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Children with sickle cell disease (SCD) demonstrate cerebral hemodynamic stress and are at high risk of strokes. We hypothesized that curative hematopoietic stem cell transplant (HSCT) normalizes cerebral hemodynamics in children with SCD compared with pre-transplant baseline. Whole-brain cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were measured by magnetic resonance imaging 1 to 3 months before and 12 to 24 months after HSCT in 10 children with SCD. Three children had prior overt strokes, 5 children had prior silent strokes, and 1 child had abnormal transcranial Doppler ultrasound velocities. CBF and OEF of HSCT recipients were compared with non-SCD control participants and with SCD participants receiving chronic red blood cell transfusion therapy (CRTT) before and after a scheduled transfusion. Seven participants received matched sibling donor HSCT, and 3 participants received 8 out of 8 matched unrelated donor HSCT. All received reduced-intensity preparation and maintained engraftment, free of hemolytic anemia and SCD symptoms. Pre-transplant, CBF (93.5 mL/100 g/min) and OEF (36.8%) were elevated compared with non-SCD control participants, declining significantly 1 to 2 years after HSCT (CBF, 72.7 mL/100 g per minute; P = .004; OEF, 27.0%; P = .002), with post-HSCT CBF and OEF similar to non-SCD control participants. Furthermore, HSCT recipients demonstrated greater reduction in CBF (−19.4 mL/100 g/min) and OEF (−8.1%) after HSCT than children with SCD receiving CRTT after a scheduled transfusion (CBF, −0.9 mL/100 g/min; P = .024; OEF, −3.3%; P = .001). Curative HSCT normalizes whole-brain hemodynamics in children with SCD. This restoration of cerebral oxygen reserve may explain stroke protection after HSCT in this high-risk patient population.

Sickle cell disease (SCD) is complicated by neurologic complications including vasculopathy, hemorrhagic or ischemic overt stroke, silent cerebral infarcts and cognitive dysfunction. Patients with SCD, even in the absence of vasculopathy or stroke, have experience cognitive dysfunction that progresses with age. Transcranial Doppler ultrasound and structural brain MRI are currently used for primary and secondary stroke prevention, but laboratory or imaging biomarkers do not currently exist that are specific to the risk of cognitive dysfunction in patients with SCD. Recent investigations have used advanced MR sequences assessing cerebral hemodynamics, white matter microstructure and functional connectivity to better understand the pathophysiology of cognitive decline in SCD, with the long-term goal of developing neuroimaging biomarkers to be used in risk prediction algorithms and to assess the efficacy of treatment options for patients with SCD.

Background: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. Methods: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Results: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P =0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P =0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P =0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P =0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P =0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P =0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P =0.053) and correlated with SCI volume (ρ=0.49, P =0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Conclusions: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury.

AIM: To investigate how combined electrographic and radiologic data inform outcomes in children after cardiac arrest. METHODS: Retrospective observational study of children admitted to the pediatric intensive care unit (PICU) of a tertiary children’s hospital with diagnosis of cardiac arrest from 2009 to 2016. The first 20 minutes of electroencephalogram (EEG) background was blindly scored. Presence and location of magnetic resonance imaging (MRI) diffusion-weighted image (DWI) abnormalities were correlated with T2-weighted signal. Outcomes were categorized using Pediatric Cerebral Performance Category (PCPC) scores at hospital discharge, with “poor outcome” reflecting a PCPC score of 4–6. Logistic regression models examined the association of EEG and MRI variables with outcome. RESULTS: 41 children met inclusion criteria and had both post-arrest EEG monitoring within 72 hours after ROSC and brain MRI performed within 8 days. Among the 19 children with poor outcome, 10 children did not survive to discharge. Severely abnormal EEG background (p

OBJECTIVES Survivors of the PICU face long-term morbidities across health domains. In this study, we detail active PICU follow-up programs (PFUPs) and identify perceptions and barriers about development and maintenance of PFUPs. METHODS A web link to an adaptive survey was distributed through organizational listservs. Descriptive statistics characterized the sample and details of existing PFUPs. Likert responses regarding benefits and barriers were summarized. RESULTS One hundred eleven respondents represented 60 institutions located in the United States (n = 55), Canada (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Details for 17 active programs were provided. Five programs included broad PICU populations, while the majority were neurocritical care (53%) focused. Despite strong agreement on the need to assess and treat morbidity across multiple health domains, 29% were physician only programs, and considerable variation existed in services provided by programs across settings. More than 80% of all respondents agreed PFUPs provide direct benefits and are essential to advancing knowledge on long-term PICU outcomes. Respondents identified “lack of support” as the most important barrier, particularly funding for providers and staff, and lack of clinical space, though successful programs overcome this challenge using a variety of funding resources. CONCLUSIONS Few systematic multidisciplinary PFUPs exist despite strong agreement about importance of this care and direct benefit to patients and families. We recommend stakeholders use our description of successful programs as a framework to develop multidisciplinary models to elevate continuity across inpatient and outpatient settings, improve patient care, and foster collaboration to advance knowledge.

Introduction: Metabolic demand changes throughout childhood as the brain develops, peaking in the 2 nd decade of life. Cerebral blood flow (CBF) is dynamic throughout childhood, likely in response to the increased metabolic demand of brain development. Cerebrovascular reactivity (CVR) reflects the ability to further increase CBF in response to a stimulus, such as carbon dioxide (CO 2 ). We hypothesized that gray matter oxygen metabolism (GM CMRO 2 ) is increased in younger children, corresponding to higher GM CBF and lower GM CVR. Methods: CVR was calculated as the proportional change of a subject’s MRI-measured blood oxygen level dependent signal in response to an increase in end-tidal CO 2 administered by the RespirAct® RA-MR™ device. GM CMRO 2 was calculated voxel-by-voxel as the product of GM CBF (arterial spin labeling), GM oxygen extraction fraction (asymmetric spin echo), and arterial oxygen content (= Hb х (oxygen saturation)х1.34). Univariate relationships were tested using Spearman’s correlation coefficient, and corrected for multiple comparisons. Results: GM CVR, CBF, and CMRO 2 were calculated for 15 healthy participants (ages 8-19, 7 male). GM CMRO 2 was highest in young children and decreased with age (ρ=-0.68, P=0.005), as did CBF (ρ =-0.67, P=0.006). CVR was lower in young children, increasing with age (ρ=0.58, P=0.02). However, while GM CVR correlated with CBF (ρ=-0.64, P=0.01) it did not significantly associate with CMRO 2 (ρ=-0.43, P=0.114). Conclusion: Although GM CMRO 2 and CVR both have age-related changes, CVR does not directly correlate with CMRO 2 . Rather, their relationship may be moderated through other influences on CBF, as further study will investigate. Figure: Linear fits and 95% confidence intervals of subject data, including age, GM CBF, and GM CMRO 2 , versus GM CVR. P-values are from Spearman’s test for monotonic correlation.

BACKGROUND AND PURPOSE: Asymmetries in the circle of Willis have been associated with several conditions, including migraines and stroke, but they may also be age-dependent. This study examined the impact of age and age-dependent changes in cerebral perfusion on circle of Willis anatomy in healthy children and adults. MATERIALS AND METHODS: We performed an observational, cross-sectional study of bright and black-blood imaging of the proximal cerebral vasculature using TOF-MRA and T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (T2-SPACE) imaging at the level of the circle of Willis in 23 healthy children and 43 healthy adults (4–74 years of age). We compared arterial diameters measured manually and cerebral perfusion via pseudocontinuous arterial spin-labeling between children and adults. RESULTS: We found that the summed cross-sectional area of the circle of Willis is larger in children than in adults, though the effect size was smaller with T2-SPACE-based measurements than with TOF-MRA. The circle of Willis is also more symmetric in children, and nonvisualized segments occur more frequently in adults than in children. Moreover, the size and symmetry of the circle of Willis correlate with cerebral perfusion. CONCLUSIONS: Our results demonstrate that the circle of Willis is different in size and symmetry in healthy children compared with adults, likely associated with developmental changes in cerebral perfusion. Further work is needed to understand why asymmetric vasculature develops in some but not all adults.

Cantu syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (K-ATP) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1-69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (>= 25%), but this percentage decreased markedly in adults.

Endovascular thrombectomy has played a major role in advancing adult stroke care and may serve a similar role in pediatric stroke care. However, there is a need to develop better evidence and infrastructure for pediatric stroke care. In this work, we review 2 experienced pediatric endovascular thrombectomy programs and examine key design features in both care environments, including a formalized protocol and workflow, integration with an adult endovascular thrombectomy workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke.

Purpose Sickle cell anemia is a blood disorder that alters the morphology and the oxygen affinity of the red blood cells. Cerebral oxygen extraction fraction measurements using quantitative BOLD contrast have been used for assessing inadequate oxygen delivery and the subsequent risk of ischemic stroke in sickle cell anemia. The BOLD signal in MRI studies relies on Δ χ do , the bulk volume susceptibility difference between fully oxygenated and fully deoxygenated blood. Several studies have measured Δ χ do for normal hemoglobin A (HbA). However, it is not known whether the value is different for sickle hemoglobin. In this study, Δ χ do was measured for both HbA and sickle hemoglobin. Methods Six sickle cell anemia patients and 6 controls were recruited. Various blood oxygenation levels were achieved through in vivo manipulations to keep the blood close to its natural state. To account for the differences in oxygen affinity, Hill's equations were used to translate partial pressure of oxygen to oxygen saturation for HbA, sickle hemoglobin, and fetal hemoglobin (HbF) separately. The pH and PCO2 corrections were performed. Temperature and magnetic field drift were controlled for. A multivariate generalized linear mixed model with random participant effect was used. Results Assuming that Δ χ do is similar for HbA and HbF and that Δ χ metHb is 5/4 of Δ χ do for HbA, it was found that the Δ χ do values for HbA and sickle hemoglobin were not statistically significantly different from each other. Conclusion The same Δ χ do value can be used for both types of hemoglobin in quantitative BOLD analysis.

ObjectiveTo determine the patient- and tissue-based relationships between cerebral hemodynamic and oxygen metabolic stress, microstructural injury, and infarct location in adults with sickle cell disease (SCD).MethodsControl participants and patients with SCD underwent brain MRI to quantify cerebral blood flow (CBF), oxygen extraction fraction (OEF), mean diffusivity (MD), and fractional anisotropy (FA) within normal-appearing white matter (NAWM) and infarcts on fluid-attenuated inversion recovery. Multivariable linear regression examined the patient- and voxel-based associations between hemodynamic and metabolic stress (defined as elevated CBF and OEF, respectively), white matter microstructure, and infarct location.ResultsOf 83 control participants and patients with SCD, adults with SCD demonstrated increased CBF (50.9 vs 38.8 mL/min/100 g,p <0.001), increased OEF (0.35 vs 0.25,p <0.001), increased MD (0.76 vs 0.72 × 10−3mm2s−1,p= 0.005), and decreased FA (0.40 vs 0.42,p= 0.021) within NAWM compared to controls. In multivariable analysis, increased OEF (β = 0.19,p= 0.035), but not CBF (β = 0.00,p= 0.340), independently predicted increased MD in the SCD cohort; neither were predictors in controls. On voxel-wise regression, the SCD cohort demonstrated widespread OEF elevation, encompassing deep white matter regions of elevated MD and reduced FA, which spatially extended beyond high-density infarct locations from the SCD cohort.ConclusionElevated OEF, a putative index of cerebral oxygen metabolic stress, may provide a metric of ischemic vulnerability that could enable individualization of therapeutic strategies in SCD. The patient- and tissue-based relationships between elevated OEF, elevated MD, and cerebral infarcts suggest that oxygen metabolic stress may underlie microstructural injury prior to the development of cerebral infarcts in SCD.

Objective: Determine seizure frequency and association with neurologic outcomes in infants undergoing extracorporeal membrane oxygenation. Identify patient or clinical factors associated with seizures or brain injury on imaging. Methods: Retrospective, single-center study including infants less than 1 year of age, who underwent extracorporeal membrane oxygenation between 2012 and 2017. Results: A total of 104 infants met study criteria including 45 patients with continuous electroencephalographic (EEG) monitoring during their extracorporeal membrane oxygenation run and 59 infants without EEG. Seizures (electrographic-only or electro-clinical) were identified in 18 of the 45 (40%). Among the 18 infants with seizures, 14 (78%) had moderate to severe brain injury, whereas only 44% of those without seizures (12 of 27) on EEG had moderate to severe brain injury ( P = .03). Cardiopulmonary resuscitation prior to extracorporeal membrane oxygenation (ECPR), mode of extracorporeal membrane oxygenation, length of stay, survival to discharge, and congenital heart disease were not associated with seizures. One of 10 patients with cyanotic congenital heart disease due to hypoplastic left heart syndrome had seizures compared with 7 of 10 patients with non–hypoplastic left heart syndrome lesions ( P = .02). Seizures were associated with moderate to severe brain injury, after adjusting for ECPR and congenital heart disease ( P = .04). Conclusions: Electrographic seizures were common in patients undergoing extracorporeal membrane oxygenation and higher than previously reported. Seizures were associated with moderate to severe abnormalities on imaging, after adjusting for ECPR and congenital heart disease. This study adds to recent literature describing the risk of seizures in patients on extracorporeal membrane oxygenation and highlights the presence of brain injuries that may be identified by routine EEG surveillance.

Extracorporeal membrane oxygenation is extracorporeal life support for life-threatening cardiopulmonary failure. Since its introduction, the use of extracorporeal membrane oxygenation has expanded to patients with more complex comorbidities without change in patient mortality rates. Although many patients survive, significant neurological complications like seizures, ischemic strokes, and intracranial hemorrhage can occur during extracorporeal membrane oxygenation care. The risks of these complications often add to the complexity of decision-making surrounding extracorporeal membrane oxygenation support. In this review, we discuss the pathophysiology and incidence of neurological complications in children supported on extracorporeal membrane oxygenation, factors influencing the incidence of these complications, commonly used neurological monitoring modalities, and outcomes for this complex patient population. We discuss the current literature on the use of electroencephalography for both seizure detection and monitoring of background electroencephalographic changes, in addition to the use of less commonly used imaging modalities like transcranial Doppler. We summarize the knowledge gaps and the lack of clinical consensus guidelines for managing these potentially life-changing neurological complications. Finally, we discuss future work to further understand the pathophysiology of extracorporeal membrane oxygenation-related neurological complications.

Ischemic and hemorrhagic stroke can occur in the setting of pediatric trauma, particularly those with head or neck injuries. The risk of stroke appears highest within the first two weeks after trauma. Stroke diagnosis may be challenging due to lack of awareness or concurrent injuries limiting detailed neurological assessment. Other injuries may also complicate stroke management, with competing priorities for blood pressure, ventilator management, or antithrombotic timing. Here we review epidemiology, clinical presentation, and diagnostic approach to blunt arterial injuries including dissection, cerebral sinovenous thrombosis, mineralizing angiopathy, stroke from abusive head trauma, and traumatic hemorrhagic stroke. Owing to the complexities and heterogeneity of concomitant injuries in stroke related to trauma, a single pathway for stroke management is impractical. Therefore providers must understand the goals and possible costs or consequences of stroke management decisions to individualize patient care. We discuss the physiological principles of cerebral perfusion and oxygen delivery, considerations for ventilator strategy when stroke and lung injury are present, and current available evidence of the risks and benefits of anticoagulation to provide a framework for multidisciplinary discussions of cerebrovascular injury management in pediatric patients with trauma.

Patients with sickle cell anemia (SCA) experience cerebral metabolic stress with an increase in oxygen extraction fraction (OEF) to compensate for reduced oxygen carrying capacity due to anemia. It remains unclear if anemia alone drives this metabolic stress. Using MRI, we collected voxel-wise OEF measurements to test our hypothesis that OEF would be elevated in anemic controls without SCA (AC) compared to healthy controls (HC), but OEF would be even higher in SCA compared to AC. Brain MRIs (N = 159) were obtained in 120 participants (34 HC, 27 AC, 59 SCA). While hemoglobin was lower in AC versus HC (p 0.001), hemoglobin was not different between AC and SCA cohorts (p = 0.459). Whole brain OEF was higher in AC compared to HC (p 0.001), but lower compared to SCA (p = 0.001). Whole brain OEF remained significantly higher in SCA compared to HC (p = 0.001) while there was no longer a difference between AC versus HC (p = 0.935) in a multivariate model controlling for age and hemoglobin. OEF peaked within the border zone regions of the brain in both SCA and AC cohorts, but the volume of white matter with regionally elevated OEF in AC was smaller (1.8%) than SCA (58.0%). While infarcts colocalized within regions of elevated OEF, more SCA participants had infarcts than AC (p 0.001). We conclude that children with SCA experience elevated OEF compared to AC and HC after controlling for the impact of anemia, suggesting that there are other pathophysiologic factors besides anemia contributing to cerebral metabolic stress in children with SCA.

Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C).Multicenter, cross-sectional study of neurological manifestations in children aged18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed.Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P 0.05.In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

Background Sleep-wake disturbances are underevaluated among children with acquired brain injury surviving critical care. We aimed to quantify severity, phenotypes, and risk factors for sleep-wake disturbances. Methods We performed a prospective cohort study of 78 children aged ≥3 years with acquired brain injury within three months of critical care hospitalization. Diagnoses included traumatic brain injury (n = 40), stroke (n = 11), infectious or inflammatory disease (n = 10), hypoxic-ischemic injury (n = 9), and other (n = 8). Sleep Disturbances Scale for Children standardized T scores measured sleep-wake disturbances. Overall sleep-wake disturbances were dichotomized as any total or subscale T score ≥60. Any T score ≥70 defined severe sleep-wake disturbances. Subscale T scores ≥60 identified sleep-wake disturbance phenotypes. Results Sleep-wake disturbances were identified in 44 (56%) children and were classified as severe in 36 (46%). Sleep-wake disturbances affected ≥33% of patients within each diagnosis and were not associated with severity of illness measures. The most common phenotype was disturbance in initiation and maintenance of sleep (47%), although 68% had multiple concurrent sleep-wake disturbance phenotypes. One third of all patients had preadmission chronic conditions, and this increased risk for sleep-wake disturbances overall (43% vs 21%, P = 0.04) and in the traumatic brain injury subgroup (52% vs 5%, P = 0.001). Conclusions Over half of children surviving critical care with acquired brain injury have sleep-wake disturbances. Most of these children have severe sleep-wake disturbances independent of severity of illness measures. Many sleep-wake disturbances phenotypes were identified, but most children had disturbance in initiation and maintenance of sleep. Our study underscores the importance of evaluating sleep-wake disturbances after acquired brain injury.

BACKGROUND/OBJECTIVE: Lingering morbidities including physical, cognitive, emotional, and psychosocial sequelae, termed the Post-Intensive Care Syndrome, persist years after pediatric neurocritical care (PNCC) hospitalization. Sleep disturbances impact other Post-Intensive Care Syndrome domains and are under-evaluated to date due to a lack of appropriate measurement tools. The present study evaluated the validity of the Sleep Disturbance Scale for Children (SDSC) to address the growing need for assessing sleep problems after PNCC. METHODS: We conducted a prospective observational study of youth aged 3–17 years with acquired brain injury (N = 69) receiving care through longitudinal PNCC programs at two tertiary academic-medical centers. Parents completed the SDSC and provided proxy reports of internalizing symptoms, health-related quality of life (HRQOL), fatigue, pain behavior, and cognitive function within 3 months of hospital discharge. Evidence for the validity of the SDSC was established by utilizing the full sample for psychosocial measure comparisons and by comparing SDSC outcomes by severity (Low Risk, Mild-Moderate Risk, and High Risk defined by reported standardized T-scores). RESULTS: Internal consistency of the SDSC was good (α = .81). Within the full sample, increased sleep disturbances on the SDSC were significantly correlated with Post-Intensive Care Syndrome measures, including worse physical (r = .65), psychological (r = .62), and cognitive (r = −.74) sequelae. Youth in the High Risk group evidenced greater dysfunction in mental acuity, pain behavior, internalizing symptoms, and social engagement. Findings revealed both statistically and clinically significant impacts of sleep disturbances as measured by the SDSC on HRQOL. CONCLUSIONS: The SDSC is a valid and reliable measure for assessing sleep disturbances in children after PNCC. Results support the use of the SDSC to measure sleep disturbances after PNCC. Targeted interventions for sleep disturbances may be key to overall patient recovery.

We describe the risk factors for peri-procedural and spontaneous arterial ischemic stroke (AIS) in children with cardiac disease.We identified children with cardiac causes of AIS enrolled in the International Pediatric Stroke Study registry from January 2003 to July 2014. Isolated patent foramen ovale was excluded. Peri-procedural AIS (those occurring during or within 72 hours of cardiac surgery, cardiac catheterization, or mechanical circulatory support) and spontaneous AIS that occurred outside of these time periods were compared.We identified 672 patients with congenital or acquired cardiac disease as the primary risk factor for AIS. Among these, 177 patients (26%) had peri-procedural AIS and 495 patients (74%) had spontaneous AIS. Among non-neonates, spontaneous AIS occurred at older ages (median 4.2 years, interquartile range 0.97 to 12.4) compared with peri-procedural AIS (median 2.4 years, interquartile range 0.35 to 6.1, P 0.001). About a third of patients in both groups had a systemic illness at the time of AIS. Patients who had spontaneous AIS were more likely to have a preceding thrombotic event (16 % versus 9 %, P = 0.02) and to have a moderate or severe neurological deficit at discharge (67% versus 33%, P = 0.01) compared to those with peri-procedural AIS.Children with cardiac disease are at risk for AIS at the time of cardiac procedures but also outside of the immediate 72 hours after procedures. Many have acute systemic illness or thrombotic event preceding AIS, suggesting that inflammatory or prothrombotic conditions could act as a stroke trigger in this susceptible population.

The outcome of children with acute ischemic stroke treated with craniectomy has not been thoroughly examined. In adults, hemicraniectomy after middle cerebral artery territory stroke and posterior decompression after posterior circulation stroke has been shown to improve outcome. Pediatric cases of hemicraniectomy for middle cerebral artery stroke and posterior decompression following posterior circulation stroke suggest relatively good outcome. There are no published data in adults or children with craniectomy after cerebral sinovenous thrombosis. Our aim was to determine the outcome of children with acute ischemic stroke treated with craniectomy in the International Pediatric Stroke Study (IPSS). We included children enrolled who had a craniectomy following stroke presentation. Of 4294 patients in IPSS, 38 children (1%) were found to have craniectomy following an ischemic stroke. Of 38 craniectomy cases, 29 had anterior circulation strokes, 5 had posterior circulation strokes, and 4 had cerebral sinovenous thromboses. The mortality rate was 8%. Overall, children who have craniectomies have significant neurologic deficits. Prospective studies are needed to examine long-term morbidity following craniectomy.

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 < .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.

The field of pediatric stroke has historically been hampered by limited evidence and small patient cohorts. However the landscape of childhood stroke is rapidly changing due in part to increasing awareness of the importance of pediatric stroke and the emergence of dedicated pediatric stroke centers, care pathways, and alert systems. Acute pediatric stroke management hinges on timely diagnosis confirmed by neuroimaging, appropriate consideration of recanalization therapies, implementation of neuroprotective measures, and attention to secondary prevention. Because pediatric stroke is highly heterogenous in etiology, management strategies must be individualized. Determining a child's underlying stroke etiology is essential to appropriately tailoring hyperacute stroke management and determining best approach to secondary prevention. Herein, we review the methods of recognition, diagnosis, management, current knowledge gaps and promising research for pediatric stroke.

Introduction: While clinical trials have demonstrated the remarkable efficacy of endovascular thrombectomy (EVT) for treating adult patients suffering from acute ischemic stroke (AIS), benefits reaped from advances in adult stroke care have unfortunately not occurred in parallel with pediatric stroke care. Randomized trials of EVT in childhood stroke are unlikely given the low incidence of stroke in children compared to adults, and despite promising outcomes in small case reports and series, EVT in children remains an off-label procedure lacking established consensus guidelines. Along with a clear need to collect prospective pediatric EVT outcome data, there is a need to enhance pediatric stroke care infrastructure to provide high-quality care to children experiencing stroke. Methods: In this work, we review two successful pediatric thrombectomy programs, examining key workflow design features that are likely to be important for other programs that aspire to implement pediatric EVT capability. Discussion: While pediatric EVT workflows will vary between centers, we identify several key elements of programmatic success shared between the two reviewed stroke programs that may serve as foundational design considerations for centers aiming to develop their own pediatric EVT programs. These elements include a formalized protocol and workflow, integration with an adult EVT workflow, simplification and automation of workflow steps, pediatric adaptations of stroke imaging, advocacy of pediatric stroke care, and collaboration between providers, among others. These essential features transcend any single hospital environment and may provide an important foundation for other pediatric centers that aim to enhance the care of children with stroke. Conclusion: EVT shows promise in reducing stroke-associated morbidity in children. To maximize the efficacy of this intervention, workflow optimizations discussed here should be implemented by centers seeking to develop local pediatric EVT capability.

PURPOSE: Seizures occur in 10% to 40% of critically ill children. We describe a phenomenon seen on color density spectral array but not raw EEG associated with seizures and acquired brain injury in pediatric patients. METHODS: We reviewed EEGs of 541 children admitted to an intensive care unit between October 2015 and August 2018. We identified 38 children (7%) with a periodic pattern on color density spectral array that oscillates every 2 to 5 minutes and was not apparent on the raw EEG tracing, termed macroperiodic oscillations (MOs). Internal validity measures and interrater agreement were assessed. We compared demographic and clinical data between those with and without MOs. RESULTS: Interrater reliability yielded a strong agreement for MOs identification (kappa: 0.778 [0.542–1.000]; P < 0.0001). There was a 76% overlap in the start and stop times of MOs among reviewers. All patients with MOs had seizures as opposed to 22.5% of the general intensive care unit monitoring population (P < 0.0001). Macroperiodic oscillations occurred before or in the midst of recurrent seizures. Patients with MOs were younger (median of 8 vs. 208 days; P < 0.001), with indications for EEG monitoring more likely to be clinical seizures (42 vs. 16%; P < 0.001) or traumatic brain injury (16 vs. 5%, P < 0.01) and had fewer premorbid neurologic conditions (10.5 vs. 33%; P < 0.01). CONCLUSIONS: Macroperiodic oscillations are a slow periodic pattern occurring over a longer time scale than periodic discharges in pediatric intensive care unit patients. This pattern is associated with seizures in young patients with acquired brain injuries.

Background Moyamoya disease and syndrome are progressive steno-occlusive cerebrovascular diseases that manifest clinically with ischemic episodes. There is evidence for the use of electroencephalography (EEG) in preoperative and long-term postoperative evaluation of these patients, as well as in the intraoperative period to monitor for changes correlated with perioperative ischemic events. However, the utility of EEG in the immediate postprocedure time period has not previously been described. Methods We review six patients who underwent pial synangiosis from 2017 to 2019. EEGs from the preoperative, intraoperative, and immediate postoperative period were evaluated, as well as clinical examination changes and subsequent interventions. Results Six patients with postoperative EEG monitoring following pial synangiosis were included. EEG data was collected preoperatively, intraoperatively, and continuously postoperatively. Preoperatively, five of six patients had normal background activity on EEG, whereas one of six had hemispheric asymmetry. Three patients had new or worsening hemispheric intracerebral asymmetry on EEG during the immediate postsurgical period. Two of these had no clinical manifestations of ischemia, and one had transient left facial weakness. All three underwent blood pressure augmentation with improvement in the asymmetry on EEG and clinical improvement in the symptomatic patient. Conclusions Although widely accepted as a useful tool during the preoperative and intraoperative periods of evaluation and management of moyamoya disease and syndrome, we propose that the use of continuous EEG in the immediate postoperative period may have potential as a useful adjunct by both detecting early clinical and subclinical intracranial ischemia.

Objective Children with sickle cell disease experience cognitive deficits even when unaffected by stroke. Using functional connectivity MRI as a potential biomarker of cognitive function, we tested our hypothesis that children with sickle cell disease would have decreased functional connectivity, and that children experiencing the greatest metabolic stress, indicated by elevated oxygen extraction fraction, would have the lowest connectivity. Methods We prospectively obtained brain MRIs and cognitive testing in healthy controls and children with sickle cell disease. Results We analyzed data from 60 participants (20 controls, 40 sickle cell disease). There was no difference in global cognition or cognitive subdomains between cohorts. However, we found decreased functional connectivity within the sensory-motor, lateral sensory-motor, auditory, salience and subcortical networks in participants with sickle cell disease compared to controls. Further, as white matter oxygen extraction fraction increased, connectivity within the visual (p = 0.008, parameter estimate [95% CI] = -0.760 [-1.297, -0.224]), default mode (p = 0.012, parameter estimate [95% CI] = -0.417 [-0.731, -0.104]), and cingulo-opercular (p = 0.009, parameter estimate [95% CI] = -0.883 [-1.517, -0.250]) networks decreased. Interpretation We conclude that there is diminished functional connectivity within these anatomically-contiguous networks in children with sickle cell disease compared to controls, even when differences are not seen with cognitive testing. Increased white matter oxygen extraction fraction was associated with decreased connectivity in select networks. These data suggest that elevated oxygen extraction fraction and disrupted functional connectivity are potentially pre-symptomatic neuroimaging biomarkers for cognitive decline in sickle cell disease. This article is protected by copyright. All rights reserved.

Background Pediatric critical care survivors often suffer persisting multisystem health problems and are left with treatment needs that go unmet due to limits in current care models. We proposed that integration of neuropsychology into neurocritical care follow-up provides incremental benefit to the identification and treatment of persisting complications and reduction in co-morbidities. Basic Procedures The aims of this study were three-fold. First, we described pilot programs at two pediatric hospitals as models for implementing systematic follow-up care with interdisciplinary clinic teams consisting of critical care, neurology, and neuropsychology. Second, we described working models specific to neuropsychological service delivery in these programs. Third, we presented preliminary data from the first six months of one of the pilot programs in order to examine incremental benefit of neuropsychology in improving patient care and parent satisfaction. Main Findings A total of 16 patients (age range three to 17 years) were seen by neuropsychology within the first six months of the program. Results showed that integration of neuropsychology into follow-up care resulted in recommendations being made for services or concerns not already addressed in 81% of cases. Parents reported high satisfaction, endorsing the highest possible rating on 96% of all items. Parents reported that neuropsychological consultation improved their understanding and communication with their child, and helped them know what to expect from their child during postacute recovery. Conclusions The results of this pilot study suggest that integration of neuropsychology into neurocritical care follow-up programs contributes to parent satisfaction and may provide incremental benefit to patient care.

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 (P < .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.

Introduction Pediatric patients with sickle cell disease (SCD) face racial bias and healthcare stigma compounded by limited age-appropriate health education. Due in part to a lack of dedicated SCD education, providers can hold misconceptions about SCD and biases against patients. Gamification improves disease education and mitigates stigma in various clinical settings. In this study, we created the GRAPES tool (Game to Raise Awareness for Patient/Provider/Public Education of SCD, www.tinyurl.com/GRAPESgame), a free, online, trivia-based educational game. We hypothesized that utilization of the GRAPES tool will improve patient and provider SCD knowledge and mitigate SCD stigma among providers. Methods The GRAPES tool is a single-player, interactive game developed using Figma, a collaborative user-interface design software. Multiple-choice questions are structured into five educational modules (science, treatment, epidemiology, myths, and symptoms) with customizable red blood cell characters and hand-drawn screens to promote user-friendliness. Hyperlinked resources and an answer booklet provide further education. To promote health literacy for users of all ages, especially children, content is written at a fifth-grade Lexile level. The GRAPES tool was tested in two cohorts at St. Louis Children's Hospital: 1) pediatric patients 10 years of age or older with any genotype of SCD and 2) registered nurses at any career stage who care for patients with SCD. Both cohorts completed a 20-question, multiple-choice knowledge questionnaire pre- and post-gameplay to assess knowledge gains. Provider healthcare experiences were assessed pre- and post-gameplay through the 17-item short-form General Perceptions About Sickle Cell Patients Scale (GPASPS, Haywood et al., 2010). Post-gameplay, both cohorts completed a satisfaction scale and provided written feedback for game improvement. Non-parametric testing was used to compare paired-sample pre- and post-assessments. Results Of the 29 pediatric hematology-oncology nurses approached, 25 nurses (18 inpatient, 7 outpatient) were recruited. 49 patients with SCD were approached, and 25 patients (20 HbSS, 2 HbSβ 0, 1 HbSC, 1 HbSβ +, 1 HPHF) consented (Table 1). Four of the patients with SCD had prior curative hematopoietic stem cell transplants. The providers worked in the nursing field for a median of 6.0 [IQR 3.0-9.0] years. Recruited participants completed all study activities, including pre- and post-gameplay assessments. Patients with SCD completed the game with a median time of 17.0 [IQR 11.5-20.5] minutes. With data from 12 providers, the median gameplay time was 12.5 [IQR 10.0-16.5] minutes. All participants (p < 0.001), including within the provider (p < 0.001) and patient (p = 0.019) cohorts, showed increase in knowledge after gameplay (Fig. 1). Both providers and patients indicated the game was of high quality and relevance (Table 2). Patients wrote: "It was helpful to know about my sickness. The treatment part was helpful," and, "The terms were helpful because I didn't know them before." One provider wrote, "I liked how there were helpful links that I could click on for more info." Some suggestions for improvement included an introductory slide about SCD and a back button. Provider negative attitudes (Q1-6, Fig. 2) were reduced (p = 0.0072) post-gameplay, but positive attitudes did not significantly change (Q7-10, Fig. 2). Providers also showed a significant decrease (p=0.0014) in the belief that patients changing their behavior around providers indicates inappropriate drug-seeking behavior (Fig. 3). Conclusion Patients and providers demonstrated significant improvement in SCD knowledge after playing GRAPES. Providers also held reduced negative attitudes towards patients with SCD post-gameplay. In the context of positive feedback from both cohorts, this study demonstrates the feasibility and acceptability of the GRAPES tool as a potential digital, behavioral intervention to decrease stigma against SCD patients and provide engaging educational materials for patients and their providers in different clinical settings. Our GRAPES tool won first prize in the 2021 NHLBI Hope for SCD Challenge (www.tinyurl.com/NIHgrapes). We are excited to continue evaluating the benefits of the GRAPES tool in a larger multi-institutional study and collaborate with the NHLBI for future dissemination among patients, families, and providers. Figure 1 Figure 1. Disclosures Badawy: Vertex Pharmaceuticals Inc: Consultancy; Bluebird Bio Inc: Consultancy; Sanofi Genzyme: Consultancy. Fields: Global Blood Therapeutics: Consultancy; Proclara Biosciences: Current equity holder in publicly-traded company.

Large-vessel vasculopathy (LVV) increases stroke risk in pediatric sickle cell disease beyond the baseline elevated stroke risk in this vulnerable population. The mechanisms underlying this added risk and its unique impact on the developing brain are not established.We analyzed magnetic resonance imaging and angiography scans of 66 children with sickle cell disease and infarcts by infarct density heatmaps and Jacobian determinants, a metric utilized to delineate focal volume change, to investigate if infarct location, volume, frequency, and cerebral atrophy differed among hemispheres with and without LVV.Infarct density heatmaps demonstrated infarct "hot spots" within the deep white matter internal border zone region in both LVV and non-LVV hemispheres, but with greater infarct density and larger infarct volumes in LVV hemispheres (2.2 mL versus 0.25 mL, P 0.001). Additional scattered cortical infarcts in the internal carotid artery territory occurred in LVV hemispheres, but were rare in non-LVV hemispheres. Jacobian determinants revealed greater atrophy in gray and white matter of the parietal lobes of LVV compared with non-LVV hemispheres.Large-vessel vasculopathy in sickle cell disease appears to increase ischemic vulnerability in the borderzone region, as demonstrated by the increased frequency and extent of infarction within deep white matter, and increased risk of focal atrophy. Scattered infarctions across the LVV-affected hemispheres suggest additional stroke etiologies of vasculopathy (i.e., thromboembolism) in addition to chronic hypoxia-ischemia.

On June 5, 2015 the International Pediatric Stroke Study and the Stroke Imaging Laboratory for Children cohosted a unique workshop focused on developing neuroimaging research in pediatric stroke. Pediatric neurologists, neuroradiologists, interventional neuroradiologists, physicists, nurse practitioners, neuropsychologists, and imaging research scientists from around the world attended this one-day meeting. Our objectives were to (1) establish a group of experts to collaborate in advancing pediatric neuroimaging for stroke, (2) develop consensus clinical and research magnetic resonance imaging protocols for pediatric stroke patients, and (3) develop imaging-based research strategies in pediatric ischemic stroke. This article provides a summary of the meeting proceedings focusing on identified challenges and solutions and outcomes from the meeting. Further details on the workshop contents and outcomes are provided in three additional articles in the current issue of Pediatric Neurology.

Children with sickle cell anemia (SCA) experience a host of neurologic complications, including cognitive dysfunction, silent and overt stroke. Oxygen extraction fraction (OEF), the percent of oxygen removed from the blood into the brain tissue, can increase to compensate for decreased oxygen delivery and maintain the cerebral metabolic rate of oxygen utilization (CMRO2), as stroke occurs with a decrease in CMRO2. Elevated OEF is an independent predictor for ischemic injury in adults without SCA. We have previously shown that OEF is increased in children with SCA compared to healthy controls. Furthermore, the region of the brain with greatest elevation in OEF in SCA co-localizes with the regions at greatest risk for stroke, and OEF indirectly correlates with hemoglobin. However, it remains unclear if OEF is only elevated due to decreased arterial oxygen content with severe anemia in SCA, or if other factors contribute to this ongoing cerebral metabolic stress. We prospectively obtained brain MRIs in children with SCA, children with non-sickle cell anemia (ACTL) and healthy controls (CTL) to test our hypothesis that all children with anemia would have elevated OEF compared to controls, but those with SCA would have more elevated OEF than children with non-sickle cell anemia. Brain MRI measured voxel-wise OEF with an asymmetric spin echo sequence. OEF processing is described in Fields et al. Blood. 2019; 133(22):2436-2444. Group comparisons were made with a Mann-WhitneyUor chi-square tests. General linear models were used to understand the difference in whole brain (WB), gray matter (GM) and white matter (WM) OEF between cohorts while controlling for hemoglobin. Table 1 describes the 78 participants (20 CTL, 17 ACTL, 41 SCA). The CTL cohort includes 11 HbAA and 9 HbAS participants; the ACTL cohort includes 4 hereditary spherocytosis, 1 congenital dyserythropoietic anemia, 1 beta thalassemia intermedia, 6 iron deficiency, 4 aplastic anemia and 1 loxoscelism participant; the SCA cohort includes 36 HbSS and 5 HbS beta thalassemia null participants. Hemoglobin was lower in the ACTL (p < 0.001) and SCA (p < 0.001) cohorts compared to CTL, but was not different between the ACTL and SCA cohorts (p = 0.682). Ninety percent of the SCA cohort was receiving hydroxyurea at a median dose of 29.1 [21.5-33.1] mg/kg/day, and none were receiving chronic transfusions. Thirty-four percent of the SCA cohort had a history of silent cerebral infarct, while none had a history of overt stroke or vasculopathy identified on screening MRA. OEF was significantly elevated in the ACTL cohort compared to the CTL cohort, but significantly lower than the SCA cohort in the WB, GM and WM (Table 1, Figure 1). Final general linear models predicting WB, GM and WM OEF used a quadratic fit for hemoglobin, and included hemoglobin, hemoglobin2, and cohort as covariates. After accounting for hemoglobin and hemoglobin2(indicating that the relationship between hemoglobin and OEF is not linear), OEF is significantly higher in the SCA cohort compared to the ACTL cohort in WB, GM and WM, while there was not a significant difference in OEF between the ACTL and CTL cohorts (Table 2, Figure 2). The volume of WM with elevated OEF was significantly higher in the ACTL cohort compared to the CTL cohort (OEF 35%: p < 0.001, OEF 37%: p < 0.001, OEF 39%: p < 0.001), but lower in ACTL cohort compared to the SCA cohort (OEF 35%: p = 0.032, OEF 37%: p = 0.028, OEF 39%: p = 0.029). We conclude that OEF is significantly higher in children with SCA compared to age- and sex-matched children that are equally anemic for reasons other than SCA. While severity of anemia was a significant predictor of OEF, cohort (SCA vs. ACTL) remained an independent predictor of OEF across the WB, GM and WM while accounting for hemoglobin. These data suggest that further investigation is required to understand additional covariates contributing to increased cerebral metabolic stress, as measured by OEF, in children with SCA, as these may be clinical targets to reduce OEF and provide further neuroprotection in this vulnerable population. Disclosures Ford: Bluebird Bio: Honoraria. Lee:Biogen: Research Funding. Fields:Global Blood Therapeutics: Other: Speaking engagement without financial compensation; Proclara Biosciences: Current equity holder in private company; Bluebird Bio: Honoraria.

Background: Children with sickle cell anemia (SCA) invoke compensatory mechanisms to meet cerebral oxygen demand in the setting of low oxygen carrying capacity. Whereas cerebral blood flow (CBF) is largely regulated by cerebral arterioles as one compensatory mechanism, we sought to determine if the cross-sectional area of the large in-flow arteries was also increased. Methods: Children and young adults with SCA underwent 3 Tesla magnetic resonance angiography (MRA) and imaging (MRI) with pseudocontinuous arterial spin labeling (pCASL) and asymmetric spin echo sequence to measure CBF and oxygen extraction fraction (OEF) respectively. Using the double oblique method, we measured artery diameters and calculated the area (A) of the vessel as A=πr 2 . The total inflow area (A T-inflow ) was the summation of the areas of distal portions of both internal carotid arteries and basilar artery. CBF, OEF, arterial oxygen content [(CaO 2 ) = 1.36*Hemoglobin*%saturation on pulse oximetry] and A T-inflow were compared between groups with nonparametric statistics. Spearman’s correlation determined relationship of A T-inflow with other variables. Results: Data was available for 29 subjects with SCA (median age 15 years (range 9-26), 45% male) and 17 age-matched controls (15y (range 9-18), 47% male) underwent scanning. Children with SCA had larger A T-inflow (36 [29, 40] mm 2 ) compared to age-matched controls (29 [26, 31] mm 2 , p=0.01). CBF and OEF were higher (p=0.001, p=0.002), and CaO 2 was lower (pT-inflow positively correlated with CBF (p=0.002) and OEF (p2 (p=0.02; Figure ). Conclusion: Increased cross sectional area of large cerebral arteries may provide an additional compensatory mechanism in SCA to augment CBF and aid in meeting cerebral oxygen demand. Further work is needed to determine if MRA measurements provide a non-invasive precursor to increased cerebral metabolic stress and stroke risk.

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, χ2 (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.

Background and Purpose— Sickle cell disease (SCD) and arteriopathy are pediatric stroke risk factors that are not mutually exclusive. The relative contributions of sickled red blood cells and arteriopathy to stroke risk are unknown, resulting in unclear guidelines for primary and secondary stroke prevention when both risk factors are present. We hypothesized that despite similarities in clinical presentation and radiographic appearance of arteriopathies, stroke evaluation and management differ in children with SCD compared with those without SCD. Methods— We compared presentation and management of children with and without SCD enrolled in the IPSS (International Pediatric Stroke Study) with acute arterial ischemic stroke, according to SCD and arteriopathy status. Regression modeling determined relative contribution of SCD and arteriopathy in variables with significant frequency differences. Results— Among 930 childhood arterial ischemic strokes, there were 98 children with SCD, 67 of whom had arteriopathy, and 466 without SCD, 392 of whom had arteriopathy. Arteriopathy, regardless of SCD status, increased likelihood of hemiparesis (odds ratio [OR], 1.94; 95% CI, 1.46–2.56) and speech abnormalities (OR, 1.67; 95% CI, 1.29–2.19). Arteriopathy also increased likelihood of headache but only among those without SCD (OR, 1.89; 95% CI, 1.40–2.55). Echocardiograms were less frequently obtained in children with SCD (OR, 0.58; 95% CI, 0.37–0.93), but the frequency of identified cardiac abnormalities was similar in both groups ( P =0.57). Children with SCD were less likely to receive antithrombotic therapy, even in the presence of arteriopathy (OR, 0.14; 95% CI, 0.08–0.22). Arteriopathy was associated with a significantly higher likelihood of antithrombotic therapy in children without SCD (OR, 5.36; 95% CI, 3.55–8.09). Conclusions— Arteriopathy, and not SCD status, was most influential of stroke presentation. However, SCD status influenced stroke management because children with SCD were less likely to have echocardiograms or receive antithrombotic therapy. Further work is needed to determine whether management differences are warranted.

Objective To determine the clinical variances between strokes and stroke mimics in a pediatric immunocompromised population that consists of children with central nervous system (CNS) and non-CNS malignancies and a history of solid organ transplantation. Methods We performed a retrospective cohort analysis of stroke alert activations in patients with high-grade gliomas, low-grade gliomas, atypical teratoid rhabdoid tumors, rare CNS tumors, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, osteosarcoma, and solid organ transplants at St. Louis Children’s Hospital between February 2013 and September 2019. We categorized final diagnoses as strokes or stroke mimics. We classified diagnoses as a neurologic emergency if the diagnosis necessitated changes in management. Results Out of 217 stroke alerts, 31 alerts occurred for 28 patients meeting inclusion criteria. All final diagnoses constituted neurologic emergencies, including: stroke (39%), chemotherapy-related neurotoxicity (29%), tumor progression (19%), and seizures/posterior reversible encephalopathy syndrome (13%). Patients meeting inclusion criteria with strokes and stroke mimics presented similarly, with the exception of altered mental status, which was more prevalent in patients with strokes than stroke mimics (p = 0.03). One child received hyperacute thrombectomy for stroke. Only 58% of children with stroke mimics had complete resolution of their presenting neurologic symptoms. Children with strokes and stroke mimics had similar mortality incidences of 33% and 37%, respectively. Conclusions Although all acute neurologic changes in immunocompromised children are not strokes, stroke mimics in this population are neither benign nor self-limited and carry long-term neurologic morbidity and mortality. This study highlights the utility of an acute stroke evaluation infrastructure and the need for acute and long-term neurology involvement in the care of these patients.

Background Children with sickle cell disease (SCD) and moyamoya may benefit from indirect cerebral revascularization surgery in addition to chronic blood transfusion therapy for infarct prevention. We sought to compare overt and silent infarct recurrence rates in children with SCD undergoing revascularization. Methods This was a retrospective cohort study of all children with SCD and moyamoya treated at two children's hospitals. Clinical events and imaging studies were reviewed. Results Twenty-seven children with SCD and confirmed moyamoya receiving chronic transfusion therapy were identified, of whom 12 underwent indirect cerebral revascularization. Two subjects had postoperative transient ischemic attacks and another had a subarachnoid blood collection, none of which caused permanent consequences. Two subjects had surgical wound infections. Among these 12 children, the rate of overt and silent infarct recurrence decreased from 13.4 infarcts/100 patient-years before revascularization to 0 infarcts/100 patient-years after revascularization (P = 0.0057); the postrevascularization infarct recurrence rate was also significantly lower than the overall infarct recurrence of 8.87 infarcts/100 patient-years in 15 children without cerebral revascularization (P = 0.025). Conclusions The rate of overt and silent infarct recurrence was significantly lower following indirect cerebral revascularization. A prospective study of cerebral revascularization in children with SCD is needed.

Introduction: Arteriopathy is a leading cause of pediatric stroke. Cerebral arteriopathies may be diffuse, such as in radiation or moyamoya arteriopathies, limiting contralateral normal comparisons. Normative data for comparison and identification of diffuse arteriopathy is not currently available. Cerebral blood flow has been shown to vary based on age and sex; therefore, we aimed to determine potential age- and sex-related differences in cerebral artery size. Method: Healthy children and young adults aged 4 - 40 years were recruited to undergo 3D time-of-flight magnetic resonance angiography (MRA). Motion-degraded studies were excluded. The mean diameters of segments of the internal carotid artery (ICA), middle cerebral artery (MCA), anterior cerebral artery (ACA), basilar artery (BA) and ophthalmic artery (OA) were manually determined using a double-oblique technique. Mixed model regression of vessel diameters determined significance of age and sex. Results: MRAs of 22 children (ages 4-21 years; 12 male) and 13 adults (ages 22-38 years; 9 male) were analyzed. On mixed model regression, younger participants maintained larger diameters for ICA (p=0.03), MCA (p Conclusion: Normal cerebral artery size in vessels contributing to brain perfusion is largest in younger children and diminishes with age, likely reflecting higher cerebral blood flows observed in younger children. Age-specific normative data is needed to identify diffuse cerebral arteriopathy in children and young adults.

Introduction: Silent cerebral infarcts (SCIs) in sickle cell disease (SCD) begin in early childhood and increase with age, affecting 50% by age 30. SCIs often occur in the watershed area, where cerebral blood flow (CBF) is low, and oxygen extraction fraction (OEF) is high. Diffusion tensor imaging (DTI) measures white matter integrity; lower fractional anisotropy (FA) and higher mean diffusivity (MD) may precede the appearance of SCIs. We hypothesized that age and oxygen metabolic stress, defined by elevated watershed OEF, are associated with disruption of white matter integrity as measured by FA and MD. Methods: Children and young adults with and without SCD were recruited for brain MRI (T1, FLAIR, pseudocontinuous arterial spin label (CBF), asymmetric spin echo (OEF) and DTI). We averaged CBF maps of non-SCD participants and created a watershed region of interest (ROI), defined as CBF Results: Fifty SCD and 53 control participants, age 6-39 years, underwent MRI. Within all normal appearing white matter, FA decreased (p Conclusion: Disruption of white matter integrity worsens with early life aging, particularly in SCD. Oxygen metabolic stress within the watershed region, a region at high risk for SCIs, is associated with lower FA and higher MD, suggesting OEF may provide an early tissue marker of ischemic vulnerability in SCD, prior to developing SCIs.

Acute ischemic stroke is a neurological emergency that can be treated with time-sensitive interventions, including intravenous thrombolysis and endovascular approaches. Extensive study has demonstrated that rapid assessment and treatment are essential for improving neurological outcome. For this reason, acute ischemic stroke was chosen as an Emergency Neurological Life Support protocol. The protocol focuses on the first hour following the onset of neurological deficit.

© 2015 Elsevier Inc. All rights reserved. Background Cardiac disease is a leading cause of stroke in children, yet limited data support the current stroke prevention and treatment recommendations. A multidisciplinary panel of clinicians was convened in February 2014 by the International Pediatric Stroke Study group to identify knowledge gaps and prioritize clinical research efforts for children with cardiac disease and stroke. Results Significant knowledge gaps exist, including a lack of data on stroke incidence, predictors, primary and secondary stroke prevention, hyperacute treatment, and outcome in children with cardiac disease. Commonly used diagnostic techniques including brain computed tomography and ultrasound have low rates of stroke detection, and diagnosis is frequently delayed. The challenges of research studies in this population include epidemiologic barriers to research such as small patient numbers, heterogeneity of cardiac disease, and coexistence of multiple risk factors. Based on stroke burden and study feasibility, studies involving mechanical circulatory support, single ventricle patients, early stroke detection strategies, and understanding secondary stroke risk factors and prevention are the highest research priorities over the next 5-10 years. The development of large-scale multicenter and multispecialty collaborative research is a critical next step. The designation of centers of expertise will assist in clinical care and research. Conclusions There is an urgent need for additional research to improve the quality of evidence in guideline recommendations for cardiogenic stroke in children. Although significant barriers to clinical research exist, multicenter and multispecialty collaboration is an important step toward advancing clinical care and research for children with cardiac disease and stroke.

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 (CaO2). We hypothesized that exchange transfusions would decrease CBF and OEF by increasing CaO2, 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; P < .001) and decreased Hb S (from 39.7% to 24.3%; P < .001). Transfusions reduced CBF (from 88 to 82.4 mL/100 g per minute; P = .004) and OEF (from 34.4% to 31.2%; P < .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 (P < .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.