Cerebral blood flow trajectories in paediatric sickle cell anaemia by age, region, and treatment associations.

Alterations in the Humoral Immunophenotype of Children with Sickle Cell Disease on Hydroxyurea

A Meta-Analytic Comparison of Cerebral Blood Flow As Measured By MRI in Children with Sickle Cell Disease Versus Healthy Controls

Background: We have previously shown that the borderzone region demonstrates ischemic physiology, with low cerebral blood flow (CBF) and increased oxygen extraction fraction (OEF), in pediatric sickle cell anemia (SCA). This region is vulnerable in SCA as evidenced by increased infarct burden. Here we studied healthy adults to determine if borderzone physiology exists in the absence of apparent vascular disease. Methods: Healthy (N=17, 33 ± 9 yr) and SCA (N=13, 28 ± 7 yr) adults were recruited from a tertiary care SCA clinic. Individuals with vascular risk factors or chronic medical or neurological diseases were excluded. SCA subjects were excluded for stroke, vasculopathy, or transfusion therapy. Brain MRIs were prospectively obtained including: T1, FLAIR, dynamic susceptibility contrast (CBF), and asymmetric spin echo (OEF). Within each subject, 3 regions of low CBF were derived by normalizing CBF to its peak CBF. For gray matter (GM), regions were: < 25 th %, 25-50 th %, and 50-75 th % of mean thalamic CBF. For white matter (WM), regions were: < 25 th %, 25-35 th %, and 35-45 th % of mean GM CBF. Mean OEF across the 3 CBF regions were compared using Friedman test to account for repeated measures (Fig*). Results: Figure demonstrates the approximated borderzone with heatmaps (# of subjects with WM CBF < 25 th %) for healthy and SCA adults, alongside average OEF maps for each cohort. Both in healthy and SCA adults, GM and WM OEF were elevated in the region of lowest CBF. Furthermore, relative tissue volumes of CBF < 25 th % were higher in SCA than controls (GM: 16 vs 11%, p<0.001; WM: 33 vs 23% p<0.001), suggesting disease may redistribute CBF, effectively enlarging the borderzone. Conclusion: We found ischemic physiology (low CBF / high OEF) in the borderzone of healthy adults. Additional stressors limiting cerebral oxygen delivery such as chronic anemia in SCA or carotid occlusion may lead to enlargement of the borderzone, further elevation of OEF, and a heightened vulnerability to infarction.

Background: Chronic blood transfusions (Tx) reduces stroke risk in pediatric sickle cell disease (SCD). Cerebral blood flow (CBF) is elevated in SCD, likely representing a compensatory mechanism to maintain cerebral oxygen metabolism (CMRO2) in the setting of reduced arterial oxygen content (CaO2) from chronic anemia. When exhausted compensatory mechanisms are unable to meet oxygen demands, stroke ensues. We measured MR-derived CBF and oxygen extraction fraction (OEF) pre- and post-Tx, hypothesizing that Tx ‘resets’ the CBF baseline by increasing CaO2 via increased hemoglobin (Hb), while maintaining cerebral oxygen delivery and metabolism. Methods: SCD children on chronic Tx were enrolled in a prospective, observational MRI study. MR-CBF and MR-OEF were acquired before and 2 hours after exchange Tx. MR-CBF and MR-OEF were measured using pseudocontinuous arterial spin labelling and a novel asymmetric spin echo sequence, respectively. CaO2 =1.35 x [Hb] x SaO2. CMRO2 = CaO2 x CBF x OEF. Results: Two SCD children underwent MRI pre- and post-Tx (six more are anticipated prior to ISC). For subject #1 (18 yo F with overt stroke), mean global CBF was 128 and 98 ml/min/100g pre- and post-Tx, respectively, indicating a 24% CBF reduction. For subject #2 (6 yo F with elevated transcranial Doppler velocities), mean global CBF was 189 and 129 ml/min/100g pre- and post-Tx, respectively, a 32% CBF reduction (Fig). Both Hb and CaO2 were increased after Tx, resulting in unchanged oxygen delivery (CaO2 x CBF) post-Tx. Moreover, OEF and CMRO2 were not significantly different pre- and post-Tx, consistent with our hypothesis that CBF increases to maintain oxygen delivery. Conclusions: Elevated CBF is likely a compensatory mechanism to maintain constant oxygen delivery in SCD children who have chronically low CaO2. In our subjects, Tx improved CaO2, allowing CBF to normalize. This reduced hemodynamic stress likely contributes to the lower stroke risk in chronically transfused SCD children.

OEF Measured with Diffuse Optical Spectroscopies As a Biomarker of Silent Stroke in Pediatric Sickle Cell Anemia

Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia

Assessment of Functional Shunting in Patients with Sickle Cell Disease

Assessment of Cerebral Blood Flow and Oxygen Extraction in Pediatric Sickle Cell Disease with Non-Invasive Diffuse Optical Spectroscopies

Functional Connectivity in Pediatric Sickle Cell Disease

Pediatric sickle cell disease (SCD) management can result in considerable caregiver distress. Parents of youth with chronic SCD pain may face the additional challenge of managing children's chronic pain and chronic illness. This study examined associations between parent psychological distress and child functioning and the moderating role of chronic pain among youth with SCD. Youth presenting to pediatric outpatient comprehensive SCD clinics and their primary caregivers completed a battery of questionnaires. Parents reported on parenting stress, parent mental and physical health, and family functioning. Children completed measures of pain characteristics, depressive symptoms, catastrophic thinking, functional disability, and quality of life. Patients (N = 73, Mage = 14.2 years, 57% female) and their caregivers (Mage = 41.1 years, 88% mothers, 88% Black) participated. Worse parent functioning was associated with worse child pain, functioning, quality of life, and depressive symptoms. Beyond the effects of SCD, chronic SCD pain magnified the negative associations between parenting stress frequency and child quality of life, parent physical health and child quality of life, and parent depressive symptoms and child depressive symptoms. Chronic pain may exacerbate the relations between parent and child functioning beyond the effects of SCD alone. The management of both SCD and chronic pain may present additional challenges for parents that limit their psychosocial functioning. Family-focused interventions to support parents and youth with chronic SCD pain are warranted to optimize health outcomes.

Alternatively Spliced Tissue Factor (asTF) Is Elevated in the Plasma of Patients with Sickle Cell Disease: Pilot Studies Performed Using a Novel asTF-Specific ELISA

Cerebral Metabolic Stress Improves after Voxelotor Treatment in Pediatric Sickle Cell Disease

Sickle cell disease (SCD) requires coordinated, specialized medical care for optimal outcomes. There are no United States (US) guidelines that define a pediatric comprehensive SCD program. We report a modified Delphi consensus-seeking process to determine essential, optimal, and suggested elements of a comprehensive pediatric SCD center. Nineteen pediatric SCD specialists participated from the US. Consensus was predefined as 2/3 agreement on each element's categorization. Twenty-six elements were considered essential (required for guideline-based SCD care), 10 were optimal (recommended but not required), and five were suggested. This work lays the foundation for a formal recognition process of pediatric comprehensive SCD centers.

Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow

Although pediatric obstructive sleep apnea (OSA) is estimated to affect 2-3% of the general population, its prevalence in sickle cell disease (SCD) is much higher, with research suggesting a prevalence rate of upwards of 40%. Despite the similar underlying pathophysiological mechanisms of neurocognitive effects in pediatric OSA and SCD, there is a scarcity of information on how these two conditions interact. The aim of this study was to better understand the contribution of sleep apnea to neurocognitive deficits in children diagnosed with SCD. This study assessed cognitive function in 26 children with comorbid SCD and OSA, 39 matched comparisons with SCD only, and 59 matched comparisons in children without a chronic health condition. There were significant differences on measures of processing speed and reading decoding, with children without a chronic health condition scoring better than both chronic health condition groups. Additionally, the no chronic health condition group performed better on a test of quantitative knowledge and reasoning and a test of visual-spatial construction than the SCD-only group. Contrary to our hypotheses, there were no between-group differences suggesting an additive impact of OSA on cognition. Exploratory analyses revealed associations within the group that had OSA showing that more severe OSA correlated with lower performance on measures of processing speed and quantitative knowledge/reasoning. Children with comorbid OSA and SCD do not present with greater deficits in cognitive functioning than children with SCD alone. However, severe OSA may confer additional risk for neurocognitive impairments.