Iron and Non-Iron-Related Characteristics of Multiple Sclerosis and Neuromyelitis Optica Lesions at 7T MRI

Discussion

Early differentiation of NMO from MS is crucial for optimal management clinically.^1,2 Although the recent availability of commercial testing for antibodies to Aquaporin-4 water has facilitated differentiation of NMO from MS, a correct diagnosis still remains challenging, particularly in those patients with NMO with multiple brain lesions on MR imaging. Many patients with NMO are still misdiagnosed with MS.²⁵ Hence, development of newer imaging biomarkers that can enable objective separation of these 2 diseases is warranted. Our analysis of the morphologic and structural features of MS and NMO supratentorial lesions by using multicontrast 7T MR imaging helps to further differentiate the 2 conditions and provides insight into lesional pathology in vivo. We found that iron deposition within a lesion (hyperintense signal on QSM) distinguished patients with MS from those with NMO with a sensitivity of 90.5% (95% CI, 69.6%–98.8%) and a specificity of 100% (95% CI, 83.9%–100%). Analysis of the signal intensity of lesions on GRE, SWI, and QSM sequences allowed us to divide all lesions into 4 patterns, of which 2 were iron-enriched and 2 were non-iron-enriched (Table 2). A characteristic feature of MS was the variety of lesion types observed: All patients with MS had lesions of >1 type, though most lesions were of pattern A, while all NMO lesions were of 1 type only (pattern A).

Using phase imaging and transverse relaxation rate (R2*) mapping on high-field MR imaging, prior studies have assessed the iron content of MS lesions qualitatively^11,12,26 and quantitatively.²⁷ However, many confounding factors are associated with these imaging techniques, including dependence on orientation and distribution of susceptibility sources that may influence the heterogeneity of phase and R2* and thereby render these images less reliable and quantifiable. QSM, on the other hand, provides more robust and quantitative evaluation of magnetic susceptibility sources such as iron, myelin, and calcium that are present in normal and diseased brain tissues.²⁸ Moreover, susceptibility is a physical quantity that is independent of imaging parameters and has the potential to distinguish and quantify different susceptible tissues.²⁹ In the present study, a recently²³ described susceptibility-weighted imaging and mapping method was used to reconstruct QSM from 3D-SWI, providing susceptibility values from different tissue compartments with high accuracy.³⁰

Our findings on 7T MR imaging that not all MS lesions have iron deposition are consistent with the earlier, lower field studies.⁹ Iron deposition may vary among individual lesions on the basis of their age and inflammatory status. We observed 4 morphologically distinct patterns of MS lesions, 2 of which were considered iron-enriched. Most non-iron-enriched MS lesions were hyperintense on GRE-T2*-weighted images and isointense and thus inconspicuous on QSM (pattern A). This pattern could be plausibly attributed to varying degrees of demyelination, edema, micronecrosis, and gliosis in chronic inactive lesions. A minority of non-iron-containing lesions demonstrated hyperintensity on both GRE-T2* and QSM images (pattern B), suggesting more acute and extensive demyelination (loss of diamagnetism, but less magnetic susceptibility effect than iron deposition) and inflammation compared with pattern A lesions. Because no tissue specimens were available to perform histopathologic/histochemical analysis from our patients, our interpretation of the imaging features was based on the prior correlative imaging and histopathologic studies.^11,12 More work is needed to ascertain the pathologic significance of susceptibility changes.

Iron-laden MS lesions with hyperintensities on QSM were of 2 patterns: iron either deposited in the center core (nodular iron-laden lesions, pattern C) or in a ringlike fashion at the lesion edge (pattern D). Previous histochemical studies showed that iron deposits were present in a subset of chronic, demyelinating active MS lesions.^11,12 The molecular pathways for iron accumulation in MS lesions are still not fully understood; however, several possible biologic mechanisms, such as iron-rich oligodendrocyte debris, iron-sequestered microglia or macrophages, and products of local microhemorrhages following venule wall damage may contribute to iron deposition.^14,15 On 3T MR imaging, Chen et al¹⁸ observed lower QSM values from acute enhancing lesions (small susceptibilities) and increased QSM values from nonenhancing lesions (high susceptibilities). This observation suggests that lesion susceptibility measured by QSM is a useful biomarker for monitoring MS disease activities. Perhaps, the preponderance of non-iron-containing lesions in MS in our study is because they were imaged long after their formative stage.

Most iron-laden lesions in our study were ringlike. Histopathologically, it has been observed that maximum accumulation of iron occurs at the edges of classic, reactive, slowly expanding chronically existing MS lesions.¹¹ In these reactive lesions, demyelination and oligodendrocyte destruction occur in a zone of variable size at the lesion border. Thus, iron-containing myelin and oligodendrocytes gradually decreased from the perilesional regions toward the lesion centers. Additionally, iron-containing microglia and macrophages that are mainly located at the edge of chronic reactive lesions undergo microglial dystrophy leading to a variable degree of iron deposition within the different compartments of the MS lesions.^11,12 Moreover, iron-laden MS lesions were well-circumscribed with well-defined margins while non-iron-laden lesions had poorly defined margins and were generally larger. The reason for this observation is not clearly understood; however, it might be because of accumulation of iron-enriched microphages or microglia cells in the iron-laden lesions or more activity associated with these lesions.

An interesting observation to emerge from our study is that the probability of finding a small venule in the center of lesions depends on the lesion pattern. All of the iron-laden MS lesions, 100% (patterns C and D), and 84% of presumed extensive demyelinating lesions (pattern B) were traversed by central venule. However, only 56% of non-iron-containing pattern A lesions had a central venule. We hypothesize that iron-containing and extensively demyelinating lesions are chronologically “younger” than the non-iron-containing pattern A lesions and, therefore, are more likely to indicate the presence of central vein. The pattern A lesions are more chronic, and a central vein may become occluded at this stage.

Only a few studies have reported QSM values from MS lesions and even fewer used 7T MR imaging combining different signal patterns on various sequences. In a 3T MR imaging study, Chen et al¹⁸ reported QSM values from MS lesions at various evolutionary stages. Investigators observed QSM values of ∼38 ppb from early-to-intermediary-aged nonenhanced iron-laden MS lesions. Slightly lower QSM values (∼30 ppb) were observed from iron-laden lesions in another study.¹⁹ In close agreement with these prior studies,^18,19 the mean QSM value in iron-laden lesions in our study was ∼44 ppb. QSM increases are seen in demyelination and iron deposition, but because iron is strongly paramagnetic, the QSM values due to iron deposition were higher than those due to loss of myelin. The susceptibility of myelin is only slightly more diamagnetic than that of CSF; therefore, a voxel completely packed with WM fibers would be expected to undergo a maximal susceptibility increase at complete demyelination (loss of diamagnetism). Therefore, susceptibility increases beyond those observed for CSF derive from sources other than demyelination.²⁸ Because ferritin, hemosiderin, and breakdown products of hemorrhage make up for a substantially high susceptibility effect, we hypothesize that higher QSM values from pattern C and D lesions further support the notion that the susceptibility of these lesions is caused predominantly by their iron content. On the other hand, pattern B lesions that also showed hyperintense signal on QSM were presumably associated with extensive demyelination, but not iron deposition, which explains why QSM values of pattern B lesions are lower than those of patterns C and D as indicated by the receiver operating characteristic analysis (Fig 5).

Another interesting observation was that only 70% of the iron-laden lesions demonstrated hypointense signal on GRE-T2*-weighted images, whereas 98% of the lesions showed hypointensity on SWI, despite similar section thickness and in-plane resolution for both of these images. In accordance with previous studies,^31,32 our observation suggests that SWI is more sensitive to susceptibility effects than GRE-T2*-weighted images, probably because SWI combines information both from phase and magnitude images to ascertain the local susceptibility changes among neighboring tissues, whereas susceptibility contrast on GRE-T2* is mainly dependent on a combination of spin-spin relaxation (T2) and magnetic field inhomogeneity. We believe that inclusion of phase information renders SWI more sensitive to susceptibility effects than GRE-T2* images.

There were some limitations to the current study. Most of the patients with MS had a diagnosis of relapsing-remitting MS. To obtain a more comprehensive understanding of the evolution of MS lesions by using multicontrast imaging, future studies would need to include patients with different types of MS (clinically isolated syndrome, secondary- and primary-progressive MS). Our patients with NMO had similar kinds of “nonspecific” subcortical lesions. A number of other kinds of NMO-specific lesions have been described³³ but were not seen in our series. Another limitation of the current study was that R2* or T2* mapping was not performed; these sequences may provide additional quantitative information for the characterization of NMO and MS lesions.