Silent Cerebral Infarcts in Sickle Cell Anemia: A Risk Factor Analysis

Kinney, Thomas R.; Sleeper, Lynn A.; Wang, Winfred C.; Zimmerman, Robert A.; Pegelow, Charles H.; Ohene‐Frempong, Kwaku; Wethers, Doris L.; Bello, Jacqueline A.; Vichinsky, Elliott; Moser, Franklin G.; Gallagher, Dianne; DeBaun, Michael R.; Platt, Orah S.; Miller, Scott T.

doi:10.1542/peds.103.3.640

Cited by 282 publications

(201 citation statements)

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“…12 In the CSSCD study, several variables, including seizure history, pain event rate, lower hemoglobin, high WBC, elevated pocked red blood cell counts, and SEN ␤-S globin gene haplotype (a measure of reduced splenic function), were associated in univariate analysis; however, only seizure history, low pain rate, higher WBC, and the presence of a SEN ␤-S globin gene haplotype were associated with risk of SCI in the final multivariable analysis. 12 Several possible explanations exist to explain the differences between the current and previous studies. First, the current study has greater than 6 times more participants with SCI.…”

Section: Discussionmentioning

confidence: 99%

“…In the most rigorous study to date, the investigators from the Cooperative Study for Sickle Cell Disease (CSSCD) described risk factors associated with SCI in 42 participants, comparing them with 188 controls with normal MRI. 12 In the final multivariable analysis, the authors found that SCI was associated with history of seizure, a relatively low frequency of pain episodes, and an elevated white blood cell (WBC) count. Elevated systolic blood pressure (SBP) measurement was not associated with SCI; however, this analysis of CSSCD data had several limitations, including misclassifications of SCI that were corrected in a subsequent evaluation 6 and a relatively small number of participants with SCI, compared with the current study.…”

Section: Introductionmentioning

confidence: 99%

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Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

DeBaun

Sarnaik

Rodeghier³

et al. 2012

Blood

190

144

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The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbS␤°thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P ‫؍‬ .018), and male sex (P ‫؍‬ .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761. IntroductionSilent cerebral infarcts (SCIs) have been recognized by neuroimaging in neurologically normal older adult populations since 1981 1 and were documented in sickle cell anemia (SCA) soon afterward. 2 As with overt stroke, SCIs represent a clinical finding that is common in older adults without SCD, but they appear during early childhood in persons with SCA. SCIs are defined as an MRI signal abnormality visible on 2 views on the T2-weighted images (axial and coronal) that must measure at least 3 mm in one dimension; further, the person deemed to have an SCI must have an absence of focal neurologic deficit compatible with the anatomic location of the brain lesion. 3 SCI is the most common form of neurologic injury among children with SCA, occurring in at least 27% before 6 years of life 4 and 37% by 14 years of life. 5 SCIs in children with SCA are associated with increased risk of future overt strokes and new or progressive SCIs. 6,7 In addition, children with SCA and SCI have been found to have poorer cognitive function The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 3684BLOOD, 19 APRIL 2012 ⅐ VOLUME 119, NUMBER 16For personal use only. on March 28, 2019. by guest www.bloodjournal.org From than children with SCA with normal MRI of the brain 8-10 or sibling controls. 10,11 Clinical and laboratory risk factors for SCI have been evaluated only sparingly. In the most rigorous study to date, the investigators from the Cooperative Study for Sickle Cell Disease (CSSCD) described risk factors associated with SCI in 42 participants, comparing them with 188 controls with ...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

DeBaun

Sarnaik

Rodeghier³

et al. 2012

Blood

190

144

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“…Stroke and silent cerebral infarction were unrelated to the clinical, hematologic, and HbF response to HU. In HU treated patients followed for 17.5 years, the incidence of stroke did not decrease [3,25,26]. HU did not prevent secondary stroke in children with SCD when transfusions therapy was switched to HU.…”

Section: E262mentioning

confidence: 99%

Cerebrovascular events in sickle cell‐beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians

et al. 2013

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Stroke is a common cause of morbidity and mortality in sickle cell disease (SCD) and silent cerebral infarction is the most common form of neurologic injury. The frequency and risk factors for new silent cerebral infarction are incompletely understood. Moreover, no recommended treatment has been established. Although hydroxyurea (HU) is recommended for SCD, concerns remain regarding its role in the prevention of cerebrovascular events, including silent cerebral infarction. A single center population of 104 Italian patients with HbS-ß thalassemia treated with HU has been followed for a mean of 11 years. Clinical evaluation and brain imaging by Magnetic Resonance Imaging were done before and during HU treatment. During follow-up, the number of sickle cell crises (86%, 7.8 6 6.9 vs. 1.2 6 0.5 per year, P < 0.0001), hospitalizations (2.5 6 2.9 vs. 0.3 6 1.5 per year, P < 0.0001), and days in the hospital (22.4 6 21.9 vs. 0.361.5 per year, P < 0.0001) decreased significantly and HbF increased from a mean of 8-20.8%. Cerebral infarcts occurred in 37.5% of patients. Among these, 6.7% had overt strokes, while 30% had new or progressive silent cerebral infarction. Stroke and silent cerebral infarction were not related to clinical hematologic or HbF response to HU. These findings suggest that in adults, HU treatment does not prevent new cerebrovascular events or the progression of existent silent cerebral infarcts in HbS-b thalassemia. A major benefit of HU is the increase in HbF; the association of high HbF and reduced cerebrovascular disease has been weak. New treatment strategies should be developed for the prevention of sickle cerebrovascular disease. Am. J. Hematol. 88:E261-E264,

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“…By 8 years of age, up to one third of children with SCA show evidence of cerebral infarction on magnetic resonance imaging (MRI). [1][2][3] Of these, 12% have overt stroke, and 22% have silent lesions on MRI. Most strokes in children with SCA (symptomatic or asymptomatic) are the result of infarction; intracranial hemorrhage becomes more common later in life.…”

Section: Introductionmentioning

confidence: 99%

Distinct HLA associations by stroke subtype in children with sickle cell anemia

Hoppe¹,

Klitz²,

Noble³

et al. 2003

Blood

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Children with sickle cell anemia (SCA) carry a 200-fold increased risk for cerebral infarction. Stroke can be the result of small-vessel (SV) or large-vessel (LV) disease. However, it is unknown whether these subtypes result from the same pathophysiologic processes. Complete HLA genotyping was performed on 231 eligible children previously enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cerebral infarction on magnetic resonance imaging (MRI) was documented in 71 patients, and 160 patients had negative findings on MRI. Based on MRI/magnetic resonance angiography (MRA) findings, infarct size, and location, 36 patients were classified as having LV stroke and 35 as having SV stroke. When comparing the total MRI؉ group with the MRI؊ group, HLA DPB1*0401 was associated with increased stroke risk (P ‫؍‬ .01), whereas DPB1*1701 (P ‫؍‬ .02) conferred protection from stroke. These DPB1 associations with stroke were attributed to the SV stroke group, in whom DPB1*0401 was associated with susceptibility (P ‫؍‬ .003) and DPB1*1701 with protection from stroke (P ‫؍‬ .06). In the LV stroke subgroup, HLA-A*0102 (P ‫؍‬ .02) and -A*2612 (P ‫؍‬ .007) conferred susceptibility, whereas -A*3301(P ‫؍‬ .04) protected from stroke. These results suggest that specific HLA alleles influence stroke risk and appear to contribute differently to SV and LV stroke subtypes. The distinct HLA associations with SV and LV stroke suggest that different pathologic processes may be involved in the development of stroke in children with SCA. If these results are confirmed in a larger study, HLA type may serve as a useful marker for the early identification of SCA patients at high risk for stroke. (Blood. 2003;

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Silent Cerebral Infarcts in Sickle Cell Anemia: A Risk Factor Analysis

Abstract: Patients with risk factors for silent infarcts should be evaluated for cerebrovascular disease. If evidence of infarction is found, consideration must be given to therapeutic intervention. At present, the appropriate treatment has not been determined.

Cited by 282 publications

References 21 publications

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin, sex, and relative high systolic blood pressure

Cerebrovascular events in sickle cell‐beta thalassemia treated with hydroxyurea: A single center prospective survey in adult Italians

Distinct HLA associations by stroke subtype in children with sickle cell anemia

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