Background Diffuse correlation spectroscopy (DCS) is a novel, non-invasive optical technique that measures an index of regional microvascular cerebral blood flow (CBF). Previously, we used DCS to demonstrate that transfusion significantly decreases CBF in SCA patients on chronic transfusion (Lee et al. 2022). This decreased response was expected because it is known that transfusion improves oxygen-carrying capacity, thereby reducing the need for compensatory hyperperfusion. However, while we observed an average decrease in CBF with transfusion, the CBF response was considerably variable across participants. In this secondary analysis, we explore factors contributing to this variability. Given that chronic inflammation, endothelial disfunction, and altered red blood cell biomechanics contribute to both macro- and microvascular complications in SCA, we test the hypothesis that microvascular CBF and its response to transfusion are associated with the presence of large vessel vasculopathy.Methods Details of the original study design can be found in (Lee et al. 2022). In brief, children with HbSS or HbSβ0 on chronic transfusion therapy were enrolled in an IRB-approved study at Children's Healthcare of Atlanta; exclusion criteria included prior history of stroke, Moyamoya, or previous surgical revascularization. An index of regional CBF was assessed in the frontal cortex immediately before and after transfusion with DCS. Vasculopathy was assessed via review of the clinical report from the most recent standard-of-care head MRI/MRA prior to and after the time of CBF measurement. Patients were considered to have vasculopathy if the report cited narrowing, stenosis, or occlusion of any cerebral vessel. Vasculopathy status was categorized as binary (present/absent) at the time of transfusion and categorically at follow-up (present pre-transfusion, never developed, developed at follow-up). To test the hypothesis that CBF and its response to transfusion are associated with vasculopathy, multivariate models were used that included terms for vasculopathy status (either at time of transfusion or at follow-up), age or sex, and their interaction, given that CBF was observed to be significantly correlated with age and CBF transfusion response was correlated with sex in the original analysis. Model fit was assessed using adjusted R2 values, and individual predictors were considered significant if p < 0.05. All models were fitted using R (version 4.4.1).ResultsA total of 28 transfusion events were included in this analysis. The cohort was all HbSS and predominantly female (75%), with a median age of 14 (IQR [11,16]) years. At the time of transfusion, 11 patients (39%) had evidence of vasculopathy on their most recent MRI/MRA, while 17 (61%) did not. The median time from MRA/MRI to transfusion was -0.76 (IQR [-0.50, -1.19]) years. Follow-up imaging was available for 26 of the 28 transfusions: 12 (43%) did not have vasculopathy, 3 (12%) developed vasculopathy, and 13 (42%) had persistent evidence of vasculopathy that was also seen on pre-transfusion imaging. The median time to follow-up imaging was 0.75 (IQR [0.34,1.51]) years. In multivariate models accounting for the effect of age, lower pre-transfusion CBF was significantly associated with the presence of vasculopathy at the time of transfusion (model R² = 0.76, p<0.001) and with vasculopathy status at follow-up (R² = 0.79, p < 0.001). Multivariate models incorporating sex revealed that pre-existing vasculopathy (R² = 0.45, p<0.001) and vasculopathy status at follow-up (R² = 0.50, p<0.001) were significantly associated with an increase in CBF in response to transfusion.Conclusions Our results show that both pre-transfusion CBF and transfusion-induced CBF response measured with DCS were significantly associated with patient vasculopathy status at the time of transfusion and at follow-up, after accounting for the effects of age and sex. Notably, the pattern of lower CBF before transfusion followed by an increase afterwards in patients with vasculopathy is opposite to the expected hemodynamic response to transfusion (Gulliams et al., 2018; Juttukonda et al., 2019; Lee et al., 2022), which suggests altered cerebral hemodynamics in these patients that warrant further investigation. Prospective studies in larger cohorts are needed to determine if DCS-measured CBF dynamics can provide a predictor for vasculopathy development in the context of chronic transfusion.

BACKGROUND:Long-term video electroencephalogram monitoring (LTVM) is critical to the detection and management of seizures. Prior work has shown that most seizures are detected within 24 hours of monitoring. In practice, many patients are monitored for longer especially those who are at higher risk for seizures. This study examines whether higher risk clinical characteristics affect seizure detection rate. METHODS:A retrospective chart review was conducted on 847 LTVM studies of patients aged 0-18 years between August 1, 2021, and January 31, 2022, for those who were acutely hospitalized. Demographic, clinical, and electroencephalogram data were reviewed and analyzed. Descriptive statistics were used to analyze data, comparing seizure yield between clinical indications and age subgroups. RESULTS:Median patient age was 1.5 years (interquartile range: 0.3-8.3 years). The most common indication for LTVM was seizure-like activity (51%, n = 429). The most common age group that utilized inpatient LTVM was infants (35%, n = 298). Seizures were detected in 22% (n = 189/847) of electroencephalograms. Median time to first detected seizure was 1.5 hours (interquartile range: 0.4-6.9 hours). Ninety-five percent of patients had seizures within 24 hours of LTVM initiation, regardless of age or indication. Comparison analysis revealed no statistical difference in overall seizure yield based on age or indication. High-risk subgroups of neonates, extracorporeal membrane oxygenation, and traumatic brain injury patients similarly did not have statistically different seizure yield on LTVM. CONCLUSIONS:Almost all patients with seizures were detected within 24 hours regardless of age or clinical indication. These results indicate the need for standardization of LTVM resources.

Abstract: Sickle cell anemia is associated with a high risk of silent cerebral infarct. In children, studies with MRI have demonstrated that regional oxygen extraction fraction (OEF) is elevated in patients with silent infarction compared to those without infarction. Here we use a non-invasive, low-cost optical technique called frequency domain near-infrared spectroscopy (FDNIRS) to demonstrate similar increases in OEF with silent infarct. These results suggest a promising role for FDNIRS in providing a biomarker of silent infarct that merits further neuroimaging in children with sickle cell anemia. Introduction:Sickle cell anemia is an inherited blood disorder that has a profound effect on the brain, including a high risk of cerebral injury. The most common neurological insult is silent cerebral infarct (SCI), which is associated with progressive cognitive decline resulting in lower IQ, poor school performance, etc. (DeBaun et al., 2020; Schatz et al., 2001). Assessment of these clinically silent injuries requires MRI, which is costly and has limited availability. Thus, current guidelines recommend a single MRI to check for SCI in early-school-age children, along with another MRI in adulthood, resulting in a retrospective, symptom-driven model of monitoring for neurological injury. To move towards a prospective, preventative model of monitoring for neurological injury in these patients, there is a clinical need for a lower cost, point-of-care biomarker of SCI that could guide neuroimaging timing and aid in individualized clinical management of these patients. Recent work with MRI has demonstrated that elevated oxygen extraction fraction (OEF) is a promising biomarker of SCI (Fields et al., 2018). Novel, low-cost optical tools can non-invasively assess OEF at the bedside. These tools, called frequency domain near infrared spectroscopy and diffuse correlation spectroscopy (FDNIRS/DCS), can quantify regional OEF in the frontal cortex as well as other hemodynamic parameters including cerebral blood flow (CBF) and cerebral blood volume (CBV) (Lee et al., 2019, Lee & Brothers et al., 2022, Brothers et al., 2024). Here we test the hypothesis that FDNIRS/DCS are sensitive to alterations in cerebral hemodynamics associated with presence of SCI in pediatric sickle cell patients. Specifically, we hypothesize that OEF measured with FDNIRS/DCS will be elevated with SCI. Methods:Children ages 5 to 18 y with sickle cell anemia (HbSS or HbSβ0-thalassemia) were enrolled at Children's Healthcare of Atlanta. All participants had a 3T head MRI with 3D FLAIR to assess SCI, followed by optical assessment with FDNIRS/DCS (within 1 day of MRI). Blood hemoglobin concentration was assessed with complete blood count on a venous sample within 1 week of FDNIRS/DCS measurement. Details of FDNIRS/DCS acquisition/analysis is described in (Lee 2022). Silent infarction was determined independently by two blinded, board-certified neuroradiologists based on criteria outlined in (Casella et al., 2010). A Wilcoxon rank-sum test was used to test whether each FDNIRS/DCS measure (OEF, CBF, CBV) was different between patients with and without evidence of SCI. Results:Thirty subjects were enrolled, with 24 of the 30 enrolled meeting study criteria. Subjects were mostly female (68%), ranging in age from 8 to 18 y, with a median (IQR) hemoglobin of 8.2 (7.4, 8.8) g/dL. Twenty out of 24 subjects (83%) were on hydroxyurea, 3/24 (13%) were on voxelotor, and 1/24 (5%) was on chronic exchange transfusion. As expected, OEF was significantly higher in patients with SCI compared to those without (median (IQR) 56 (54, 58) vs. 47 (44, 55) %, p=0.013). No differences in CBF (p=0.97), CBV (p=0.85), blood hemoglobin (p=0.91), age (p=0.97), hydroxyurea usage (p=0.88), or voxelotor usage (p=0.93) were observed. Conclusion: Recruitment for this study is ongoing. These preliminary results suggest that FDNIRS/DCS may be sensitive to regional elevations in OEF in patients with silent infarct, indicating a potential role for FDNIRS/DCS in point of care neuromonitoring of these patients.

•The morbidity of pediatric arterial ischemic stroke is greater than that of adults.•Common etiologies include non-atherosclerotic arteriopathies and cardioembolism.•Common etiologies of arteriopathies include moyamoya and focal cerebral arteriopathy.•Minor infections increases the risk of stroke in children.•Vaccination confers a protective effect in pediatric patients against stroke.