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ObjectiveTo test the hypothesis that cerebral blood flow (CBF) assessed with arterial spin labelling (ASL) MRI is increased and standardised neurological examination is altered in infants with neonatal opioid withdrawal syndrome (NOWS) compared with those without.DesignProspective cohort study.SettingLevel IV neonatal intensive care unit and outpatient primary care centre.ParticipantsInfants with NOWS receiving pharmacological treatment and unexposed controls matched for gestational age at birth and post-menstrual age at MRI.Main outcomesCBF assessed by ASL on non-sedated 3-Tesla MRI and standardised Hammersmith Neonatal Neurological Examination (HNNE) within 14 days of birth.ResultsThirty infants with NOWS and 31 control infants were enrolled and included in the final analysis. Global CBF across the brain was higher in the NOWS group compared with controls (14.2 mL/100 g/min±5.5 vs 10.7 mL/100 g/min±4.3, mean±SD, Cohen’s d=0.72). HNNE total optimality score was lower in the NOWS group compared with controls (25.9±3.6 vs 28.4±2.4, mean±SD, Cohen’s d=0.81). A penalised logistic regression model including both CBF and HNNE items discriminated best between the two groups.ConclusionsIncreased cerebral perfusion and neurological examination abnormalities characterise infants with NOWS compared with those without intrauterine drug exposure and suggest prenatal substance exposure affects fetal brain development. Identifying neurological and neuroimaging characteristics of infants with NOWS can contribute to understanding mechanisms underlying later outcomes and to designing potential new treatments.

The sacral ratio has been used as a tool for evaluating sacral development in patients with anorectal malformations. Sacral ratios can be calculated by obtaining sacral radiographs in the anteroposterior (AP) and lateral planes. The objective of the study was to determine the correlation and agreement in sacral ratio calculations. In this single institution retrospective cohort study, we reviewed medical charts of all pediatric anorectal malformation patients treated between March 2014 and September 2018 who had both AP and lateral images of their sacrum. All sacral ratios were measured by three radiologists. Pearson’s correlation coefficients and corresponding 95% confidence intervals (CIs) were used to assess the correlation between the AP and lateral radiographs. A weighted Kappa statistic was used to measure the agreement between how the AP and lateral sacral ratios categorized observations into risk groups. Our initial cohort consisted of 646 observations from patients with anorectal malformations who had radiographs obtained in both AP and lateral planes. We excluded all observations (n=76) where the radiographs were deemed to be inadequate or not appropriately centered to measure sacral ratio. For a given pair of measurements, the mean lateral sacral ratio was 0.07 units greater than the AP plane (95% CI 0.06–0.09, paired t-test P-value

Aim: To examine associations between the deep medullary vein white matter injury global severity scoring system and neurodevelopmental impairment. Methods: This is a prospective observational cohort study of infants born at ≥32 weeks, diagnosed with deep medullary vein thrombosis and infarction on neuroimaging in the first month of life. Developmental testing was performed using validated measures for early, preschool, and school-age follow-up. Results: Nineteen (37%) patients had major neurodevelopmental impairment. Global severity score was higher among patients with neurodevelopmental impairment (21.6 vs 13.4, P = .04). Overall, 78% of patients with epilepsy had neurodevelopmental impairment. A greater degree of asymmetry with right-sided injury predominance was associated with lower Bayley-III cognitive scores and presence of neurodevelopmental impairment ( P < .01). Conclusions: Results suggest a need for targeted clinical surveillance for patients with a high global severity score and/or asymmetric, predominantly right cerebral white matter injury and for those who develop epilepsy.

Ependymal tumors are the third most common brain tumor under 14 years old. Even though metastatic disease is a rare event, it affects mostly young children and carries an adverse prognosis. The factors associated with dissemination and the best treatment approach have not yet been established and there is limited published data on how to manage metastatic disease, especially in patients under 3 years of age. We provide a review of the literature on clinical characteristics and radiation-sparing treatments for metastatic ependymoma in children under 3 years of age treated. The majority (73%) of the identified cases were above 12 months old and had the PF as the primary site at diagnosis. Chemotherapy-based approaches, in different regimens, were used with radiation reserved for progression or relapse. The prognosis varied among the studies, with an average of 50%-58% overall survival. This study also describes the case of a 7-month-old boy with metastatic posterior fossa (PF) ependymoma, for whom we identified a novel SPECC1L-RAF1 gene fusion using a patient-centric comprehensive molecular profiling protocol. The patient was successfully treated with intensive induction chemotherapy followed by high-dose chemotherapy and autologous hematopoietic progenitor cell rescue (AuHSCR). Currently, the patient is in continuous remission 5 years after his diagnosis, without radiation therapy. The understanding of the available therapeutic approaches may assist physicians in their management of such patients. This report also opens the perspective of newly identified molecular alterations in metastatic ependymomas that might drive more chemo-sensitive tumors.

T1-weighted post-contrast MRI is essential in brain protocols. We demonstrate the feasibility and utility of a 3D non-Cartesian radial acquisition in children.To compare bulk motion artifacts, image quality, and lesion conspicuity in 3D T1-weighted post-contrast brain MRI between a new fat-suppressed radial gradient-echo and a traditional non-fat-suppressed inversion-recovery Cartesian gradient-echo sequence.Images from 53 patients acquired at 3 Tesla were compared. Three radiologists rated the images in three categories, including the presence of bulk motion and whether it impacted diagnosis, whether one sequence was preferred over the other in overall image quality and conspicuity of vascular structures and lesions, and whether diagnosis was possible if only the new fat-suppressed radial acquisition was obtained.The Fleiss' kappa for inter-rater agreement was 0.67 for bulk motion and 0.54 for sequence preference. Of the 53 cases, 56% were identified to have significant motion on conventional imaging, while only 13% had motion artifacts on the radial acquisition (p 0.05). There were no cases where motion was seen on the radial acquisition but not on conventional imaging. Both sequences were equally preferred in 87% of the cases. All radiologists agreed that the radial approach had lower gray-white matter contrast than the conventional inversion-recovery method, but preferred the former for making diagnosis in uncooperative patients.We demonstrate the potential utility of a fat-suppressed 3D T1-weighted post-contrast brain gradient-echo sequence in children. The technique is useful in non-sedate pediatric imaging due to its reduced sensitivity to bulk motion.

Background We report a patient with primary central nervous system mixed malignant germ cell tumor (GCT) who presented with recurrent malignant germinomatous infiltration of the retina. Case Description A 10-year-old girl initially presented with a large suprasellar mixed malignant GCT with a near-complete response after initial induction of chemotherapy and irradiation. Three and a half years after initial therapy, she presented with progressively worsening vision in her left eye. Magnetic resonance imaging showed infiltrative changes within the left optic nerve but no discrete mass. Serum and cerebrospinal fluid tumor markers were not elevated and cerebrospinal fluid cytology was negative. Left optic nerve biopsy confirmed the presence of mature teratoma and pure germinoma components. She was treated with gross-total resection of the left eye and optic nerve and chemotherapy. Histopathologic evaluation of the optic nerve showed only mature teratoma elements, but with pure germinoma cells infiltrating the inner layers of the retina. Conclusions Loco-regional extension of suprasellar GCT to the optic nerve is not uncommon; however, to the best of our knowledge, infiltration of the tumor into the retina is not reported in the literature. Early detection of optic pathway involvement and proper delineation of the irradiation field may prevent GCT infiltration of the retina with subsequent vision loss.

Meningiomas are a central nervous system tumor primarily afflicting adults, with

ObjectiveMany genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic etiology in epilepsy and aim to discover somatic alterations in epilepsy-affected brain tissue.MethodsWe have pursued a research study to identify brain somatic mosaicism, using next-generation sequencing (NGS) technologies, in patients with treatment refractory epilepsy who have undergone surgical resection of affected brain tissue.ResultsWe used an integrated combination of NGS techniques and conventional approaches (radiology, histopathology, and electrophysiology) to comprehensively characterize multiple brain regions from a single patient with intractable epilepsy. We present a 3-year-old male patient with West syndrome and intractable tonic seizures in whom we identified a pathogenic frameshift somatic variant in SLC35A2, present at a range of variant allele fractions (4.2%–19.5%) in 12 different brain tissues detected by targeted sequencing. The proportion of the SLC35A2 variant correlated with severity and location of neurophysiology and neuroimaging abnormalities for each tissue.ConclusionsOur findings support the importance of tissue-based sequencing and highlight a correlation in our patient between SLC35A2 variant allele fractions and the severity of epileptogenic phenotypes in different brain tissues obtained from a grid-based resection of clinically defined epileptogenic regions.

Traumatic brain injury (TBI) is a common condition with many potential acute and chronic neurological consequences. Standard initial radiographic evaluation includes noncontrast head CT scanning to rapidly evaluate for pathology that might require intervention. The availability of fast, relatively inexpensive CT imaging has fundamentally changed the clinician's ability to noninvasively visualize neuroanatomy. However, in the context of TBI, limitations of head CT without contrast include poor prognostic ability, inability to analyze cerebral perfusion status, and poor visualization of underlying posttraumatic changes to brain parenchyma. Here, the authors review emerging advanced imaging for evaluation of both acute and chronic TBI and include QuickBrain MRI as an initial imaging modality. Dynamic susceptibility-weighted contrast-enhanced perfusion MRI, MR arterial spin labeling, and perfusion CT are reviewed as methods for examining cerebral blood flow following TBI. The authors evaluate MR-based diffusion tensor imaging and functional MRI for prognostication of recovery post-TBI. Finally, MR elastography, MR spectroscopy, and convolutional neural networks are examined as future tools in TBI management. Many imaging technologies are being developed and studied in TBI, and some of these may hold promise in improving the understanding and management of TBI. ABBREVIATIONS ASL = arterial spin labeling; CNN = convolutional neural network; CTP = perfusion CT; DAI = diffuse axonal injury; DMN = default mode network; DOC = disorders of consciousness; DTI = diffusion tensor imaging; FA = fractional anisotropy; fMRI = functional MRI; GCS = Glasgow Coma Scale; MD = mean diffusivity; MRE = MR elastography; MRS = MR spectroscopy; mTBI = mild TBI; NAA = N-acetylaspartate; SWI = susceptibility-weighted imaging; TBI = traumatic brain injury; UHF = ultra-high field.

MRI methods that have reduced sensitivity to motion are attractive in pediatric applications. In spine imaging, physiologic motion such as respiration and cerebrospinal fluid pulsation can hamper diagnostic image quality. We compare a 3D T1-weighted non-Cartesian radial acquisition with a conventional Cartesian 2D turbo-spin-echo (TSE) acquisition in axial post-contrast spine imaging at 3T. Thirty-two patients (mean age 12.2 ± 5.3 years) scheduled for routine clinical spine exams with contrast were enrolled. Three pediatric neuroradiologists compared the two sequences and assessed the presence of motion, the conspicuity of nerve roots, and whether one of the sequences was preferred in visualizing pathology using Likert scales. The Fleiss’ kappa statistic for inter-rater agreement was 0.29 (95% confidence interval, 0.15–0.43) for the presence of motion, 0.30 (0.21–0.38) for conspicuity, and 0.37 (0.19–0.55) for sequence preference. Radial images were less sensitive to motion than TSE (p

Background/Aims: Increasing attention has been given to the possible association of cervical spine (c-spine) injuries with abusive head trauma (AHT). The aims of this study were to describe c-spine MRI findings in hospitalized AHT patients. Methods: This is a retrospective study of children under the age of 5 years with AHT admitted to hospital in 2004-2013. Those with c-spine MRI were identified, and the images were reviewed. Results: 250 AHT cases were identified, with 34 (14%) undergoing c-spine MRI. Eleven patients (32%) had 25 findings, including hematoma in 2, occiput-C1-C2 edema in 3, prevertebral edema in 6, facet edema in 2, and interspinous and/or muscular edema in 10. No patients had a clinically evident c-spine injury, a clinically unstable c-spine, or required c-spine surgery. Conclusions: C-spine MRI may identify abnormalities not apparent upon physical examination and the procedure should therefore be considered in cases of suspected AHT.

OBJECTIVESporadic meningiomas have been classified in many different ways. Radiographically, these lesions can be described as occurring in either typical or atypical locations. The purpose of this study was to determine if there are any histopathological differences between sporadic meningiomas that arise in these varying locations in children.METHODSThe neuroimaging, histopathological findings, and clinical records in patients with sporadic pediatric meningiomas not associated with neurofibromatosis Type 2 or prior radiation therapy were retrospectively reviewed. Tumors were classified by radiological findings as either typical or atypical, and they were categorized histopathologically by using the latest WHO nomenclature and grading criteria.RESULTSFifteen sporadic meningiomas in pediatric patients were biopsied or resected at the authors’ institution between 1989 and 2013. Five (33%) were typical in radiographic appearance and/or location and 10 (67%) were atypical. Four (80%) typical meningiomas were WHO Grade I tumors. Most (60%) of the atypical meningiomas were WHO Grade II or III.CONCLUSIONSThis study is the largest series of sporadic pediatric meningiomas in atypical locations to date. Although sporadic meningiomas are relatively infrequent in children, those with atypical imaging, specifically those with apparently intraparenchymal and intraosseous locations, may be more common than previously recognized. In this study, pediatric sporadic meningiomas arising in atypical locations, in particular intraparenchymal meningiomas, may be of higher histopathological grade. The authors’ findings should alert clinicians to the potential for more aggressive clinical behavior in these tumors.

Metastatic disease at initial presentation of intracranial ependymoma is an uncommon occurrence with only rare reports of survival and is reportedly more prevalent in the youngest of children. Clinical and molecular characteristics associated with metastatic presentation, their prognostic implications, as well as optimal treatment options for such patients, have not been identified. CASE REPORT: A seven months old child presented with posterior fossa anaplastic ependymoma; following sub-total resection of primary tumor, a spine MRI revealed leptomeningeal dissemination along the cervical spinal cord and nerve roots of the cauda equina. The patient was successfully treated with five cycles of intensive induction chemotherapy (as per Head Start with high-dose methotrexate) followed by three sequential cycles of marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) without irradiation; he is currently without evidence of the disease now 60 months following initial diagnosis. MOLECULAR/GENOMIC RESULTS: The patient was enrolled on a patient-centric comprehensive molecular profiling protocol, which included paired tumor-normal whole-exome sequencing, RNA sequencing of the disease-involved tissue, and DNA methylation classification. The genomic profile of the tumor was relatively unremarkable, revealing only a terminal gain of chromosome 3p and a terminal deletion of chromosome 22q, suggestive of an unbalanced translocation. Using RNA sequencing, we identified a novel SPECC1L-RAF1 gene fusion. The tumor harbors unique transcriptomic and DNA methylation profiles, failing to discretely classify with well-established ependymoma subgroups. CONCLUSION: Use of genomic profiling techniques provides meaningful information for disease characterization allowing for further expansion of the molecular spectrum associated with malignant disease.

Objectives We attempted to demonstrate the clinical applicability and utility of a three-dimensional multidelay arterial spin labeling magnetic resonance imaging technique in pediatric neuroimaging through a series of case studies. Methods Whole-brain three-dimensional multidelay arterial spin labeling data were acquired in five pediatric patients with different neurological conditions using 3 mm to 4 mm slices and a scan time of six to seven minutes. Results Three-dimensional multidelay arterial spin labeling provided complementary diagnostic information via quantitative cerebral blood flow and arterial transit time maps. Conclusions Three-dimensional multidelay arterial spin labeling sequence provides simultaneous quantification of cerebral blood flow and arterial transit time and is feasible for pediatric patients.

BACKGROUND Noonan syndrome (NS) is associated with germline Ras signaling pathway mutations, RAS overactivation and increased tumorigenesis risk. Rosette-forming glioneuronal tumors (RFGT) are rare indolent tumors. We report the molecular profiling of two patients with NS and RFGT. PATIENT 1: A 22-year-old male with NS was diagnosed with RFGT after partial tumor resection followed by focal irradiation. He was enrolled on a comprehensive genomic profiling study involving paired tumor-normal whole exome sequencing and RNA sequencing of the disease-involved tissue, revealing a germline PTPN11 alteration (p.Gly60Ala) consistent with NS, and a somatic deletion (p.Ile442_Thr454del) in PIK3R1 and a somatic variant (p.Lys656Glu) in FGFR1 with concomitant increased expression of PIK3R1 and FGFR1 by RNA-sequencing. The patient remains without tumor progression now nine months since irradiation. PATIENT 2: A 19-year-old male with persistent headaches, underwent a brain MRI demonstrated multiple abnormal signals in the pineal region and midbrain. He had a stereotactic biopsy revealing RFGT. He was enrolled on the genomic study revealing a germline PTPN11 alteration (p.Asn308Asp) resulting in a new diagnosis of NS. Several family members were subsequently identified with clinical features of NS, including his mother and two siblings, enabling appropriate counseling. Two somatic variants were found in trans in PIK3R1 (p.Thr454_Phe456del and p.Glu451_Asn453delinsAsp), and a somatic variant (p.Val695Met) in FGFR1, with resultant overexpression of PIK3R1. The patient is monitored with surveillance imaging. CONCLUSION We report the molecular profiling of two patients with NS and RFGT; strongly suggesting their connection to RASopathies through the overactivation of the MAPK and PI3K/AKT/mTOR signaling pathways.

3D pseudocontinuous arterial spin labeling (pCASL) with a single post-labeling delay time is commonly used to measure cerebral blood flow (CBF). Multi-phase pCASL has been developed to simultaneously estimate CBF and arterial transit time (ATT).To evaluate the clinical feasibility of multi-phase 3D pCASL in pediatric patients, and to compare the estimation of ATT and CBF via linear weighted-delay and traditional non-linear iterative curve-fitting routines.Forty patients (average age: 8.6 y, 5 d-22.4 y) referred for routine brain MRI underwent additional 5-7 min of pCASL scans at 3T using 5 PLDs between 300 and 2300 ms. Data were post-processed by two algorithms for estimating CBF and ATT. Average CBF and ATT values were computed for vascular territories including the anterior, middle and posterior cerebral arteries as well as regions based on the Alberta Stroke Program Early CT Score template. Pearson correlation coefficients and linear regression were used for statistical analysis. The clinical value of multi-phase CASL was evaluated by a neuroradiologist based on asymmetric CBF and ATT maps in patients.All pCASL scans were successfully completed, generating diagnostic results. CBF computed from weighted-delay and curve-fitting methods agreed strongly, with Pearson correlation coefficients ranging from 0.97-0.99 across the measured regions (p 0.05). Correlation coefficients for ATT ranged from 0.87-0.96 (p 0.05). CBF and ATT maps were found to add valuable information to clinical diagnosis in 17 of 40 pediatric patients.Our preliminary results demonstrate the feasibility and potential clinical utility of multi-phase pCASL for simultaneous CBF and ATT quantification in pediatric patients.

To investigate the effects of mild traumatic brain injury (mTBI) in children on symptom ratings of behavior problems across the first-year postinjury.Emergency departments of 2 regional children's hospitals.Parents of 176 children with mTBI and 90 children with orthopedic injury aged 8 to 15 years.Group comparisons of postinjury parent and teacher ratings of child behavior problems controlling for background factors.Child Behavior Checklist and Teacher's Report Form.For younger but not older children in the sample, children with mTBI compared with children with orthopedic injury had higher postinjury ratings on the Child Behavior Checklist Total Behavior Problem scale (t264 = 3.34, P.001) and higher rates of T-scores of 60 or more on this scale (odds ratio = 3.00; 95% confidence interval, 1.33-6.77; P = .008). For children with mTBI, hospitalization, motor vehicle accidents, loss of consciousness, and magnetic resonance imaging abnormality were associated with higher parent or teacher ratings.School-aged children with mTBI are at risk for persistent symptoms of behavior problems, especially if mTBI is more severe or occurs at a younger age. The findings justify monitoring of behavior long after injury and further research to identify risk factors for these symptoms and their association with clinical disorders.

Objective: To examine the relative contributions of injury characteristics and noninjury child and family factors as predictors of postconcussive symptoms (PCS) following mild traumatic brain injury (TBI) in children. Method: Participants were 8- to 15-year-old children, 186 with mild TBI and 99 with mild orthopedic injuries (OI). Parents and children rated PCS shortly after injury and at 1, 3, and 12 months postinjury. Hierarchical regression analyses were conducted to predict PCS from (1) demographic variables; (2) premorbid child factors (WASI IQ; WRAT-3 Reading; Child Behavior Checklist; ratings of preinjury PCS); (3) family factors (Family Assessment Device General Functioning Scale; Brief Symptom Inventory; and Life Stressors and Social Resources Inventory); and (4) injury group (OI, mild TBI with loss of consciousness [LOC] and associated injuries [AI], mild TBI with LOC but without AI, mild TBI without LOC but with AI, and mild TBI without LOC or AI). Results: Injury group predicted parent and child ratings of PCS but showed a decreasing contribution over time. Demographic variables consistently predicted symptom ratings across time. Premorbid child factors, especially retrospective ratings of premorbid symptoms, accounted for the most variance in symptom ratings. Family factors, particularly parent adjustment, consistently predicted parent, but not child, ratings of PCS. Conclusions: Injury characteristics predict PCS in the first months following mild TBI but show a decreasing contribution over time. In contrast, noninjury factors are more consistently related to persistent PCS. (PsycINFO Database Record (c) 2013 APA, all rights reserved). Language: en

OBJECTIVES:: To assess whether postconcussive symptoms (PCS) can be used to discriminate injury severity among children with mild traumatic brain injury (TBI). PARTICIPANTS:: One hundred eighty-six children with mild TBI, divided into high and low injury severity depending on whether the injury was associated with a loss of consciousness (LOC), and a comparison group of 99 children with orthopedic injuries (OI), all aged 8 to 15 years at the time of injury. MAIN MEASURES:: Parent-rated frequency and severity of PCS at initial assessment within 2 weeks postinjury and again at 3 and 12 months postinjury. RESULTS:: Ratings of PCS obtained at the initial and 3-month assessments differentiated children with mild TBI from OI, although only ratings at the initial assessment discriminated among all 3 groups. Somatic PCS accounted for most of the discriminatory power. CONCLUSIONS:: Overall, the accuracy of group classification was relatively modest, with a large proportion of misclassifications of children in the mild-TBI groups. Although children with mild TBI have more PCS than children with OI, PCS do not permit sufficiently accurate discrimination of mild TBI and injury severity to warrant diagnostic decisions at this time. Language: en

This study examined whether children's coping strategies are related to post-concussive symptoms following mild traumatic brain injury (TBI) versus orthopedic injury (OI). Participants were 8- to 15-year-old children with mild TBI (n = 167) or OI (n = 84). They rated their current preferred coping strategies and post-injury symptoms at 2 weeks (baseline) and 1, 3, and 12 months post-injury. Children's reported use of coping strategies did not vary significantly over time, so their baseline coping ratings were examined as predictors of post-concussive symptoms across time. Self-ratings of symptoms were positively related to emotion-focused strategies and negatively related to problem-focused engagement after both mild TBI and OI. Higher problem-focused disengagement predicted larger group differences in children's ratings of symptoms, suggesting that problem-focused disengagement moderates the effects of mild TBI. Coping strategies collectively accounted for approximately 10–15% of the variance in children's post-concussive symptoms over time. The findings suggest that coping may play an important role in accounting for children's perceptions of post-concussive symptoms after mild TBI. (JINS, 2011, 17, 317–326)

The level of parent-child agreement on post-concussive symptoms (PCS) was examined in children following mild traumatic brain injuries (TBI). As part of a larger longitudinal study, 186 children with mild TBI and 99 with orthopedic injuries (OI), from 8 to 15 years of age, were recruited prospectively. Parents and children completed the PCS Interview (PCS-I) and the Health and Behavior Inventory (HBI) at 2 weeks, 1 month, 3 months and 12 months post-injury. Item-level correlations between child and parent ratings on both measures of PCS were significant but modest in both groups. Parent-child correlations for composite scales on the HBI and the total score on the PCS-I were significant in both groups, but somewhat higher in the OI group than in the mild TBI Group. Mean symptom ratings tended to be significantly higher for children as compared to parents, especially for somatic symptoms. Parents and children display modest agreement when reporting PCS; their ratings correlate significantly, but children report higher mean levels of symptoms than parents.

The occurrence of postconcussive symptoms (PCS) following mild traumatic brain injury (TBI) in children may depend on cognitive reserve capacity. This prospective, longitudinal study examined whether the relationship between mild TBI and PCS is moderated by cognitive ability, which served as a proxy for cognitive reserve. Participants included 182 children with mild TBI and 99 children with orthopedic injuries (OI), ranging from 8 to 15 years of age when injured. Mild TBI were classified as complicated (n= 32) or uncomplicated (n= 150) depending on whether they were associated with trauma-related intracranial abnormalities on magnetic resonance imaging. PCS were assessed initially within 3 weeks of injury, and again at 1, 3, and 12 months post injury. The initial assessment also included standardized tests of children’s cognitive skills and retrospective parent ratings of pre-injury symptoms. Hierarchical linear modeling indicated that ratings of PCS were moderated jointly by cognitive ability and injury severity. Children of lower cognitive ability with a complicated mild TBI were especially prone to cognitive symptoms across time according to parents and to high acute levels of PCS according to children’s self-ratings. Cognitive reserve is an important moderator of the outcomes of mild TBI in children and adolescents. (JINS, 2010,16, 94–105.)

Traumatic brain injuries (TBIs) are a leading cause of death and disability among children and adolescents.1 Moderate and severe TBIs account for most of the mortality and morbidity in children.2 However, mild injuries represent the vast majority of TBIs.3 Approximately 500 000 children aged 14 and younger sustain TBIs resulting in emergency department visits annually in the United States, and 80% to 90% of TBIs can be classified as mild.1,3 Even if only a small proportion of children with mild TBIs suffer negative outcomes, then mild TBI is a serious public health problem. Recent reviews have suggested that mild TBIs have little short- or long-term effect on children.4–6 However, most previous studies of mild TBIs have assessed outcomes by using standardized tests of cognitive abilities or broad-based ratings of behavioral adjustment. Few studies have focused specifically on postconcussive symptoms (PCSs). PCSs are subjective somatic, cognitive, and emotional problems that are embodied in the diagnostic criteria for postconcussion syndrome in the International Classification of Diseases, 10th Revision,7 as well as in the research criteria for postconcussional disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.8 Of the limited studies conducted to date, most have suggested that PCSs are more common and severe in children with mild TBIs than in children with injuries not involving the head or in healthy children matched for sociodemographics.9–13 Group differences in PCSs tend to be most pronounced shortly after the injury and to resolve over time, although the likelihood that PCSs will persist and be associated with psychosocial morbidity after mild TBI in children remains uncertain, because only a handful of studies have followed children for more than a few months.11,14–15 The etiology of PCSs after mild TBI remains a topic of debate. The controversy is often framed in terms of “psychogenesis versus physiogenesis.”16–17 Proponents of psychogenesis argue that PCSs reflect children’s premorbid adjustment, postinjury psychological or family factors, or outright malingering in the context of litigation.11,18–19 In contrast, proponents of physiogenesis point to experimental studies of nonhuman animals and clinical research with humans suggesting that mild TBI can result in acute neuropathology and abnormalities in brain function20–22 and that the occurrence of PCSs after mild TBI may be transiently associated with deficits on standardized cognitive testing and abnormalities on neuroimaging.13,23–25 Much of the existing research on mild TBI in children suffers from methodologic shortcomings that preclude a resolution of this controversy.26,27 One of the major limitations of previous research involves vague and inconsistent definitions of mild TBI.28 Most studies have defined mild TBI in part based on Glasgow Coma Scale (GCS)29 scores ranging from 13 to 15, but the studies have been inconsistent in their use of other criteria, such as presence or duration of unconsciousness or posttraumatic amnesia. Children with positive findings on neuroimaging have often been omitted, despite evidence suggesting that so-called “complicated” mild TBI (ie, GCS score of 13–15 but with intracranial abnormalities on neuroimaging) are associated with a higher risk of negative sequelae.30,31 Another shortcoming of the existing literature is that statistical analyses reflect an underlying assumption that children with mild TBI are a homogenous group. Thus, most analyses compare the mean level of PCSs of children with mild TBI to that of a comparison group. However, the assumption of homogeneity may be incorrect, and individual children may display significant variations in PCSs, particularly when studied across time. The advent of techniques such as mixture modeling, which can be used to empirically identify latent classes of individuals based on different developmental trajectories, should enable a more sophisticated examination of individual outcomes of mild TBI and the clinical features that are related to them.32,33 We recently completed a prospective, longitudinal study intended to clarify the outcomes of mild TBI in children.27 The study focused specifically on PCSs and was designed to address the methodologic shortcomings of previous research. Participants were children with mild TBI or with orthopedic injuries (OIs). Mild TBIs were defined based on specific inclusion and exclusion criteria encompassing a range of severity. Parents rated PCSs at multiple times during the first year after injury. Preinjury symptoms were measured retrospectively shortly after the injury. Multiple acute clinical features were documented to assess the severity of mild TBIs. Developmental trajectory analysis was used to classify individual children in terms of their patterns of PCSs across time. In this article, we examine whether mild TBI, as well as specific clinical features indicative of brain injury, are associated with different trajectories of PCSs as compared with OI.

Background Diffuse excessive high signal intensity abnormality is the most common finding on term-equivalent age magnetic resonance imaging in extremely preterm infants. Yet its clinical significance remains a matter of debate, in part because of a lack of prior imaging–pathology correlational studies. Patient Presentations We present two 24-week-gestation infants with complicated clinical courses who died at 33 and 46 weeks postmenstrual age with magnetic resonance imaging evidence of diffuse excessive high signal intensity. Two patients with periventricular leukomalacia and two without injury were examined for comparison. Immunohistochemistry characterized the presence of reactive astrocytes, microglia, myelin, and axons. Infants with periventricular leukomalacia demonstrated the typical microscopic necrosis with spheroids, gliosis/microgliosis with reduction in stainable myelin and axons. Infants with diffuse excessive high signal intensity showed vacuolated regions with increased reactive astrocytes and microglia and fewer oligodendroglial cell bodies/processes and dramatic reduction in axon number. Conclusion These two individuals with diffuse excessive high signal intensity exhibited pathologic characteristics that were overlapping but distinct from those of periventricular leukomalacia.

A 6-week-old girl presenting with severe weakness, hypotonia, gastroesophageal reflux, and microcephaly as well as dysmorphic features including micrognathia and high arched palate was also found to have pontocerebellar hypoplasia. She died of acute pneumonia at age 6 months. Her younger brother also had generalized hypotonia, weakness, areflexia, and tongue fasciculations and was also noted to have pontocerebellar hypoplasia revealed by brain magnetic resonance imaging. We herein briefly review familial spinal muscular atrophy with type 1 pontocerebellar hypoplasia in children.

OBJECTIVE To examine reliable change in postconcussive symptoms and its functional consequences among children with mild traumatic brain injury (TBI) over the first year postinjury as compared with children with orthopedic injuries. DESIGN Prospective, longitudinal cohort. SETTING Emergency departments at 2 children's hospitals. PARTICIPANTS Eight- to 15-year-old children with mild TBI (n = 186) or orthopedic injuries (n = 99). MAIN EXPOSURE Closed-head or orthopedic trauma. MAIN OUTCOME MEASURES Parents rated preinjury symptoms retrospectively shortly after injury and postconcussive symptoms at 2 weeks and 3 and 12 months postinjury. A regression-based approach was used to determine whether each child displayed reliable increases in postconcussive symptoms at each postinjury occasion. Health-related quality of life was assessed at 3 and 12 months postinjury. Information regarding children's educational programming was collected at the initial and 12-month assessments. RESULTS Children with mild TBI were significantly more likely than those with orthopedic injuries to show reliable increases in both cognitive and somatic symptoms. Group differences in the likelihood of reliable increases became less common with time for somatic symptoms but persisted to 12 months postinjury for cognitive symptoms. Among children with mild TBI, reliable increases in symptoms were more common among children with loss of consciousness or abnormalities on neuroimaging. Reliable increases in symptoms were associated with significant declines in health-related quality of life and an increased likelihood of educational intervention. CONCLUSION Many children with mild TBI show reliable increases in postconcussive symptoms that are associated with significant functional impairment in their daily lives.

Objectives Mild traumatic brain injury (TBI) and injury-related outcomes such as postconcussive symptoms (PCS) may influence health-related quality of life (HRQOL) in children. Methods We evaluated HRQOL in 186 8- to 15-year-old children with mild TBI and 99 children with orthopedic injuries (OI). Parents rated the frequency and severity of PCS at an initial assessment within 2-weeks postinjury and rated HRQOL at 3- and 12-months postinjury. Results The mild TBI and OI groups did not differ in psychosocial HRQOL, but the mild TBI group showed lower physical HRQOL at the 12-month follow-up. Somatic PCS were a significant predictor of physical HRQOL over time, and both cognitive and somatic PCS were significant predictors of psychosocial HRQOL over time. Children with higher PCS at the initial assessment had lower HRQOL scores at later time points. Conclusions Effective management of PCS may be associated with improvements in HRQOL following pediatric mild TBI.

To investigate post-concussive symptoms (PCS) following mild pediatric traumatic brain injury (mTBI), 8- to 15-year old children with mTBI (n=186) and a comparison group with uncomplicated orthopedic injuries (OI, n=99) were recruited from two emergency departments. Parent and child ratings of PCS and symptom counts were obtained within 3 weeks after injury (baseline) and at 1, 3, and 12 months post injury. The mTBI group also completed magnetic resonance imaging (MRI) at baseline. Group differences were examined using growth modeling, controlling for age at injury, sex, socioeconomic status (SES), and (for parent-based measures) preinjury symptom levels. Relative to the OI group, the mTBI group had higher ratings of somatic PCS and parent counts of PCS at the initial assessments, but higher parent ratings of cognitive PCS and child counts of PCS throughout follow-up. Higher levels of PCS in the mTBI group were associated with motor-vehicle-related trauma, loss of consciousness, neuroimaging abnormalities, and hospitalization. The findings validate both transient and persistent PCS in children with mTBI and document associations of symptoms with injury and non-injury factors.

To investigate the occurrence of post-concussive symptoms (PCS) and symptoms of post-traumatic stress disorder (PTSD) in children following mild traumatic brain injuries (TBI).Longitudinal study comparing the outcomes of mild TBI and orthopaedic injuries (OI) in children aged 8-15.One hundred and eighty-six children with mild TBI and 99 with OI were recruited prospectively. Parents rated children's PCS and symptoms of PTSD at 2 weeks, 3 months and 12 months post-injury. One hundred and sixty-seven with mild TBI and 84 with OI completed all assessments.Controlling for symptoms of PTSD, the mild TBI group demonstrated more PCS than the OI group, although the magnitude of group differences diminished with time. Controlling for PCS, the OI group displayed more symptoms of PTSD than the mild TBI group at baseline, but not thereafter. Symptoms of PTSD and PCS were correlated significantly, but more highly in the OI group than the mild TBI group.Although PCS and symptoms of PTSD are correlated, children with mild TBI are more distinguishable from children with OI based on PCS than on symptoms of PTSD. The latter symptoms, moreover, do not account for increased PCS following mild TBI in children.

The epsilon4 allele of the apolipoprotein E (APOE) gene has been linked to negative outcomes among adults with traumatic brain injury (TBI) across the spectrum of severity, with preliminary evidence suggesting a similar pattern among children. This study investigated the relationship of the APOE epsilon4 allele to outcomes in children with mild TBI. Participants in this prospective, longitudinal study included 99 children with mild TBI between the ages of 8 and 15 recruited from consecutive admissions to Emergency Departments at two large children's hospitals. Outcomes were assessed acutely in the Emergency Department and at follow-ups at 2 weeks, 3 months, and 12 months post-injury. Among the 99 participants, 28 had at least one epsilon4 allele. Children with and without an epsilon4 allele did not differ demographically. Children with an epsilon4 allele were significantly more likely than those without an epsilon4 allele to have a Glasgow Coma Scale score of less than 15, but the groups did not differ on any other measures of injury severity. Those with an epsilon4 allele exhibited better performance than children without an epsilon4 allele on a test of constructional skill, but the groups did not differ on any other neuropsychological tests. Children with and without an epsilon4 allele also did not differ on measures of post-concussive symptoms. Overall, the findings suggest that the APOE epsilon4 allele is not consistently related to the outcomes of mild TBI in children.

This study sought to examine the effects of mild traumatic brain injury (TBI) on executive functions in school-aged children.The prospective, longitudinal study involved 8-15 year old children, 186 with mild TBI and 99 with mild orthopaedic injuries (OI). They were administered the Stockings of Cambridge and Spatial Working Memory sub-tests from the Cambridge Neuropsychological Testing Automated Battery (CANTAB) approximately 10 days, 3 months and 12 months post-injury. Parents completed the Behavior Rating Inventory of Executive Functions (BRIEF) on each occasion, with ratings at the initial assessment intended to assess pre-morbid functioning retrospectively.On the CANTAB, the groups did not differ on the Stockings of Cambridge and the mild TBI group unexpectedly performed better than the OI group on Spatial Working Memory. On the BRIEF, children with mild TBI showed a marginally significant trend toward more problems than the OI group on the Metacognition Index composite. The only BRIEF sub-scale on which they demonstrated significantly more problems was Organization of Materials. The presence of intracranial abnormalities on MRI was associated with more problems on the BRIEF Organization of Materials sub-scale at 3 months, but other findings were not consistent with hypothesized effects of TBI severity. The CANTAB sub-tests were significant predictors of later ratings on the BRIEF, but accounted for modest variance.Children with mild TBI show limited evidence of deficits in executive functions, either cognitively or behaviourally, irrespective of injury characteristics. Cognitive tests of executive functions are modest predictors of ratings of executive functions in everyday life, for children both with and without mild TBI.

Background Nontraumatic intracranial hemorrhages (ICHs) are uncommon in children, but are important causes of death and injury. Objectives To determine whether the risk factors for ICH have changed compared with those in earlier published series and to estimate the residual deficits in the survivors. Design, Setting, and Patients We performed a retrospective review of patients admitted to a single tertiary care, academic pediatric hospital from January 1, 2000, through May 31, 2007. Records were retrieved if the diagnostic codes from the International Classification of Diseases, Ninth Revision , were pertinent to ICHs. We searched reports from computed tomograms and magnetic resonance images of the brain for terms pertaining to ICH. Main Outcome Measures Risk factors and functional outcome. Secondary measures were hemorrhage type and clinical presentation. Results We identified 85 children who had nontraumatic ICH. There were 10 subarachnoid, 61 intracerebral, and 14 subdural hemorrhages. Intracranial vascular anomalies were the most frequent risk factor, followed by congenital heart disease and brain tumors. Arteriovenous malformations did not account for as large a percentage as in previous studies. Twenty-nine children died. Of the 48 survivors for whom follow-up information was available, 26 had no reported deficits and 22 had deficits ranging from mild to severe. Conclusions In this series, brain tumors and congenital heart disease accounted for a greater proportion of ICHs than in previous studies. The mortality due to ICH remains high but may be related as much to the severity of the underlying illnesses as to the hemorrhage itself. We found significant long-term morbidity, but more than half of the survivors for whom follow-up data were available had no detectable deficits. A long-term outcome study of pediatric ICH is needed.

We describe aggressive immunosuppressive treatment of an adolescent with Susac's syndrome (SS), a disease of the microvasculature in the brain, retina, and inner ear. Because the immunopathogenesis of SS appears to have much in common with that of juvenile dermatomyositis (JDM), the patient was treated with an approach that has been effective for severe JDM. The patient's outcome provides evidence for the importance of prompt, aggressive, and sustained immunosuppressive treatment of encephalopathic SS.

Leigh disease, subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder often seen in infancy or childhood but rarely reported in adults. Genetic heterogeneity is well recognized, and the associated etiologies include both mitochondrial and nuclear DNA defects. We describe an infant presenting with developmental delay and then progressive multisystem disorder and neuroradiologic features of Leigh disease. He and his maternal relatives all have the A8344G mitochondrial DNA mutation. However, only minor clinical features are seen in his maternal relatives, with migraine being the most common problem. Additionally, the A8344G mitochondrial DNA mutation is associated with spinocerebellar degeneration, other nonspecific mitochondrial encephalomyopathies, atypical Charcot-Marie-Tooth disease, and progressive external ophthalmoplegia. The A8344G mitochondrial DNA mutation may present with Leigh disease or other different atypical clinical features without myoclonic epilepsy and ragged red fibers. ( J Child Neurol 2003; 18: 62—64).

Pituitary hyperplasia secondary to primary hypothyroidism and subsequent regression following thyroid replacement has been well described. We report a 12 year-old male who was retrospectively found to have progressive pituitary hyperplasia over the course of 2 years prior to his diagnosis of primary hypothyroidism, as documented on annual brain magnetic resonance imaging (MRI) for Arnold Chiari Type 1 malformation. He presented to Endocrinology with a 2-year history of fatigue, worsening daily headaches and linear growth deceleration. The diagnosis of primary hypothyroidism as the cause for his pituitary hyperplasia was made. He was started on levothyroxine with subsequent regression of pituitary hyperplasia demonstrated on repeat brain MRI six months later. This case is the first that demonstrates progressive pituitary hyperplasia from early in the course to diagnosis of hypothyroidism. It also illustrates that pituitary hyperplasia noted on routine brain MRI can be a presenting sign of primary hypothyroidism that should prompt endocrinologic evaluation.

To examine the incidence and neuropsychological, behavioral, and neuroimaging correlates of postconcussive symptoms (PCS) in children with mild closed head injuries (CHI).26 Children with mild CHI and 8 of their uninjured siblings, from 8 to 15 years old, were recruited prospectively and assessed at baseline (ie, within 7 days of injury) and at 3 months postinjury. Parents rated PCS, motivation and affective lability, and behavioral adjustment. Baseline ratings assessed premorbid functioning retrospectively, and follow-up ratings assessed postinjury status. On both occasions, children completed neuropsychological testing, and those with mild CHI also underwent magnetic resonance imaging (MRI).Children with mild CHI did not differ from siblings in baseline ratings of premorbid PCS but displayed higher ratings on several PCS at 3 months postinjury. Thirty-five percent of children with mild CHI showed increases in PCS, compared with baseline premorbid ratings, but none of the siblings did so. Children with mild CHI whose PCS increased from premorbid levels showed poorer neuropsychological functioning at baseline than did children whose PCS did not increase, although the differences had partially resolved by 3 months. They also displayed decreased motivation over time. Their behavioral adjustment was poorer and they had smaller white matter volumes on MRI, but the latter differences were present at baseline and did not change over time, suggesting that they existed prior to the injury.Postinjury increases in PCS occur in a sizable minority of children with mild CHI and more often than among uninjured siblings. Increases in PCS following mild CHI are associated with premorbid neurological and psychosocial vulnerability, but also with postinjury decrements in neuropsychological and neurobehavioral functioning.