No abstract

Elevated OEF in the deep white matter identifies a signature of metabolically stressed brain tissue at increased stroke risk in pediatric patients with SCD. We propose that border zone physiology, exacerbated by chronic anemic hypoxia, explains the high risk in this region.

Blood transfusions are the mainstay of stroke prevention in pediatric sickle cell anemia (SCA), but the physiology conferring this benefit is unclear. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) are elevated in SCA, likely compensating for reduced arterial oxygen content (CaO). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO, thereby relieving cerebral oxygen metabolic stress. Twenty-one children with SCA receiving chronic transfusion therapy (CTT) underwent magnetic resonance imaging before and after exchange transfusions. Arterial spin labeling and asymmetric spin echo sequences measured CBF and OEF, respectively, which were compared pre- and posttransfusion. Volumes of tissue with OEF above successive thresholds (36%, 38%, and 40%), as a metric of regional metabolic stress, were compared pre- and posttransfusion. Transfusions increased hemoglobin (Hb; from 9.1 to 10.3 g/dL; < .001) and decreased Hb S (from 39.7% to 24.3%; < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; = .004) and OEF (from 34.4% to 31.2%; < .001). At all thresholds, transfusions reduced the volume of peak OEF found in the deep white matter, a location at high infarct risk in SCA ( < .001). Reduction of elevated CBF and OEF, both globally and regionally, suggests that CTT mitigates infarct risk in pediatric SCA by relieving cerebral metabolic stress at patient- and tissue-specific levels.

Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density ( < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs.

Chronic transfusion therapy (CTT) prevents stroke in selected patients with sickle cell anemia (SCA). We have shown that CTT mitigates signatures of cerebral metabolic stress, reflected by elevated oxygen extraction fraction (OEF), which likely drives stroke risk reduction. The region of highest OEF falls within the border zone, where cerebral blood flow (CBF) nadirs; OEF in this region was reduced after CTT. The neuroprotective efficacy of hydroxyurea (HU) remains unclear. To test our hypothesis that patients receiving HU therapy have lower cerebral metabolic stress compared with patients not receiving disease-modifying therapy, we prospectively obtained brain magnetic resonance imaging scans with voxel-wise measurements of CBF and OEF in 84 participants with SCA who were grouped by therapy: no disease-modifying therapy, HU, or CTT. There was no difference in whole-brain CBF among the 3 cohorts (P = .148). However, whole-brain OEF was significantly different (P &lt; .001): participants without disease-modifying therapy had the highest OEF (median 42.9% [interquartile range (IQR) 39.1%-49.1%]), followed by HU treatment (median 40.7% [IQR 34.9%-43.6%]), whereas CTT treatment had the lowest values (median 35.3% [IQR 32.2%-38.9%]). Moreover, the percentage of white matter at highest risk for ischemia, defined by OEF greater than 40% and 42.5%, was lower in the HU cohort compared with the untreated cohort (P = .025 and P = .034 respectively), but higher compared with the CTT cohort (P = .018 and P = .029 respectively). We conclude that HU may offer neuroprotection by mitigating cerebral metabolic stress in patients with SCA, but not to the same degree as CTT.

No abstract

SUMMARY Purpose Refractory status epilepticus (RSE) is a life-threatening emergency, demonstrating, by definition, significant pharmacoresistance. We describe five cases of pediatric RSE treated with mild hypothermia. Methods Retrospective chart review was performed of records of children who received hypothermia for RSE at two tertiary-care pediatric hospitals between 2009 and 2012. Key Findings Five children with RSE received mild hypothermia (32–35°C). Hypothermia reduced seizure burden during and after treatment in all cases. Prior to initiation of hypothermia, four children (80%) received pentobarbital infusions to treat RSE, but relapsed after pentobarbital discontinuation. No child relapsed after treatment with hypothermia. One child died after redirection of care. Remaining four children were discharged. Significance This is the largest pediatric case series reporting treatment of RSE with mild hypothermia. Hypothermia decreased seizure burden during and after pediatric RSE and may prevent RSE relapse.

Individuals with sickle cell disease (SCD) experience cognitive deficits; however, it remains unclear whether medical treatments for SCD improve cognition. Given that executive abilities are typically impaired in individuals with SCD, they were the focus of the current study. Our primary hypothesis was that executive abilities would be higher acutely soon after a blood transfusion in children and young adults with SCD. We used tests from the NIH Toolbox to assess executive abilities in 27 participants with SCD receiving chronic transfusion in comparison to 34 participants with SCD receiving hydroxyurea (HU) and 41 non-SCD demographically matched controls, all of whom were tested at two time points. Participants in the transfusion group completed cognitive testing within 3 days after a transfusion (soon after transfusion) and then within 3 days before their next transfusion (long after transfusion) over an interval of 3-7 weeks. We found that executive abilities were significantly poorer for the transfusion and HU groups than for the control group. In support of our primary hypothesis, executive abilities for the transfusion group were significantly better soon after a transfusion compared to long after a transfusion, 2 (1) = 17.8, P < .0001. Our results demonstrate that executive abilities were higher acutely following a blood transfusion. These findings have implications for daily functioning, medical decision making, and academic achievement in children and young adults with SCD.