Over the last years, it has become apparent that some MS brain lesions are more detrimental than others. One MS lesion subtype that is specifically attracting attention is the “iron rim containing lesion” or IRL. A ‘normal’ MS lesion represents inflamed brain tissue. Over time, the ‘normal’ MS lesion is likely to shrink a little bit because of the resolution of inflammation-induced swelling and the loss of myelin and axons. However, some lesions seem to be expanding rather than shrinking over time, albeit slowly. We can distinguish these bad lesion cops from less bad lesion cops (nu such thing as a good lesion) by looking at the presence of an iron rim with a special MRI sequence (susceptibility-weighted imaging). This iron rim corresponds to an edge of macrophages/microglia that are actively phagocytosing or eating myelin. As the destruction of oligodendrocytes and myelin leads to the release of their iron content, this binge eating leads to piling up iron. Consequentially, these IRLs are more destructive with a tendency to leave black-holes, which we know are associated with more loss of axons.
There is now a new study that provides interesting longitudinal data on these IRLs in 33 pwMS. The study was also able to document the appearance of some new IRLs. In the study, there were 16 new IRLs in 6/33 pwMS during follow-up. Interestingly, 10/16 new IRLs were seen in 2/6 patients which were both very early in their disease course. When a new IRL was formed, iron accumulated diffusely in the lesion. Subsequently, the iron became organised as a rim around the lesion and over time the iron rim (but not the lesion itself) could disappear. As many IRLs were already present at study onset, the study did not allow to document whether gadolinium-enhancement and thus florid inflammation preceded the formation of these lesions. These observations imply that you do not necessarily develop more IRL’s when living longer with MS. Some of the lesions that we label as ‘normal’ MS lesions might have been IRLs in a previous life. Hence, there is a continuum between chronically active IRLs and inactive lesions.
Unfortunately, it is not possible (yet) to visualise the iron rims on the routine brain scans we do in the context MS follow-up; visualising the iron rim is still in a research phase. Nonetheless: new data, new wanderings on the topic:
First, IRLs clearly provide real-time information about the destructiveness of a chronic active MS lesions. When they expand locally, they might be the underlying substrate for progression and thus new or expanding disability. An IRL in a motor pathway can cause progressive weakness down one side of the body. However, it is currently unclear if these IRLs are only locally destructive or whether they also mark more widespread neurodegeneration which would potentially result into an increase of neurofilament levels (= brain debris marker) or thinning of the retina measured by OCT. In other words: Do we need to monitor and target them separately?, or do they correlate with other markers of neurodegeneration in MS?
The key second question to solve is what triggers the formation of these iron rims: Does an IRL always appear after an inflammatory brain insult (i.e. gadolinium enhancement)? In this situation, the microglia would be responding to something in the surrounding tissue that is activating them, and they are basically doing their job by clearing this trigger. Or can they appear spontaneously in regions that have never been inflamed before? The latter is less likely based on the current data but would point to an intrinsic dysfunction of the microglia (and would be difficult to treat).
Third, a philosophical question that applies to many things in life: how can we get rid of it when it’s already there. Currently available DMT’s could potentially prevent the formation of new IRLs by preventing the appearance of new inflammatory lesions. However, if IRLs are already present at baseline, it is unlikely for DMTs to have a big impact. DMT’s namely work on B/T cells while the rim is full of macrophages. The available data on Ocrevus showed that the drug has only a very limited effect on the destructive nature of existing (iron rim) expanding lesions. If an individual has more IRLs at baseline, do we manage expectations about our ability to control their disease with a DMT? Would it be advantageous to refer them for aHSCT or Lemtrada instead of Ocrevus?
Altogether, IRLs are a more destructive lesion subtype that is present early in the MS disease course. When they are present, it becomes very difficult to label someone as a real NEDA or ‘no evidence of disease activity’, irrespective of other factors. This means that even if there are no entirely new lesions on MRI and no clinical relapses, there would be still a fair chance of disease progression. Unfortunately, there are still a lot of unknowns about how to “trim the iron rim”, especially DMT-wise, making it difficult to use the marker in practice. To be continued in the next decade!
Disclaimer: Please note that the opinions expressed here are those of Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Brain. 2021 Apr 12;144(3):833-847. doi: 10.1093/brain/awaa436.
Assunta Dal-Bianco 1, Günther Grabner 1 2, Claudia Kronnerwetter 3, Michael Weber 3, Barbara Kornek 1, Gregor Kasprian 3, Thomas Berger 1, Fritz Leutmezer 1, Paulus Stefan Rommer 1, Siegfried Trattnig 3, Hans Lassmann 4, Simon Hametner 1Affiliations expand
- PMID: 33484118
- DOI: 10.1093/brain/awaa436
Recent data suggest that multiple sclerosis white matter lesions surrounded by a rim of iron containing microglia, termed iron rim lesions, signify patients with more severe disease course and a propensity to develop progressive multiple sclerosis. So far, however, little is known regarding the dynamics of iron rim lesions over long-time follow-up. In a prospective longitudinal cohort study in 33 patients (17 females; 30 relapsing-remitting, three secondary progressive multiple sclerosis; median age 36.6 years (18.6-62.6), we characterized the evolution of iron rim lesions by MRI at 7 T with annual scanning. The longest follow-up was 7 years in a subgroup of eight patients. Median and mean observation period were 1 (0-7) and 2.9 (±2.6) years, respectively. Images were acquired using a fluid-attenuated inversion recovery sequence fused with iron-sensitive MRI phase data, termed FLAIR-SWI, as well as a magnetization prepared two rapid acquisition gradient echoes, termed MP2RAGE. Volumes and T1 relaxation times of lesions with and without iron rims were assessed by manual segmentation. The pathological substrates of periplaque signal changes outside the iron rims were corroborated by targeted histological analysis on 17 post-mortem cases (10 females; two relapsing-remitting, 13 secondary progressive and two primary progressive multiple sclerosis; median age 66 years (34-88), four of them with available post-mortem 7 T MRI data. We observed 16 nascent iron rim lesions, which mainly formed in relapsing-remitting multiple sclerosis. Iron rim lesion fraction was significantly higher in relapsing-remitting than progressive disease (17.8 versus 7.2%; P < 0.001). In secondary progressive multiple sclerosis only, iron rim lesions showed significantly different volume dynamics (P < 0.034) compared with non-rim lesions, which significantly shrank with time in both relapsing-remitting (P < 0.001) and secondary progressive multiple sclerosis (P < 0.004). The iron rims themselves gradually diminished with time (P < 0.008). Compared with relapsing-remitting multiple sclerosis, iron rim lesions in secondary progressive multiple sclerosis were significantly more destructive than non-iron rim lesions (P < 0.001), reflected by prolonged lesional T1 relaxation times and by progressively increasing changes ascribed to secondary axonal degeneration in the periplaque white matter. Our study for the first time shows that chronic active lesions in multiple sclerosis patients evolve over many years after their initial formation. The dynamics of iron rim lesions thus provide one explanation for progressive brain damage and disability accrual in patients. Their systematic recording might become useful as a tool for predicting disease progression and monitoring treatment in progressive multiple sclerosis.