Silent Cerebral Infarcts in Children With Sickle Cell Anemia

Abstract

Source: Debaun MR, Sarnaik SA, Rodeghier MJ, et al. Associated risk factors for silent cerebral infarcts in sickle cell anemia: low baseline hemoglobin and relative high systolic blood pressure. Blood. Epub 2011 Nov 17; doi: 10.1182/blood-2011-05-349621Investigators from 29 clinical sites in the United States conducted the Silent Cerebral Infarct Transfusion (SIT) Trial to assess the risk factors for silent cerebral infarcts (SCI). In this cross-sectional study, children with sickle cell anemia (SCA) between the ages of 5 and 15 years with no history of overt stroke or seizures were evaluated with magnetic resonance imaging (MRI) of the brain to screen for SCI. SCI was radiographically defined as MRI signal abnormality measuring at least 3 mm on the T-2 weighted images judged by two of three neuroradiologists on a central review committee. SCI was determined to be truly silent by a central neurology committee’s review of the local neurologist’s examination and the patient’s MRI findings. Clinical history and baseline laboratory values were examined to determine potential risk factors for SCI.Study data were analyzed on 814 participants; the mean age of enrolled children was 9.1 years and 50.7% were male. SCIs were diagnosed in 30.8% (n=251) of study patients. In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P<.001), higher baseline systolic blood pressure (SBP) (P=.013), and male gender (P=.026) were all associated with a significantly increased risk of a SCI. The odds ratio for SCIs for patients with a hemoglobin less than 7.6 g/dl or SBP greater than 112 mm/Hg were 2.12 and 1.73, respectively. Those individuals who had both a hemoglobin less than 7.6 and SBP greater than 104 had the highest odds of a SCI. In addition, 83% (5 of 6) of patients who carried a diagnosis of hypertension had a higher rate of SCIs than the other study participants (P=.012).The investigators conclude that lower hemoglobin concentration and higher SBP are risk factors for SCI in children with SCA. Further research is needed to determine if interventions targeting these risk factors, such as hydroxyurea, blood transfusion therapy, or antihypertensive medications, can be effective in preventing SCIs.Dr Villella has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Although previous investigators have also identified SCIs in approximately one third of patients with SCA, this study is the first to identify a lower baseline hemoglobin and higher SBP as risk factors for SCI in a large multicenter setting.1–3 SCIs may be silent, but they are not benign. SCIs in children with SCA are associated with an increased risk of overt stroke as well as progressive SCIs.4 Additionally, SCIs are associated with poorer cognitive function and school performance as compared to children with SCA without SCIs as well as sibling controls.5–6 Even more concerning is the finding that cognitive function appears to worsen over time in children with SCA and SCIs.7 As children mature and develop into young adults, they may be silently losing IQ points. Indeed, a recent study showed that asymptomatic adults with SCA have significantly lower performance IQs as compared to matched controls.8These findings have important implications for all pediatric practitioners. Many children do not live in close proximity to a sickle cell center and therefore the responsibility of providing health maintenance for these children can fall onto the shoulders of the primary care giver. The American Academy of Pediatrics recommends that all children with SCA receive a thorough assessment of school attendance and performance with consideration for formal neurocognitive testing.9 MRI of the brain should also be considered for children struggling in school, although this remains controversial since a proven intervention to prevent or limit SCIs is lacking. Neurocognitive testing, however, can be extremely helpful in identifying cognitive deficiencies and helping the family and school to optimize the child’s learning environment.There is strong evidence that SCIs in children with SCA are common and associated with significant morbidity. Studies evaluating potential interventions are desperately needed. By identifying risk factors for SCI in this study, the investigators have uncovered potential therapeutic targets which may respond to interventions to decrease the proportion of sickle cells and thereby increase cerebral blood flow, such as hydroxyurea and chronic blood transfusion therapy, or decrease blood pressure through the use of antihypertensive medications. Thankfully, the investigators of the SIT trial are addressing this as well. Patients enrolled into SIT are randomized to receive chronic blood transfusion therapy or standard observation. Follow-up imaging and neurocognitive testing is then performed to ascertain whether chronic blood transfusion therapy can prevent progression of SCIs and stabilize cognitive function. We anxiously await the results.