Journal Club

MR Imaging of Relapsing Multiple Sclerosis Patients Using Ultra-Small-Particle Iron Oxide and Compared with Gadolinium

Dousset V, Brochet B, Deloire MS, Lagoarde L, Barroso B, Caille JM, Petry KG.
AJNR Am J Neuroradiol 2006;27:1000–5

Summary: The infiltration of hematogenous inflammatory cells as T cells, B cells, and macrophages across the bloodbrain barrier (BBB) is a key point in the development of multiple sclerosis lesions. Previous experimental MR investigations have applied new iron-based contrast media (ultra-small-particle iron oxide, USPIO) in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. These particles accumulate in phagocytic cells resulting in a signal loss on T2*-w images. By iron-labelling the migration of these cells to inflammatory central nervous lesions can be followed in vivo. The authors present the first clinical MR study in patients with MS applying both USPIO and gadolinium. After USPIO injection, 33 acute MS lesions in 9 patients showed USPIO uptake. Lesions were seen as high signal intensities on T1-weighted images and low signal intensities on T2-weighted images. Gadolinium enhancement was seen in 31 of these lesions in 7 patients. These 7 patients presented 24 gadolinium-enhancing lesions that did not enhance with USPIO. Two patients showed USPIO-enhanced lesions but no gadolinium-enhanced lesions. Taken together with earlier findings obtained in experimental models or in human stroke, the visualization of macrophage activity in vivo with USPIO characterizes a distinct cellular and inflammatory event of the dynamic process of MS lesion formation. The macrophage activity information obtained with USPIO is distinct and complementary to the increased BBB permeability seen with gadolinium.

Comment

This is the first clinical study demonstrating the feasibility of in vivo tracking of inflammatory cells in multiple sclerosis. Current MR-techniques in MS demonstrate unspecific tissue alterations like edema, demyelination, or disruption of the blood-brain-barrier. The infiltration of phagocytic cells in the brain represents an early and crucial step in the formation of MS lesions since these cells promote the ensuing tissue damage. By visualizing these cells in vivo, we may have a tool to early identify hyperacute inflammatory lesions. This may also be a new marker to initiate and monitor therapeutic interventions, which has already been shown experimentally [1].

In this study, USPIO and gadolinium enhancement were independent events, indicating a different pathophysiological background. Nine of 10 patients revealed cerebral USPIO enhancement, whereas one patient without a cerebral iron-enhancing lesion featured an iron-positive spinal lesion (personal communication). This indicates that ongoing infiltration of inflammatory cells is a frequent event in multiple sclerosis, even in the absence of a disrupted blood-brain-barrier. The precise clinical significance of gadolinium enhancement remains unknown. Although it is considered a predictor with moderate ability for the occurrence of relapses, it is not predictive for cumulative impairment or disability [2]. This discrepancy supports the idea that various pathogenic mechanisms are operative in the occurrence of relapses and in the development of long-term disability in MS. Therefore, some inflammatory gadoliniumenhanced lesions may not experience tissue destruction. The MR imaging of phagocytic cells may provide a stronger predictor for MS disease development than the imaging of increased BBB permeability. More longitudinal clinical studies are needed to determine the predictive meaning of both gadolinium- and/or USPIOenhanced lesions for impairment and disability.

Imaging of inflammation with iron particles not only applies to multiple sclerosis but offers a wide range of new diagnostic approaches. The information obtained with iron particles is completely different than with gadolinium since the disruption of the blood brain barrier is an independent event of the iron accumulation, which indicates the presence of intracellular iron in inflammatory cells. This principle could also be demonstrated in human stroke, brain tumours, and carotid artery disease [3]. Since in these disorders iron-labelled phagocytes are the crucial effector cells for tissue damage, we may have a surrogate parameter for both early diagnosis and treatment of acute inflammation.

References

1. Floris S, Blezer EL, Schreibelt G, et al. Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 2004;127:616–27.
2. Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet 1999; 353:964–9.
3. Corot C, Petry KG, Trivedi R, et al. Macrophage imaging in central nervous system and in carotid atherosclerotic plaque using ultrasmall superparamagnetic iron oxide in magnetic resonance imaging. Invest Radiol 2004;39:619–25.

(submitted: July 21, 2006)

M. Bendszus, Würzburg