, is unable to further adapt. Our results argue for early treatment of SCA children with marked hemolytic anemia to avoid cerebral injury in case of acute hypoxia, anemia or increased metabolic demand.