Bronwyn E. Hamilton

Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review

Superparamagnetic iron oxide nanoparticles have diverse diagnostic and potential therapeutic applications in the central nervous system (CNS). They are useful as magnetic resonance imaging (MRI) contrast agents to evaluate: areas of blood–brain barrier (BBB) dysfunction related to tumors and other neuroinflammatory pathologies, the cerebrovasculature using perfusion-weighted MRI sequences, and in vivo cellular tracking in CNS disease or injury. Novel, targeted, nanoparticle synthesis strategies will allow for a rapidly expanding range of applications in patients with brain tumors, cerebral ischemia or stroke, carotid atherosclerosis, multiple sclerosis, traumatic brain injury, and epilepsy. These strategies may ultimately improve disease detection, therapeutic monitoring, and treatment efficacy especially in the context of antiangiogenic chemotherapy and antiinflammatory medications. The purpose of this review is to outline the current status of superparamagnetic iron oxide nanoparticles in the context of biomedical nanotechnology as they apply to diagnostic MRI and potential therapeutic applications in neurooncology and other CNS inflammatory conditions.

Ultrasmall superparamagnetic iron oxides (USPIOs): A future alternative magnetic resonance (MR) contrast agent for patients at risk for nephrogenic systemic fibrosis (NSF)?

Gadolinium (Gd) based contrast agents (GBCAs) in magnetic resonance imaging (MRI) are used in daily clinical practice and appear safe in most patients; however, nephrogenic systemic fibrosis (NSF) is a recently recognized severe complication associated with GBCAs. It affects primarily patients with renal disease, such as stage 4 or 5 chronic kidney disease (CKD; glomerular filtration rate <30 ml/min per 1.73 m(2)), acute kidney injury, or kidney and liver transplant recipients with kidney dysfunction. Contrast-enhanced MRI and computed tomography (CT) scans provide important clinical information and influence patient management. An alternative contrast agent is needed to obtain adequate imaging results while avoiding the risk of NSF in this vulnerable patient group. One potential alternative is ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, which provide enhancement characteristics similar to GBCAs. We review our experience in approximately 150 patients on the potential benefits of the USPIOs ferumoxtran-10 and ferumoxytol. We focus on central nervous system (CNS) MRI but also review imaging of other vascular beds. Safety studies, including USPIO administration (ferumoxytol) as iron supplement therapy in CKD patients on and not on dialysis, suggest that decreased kidney function does not alter the safety profile. We conclude that for both CNS MR imaging and MR angiography, USPIO agents like ferumoxytol are a viable option for patients at risk for NSF.

Potential for Differentiation of Pseudoprogression From True Tumor Progression With Dynamic Susceptibility-Weighted Contrast-Enhanced Magnetic Resonance Imaging Using Ferumoxytol vs. Gadoteridol: A Pilot Study

PURPOSE We evaluated dynamic susceptibility-weighted contrast-enhanced magnetic resonance imaging (DSC-MRI) using gadoteridol in comparison to the iron oxide nanoparticle blood pool agent, ferumoxytol, in patients with glioblastoma multiforme (GBM) who received standard radiochemotherapy (RCT). METHODS AND MATERIALS Fourteen patients with GBM received standard RCT and underwent 19 MRI sessions that included DSC-MRI acquisitions with gadoteridol on Day 1 and ferumoxytol on Day 2. Relative cerebral blood volume (rCBV) values were calculated from DSC data obtained from each contrast agent. T1-weighted acquisition post-gadoteridol administration was used to identify enhancing regions. RESULTS In seven MRI sessions of clinically presumptive active tumor, gadoteridol-DSC showed low rCBV in three and high rCBV in four, whereas ferumoxytol-DSC showed high rCBV in all seven sessions (p = 0.002). After RCT, seven MRI sessions showed increased gadoteridol contrast enhancement on T1-weighted scans coupled with low rCBV without significant differences between contrast agents (p = 0.9). Based on post-gadoteridol T1-weighted scans, DSC-MRI, and clinical presentation, four patterns of response to RCT were observed: regression, pseudoprogression, true progression, and mixed response. CONCLUSION We conclude that DSC-MRI with a blood pool agent such as ferumoxytol may provide a better monitor of tumor rCBV than DSC-MRI with gadoteridol. Lesions demonstrating increased enhancement on T1-weighted MRI coupled with low ferumoxytol rCBV are likely exhibiting pseudoprogression, whereas high rCBV with ferumoxytol is a better marker than gadoteridol for determining active tumor. These interesting pilot observations suggest that ferumoxytol may differentiate tumor progression from pseudoprogression and warrant further investigation.

Pseudoprogression of Glioblastoma after Chemo- and Radiation Therapy: Diagnosis by Using Dynamic Susceptibility-weighted Contrast-enhanced Perfusion MR Imaging with Ferumoxytol versus Gadoteridol and Correlation with Survival

PURPOSE To compare gadoteridol and ferumoxytol for measurement of relative cerebral blood volume (rCBV) in patients with glioblastoma multiforme (GBM) who showed progressive disease at conventional magnetic resonance (MR) imaging after chemo- and radiation therapy (hereafter, chemoradiotherapy) and to correlate rCBV with survival. MATERIALS AND METHODS Informed consent was obtained from all participants before enrollment in one of four institutional review board-approved protocols. Contrast agent leakage maps and rCBV were derived from perfusion MR imaging with gadoteridol and ferumoxytol in 19 patients with apparently progressive GBM on conventional MR images after chemoradiotherapy. Patients were classified as having high rCBV (>1.75), indicating tumor, and low rCBV (≤ 1.75), indicating pseudoprogression, for each contrast agent separately, and with or without contrast agent leakage correction for imaging with gadoteridol. Statistical analysis was performed by using Kaplan-Meier survival plots with the log-rank test and Cox proportional hazards models. RESULTS With ferumoxytol, rCBV was low in nine (47%) patients, with median overall survival (mOS) of 591 days, and high rCBV in 10 (53%) patients, with mOS of 163 days. A hazard ratio of 0.098 (P = .004) indicated significantly improved survival. With gadoteridol, rCBV was low in 14 (74%) patients, with mOS of 474 days, and high in five (26%), with mOS of 156 days and a nonsignificant hazard ratio of 0.339 (P = .093). Five patients with mismatched high rCBV with ferumoxytol and low rCBV with gadoteridol had an mOS of 171 days. When leakage correction was applied, rCBV with gadoteridol was significantly associated with survival (hazard ratio, 0.12; P = .003). CONCLUSION Ferumoxytol as a blood pool agent facilitates differentiation between tumor progression and pseudoprogression, appears to be a good prognostic biomarker, and unlike gadoteridol, does not require contrast agent leakage correction.

Qualitative Comparison of 3-T and 1.5-T MRI in the Evaluation of Epilepsy

OBJECTIVE MRI at 3 T, which has a higher signal-to-noise ratio than 1.5-T MRI, is potentially more sensitive and specific at delineating epileptogenic lesions and may influence management of refractory epilepsy. The purposes of the current study were to compare image quality of 3-T MRI with that of 1.5-T MRI in the evaluation of epilepsy and, in cases of focal epilepsy, to compare the two field strengths in terms of lesion detection and characterization. MATERIALS AND METHODS Retrospective review was performed on 50 sets of MR images of 25 patients who underwent both 3-T and 1.5-T brain imaging with a dedicated epilepsy protocol, including fast spin-echo T2-weighted, coronal FLAIR, coronal fast multiplanar inversion recovery, and 3D spoiled gradient-recalled echo pulse sequences. Parameters assessed were distortion and artifact, lesion conspicuity, gray-white matter differentiation, and motion. Each pulse sequence was graded on a 4-point scale. Reviewers performed qualitative assessments of the site of abnormality and the most likely diagnosis. RESULTS MRI at 3 T outperformed MRI at 1.5 T in all four parameters and was statistically superior (p < 0.05) to 1.5-T MRI in all categories except motion. On 3-T MRI, lesions were detected in 65 of 74 cases compared with 55 of 74 cases at 1.5 T (p = 0.0364), and lesions were accurately characterized in 63 of 74 cases compared with 51 of 74 cases at 1.5 T (p = 0.0194). The odds ratios showed identification of a focal epileptogenic lesion with 3-T MRI 2.57 times as likely as identification with 1.5-T MRI and accurate characterization of lesions 2.66 times as likely as characterization with 1.5-T MRI. CONCLUSION In evaluation of epilepsy, MRI at 3 T performed better than 1.5-T MRI in image quality, detection of structural lesions, and characterization of lesions. High-field-strength imaging should be considered for patients with intractable epilepsy and normal or equivocal findings on 1.5-T MRI.

Radiographic evaluation of trigeminal neurovascular compression in patients with and without trigeminal neuralgia.

OBJECT Neurovascular compression (NVC) of the trigeminal nerve is associated with trigeminal neuralgia (TN), but also occurs in many patients without facial pain. This study is designed to identify anatomical characteristics of NVC associated with TN. METHODS Thirty patients with Type 1 TN (intermittent shocklike pain) and 15 patients without facial pain underwent imaging for analysis of 30 trigeminal nerves ipsilateral to TN symptoms, 30 contralateral to TN symptoms, and 30 in asymptomatic patients. Patients underwent 3-T MR imaging including balanced fast-field echo and MR angiography. Images were fused and reconstructed into virtual cisternoscopy images that were evaluated to determine the presence and degree of NVC. Reconstructed coronal images were used to measure nerve diameter and crosssectional area. RESULTS The incidence of arterial NVC in asymptomatic nerves, nerves contralateral to TN symptoms, and nerves ipsilateral to TN symptoms was 17%, 43%, and 57%, respectively. The difference between symptomatic and asymptomatic nerves was significant regarding the presence of NVC, nerve distortion, and the site of compression (p < 0.001, Fisher exact test). The most significant predictors of TN were compression of the proximal nerve (odds ratio 10.4) and nerve indentation or displacement (odds ratio 4.3). There was a tendency for the development of increasingly severe nerve compression with more advanced patient age across all groups. Decreased nerve size was observed in patients with TN but did not correlate with the presence or extent of NVC. CONCLUSIONS Trigeminal NVC occurs in asymptomatic patients but is more severe and more proximal in patients with TN. This information may help identify patients who are likely to benefit from microvascular decompression.

Preoperative visualization of neurovascular anatomy in trigeminal neuralgia

OBJECT The authors report on a novel technique to identify neurovascular compression in trigeminal neuralgia (TN). Using 3D reconstructed high-resolution balanced fast-field echo (BFFE) images fused with 3D time-of-flight (TOF) magnetic resonance (MR) angiography and Gd-enhanced 3D spoiled gradient recalled sequence, it is possible to objectively visualize the trigeminal nerve and nearby arteries and veins. METHODS Magnetic resonance imaging was performed in 18 patients with unilateral TN using 3 sequences: BFFE, 3D TOF angiography, and 3D Gd-enhanced imaging. The images were imported into OsiriX imaging software; after their fusion, a 3D false-color reconstruction was produced using surface rendering. The reconstructed images objectively differentiate nerves and vessels and can be viewed from any angle, including the anticipated surgical approach. RESULTS Fifteen patients were predicted to have neurovascular compression on the symptomatic side (9 arterial and 6 venous compressions). All patients had a vascular structure that was identical in location and configuration to that predicted on preoperative analysis. The 3 patients without predicted compression underwent surgical exploration because they manifested the classic symptoms. As expected, exploration in 2 of these patients revealed no offending vessel. The third patient had a small vein embedded in the trigeminal nerve that was beyond the resolution of the 3D Gd-enhanced study. CONCLUSIONS Combining BFFE with MR angiography and Gd-enhanced MR images capitalizes on the advantages of both techniques, enabling MR angiography and contrast-enhanced MR imaging discrimination of vascular structures at BFFE resolution. This results in an unambiguous 3D image that can be used to identify the neurovascular compression and plan the surgical approach.

Evaluation of pseudoprogression in patients with glioblastoma multiforme using dynamic magnetic resonance imaging with ferumoxytol calls RANO criteria into question

BACKGROUND Diagnosis of pseudoprogression in patients with glioblastoma multiforme (GBM) is limited by Response Assessment in Neuro-Oncology (RANO) criteria to 3 months after chemoradiotherapy (CRT). Frequency of pseudoprogression occurring beyond this time limit was determined. Survival comparison was made between pseudoprogression and true progression patients as determined by using perfusion magnetic resonance imaging with ferumoxytol (p-MRI-Fe). METHODS Fifty-six patients with GBM who demonstrated conventional findings concerning for progression of disease post CRT were enrolled in institutional review board-approved MRI protocols. Dynamic susceptibility-weighted contrast-enhanced p-MRI-Fe was used to distinguish true progression from pseudoprogression using relative cerebral blood volume (rCBV) values. rCBV of 1.75 was assigned as the cutoff value. Participants were followed up using RANO criteria, and survival data were analyzed. RESULTS Twenty-seven participants (48.2%) experienced pseudoprogression. Pseudoprogression occurred later than 3 months post CRT in 8 (29.6%) of these 27 participants (ie, 8 [14.3%] of the 56 patients meeting the inclusion criteria). Overall survival was significantly longer in participants with pseudoprogression (35.2 months) compared with those who never experienced pseudoprogression (14.3 months; P < .001). CONCLUSIONS Pseudoprogression presented after 3 months post CRT in a considerable portion of patients with GBM, which raises doubts about the value of the 3-month time limit of the RANO criteria. Accurate rCBV measurement (eg, p-MRI-Fe) is suggested when there are radiographical concerns about progression of disease in GBM patients, regardless of any time limit. Pseudoprogression correlates with significantly better survival outcomes.

MRI Using Ferumoxytol Improves the Visualization of Central Nervous System Vascular Malformations

Background and Purpose— Central nervous system vascular malformations (VMs) result from abnormal vasculo- and/or angiogenesis. Cavernomas and arteriovenous malformations are also sites of active inflammation. The aim of this study was to determine whether MRI detection of VMs can be improved by administration of ferumoxytol iron oxide nanoparticle, which acts as a blood pool agent at early time points and an inflammatory marker when taken up by tissue macrophages. Methods— Nineteen patients (11 men, 8 women; mean age, 47.5 years) with central nervous system VMs underwent 3-T MRI both with gadoteridol and ferumoxytol. The ferumoxytol-induced signal changes on the T1-, T2-, and susceptibility-weighted images were analyzed at 25 minutes (range, 21 to 30 minutes) and 24 hours (range, 22 to 27 hours). Results— Thirty-five lesions (capillary telangiectasia, n=6; cavernoma, n=21; developmental venous anomaly, n=7; arteriovenous malformation, n=1) were seen on the pre- and postgadoteridol images. The postferumoxytol susceptibility-weighted sequences revealed 5 additional VMs (3 capillary telangiectasias, 2 cavernomas) and demonstrated further tributary veins in all patients with developmental venous anomalies. The 24-hour T1 and T2 ferumoxytol-related signal abnormalities were inconsistent among patients and within VM types. No additional area of T1 or T2 enhancement was noted with ferumoxytol compared with gadoteridol in any lesion. Conclusions— Our findings indicate that the blood pool agent ferumoxytol provides important information about the number and true extent of VMs on the susceptibility-weighted MRI. The use of ferumoxytol as a macrophage imaging agent in the visualization of inflammatory cells within and around the lesions warrants further investigation.

Comparative analysis of ferumoxytol and gadoteridol enhancement using T1- and T2-weighted MRI in neuroimaging.

OBJECTIVE Ferumoxytol, an ultrasmall superparamagnetic iron oxide particle, has been suggested as a potential alternative MRI contrast agent in patients with renal failure. We compared ferumoxytol to gadoteridol enhancement on T1- and T2-weighted MRI in CNS disorders to explore its diagnostic utility. SUBJECTS AND METHODS Data were collected from three protocols in 70 adults who underwent alternate-day gadoteridol- and ferumoxytol-enhanced MRI using identical parameters. Two neuroradiologists measured lesion-enhancing size and intensity on contrast-enhanced T1-weighted images in consensus. T2-weighted images were evaluated for the presence of contrast-enhanced hypointensity. Mixed model repeated measures analysis of variance determined differences between T1-weighted enhancement size and intensity for individual protocols and group. RESULTS After exclusions, 49 MRI studies in 29 men and 20 women (mean age, 51 years) were assessed. T1-weighted estimated enhancing sizes were different between agents (p = 0.0456) as a group; however, no differences were observed with untreated gliomas (n = 17) in two protocols (p = 1.0 and p = 0.99, respectively). Differences in T1-weighted enhancement intensity between agents were significant for the group overall (p = 0.0006); however, three-way interactions were not significant (p = 0.1233). T2-weighted images were assessed for contrast-enhanced hypointensity, observed in 26 of 49 (53%) ferumoxytol and zero of 49 (0%) gadoteridol scans. CONCLUSION Ferumoxytol may be a useful MRI contrast agent in patients who are unable to receive gadolinium-based contrast agents. Greater experience with a wider variety of disorders is necessary to understand differences in enhancement with ferumoxytol compared with gadolinium-based contrast agents, given their different mechanisms of action.