Current state of pediatric neuro-oncology imaging, challenges and future directions.

Imaging plays a central role in neuro-oncology including primary diagnosis, treatment planning, and surveillance of tumors. The emergence of quantitative imaging and radiomics provided an uprecedented opportunity to compile mineable databases that can be utilized in a variety of applications. In this review, we aim to summarize the current state of conventional and advanced imaging techniques, standardization efforts, fast protocols, contrast and sedation in pediatric neuro-oncologic imaging, radiomics-radiogenomics, multi-omics and molecular imaging approaches. We will also address the existing challenges and discuss future directions.

Pediatric Brain Maturation and Migration Disorders.

Neurodevelopmental disorders, including neuronal migration disorders, are best understood in the context of altered normal development. Neurons normally migrate from their site of origin to their (usually cortical) destination using a wide range of molecular and cellular signaling as a guide. In the case of abnormal migration neurons: (1) do not migrate and remain at their site of origin; (2) incompletely migrate and remain within the white matter; (3) migrate to the cortex but fail to organize correctly; or (4) over-migrate, beyond the cortex. In this review, we discuss normal brain development, along with the malformations that result from these different migration abnormalities.

Clinical Assessment of Deep Learning-based Super-Resolution for 3D Volumetric Brain MRI.

Artificial intelligence (AI)-based image enhancement has the potential to reduce scan times while improving signal-to-noise ratio (SNR) and maintaining spatial resolution. This study prospectively evaluated AI-based image enhancement in 32 consecutive patients undergoing clinical brain MRI. Standard-of-care (SOC) three-dimensional (3D) T1 precontrast, 3D T2 fluid-attenuated inversion recovery, and 3D T1 postcontrast sequences were performed along with 45% faster versions of these sequences using half the number of phase-encoding steps. Images from the faster sequences were processed by a Food and Drug Administration-cleared AI-based image enhancement software for resolution enhancement. Four board-certified neuroradiologists scored the SOC and AI-enhanced image series independently on a five-point Likert scale for image SNR, anatomic conspicuity, overall image quality, imaging artifacts, and diagnostic confidence. While interrater κ was low to fair, the AI-enhanced scans were noninferior for all metrics and actually demonstrated a qualitative SNR improvement. Quantitative analyses showed that the AI software restored the high spatial resolution of small structures, such as the septum pellucidum. In conclusion, AI-based software can achieve noninferior image quality for 3D brain MRI sequences with a 45% scan time reduction, potentially improving the patient experience and scanner efficiency without sacrificing diagnostic quality. Keywords: MR Imaging, CNS, Brain/Brain Stem, Reconstruction Algorithms © RSNA, 2022.

Technical and practical tips for performing brain magnetic resonance imaging in premature neonates.

MR imaging of premature neonates is challenging due to their small size, need for temperature support and monitoring, and immature central nervous system. Use of MR compatible incubators and MR compatible monitoring apparatus, careful selection of imaging protocols, and real time review of images by a radiologist can streamline the imaging process and improve image quality. Imaging should be focused upon (1) the child's biorhythms (imaging during sleep cycles), (2) minimizing delays during transport and (3) delaying noisy MR sequences until the end of an examination. Successful imaging of premature neonates requires teamwork: advanced planning, careful communication among neonatologists, nurses, and radiologists, established imaging protocols, and coordination among team members during all aspects of the process.

Effects of ventricular entry on patient outcome during glioblastoma resection.

OBJECTIVE: Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with worse prognoses; however, the interaction between these two factors is poorly understood. Given the benefit of maximal tumor resection, it is imperative for surgical planning and technique to know if VE has negative consequences for patient survival and tumor dissemination. METHODS: The University of California, San Francisco tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma (GBM) who underwent resection by the senior author between 2013 and 2018. Tumor location with respect to the subventricular zone (SVZ), size, and extent of resection were assessed using pre- and postoperative imaging. VE was determined by postoperative imaging and/or the operative report. RESULTS: In this 200-patient cohort of newly diagnosed and recurrent GBM, 26.5% of patients had VE during resection. Patients with VE were more likely to have preexisting subependymal disease (41.5% vs 15.0%, p < 0.001). Comparing patients with VE to those without VE, there was no difference in the rates of postoperative hydrocephalus (1.9% vs 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs 3.4%, p = 0.17), pseudomeningoceles (7.5% vs 5.4%, p = 0.58), or subdural hematomas (11.3% vs 3.4%, p = 0.07). Importantly, rates of subsequent leptomeningeal disease (7.5% vs 10.2%, p = 0.57) and distant parenchymal recurrence (17.0% vs 23.1%, p = 0.35) were not different between the groups. Newly diagnosed patients with tumors contacting the SVZ (type I or II) had worse survival than patients with tumors that did not contact the SVZ (type III or IV) (1.27 vs 1.84 years, p = 0.014, HR 1.8, 95% CI 1.08-3.03), but VE was not associated with worse survival in these patients with high-risk SVZ type I and II tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, 95% CI 0.26-1.34). CONCLUSIONS: VE was well tolerated, with postoperative complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, although survival was worse for patients with preoperative subependymal disease, VE did not change survival for patients with tumors contacting the ventricle. Therefore, VE during GBM resection is not associated with adverse patient outcomes and should be used by surgeons to enhance extent of resection.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective cohort; evidence: class II.

Cerebrovascular complications of coccidioidomycosis meningitis: Case report and systematic review.

Coccidioidomycosis exposure is common in the southwest United States and northern Mexico. Dissemination to the meninges is the most severe form of progression. Although ischemic strokes are well-reported in these patients, other cerebrovascular complications of coccidioidomycosis meningitis (CM), as well as their treatment options and outcomes, have not been systematically studied. We present a uniquely severe case of CM with several cerebrovascular complications. We also systematically queried PubMed and EMBASE databases, including articles published before April 2020 reporting human patients with CM-induced cerebrovascular pathology other than ischemic infarcts. Sixteen articles met inclusion criteria, which describe 6 patients with aneurysmal hemorrhage, 10 with non-aneurysmal hemorrhage, one with vasospasm, and one with transient ischemic attacks. CM-associated aneurysms invariably presented with hemorrhage. These were universally fatal until the past decade, when advances in surgical clipping and/or combined surgical and endovascular treatment have improved outcomes. We found that non-aneurysmal intracranial hemorrhages were limited to male patients, involved a diverse set of intracranial vasculature, and had a mortality rate surpassing 80%. Vasospasm was reported once, and was treated with percutaneous transluminal angioplasty. Transient ischemic attacks were reported once, and were successfully treated with fluconazole and dexamethasone. This review suggests that CM can present with a wide array of cerebrovascular complications, including ischemic infarcts, aneurysmogenesis, non-aneurysmal intracranial hemorrhage, vasospasm, and transient ischemic attacks. Mortality has improved over time due to advances in surgical and endovascular treatment modalities. The exception is non-aneurysmal intracranial hemorrhage, which remains associated with high mortality rates and few targeted therapeutic options.

MR Imaging of Normal Brain Development.

Normal brain development is best evaluated by MR imaging in the fetal and pediatric patient. As the developing brain grows, myelinates, and sulcates rapidly, understanding the normal appearance of the brain throughout development is critical. The fetal brain can be evaluated by MR imaging after 16 weeks gestational age, both morphologically and biometrically. Sulcation of the fetal brain lags behind premature neonates of equivalent gestational age. Sensory axons generally myelinate before motor axons with central to peripheral and dorsal to ventral myelination gradients. By 2 years of age, the brain has a near adult appearance by conventional anatomic MR imaging.

Challenges in pediatric neuroimaging.

Pediatric neuroimaging is challenging due the rapid structural, metabolic, and functional changes that occur in the developing brain. A specially trained team is needed to produce high quality diagnostic images in children, due to their small physical size and immaturity. Patient motion, cooperation and medical condition dictate the methods and equipment used. A customized approach tailored to each child's age and functional status with the appropriate combination of dedicated staff, imaging hardware, and software is key; these range from low-tech techniques, such as feed and swaddle, to specialized small bore MRI scanners, MRI compatible incubators and neonatal head coils. New pre-and post-processing techniques can also compensate for the motion artifacts and low signal that often degrade neonatal scans.

Abnormal Morphology of Select Cortical and Subcortical Regions in Neurofibromatosis Type 1.

Purpose To evaluate whether patients with neurofibromatosis type 1 (NF1)-a multisystem neurodevelopmental disorder with myriad imaging manifestations, including focal transient myelin vacuolization within the deep gray nuclei, brainstem, and cerebellum-exhibit differences in cortical and subcortical structures, particularly in subcortical regions where these abnormalities manifest. Materials and Methods In this retrospective study, by using clinically obtained three-dimensional T1-weighted MR images and established image analysis methods, 10 intracranial volume-corrected subcortical and 34 cortical regions of interest (ROIs) were quantitatively assessed in 32 patients with NF1 and 245 age- and sex-matched healthy control subjects. By using linear models, ROI cortical thicknesses and volumes were compared between patients with NF1 and control subjects, as a function of age. With hierarchic cluster analysis and partial correlations, differences in the pattern of association between cortical and subcortical ROI volumes in patients with NF1 and control subjects were also evaluated. Results Patients with NF1 exhibited larger subcortical volumes and thicker cortices of select regions, particularly the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami, and occipital cortices. For the thalami and pallida and 22 cortical ROIs in patients with NF1, a significant inverse association between volume and age was found, suggesting that volumes decrease with increasing age. Moreover, compared with those in control subjects, ROIs in patients with NF1 exhibited a distinct pattern of clustering and partial correlations. Discussion Neurofibromatosis type 1 is characterized by larger subcortical volumes and thicker cortices of select structures. Most apparent within the hippocampi, amygdalae, cerebellar white matter, ventral diencephalon, thalami and occipital cortices, these neurofibromatosis type 1-associated volumetric changes may, in part, be age dependent. © RSNA, 2018 Online supplemental material is available for this article.

Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex.

Tuberous sclerosis complex (TSC), a heritable neurodevelopmental disorder, is caused by mutations in the TSC1 or TSC2 genes. To date, there has been little work to elucidate regional TSC1 and TSC2 gene expression within the human brain, how it changes with age, and how it may influence disease. Using a publicly available microarray dataset, we found that TSC1 and TSC2 gene expression was highest within the adult neo-cerebellum and that this pattern of increased cerebellar expression was maintained throughout postnatal development. During mid-gestational fetal development, however, TSC1 and TSC2 expression was highest in the cortical plate. Using a bioinformatics approach to explore protein and genetic interactions, we confirmed extensive connections between TSC1/TSC2 and the other genes that comprise the mammalian target of rapamycin (mTOR) pathway, and show that the mTOR pathway genes with the highest connectivity are also selectively expressed within the cerebellum. Finally, compared to age-matched controls, we found increased cerebellar volumes in pediatric TSC patients without current exposure to antiepileptic drugs. Considered together, these findings suggest that the cerebellum may play a central role in TSC pathogenesis and may contribute to the cognitive impairment, including the high incidence of autism spectrum disorder, observed in the TSC population.

CXCR4 involvement in neurodegenerative diseases.

Neurodegenerative diseases likely share common underlying pathobiology. Although prior work has identified susceptibility loci associated with various dementias, few, if any, studies have systematically evaluated shared genetic risk across several neurodegenerative diseases. Using genome-wide association data from large studies (total n = 82,337 cases and controls), we utilized a previously validated approach to identify genetic overlap and reveal common pathways between progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), Parkinson's disease (PD) and Alzheimer's disease (AD). In addition to the MAPT H1 haplotype, we identified a variant near the chemokine receptor CXCR4 that was jointly associated with increased risk for PSP and PD. Using bioinformatics tools, we found strong physical interactions between CXCR4 and four microglia related genes, namely CXCL12, TLR2, RALB, and CCR5. Evaluating gene expression from post-mortem brain tissue, we found that expression of CXCR4 and microglial genes functionally related to CXCR4 was dysregulated across a number of neurodegenerative diseases. Furthermore, in a mouse model of tauopathy, expression of CXCR4 and functionally associated genes was significantly altered in regions of the mouse brain that accumulate neurofibrillary tangles most robustly. Beyond MAPT, we show dysregulation of CXCR4 expression in PSP, PD, and FTD brains, and mouse models of tau pathology. Our multi-modal findings suggest that abnormal signaling across a 'network' of microglial genes may contribute to neurodegeneration and may have potential implications for clinical trials targeting immune dysfunction in patients with neurodegenerative diseases.

Pediatric neuro MRI: tricks to minimize sedation.

Magnetic resonance imaging (MRI) is the workhorse modality in pediatric neuroimaging because it provides excellent soft-tissue contrast without ionizing radiation. Until recently, studies were uninterpretable without sedation; however, given development of shorter sequences, sequences that correct for motion, and studies showing the potentially deleterious effects of sedation on immature laboratory animals, it is prudent to minimize sedation when possible. This manuscript provides basic guidelines for performing pediatric neuro MRI without sedation by both modifying technical factors to reduce scan time and noise, and using a multi-disciplinary team to coordinate imaging with the patient's biorhythms.

Bevacizumab: radiation combination produces restricted diffusion on brain MRI.

AIMS: The purpose of this paper is to investigate the effect of bevacizumab (BEV) on the diffusion properties of irradiated brain gliomas. MATERIALS & METHODS: Neuroimaging studies and medical records of 44 patients undergoing treatment for cerebral gliomas were reviewed. MRIs were analyzed for presence of restricted diffusion, time to onset, pattern/location, duration of restriction, and persistence of restriction post-treatment with BEV. RESULTS: Patchy confluent areas of diffusion restriction on MRI were found in 12 patients. All 12 patients received radiation therapy followed by BEV therapy. Diffusion restriction appeared 3 to 21 months after onset of radiation and 1 to 6 months after starting BEV therapy, increased in size over time, and persisted up to 23 months while on BEV. Restricted diffusion was observed in areas that received 60 Gy or more of radiation. Areas of restricted diffusion showed low T1 and increased T2 signal intensity, minimal or no contrast enhancement, and low cerebral blood volume. A thin perimeter of susceptibility outlined the restricted areas on susceptibility-weighted images in nine patients (75%). Small focal areas of tumor recurrence within larger regions of restricted diffusion were evident in only four patients (33%). In seven patients (58%) the area of restricted diffusion showed necrosis or radiation change on histology or no metabolic activity on MR spectroscopy or PET. CONCLUSION: Restricted diffusion associated with BEV-treated cerebral gliomas occurs in regions of high-dose radiation and does not indicate high-cellularity of tumor recurrence.