Publications by authors named "Michael Iv"

53 Publications

Clinical Review of Computed Tomography and MR Perfusion Imaging in Neuro-Oncology.

Radiol Clin North Am 2021 May 23;59(3):323-334. Epub 2021 Mar 23.

Division of Neuroimaging and Neurointervention, Department of Radiology, Stanford University, 300 Pasteur Drive, Grant Building, Room S031E, Stanford, CA 94305-5105, USA. Electronic address:

Neuroimaging plays an essential role in the initial diagnosis and continued surveillance of intracranial neoplasms. The advent of perfusion techniques with computed tomography and MR imaging have proven useful in neuro-oncology, offering enhanced approaches for tumor grading, guiding stereotactic biopsies, and monitoring treatment efficacy. Perfusion imaging can help to identify treatment-related processes, such as radiation necrosis, pseudoprogression, and pseudoregression, and can help to inform treatment-related decision making. Perfusion imaging is useful to differentiate between tumor types and between tumor and nonneoplastic conditions. This article reviews the clinical relevance and implications of perfusion imaging in neuro-oncology and highlights promising perfusion biomarkers.
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http://dx.doi.org/10.1016/j.rcl.2021.01.002DOI Listing
May 2021

Handling missing MRI sequences in deep learning segmentation of brain metastases: a multicenter study.

NPJ Digit Med 2021 Feb 22;4(1):33. Epub 2021 Feb 22.

Department of Radiology, Stanford University, Stanford, USA.

The purpose of this study was to assess the clinical value of a deep learning (DL) model for automatic detection and segmentation of brain metastases, in which a neural network is trained on four distinct MRI sequences using an input-level dropout layer, thus simulating the scenario of missing MRI sequences by training on the full set and all possible subsets of the input data. This retrospective, multicenter study, evaluated 165 patients with brain metastases. The proposed input-level dropout (ILD) model was trained on multisequence MRI from 100 patients and validated/tested on 10/55 patients, in which the test set was missing one of the four MRI sequences used for training. The segmentation results were compared with the performance of a state-of-the-art DeepLab V3 model. The MR sequences in the training set included pre-gadolinium and post-gadolinium (Gd) T1-weighted 3D fast spin echo, post-Gd T1-weighted inversion recovery (IR) prepped fast spoiled gradient echo, and 3D fluid attenuated inversion recovery (FLAIR), whereas the test set did not include the IR prepped image-series. The ground truth segmentations were established by experienced neuroradiologists. The results were evaluated using precision, recall, Intersection over union (IoU)-score and Dice score, and receiver operating characteristics (ROC) curve statistics, while the Wilcoxon rank sum test was used to compare the performance of the two neural networks. The area under the ROC curve (AUC), averaged across all test cases, was 0.989 ± 0.029 for the ILD-model and 0.989 ± 0.023 for the DeepLab V3 model (p = 0.62). The ILD-model showed a significantly higher Dice score (0.795 ± 0.104 vs. 0.774 ± 0.104, p = 0.017), and IoU-score (0.561 ± 0.225 vs. 0.492 ± 0.186, p < 0.001) compared to the DeepLab V3 model, and a significantly lower average false positive rate of 3.6/patient vs. 7.0/patient (p < 0.001) using a 10 mm lesion-size limit. The ILD-model, trained on all possible combinations of four MRI sequences, may facilitate accurate detection and segmentation of brain metastases on a multicenter basis, even when the test cohort is missing input MRI sequences.
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http://dx.doi.org/10.1038/s41746-021-00398-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900111PMC
February 2021

Neuroimaging in the Era of the Evolving WHO Classification of Brain Tumors, From the Special Series on Cancer Staging.

AJR Am J Roentgenol 2021 May 6:1-13. Epub 2021 May 6.

Department of Radiology, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom.

The inclusion of molecular and genetic information with histopathologic information defines the framework for brain tumor classification and grading. This framework is reflected in the major restructuring of the WHO brain tumor classification system in 2016 and in numerous subsequent proposed updates reflecting ongoing developments in understanding the impact of tumor genotype on classification and grading. This incorporation of molecular and genetic features improves tumor diagnosis and prediction of tumor behavior and response to treatment. Neuroimaging is essential for the noninvasive assessment of pretreatment tumor grading and for identification and determination of therapeutic efficacy. Use of conventional neuroimaging and physiologic imaging techniques, such as diffusion- and perfusion-weighted MRI, can increase diagnostic confidence before and after treatment. Although the use of neuroimaging to consistently determine tumor genetics is not yet robust, promising developments are on the horizon. Given the complexity of the brain tumor microenvironment, the development and implementation of a standardized reporting system can aid in conveying to radiologists, referring providers, and patients important information about brain tumor response to treatment. The purpose of this article is to review the current state and role of neuroimaging in this continuously evolving field.
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http://dx.doi.org/10.2214/AJR.20.25246DOI Listing
May 2021

Management of brain tumors presenting in pregnancy: a case series and systematic review.

Am J Obstet Gynecol MFM 2021 01 17;3(1):100256. Epub 2020 Oct 17.

Departments of Neurosurgery, Stanford University School of Medicine, Stanford, CA. Electronic address:

Patients who present with brain tumors during pregnancy require unique imaging and neurosurgical, obstetrical, and anesthetic considerations. Here, we review the literature and discuss the management of patients who present with brain tumors during pregnancy. Between 2009 and 2019, 9 patients were diagnosed at our institution with brain tumors during pregnancy. Clinical information was extracted from the electronic medical records. The median age at presentation was 29 years (range, 25-38 years). The most common symptoms at presentation included headache (n=5), visual changes (n=4), hemiparesis (n=3), and seizures (n=3). The median gestational age at presentation was 20.5 weeks (range, 11-37 weeks). Of note, 8 patients (89%) delivered healthy newborns, and 1 patient terminated her pregnancy. In addition, 5 patients (56%) required neurosurgical procedures during pregnancy (gestational ages, 14-37 weeks) because of disease progression (n=2) or neurologic instability (n=3). There was 1 episode of postneurosurgery morbidity (pulmonary embolism [PE]) and no surgical maternal mortality. The median length of follow-up was 15 months (range, 6-45 months). In cases demonstrating unstable or progressive neurosurgical status past the point of fetal viability, neurosurgical intervention should be considered. The physiological and pharmacodynamic changes of pregnancy substantially affect anesthetic management. Pregnancy termination should be discussed and offered to the patient when aggressive disease necessitates immediate treatment and the fetal gestational age remains previable, although neurologically stable patients may be able to continue the pregnancy to term. Ultimately, pregnant patients with brain tumors require an individualized approach to their care under the guidance of a multidisciplinary team.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100256DOI Listing
January 2021

Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease.

J Alzheimers Dis 2020 ;78(3):1229-1236

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.

Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma.

Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels.

Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models.

Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p < 0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOEɛ4 carriers.

Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOEɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.
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http://dx.doi.org/10.3233/JAD-200656DOI Listing
January 2020

Simultaneous time of flight-MRA and T2* imaging for cerebrovascular MRI.

Neuroradiology 2021 Feb 18;63(2):243-251. Epub 2020 Sep 18.

Department of Radiology, Stanford University, Stanford, CA, USA.

Purpose: 3D multi-echo gradient-recalled echo (ME-GRE) can simultaneously generate time-of-flight magnetic resonance angiography (pTOF) in addition to T2*-based susceptibility-weighted images (SWI). We assessed the clinical performance of pTOF generated from a 3D ME-GRE acquisition compared with conventional TOF-MRA (cTOF).

Methods: Eighty consecutive children were retrospectively identified who obtained 3D ME-GRE alongside cTOF. Two blinded readers independently assessed pTOF derived from 3D ME-GRE and compared them with cTOF. A 5-point Likert scale was used to rank lesion conspicuity and to assess for diagnostic confidence.

Results: Across 80 pediatric neurovascular pathologies, a similar number of lesions were reported on pTOF and cTOF (43-40%, respectively, p > 0.05). Rating of lesion conspicuity was higher with cTOF (4.5 ± 1.0) as compared with pTOF (4.0 ± 0.7), but this was not significantly different (p = 0.06). Diagnostic confidence was rated higher with cTOF (4.8 ± 0.5) than that of pTOF (3.7 ± 0.6; p < 0.001). Overall, the inter-rater agreement between two readers for lesion count on pTOF was classified as almost perfect (κ = 0.98, 96% CI 0.8-1.0).

Conclusions: In this study, TOF-MRA simultaneously generated in addition to SWI from 3D MR-GRE can serve as a diagnostic adjunct, particularly for proximal vessel disease and when conventional TOF-MRA images are absent.
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http://dx.doi.org/10.1007/s00234-020-02499-5DOI Listing
February 2021

Brain Iron Assessment after Ferumoxytol-enhanced MRI in Children and Young Adults with Arteriovenous Malformations: A Case-Control Study.

Radiology 2020 Nov 15;297(2):438-446. Epub 2020 Sep 15.

From the Department of Radiology, Division of Neuroimaging and Neurointervention (M.I.), Department of Pathology (J.L.), Department of Radiology, Lucas Center (S.J.H., M.E.M., J.R.), and Department of Neurosurgery, Division of Pediatric Neurosurgery (G.A.G.), Stanford University, Stanford, Calif; Department of Radiology, Pediatric MRI and CT, Division of Pediatric Radiology, Lucile Packard Children's Hospital, Stanford University, 725 Welch Rd, Room G516, Palo Alto, CA 94304 (M.I., N.N.N., S.N., Y.Z., K.W.Y.); and Department of Neurosurgery, Division of Pediatric Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT (S.H.C.). From the 2018 RSNA Annual Meeting.

Background Iron oxide nanoparticles are an alternative contrast agent for MRI. Gadolinium deposition has raised safety concerns, but it is unknown whether ferumoxytol administration also deposits in the brain. Purpose To investigate whether there are signal intensity changes in the brain at multiecho gradient imaging following ferumoxytol exposure in children and young adults. Materials and Methods This retrospective case-control study included children and young adults, matched for age and sex, with brain arteriovenous malformations who received at least one dose of ferumoxytol from January 2014 to January 2018. In participants who underwent at least two brain MRI examinations (subgroup), the first and last available examinations were analyzed. Regions of interests were placed around deep gray structures on quantitative susceptibility mapping and R2* images. Mean susceptibility and R2* values of regions of interests were recorded. Measurements were assessed by linear regression analyses: a between-group comparison of ferumoxytol-exposed and unexposed participants and a within-group (subgroup) comparison before and after exposure. Results Seventeen participants (mean age ± standard deviation, 13 years ± 5; nine male) were in the ferumoxytol-exposed (case) group, 21 (mean age, 14 years ± 5; 11 male) were in the control group, and nine (mean age, 12 years ± 6; four male) were in the subgroup. The mean number of ferumoxytol administrations was 2 ± 1 (range, one to four). Mean susceptibility (in parts per million [ppm]) and R2* (in inverse seconds [sec]) values of the dentate (case participants: 0.06 ppm ± 0.04 and 23.87 sec ± 4.13; control participants: 0.02 ppm ± 0.03 and 21.7 sec ± 5.26), substantia nigrae (case participants: 0.08 ppm ± 0.06 and 27.46 sec ± 5.58; control participants: 0.04 ppm ± 0.05 and 24.96 sec ± 5.3), globus pallidi (case participants: 0.14 ppm ± 0.05 and 30.75 sec ± 5.14; control participants: 0.08 ppm ± 0.07 and 28.82 sec ± 6.62), putamina (case participants: 0.03 ppm ± 0.02 and 20.63 sec ± 2.44; control participants: 0.02 ppm ± 0.02 and 19.65 sec ± 3.6), caudate (case participants: -0.1 ppm ± 0.04 and 18.21 sec ± 3.1; control participants: -0.06 ppm ± 0.05 and 18.83 sec ± 3.32), and thalami (case participants: 0 ppm ± 0.03 and 16.49 sec ± 3.6; control participants: 0.02 ppm ± 0.02 and 18.38 sec ± 2.09) did not differ between groups (susceptibility, = .21; R2*, = .24). For the subgroup, the mean interval between the first and last ferumoxytol administration was 14 months ± 8 (range, 1-25 months). Mean susceptibility and R2* values of the dentate (first MRI: 0.06 ppm ± 0.05 and 25.78 sec ± 5.9; last MRI: 0.06 ppm ± 0.02 and 25.55 sec ± 4.71), substantia nigrae (first MRI: 0.06 ppm ± 0.06 and 28.26 sec ± 9.56; last MRI: 0.07 ppm ± 0.06 and 25.65 sec ± 6.37), globus pallidi (first MRI: 0.13 ppm ± 0.07 and 27.53 sec ± 8.88; last MRI: 0.14 ppm ± 0.06 and 29.78 sec ± 6.54), putamina (first MRI: 0.03 ppm ± 0.03 and 19.78 sec ± 3.51; last MRI: 0.03 ppm ± 0.02 and 19.73 sec ± 3.01), caudate (first MRI: -0.09 ppm ± 0.05 and 21.38 sec ± 4.72; last MRI: -0.1 ppm ± 0.05 and 18.75 sec ± 2.68), and thalami (first MRI: 0.01 ppm ± 0.02 and 17.65 sec ± 5.16; last MRI: 0 ppm ± 0.02 and 15.32 sec ± 2.49) did not differ between the first and last MRI examinations (susceptibility, = .95; R2*, = .54). Conclusion No overall significant differences were found in susceptibility and R2* values of deep gray structures to suggest retained iron in the brain between ferumoxytol-exposed and unexposed children and young adults with arteriovenous malformations and in those exposed to ferumoxytol over time. © RSNA, 2020.
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http://dx.doi.org/10.1148/radiol.2020200378DOI Listing
November 2020

Critical illness-associated cerebral microbleeds in severe COVID-19 infection.

Clin Imaging 2020 Dec 29;68:239-241. Epub 2020 Aug 29.

Department of Radiology, Division of Neuroimaging and Neurointervention, Stanford University, Stanford, CA, United States of America.

Neurologic complications of COVID-19 infection have been recently described and include dizziness, headache, loss of taste and smell, stroke, and encephalopathy. Brain MRI in these patients have revealed various findings including ischemia, hemorrhage, inflammation, and demyelination. In this article, we report a case of critical illness-associated cerebral microbleeds identified on MRI in a patient with severe COVID-19 infection and discuss the potential etiologies of these neuroimaging findings.
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http://dx.doi.org/10.1016/j.clinimag.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832150PMC
December 2020

Brain iron deposition after Ferumoxytol-enhanced MRI: A study of Porcine Brains.

Nanotheranostics 2020 18;4(4):195-200. Epub 2020 Jun 18.

Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, CA, USA.

Recent evidence of gadolinium deposition in the brain has raised safety concerns. Iron oxide nanoparticles are re-emerging as promising alternative MR contrast agents, because the iron core can be metabolized. However, long-term follow up studies of the brain after intravenous iron oxide administration have not been reported thus far. In this study, we investigated, if intravenously administered ferumoxytol nanoparticles are deposited in porcine brains. In an animal care and use committee-approved prospective case-control study, ten Göttingen minipigs received either intravenous ferumoxytol injections at a dose of 5 mg Fe/kg (n=4) or remained untreated (n=6). Nine to twelve months later, pigs were sacrificed and the brains of all pigs underwent MRI at 7T with T2 and T2*-weighted sequences. MRI scans were evaluated by measuring R2* values (R2*=1000/T2*) of the bilateral caudate nucleus, lentiform nucleus, thalamus, dentate nucleus, and choroid plexus. Pig brains were sectioned and stained with Prussian blue and evaluated for iron deposition using a semiquantitative scoring system. Data of ferumoxytol exposed and unexposed groups were compared with an unpaired t-test and a Mann-Whitney U test. T2 and T2* signal of the different brain regions was not visually different between ferumoxytol exposed and unexposed controls. There were no significant differences in R2* values of the different brain regions in the ferumoxytol exposed group compared to controls (p>0.05). Prussian blue stains of the same brain regions, scored according to a semiquantitative score, were not significantly different either between the ferumoxytol exposed group and unexposed controls (p>0.05). Our study shows that intravenous ferumoxytol doses of 5-10 mg Fe/kg do not lead to iron deposition in the brain of pigs. We suggest iron oxide nanoparticles as a promising alternative for gadolinium-enhanced MRI.
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http://dx.doi.org/10.7150/ntno.46356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332795PMC
April 2021

Ballistic transport and quantum unfurling in molecular junctions via minimal representations of quantum master equations.

J Chem Phys 2020 May;152(18):184112

Schulich Faculty of Chemistry, Technion - Israel Institute of Technology, Haifa 32000, Israel.

Quantum furling and unfurling are inelastic transitions between localized and delocalized electronic states. We predict scenarios where these processes govern charge transport through donor-bridge-acceptor molecular junctions. Like in the case of ballistic transport, the resulting currents are nearly independent of the molecular bridge length. However, currents involving quantum furling and unfurling processes can be controlled by the coupling to vibrations in the intra-molecular and the extra-molecular environment, which can be experimentally tuned. Our study is based on rate equations for exchange of energy (bosons) and particles (fermions) between the molecular bridge and its environment. An efficient algorithm is introduced for a compact representation of the relevant rate equations, which utilizes the redundancies in the rate matrix and the sparsity of the creation and annihilation operators in the molecular Fock space.
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http://dx.doi.org/10.1063/5.0005412DOI Listing
May 2020

Advanced Imaging of Brain Metastases: From Augmenting Visualization and Improving Diagnosis to Evaluating Treatment Response.

Front Neurol 2020 15;11:270. Epub 2020 Apr 15.

Stanford University Medical Center, Stanford, CA, United States.

Early detection of brain metastases and differentiation from other neuropathologies is crucial. Although biopsy is often required for definitive diagnosis, imaging can provide useful information. After treatment commences, imaging is also performed to assess the efficacy of treatment. Contrast-enhanced magnetic resonance imaging (MRI) is the traditional imaging method for the evaluation of brain metastases, as it provides information about lesion size, morphology, and macroscopic properties. Newer MRI sequences have been developed to increase the conspicuity of detecting enhancing metastases. Other advanced MRI techniques, that have the capability to probe beyond the anatomic structure, are available to characterize micro-structures, cellularity, physiology, perfusion, and metabolism. Artificial intelligence provides powerful computational tools for detection, segmentation, classification, prediction, and prognosis. We highlight and review a few advanced MRI techniques for the assessment of brain metastases-specifically for (1) diagnosis, including differentiating between malignancy types and (2) evaluation of treatment response, including the differentiation between radiation necrosis and disease progression.
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http://dx.doi.org/10.3389/fneur.2020.00270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174761PMC
April 2020

Utilization of Novel High-Resolution, MRI-Based Vascular Imaging Modality for Preoperative Stereoelectroencephalography Planning in Children: A Technical Note.

Stereotact Funct Neurosurg 2020 14;98(1):1-7. Epub 2020 Feb 14.

Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA,

Introduction: Stereoelectroencephalography (SEEG) is a powerful intracranial diagnostic tool that requires accurate imaging for proper electrode trajectory planning to ensure efficacy and maximize patient safety. Computed tomography (CT) angiography and digital subtraction angiography are commonly used, but recent developments in magnetic resonance angiography allow for high-resolution vascular visualization without added risks of radiation. We report on the accuracy of electrode placement under robotic assistance planning utilizing a novel high-resolution magnetic resonance imaging (MRI)-based imaging modality.

Methods: Sixteen pediatric patients between February 2014 and October 2017 underwent SEEG exploration for epileptogenic zone localization. A gadolinium-enhanced 3D T1-weighted spoiled gradient recalled echo sequence with minimum echo time and repetition time was applied for background parenchymal suppression and vascular enhancement. Electrode placement accuracy was determined by analyzing postoperative CT scans laid over preoperative virtual electrode trajectory paths. Entry point, target point, and closest vessel intersection were measured.

Results: For any intersection along the trajectory path, 57 intersected vessels were measured. The mean diameter of an intersected vessel was 1.0343 ± 0.1721 mm, and 21.05% of intersections involved superficial vessels. There were 157 overall intersection + near-miss events. The mean diameter for an involved vessel was 1.0236 ± 0.0928 mm, and superficial vessels were involved in 20.13%. Looking only at final electrode target, 3 intersection events were observed. The mean diameter of an intersected vessel was 1.0125 ± 0.2227 mm. For intersection + near-miss events, 24 were measured. An involved vessel's mean diameter was 1.1028 ± 0.2634 mm. For non-entry point intersections, 45 intersected vessels were measured. The mean diameter for intersected vessels was 0.9526 ± 0.0689 mm. For non-entry point intersections + near misses, 126 events were observed. The mean diameter for involved vessels was 0.9826 ± 0.1008 mm.

Conclusion: We believe this novel sequence allows better identification of superficial and deeper subcortical vessels compared to conventional T1-weighted gadolinium-enhanced MRI.
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http://dx.doi.org/10.1159/000503693DOI Listing
February 2020

The effects of repetitive transcranial magnetic stimulation in older adults with mild cognitive impairment: a protocol for a randomized, controlled three-arm trial.

BMC Neurol 2019 Dec 16;19(1):326. Epub 2019 Dec 16.

US Department of Veterans Affairs (VA) Palo Alto Health Care System (151Y), Sierra-Pacific Mental Illness Research Education Clinical Center (MIRECC), 3801 Miranda Avenue, Palo Alto, CA, 94304-1207, USA.

Background: Mild Cognitive Impairment (MCI) carries a high risk of progression to Alzheimer's disease (AD) dementia. Previous clinical trials testing whether cholinesterase inhibitors can slow the rate of progression from MCI to AD dementia have yielded disappointing results. However, recent studies of the effects of repetitive transcranial magnetic stimulation (rTMS) in AD have demonstrated improvements in cognitive function. Because few rTMS trials have been conducted in MCI, we designed a trial to test the short-term efficacy of rTMS in MCI. Yet, in both MCI and AD, we know little about what site of stimulation would be ideal for improving cognitive function. Therefore, two cortical sites will be investigated in this trial: (1) the dorsolateral prefrontal cortex (DLPFC), which has been well studied for treatment of major depressive disorder; and (2) the lateral parietal cortex (LPC), a novel site with connectivity to AD-relevant limbic regions.

Methods/design: In this single-site trial, we plan to enroll 99 participants with single or multi-domain amnestic MCI. We will randomize participants to one of three groups: (1) Active DLPFC rTMS; (2) Active LPC rTMS; and (3) Sham rTMS (evenly split between DLPFC and LPC locations). After completing 20 bilateral rTMS treatment sessions, participants will be followed for 6 months to test short-term efficacy and track durability of effects. The primary efficacy measure is the California Verbal Learning Test-II (CVLT-II), assessed 1 week after intervention. Secondary analyses will examine effects of rTMS on other cognitive measures, symptoms of depression, and brain function with respect to the site of stimulation. Finally, selected biomarkers will be analyzed to explore predictors of response and mechanisms of action.

Discussion: The primary aim of this trial is to test the short-term efficacy of rTMS in MCI. Additionally, the project will provide information on the durability of cognitive effects and potentially distinct effects of stimulating DLPFC versus LPC regions. Future efforts would be directed toward better understanding therapeutic mechanisms and optimizing rTMS for treatment of MCI. Ultimately, if rTMS can be utilized to slow the rate of progression to AD dementia, this will be a significant advancement in the field.

Trial Registration: Clinical Trials NCT03331796. Registered 6 November 2017, https://clinicaltrials.gov/ct2/show/NCT03331796. All items from the World Health Organization Trial Registration Data Set are listed in Appendix A.

Protocol Version: This report is based on version 1, approved by the DSMB on 30 November, 2017 and amended on 14 August, 2018 and 19 September, 2019.
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http://dx.doi.org/10.1186/s12883-019-1552-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912947PMC
December 2019

Altered cerebral perfusion in children with Langerhans cell histiocytosis after chemotherapy.

Pediatr Blood Cancer 2020 03 4;67(3):e28104. Epub 2019 Dec 4.

Department of Radiology, Lucile Packard Children's Hospital, School of Medicine, Stanford University, Palo Alto, California.

Background And Purpose: Children with Langerhans cell histiocytosis (LCH) may develop a wide array of neurological symptoms, but associated cerebral physiologic changes are poorly understood. We examined cerebral hemodynamic properties of pediatric LCH using arterial spin-labeling (ASL) perfusion magnetic resonance imaging (MRI).

Materials And Methods: A retrospective study was performed in 23 children with biopsy-proven LCH. Analysis was performed on routine brain MRI obtained before or after therapy. Region of interest (ROI) methodology was used to determine ASL cerebral blood flow (CBF) (mL/100 g/min) in the following bilateral regions: angular gyrus, anterior prefrontal cortex, orbitofrontal cortex, dorsal anterior cingulate cortex, and hippocampus. Quantile (median) regression was performed for each ROI location. CBF patterns were compared between pre- and posttreatment LCH patients as well as with age-matched healthy controls.

Results: Significantly reduced CBF was seen in posttreatment children with LCH compared to age-matched controls in angular gyrus (P = .046), anterior prefrontal cortex (P = .039), and dorsal anterior cingulate cortex (P = .023). Further analysis revealed dominant perfusion abnormalities in the right hemisphere. No significant perfusion differences were observed in the hippocampus or orbitofrontal cortex.

Conclusion: Perfusion in specific cerebral regions may be consistently reduced in children with LCH, and may represent effects of underlying disease physiology and/or sequelae of chemotherapy. Studies that combine a formal cognitive assessment and hemodynamic data may further provide insight into perfusion deficits associated with the disease and the potential neurotoxic effects in children treated by chemotherapy.
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http://dx.doi.org/10.1002/pbc.28104DOI Listing
March 2020

Patient-specific 3-dimensionally printed models for neurosurgical planning and education.

Neurosurg Focus 2019 12;47(6):E12

Departments of4Neurosurgery and.

Objective: Advances in 3-dimensional (3D) printing technology permit the rapid creation of detailed anatomical models. Integration of this technology into neurosurgical practice is still in its nascence, however. One potential application is to create models depicting neurosurgical pathology. The goal of this study was to assess the clinical value of patient-specific 3D printed models for neurosurgical planning and education.

Methods: The authors created life-sized, patient-specific models for 4 preoperative cases. Three of the cases involved adults (2 patients with petroclival meningioma and 1 with trigeminal neuralgia) and the remaining case involved a pediatric patient with craniopharyngioma. Models were derived from routine clinical imaging sequences and manufactured using commercially available software and hardware.

Results: Life-sized, 3D printed models depicting bony, vascular, and neural pathology relevant to each case were successfully manufactured. A variety of commercially available software and hardware were used to create and print each model from radiological sequences. The models for the adult cases were printed in separate pieces, which had to be painted by hand, and could be disassembled for detailed study, while the model for the pediatric case was printed as a single piece in separate-colored resins and could not be disassembled for study. Two of the models were used for patient education, and all were used for presurgical planning by the surgeon.

Conclusions: Patient-specific 3D printed models are useful to neurosurgical practice. They may be used as a visualization aid for surgeons and patients, or for education of trainees.
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http://dx.doi.org/10.3171/2019.9.FOCUS19511DOI Listing
December 2019

Noncontrast T2-Weighted Magnetic Resonance Imaging Sequences for Long-Term Monitoring of Asymptomatic Convexity Meningiomas.

World Neurosurg 2020 Mar 14;135:e100-e105. Epub 2019 Nov 14.

Department of Neurosurgery, Stanford University, Stanford, California, USA. Electronic address:

Background: Gadolinium-based contrast agents (GBCAs) used to enhance magnetic resonance imaging (MRI) scans have been linked to tissue deposition, including in the brain. The management of indolent tumors such as meningiomas requires frequent MRI scans to monitor for interval growth. Given concern regarding GBCA deposition, we sought to determine if noncontrast MRI scans in patients with asymptomatic meningiomas were equivalent to GBCA-enhanced MRI scans in surveillance monitoring.

Methods: This institutional review board-approved retrospective chart review included 106 MRI sequences from 18 patients. Inclusion criteria were adult patients with asymptomatic meningiomas who received baseline contrast-enhanced and noncontrast axial brain MRI scan. Exclusion criteria included the following: 1) baseline or follow-up axial images were not available for review, 2) baseline scan was obtained without contrast, and 3) diagnosis of meningioma was uncertain. Percent tumor growth was measured by comparing cross-sectional area at maximum tumor diameter from the earliest and most recent scans. For each patient, change in tumor size over time was compared using T1 + contrast, T2, and T2 fluid-attenuated inversion recovery (FLAIR) sequences. These were compared with a qualitative consensus reading by a neurosurgeon and a neuroradiologist.

Results: Measured change of greater than 10% was taken to represent tumor growth. In 17 out of 18 patients, measurement of noncontrast studies (T2 and T2 FLAIR) matched consensus. For one patient, imaging on T2 suggested 11% growth, whereas T2 FLAIR and overall consensus was stability.

Conclusions: Our study provides evidence that noncontrasted MRI scans are equivalent to contrast-weighted MRI scans to follow change in tumor size over time in asymptomatic meningiomas.
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http://dx.doi.org/10.1016/j.wneu.2019.11.051DOI Listing
March 2020

Nodular Leptomeningeal Disease-A Distinct Pattern of Recurrence After Postresection Stereotactic Radiosurgery for Brain Metastases: A Multi-institutional Study of Interobserver Reliability.

Int J Radiat Oncol Biol Phys 2020 03 10;106(3):579-586. Epub 2019 Oct 10.

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California. Electronic address:

Purpose: For brain metastases, surgical resection with postoperative stereotactic radiosurgery is an emerging standard of care. Postoperative cavity stereotactic radiosurgery is associated with a specific, underrecognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease. We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve interrater reliability (IRR) and validity in diagnosing LMD.

Methods And Materials: Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system expertise, completed a 2-phase survey that included magnetic resonance imaging and treatment information for 30 patients. In the "pretraining" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "posttraining" phase and relabeled the 30 cases using the 4 following labels: LR, DR, classical leptomeningeal disease, and nLMD.

Results: IRR increased 34% after training (Fleiss' Kappa K = 0.41 to K = 0.55, P < .001). IRR increased most among non-central nervous system specialists (+58%, P < .001). Before training, IRR was lowest for LMD (K = 0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD.

Conclusions: This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.
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http://dx.doi.org/10.1016/j.ijrobp.2019.10.002DOI Listing
March 2020

Macrophage Exclusion after Radiation Therapy (MERT): A First in Human Phase I/II Trial using a CXCR4 Inhibitor in Glioblastoma.

Clin Cancer Res 2019 12 19;25(23):6948-6957. Epub 2019 Sep 19.

Department of Neurology, Division of Neuro Oncology, Stanford, California.

Purpose: Preclinical studies have demonstrated that postirradiation tumor revascularization is dependent on a stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-driven process in which myeloid cells are recruited from bone marrow. Blocking this axis results in survival improvement in preclinical models of solid tumors, including glioblastoma (GBM). We conducted a phase I/II study to determine the safety and efficacy of Macrophage Exclusion after Radiation Therapy (MERT) using the reversible CXCR4 inhibitor plerixafor in patients with newly diagnosed glioblastoma.

Patients And Methods: We enrolled nine patients in the phase I study and an additional 20 patients in phase II using a modified toxicity probability interval (mTPI) design. Plerixafor was continuously infused intravenously via a peripherally inserted central catheter (PICC) line for 4 consecutive weeks beginning at day 35 of conventional treatment with concurrent chemoradiation. Blood serum samples were obtained for pharmacokinetic analysis. Additional studies included relative cerebral blood volume (rCBV) analysis using MRI and histopathology analysis of recurrent tumors.

Results: Plerixafor was well tolerated with no drug-attributable grade 3 toxicities observed. At the maximum dose of 400 μg/kg/day, biomarker analysis found suprathreshold plerixafor serum levels and an increase in plasma SDF-1 levels. Median overall survival was 21.3 months [95% confidence interval (CI), 15.9-NA] with a progression-free survival of 14.5 months (95% CI, 11.9-NA). MRI and histopathology support the mechanism of action to inhibit postirradiation tumor revascularization.

Conclusions: Infusion of the CXCR4 inhibitor plerixafor was well tolerated as an adjunct to standard chemoirradiation in patients with newly diagnosed GBM and improves local control of tumor recurrences.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891194PMC
December 2019

Arterial Spin-Labeling MRI Identifies Hypervascular Meningiomas.

AJR Am J Roentgenol 2019 11 30;213(5):1124-1128. Epub 2019 Jul 30.

Department of Radiology, Division of Neuroimaging and Neurointervention, Stanford University, Stanford University Medical Center, 300 Pasteur Dr, Grant Bldg, Rm S031E, Stanford, CA 94305.

Preoperative identification of hypervascular meningiomas can potentially detect those that may benefit from presurgical embolization, which may help to minimize intraoperative blood loss. In this study, we investigate if increased blood flow within meningiomas seen on arterial spin-labeling (ASL) MRI correlates with increased tumor vascularity seen on digital subtraction angiography (DSA). A retrospective study was performed of 39 meningiomas in 34 patients who underwent ASL MRI and DSA between January 2008 and January 2017. Two raters independently calculated normalized tumor blood flow (TBF) on postprocessed ASL images using ROI analysis. They also recorded the presence or absence of tumor blush on DSA in each case. Interrater agreement was assessed with intraclass correlation coefficient (ICC). Performance of ASL MRI to identify tumor blush was determined with area under the ROC curve (AUC). In 27 female and seven male patients (mean age, 62.8 years), mean normalized TBF for meningiomas with tumor blush on DSA was significantly higher than those without tumor blush ( < 0.001). Mean normalized TBF for the group with tumor blush and the group without tumor blush group was 4.7 ± 1.1 and 1.5 ± 1.1, respectively, for rater 1 and 4.9 ± 5.3 and 1.5 ± 1.1, respectively, for rater 2. ICC was excellent (0.91). AUC for using normalized TBF to identify tumor vascularity on DSA was 0.82 (95% CI, 0.72-0.91), and a normalized TBF cut point of 2.7 yielded 88% sensitivity and 67% specificity. ASL MRI shows potential as a noninvasive screening tool for identifying hypervascular meningiomas.
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http://dx.doi.org/10.2214/AJR.18.21026DOI Listing
November 2019

Utility of a Quantitative Approach Using Diffusion Tensor Imaging for Prognostication Regarding Motor and Functional Outcomes in Patients With Surgically Resected Deep Intracranial Cavernous Malformations.

Neurosurgery 2020 05;86(5):665-675

Stanford Stroke Center, Department of Neurosurgery, Stanford University School of Medicine, Stanford, California.

Background: Resection of deep intracranial cavernous malformations (CMs) is associated with a higher risk of neurological deterioration and uncertainty regarding clinical outcomes.

Objective: To examine diffusion tractography imaging (DTI) data evaluating the corticospinal tract (CST) in relation to motor and functional outcomes in patients with surgically resected deep CMs.

Methods: Perilesional CST was characterized as disrupted, displaced, or normal. Mean fractional anisotropy (FA) values were obtained for whole ipsilateral CST and in 3 regions: subcortical (proximal), perilesional, and distally. Mean FA values in anatomically equivalent regions in the contralateral CST were obtained. Clinical and radiological data were collected independently. Multivariable regression analysis was used for statistical analysis.

Results: A total of 18 patients [brainstem (15) and thalamus/basal ganglia (3); median follow-up: 270 d] were identified over 2 yr. The CST was identified preoperatively as disrupted (6), displaced (8), and normal (4). Five of 6 patients with disruption had weakness. Higher preoperative mean FA values for distal ipsilateral CST segment were associated with better preoperative lower (P < .001), upper limb (P = .004), postoperative lower (P = .005), and upper limb (P < .001) motor examination. Preoperative mean FA values for distal ipsilateral CST segment (P = .001) and contralateral perilesional CST segment (P < .001) were negatively associated with postoperative modified Rankin scale scores.

Conclusion: Lower preoperative mean FA values for overall and defined CST segments corresponded to worse patient pre- and postoperative motor examination and/or functional status. FA value for the distal ipsilateral CST segment has prognostic potential with respect to clinical outcomes.
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http://dx.doi.org/10.1093/neuros/nyz259DOI Listing
May 2020

Ferumoxytol-enhanced MRI for surveillance of pediatric cerebral arteriovenous malformations.

J Neurosurg Pediatr 2019 Jul 19:1-8. Epub 2019 Jul 19.

2Department of Radiology, Lucile Packard Children's Hospital, Stanford University School of Medicine.

Objective: Children with intracranial arteriovenous malformations (AVMs) undergo digital DSA for lesion surveillance following their initial diagnosis. However, DSA carries risks of radiation exposure, particularly for the growing pediatric brain and over lifetime. The authors evaluated whether MRI enhanced with a blood pool ferumoxytol (Fe) contrast agent (Fe-MRI) can be used for surveillance of residual or recurrent AVMs.

Methods: A retrospective cohort was assembled of children with an established AVM diagnosis who underwent surveillance by both DSA and 3-T Fe-MRI from 2014 to 2016. Two neuroradiologists blinded to the DSA results independently assessed Fe-enhanced T1-weighted spoiled gradient recalled acquisition in steady state (Fe-SPGR) scans and, if available, arterial spin labeling (ASL) perfusion scans for residual or recurrent AVMs. Diagnostic confidence was examined using a Likert scale. Sensitivity, specificity, and intermodality reliability were determined using DSA studies as the gold standard. Radiation exposure related to DSA was calculated as total dose area product (TDAP) and effective dose.

Results: Fifteen patients were included in this study (mean age 10 years, range 3-15 years). The mean time between the first surveillance DSA and Fe-MRI studies was 17 days (SD 47). Intermodality agreement was excellent between Fe-SPGR and DSA (κ = 1.00) but poor between ASL and DSA (κ = 0.53; 95% CI 0.18-0.89). The sensitivity and specificity for detecting residual AVMs using Fe-SPGR were 100% and 100%, and using ASL they were 72% and 100%, respectively. Radiologists reported overall high diagnostic confidence using Fe-SPGR. On average, patients received two surveillance DSA studies over the study period, which on average equated to a TDAP of 117.2 Gy×cm2 (95% CI 77.2-157.4 Gy×cm2) and an effective dose of 7.8 mSv (95% CI 4.4-8.8 mSv).

Conclusions: Fe-MRI performed similarly to DSA for the surveillance of residual AVMs. Future multicenter studies could further investigate the efficacy of Fe-MRI as a noninvasive alternative to DSA for monitoring AVMs in children.
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http://dx.doi.org/10.3171/2019.5.PEDS1957DOI Listing
July 2019

Physiological motion of the optic chiasm and its impact on stereotactic radiosurgery dose.

Br J Radiol 2019 Jul 22;92(1099):20190170. Epub 2019 May 22.

1 Department of Radiation Oncology, Stanford University , Stanford, CA , United States of America.

Objective: Avoidance of radiation-induced optic neuropathy (RION) from stereotactic radiosurgery (SRS) requires precise anatomical localization; however, no prior studies have characterized the physiologic motion of the optic chiasm. We measured the extent of chiasm motion and its impact on SRS dose.

Methods: In this cross-sectional study, serial MRI was performed in multiple planes in 11 human subjects without optic pathway abnormalities to determine chiasm motion across time. Subsequently, the measured displacement was applied to the hypothetical chiasm dose received in 11 patients treated with SRS to a perichiasmatic lesion.

Results: On sagittal images, the average anteroposterior chiasm displacement was 0.51 mm [95% confidence interval (CI) 0.27 - 0.75 mm], and the average superior-inferior displacement was 0.48 mm (95% CI 0.22 - 0.74 mm). On coronal images, the average superior-inferior displacement was 0.42 mm (95% CI 0.13 - 0.71 mm), and the average lateral displacement was 0.75 mm (95% CI 0.42 - 1.08 mm). In 11 patients who underwent SRS to a perichiasmatic lesion, the average displacements increased the maximum chiasm dose (Dmax) by a mean of 14 % (range 6-23 %; < 0.001).

Conclusion: Average motion of the optic chiasm was approximately 0.50-0.75 mm, which increased chiasm Dmax by a mean of 14%. In the occasional patient with higher-than-average chiasm motion in a region of steep dose gradient, the increase in chiasm Dmax and risk of RION could be even larger. Similarly, previously reported chiasm dose constraints may underestimate the true dose received during radiosurgery.

Advances In Knowledge: To limit the risk of RION, clinicians may consider adding a 0.50-0.75 mm expansion to the chiasm avoidance structure.
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http://dx.doi.org/10.1259/bjr.20190170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636279PMC
July 2019

Deep learning enables automatic detection and segmentation of brain metastases on multisequence MRI.

J Magn Reson Imaging 2020 01 2;51(1):175-182. Epub 2019 May 2.

Department of Radiology, Stanford University, Stanford, California, USA.

Background: Detecting and segmenting brain metastases is a tedious and time-consuming task for many radiologists, particularly with the growing use of multisequence 3D imaging.

Purpose: To demonstrate automated detection and segmentation of brain metastases on multisequence MRI using a deep-learning approach based on a fully convolution neural network (CNN).

Study Type: Retrospective.

Population: In all, 156 patients with brain metastases from several primary cancers were included.

Field Strength: 1.5T and 3T. [Correction added on May 24, 2019, after first online publication: In the preceding sentence, the first field strength listed was corrected.] SEQUENCE: Pretherapy MR images included pre- and postgadolinium T -weighted 3D fast spin echo (CUBE), postgadolinium T -weighted 3D axial IR-prepped FSPGR (BRAVO), and 3D CUBE fluid attenuated inversion recovery (FLAIR).

Assessment: The ground truth was established by manual delineation by two experienced neuroradiologists. CNN training/development was performed using 100 and 5 patients, respectively, with a 2.5D network based on a GoogLeNet architecture. The results were evaluated in 51 patients, equally separated into those with few (1-3), multiple (4-10), and many (>10) lesions.

Statistical Tests: Network performance was evaluated using precision, recall, Dice/F1 score, and receiver operating characteristic (ROC) curve statistics. For an optimal probability threshold, detection and segmentation performance was assessed on a per-metastasis basis. The Wilcoxon rank sum test was used to test the differences between patient subgroups.

Results: The area under the ROC curve (AUC), averaged across all patients, was 0.98 ± 0.04. The AUC in the subgroups was 0.99 ± 0.01, 0.97 ± 0.05, and 0.97 ± 0.03 for patients having 1-3, 4-10, and >10 metastases, respectively. Using an average optimal probability threshold determined by the development set, precision, recall, and Dice score were 0.79 ± 0.20, 0.53 ± 0.22, and 0.79 ± 0.12, respectively. At the same probability threshold, the network showed an average false-positive rate of 8.3/patient (no lesion-size limit) and 3.4/patient (10 mm lesion size limit).

Data Conclusion: A deep-learning approach using multisequence MRI can automatically detect and segment brain metastases with high accuracy.

Level Of Evidence: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:175-182.
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http://dx.doi.org/10.1002/jmri.26766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199496PMC
January 2020

Arterial-spin labeling MRI identifies residual cerebral arteriovenous malformation following stereotactic radiosurgery treatment.

J Neuroradiol 2020 Feb 15;47(1):13-19. Epub 2019 Jan 15.

Department of Radiology, Neuroimaging and Neurointervention Division, Stanford University Hospital, 300, Pasteur Drive, Stanford, CA 94305, US.

Background And Purpose: Brain arteriovenous malformation (AVM) treatment by stereotactic radiosurgery (SRS) is effective, but AVM obliteration following SRS may take two years or longer. MRI with arterial-spin labeling (ASL) may detect brain AVMs with high sensitivity. We determined whether brain MRI with ASL may accurately detect residual AVM following SRS treatment.

Materials And Methods: We performed a retrospective cohort study of patients who underwent brain AVM evaluation by DSA between June 2010 and June 2015. Inclusion criteria were: (1) AVM treatment by SRS, (2) follow-up MRI with ASL at least 30 months after SRS, (3) DSA within 3 months of the follow-up MRI with ASL, and (4) no intervening AVM treatment between the MRI and DSA. Four neuroradiologists blindly and independently reviewed follow-up MRIs. Primary outcome measure was residual AVM indicated by abnormal venous ASL signal.

Results: 15 patients (12 females, mean age 29 years) met inclusion criteria. There were three posterior fossa AVMs and 12 supratentorial AVMs. Spetzler-Martin (SM) Grades were: SM1 (8%), SM2 (33%), SM3 (17%), SM4 (25%), and SM5 (17%). DSA demonstrated residual AVM in 10 patients. The pooled sensitivity, specificity, positive predictive value, and negative predictive value of venous ASL signal for predicting residual AVM were 100% (95% CI: 0.9-1.0), 95% (95% CI: 0.7-1.0), 98% (95% CI: 0.9-1.0), and 100% (95% CI: 0.8-1.0), respectively. High inter-reader agreement as found by Fleiss' Kappa analysis (k = 0.92; 95% CI: 0.8-1.0; P < 0.0001).

Conclusions: ASL is highly sensitive and specific in the detection of residual cerebral AVM following SRS treatment.
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http://dx.doi.org/10.1016/j.neurad.2018.12.004DOI Listing
February 2020

Malignant optic glioma masked by suspected optic neuritis and central retinal vein occlusion.

Radiol Case Rep 2019 Feb 13;14(2):226-229. Epub 2018 Nov 13.

Division of Neuroradiology, Department of Radiology, Stanford University School of Medicine, 300 Pasteur Drive, Room S-047, Stanford, CA 94305-5105, USA.

Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity.
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http://dx.doi.org/10.1016/j.radcr.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234704PMC
February 2019

Quantification of Macrophages in High-Grade Gliomas by Using Ferumoxytol-enhanced MRI: A Pilot Study.

Radiology 2019 01 6;290(1):198-206. Epub 2018 Nov 6.

From the Departments of Radiology (M.I., P.R., H.E.D.L., M.W., K.W.Y.) and Pathology (P.S., H.V.), Stanford University Medical Center, 300 Pasteur Dr, Grant Building, Room S031E, Stanford, CA 94305; Richard M. Lucas Center for Imaging (S.H., M.M.) and Departments of Medicine (Biomedical Informatics Research) (A.G.), Neurosurgery (G.H., G.L., S.C.), and Neurology (Neuro-Oncology) (R.T.), Stanford University, Stanford, Calif.

Purpose To investigate ferumoxytol-enhanced MRI as a noninvasive imaging biomarker of macrophages in adults with high-grade gliomas. Materials and Methods In this prospective study, adults with high-grade gliomas were enrolled between July 2015 and July 2017. Each participant was administered intravenous ferumoxytol (5 mg/kg) and underwent 3.0-T MRI 24 hours later. Two sites in each tumor were selected for intraoperative sampling on the basis of the degree of ferumoxytol-induced signal change. Susceptibility and the relaxation rates R2* (1/T2*) and R2 (1/T2) were obtained by region-of-interest analysis by using the respective postprocessed maps. Each sample was stained with Prussian blue, CD68, CD163, and glial fibrillary acidic protein. Pearson correlation and linear mixed models were performed to assess the relationship between imaging measurements and number of 400× magnification high-power fields with iron-containing macrophages. Results Ten adults (four male participants [mean age, 65 years ± 9 {standard deviation}; age range, 57-74 years] and six female participants [mean age, 53 years ± 12 years; age range, 32-65 years]; mean age of all participants, 58 years ± 12 [age range, 32-74 years]) with high-grade gliomas were included. Significant positive correlations were found between susceptibility, R2*, and R2' and the number of high-power fields with CD163-positive (r range, 0.64-0.71; P < .01) and CD68-positive (r range, 0.55-0.57; P value range, .01-.02) iron-containing macrophages. No significant correlation was found between R2 and CD163-positive (r = 0.33; P = .16) and CD68-positive (r = 0.24; P = .32) iron-containing macrophages. Similar significance results were obtained with linear mixed models. At histopathologic analysis, iron particles were found only in macrophages; none was found in glial fibrillary acidic protein-positive tumor cells. Conclusion MRI measurements of susceptibility, R2*, and R2' (R2* - R2) obtained after ferumoxytol administration correlate with iron-containing macrophage concentration, and this shows their potential as quantitative imaging markers of macrophages in malignant gliomas. © RSNA, 2018 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2018181204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312434PMC
January 2019

Pediatric Stroke Imaging.

Pediatr Neurol 2018 09 9;86:5-18. Epub 2018 Jul 9.

Stanford University and Medical Center, Department of Radiology, Neuroradiology Section, Stanford, CA. Electronic address:

Background: Pediatric stroke is a distinct clinical entity as compared with that in adults due to its unique and diverse set of etiologies. Furthermore, the role and application of diagnostic imaging has specific constraints and considerations. The intention of this article is to review these concepts in a thorough manner to offer a pediatric stroke imaging framework that providers can employ when taking care of these patients.

Methods: A comprehensive primary and secondary literature review was performed with specific attention to the common causes of pediatric stroke, appropriate use of neuroimaging, specific imaging findings, and developing techniques which may improve our ability to accurately diagnose these patients.

Results: Findings from this literature review were synthesized and summarized in order to thoroughly review the aforementioned concepts and outline the current consensus-based approach to diagnostic imaging in pediatric stroke. Furthermore, imaging findings drawn from patients seen in our institution are demonstrated to familiarize readers with pediatric stroke neuroimaging.

Conclusions: The challenges posed by pediatric stroke can be mitigated, in part, by the thoughtful application of diagnostic imaging, with the ultimate hope of improving outcomes for these vulnerable patients.
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http://dx.doi.org/10.1016/j.pediatrneurol.2018.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215731PMC
September 2018

Formulation of Long-Range Transport Rates through Molecular Bridges: From Unfurling to Hopping.

J Phys Chem Lett 2018 Aug 12;9(15):4139-4145. Epub 2018 Jul 12.

Weak fluctuations about the rigid equilibrium structure of ordered molecular bridges drive charge transfer in donor-bridge-acceptor systems via quantum unfurling, which differs from both hopping and ballistic transfer, yet static disorder (low frequency motions) in the bridge is shown to induce a change of mechanism from unfurling to hopping when local fluctuations along the molecular bridge are uncorrelated. Remarkably, these two different transport mechanisms manifest in similar charge-transfer rates, which are nearly independent of the molecular bridge length. We propose an experimental test for distinguishing unfurling from hopping in DNA models with different helix directionality. A unified formulation explains the apparent similarity in the length dependence of the transfer rate despite the difference in the underlying transport mechanisms.
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http://dx.doi.org/10.1021/acs.jpclett.8b01581DOI Listing
August 2018

Practical Pearl: Use of MRI to Differentiate Pseudo-subarachnoid Hemorrhage from True Subarachnoid Hemorrhage.

Neurocrit Care 2018 08;29(1):113-118

Department of Neurosurgery, Stanford University School of Medicine, Stanford University Medical Center, 300 Pasteur Dr. MC5327, Stanford, CA, 94303, USA.

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http://dx.doi.org/10.1007/s12028-018-0547-3DOI Listing
August 2018

High-resolution 3D volumetric contrast-enhanced MR angiography with a blood pool agent (ferumoxytol) for diagnostic evaluation of pediatric brain arteriovenous malformations.

J Neurosurg Pediatr 2018 09 8;22(3):251-260. Epub 2018 Jun 8.

2Department of Radiology, Lucile Packard Children's Hospital, Palo Alto.

OBJECTIVE Patients with brain arteriovenous malformations (AVMs) often require repeat imaging with MRI or MR angiography (MRA), CT angiography (CTA), and digital subtraction angiography (DSA). The ideal imaging modality provides excellent vascular visualization without incurring added risks, such as radiation exposure. The purpose of this study is to evaluate the performance of ferumoxytol-enhanced MRA using a high-resolution 3D volumetric sequence (fe-SPGR) for visualizing and grading pediatric brain AVMs in comparison with CTA and DSA, which is the current imaging gold standard. METHODS In this retrospective cohort study, 21 patients with AVMs evaluated by fe-SPGR, CTA, and DSA between April 2014 and August 2017 were included. Two experienced raters graded AVMs using Spetzler-Martin criteria on all imaging studies. Lesion conspicuity (LC) and diagnostic confidence (DC) were assessed using a 5-point Likert scale, and interrater agreement was determined. The Kruskal-Wallis test was performed to assess the raters' grades and scores of LC and DC, with subsequent post hoc pairwise comparisons to assess for statistically significant differences between pairs of groups at p < 0.05. RESULTS Assigned Spetzler-Martin grades for AVMs on DSA, fe-SPGR, and CTA were not significantly different (p = 0.991). LC and DC scores were higher with fe-SPGR than with CTA (p < 0.05). A significant difference in LC scores was found between CTA and fe-SPGR (p < 0.001) and CTA and DSA (p < 0.001) but not between fe-SPGR and DSA (p = 0.146). A significant difference in DC scores was found among DSA, fe-SPGR, and CTA (p < 0.001) and between all pairs of the groups (p < 0.05). Interrater agreement was good to very good for all image groups (κ = 0.77-1.0, p < 0.001). CONCLUSIONS Fe-SPGR performed robustly in the diagnostic evaluation of brain AVMs, with improved visual depiction of AVMs compared with CTA and comparable Spetzler-Martin grading relative to CTA and DSA.
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http://dx.doi.org/10.3171/2018.3.PEDS17723DOI Listing
September 2018