Preterm Neuroimaging and School-Age Cognitive Outcomes.

BACKGROUND AND OBJECTIVES: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value. METHODS: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors. RESULTS: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging. CONCLUSIONS: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes.

Brain Perfusion and Diffusion Abnormalities in Children Treated for Posterior Fossa Brain Tumors.

OBJECTIVE: To compare cerebral perfusion and diffusion in survivors of childhood posterior fossa brain tumor with neurologically normal controls and correlate differences with cognitive dysfunction. STUDY DESIGN: We analyzed retrospectively arterial spin-labeled cerebral blood flow (CBF) and apparent diffusion coefficient (ADC) in 21 patients with medulloblastoma (MB), 18 patients with pilocytic astrocytoma (PA), and 64 neurologically normal children. We generated ANCOVA models to evaluate treatment effects on the cerebral cortex, thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens, and cerebral white matter at time points an average of 5.7 years after original diagnosis. A retrospective review of patient charts identified 12 patients with neurocognitive data and in whom the relationship between IQ and magnetic resonance imaging variables was assessed for each brain structure. RESULTS: Patients with MB (all treated with surgery, chemotherapy, and radiation) had significantly lower global CBF relative to controls (10%-23% lower, varying by anatomic region, all adjusted P?

Acute Perinatal Sentinel Events, Neonatal Brain Injury Pattern, and Outcome of Infants Undergoing a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

Infants with perinatal sentinel events in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Hypothermia for Encephalopathy Trial had more basal ganglia and thalamus lesions on brain magnetic resonance imaging but similar neurodevelopmental outcomes at 18 months of age than infants without perinatal sentinel events. Outcomes correlated with the neonatal magnetic resonance imaging findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005772.

Neonatal Magnetic Resonance Imaging Pattern of Brain Injury as a Biomarker of Childhood Outcomes following a Trial of Hypothermia for Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVE: To examine the ability of magnetic resonance imaging (MRI) patterns of neonatal brain injury defined by the National Institute of Child Health and Human Development Neonatal Research Network to predict death or IQ at 6-7 years of age following hypothermia for neonatal encephalopathy. STUDY DESIGN: Out of 208 participants, 124 had MRI and primary outcome (death or IQ <70) data. The relationship between injury pattern and outcome was assessed. RESULTS: Death or IQ <70 occurred in 4 of 50 (8%) of children with pattern 0 (normal MRI), 1 of 6 (17%) with 1A (minimal cerebral lesions), 1 of 4 (25%) with 1B (extensive cerebral lesions), 3 of 8 (38%) with 2A (basal ganglia thalamic, anterior or posterior limb of internal capsule, or watershed infarction), 32 of 49 (65%) with 2B (2A with cerebral lesions), and 7 of 7 (100%) with pattern 3 (hemispheric devastation), P < .001; this association was also seen within hypothermia and control subgroups. IQ was 90 ± 13 among the 46 children with a normal MRI and 69 ± 25 among the 50 children with an abnormal MRI. In childhood, for a normal outcome, a normal neonatal MRI had a sensitivity of 61%, specificity of 92%, a positive predictive value of 92%, and a negative predictive value of 59%; for death or IQ <70, the 2B and 3 pattern combined had a sensitivity of 81%, specificity of 78%, positive predictive value of 70%, and a negative predictive value of 87%. CONCLUSIONS: The Neonatal Research Network MRI pattern of neonatal brain injury is a biomarker of neurodevelopmental outcome at 6-7 years of age. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00005772.

Intensity-Corrected Dual-Echo Echo-Planar Imaging (DE-EPI) for Improved Pediatric Brain Diffusion Imaging.

Here we investigate the utility of a dual-echo Echo-Planar Imaging (DE-EPI) Diffusion Weighted Imaging (DWI) approach to improve lesion conspicuity in pediatric imaging. This method delivers two 'echo images' for one diffusion-preparation period. We also demonstrate how the echoes can be utilized to remove transmit/receive coil-induced and static magnetic field intensity modulations on both echo images, which often mimic pathology and thereby pose diagnostic challenges. DE-EPI DWI data were acquired in 18 pediatric patients with abnormal diffusion lesions, and 46 pediatric patient controls at 3T. Echo1 [TE = 45ms] and Echo2 [TE = 86ms] were corrected for signal intensity variation across the images by exploiting the images equivalent coil-sensitivity and susceptibility-induced modulations. Two neuroradiologists independently reviewed Echo1 and Echo2 and their intensity-corrected variants (cEcho1 and cEcho2) on a 7-point Likert scale, with grading on lesion conspicuity diagnostic confidence. The apparent diffusion coefficient (ADC) map from Echo1 was used to validate presence of true pathology. Echo2 was unanimously favored over Echo1 for its sensitivity for detecting acute brain injury, with a mean respective lesion conspicuity of 5.7/4.4 (p < 0.005) and diagnostic confidence of 5.1/4.3 (p = 0.025). cEcho2 was rated higher than cEcho1, with a mean respective lesion conspicuity of 5.5/4.3 (p < 0.005) and diagnostic confidence of 5.4/4.4 (p < 0.005). cEcho2 was favored over all echoes for its diagnostic reliability, particularly in regions close to the head coil. This work concludes that DE-EPI DWI is a useful alternative to conventional single-echo EPI DWI, whereby Echo2 and cEcho2 allows for improved lesion detection and overall higher diagnostic confidence.

Decreased tumor apparent diffusion coefficient correlates with objective response of pediatric low-grade glioma to bevacizumab.

Recent small, retrospective series suggest bevacizumab may be a therapeutic option for recurrent pediatric low-grade glioma (LGG). Assessment of therapeutic responses is complicated by the unpredictable natural history of these tumors. Because diffusion-weighted imaging quantifies microscopic water motion affected by cellular density and histologic features, we hypothesized that it may be helpful in monitoring therapeutic response of LGG to bevacizumab. We retrospectively reviewed eight consecutive patients, median age 4.8 (range 2.3-12.3) years at initiation of bevacizumab therapy for recurrent or refractory LGG. Patients received 10 mg/kg/dose every 2 weeks (median 16 doses/therapy course). Mean apparent diffusion coefficient (ADC) was measured and analyzed in respect to tumor volume. Following the first treatment course, seven of eight patients had reduced tumor volume (≥25 %) and ADC. The median decrease in tumor volume was 47% (range -6 to 78 %) and the median decrease in ADC was 14 % (range -5 to 30 %). The ADC was significantly decreased during therapy, whereas the decrease in volume was seen only after therapy completion. There was a positive correlation between percent change in tumor volume and ADC (p < 0.05). We report a decrease in tumor ADC during initial bevacizumab therapy that is accompanied by a decrease in volume following therapy. Imaging changes in microscopic water motion associated with histology may be useful in monitoring the therapeutic response of LGG to bevacizumab.

Neuroimaging and neurodevelopmental outcome in extremely preterm infants.

BACKGROUND: Extremely preterm infants are at risk for neurodevelopmental impairment (NDI). Early cranial ultrasound (CUS) is usual practice, but near-term brain MRI has been reported to better predict outcomes. We prospectively evaluated MRI white matter abnormality (WMA) and cerebellar lesions, and serial CUS adverse findings as predictors of outcomes at 18 to 22 months' corrected age. METHODS: Early and late CUS, and brain MRI were read by masked central readers, in a large cohort (n = 480) of infants <28 weeks' gestation surviving to near term in the Neonatal Research Network. Outcomes included NDI or death after neuroimaging, and significant gross motor impairment or death, with NDI defined as cognitive composite score <70, significant gross motor impairment, and severe hearing or visual impairment. Multivariable models evaluated the relative predictive value of neuroimaging while controlling for other factors. RESULTS: Of 480 infants, 15 died and 20 were lost. Increasing severity of WMA and significant cerebellar lesions on MRI were associated with adverse outcomes. Cerebellar lesions were rarely identified by CUS. In full multivariable models, both late CUS and MRI, but not early CUS, remained independently associated with NDI or death (MRI cerebellar lesions: odds ratio, 3.0 [95% confidence interval: 1.3-6.8]; late CUS: odds ratio, 9.8 [95% confidence interval: 2.8-35]), and significant gross motor impairment or death. In models that did not include late CUS, MRI moderate-severe WMA was independently associated with adverse outcomes. CONCLUSIONS: Both late CUS and near-term MRI abnormalities were associated with outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of near-term neuroimaging.

Effect of number of acquisitions in diffusion tensor imaging of the pediatric brain: optimizing scan time and diagnostic experience.

BACKGROUND AND PURPOSE: Diffusion tensor imaging (DTI) is useful for multiple clinical applications, but its routine implementation for children may be difficult due to long scan times. This study evaluates the impact of decreasing the number of DTI acquisitions (NEX) on interpretability of pediatric brain DTI. METHODS: 15 children with MRI-visible neuropathologies were imaged at 3T using our motion-corrected, parallel imaging- accelerated DT-EPI technique with 3 NEX (scan time 8.25 min). Using these acquisitions, NEX = 1 (scan time 2.75 min) and NEX = 2 (scan time 5.5 min) images were simulated. Two neuroradiologists scored diffusion-weighted images (DWI), apparent diffusion coefficient (ADC), fractional anisotropy (FA), and first eigenvector color-encoded (EV) images from each NEX for perceived SNR, lesion conspicuity and clinical confidence. ROI FA/ADC and image SNR values were also compared across NEX. RESULTS: NEX = 2 perceived SNR, lesion conspicuity, and clinical confidence were not inferior to NEX = 3 images. NEX = 1 images showed comparable lesion conspicuity and clinical confidence as NEX = 3, but inferior perceived SNR. FA and ADC ROI measurements demonstrated no significant difference across NEX. The greatest SNR increase was seen between NEX = 1 and NEX = 2. CONCLUSION: Reducing NEX to shorten imaging time may impact clinical utility in a manner that does not directly correspond with SNR changes.

Diffusion-weighted MRI derived apparent diffusion coefficient identifies prognostically distinct subgroups of pediatric diffuse intrinsic pontine glioma.

While pediatric diffuse intrinsic pontine gliomas (DIPG) remain fatal, recent data have shown subgroups with distinct molecular biology and clinical behavior. We hypothesized that diffusion-weighted MRI can be used as a prognostic marker to stratify DIPG subsets with distinct clinical behavior. Apparent diffusion coefficient (ADC) values derived from diffusion-weighted MRI were computed in 20 consecutive children with treatment-naïve DIPG tumors. The median ADC for the cohort was used to stratify the tumors into low and high ADC groups. Survival, gender, therapy, and potential steroid effects were compared between the ADC groups. Median age at diagnosis was 6.6 (range 2.3-13.2) years, with median follow-up seven (range 1-36) months. There were 14 boys and six girls. Seventeen patients received radiotherapy, five received chemotherapy, and six underwent cerebrospinal fluid diversion. The median ADC of 1,295 × 10(-6) mm(2)/s for the cohort partitioned tumors into low or high diffusion groups, which had distinct median survivals of 3 and 13 months, respectively (log-rank p < 0.001). Low ADC tumors were found only in boys, whereas high ADC tumors were found in both boys and girls. Available tissue specimens in three low ADC tumors demonstrated high-grade histology, whereas one high ADC tumor demonstrated low-grade histology with a histone H3.1 K27M mutation and high-grade metastatic lesion at autopsy. ADC derived from diffusion-weighted MRI may identify prognostically distinct subgroups of pediatric DIPG.

Increased focal hemosiderin deposition in pediatric medulloblastoma patients receiving radiotherapy at a later age.

OBJECT: Focal hemosiderin deposition (FHD) is commonly observed on brain MRI scans of patients treated for childhood medulloblastoma (MB). The authors sought to determine the clinical significance of FHD and its relationship to patient age, radiation dose, and cognitive outcomes. METHODS: A single-institution retrospective study of 93 MB patients at Lucile Packard Children's Hospital at Stanford from 1998 to 2011 identified 41 patients with a negative baseline MRI scan and at least 2 posttreatment MRI scans obtained with T2* gradient recalled echo (GRE). The number and cumulative rate of FHDs detectable by GRE were compared between patients aged 6 years and younger (early age) and aged 7-21 years (late age) at the time of radiotherapy (RT) and between low-dose (1800-2340 cGy) and high-dose (2920-3960 cGy) RT. RESULTS: The median age at MB diagnosis was 7.3 years (range 0.9-21.0 years), the median clinical follow-up period was 5.8 years (range 0.8-13.4 years), and the median 5-year overall survival was 81% ± 7%. Of 30 school-aged children with MB, 21 (70%) required special education, and the median IQ of 10 tested patients was 100 (range 50-118). Thirty-three patients (80%) had FHD after a median latency of 1.9 years (range 0.1-5.9 years). Ninety-four percent (436 of 466) of the lesions arose in the supratentorial region of the brain, whereas 29 (6%) resided in the brainstem or the cerebellum. No spinal lesions were observed on routine spine MRI scans using T2 fast spin echo imaging. The mean cumulative lesion rate per year was 2.23 ± 3.05, and this rate was higher in older children at the time of RT compared with younger children (3.23 vs 0.67 per year, p = 0.002) but did not differ among different RT doses (p = 0.395). A child's IQ or need for special education showed no significant correlation with the rate of lesion development or number of lesions. None of the lesions resulted in symptomatic hemorrhage that required surgical intervention. CONCLUSIONS: More FHD was observed in children treated for MB at the older ages than in those treated at the younger ages. There was no significant association of the incidence of FHD with radiation dose or cognitive outcomes, and none of the lesions required surgical intervention.

Distinctive MRI features of pediatric medulloblastoma subtypes.

OBJECTIVE: We hypothesized that the apparent diffusion coefficient (ADC) and other MRI features can be used to predict medulloblastoma histologic subtypes, as defined by the World Health Organization (WHO) in WHO Classification of Tumours of the Central Nervous System. MATERIALS AND METHODS: A retrospective review of pediatric patients with medulloblastoma between 1989 and 2011 identified 38 patients with both pretreatment MRI and original pathology slides. The mean and minimum tumor ADC values and conventional MRI features were compared among medulloblastoma histologic subtypes. RESULTS: The cohort of 38 patients included the following histologic subtypes: 24 classic medulloblastomas, nine large cell (LC) or anaplastic medulloblastomas, four desmoplastic medulloblastomas, and one medulloblastoma with extensive nodularity. The median age at diagnosis was 8 years (range, 1-21 years) and the median follow-up time was 33 months (range, 0-150 months). The mean ADC (× 10(-3) mm(2)/s) was lower in classic medulloblastoma (0.733 ± 0.046 [SD]) than in LC or anaplastic medulloblastoma (0.935 ± 0.127) (Mann-Whitney test, p = 0.004). Similarly, the minimum ADC was lower in classic medulloblastoma (average ± SD, 0.464 ± 0.056) than in LC or anaplastic medulloblastoma (0.630 ± 0.053) (p = 0.004). The MRI finding of focal cysts correlated with the classic and desmoplastic subtypes (Fisher exact test, p = 0.026). Leptomeningeal enhancement positively correlated with the LC or anaplastic medulloblastoma subtype and inversely correlated with the classic medulloblastoma and desmoplastic medulloblastoma subtypes (p = 0.04). Ring enhancement correlated with tumor necrosis (p = 0.022) and with the LC or anaplastic medulloblastoma histologic subtype (p < 0.001). CONCLUSION: The LC or anaplastic medulloblastoma subtype was associated with increased ADC and with ring enhancement, the latter of which correlated with tumor necrosis. These features could be considered in the evaluation of high-risk medulloblastoma subtypes.

Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy.

OBJECTIVE: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. DESIGN AND PATIENTS: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. RESULTS: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. CONCLUSIONS: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy.

Diffusion tensor imaging (DTI) with retrospective motion correction for large-scale pediatric imaging.

PURPOSE: To develop and implement a clinical DTI technique suitable for the pediatric setting that retrospectively corrects for large motion without the need for rescanning and/or reacquisition strategies, and to deliver high-quality DTI images (both in the presence and absence of large motion) using procedures that reduce image noise and artifacts. MATERIALS AND METHODS: We implemented an in-house built generalized autocalibrating partially parallel acquisitions (GRAPPA)-accelerated diffusion tensor (DT) echo-planar imaging (EPI) sequence at 1.5T and 3T on 1600 patients between 1 month and 18 years old. To reconstruct the data, we developed a fully automated tailored reconstruction software that selects the best GRAPPA and ghost calibration weights; does 3D rigid-body realignment with importance weighting; and employs phase correction and complex averaging to lower Rician noise and reduce phase artifacts. For select cases we investigated the use of an additional volume rejection criterion and b-matrix correction for large motion. RESULTS: The DTI image reconstruction procedures developed here were extremely robust in correcting for motion, failing on only three subjects, while providing the radiologists high-quality data for routine evaluation. CONCLUSION: This work suggests that, apart from the rare instance of continuous motion throughout the scan, high-quality DTI brain data can be acquired using our proposed integrated sequence and reconstruction that uses a retrospective approach to motion correction. In addition, we demonstrate a substantial improvement in overall image quality by combining phase correction with complex averaging, which reduces the Rician noise that biases noisy data.

Liposomal cytarabine for central nervous system embryonal tumors in children and young adults.

To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.

Imaging of nonaccidental injury and the mimics: issues and controversies in the era of evidence-based medicine.

Because of the controversy involving the determination of child abuse, or nonaccidental injury (NAI), radiologists must be familiar with the issues, literature, and principles of evidence-based medicine to understand the role of imaging. Children with suspected NAI must receive protective evaluation along with a timely and complete clinical and imaging work-up. Imaging findings cannot stand alone and must be correlated with clinical findings, laboratory testing, and pathologic and forensic examinations. Only the child protection investigation may provide the basis for inflicted injury in the context of supportive clinical, imaging, biomechanical, or pathology findings.

Infant acute life-threatening event--dysphagic choking versus nonaccidental injury.

A 4-month-old male infant presented to the emergency room with a history of choking while bottle feeding at home, and was found by emergency medical services (EMS) to be apneic and pulseless. He subsequently developed disseminated intravascular coagulopathy and died. Computed tomography (CT) and magnetic resonance imaging (MRI) showed subdural hemorrhages (SDHs), subarachnoid hemorrhage (SAH), and retinal hemorrhages (RHs), along with findings of hypoxic-ischemic encephalopathy (HIE). The caretaker account appeared to be inconsistent with the clinical and imaging features, and a diagnosis of nonaccidental injury with "shaken baby syndrome" was made. The autopsy revealed diffuse anoxic central nervous system (CNS) changes with marked edema, SAH, and SDH, but no evidence of "CNS trauma." Although NAI could not be ruled out, the autopsy findings provided further evidence that the child's injury could result from a dysphagic choking type of acute life threatening event (ALTE) as consistently described by the caretaker.

Neuroimaging advances in holoprosencephaly: Refining the spectrum of the midline malformation.

Holoprosencephaly (HPE) is a complex congenital brain malformation characterized by failure of the forebrain to bifurcate into two hemispheres, a process normally completed by the fifth week of gestation. Modern high-resolution brain magnetic resonance imaging (MRI) has allowed detailed analysis of the cortical, white matter, and deep gray structural anomalies in HPE in living humans. This has led to better classification of types of HPE, identification of newer subtypes, and understanding of the pathogenesis. Currently, there are four generally accepted subtypes of HPE: alobar, semilobar, lobar, and middle interhemispheric variant. These subtypes are defined primarily by the degree and region of neocortical nonseparation. Rather than there being four discrete subtypes of HPE, we believe that there is a continuum of midline neocortical nonseparation resulting in a spectrum disorder. Many patients with HPE fall within the border zone between the neighboring subtypes. In addition, there are patients with very mild HPE, where the nonseparation is restricted to the preoptic (suprachiasmic) area. In addition to the neocortex, other midline structures such as the thalami, hypothalamic nuclei, and basal ganglia are often nonseparated in HPE. The cortical and subcortical involvements in HPE are thought to occur due to a disruption in the ventral patterning process during development. The severity of the abnormalities in these structures determines the severity of the neurodevelopmental outcome and associated sequelae.