Transcranial Doppler and Magnetic Resonance in Tanzanian Children With Sickle Cell Disease

Kija, Edward; Saunders, Dawn; Munubhi, Emmanuel; Darekar, Angela; Barker, Simon; Cox, Timothy C.; Mango, Mechris; Soka, Deogratius; Komba, Joyce; Nkya, Deogratias A.; Cox, Sharon; Kirkham, Fenella J.; Newton, Charles R.

doi:10.1161/strokeaha.118.018920

Cited by 19 publications

(33 citation statements)

References 30 publications

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“…18 The association with indirect bilirubin as well as reticulocytosis suggests that the hemolytic rate is important, although reticulocytosis may also be related to erythropoiesis in response to chronic anemia and hypoxemia. 18 Abnormal CBFV (!200 cm/s) appears to be much less common in this study and other East African cohorts 15,23 than the 10% reported in studies from the United States, where the majority of people with SCD are of West African origin. Differences in mechanisms of vascular injury in patients with SCD residing in East Africa compared with those residing in Europe or the United States may be due to differences in genetics (e.g., haplotypes), burden of infection, environmental exposures including nutrition, and access to quality health care.…”

Section: Mricontrasting

confidence: 74%

“…The small proportion of patient with CBFV !200 cm/s could also be related to a more rapid progression of arteriopathy in East African patients. 15 In this study of asymptomatic children with SCD, those with non-normal TCD were not significantly more likely to have intracranial vasculopathy on MRA, whereas in children with stroke, Helton et al 31 found higher rates of and more severe intracranial stenosis on MRA if TCD showed low or uninterpretable MCA velocities. Those with non-normal TCD with normal intracranial MRA might have extracranial vasculopathy; future studies should include MRA of the carotid and vertebral arteries in the neck.…”

Section: Mrimentioning

confidence: 59%

“…Among 49 of 67 patients who also had brain magnetic resonance imaging (MRI), 14% had stroke and 29% had SCI. 15 However, little is known on the prevalence of vasculopathy on magnetic resonance angiography (MRA) in asymptomatic patients with SCA anywhere in the world 16 and there are few data on any association with SCI, TCD measures, 17 or previous exposure to hemolysis or hypoxia. 18,19 We hypothesized that vasculopathy, detected by MRA and TCD, would be more common in neurologically asymptomatic children with SCA and adolescents with SCI.…”

Section: Introductionmentioning

confidence: 99%

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Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

Jacob

Saunders

Sangeda

et al. 2020

Pediatric Neurology

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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.

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Section: Mricontrasting

confidence: 74%

Section: Mrimentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

Jacob

Saunders

Sangeda

et al. 2020

Pediatric Neurology

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Genetic modifiers of long‐term survival in sickle cell anemia

Wonkam

Chimusa

Mnika

et al. 2020

Clinical & Translational Med

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Background Sickle cell anemia (SCA) is a clinically heterogeneous, monogenic disorder. Medical care has less‐than‐optimal impact on clinical outcomes in SCA in Africa due to several factors, including patient accessibility, poor access to resources, and non‐availability of specific effective interventions for SCA. Methods Against this background, we investigated 192 African participants who underwent whole exome sequencing. Participants included 105 SCA patients spanning variable clinical expression: a “long survivor” group (age over 40 years), a “stroke” group (at least one episode of overt stroke), and a “random” group (patients younger than 40 years without overt cerebrovascular disease). Fifty‐eight ethnically matched homozygous hemoglobin A controls were also studied. Findings were validated in an independently recruited sample of 29 SCA patients. Statistical significance of the mutational burden of deleterious and loss‐of‐function variants per gene against a null model was estimated for each group, and gene‐set association tests were conducted to test differences between groups. Results In the “long survivor” group, deleterious/loss‐of‐function variants were enriched in genes including CLCN6 (a voltage‐dependent chloride channel for which rare deleterious variants have been associated with lower blood pressure) and OGHDL (important in arginine metabolism, which is a therapeutic target in SCA). In the “stroke” group, significant genes implicated were associated with increased activity of the blood coagulation cascade and increased complement activation, for example, SERPINC1, which encodes antithrombin. Oxidative stress and glutamate biosynthesis pathways were enriched in “long survivors” group. Published transcriptomic evidence provides functional support for the role of the identified pathways. Conclusions This study provides new gene sets that contribute to variability in clinical expression of SCA. Identified genes and pathways suggest new avenues for other interventions.

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“…4 Three-quarters of the SCA disease burden is in Africa, and Tanzania is ranked fourth globally. 5 We have been screening for stroke risk using TCD ultrasonography at Muhimbili hospital since 2004. In a study of 200 patients undergoing TCD ultrasonography, of whom 60 with TCD abnormalities had MRI scans, the prevalence of stroke was 11.5% and the presence of SCI was 37% (verbal communication).…”

Section: Background Sickle Cell Anemia Neurologic Complicationsmentioning

confidence: 99%