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Table S1: Detailed descriptions of all grade neurotoxicity; Table S2: Correlation between CAR T cell phenotype and neurotoxicity; Table S3: Correlation between CSF cytokines and CSF protein concentrations; Table S4: Definitions of CRS

Figure S1: Detailed time course of neurotoxicity for each patient; Figure S2: Serum cytokines in relation to tocilizumab and corticosteroid administration; Figure S3: Hematopoietic toxicity and coagulopathy in severe neurotoxicity; Figure S4: Angiopoietin 1 and 2 alterations in severe neurotoxicity

BACKGROUND AND PURPOSE: To determine the ability of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to predict long-term response of brain metastases prior to and within 72 hours of stereotactic radiosurgery (SRS). METHODS: In this prospective pilot study, multiple b-value DWI and T1-weighted DCE-MRI were performed in patients with brain metastases before and within 72 hours following SRS. Diffusion-weighted (DW) images were analyzed using the monoexponential and intravoxel incoherent motion (IVIM) models. DCE-MRI data were analyzed using the extended Tofts pharmacokinetic model. The parameters obtained with these methods were correlated with brain metastasis outcomes according to modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. RESULTS: We included 25 lesions from 16 patients; 16 patients underwent pre-SRS MRI and 12/16 patients underwent both pre- and early (within 72 hours) post-SRS MRI. The perfusion fraction (f) derived from IVIM early post-SRS was higher in lesions demonstrating progressive disease than in lesions demonstrating stable disease, partial response, or complete response (q = 0.041). Pre-SRS extracellular extravascular volume fraction, v(e), and volume transfer coefficient, k(trans), derived from DCE-MRI were higher in non-responders versus responders (q = 0.041). CONCLUSIONS: Quantitative DWI and DCE-MRI are feasible imaging methods in the pre- and early (within 72 hours) post-SRS evaluation of brain metastases. DWI- and DCE-MRI-derived parameters demonstrated physiologic changes (tumor cellularity and vascularity) and offer potentially useful biomarkers that can predict treatment response. This allows for initiation of alternate therapies within an effective time window that may help prevent disease progression.

INTRODUCTION Treatment of primary CNS lymphoma (PCNSL) has rapidly evolved, emphasizing improved efficacy while reducing neurotoxicity. PCNSL has historically been considered a multifocal disease and many patients relapse after first-line therapy. We evaluated relapse patterns in a large cohort of contemporarily treated patients. METHODS Consecutive PCNSL patients treated at MSKCC between 1983-2020 were analyzed. T1 post-contrast-enhancing disease on baseline MRI was characterized. Site of initial relapse was characterized as purely local (involving/adjacent to initial site) vs distant intraparenchymal, or other (e.g., both local and distant, systemic, ocular). Progression-free survival (PFS) was evaluated using Kaplan Meier methods. RESULTS Of 645 patients, 564 were eligible for analysis (diffuse large B-cell histology, sufficient data, ≥ 1 MRI response assessment). Median follow-up was 2.7 years (IQR 1.2-5.6). Median age was 63 years (range 19-90). Baseline disease was often supratentorial (420, 74%), multifocal (274, 49%), and bilateral (224, 40%). Fewer had leptomeningeal disease (94/430 CSF+, 22%; 117/559 radiographically positive, 21%). Most received methotrexate (MTX)-based induction (534, 96%), most commonly rituximab, MTX, procarbazine, vincristine (R-MVP; 257, 46%) or MVP (144, 26%). Overall, 286 (51%) patients relapsed with a median PFS of 2.1 years (95% CI 1.8-2.5). Of 275 characterizable relapses, 75 (27%) were exclusively local intraparenchymal, 91 (33%) were distant intraparenchymal, and 109 (40%) were other. Baseline unifocal disease often relapsed unifocally (66/118 baseline unifocal; 56%). Of 126 unifocal relapses, 45 (36%) were local. Of 202 patients with baseline supratentorial disease, 152 (75%) relapsed supratentorially. Unilateral relapses often remain ipsilateral (49% left- and 54% right-hemispheric lesions at baseline and relapse). CONCLUSIONS In a large PCNSL cohort, relapses often maintained baseline characteristics. For a disease historically considered multifocal, a substantial proportion of relapses were local. Future analyses will evaluate predictors of relapse, which can further efforts in informing personalization of treatment in the era of cellular therapies.

BACKGROUND: Resting-state functional MRI holds substantial potential for clinical application, but limitations exist in current understanding of how tumors exert local effects on resting-state functional MRI readings. PURPOSE: To investigate the association between tumors, tumor characteristics, and changes in resting-state connectivity, to explore neurovascular uncoupling as a mechanism underlying these changes, and to evaluate seeding methodologies as a clinical tool. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant observational retrospective study of patients with glioma who underwent MRI and resting-state functional MRI between January 2016 and July 2017. Interhemispheric symmetry of connectivity was assessed in the hand motor region, incorporating tumor position, perfusion, grade, and connectivity generated from seed-based correlation. Statistical analysis was performed by using one-tailed t tests, Wilcoxon rank sum tests, one-way analysis of variance, Pearson correlation, and Spearman rank correlation, with significance at P < .05. RESULTS: Data in a total of 45 patients with glioma (mean age, 51.3 years ± 14.3 [standard deviation]) were compared with those in 10 healthy control subjects (mean age, 50.3 years ± 17.2). Patients showed loss of symmetry in measures of hand motor resting-state connectivity compared with control subjects (P < .05). Tumor distance from the ipsilateral hand motor (IHM) region correlated with the degree (R = 0.38, P = .01) and strength (R = 0.33, P = .03) of resting-state connectivity. In patients with World Health Organization grade IV glioblastomas 40 mm or less from the IHM region, loss of symmetry in strength of resting-state connectivity was correlated with tumor perfusion (R = 0.74, P < .01). In patients with gliomas 40 mm or less from the IHM region, seeding the nontumor hemisphere yielded less asymmetric hand motor resting-state connectivity than seeding the tumor hemisphere (connectivity seeded:contralateral = 1.34 nontumor vs 1.38 tumor hemisphere seeded; P = .03, false discovery rate threshold = 0.01). CONCLUSION: Hand motor resting-state connectivity was less symmetrical in a tumor distance–dependent manner in patients with glioma. Differences in resting-state connectivity may be false-negative results driven by a neurovascular uncoupling mechanism. Seeding from the nontumor hemisphere may attenuate asymmetry in patients with tumors near ipsilateral hand motor cortices. © RSNA, 2020 Online supplemental material is available for this article.

Gliomas comprise the most common type of primary brain tumor, are highly invasive, and often fatal. IDH-mutated gliomas are particularly challenging to image and there is currently no clinically accepted method for identifying the extent of tumor burden in these neoplasms. This uncertainty poses a challenge to clinicians who must balance the need to treat the tumor while sparing healthy brain from iatrogenic damage. The purpose of this study was to investigate the feasibility of using resting-state blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) to detect glioma-related asynchrony in vascular dynamics for distinguishing tumor from healthy brain.Twenty-four stereotactically localized biopsies were obtained during open surgical resection from ten treatment-naïve patients with IDH-mutated gliomas who received standard-of-care preoperative imaging as well as echo-planar resting-state BOLD fMRI. Signal intensity for BOLD asynchrony and standard-of-care imaging was compared to cell counts of total cellularity (HE), tumor density (IDH1Sox2), cellular proliferation (Ki67), and neuronal density (NeuN), for each corresponding sample.BOLD asynchrony was directly related to total cellularity (HE, P = 4 × 10-5), tumor density (IDH1, P = 4 × 10-5; Sox2, P = 3 × 10-5), cellular proliferation (Ki67, P = .002), and inversely related to neuronal density (NeuN, P = 1 × 10-4).Asynchrony in vascular dynamics, as measured by resting-state BOLD fMRI, correlates with tumor burden and provides a radiographic delineation of tumor boundaries in IDH-mutated gliomas.

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction. Here we show that a particularly vulnerable population with neurologic manifestations of COVID-19 harbor an influx of inflammatory cytokines within the cerebrospinal fluid in the absence of viral neuro-invasion. The majority of these inflammatory mediators are driven by type 2 interferon and are known to induce neuronal injury in other disease models. Levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks following convalescence from the acute respiratory infection. These prolonged neurologic sequelae following a systemic cytokine release syndrome lead to long-term neurocognitive dysfunction with a wide range of phenotypes.

Resting state functional connectivity magnetic resonance imaging (rsfcMRI) has become a key component of investigations of neurocognitive and psychiatric behaviors. Over the past two decades, several methods and paradigms have been adopted to utilize and interpret data from resting-state fluctuations in the brain. These findings have increased our understanding of changes in many disease states. As the amount of resting state data available for research increases with big datasets and data-sharing projects, it is important to review the established traditional analysis methods and recognize areas where research methodology can be adapted to better accommodate the scale and complexity of rsfcMRI analysis. In this paper, we review established methods of analysis as well as areas that have been receiving increasing attention such as dynamic rsfcMRI, independent vector analysis, multiband rsfcMRI and network of networks.

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958–71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899

Objective FSE sequences play key roles in neck MRI despite the susceptibility issues in neck region. Iterative decomposition of asymmetric echoes (IDEAL, GE) is a promising method that separates fat and water images resulting in high SNR and improved fat suppression. We tested how neck tissue contrasts, image artifacts and fat separation as opposed to fat suppression in terms of image quality compare between routine and IDEAL FSE. Methods IDEAL based and routine T1 and T2-weighted FSE sequences were applied for neck MRI at 1.5T and 3T. Overall image quality including fat suppression, tissue contrast, image artifacts and lesion conspicuity were subjectively assessed for 20 patients clinically indicated for neck MRI. Quantitative tissue contrast estimates from parotid area were compared between IDEAL and routine FSE for 7 patients. Four patients with oncocytoma were also reviewed to assess benefits of separately reconstructed fat specific image sets. Results Subjective tissue contrast and overall image quality including image sharpness, fat suppression and image artifacts were superior for IDEAL sequences. For oncocytoma fat specific IDEAL images provided additional information. Objective CNR estimates from a central slice were equivalent for IDEAL and routine FSE at both field strengths. Conclusions We demonstrated that high SNR inherent in IDEAL FSE consistently translates into high tissue contrast with image quality advantages in neck anatomy where large susceptibility variation and physiological motions reduce image quality for conventional FSE T1 and T2. However, the objective contrast estimates for parotid gland at isocenter were statistically equivalent for IDEAL and conventional FSE perhaps because at or near isocenter routine FSE works well. Additionally, fat specific IDEAL image sets add to diagnostic specificity for fat deficient lesions.

Background: COVID-19 is associated with a wide spectrum of neurologic manifestations, which can emerge weeks to months after the initial infection. Cancer patients are at a heightened risk of severe infections due to their immunocompromised status. Leading hypotheses predict that SARS-CoV-2 neuroinvasion or neurologic toxicity from the systemic cytokine storm may account for neurologic dysfunction. Methods: We prospectively evaluated cancer patients with confirmed SARS-CoV-2 infection and subsequent neurologic manifestations at an NCI-designated cancer center. Evaluations included neurologic examinations, brain imaging, electroencephalogram, and cerebrospinal fluid (CSF) analysis for SARS-CoV-2 detection by RT-PCR for viral RNA and ELISA for nucleocapsid (N) and spike (S2) proteins. Additional proteomic analysis compared the CSF of patients with COVID-19 (CoV+) to cancer- and brain metastasis-matched COVID-19-negative controls (CoV-), and to patients with other cancer-associated neuroinflammatory conditions, including immune effector cell-associated neurotoxicity syndrome (ICANS) and autoimmune encephalitis. Results: Between May and July 2020, we evaluated 18 COVID-19-positive cancer patients with a wide range of solid tumor and hematologic malignancies. Thirteen (72.2%) of our patients received tumor-directed treatment within 30 days of SARS-CoV-2 infection. Neurologic diagnoses include protracted critical care delirium (N=10), limbic encephalitis (N=4), refractory headaches (N=2), rhombencephalitis (N=1), and large-territory infarctions (N=1). A median delay of 19 days (range 0-77) existed between onset of respiratory symptoms and neurologic manifestations. Among 13 patients who underwent CSF analysis, there was no evidence of SARS-CoV-2 neuroinvasion by RT-PCR in the CSF (N=13) or by N and S2 protein detection (N=10). Targeted proteomic analysis detected a significant accumulation of IL-6 and -8, IFN-gamma, CXCL-1, -6, -9, -10, and -11, CCL-8 and -20, MMP-10 and 4E-BP1 in the CSF of CoV+ patients (N=10) relative to matched CoV- controls (pooled, p=0.029). Combined analysis of these 12 inflammatory mediators revealed CoV+ cytokine levels approaching that of ICANS. CSF MMP-10, a marker of neurodegeneration, correlated with neurologic dysfunction by Karnofsky performance status (p=0.011) and by disability rating scale (p=0.086) at the time of lumbar puncture. Conclusion: A durable accumulation of IFN-gamma-mediated cytokines is detected in the CSF of cancer patients with neurologic manifestations of COVID-19, in the absence of detectable neuroinvasion. We hypothesize that cytokine-mediated neuroinflammation is responsible for the prolonged neurologic sequela of COVID-19. Our findings suggest a potential role for anti-inflammatory treatments in the management of such patients. Citation Format: Jessica A. Wilcox, Jan Remsik, N. Esther Babady, Tracy A. McMillen, Behroze A. Vachha, Neil A. Halpern, Vikram Dhawan, Marc Rosenblum, Christine A. Iacobuzio-Donahue, Edward K. Avila, Bianca Santomasso, Adrienne Boire. An inflammatory leptomeningeal signature in cancer patients with neurologic manifestations of COVID-19 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 703.

INTRODUCTION: Functional MR imaging is increasingly being used for presurgical language assessment in the treatment of patients with brain tumors, epilepsy, vascular malformations, and other conditions. The inherent complexity of fMRI, which includes numerous processing steps and selective analyses, is compounded by institution-unique approaches to patient training, paradigm choice, and an eclectic array of postprocessing options from various vendors. Consequently, institutions perform fMRI in such markedly different manners that data sharing, comparison, and generalization of results are difficult. The American Society of Functional Neuroradiology proposes widespread adoption of common fMRI language paradigms as the first step in countering this lost opportunity to advance our knowledge and improve patient care. LANGUAGE PARADIGM REVIEW PROCESS: A taskforce of American Society of Functional Neuroradiology members from multiple institutions used a broad literature review, member polls, and expert opinion to converge on 2 sets of standard language paradigms that strike a balance between ease of application and clinical usefulness. ASFNR RECOMMENDATIONS: The taskforce generated an adult language paradigm algorithm for presurgical language assessment including the following tasks: Sentence Completion, Silent Word Generation, Rhyming, Object Naming, and/or Passive Story Listening. The pediatric algorithm includes the following tasks: Sentence Completion, Rhyming, Antonym Generation, or Passive Story Listening. DISCUSSION: Convergence of fMRI language paradigms across institutions offers the first step in providing a “Rosetta Stone” that provides a common reference point with which to compare and contrast the usefulness and reliability of fMRI data. From this common language task battery, future refinements and improvements are anticipated, particularly as objective measures of reliability become available. Some commonality of practice is a necessary first step to develop a foundation on which to improve the clinical utility of this field.

BACKGROUND: Imaging criteria to evaluate the response of brain metastases to stereotactic radiosurgery (SRS) in the early posttreatment period remains a crucial unmet need. The aim of this study is to correlate early (within 12 wk) posttreatment perfusion MRI changes with long-term outcomes after treatment of lung cancer brain metastases with SRS. METHODS: Pre- and posttreatment perfusion MRI scans were obtained in patients treated with SRS for intact non–small cell lung cancer brain metastases. Time-dependent leakage (K(trans)), blood plasma volume (Vp), and extracellular extravascular volume (Ve) were calculated for each lesion. Patients were followed longitudinally with serial MRI until death, progression, or intervention (whole brain radiation or surgery). RESULTS: We included 53 lesions treated with SRS from 41 total patients. Median follow-up after treatment was 11 months. Actuarial local control at one year was 85%. Univariate analysis demonstrated a significant difference (P = 0.032) in posttreatment K(trans) SD between patients with progressive disease (mean = 0.0317) and without progressive disease (mean = 0.0219). A posttreatment K(trans) SD cutoff value of 0.017 was highly sensitive (89%) for predicting progressive disease and no progressive disease. Early posttreatment volume change was not associated with outcome (P = 0.941). CONCLUSION: Posttreatment K(trans) SD may be used as an early posttreatment imaging biomarker to help predict long-term response of lung cancer brain metastases to SRS. This can help identify patients who will ultimately fail SRS and allow for timelier adjustment in treatment approach. These data should be prospectively validated in larger patient cohorts and other histologies.

BACKGROUND AND PURPOSE: A recent study using task-based fMRI demonstrated that the middle frontal gyrus is comparable with Broca9s area in its ability to determine language laterality using a measure of verbal fluency. This study investigated whether the middle frontal gyrus can be used as an indicator for language-hemispheric dominance in patients with brain tumors using task-free resting-state fMRI. We hypothesized that no significant difference in language lateralization would occur between the middle frontal gyrus and Broca area and that the middle frontal gyrus can serve as a simple and reliable means of measuring language laterality. MATERIALS AND METHODS: Using resting-state fMRI, we compared the middle frontal gyrus with the Broca area in 51 patients with glial neoplasms for voxel activation, the language laterality index, and the effect of tumor grade on the laterality index. The laterality index derived by resting-state fMRI and task-based fMRI was compared in a subset of 40 patients. RESULTS: Voxel activations in the left middle frontal gyrus and left Broca area were positively correlated ( r = 0.47, P r = 0.56, P CONCLUSIONS: The middle frontal gyrus is comparable with the Broca area in its ability to determine hemispheric dominance for language using resting-state fMRI. Our results suggest the addition of resting-state fMRI of the middle frontal gyrus to the list of noninvasive modalities that could be used in patients with gliomas to evaluate hemispheric dominance of language before tumor resection. In patients who cannot participate in traditional task-based fMRI, resting-state fMRI offers a task-free alternate to presurgically map the eloquent cortex.

SARS-CoV-2 infection induces a wide spectrum of neurologic dysfunction that emerges weeks after the acute respiratory infection. To better understand this pathology, we prospectively analyzed of a cohort of cancer patients with neurologic manifestations of COVID-19, including a targeted proteomics analysis of the cerebrospinal fluid. We find that cancer patients with neurologic sequelae of COVID-19 harbor leptomeningeal inflammatory cytokines in the absence of viral neuroinvasion. The majority of these inflammatory mediators are driven by type II interferon and are known to induce neuronal injury in other disease states. In these patients, levels of matrix metalloproteinase-10 within the spinal fluid correlate with the degree of neurologic dysfunction. Furthermore, this neuroinflammatory process persists weeks after convalescence from acute respiratory infection. These prolonged neurologic sequelae following systemic cytokine release syndrome lead to long-term neurocognitive dysfunction. Our findings suggest a role for anti-inflammatory treatment(s) in the management of neurologic complications of COVID-19 infection., Graphical abstract, Remsik et al. analyze the cerebrospinal fluid of cancer patients with neurologic symptoms of COVID-19 and detect unique markers of inflammation and neurodegeneration, present weeks after initial SARS-CoV-2 infection. Cytokine storming, both systemically and intracranially, likely contribute to neurologic dysfunction, indicating a potential therapeutic target for investigation.

PURPOSE: Prediction of clinical outcomes in patients with primary central nervous system lymphoma (PCNSL) is important for optimization of treatment planning. Quantitative imaging biomarkers for PCNSL have not yet been established. This study evaluated the prognostic value of pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging for progression-free survival (PFS) in patients with PCNSL. METHODS: Pretreatment dynamic contrast-enhanced MRI and diffusion-weighted imaging were retrospectively analyzed in 18 immunocompetent patients with PCNSL. Volumes of interest encompassing the tumors were assessed for measurements of blood plasma volume (Vp), volume transfer constant (K(trans)), and apparent diffusion coefficient. Patients were divided into short and long PFS groups based on median PFS. Imaging and clinical variables were correlated with PFS. RESULTS: Median PFS was 19.6 months. Lower Vp(mean) and K(trans)(mean) values increased risk for rapid progression (< 19.6 months). Receiver operating characteristic curve analysis demonstrated an optimal Vp(mean) cutoff value of 2.29 (area under the curve [AUC] = 0.74, sensitivity and specificity = 0.78, p = 0.023) for separating patients with short and long PFS. The optimal K(trans)(mean) cutoff was 0.08 (AUC = 0.74, sensitivity = 0.67, specificity = 0.78, p = 0.025). Kaplan–Meier survival analysis with log-rank test demonstrated significantly (p = 0.015) increased risk of rapid progression for patients with Vp(mean) < 2.29. Vp(mean) was significantly (p = 0.03) associated with PFS on univariate Cox analysis. Apparent diffusion coefficient values and clinical factors did not influence PFS. CONCLUSIONS: Pretreatment Vp and K(trans) derived from dynamic contrast-enhanced MRI may be novel prognostic quantitative imaging biomarkers of progression-free survival in patients with PCNSL. These data should be prospectively validated in larger patient cohorts.

The primary hand motor region is classically believed to be in the “hand knob” area in the precentral gyrus (PCG). However, hand motor task-based activation is often localized outside this area. The purpose of this study is to investigate the structural and functional connectivity driven by different seed locations corresponding to the little, index, and thumb in the PCG using probabilistic diffusion tractography (PDT) and resting-state functional magnetic resonance imaging (rfMRI). Twelve healthy subjects had three regions of interest (ROIs) placed in the left PCG: lateral to the hand knob (thumb area), within the hand knob (index finger area), and medial to the hand knob (little finger area). Connectivity maps were generated using PDT and rfMRI. Individual and group level analyses were performed. Results show that the greatest hand motor connectivity between both hemispheres was obtained using the ROI positioned just lateral to the hand knob in the PCG (the thumb area). The number of connected voxels in the PCG between the two hemispheres was greatest in the lateral-most ROI (the thumb area): 279 compared with 13 for the medial-most ROI and 9 for the central hand knob ROI. Similarly, the highest white matter connectivity between the two hemispheres resulted from the ROI placed in the lateral portion of PCG (p

Neuroimaging plays a key role in the initial work-up of patients with symptoms of acute stroke. Understanding the advantages and limitations of available CT and MR imaging techniques and how to use them optimally in the emergency setting is crucial for accurately making the diagnosis of acute stroke and for rapidly determining appropriate treatment.

Background and Purpose— Major anterior circulation ischemic strokes caused by occlusion of the distal internal carotid artery or proximal middle cerebral artery or both account for about one third of ischemic strokes with mostly poor outcomes. These strokes are treatable by intravenous tissue-type plasminogen activator and endovascular methods. However, dynamics of infarct growth in these strokes are poorly documented. The purpose was to help understand infarct growth dynamics by measuring acute infarct size with diffusion-weighted imaging (DWI) at known times after stroke onset in patients with documented internal carotid artery/middle cerebral artery occlusions. Methods— Retrospectively, we included 47 consecutive patients with documented internal carotid artery/middle cerebral artery occlusions who underwent DWI within 30 hours of stroke onset. Prospectively, 139 patients were identified using the same inclusion criteria. DWI lesion volumes were measured and correlated to time since stroke onset. Perfusion data were reviewed in those who underwent perfusion imaging. Results— Acute infarct volumes ranged from 0.41 to 318.3 mL. Infarct size and time did not correlate ( R 2 =0.001). The majority of patients had DWI lesions that were 8 hours after stroke onset. DWI lesions corresponded to areas of greatly reduced perfusion. Conclusions— Poor correlation between infarct volume and time after stroke onset suggests that there are factors more powerful than time in determining infarct size within the first 30 hours. The observations suggest that highly variable cerebral perfusion via the collateral circulation may primarily determine infarct growth dynamics. If verified, clinical implications include the possibility of treating many patients outside traditional time windows.

Purpose To characterize the MRI features of the petromastoid canal in children with sensorineural hearing loss (SNHL) and in normal infants. Materials and Methods High resolution MRI examinations of 564 children who were evaluated for SNHL and brain MRI examinations of 112 infants who had normal studies were studied independently by two reviewers. Results In SNHL group, visibility of the PMC decreased for right and left PMC (P 0.05). In the normal group, the PMC visibility decreased with increasing age (right P = 0.0001, left P = 0.001). In the normal group also, as age increased, the PMC width decreased for both PMCs (right, P = 0.0006; left, P = 0.03). Conclusion The PMC is more frequently visualized in young children. Its visibility and width are not associated with abnormalities of membranous labyrinth and cochlear nerves. J. Magn. Reson. Imaging 2014;39:966–971. © 2013 Wiley Periodicals, Inc.

Altered communication (hoarseness, dysphonia, and breathy voice) that can result from vocal fold paralysis, secondary to numerous etiologies, may be amenable to surgical restoration. In this article, both traditional and cutting-edge phonosurgical procedures targeting the symptoms resulting from vocal fold paralysis are reviewed, with emphasis on the characteristic imaging appearances of various injectable materials, implants, and augmentation procedures used in the treatment of vocal fold paralysis. In addition, complications of injection laryngoplasty and medialization laryngoplasty are illustrated. Familiarity with the expected imaging changes following treatment of vocal fold paralysis may prevent the misinterpretation of posttreatment changes as pathology. Identifying common complications related to injection laryngoplasty and localization of displaced implants is crucial in determining specific management in patients who have undergone phonosurgical procedures for the management of vocal fold paralysis.

Extant literature is mixed regarding risk of metabolic acidosis after enteroplasty for myelomeningocele. This study is the first known attempt to describe the pattern of developing metabolic acidosis in a group of children who underwent enteroplasty and served as their own controls. Multiple preoperative and postoperative laboratory measures for each child were obtained for comparison.This retrospective cohort study allowed participants to serve as their own controls for pre-intervention and post-intervention analysis. The setting was a tertiary, university affiliated, interdisciplinary spina bifida program. All patients followed in the spina bifida program who had undergone ileal or colonic enteroplasty were included for review (total 113). Strict exclusion criteria were preoperatively diagnosed renal insufficiency, preexisting metabolic acidosis consistent with renal tubular acidosis (pH less than 7.35, bicarbonate 20 mmol/l or less) and history of augmentation using gastric or ureteral tissue. Final analysis included 71 children who met inclusion criteria. Children in our spina bifida program periodically undergo routine laboratory evaluation of electrolytes, blood urea nitrogen, creatinine, blood count, and venous blood gases including pH, bicarbonate and partial pressure of carbon dioxide. Primary outcome measures were comparative shifts in blood gases and electrolytes that would confirm the new onset of metabolic acidosis after enteroplasty. Changes in electrolytes and serum creatinine were secondary outcome measures to identify potential markers for postoperative effects. With each child as his/her own control, analysis included paired t tests.No statistically significant differences (p0.05) were found when comparing laboratory values before and after bladder augmentation, including pH, bicarbonate, partial pressure of carbon dioxide and electrolytes. No child had metabolic acidosis based on the aforementioned criteria. Followup ranged from 1 to 138 months after enteroplasty (mean 46.8). Respiratory compensation was considered in the analysis, and no difference in partial pressure of carbon dioxide following surgery was noted (p = 0.65).To our knowledge no previous study has examined the matched paired results of before and after development of metabolic acidosis among children (serving as their own controls) with myelomeningocele undergoing ileal or colonic enteroplasty. The negative statistical results in this controlled cohort are clinically significant. If a child with myelomeningocele has metabolic acidosis after enteroplasty, other clinical reasons beyond the effects of surgery warrant careful consideration.

Introduction This study examines the effect of family environment on language performance in children with myelomeningocele compared with age- and education-matched controls selected from the same geographic region. Methods Seventy-five monolingual (English) speaking children with myelomeningocele [males: 30; ages: 7–16 years; mean age: 10 years 1 month, standard deviation (SD) 2 years 7 months] and 35 typically developing children (males: 16; ages 7–16 years; mean age: 10 years 9 months, SD 2 years 6 months) participated in the study. The Comprehensive Assessment of Spoken Language (CASL) and the Wechsler tests of intelligence were administered individually to all participants. The CASL measures four subsystems: lexical, syntactic, supralinguistic and pragmatic. Parents completed the Family Environment Scale (FES) questionnaire and provided background demographic information. Standard independent sample t-tests, chi-squared and Fisher's exact tests were used to make simple comparisons between groups for age, socio-economic status, gender and ethnicity. Spearman correlation coefficients were used to detect associations between language and FES data. Group differences for the language and FES scores were analysed with a multivariate analysis of variance at a P-value of 0.05. Results For the myelomeningocele group, both Spearman correlation and partial correlation analyses revealed statistically significant positive relationships for the FES ‘intellectual–cultural orientation’ (ICO) variable and language performance in all subsystems (P < 0.01). For controls, positive associations were seen between: (1) ICO and lexical/semantic and syntactic subsystems; and (2) FES ‘independence’ and lexical/semantic and supralinguistic tasks. Conclusions The relationship between language performance and family environment appears statistically and intuitively sound. As in our previous study, the positive link between family focus on intellectually and culturally enhancing activities and language performance among children with myelomeningocele and shunted hydrocephalus remains robust. Knowledge of this relationship should assist parents and professionals in supporting language development through activities within the natural learning environment.

With strides in stem cell biology, cell engineering and molecular therapy, the transplantation of cells to produce therapeutic molecules endogenously is an attractive and achievable alternative to the use of exogenous drugs. The encapsulation of such cell transplants in semi-permeable, nanoporous constructs is often required to protect them from immune attack and to prevent their proliferation in the host. However, effective graft immunoisolation has been mostly elusive owing to the absence of a high-throughput method to create precisely controlled, high-aspect-ratio nanopores. To address the clinical need for effective cell encapsulation and immunoisolation, we devised a biocompatible cell-encapsulating microcontainer and a method to create highly anisotropic nanopores in the micro-container’s surface. To evaluate the efficacy of these nanopores in oxygenating the encapsulated cells, we engineered 9L rat glioma cells to bioluminesce under hypoxic conditions. The methods described above should aid in evaluating the long term survival and efficacy of cellular grafts.

This article reviews a variety of congenital and developmental disorders of the pediatric orbit with particular emphasis on ocular lesions, followed by a description of developmental and neoplastic orbital and ocular masses. The relationship of these diseases to various syndromes and/or known genetic mutations is also highlighted.

To prospectively determine anomalies of limbic tracts and to describe the relationship between these anomalies, seen on diffusion-tensor magnetic resonance (MR) and fiber tract (FT) reconstruction images, and learning and memory in children with myelomeningocele (MM) and Chiari II malformation.The investigation was HIPAA compliant and approved by institutional review boards; informed consent was obtained. In seven male and six female patients (aged 6 months to 16 years) with MM and Chiari II malformation, diffusion-tensor imaging and FT reconstruction were performed. FT reconstruction was generated with fractional anisotropy continuous tracking algorithm and manually drawn regions of interest. Limbic tract abnormalities were assessed on FT reconstruction images by an experienced pediatric neuroradiologist blinded to results of cognitive testing. Nine patients met criteria for memory and learning testing by a trained cognitive neuroscientist blinded to MR results. Exact Wilcoxon rank sum test was used to compare performance with learning and memory tasks in two groups.Eleven of 13 patients had defects within fornices and/or cingulum; three patients had aberrant fibers of cingulum. In nine patients, six had deficits in general memory; four, in learning; and four, in both. Atresia or hypoplasia of crura and body of fornices was noted in six patients with memory deficits and four patients with learning deficits. Five of six patients with memory deficits and three of four with learning deficits had hypoplasia or atresia of cingulum. Exact Wilcoxon rank sum test demonstrated significantly poorer performance for nonverbal immediate recall tasks in patients with anomalies of the fornix compared with those without (P = .04, exact two-tailed test).Diffusion-tensor and FT reconstruction images revealed that limbic fiber abnormalities were common in patients with MM and Chiari II malformation. Nonverbal immediate recall task performance appeared to be related to abnormalities of the fornix.

Background Previously, our studies demonstrated language differences impacting academic performance among children with myelomeningocele and shunted hydrocephalus (MMSH). This follow-up study considers the environmental facilitators within families (achievement orientation, intellectual–cultural orientation, active recreational orientation, independence) among a cohort of children with MMSH and their relationship to language performance. Methods Fifty-eight monolingual, English-speaking children (36 females; mean age: 10.1 years; age range: 7–16 years) with MMSH were evaluated. Exclusionary criteria were prior shunt infection; seizure or shunt malfunction within the previous 3 months; uncorrected visual or auditory impairments; prior diagnoses of mental retardation or attention deficit disorder. The Comprehensive Assessment of Spoken Language (CASL) and the Wechsler Abbreviated Scale of Intelligence (WASI) were administered individually to all participants. The CASL Measures four subsystems: lexical, syntactic, supralinguistic and pragmatic. Parents completed the Family Environment Scale (FES) questionnaire and provided background demographic information. Spearman correlation analyses and partial correlation analyses were performed. Results Mean intelligence scores for the MMSH group: full scale IQ 92.2 (SD = 11.9). The CASL revealed statistically significant difficulty for supralinguistic and pragmatic (or social) language tasks. FES scores fell within the average range for the group. Spearman correlation and partial correlation analyses revealed statistically significant positive relationships for the FES ‘intellectual–cultural orientation’ variable and performance within the four language subsystems. Socio-economic status (SES) characteristics were analyzed and did not discriminate language performance when the intellectual–cultural orientation factor was taken into account. Conclusion The role of family facilitators on language skills in children with MMSH has not previously been described. The relationship between language performance and the families’ value on intellectual/cultural activities seems both statistically and intuitively sound. Focused interest in the integration of family values and practices should assist developmental specialists in supporting families and children within their most natural environment.

Objective: This comparative cohort study examined language differences in young children (preschool to first grade) with myelomeningocele and shunted hydrocephalus (MM/SH). Method: A well-validated, standardized language test was administered to 17 children with MM/SH (age range 4–6 years) and 16 age-matched, nonaffected children. Results: Standard scores were obtained within lexical/semantic, syntactic, and pragmatic domains. An analysis of performance on individual subtests within the lexical/semantic domain was striking. Children with MM/SH performed significantly worse (p < 0.01) on a test measuring the comprehension of words representing important early learning concepts and on pragmatic tasks that measured their ability to use language functionally in social situations. Conclusions: Words representing basic precepts and concepts are commonly used in instructions to children in early childhood. Difficulty with functional pragmatic language results in suboptimal communication skills. Academic and community implications are discussed.

The early detection and specific diagnosis of viral infections of the central nervous system are important because many of these diseases are potentially treatable. However, clinical symptoms and physical examination are often nonspecific, and rapid diagnostic tests are available for some, but not all, viruses. Neuroimaging, in conjunction with clinical history and laboratory tests, plays an important role in narrowing the differential diagnoses. In this article, we review the clinical features, imaging characteristics, diagnosis, and treatment of the more common viral infections and prions that involve the central nervous system.

To characterize the MRI features of the petromastoid canal in children with sensorineural hearing loss (SNHL) and in normal infants.High resolution MRI examinations of 564 children who were evaluated for SNHL and brain MRI examinations of 112 infants who had normal studies were studied independently by two reviewers.In SNHL group, visibility of the PMC decreased for right and left PMC (P0.001). The width of the right PMC significantly decreased as age increased (P0.0001). There was no relation between abnormalities of membranous labyrinth and cochlear nerve and PMC visibility in children with SNHL (p0.05). In the normal group, the PMC visibility decreased with increasing age (right P = 0.0001, left P = 0.001). In the normal group also, as age increased, the PMC width decreased for both PMCs (right, P = 0.0006; left, P = 0.03).The PMC is more frequently visualized in young children. Its visibility and width are not associated with abnormalities of membranous labyrinth and cochlear nerves.

Hypertrophy of the optic nerves and optic chiasm is described in a 5-month-old boy with infantile Krabbe disease. Optic nerve and optic chiasm hypertrophy is a rarely described feature of Krabbe disease. The areas of the prechiasmatic optic nerves and optic chiasm were measured and compared with those of 26 age-matched controls. The areas of the prechiasmatic optic nerves and optic chiasm were 132% and 53% greater than normal, respectively.

Purpose To compare objective and subjective image quality in neck CT images acquired at different tube current–time products (275 mA s and 340 mA s) and reconstructed with filtered-back-projection (FBP) and adaptive statistical iterative reconstruction (ASIR). Materials and methods HIPAA-compliant study with IRB approval and waiver of informed consent. 66 consecutive patients were randomly assigned to undergo contrast-enhanced neck CT at a standard tube-current–time-product (340 mA s; n = 33) or reduced tube-current–time-product (275 mA s, n = 33). Data sets were reconstructed with FBP and 2 levels (30%, 40%) of ASIR-FBP blending at 340 mA s and 275 mA s. Two neuroradiologists assessed subjective image quality in a blinded and randomized manner. Volume CT dose index (CTDIvol), dose-length-product (DLP), effective dose, and objective image noise were recorded. Signal-to-noise ratio (SNR) was computed as mean attenuation in a region of interest in the sternocleidomastoid muscle divided by image noise. Results Compared with FBP, ASIR resulted in a reduction of image noise at both 340 mA s and 275 mA s. Reduction of tube current from 340 mA s to 275 mA s resulted in an increase in mean objective image noise (p = 0.02) and a decrease in SNR (p = 0.03) when images were reconstructed with FBP. However, when the 275 mA s images were reconstructed using ASIR, the mean objective image noise and SNR were similar to those of the standard 340 mA s CT images reconstructed with FBP (p > 0.05). Subjective image noise was ranked by both raters as either average or less-than-average irrespective of the tube current and iterative reconstruction technique. Conclusion Adapting ASIR into neck CT protocols reduced effective dose by 17% without compromising image quality.

Simple cyst Benign developmental hepatic cyst von Meyenburg complex Caroli disease Adult polycystic liver disease Complex cyst Neoplasm Biliary cystadenoma or cystadenocarcinoma Cystic metastases Hepatocellular carcinoma Cavernous hemangioma Embryonal sarcoma Inflammatory or infectious Abscess Pyogenic Amebic Echinococcal cyst Postraumatic and miscellaneous Pseudocyst Hematoma Biloma Infected or hemorrhagic cysts Cystic liver lesions, or fluid-containing lesions of the liver, are commonly encountered findings on radiologic examinations that may represent a broad spectrum of entities ranging from benign developmental cysts to malignant neoplasms (Table 1). The wide range of pathologic processes that may result in cystic liver lesions can present a difficult diagnostic conundrum. The radiologist must carefully assess such imaging features as location, size, and unifocal or multifocal nature of the cyst or cysts as well as evaluate cyst complexity and associated findings. In addition, because radiologic features of various cystic liver lesions overlap, it is necessary to integrate imaging with clinical and laboratory findings to allow more definitive diagnosis. An important first step in narrowing the differential diagnosis is to determine the presence or absence of complex features in cystic liver lesions. To this end, fluid-containing liver lesions can be grouped broadly into simple or complex cysts. Vachha et al. Cystic Lesions of the Liver

Present-day islet encapsulation techniques such as polymer microcapsules and microelectromechanical system (MEMS)-based biocapsules have shown promise in insulin replacement therapy, but they each have limitations—the permeability characteristics of existing polymeric capsules cannot be strictly controlled because of tortuosity and the large size of present-day MEMS biocapsules leads to necrotic regions within the encapsulation volume. We report on a new microcontainer to encapsulate and immunoprotect islets/β cells that may be used for allo- or xenotransplantation in cell-based therapy. The microcontainers have membranes containing nanoslots to permit the bidirectional transport of nutrients, secretagogues, and cellular products while immunoprotecting the encapsulated cells. The 300-μm microcontainers were fabricated from an epoxy-based polymer, SU-8, with 50-μm-thick walls. Arrays of 25-nm wide slots were created in the SU-8 microcontainer lid. Isolated mouse islets were encapsulated in the microcontainer, and their physiological response to glucose was studied with fluorescence and two-photon imaging over 48 hours. The physiological response of the encapsulated islets was indistinguishable from controls. An agarose-filled microcontainer was imaged with magnetic resonance imaging to demonstrate the feasibility of future noninvasive, in vivo imaging. The SU-8 microcontainers maintained mechanical integrity upon islet loading and mechanical manipulation. Islet encapsulation, as well as the ability to visualize islet function within these transparent microcontainers, was demonstrated.

To determine whether there are detectable differences in tensor metrics between children who read normally and children with simple developmental dyslexia and/or differences between the right and left hemispheres in these groups by using 3.0-T diffusion-tensor (DT) magnetic resonance (MR) imaging focused on the superior longitudinal fasciculus (SLF), inferior fronto-occipital and inferior longitudinal fasciculi (IFO-ILF), and posterior limb of the internal capsule (PLIC).This was a prospective, HIPAA-compliant institutional review board-approved investigation with written informed parental consent. Nineteen English-speaking, right-handed children with a normal IQ and developmental dyslexia (16 male, three female; age range, 6-16 years; mean age, 9.9 years) and 18 normal-reading, age-matched pediatric control subjects (13 male, five female; age range, 6-15 years; mean age, 10.0 years) underwent DT imaging (30 directions, three signals acquired, voxel size of 2 mm). Regions of interest were placed on the SLF, IFO-ILF, and PLIC, and tensor metrics were calculated. Statistical analyses of differences in cognitive function between the dyslexic and control groups were performed by using the two-sample t test. Differences in tensor metrics were examined by using analysis of covariance models.In the control subjects, the fractional anisotropy (FA) of all tracts studied increased with age. In the dyslexic subjects, the age-related increases in FA in the SLF were most similar to those in the control subjects (P = .504), while mean FA values for the IFO-ILF (P = .009) and PLIC (P.0001) were higher than those in the control subjects up to around 11 years of age, after which they were lower. Apparent diffusion coefficients consistently decreased in both groups. There was a nonsignificant increase in mean axial diffusivity in the IFO-ILF in the control group but not in the dyslexia group. Increases in axial diffusivity seen in the PLIC in the control group were not seen in the dyslexia group. There were no marked differences in tensor metrics between the left and right hemispheres within or between the two groups.Findings at 3.0-T DT imaging suggest that white matter differences in dyslexic children are not limited to the portion of the brain traditionally considered to be integral to word recognition and processing.

BackgroundSelective learning is the ability to select items of relevance from among less important items. Limited evidence exists regarding the efficiency with which children with spina bifida-myelomeningocele and shunted hydrocephalus (SB/SH) are able to learn information. This report describes initial data related to components of learning and metacognitive skills in children with SB/SH.MethodsTwenty six children with SB/SH and 26 controls (age: 7 – 16 y) with average intelligence, and monolingual English-speaking backgrounds participated in the study. Exclusion criteria for the SB/SH group were: prior history of shunt infection, history of seizure or shunt malfunction within the previous three months, prior diagnoses of attention disorders and/or clinical depression. Children were presented lists of words with equal exemplars each of two distinct semantic categories (e.g. fruits, animals), and told to make as high a score as possible by learning the words. The value of the words was designated by category membership (e.g. animals = low value; fruits = high value). The total number of words learned across three learning trials was used to determine memory span. Selective learning efficiency (SLE) was computed as the efficiency with which items of greater value were selectively learned across three trials.ResultsChildren with SB/SH did worse than controls on memory span (P< 0.05). Although SLE was not significantly different between groups, when asked what strategy was used in the selective learning tasks, 65% of the SB/SH children said they tried to remember all words (inefficient strategy). In contrast, 85% of controls said they tried to remember the higher value words – the more efficient strategy.ConclusionSuccess in school is often dependent on the ability to recall important facts selectively and ignore less important information. Children with SB/SH in our study had a poor memory span and were unable to monitor and report an efficient and workable metacognitive strategy required to remember a list of words. Preliminary findings may begin to explain our previous clinical and research findings wherein children with SB/SH often focus on extraneous details, but demonstrate difficulty remembering the main gist of a story/event.

Objective. Description of temperament profiles of children has largely been reported in typically developing populations. Children undergo individual- ized assessments of achievement (developmental/aca- demic) and receive individualized interventions. In con- trast, their individual behavioral styles are not evaluated as completely, if at all. For children with developmental disabilities, description of temperament characteristics can provide better understanding of the already complex child. This study describes temperament characteristics in a group of children with myelomeningocele and shunted hydrocephalus (MM/SH). Methods. A consecutive cohort study with historical control group measuring temperament characteristics was conducted at a tertiary-level, university affiliated, interdisciplinary spina bifida program. Analysis in- cludes group comparisons. Primary caregivers of 46 chil- dren (age range: 5-12 years) with MM/SH completed age-appropriate Carey Temperament Scales question- naires as a component of a larger developmental study. The Carey Temperament Scales comprise a series of be- havioral rating instruments that assess 9 temperament characteristics: activity, adaptability, approach-with- drawal, mood, intensity, attention/persistence, distracti- bility, sensory threshold, and rhythmicity/predictability. The Carey questionnaires used in this study were (1) the Behavioral Style Questionnaire for children aged 5 to 7 years and (2) the Middle Childhood Temperament Ques- tionnaire for those aged 8 to 12 years. Both question- naires assess the same temperament characteristics; the contexts within which items were rated were designed to better reflect developmental levels. Children were ex- cluded when there were comorbid diagnoses of atten- tion-deficit/hyperactivity disorder or mental retardation. Results. One-sample normal tests (Bonferroni cor- rected) revealed that children within the MM/SH group differed significantly from the standardized population in 5 dimensions: (1) adaptability (less adaptable), (2) ap- proach/withdrawal (poor first approach/greater with- drawal), (3) distractibility (more distractible), (4) atten- tion/persistence (less attentive/persistent), and (5) predictability/rhythm (less predictable). Caregiver per- ceptions of having a difficult-to-manage child were sig- nificantly correlated with negative mood, more intensity of response, and less adaptability. Conclusions. Temperament profiles previously de- scribed in typically developing populations (eg, "easy" or "difficult child") were not prominent profiles in this group of children with MM/SH. A constellation of tem- perament characteristics not commonly recognized may place these children at risk for being contributors to and recipients of misunderstandings of social cues and have implications for successful learning within academic, home/community, and medical settings. Pediatrics 2005; 115:e58-e63. URL: www.pediatrics.org/cgi/doi/10.1542/ peds.2004-0797; hydrocephalus, myelomeningocele, tem- perament, parental perceptions, early intervention.

Neurogenic compromise of vocal fold function exists along a continuum encompassing vocal cord hypomobility (paresis) to vocal fold immobility (paralysis) with varying degrees and patterns of reinnervation. Vocal fold paralysis (VFP) may result from injury to the vagus or the recurrent laryngeal nerves anywhere along their course from the brainstem to the larynx. In this article, we review the anatomy of the vagus and recurrent laryngeal nerves and examine the various etiologies of VFP. Selected cases are presented with discussion of key imaging features of VFP including radiologic findings specific to central vagal neuropathy and peripheral recurrent nerve paralysis.