Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease

Guilliams, Kristin P.; Fields, Melanie E.; Dowling, Michael M.

doi:10.1161/strokeaha.118.020482

Cited by 31 publications

(54 citation statements)

References 94 publications

(101 reference statements)

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“…4,8,31 MRA Vasculopathy on MRA has various definitions, and there are few data on prevalence in unselected children with SCA with normal neurology by history and examination. 16 The prevalence of MRAdetected stenosis (grade 2 vasculopathy) in this study was 7%, slightly lower than the prevalence of stenosis (10% to 15%) in previous studies of children without prior stroke 3,32 and much lower than the reported 33% to 55% prevalence of stenosis in children with stroke and abnormal TCD. 27,33 In a study using the same definitions in children without previous stroke, 18 the overall prevalence of vasculopathy on MRA was 64%, compared with 18% in the current study.…”

Section: Mricontrasting

confidence: 76%

“…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%

“…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. We also hypothesized that clinical events and laboratory markers of anemia (e.g., hemoglobin), hemolysis (e.g., reticulocyte count, indirect bilirubin), and hypoxic exposure (e.g., low arterial oxygen content) 16,20 would predict SCI and vasculopathy. We specifically studied (1) prevalence of SCI and vasculopathy; (2) comparison between presence of SCI and age, sex, clinical variables, CBFV on TCD, laboratory variables at the time of and before MRI, and presence of intracranial vasculopathy on MRA; and (3) comparison between presence of vasculopathy on MRA and CBFV on TCD and laboratory variables at the time of and before MRI.…”

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: 76%

Section: Introductionmentioning

confidence: 99%

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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“…The distribution of SCI is similar, with up to 90% of SCI reportedly occurring in a relatively small deep watershed white matter region, encompassing only 5.6% of brain volume (31). SCI and overt ischemic stroke are often indistinguishable on MRI (32), and several authors have suggested that it may be differences in lesion size and location, rather than underlying physiological mechanism, that determines whether an ischemic insult is accompanied by focal symptoms (ischemic stroke) or goes undetected [SCI; (33)].…”

Section: Stroke and Cerebrovascular Diseasementioning

confidence: 99%

“…Both in addition to, and in the absence of, overt stroke and SCI, vasculopathy on MR angiography (MRA) is common in SCD patients (32). Although vasculopathy definitions have varied considerably between studies, intra- and extra- cranial steno-occlusive arteriopathy, often involving the distal internal carotid and the proximal anterior and middle cerebral arteries, are frequently reported, particularly in patients with overt ischemic stroke (34, 35), and SCI (24).…”

Section: Stroke and Cerebrovascular Diseasementioning

confidence: 99%

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

et al. 2019

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It is well-established that patients with sickle cell disease (SCD) are at substantial risk of neurological complications, including overt and silent stroke, microstructural injury, and cognitive difficulties. Yet the underlying mechanisms remain poorly understood, partly because findings have largely been considered in isolation. Here, we review mechanistic pathways for which there is accumulating evidence and propose an integrative systems-biology framework for understanding neurological risk. Drawing upon work from other vascular beds in SCD, as well as the wider stroke literature, we propose that macro-circulatory hyper-perfusion, regions of relative micro-circulatory hypo-perfusion, and an exhaustion of cerebral reserve mechanisms, together lead to a state of cerebral vascular instability. We suggest that in this state, tissue oxygen supply is fragile and easily perturbed by changes in clinical condition, with the potential for stroke and/or microstructural injury if metabolic demand exceeds tissue oxygenation. This framework brings together recent developments in the field, highlights outstanding questions, and offers a first step toward a linking pathophysiological explanation of neurological risk that may help inform future screening and treatment strategies.

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Changes in indicators of cerebral metabolic stress following treatment with voxelotor in children and adolescents with sickle cell anemia

Heitzer,

Zou,

Hodges

et al. 2024

eJHaem

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Voxelotor is a small molecule that reduces the polymerization of sickle hemoglobin by increasing its affinity for oxygen. In patients with sickle cell anemia, it has been postulated that increasing hemoglobin‐oxygen affinity could limit oxygen offloading from hemoglobin, causing an increase in cerebral metabolic stress. To investigate this hypothetical concern, we used multimodal brain imaging to define the effects of voxelotor on cerebral blood flow and oxygen extraction. We followed four patients for 2–5 months during and/or after voxelotor therapy. This study showed no observable increase in cerebral blood flow or oxygen extraction fraction during treatment.

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Advances in Understanding Ischemic Stroke Physiology and the Impact of Vasculopathy in Children With Sickle Cell Disease

Cited by 31 publications

References 94 publications

Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

Cerebral Infarcts and Vasculopathy in Tanzanian Children With Sickle Cell Anemia

Vascular Instability and Neurological Morbidity in Sickle Cell Disease: An Integrative Framework

Changes in indicators of cerebral metabolic stress following treatment with voxelotor in children and adolescents with sickle cell anemia

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