Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder.

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.

Unsupervised abnormality detection in neonatal MRI brain scans using deep learning.

Analysis of 3D medical imaging data has been a large topic of focus in the area of Machine Learning/Artificial Intelligence, though little work has been done in algorithmic (particularly unsupervised) analysis of neonatal brain MRI's. A myriad of conditions can manifest at an early age, including neonatal encephalopathy (NE), which can result in lifelong physical consequences. As such, there is a dire need for better biomarkers of NE and other conditions. The objective of the study is to improve identification of anomalies and prognostication of neonatal MRI brain scans. We introduce a framework designed to support the analysis and assessment of neonatal MRI brain scans, the results of which can be used as an aid to neuroradiologists. We explored the efficacy of the framework through iterations of several deep convolutional Autoencoder (AE) unsupervised modeling architectures designed to learn normalcy of the neonatal brain structure. We tested this framework on the developing human connectome project (dHCP) dataset with 97 patients that were previously categorized by severity. Our framework demonstrated the model's ability to identify and distinguish subtle morphological signatures present in brain structures. Normal and abnormal neonatal brain scans can be distinguished with reasonable accuracy, correctly categorizing them in up to 83% of cases. Most critically, new brain anomalies originally missed during the radiological reading were identified and corroborated by a neuroradiologist. This framework and our modeling approach demonstrate an ability to improve prognostication of neonatal brain conditions and are able to localize new anomalies.

Fetal-placental MR angiography at 1.5 T and 3 T.

OBJECTIVES: The objective of this work was to investigate the application of 2D Time-of-Flight (TOF) magnetic resonance angiography (MRA) to observe the placental vasculature at both 1.5 T and 3 T. METHODS: Fifteen appropriate for gestational age (AGA) (GA: 29.7 ± 3.4 weeks; GA range: 23 and 6/7 weeks to 36 and 2/7 weeks) and eleven patients with an abnormal singleton pregnancy (GA: 31.4 ± 4.4 weeks; GA range: 24 weeks to 35 and 2/7 weeks) were recruited in the study. Three AGA patients were scanned twice at different gestational ages. Patients were scanned either at 3 T or 1.5 T using both T2-HASTE and 2D TOF to image the entire placental vasculature. RESULTS: The umbilical, chorionic vessels, stem vessels, arcuate arteries, radial arteries, and spiral arteries were shown in most of the subjects. Hyrtl's anastomosis was found in two subjects in the 1.5 T data. The uterine arteries were observed in more than half of the subjects. For those patients scanned twice, the same spiral arteries were identified in both scans. CONCLUSIONS: 2D TOF is a technique that can be applied in studying the fetal-placental vasculature at both 1.5 T and 3 T.

Neonatal encephalopathy prediction of poor outcome with diffusion-weighted imaging connectome and fixel-based analysis.

BACKGROUND: Better biomarkers of eventual outcome are needed for neonatal encephalopathy. To identify the most potent neonatal imaging marker associated with 2-year outcomes, we retrospectively performed diffusion-weighted imaging connectome (DWIC) and fixel-based analysis (FBA) on magnetic resonance imaging (MRI) obtained in the first 4 weeks of life in term neonatal encephalopathy newborns. METHODS: Diffusion tractography was available in 15 out of 24 babies with MRI, five each with normal, abnormal motor outcome, or death. All 15 except one underwent hypothermia as initial treatment. In abnormal motor and death groups, DWIC found 19 white matter pathways with severely disrupted fiber orientation distributions. RESULTS: Using random forest classification, these disruptions predicted the follow-up outcomes with 89-99% accuracy. These pathways showed reduced integrity in abnormal motor and death vs. normal tone groups (p < 10-6). Using ranked supervised multi-view canonical correlation and depicting just three of the five dimensions of the analysis, the abnormal motor and death were clearly differentiated from each other and the normal tone group. CONCLUSIONS: This study suggests that a machine-learning model for prediction using early DWIC and FBA could be a possible way of developing biomarkers in large MRI datasets having clinical outcomes. IMPACT: Early connectome and FBA of clinically acquired DWI provide a new noninvasive imaging tool to predict the long-term motor outcomes after birth, based on the severity of white matter injury. Disrupted white matter connectivity as a novel neonatal marker achieves high accuracy of 89-99% to predict 2-year motor outcomes using conventional machine-learning classification. The proposed neonatal marker may allow better prognostication that is important to elucidate neural repair mechanisms and evaluate treatment modalities in neonatal encephalopathy.

Rates and clinical impact of discordant X-ray and CT imaging in transfers to a pediatric emergency department.

OBJECTIVES: Children are often transferred to a Pediatric Emergency Department (PED) for definitive care after completion of diagnostic imaging. There is a paucity of data on the concordance rates of interpretation of imaging studies between referral and PED. Our objective is to describe the rates and clinical impact of discordant interpretation of X-rays and CT in children transferred to a PED. METHODS: This was a retrospective cohort study of patients over a 12-month period from 12/1/2017-11/30/2018 with X-ray (XR) and CT performed prior to transfer to our PED. We compared referral radiology interpretations to those of pediatric radiologists to determine concordance. Encounters with discordant imaging interpretations were further evaluated for clinical impact (none, minor or major) based on need for additional laboratory workup, consultation, and changes in management and disposition. RESULTS: We analyzed 899 patient encounters. There were high rates of concordance in both XR and CT interpretation (668/743; 89.9%, 95% CI 0.87-0.91 and 205/235; 87.2%, 95% CI 0.82-0.91, respectively). XR discordance resulted in minor clinical impact in 34 patients (45%, 95% CI 0.35-0.57) and a major clinical impact in 28 patients (37%, 95% CI 0.27-0.49). CT discordance resulted in minor clinical impact in 10 patients (33%, 95% CI 0.19-0.51) of patients and major clinical impact in 15 patients (50%, 95% CI 0.33-0.67). The most common discordances with major clinical impact were related to pneumonia on XR chest and appendicitis or inflammatory bowel disease on CT abdomen. CONCLUSIONS: In patients transferred to the PED, concordance of XR and CT interpretations was high. A majority of discordant interpretations led to clinical impact meaningful to the patient and emergency medicine (EM) physician. Referring EM physicians might consider the benefit of pediatric radiology consultation upon transfer, especially for imaging diagnoses related to pneumonia, appendicitis, or inflammatory bowel disease.

Familial Hydrocephalus and Dysgenesis of the Corpus Callosum Associated with Xp22.33 Duplication and Stenosis of the Aqueduct of Sylvius with X-Linked Recessive Inheritance Pattern.

INTRODUCTION: X-linked recessive mutations predominantly affect male fetuses with milder or no abnormalities in female siblings. Most reports show only one affected member in the family. We are reporting a family affected with hydrocephalus, stenosis of the aqueduct of Sylvius, dysgenesis of the corpus callosum, and Xp22.33 microduplication. CASE PRESENTATION: Eighteen-year-old patient was evaluated for her 2 pregnancies; the first was a male fetus with severe hydrocephalus and the second a female fetus with mild hydrocephalus. Postnatal MRI evaluation of the male neonate revealed stenosis of the aqueduct of Sylvius, dysgenesis of the corpus callosum, and severe hydrocephalus requiring ventriculoperitoneal shunt. Postnatal MRI evaluation of the female neonate revealed mild hydrocephalus, stenosis of the aqueduct of Sylvius, and mild dysgenesis of the corpus callosum. The female baby did not require surgical intervention. Genetic testing of the mother and the 2 children revealed a 439 Kb duplication of Xp22.33. DISCUSSION: This family demonstrates typical X-linked recessive heritability. X-inactivation is a compensatory mechanism that explains the mild symptoms of the female child and the severe symptoms of the male child. This familial case shows the importance of prenatal testing and genetic counseling and testing, including karyotype and chromosomal microarray.

Quantitative Flow Imaging in Human Umbilical Vessels In Utero Using Nongated 2D Phase Contrast MRI.

BACKGROUND: Volumetric assessment of afferent blood flow rate provides a measure of global organ perfusion. Phase-contrast magnetic resonance imaging (PCMRI) is a reliable tool for volumetric flow quantification, but given the challenges with motion and lack of physiologic gating signal, such studies, in vivo on the human placenta, are scant. PURPOSE: To evaluate and apply a nongated (ng) PCMRI technique for quantifying blood flow rates in utero in umbilical vessels. STUDY TYPE: Prospective study design. STUDY POPULATION: Twenty-four pregnant women with median gestational age (GA) 30 4/7 weeks and interquartile range (IQR) 8 1/7 weeks. FIELD STRENGTH/SEQUENCE: All scans were performed on a 3.0T Siemens Verio system using the ng-PCMRI technique. ASSESSMENT: The GA-dependent increase in umbilical vein (UV) and arterial (UA) flow was compared to previously published values. Systematic error to be expected from ng-PCMRI, in the context of pulsatile UA flow and partial voluming, was studied through Monte-Carlo simulations, as a function of resolution and number of averages. STATISTICAL TESTS: Correlation between the UA and UV was evaluated using a generalized linear model. RESULTS: Simulations showed that ng-PCMRI measurement variance reduced by increasing the number of averages. For vessels on the order of 2 voxels in radius, partial voluming led to 10% underestimation in the flow. In fetuses, the average flow rates in UAs and UV were measured to be 203 ± 80 ml/min and 232 ± 92 ml/min and the normalized average flow rates were 140 ± 59 ml/min/kg and 155 ± 57 ml/min/kg, respectively. Excellent correlation was found between the total arterial flow vs. corresponding venous flow, with a slope of 1.08 (P = 0.036). DATA CONCLUSION: Ng-PCMRI can provide accurate volumetric flow measurements in utero in the human umbilical vessels. Care needs to be taken to ensure sufficiently high-resolution data are acquired to minimize partial voluming-related errors. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage 1 J. Magn. Reson. Imaging 2017.

Magnetic resonance angiography of fetal vasculature at 3.0 T.

Magnetic resonance angiography has not been used much previously for visualizing fetal vessels in utero for reasons that include a contraindication for the use of exogenous contrast agents, maternal respiratory motion and fetal motion. In this work, we report the feasibility of using an appropriately modified clinical time-of-flight magnetic resonance imaging sequence for non-contrast angiography of human fetal and placental vessels at 3.0 T. Using this 2D angiography technique, it is possible to visualize fetal vascular networks in late pregnancy. KEY POINTS: • 3D-visualization of fetal vasculature is feasible using non-contrast MRA at 3.0 T. • Visualization of placental vasculature is also possible with this method. • Fetal MRA can serve as a vascular localizer for quantitative MRI studies. • This method can be extended to 1.5 T.

Age-related increases in long-range connectivity in fetal functional neural connectivity networks in utero.

Formation of operational neural networks is one of the most significant accomplishments of human fetal brain growth. Recent advances in functional magnetic resonance imaging (fMRI) have made it possible to obtain information about brain function during fetal development. Specifically, resting-state fMRI and novel signal covariation approaches have opened up a new avenue for non-invasive assessment of neural functional connectivity (FC) before birth. Early studies in this area have unearthed new insights about principles of prenatal brain function. However, very little is known about the emergence and maturation of neural networks during fetal life. Here, we obtained cross-sectional rs-fMRI data from 39 fetuses between 24 and 38 weeks postconceptual age to examine patterns of connectivity across ten neural FC networks. We identified primitive forms of motor, visual, default mode, thalamic, and temporal networks in the human fetal brain. We discovered the first evidence of increased long-range, cerebral-cerebellar, cortical-subcortical, and intra-hemispheric FC with advancing fetal age. Continued aggregation of data about fundamental neural connectivity systems in utero is essential to establishing principles of connectomics at the beginning of human life. Normative data provides a vital context against which to compare instances of abnormal neurobiological development.

The clinical relevance of fetal MRI in the diagnosis of Type IV cystic sacrococcygeal teratoma--a review.

The introduction of fetal magnetic resonance imaging (MRI) has improved the prenatal evaluation of uterine, placental and fetal anatomy. However, its utilization has mostly been restricted to fetal central nervous system anomalies. We review how adjunct fetal MRI was performed and diagnosis of cystic type IV sacrococcygeal teratoma was made. We also discuss the clinical relevance of fetal MRI in differentiating this lesion from other selected abdominal/pelvic cystic malformations and lesions.

MR imaging of the fetal brain at 1.5T and 3.0T field strengths: comparing specific absorption rate (SAR) and image quality.

OBJECTIVES: Our two objectives were to evaluate the feasibility of fetal brain magnetic resonance imaging (MRI) using a fast spin echo sequence at 3.0T field strength with low radio frequency (rf) energy deposition (as measured by specific absorption rate: SAR) and to compare image quality, tissue contrast and conspicuity between 1.5T and 3.0T MRI. METHODS: T2 weighted images of the fetal brain at 1.5T were compared to similar data obtained in the same fetus using a modified sequence at 3.0T. Quantitative whole-body SAR and normalized image signal to noise ratio (SNR), a nominal scoring scheme based evaluation of diagnostic image quality, and tissue contrast and conspicuity for specific anatomical structures in the brain were compared between 1.5T and 3.0T. RESULTS: Twelve pregnant women underwent both 1.5T and 3.0T MRI examinations. The image SNR was significantly higher (P=0.03) and whole-body SAR was significantly lower (P<0.0001) for images obtained at 3.0T compared to 1.5T. All cases at both field strengths were scored as having diagnostic image quality. Images from 3.0T MRI (compared to 1.5T) were equal (57%; 21/37) or superior (35%; 13/37) for tissue contrast and equal (61%; 20/33) or superior (33%, 11/33) for conspicuity. CONCLUSIONS: It is possible to obtain fetal brain images with higher resolution and better SNR at 3.0T with simultaneous reduction in SAR compared to 1.5T. Images of the fetal brain obtained at 3.0T demonstrated superior tissue contrast and conspicuity compared to 1.5T.

MR venography of the fetal brain using susceptibility weighted imaging.

PURPOSE: To evaluate the feasibility of performing fetal brain magnetic resonance venography using susceptibility weighted imaging (SWI). MATERIALS AND METHODS: After obtaining informed consent, pregnant women in the second and third trimester were imaged using a modified SWI sequence. Fetal SWI acquisition was repeated when fetal or maternal motion was encountered. The median and maximum number of times an SWI sequence was repeated was four and six respectively. All SWI image data were systematically evaluated by a pediatric neuroradiologist for image quality using an ordinal scoring scheme: 1. diagnostic; 2. diagnostic with artifacts; and 3. nondiagnostic. The best score in an individual fetus was used for further statistical analysis. Visibility of venous vasculature was also scored using a dichotomous variable. A subset of SWI data was re-evaluated by the first and independently by a second pediatric neuroradiologist. Kappa coefficients were computed to assess intra-rater and inter-rater reliability. RESULTS: SWI image data from a total of 22 fetuses were analyzed. Median gestational age and interquartile range of the fetuses imaged were 32 (29.9-34.9) weeks. In 68.2% of the cases (n = 15), there was no artifact; 22.7% (n = 5) had minor artifacts and 9.1% (n = 2) of the data was of nondiagnostic quality. Cerebral venous vasculature was visible in 86.4% (n = 19) of the cases. Substantial agreement (Kappa = 0.73; 95% confidence interval 0.44-1.00)) was observed for intra-rater reliability and moderate agreement (Kappa = 0.48; 95% confidence interval 0.19-0.77) was observed for inter-rater reliability. CONCLUSION: It is feasible to perform fetal brain venography in humans using SWI.

Clinical and neuroimaging findings in neonatal herpes simplex virus infection.

In a retrospective review of infants with neonatal herpes simplex virus disease (n=29), we found bilateral multilobar (n=8), pontine (n=3), thalamic (n=6), and internal capsule and corticospinal tract (n=5) involvement on magnetic resonance imaging (MRI). Diffusion-weighted imaging (n=6) performed early revealed additional involvement than detected by conventional MRI. Neurodevelopmental sequelae were correlated with MRI abnormalities. Our findings demonstrate that MRI, including diffusion-weighted imaging, is a valuable prognostic adjunct in neonatal herpes simplex virus disease.

Measuring venous blood oxygenation in fetal brain using susceptibility-weighted imaging.

PURPOSE: To evaluate fetal cerebral venous blood oxygenation, Yv, using principles of MR susceptometry. MATERIALS AND METHODS: A cohort of 19 pregnant subjects, with a mean gestational age of 31.6 ± 4.7 weeks were imaged using a modified susceptibility-weighted imaging (SWI) sequence. Data quality was first assessed for feasibility of oxygen saturation measurement, and data from five subjects (mean ± std gestational age of 33.7 ± 3.6 weeks) were then chosen for further quantitative analysis. SWI phase in the superior sagittal sinus was used to evaluate oxygen saturation using the principles of MR susceptometry. Systematic error in the measured Y(v) values was studied through simulations. RESULTS: Simulations showed that the systematic error in Yv depended upon the assumed angle of the vessel, θ, relative to the main magnetic field and the error in that vessel angle δθ. For the typical vessel angle of θ = 30° encountered in the fetal data analyzed, a δθ as large as ±20° led to an absolute error, δYv, of less than 11%. The measured mean oxygen saturation across the five fetuses was 66% ± 9.4%. This average cerebral venous blood oxygenation value is in close agreement with values in the published literature. CONCLUSION: We have reported the first in vivo measurement of human fetal cerebral venous oxygen saturation using MRI.

Intrinsic functional brain architecture derived from graph theoretical analysis in the human fetus.

The human brain undergoes dramatic maturational changes during late stages of fetal and early postnatal life. The importance of this period to the establishment of healthy neural connectivity is apparent in the high incidence of neural injury in preterm infants, in whom untimely exposure to ex-uterine factors interrupts neural connectivity. Though the relevance of this period to human neuroscience is apparent, little is known about functional neural networks in human fetal life. Here, we apply graph theoretical analysis to examine human fetal brain connectivity. Utilizing resting state functional magnetic resonance imaging (fMRI) data from 33 healthy human fetuses, 19 to 39 weeks gestational age (GA), our analyses reveal that the human fetal brain has modular organization and modules overlap functional systems observed postnatally. Age-related differences between younger (GA <31 weeks) and older (GA≥31 weeks) fetuses demonstrate that brain modularity decreases, and connectivity of the posterior cingulate to other brain networks becomes more negative, with advancing GA. By mimicking functional principles observed postnatally, these results support early emerging capacity for information processing in the human fetal brain. Current technical limitations, as well as the potential for fetal fMRI to one day produce major discoveries about fetal origins or antecedents of neural injury or disease are discussed.

Cross-hemispheric functional connectivity in the human fetal brain.

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.