Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

Abstract

Background: Cerebral infarcts and vasculopathy in neurologically asymptomatic children with sickle cell anemia (SCA) have received little attention in African settings. This study aimed to establish the prevalence of silent cerebral infarcts (SCI) and vasculopathy and determine associations with exposure to chronic hemolysis, anemia, and hypoxia. Methods: We prospectively studied 224 children with SCA with transcranial Doppler (TCD), and magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA). Regressions were undertaken with contemporaneous hemoglobin, reticulocyte count, mean prior hemoglobin, oxygen content, reticulocyte count, and indirect bilirubin. Results: Prevalence of SCI was 27% (61 of 224); cerebral blood flow velocity was abnormal (>200 cm/s) in three and conditional (>170<200 cm/s) in one. Vasculopathy grades 2 (stenosis) and 3 (occlusion) occurred in 16 (7%) and two (1%), respectively; none had grade 4 (moyamoya). SCI was associated with vasculopathy on MRA (odds ratio 2.68; 95% confidence intervals [95% CI] 1.32 to 5.46; P ¼ 0.007) and mean prior indirect bilirubin (odds ratio 1.02, 95% CI 1.00 to 1.03, P ¼ 0.024; n ¼ 83) but not age, sex, nonnormal TCD, or contemporaneous hemoglobin. Vasculopathy was associated with mean prior values for hemoglobin (odds ratio 0.33, 95% CI 0.16 to 0.69, P ¼ 0.003; n ¼ 87), oxygen content (odds ratio 0.43, 95% CI 0.25 to 0.74, P ¼ 0.003), reticulocytes (odds ratio 1.20, 95% CI 1.01-1.42, P ¼ 0.041; n ¼ 77), and indirect bilirubin (odds ratio 1.02, 95% CI 1.01 to 1.04, P ¼ 0.009). Conclusions: SCI and vasculopathy on MRA are common in neurologically asymptomatic children with SCA living in Africa, even when TCD is normal. Children with vasculopathy on MRA are at increased risk of SCI. Longitudinal exposure to anemia, hypoxia, and hemolysis appear to be risk factors for vasculopathy.

Association of alpha‐thalassemia and Glucose‐6‐Phosphate Dehydrogenase deficiency with transcranial Doppler ultrasonography in Nigerian children with sickle cell anemia

“…In contrast to our study, abnormal TCD measured according to STOP protocol did not show association with alpha‐thalassemia trait in the Tanzanian children with sickle cell anemia but confirmed protective effect of alpha‐thalassemia against abnormally low cerebral blood flow velocity 15 . It is likely that the higher frequency of alpha‐thalassemia trait in the Tanzanian cohort, which is linked with the Bantu β‐globin haplotype accounts for the lower prevalence of abnormal TCD 15,33 . Meanwhile, higher prevalence of 10–16% abnormal TCD has been reported in other studies 3,14 …”

MRI detection of brain abnormality in sickle cell disease

“…Anterior cerebral circulation vasculopathy is well recognized in patients with stroke in the context of SCD on digital subtraction contrast angiography [41], which shows the anatomy of the vessel wall. MRA may also visualize abnormal vessels [9][10][11]13,35,[42][43][44][45], although this depends on disturbance to vessel flow or 'turbulence.' Data from non-sickle pediatric stroke suggest that large vessel disease is detected by MRA as well as digital subtraction angiography [46].…”

“…Despite these concerns, MRA is used in protocols for screening asymptomatic patients as it is noninvasive. For MRA of the intracranial vessels, signal dropout in the distal internal carotid artery (ICA) and the proximal middle (MCA) and anterior cerebral arteries (ACA) is typical (Figure 5) [9][10][11]13,35,[42][43][44][45]. Occlusion may be associated with the development of bypassing collateral vessels, known as moyamoya (Figure 2D), from the Japanese expression describing the angiogram appearing like a 'puff of smoke' [49].…”

“…Although this allows understanding in the context of previous experience with digital subtraction angiography, unless surgery is contemplated, this invasive imaging technique is rarely used now for ischemic stroke, even in symptomatic patients with SCD, so there are few data for comparison. Alternatively, signal dropout or turbulence on MRA may be graded as none (grade 0), mild (grade 1), moderate (grade 2), or severe with or without collaterals (grade 3) ( Figure 5 ) [ 11 , 13 , 24 , 45 ], or even as normal or abnormal [ 35 ]. The available data suggest that even mild abnormality is associated with tissue compromise [ 24 , 35 ]; this may be a useful research strategy given that studies comparing MRA with digital subtraction angiography would be unethical in asymptomatic patients.…”

“…Since the mid-1980s, magnetic resonance imaging (MRI) has been used to investigate brain pathology in SCD patients presenting with acute neurological symptoms and signs, in emergency and rehabilitation settings, and in observational cohort studies [1]. Techniques used clinically include T1-, T2-fluid attenuated inversion recovery (T2-FLAIR), T2*, susceptibility and diffusion weighted MRI, and time-of-flight angiography (MRA) and venography (MRV) (Table 1, Figure 1) The imaging has typically been interpreted qualitatively by neuroradiologists with variable degrees of specific training, using a number of different grading schemes and rating scales for MRI and MRA [5][6][7][8][9][10][11][12][13]. More recently, structural and hemodynamic quantitative approaches, including T1, diffusion, perfusion, quantitative susceptibility mapping (QSM), and functional MRI (Figure 1), in humans and in animal models of SCD interpreted by neuroscientists have allowed insight into potential mechanisms of neurological and neurocognitive compromise (Figure 1) [4,[14][15][16].…”