Moyamoya Disease Predicts Progression of Cerebral Vasculopathy in Patients with Sickle Cell Disease Despite Chronic Transfusion Therapy

Introduction: Patients with sickle cell disease (SCD) develop multi-organ complications due to hemolysis, inflammation, and vascular occlusion that results in small vessel obstruction throughout the body.  In the brain, however, large cerebral vessels are also damaged resulting in occlusion or stenosis and subsequent development of abnormal collateral vasculature and moyamoya disease. Chronic red cell transfusion (CRCT) therapy significantly reduces the risk of stroke in children with abnormal transcranial doppler (TCD) studies and is also effective in reducing stroke recurrence in those with a history of overt or silent stroke; however, it is unclear if CRCT halts or reverses the progression of vasculopathy.  The present study evaluated cerebrovascular stenosis and moya moya disease as risk factors for progression of vasculopathy over time in a cohort of patients with SCD who were started on CRCT therapy as children for stroke prevention.

Methods: A retrospective cohort study (with IRB approval) was used to evaluate cerebrovascular changes in patients on CRCT.  Patients were included in the study if they had received CRCT for stroke prevention for at least 12 months and had at least two serial magnetic resonance imaging and angiography (MRI/MRA) studies for review. For the imaging analysis, the patient’s MRI/MRA closest to the initiation of CRCT (i.e. baseline imaging) was compared to the most recent imaging available by a neuro radiologist who was blind to the patient’s clinical history. Additional demographic information included the patient’s current age, gender, indication for CRCT, years on CRCT, and laboratory results for pre-transfusion % hemoglobin S (HbS).

Results: Forty patients with SCD (current age: M = 16.48, SD = 5.10; 23 male, 17 female) were included. Average duration of CRCT therapy was 9.96 years (SD = 5.67) and average pre-transfusion HbS levels were 42.52% (SD = 9.88). Patients were initiated on therapy due to: overt stroke (n = 19), silent stroke (n = 2), and abnormal TCD (n = 20). Of the 20 patients initiated on therapy due to abnormal TCD, 7 were found to have abnormal MRI at baseline consistent with silent stroke. One of these patients was also found to have co-occurring moyamoya disease, despite no evidence of prior overt stroke. At baseline, 45% (n = 18) of patients had abnormal MRA and 25% (n = 10) had moyamoya disease. Progression of vasculopathy occurred in 15% (n = 6) of patients, all of whom had a history of moya moya disease at baseline (5 patients with overt stroke and 1 with silent stroke). Of the remaining 3 patients with moya moya disease at baseline, 2 remained stable with no improvement and 1 demonstrated improvement on MRA. For patients with abnormal MRA, but no history of moya moya disease (n = 9), 5 demonstrated improvement (2 patients with silent stroke and 3 with overt stroke).

Conclusions: Progression of vasculopathy was common among patients with baseline moyamoya disease despite CRCT. Also notable, however, was improvement in vasculopathy (as defined by reduction of stenosis) in 6 patients, the majority of whom had not developed moyamoya prior to the initiation of CRCT suggesting that more mild vasculopathy can be reversed with early intervention. Patients with moya moya disease warrant ongoing annual assessment as they may require vascular bypass to prevent further worsening. Future large, multi-site investigations are needed to identify improved biomarkers and further understand characteristics of patients who demonstrate improvement versus progression of vasculopathy on CRCT.