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- What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent
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- Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL
Eighteen patients received both gadolinium-based contrast agents GBCAs and 1 of 2 USPIO contrast agents ferumoxytol and ferumoxtran 24 hours apart, which allowed direct comparative analysis. Conventional T1- and T2-weighted MRI were acquired before and after contrast administration in all patients, and perfusion MRI for relative cerebral blood volume rCBV assessment was obtained in all 9 patients receiving ferumoxytol.
Unlike GBCA, ultrasmall superparamagnetic iron oxide USPIO nanoparticles act as blood pool agents immediately after administration, but they are later taken up by inflammatory cells e.
The study was sponsored by the NIH, and all participants provided written informed consent. Exclusion criteria have been reported previously. The imaging protocol consisted of 3 consecutive days of MRI scans. Gadoteridol was injected as an IV bolus at a dose of 0. Ferumoxtran preceded ferumoxytol, with similar MRI properties. Manufacturing of ferumoxytran was discontinued when ferumoxytol became available. Ferumoxtran 2.
All contrast dosages have been used in previous human and preclinical studies. The 11 patients who received ferumoxtran were unable to have perfusion-weighted imaging PWI since this contrast agent cannot be given via rapid IV bolus because of the risk of anaphylactoid reactions.
The total ferumoxytol dose mg was diluted in 17 mL of saline. Then, patients received the remainder of the dose mg over 15 minutes.
All patients were followed for 1 month to note possible adverse reactions. All images from each patient were evaluated in a matched-pair fashion by the same neuroradiologist. Image assessment consisted of the following steps: 1 quantification of the total number of enhancing brain lesions on the T1-weighted gadoteridol-enhanced scan compared with the noncontrast T1-weighted scan; 2 quantification of brain lesions on T1- and T2-weighted scans 24 hours after USPIO administration compared with noncontrast T1- and T2-weighted scans; and 3 evaluation of postcontrast USPIO and GBCA scans for leptomeningeal disease.
All first-pass DSC-MRI data were processed using Lupe Lund University Perfusion Evaluation, Sweden perfusion image analysis software and the simple singular value decomposition—based calculation method as described by Ostergaard et al.
Arterial input function was determined from the middle cerebral artery contralateral to the enhancing lesion.
Color-coded relative cerebral blood volume rCBV maps were created on a voxel-wise basis. Normal white matter within the contralateral hemisphere was used as the internal reference standard; rCBV values were calculated by dividing the maximal rCBV in the enhancing lesion by that of contralateral normal-appearing white matter.
Two patients showed localized leptomeningeal enhancement on post-USPIO imaging around the primary tumor site, but only one of these showed comparable leptomeningeal enhancement with GBCA. We did not see diffuse leptomeningeal enhancement in any case. Eight of those 9 patients had enhancing lesions amenable for rCBV calculation, whereas one posttherapy patient did not.
As an example of intense iron labeling using USPIO-based contrast compared with GBCA, we evaluated a year-old woman who presented with progressive memory loss and confusion table 1 , patient 1. After USPIO administration, iron uptake by inflammatory cells appears profoundly hypointense in the centers of lesions figure 1E that are otherwise hyperintense on noncontrasted T2-weighted MRI figure 1D.
The patient underwent stereotactic needle biopsy of the right frontal T2-hypointense lesion seen on the postferumoxytol scan, which confirmed the suspected diagnosis of diffuse large B-cell lymphoma.
MRIs from case 1. A T1-weighted MRI without contrast agent. Note, however, that the relatively minimal mass effect for lesion extent and incomplete enhancing rims are more typical of demyelinating disease.
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D T2-weighted MRI without contrast shows multifocal confluent areas of T2 hyperintensity in white matter. A year-old woman presenting with several weeks of fatigue and confusion was referred with a provisional diagnosis of CNSL table 1 , patient 2.
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Neurologic examination showed gait instability. MRI showed an area of T2 signal abnormality and enhancement in the right deep frontal white matter and basal ganglia extending into the hypothalamus on post-GBCA T1-weighted images figure 2, A and B.
After nondiagnostic lumbar puncture, a stereotactic needle biopsy was performed, targeting the enhancement on the post-GBCA T1-weighted scan. Histologic evaluation showed only gliosis. She underwent repeat stereotactic needle biopsy targeting the area of T2-weighted hypointense signal, which revealed demyelination with intact axons, suggesting a diagnosis of multiple sclerosis.
A—C MRIs from case 2.
What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent
C T2-weighted MRI, 24 hours after administration of ferumoxytol, shows a markedly hypointense area suggesting the area of maximal iron uptake arrow , which was the target of a second biopsy revealing demyelination. Arrows show areas of intense iron uptake on both sequences. F—I MRIs from case 4.
Biopsy confirmed diagnosis of tumefactive demyelination. NSF is an idiopathic and potentially fatal complication that may occur after gadolinium administration in patients with renal insufficiency. The proposed mechanism for development of such fibrosis involves decreased renal clearance of GBCA resulting in deposition in the skin and other organs. The end result is multiorgan fibrosis causing skin contractures, intense pruritus, and potential cardiac and respiratory failure.
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Images acquired before treatment figure 2D showed a left-frontal enhancing mass consistent with PTLD, which was confirmed with biopsy. A year-old woman presented with a right homonymous hemianopsia and a rapidly expanding left occipital lesion on standard MRI with GBCA table 1 , patient 5; figure 2G. A craniotomy was planned for resection of the lesion. Because the GBCA-based imaging suggested that the enhancing mass was high-grade neoplasm but low blood volume was noted upon perfusion imaging, the decision was made to instead perform a needle biopsy.
The biopsy revealed destruction of myelin with intact axons, and CSF studies showed oligoclonal bands with an increased immunoglobulin G synthesis rate. The neurology team then managed her tumefactive demyelination.
Noncontrast MRI revealed an expansile lesion in the pons. He underwent imaging before and 24 hours after the administration of ferumoxytol figure 3, A and B ; USPIO contrast images showed intense USPIO uptake in the pons, which correlated with hyperintense T2-weighted signal abnormality on precontrast imaging figure 3C. Rather than proceed with a potentially morbid biopsy, follow-up MRI at 6 weeks and 6 months were obtained, and showed that the lesion had regressed.
A presumptive diagnosis of acute demyelinating encephalomyelitis was made by neurologic consultants. MRIs from case 5. A Precontrast T1 imaging shows mild pontine expansion and slightly decreased T1 signal throughout.
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C An axial T2-weighted precontrast image shows patchy nonspecific increased T2 signal within the pons arrow. T2-weighted images 24 hours after USPIO administration showed a markedly hypointense signal suggesting intense iron uptake by lymphoid cells figure 4B and the diagnosis was confirmed with biopsy.
The patient tolerated PTLD treatment well and was neurologically stable. One month after treatment, she developed a deep vein thrombosis; MRI without contrast was performed before initiation of anticoagulation.
T2-weighted MRI showed focal hypointensity figure 4C concerning for brainstem hemorrhage. This resulted in placement of an IV filter instead of anticoagulation therapy. However, it is important to recognize that acute brainstem hemorrhage was highly unlikely given the patient's stable neurologic examination. The findings were thought to represent residual USPIO contrast, given relatively diminished similar pattern of signal abnormality to prior ferumoxytol-enhanced MRI with overall decreased mass effect.
Noncontrast head CT performed within 24 hours confirmed no hyperdensity in the brainstem to suggest recent hemorrhage. Surveillance MRI scans without contrast at 3 months showed continued decrease in T2 signal hypointensity figure 4D. MRIs from case 6.
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A Pretreatment image without contrast shows increased T2 signal abnormality and mild mass effect in the pons and right cerebellum.
B T2-weighted image 24 hours after initial ferumoxytol imaging shows intense iron uptake arrow. Reprinted with permission from the American Journal of Roentgenology.
T2 hypointense areas arrow were initially misinterpreted as asymptomatic brainstem hemorrhage but likely represented residual iron-labeled inflammatory cells because a noncontrast CT showed no hyperdensity in the brainstem not shown. D Punctate T2 hypointense signal remained arrow , but was diminished 3 months after ferumoxytol administration. Second, ferumoxytol-based DSC PWI may offer discrimination of inflammatory diseases such as demyelination from neoplastic disorders.
Preclinical studies in animal models have shown via histologic analysis that hypointense foci on delayed 24 hours T2-weighted MRI in the brain correspond with iron staining of phagocytic cells such as macrophages , and efforts to confirm these findings in human biopsy specimens are ongoing. Determining whether localization is primarily within inflammatory phagocytic cells intracellular or interstitial due to slower extravascular leakage compared with GBCA remains an ongoing project.
DSC-based perfusion studies in this series were based only on ferumoxytol because it can be given via IV bolus injection without the risk of anaphylactoid reactions due to mast cell degranulation that were relatively common with earlier iron oxide nanoparticle preparations such as ferumoxtran This situation may be particularly problematic for renal transplant patients, who are at risk of both NSF and PTLD, given immunosuppression.
Ferumoxytol-enhanced MRI offers a diagnostic opportunity without the attendant risks.
Using iron oxide nanoparticles to diagnose CNS inflammatory diseases and PCNSL
However, increased use of USPIO-based imaging agents over time will surely result in awareness of this possibility. Noncontrast head CT may also resolve any question of hemorrhage, as in the case presented here.
The authors thank Aliana Culp for her assistance with word processing for the manuscript. Supplemental data at www. Farrell and B. Hamilton: critical revision of the manuscript for important intellectual content, analysis and interpretation. Rimely, M.
Nasseri, and S. Gahramanov: analysis and interpretation, acquisition of data. Lacy: acquisition of data. Frenkel, N. Doolittle, and P. Jacobs: critical revision of the manuscript for important intellectual content. Neuwelt: critical revision of the manuscript for important intellectual content, study supervision.
Farrell, B. Hamilton, E. Nasseri, S.
Gahramanov, C. Lacy, E. Jacobs report no disclosures.