Regional and bilateral MRI and gene signatures in facioscapulohumeral dystrophy: implications for clinical trial design and mechanisms of disease progression.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA, indicating that regional biopsies can accurately measure progression in the whole muscle and providing a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design. An unanticipated finding was the strong correlations of molecular signatures in the bilateral comparisons, including markers of B-cells and other immune cell populations, suggesting that a systemic immune cell infiltration of skeletal muscle might have a role in disease progression.

Variants in PTEN Are Associated With a Diverse Spectrum of Cortical Dysplasia.

BACKGROUND: Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited. METHODS: Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging. RESULTS: Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants. CONCLUSIONS: A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.

Validation of the association between MRI and gene signatures in facioscapulohumeral dystrophy muscle: implications for clinical trial design.

Identifying the aberrant expression of DUX4 in skeletal muscle as the cause of facioscapulohumeral dystrophy (FSHD) has led to rational therapeutic development and clinical trials. Several studies support the use of MRI characteristics and the expression of DUX4-regulated genes in muscle biopsies as biomarkers of FSHD disease activity and progression, but reproducibility across studies needs further validation. We performed lower-extremity MRI and muscle biopsies in the mid-portion of the tibialis anterior (TA) muscles bilaterally in FSHD subjects and validated our prior reports of the strong association between MRI characteristics and expression of genes regulated by DUX4 and other gene categories associated with FSHD disease activity. We further show that measurements of normalized fat content in the entire TA muscle strongly predict molecular signatures in the mid-portion of the TA. Together with moderate-to-strong correlations of gene signatures and MRI characteristics between the TA muscles bilaterally, these results suggest a whole muscle model of disease progression and provide a strong basis for inclusion of MRI and molecular biomarkers in clinical trial design.

Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Gadolinium retention: should pediatric radiologists be concerned, and how to frame conversations with families.

Gadolinium retention in the brain and other organs has recently been identified by imaging and confirmed histologically. No direct clinical effects of gadolinium retention, which occurs after gadolinium-based contrast agent (GBCA) administration for MRI, have been scientifically accepted at this time. However, there is understandable concern among medical professionals and the public about the potential effects of gadolinium retention, particularly in the brain. Part of this concern might stem from the identification of nephrogenic systemic fibrosis caused by GBCAs in people with severe renal failure in 2006. This article briefly describes the characteristics of GBCAs; reviews and differentiates gadolinium retention, nephrogenic systemic fibrosis, and "gadolinium deposition disease" or "gadolinium toxicity"; and discusses societal guidelines and current usage in children. With the belief that GBCAs should not be withheld for appropriate indications in the absence of evidence of its potential risks, we offer a framework for determining when GBCA use is appropriate and suggestions for discussing its risks and benefits with children and their families.

Non-inferiority of a non-gadolinium-enhanced magnetic resonance imaging follow-up protocol for isolated optic pathway gliomas.

BACKGROUND: Pediatric patients with optic pathway gliomas (OPGs) typically undergo a large number of follow-up MRI brain exams with gadolinium-based contrast media (GBCM), which have been associated with gadolinium tissue retention. Therefore, careful consideration of GBCM use in these children is warranted. OBJECTIVE: To investigate whether GBCM is necessary for OPG MR imaging response assessment using a blinded, non-inferiority, multi-reader study. MATERIALS AND METHODS: We identified children with OPG and either stable disease or change in tumor size on MRI using a regional cancer registry serving the U.S. Pacific Northwest. For each child, the two relevant, consecutive MRI studies were anonymized and standardized into two imaging sets excluding or including GBCM-enhanced images. Exam pairs were compiled from 42 children with isolated OPG (19 with neurofibromatosis type 1), from a population of 106 children with OPG. We included 28 exam pairs in which there was a change in size between exams. Seven pediatric radiologists measured tumor sizes during three blinded sessions, spaced by at least 1 week. The first measuring session excluded GBCM-enhanced sequences; the others did not. The primary endpoint was intra-reader agreement for ≥ 25% change in axial cross-product measurement, using a 12% non-inferiority threshold. RESULTS: Analysis demonstrated an overall 1.2% difference (95% confidence interval, -3.2% to 5.5%) for intra-reader agreement using a non-GBCM-enhanced protocol and background variability. CONCLUSION: A non-GBCM-enhanced protocol was non-inferior to a GBCM-enhanced protocol for assessing change in size of isolated OPGs on follow-up MRI exams.

A clinically applicable functional MRI memory paradigm for use with pediatric patients.

OBJECTIVE: Clinically employable functional MRI (fMRI) memory paradigms are not yet established for pediatric patient epilepsy surgery workups. Seeking to establish such a paradigm, we evaluated the effectiveness of memory fMRI tasks we developed by quantifying individual activation in a clinical pediatric setting, analyzing patterns of activation relative to the side of temporal lobe (TL) pathology, and comparing fMRI and Wada test results. METHODS: We retrospectively identified 72 patients aged 6.7-20.9 years with pathology (seizure focus and/or tumor) limited to the TL who had attempted memory and language fMRI tasks over a 9-year period as part of presurgical workups. Memory fMRI tasks required visualization of autobiographical memories in a block design alternating with covert counting. Language fMRI protocols involved verb and sentence generation. Scans were both qualitatively interpreted and quantitatively assessed for blood oxygenation level dependent (BOLD) signal change using region of interest (ROI) masks. We calculated the percentage of successfully scanned individual cases, compared 2 memory task activation masks in cases with left versus right TL pathology, and compared fMRI with Wada tests when available. Patients who had viable fMRI and Wada tests had generally concordant results. RESULTS: Of the 72 cases, 60 (83%), aged 7.6-20.9 years, successfully performed the memory fMRI tasks and 12 (17%) failed. Eleven of 12 unsuccessful scans were due to motion and/or inability to perform the tasks, and the success of a twelfth was indeterminate due to orthodontic metal artifact. Seven of the successful 60 cases had distorted anatomy that precluded employing predetermined masks for quantitative analysis. Successful fMRI memory studies showed bilateral mesial temporal activation and quantitatively demonstrated: (1) left activation (L-ACT) less than right activation (R-ACT) in cases with left temporal lobe (L-TL) pathology, (2) nonsignificant R-ACT less than L-ACT in cases with right temporal lobe (R-TL) pathology, and (3) lower L-ACT plus R-ACT activation for cases with L-TL versus R-TL pathology. Patients who had viable fMRI and Wada tests had generally concordant results. SIGNIFICANCE: This study demonstrates evidence of an fMRI memory task paradigm that elicits reliable activation at the individual level and can generally be accomplished in clinically involved pediatric patients. This autobiographical memory paradigm showed activation in mesial TL structures, and cases with left compared to right TL pathology showed differences in activation consistent with extant literature in TL epilepsy. Further studies will be required to assess outcome prediction.

Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.

OBJECTIVES: To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. STUDY DESIGN: The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. RESULTS: One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. CONCLUSIONS: Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.

Quantitative Assessment of the Intracranial Vasculature of Infants and Adults Using iCafe (Intracranial Artery Feature Extraction).

Comprehensive quantification of intracranial artery features may help to assess and understand regional variations of blood supply during early brain development and aging. We analyzed vasculature features of 27 healthy infants during natural sleep, 13 infants at 7-months (7.3 ± 1.0 month), and 14 infants at 12-months (11.7 ± 0.4 month), and 13 older healthy, awake adults (62.8 ± 8.7 years) to investigate age-related vascular differences as a preliminary study of vascular changes associated with brain development. 3D time-of-flight (TOF) magnetic resonance angiography (MRA) acquisitions were processed in iCafe, a technique to quantify arterial features (http://icafe.clatfd.cn), to characterize intracranial vasculature. Overall, adult subjects were found to have increased ACA length, tortuosity, and vasculature density compared to both 7-month-old and 12-month-old infants, as well as MCA length compared to 7-month-old infants. No brain laterality differences were observed for any vascular measures in either infant or adult age groups. Reduced skull and brain sharpness, indicative of increased head motion and brain/vascular pulsation, respectively, were observed in infants but not correlated with length, tortuosity, or vasculature density measures. Quantitative analysis of TOF MRA using iCafe may provide an objective approach for systematic study of infant brain vascular development and for clinical assessment of adult and pediatric brain vascular diseases.

Focal Cerebral Arteriopathy of Childhood: Clinical and Imaging Correlates.

Background and Purpose: Focal cerebral arteriopathy (FCA) of childhood with unilateral stenosis of the anterior circulation is reported to account for up to one-quarter of childhood arterial ischemic stroke, with stroke recurrence in 25% of cases. Limited knowledge regarding pathophysiology and outcome results in inconsistent treatment of FCA. Methods: Children with arterial ischemic stroke due to FCA between January 1, 2009, and January 1, 2019, were retrospectively identified at our institution which serves the US Pacific Northwest region. Electronic health record data, including neuroimaging studies, were reviewed, and the Pediatric Stroke Outcome Measure at 1 year was determined as the primary clinical end point. Results: Fifteen children were diagnosed with FCA, accounting for 19% of children with cerebral arteriopathies (n=77). Among children with FCA, the median age at the time of stroke was 6.8 years (Q1­Q3, 1.9­14.0 years). Four (20%) patients had worsening stroke, 3 of whom had concurrent infection. Three (20%) FCA cases were treated with steroids, one of whom had worsening stroke. Median Pediatric Stroke Outcome Measure at 1 year was 1.0 (Q1­Q3, 0.6­2.0). Variability in arteriopathy severity was observed within many patients. Patients with more severe arteriopathy using the Focal Cerebral Arteriopathy Severity Score had larger strokes and were more likely to have worsening stroke. The most common long-term neurological deficit was hemiparesis, which was present in 11 (73%) patients and associated with middle cerebral artery arteriopathy and infarcts. Conclusions: FCA may be less common than previously reported. Neuroimaging in FCA can help identify patients at greater risk for worsening stroke.

Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy.

BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. METHODS: We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. RESULTS: There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. CONCLUSIONS: Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.

Deep medullary vein engorgement and superficial medullary vein engorgement: two patterns of perinatal venous stroke.

Perinatal venous stroke has classically been attributed to cerebral sinovenous thrombosis with resultant congestion or thrombosis of the small veins draining the cerebrum. Advances in brain MRI, in particular susceptibility-weighted imaging, have enabled the visualization of the engorged small intracerebral veins, and the spectrum of perinatal venous stroke has expanded to include isolated congestion or thrombosis of the deep medullary veins and the superficial intracerebral veins. Congestion or thrombosis of the deep medullary veins or the superficial intracerebral veins can result in vasogenic edema, cytotoxic edema or hemorrhage in the territory of disrupted venous flow. Deep medullary vein engorgement and superficial medullary vein engorgement have characteristic findings on MRI and should be differentiated from neonatal hemorrhagic stroke.

Rapid Magnetic Resonance Imaging of the Spine in Neonates with Spinal Dysraphism.

BACKGROUND: The use of nonsedated T2-weighted Half-Fourier Acquisition Single-shot Turbo spin Echo magnetic resonance imaging (MRI) sequences in screening for spinal cord syrinx in neonates with spinal dysraphism has not been reported in the literature. We sought to review our experience using T2-weighted Half-Fourier Acquisition Single-shot Turbo spin Echo imaging of the spine (i.e., rapid spine MRI) in nonsedated neonates for detecting spinal cord syrinx in neonates with spinal dysraphism. METHODS: We performed a retrospective search of our radiology database for neonates with spinal dysraphism who had rapid spine MRI between May 2017 and February 2020. The images were reviewed in conjunction with clinical findings and standard spine imaging, when available. RESULTS: Thirty studies (in 29 neonates) fulfilled our inclusion criteria. Of the 26 neonates with myelomeningocele, 5 of them (19%) had spinal cord syrinx identified on neonatal rapid spine MRI. An additional 2 patients developed syrinx by 2 years of age. Potential pitfalls identified in interpreting rapid spine MRI include motion artifacts and distinguishing a severe holocord syrinx from a truncated spinal cord. CONCLUSIONS: Rapid spine MRI acquired without sedation or anesthesia may be used as a screening technique to detect spinal cord syrinx in neonates with spinal dysraphism.

Structural MRI and tract-based spatial statistical analysis of diffusion tensor imaging in children with hemimegalencephaly.

PURPOSE: To investigate the gross white matter abnormalities in the structural brain MR imaging as well as white matter microstructural alterations using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging (DTI) in both affected and contralateral cerebral hemispheres of children with hemimegalencephaly (HMEG). METHODS: From 2003 to 2019, we retrospectively reviewed brain MR images in 20 children (11 boys, 2 days-16.5 years) with HMEG, focusing on gross white matter abnormalities. DTI was evaluated in 12 patients (8 boys, 3 months-16.5 years) with HMEG and 12 age-, sex-, and magnetic field strength-matched control subjects. TBSS analysis was performed to analyze main white matter tracts. Regions of significant differences in fractional anisotropy (FA) were determined between HMEG and control subjects and between affected and contralateral hemispheres of HMEG. RESULTS: Gross white matter abnormalities were noted in both affected (n = 20, 100%) and contralateral hemisphere (n = 4, 20%) of HMEG. FA values were significantly decreased in both hemispheres of HMEG, compared with control subjects (P < 0.05). Contralateral hemispheres of HMEG showed regions with significantly decreased FA values compared with affected hemispheres (P < 0.05). CONCLUSIONS: In addition to gross white matter abnormalities particularly evident in affected hemispheres, DTI analysis detected widespread microstructural alterations in both affected and contralateral hemispheres in HMEG suggesting HMEG may involve broader abnormalities in neuronal networks.

A novel algorithm for refining cerebral vascular measurements in infants and adults.

BACKGROUND: Comprehensive quantification of intracranial vascular characteristics by vascular tracing provides an objective clinical assessment of vascular structure. However, weak signal or low contrast in small distal arteries, artifacts due to volitional motion, and vascular pulsation are challenges for accurate vessel tracing from 3D time-of-flight (3D-TOF) magnetic resonance angiography (MRA) images. NEW METHOD: A vascular measurement refinement algorithm is developed and validated for robust quantification of intracranial vasculature from 3D-TOF MRA. After automated vascular tracing, centerline positions, lumen radii and centerline deviations are jointly optimized to restrict traces to within vascular regions in the straightened curved planar reformation (CPR) views. The algorithm is validated on simulated vascular images and on repeat 3D-TOF MRA acquired from infants and adults. RESULTS: The refinement algorithm can reliably estimate vascular radius and correct deviated centerlines. For the simulated vascular image with noise level of 1 and deviation of centerline of 3, the mean radius difference is below 15.3 % for scan-rescan reliability. Vascular features from repeated clinical scans show significantly improved measurement agreement, with intra-class correlation coefficient (ICC) improvement from 0.55 to 0.7 for infants and from 0.59 to 0.92 for adults. COMPARISON WITH EXISTING METHODS: The refinement algorithm is novel because it utilizes straightened CPR views that incorporate information from the entire artery. In addition, the optimization corrects centerline positions, lumen radii and centerline deviations simultaneously. CONCLUSIONS: Intracranial vasculature quantification using a novel refinement algorithm for vascular tracing improves the reliability of vascular feature measurements in both infants and adults.

Magnetic resonance imaging correlates with electrical impedance myography in facioscapulohumeral muscular dystrophy.

INTRODUCTION: Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM variables with muscle structure measured by MRI. METHODS: We evaluated 20 patients with FSHD at two centers, comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHZ) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF). RESULTS: While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (ρ = -0.71, P < .001) and FF (ρ = -0.74, P < .001). DISCUSSION: This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials.

Risk of Intracranial Hemorrhage Following Intravenous tPA (Tissue-Type Plasminogen Activator) for Acute Stroke Is Low in Children.

Background and Purpose- Data regarding the safety and efficacy of intravenous tPA (tissue-type plasminogen activator) in childhood acute arterial ischemic stroke are inadequate. The TIPS trial (Thrombolysis in Pediatric Stroke; National Institutes of Health grant R01NS065848)-a prospective safety and dose-finding trial of intravenous tPA in acute childhood stroke-was closed for lack of accrual. TIPS sites have subsequently treated children with acute stroke in accordance with established institutional protocols supporting data collection on outcomes. Methods- Data on children treated with intravenous tPA for neuroimaging-confirmed arterial ischemic stroke were collected retrospectively from 16 former TIPS sites to establish preliminary safety data. Participating sites were required to report all children who were treated with intravenous tPA to minimize reporting bias. Symptomatic intracranial hemorrhage (SICH) was defined as ECASS (European Cooperative Acute Stroke Study) II parenchymal hematoma type 2 or any intracranial hemorrhage associated with neurological deterioration within 36 following tPA administration. A Bayesian beta-binomial model for risk of SICH following intravenous tPA was fit using a prior distribution based on the risk level in young adults (1.7%); to test for robustness, the model was also fit with uninformative and conservative priors. Results- Twenty-six children (age range, 1.1-17 years; median, 14 years; 12 boys) with stroke and a median pediatric National Institutes of Health Stroke Scale score of 14 were treated with intravenous tPA within 2 to 4.5 hours (median, 3.0 hours) after stroke onset. No patient had SICH. Two children developed epistaxis. Conclusions- The estimated risk of SICH after tPA in children is 2.1% (95% highest posterior density interval, 0.0%-6.7%; mode, 0.9%). Regardless of prior assumption, there is at least a 98% chance that the risk is <15% and at least a 93% chance that the risk is <10%. These results suggest that the overall risk of SICH after intravenous tPA in children with acute arterial ischemic stroke, when given within 4.5 hours after symptom onset, is low.

An update on the use of an arterial closure device following femoral arterial puncture in children.

BACKGROUND: The use of arterial closure devices in achieving femoral hemostasis has been well documented in adults but insufficiently studied in the pediatric population. An earlier study from our institution of 40 Angio-Seal devices in 38 patients concluded that the arterial closure device is safe in children with only a single minor complication. Ongoing experience with this device at our institution, however, suggests a higher rate of complication. OBJECTIVE: To retrospectively evaluate the safety and efficacy of the Angio-Seal in a pediatric population. MATERIALS AND METHODS: A retrospective analysis reviewed all cases in which the Angio-Seal was deployed from June 2011 to September 2017. Peri-procedural documentation was reviewed for pre-procedure labs, clinical effectiveness in achieving hemostasis and complications related to the use of this device. Logistic regression analysis was also used to evaluate the relationship between patient demographic, vessel size and indication for angiography, and the presence or absence of complications. RESULTS: During the study period, 48 additional Angio-Seal devices were deployed in 41 consecutive patients. Five patients were excluded for being older than 18 years. The mean age of the patients was 13.3 years (range: 4-18 years) with 18 patients female. The mean common femoral artery diameter was 5.98 mm in short axis diameter (range: 4-9 mm). Complications were present in 6/43 cases (14%) including 3 minor and 3 major complications that included additional procedures. No significant relationship was identified between vessel size, age and the indication for angiography, and the rate of complication on logistic regression analysis. CONCLUSION: While percutaneous arterial closure devices can be efficacious for achieving hemostasis, our experience demonstrates a higher rate of complications in children, contrary to a previous report. The deployment of such devices should be performed with prejudice in this population.

Conformal Radiation Therapy for Pediatric Patients with Low-Grade Glioma: Results from the Children's Oncology Group Phase 2 Study ACNS0221.

PURPOSE: To determine the rate of marginal relapse, progression-free survival (PFS), and overall survival (OS) in patients with pediatric low-grade glioma (PLGG) treated with conformal radiation therapy (CRT) with a clinical target volume (CTV) margin of 5 mm in the Children's Oncology Group trial ACNS0221. METHODS AND MATERIALS: Patients aged 3 to 21 years with unresectable progressive, recurrent, or residual PLGG were eligible for this study. Patients younger than 10 years were required to have received at least 1 chemotherapy course. Patients with neurofibromatosis type I were not eligible. All patients underwent magnetic resonance imaging-based planning and received 54 Gy CRT in 30 fractions with a 5-mm CTV margin. RESULTS: Of 85 eligible patients (median age, 13.6 years) treated between March 2006 and December 2010, 14 were younger than 10 years and 36 received prior chemotherapy. Sixty-six had pilocytic astrocytoma, 15 had other histologic subtypes, and 4 had unbiopsied chiasmatic lesions. Events included 23 relapses (19 central, 4 distant, and no marginal) and 7 deaths. At a median follow-up of 5.15 years, 5-year PFS was 71% ± 6% and OS was 93% ± 4%. Male sex (P = .068) and large tumor size (P = .050) trended toward significance for association with decreased PFS. Age, histology, tumor location, time between diagnosis and study entry, and MIB-1 status were not associated with PFS. OS was negatively associated with male sex (P = .064), non-pilocytic astrocytoma histology (P = .010), and large tumor size (P = .0089). CONCLUSIONS: For patients with PLGG, CRT with a CTV margin of 5 mm yields an acceptable PFS and does not lead to a high rate of marginal relapse.