Burden of neurological and neurocognitive impairment in pediatric sickle cell anemia in Uganda (BRAIN SAFE): a cross-sectional study

Abstract

BackgroundChildren with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations in sub-Saharan Africa are limited.MethodsWe aimed to establish the frequency and types of pediatric brain injury in a cross-sectional study at a large SCA clinic in Kampala, Uganda in a randomly selected sample of 265 patients with HbSS ages 1–12 years. Brain injury was defined as one or more abnormality on standardized testing: neurocognitive impairment using an age-appropriate test battery, prior stroke by examination or transcranial Doppler (TCD) velocities associated with stroke risk in children with SCA (cerebral arterial time averaged mean maximum velocity ≥ 170 cm/second).ResultsMean age was 5.5 ± 2.9 years; 52.3% were male. Mean hemoglobin was 7.3 ± 1.01 g/dl; 76.4% had hemoglobin < 8.0 g/dl. Using established international standards, 14.7% were malnourished, and was more common in children ages 5–12. Overall, 57 (21.5%) subjects had one to three abnormal primary testing. Neurocognitive dysfunction was found in 27, while prior stroke was detected in 15 (5.7%). The most frequent abnormality was elevated TCD velocity 43 (18.1%), of which five (2.1%) were in the highest velocity range of abnormal. Only impaired neurocognitive dysfunction increased with age (OR 1.44, 95%CI 1.23–1.68), p < 0.001). In univariate models, malnutrition defined as wasting (weight-for-height ≤ −2SD), but not sex or hemoglobin, was modestly related to elevated TCD (OR 1.37, 95%CI 1.01–1.86, p = 0.04). In adjusted models, neurocognitive dysfunction was strongly related to prior stroke (OR 6.88, 95%CI 1.95–24.3, p = .003) and to abnormal TCD (OR 4.37, 95%CI 1.30, p = 0.02). In a subset of 81 subjects who were enriched for other abnormal results, magnetic resonance imaging and angiography (MRI/MRA) detected infarcts and/or arterial stenosis in 52%. Thirteen subjects (25%) with abnormal imaging had no other abnormalities detected.ConclusionsThe high frequency of neurocognitive impairment or other abnormal results describes a large burden of pediatric SCA brain disease in Uganda. Evaluation by any single modality would have underestimated the impact of SCA. Testing the impact of hydroxyurea or other available disease-modifying interventions for reducing or preventing SCA brain effects is warranted.

Burden of central nervous system complications in sickle cell disease: A systematic review and meta‐analysis

“…In total, 31% of the included studies were retrospective observational (10 of 32 studies), [18][19][20][21][22][23][24][25][26][27] 31% cross-sectional (10 studies), 16,[28][29][30][31][32][33][34][35][36] 28% prospective (9), 17,[37][38][39][40][41][42][43][44] and 9% randomized controlled trials (3). [45][46][47] Study size varied widely from 16 to 4485 individuals with SCD and CNS complications.…”

Genetic modifiers of long‐term survival in sickle cell anemia

“…In addition, we focused on overt stroke, without brain imaging than could have further substratified this phenotype as ischemic or hemorrhagic, and identified subclinical infarcts, that are also found in SCD in children in Africa. 36,37 These sub-classifications could have allowed differential exploration of genetic protective and pathophysiologic risk factors, for example, variants in genes in hemolysis pathways for ischemic stroke, and variants in genes of vasculopathy, hypertension, and connective tissues pathways for hemorrhagic stroke. However, it should be noted that our focus is on a severe event (overt stroke), not on silent subclinical events, which, by definition, do not represent severe clinical events.…”

“…The stroke group consisted of patients with overt stroke and would therefore not have captured patients with silent cerebrovascular events. In addition, we focused on overt stroke, without brain imaging than could have further sub‐stratified this phenotype as ischemic or hemorrhagic, and identified subclinical infarcts, that are also found in SCD in children in Africa 36,37 . These sub‐classifications could have allowed differential exploration of genetic protective and pathophysiologic risk factors, for example, variants in genes in hemolysis pathways for ischemic stroke, and variants in genes of vasculopathy, hypertension, and connective tissues pathways for hemorrhagic stroke.…”

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].…”