Melissa C. Gindville

Non-invasive imaging of oxygen extraction fraction in adults with sickle cell anaemia

Sickle cell anaemia is a monogenetic disorder with a high incidence of stroke. While stroke screening procedures exist for children with sickle cell anaemia, no accepted screening procedures exist for assessing stroke risk in adults. The purpose of this study is to use novel magnetic resonance imaging methods to evaluate physiological relationships between oxygen extraction fraction, cerebral blood flow, and clinical markers of cerebrovascular impairment in adults with sickle cell anaemia. The specific goal is to determine to what extent elevated oxygen extraction fraction may be uniquely present in patients with higher levels of clinical impairment and therefore may represent a candidate biomarker of stroke risk. Neurological evaluation, structural imaging, and the non-invasive T2-relaxation-under-spin-tagging magnetic resonance imaging method were applied in sickle cell anaemia (n = 34) and healthy race-matched control (n = 11) volunteers without sickle cell trait to assess whole-brain oxygen extraction fraction, cerebral blood flow, degree of vasculopathy, severity of anaemia, and presence of prior infarct; findings were interpreted in the context of physiological models. Cerebral blood flow and oxygen extraction fraction were elevated (P < 0.05) in participants with sickle cell anaemia (n = 27) not receiving monthly blood transfusions (interquartile range cerebral blood flow = 46.2-56.8 ml/100 g/min; oxygen extraction fraction = 0.39-0.50) relative to controls (interquartile range cerebral blood flow = 40.8-46.3 ml/100 g/min; oxygen extraction fraction = 0.33-0.38). Oxygen extraction fraction (P < 0.0001) but not cerebral blood flow was increased in participants with higher levels of clinical impairment. These data provide support for T2-relaxation-under-spin-tagging being able to quickly and non-invasively detect elevated oxygen extraction fraction in individuals with sickle cell anaemia with higher levels of clinical impairment. Our results support the premise that magnetic resonance imaging-based assessment of elevated oxygen extraction fraction might be a viable screening tool for evaluating stroke risk in adults with sickle cell anaemia.

Silent cerebral infarcts and cerebral aneurysms are prevalent in adults with sickle cell anemia.

To the editor: Silent cerebral infarcts (SCIs) are the most commonly recognized cause of neurologic injury in patients with sickle cell anemia (SCA), identified in ≥20% of children. In children with SCA, SCIs are associated with an average 5 full-scale IQ point decrement,[1][1] poor academic

Pediatric Acute Stroke Protocol Activation in a Children’s Hospital Emergency Department

Background and Purpose— Pediatric acute stroke teams are a new phenomenon. We sought to characterize the final diagnoses of children with brain attacks in the emergency department where the pediatric acute stroke protocol was activated and to describe the time to neurological evaluation and neuroimaging. Methods— Clinical and demographic information was obtained from a quality improvement database and medical records for consecutive patients (age, ⩽20 years) presenting to a single institution’s pediatric emergency department where the acute stroke protocol was activated between April 2011 and October 2014. Stroke protocol activation means that a neurology resident evaluates the child within 15 minutes, and urgent magnetic resonance imaging is available. Results— There were 124 stroke alerts (age, 11.2±5.2 years; 63 boys/61 girls); 30 were confirmed strokes and 2 children had a transient ischemic attack. Forty-six of 124 (37%) cases were healthy children without any significant medical history. Nonstroke neurological emergencies were found in 17 children (14%); the majority were meningitis/encephalitis (n=5) or intracranial neoplasm (n=4). Other common final diagnoses were complex migraine (17%) and seizure (15%). All children except 1 had urgent neuroimaging. Magnetic resonance imaging was the first study in 76%. The median time from emergency department arrival to magnetic resonance imaging was 94 minutes (interquartile range, 49–151 minutes); the median time to computed tomography was 59 minutes (interquartile range, 40–112 minutes). Conclusions— Of pediatric brain attacks, 24% were stroke, 2% were transient ischemic attack, and 14% were other neurological emergencies. Together, 40% had a stroke or other neurological emergency, underscoring the need for prompt evaluation and management of children with brain attacks.

Pediatric Intracerebral Hemorrhage Score: A Simple Grading Scale for Intracerebral Hemorrhage in Children

Background and Purpose— The intracerebral hemorrhage (ICH) score is the most commonly used clinical grading scale for outcome prediction after adult ICH. We created a similar scale in children to inform clinical care and assist in clinical research. Methods— Children, full-term newborns to 18 years, with spontaneous ICH were prospectively enrolled from 2007 to 2012 at 3 centers. The pediatric ICH score was created by identifying factors associated with poor outcome. The score’s ability to detect moderate disability or worse and severe disability or death was examined with sensitivity, specificity, and area under the receiver operating characteristic curve. Results— The pediatric ICH score components include ICH volume >2% to 3.99% of total brain volume (TBV): 1 point; ICH volume ≥4% TBV: 2 points; acute hydrocephalus: 1 point; herniation: 1 point; and infratentorial location: 1 point. The score ranges from 0 to 5. At 3-month follow-up of 60 children, 10 were severely disabled or dead, 30 had moderate disability, and 20 had good recovery. A pediatric ICH score ≥1 predicted moderate disability or worse with a sensitivity of 75% (95% confidence interval [CI], 59% to 87%) and a specificity of 70% (95% CI, 46% to 88%). A pediatric ICH score ≥2 predicted severe disability or death with a sensitivity and specificity of 90% (95% CI, 55% to 99%) and 68% (95% CI, 53% to 80%), respectively. The area under the receiver operating characteristic curve for classifying outcome as severe disability or death was 0.88 (95% CI, 0.78–0.97). Conclusions— The pediatric ICH score is a simple clinical grading scale that may ultimately be used for risk stratification, clinical care, and research.

Cerebral hemodynamics and pseudo-continuous arterial spin labeling considerations in adults with sickle cell anemia

Sickle cell anemia (SCA) is a genetic disorder resulting in reduced oxygen carrying capacity and elevated stroke risk. Pseudo‐continuous arterial spin labeling (pCASL) measures of cerebral blood flow (CBF) may have relevance for stroke risk assessment; however, the effects of elevated flow velocity and reduced bolus arrival time (BAT) on CBF quantification in SCA patients have not been thoroughly characterized, and pCASL model parameters used in healthy adults are often applied to patients with SCA. Here, cervical arterial flow velocities and pCASL labeling efficiencies were computed in adults with SCA (n = 19) and age‐ and race‐matched controls without sickle trait (n = 7) using pCASL in sequence with phase contrast MR angiography (MRA). Controls (n = 7) and a subgroup of patients (n = 8) also underwent multi‐post‐labeling‐delay pCASL for BAT assessment. Mean flow velocities were elevated in SCA adults (velocity = 28.3 ± 4.1 cm/s) compared with controls (velocity = 24.5 ± 3.8 cm/s), and mean pCASL labeling efficiency (α) was reduced in SCA adults (α = 0.72) relative to controls (α = 0.91). In patients, mean whole‐brain CBF from phase contrast MRA was 91.8 ± 18.1 ml/100 g/min, while mean pCASL CBF when assuming a constant labeling efficiency of 0.86 was 75.2 ± 17.3 ml/100 g/min (p < 0.01), resulting in a mean absolute quantification error of 23% when a labeling efficiency appropriate for controls was assumed. This difference cannot be accounted for by BAT (whole‐brain BAT: control, 1.13 ± 0.06 s; SCA, 1.02 ± 0.09 s) or tissue T1 variation. In conclusion, BAT variation influences pCASL quantification less than elevated cervical arterial velocity and labeling efficiency variation in SCA adults; thus, a lower labeling efficiency (α = 0.72) or subject‐specific labeling efficiency should be incorporated for SCA patients.

Cognitive and attentional functioning in adolescents and young adults with Tetralogy of Fallot and d-transposition of the great arteries

The objective of this study is to investigate cognitive and attentional function in adolescents and young adults with operated congenital heart disease. Previous research has indicated that children with congenital heart disease have deficits in broad areas of cognitive function. However, less attention has been given to survivors as they grow into adolescence and early adulthood. The participants were 18 non-syndromic adolescents and young adults with tetralogy of Fallot and d-transposition of the great arteries that required cardiac surgery before the age of 5 years, and 18 healthy, unaffected siblings (11–22 years of age for both groups). Cases with congenital heart disease and their siblings were administered Wechsler Intelligence scales and reported attention problems using the Achenbach System of Empirically Based Assessments. Cases were compared to both healthy siblings and established norms. Cases performed significantly lower than siblings on full scale IQ and processing speed, and significantly lower than norms on perceptual reasoning. Cases also reported more attention problems compared to both siblings and norms. Effect sizes varied with medium-to-large effects for processing speed, perceptual reasoning, working memory, and attention problems. Findings suggest that neurocognitive function may continue to be affected for congenital heart disease survivors in adolescence and young adulthood, and that comparisons to established norms may underestimate neurocognitive vulnerabilities.

Cognitive functioning over 2 years after intracerebral hemorrhage in school-aged children

Previous research investigating outcomes after pediatric intracerebral hemorrhage (ICH) has generally been limited to global and sensorimotor outcomes. This study examined cognitive outcomes after spontaneous ICH in school‐aged children with serial assessments over 2 years after stroke.

Association of Blood Pressure, Blood Glucose, and Temperature With Neurological Outcome After Childhood Stroke

IMPORTANCE To our knowledge, no evidence-based guidelines are available for the best medical management of blood pressure, blood glucose levels, and temperature in pediatric patients after arterial ischemic stroke. OBJECTIVE To determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome. DESIGN, SETTING, AND PARTICIPANTS We performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between January 2009 and December 2013 at a tertiary academic childrens hospital. Ninety-eight children with stroke were identified by an International Classification of Diseases, Ninth Revision, code search and medical record review. Blood pressure, blood glucose, and temperature data were collected for 5 days after the stroke. Hypertension was defined as systolic blood pressure at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days. Hypotension was defined as systolic and/or diastolic blood pressure below the fifth percentile for age, sex, and height for 2 consecutive recordings. Hyperglycemia was defined as a blood glucose level of 200 mg/dL or greater. Morbidity and mortality at 3 months were documented. Data analyses were performed from July 1, 2014, to December 31, 2015. INTERVENTIONS OR EXPOSURES Abnormal blood pressure, blood glucose levels, and fever in the setting of arterial ischemic stroke. MAIN OUTCOMES AND MEASURES The a priori outcome measure was poor clinical outcome, defined as a Pediatric Stroke Outcome Measure score of 1 or greater, which represents a moderate neurological deficit. RESULTS The median (interquartile range) age of the 98 children was 6.0 (0.6-14.3) years, and 58 (59.2%) were male. Hypertension was present in 64 (65.3%), hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). The strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% CI, 2.0-15.4; P = .001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% CI, 1.2-12.4; P = .02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at 3-month follow-up and was not associated with poor neurological outcome. CONCLUSIONS AND RELEVANCE Abnormalities of blood pressure, blood glucose levels, and temperature are prevalent in children with arterial ischemic stroke. Infarct volume and hyperglycemia were associated with poor neurological outcome but hypertension and fever were not. Prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.

Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients

Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38–0.45) compared to controls (interquartile range = 0.29–0.38), similar to participants with SCA (interquartile range = 0.37–0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF.

Preliminary evidence for cerebral capillary shunting in adults with sickle cell anemia

Elevated flow velocities in adults with sickle cell anemia (SCA) may cause rapid erythrocyte transit through capillaries. This phenomenon could present as dural venous sinus hyperintensity on arterial spin labeling (ASL)-MRI and could be indicative of capillary shunting. Here, the prevalence of ASL venous hyperintensities and association with relevant physiology in adults with SCA was investigated. SCA (n = 46) and age-matched control (n = 16) volunteers were recruited for 3.0 T MRI. Pseudo-continuous ASL-MRI was acquired for cerebral blood flow (CBF) calculation and venous hyperintensity determination; venous signal intensity and a categorical venous score (three raters; 0 = no hyperintensity, 1 = focal hyperintensity, and 2 = diffuse hyperintensity) were recorded. Flow velocity in cervical internal carotid artery segments was determined from phase contrast data (venc = 40 cm/s) and whole-brain oxygen extraction fraction (OEF) was determined from T2-relaxation-under-spin-tagging MRI. Cerebral metabolic rate of oxygen was calculated as the product of OEF, CBF, and blood oxygen content. ASL venous hyperintensities were significantly (p < 0.001) more prevalent in SCA (65%) relative to control (6%) participants and were associated with elevated flow velocities (p = 0.03). CBF (p < 0.001), but not OEF, increased with increasing hyperintensity score. Prospective trials that evaluate this construct as a possible marker of impaired oxygen delivery and stroke risk may be warranted.