MS lesions that smoulder

M
Frontiers | Significance and In Vivo Detection of Iron-Laden Microglia in  White Matter Multiple Sclerosis Lesions | Immunology
Iron Rims image from Frontiers

The characteristic feature of is multi-focal inflammatory activity; an infiltration of immune cells leading to loss of myelin and axons within these areas creating the appearance of round lesions.

The natural evolution of these lesions like any area of injury in the rest of the body and shrink to a certain degree overtime. A fraction, however, continue to smoulder. These so-called smouldering lesions have been linked to disease progression in MS and have attracted extensive interest from the MRI bods to discover what they mean.

At the microscopic level, these lesions contain an iron-based rim of immune cells called microglia and macrophages that can imaged (see figure below). They are found in 50-66% of MS lesions and in RRMS and progressive MS.

Smoldering' Rimmed Lesions in MS Linked to Worse Outcomes
Smoldering iron-rimmed lesion in MS (image from Medscape)

In a follow up study spanning 7 years, a group in Austria studied the evolution of these iron rims. They found that they were most prominent in the RRMS phase but persisted into the progressive phase. Initially, the iron builds up diffusely throughout the lesions, and then overtime are only retained in the macrophages and microglia at the chronic active lesion edges.

These rims have the potential to increase the size of the MS lesion; within their first year they grow slowly, at times fusing with nearby lesions becoming larger. This is opposite to that of non-iron rimmed lesions that generally shrink with time. Overall, however, you’d be glad to heat that the expansion of the iron-rimmed lesions is limited and do not continue to involve the whole brain. The largest one observed in this study measured at 36.5mm in diameter at the end of 7 years.

Volume dynamics of IRLs and non-IRLs. (A) Volume changes of IRLs (black) and non-IRLs (grey) over 7 years stratified into relapsing-remitting and secondary progressive multiple sclerosis, given as percentage relative to baseline, which was set to 100%. Mean values are plotted with 95% confidence intervals (bars). (B) Mean T1 relaxation times of non-IRLs (light grey), IRLs (dark grey) and NAWM (white) within a 1-year interval stratified into relapsing-remitting and secondary progressive multiple sclerosis and based on MP2RAGE relaxation maps. (C and D) Percentage of non-IRLs and IRLs with volume change at FLAIR-SWI over 7 years (C) and at MP2RAGE over 1 year (D) stratified into relapsing-remitting and secondary progressive multiple sclerosis. Definitions: growing, ≥10% volume increase; shrinking, ≤10% volume loss; stability, in-between compared to baseline. Numbers of analysed lesions are given in parentheses. P-values in A indicate separate volume developments within IRLs and non-IRLs. FU = follow-up; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.
Volume dynamics of IRLs and non-IRLs. (A) Volume changes of IRLs (black) and non-IRLs (grey) over 7 years stratified into relapsing-remitting and secondary progressive multiple sclerosis, given as percentage relative to baseline, which was set to 100%. Mean values are plotted with 95% confidence intervals (bars). (B) Mean T1 relaxation times of non-IRLs (light grey), IRLs (dark grey) and NAWM (white) within a 1-year interval stratified into relapsing-remitting and secondary progressive multiple sclerosis and based on MP2RAGE relaxation maps. (C and D) Percentage of non-IRLs and IRLs with volume change at FLAIR-SWI over 7 years (C) and at MP2RAGE over 1 year (D) stratified into relapsing-remitting and secondary progressive multiple sclerosis. Definitions: growing, ≥10% volume increase; shrinking, ≤10% volume loss; stability, in-between compared to baseline. Numbers of analysed lesions are given in parentheses. P-values in A indicate separate volume developments within IRLs and non-IRLs. FU = follow-up; RRMS = relapsing-remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis.

There is also waning of the iron rims themselves, with the maximum intensity visualized as soon as it was morphologically fully developed, suggesting that they become inactive overtime. But, as they are more destructive (see Figure 2A above) there may be merit in monitoring these closely outside of research settings. The sequences for this type of imaging don’t necessarily require a 7T MRI scanner and acquisitions can be made on lower intensity machines.

Abstract

Brain. 2021 Jan 23;awaa436. doi: 10.1093/brain/awaa436. Online ahead of print.

Long-term evolution of multiple sclerosis iron rim lesions in 7 T MRI

Assunta Dal-Bianco Günther Grabner Claudia KronnerwetterMichael WeberBarbara KornekGregor Kasprian Thomas Berger Fritz Leutmezer  Paulus Stefan Rommer Siegfried Trattnig Hans Lassmann Simon Hametner

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.

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Neuro Doc Gnanapavan

11 comments

  • Nice study with HPE/correlates. The problem is that 7T MRIs, approved for use in 2017 by the FDA in the USA are conspicuous by their absence at MAJOR university settings, let alone community hospitals. I would reckon that the lack of 7T MRIs in the UK is much more widespread. In the USA, it is reported that about 25-30 major Universities have them. So what does that mean for the rest of us ?

    Well, those ensconed in those large Universities get to write articles/garner awards/grants, etc and hypothesize while the rest of sheep, w no other options, read about these ‘findings’.

    Is there a possibility that the Federal Government would make a 14 million-dollar price tag (presumed price, according to an article I had read for a 7T MRI scanner) disappear by footing the bill itself and making sure that every single state in the US of A that has a University and which boasts as the best in that state, gets one in the name of ‘equity’ ? Then we have parity and everyone understands (or should understand) what the other person is talking about where 7T data are discussed. Otherwise the other guy is playing with a Butterfly (in table tennis lingo) and the rest of us are hacking it with a home-made blade. It doesn’t match up.

    • So the iron rims can be performed on 3T machines and even 1.5T MRIs.
      http://www.ajnr.org/content/early/2020/05/21/ajnr.A6547
      Every hospital should find this now accessible.
      The reasons to invest in a 7T machine are to characterise cortical lesions that a lot of young-onset MS may have with difficulties in cognition, for example. Cortical lesions are hardly visible in the lower Tesla machines.

      • Yes but cortical and subpial lesions, and central vein sign type lesion evaluations although also are possible on 3T, are much better visualized on 7T.

        The truth about 1.5 T and 3.0 T iron rim evaluations by a neuroradiologist is that no one comments about them !!!

        SWI at most university centers involving routine MRIs are just not done presumably because they consume time. To see iron at the edge or periphery of a lesion, SWI is perhaps the best, correct?

        • Yes, it’s a fused FLAIR/SWI image. The addition of SWI to the acquisition doesn’t add a significant time to the protocol. In fact a lot of trusts still do a ADC/DWI acquisition for MS that can be dropped if there is concern over scan times. We do do central vein imaging on our 3T scanners at Barts Health – Dr K pushed for this, and has been a useful addition to our MS imaging.

          • One of the draw backs of 7T is that if you have some claustrophobia – no chance.

          • Thnx for the tip !

            Obviously you guys are a cut above the fray as it were. You have an A1 MS team. Most MS centers have a two-person team, if that !

            Dropping sequences on MRI ? Again, Barts MS is different and dynamic!

    • With all due respect for the need for research, I am more interested if I should try to get a 7T scan as a patient with fairly diffuse scans. Any advantage for treatment decisions?

      • An interesting question, a 7T scan will be more informative as it would be more detailed. But, you will not be able to compare this with a 3T or 1.5T for the same reasons. Going forward, your scans will need to be on 7T machine. Having said this, I hear though the grapevine 7T with contrast picks up more enhancing activity – so even a single scan with contrast may prove to be more useful.

        • Thanks – The lack of comparability so far dissuaded me from pursuing this further. Might still discuss with my neuro when my annual scan comes up in summer. Maybe given the diffuse scans a case could be made.

          Not sure how repeated 7t availability would look like, either.

  • LONGITUDINAL MRI HISTORY OF LESION REPAIR BASED ON THE PRESENCE OR ABSENCE OF A 7T PARAMAGNETIC RIM
    Martina Absinta MD PhD, Govind Nair PhD, Pascal Sati PhD, Daniel S. Reich MD PhD
    National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, MD, USA

    In vivo monitoring of chronic inflammation and of
    repair/remyelination is crucial for the identification of new
    biological targets.
    • Paramagnetic rims on 7T susceptibility-based MRI
    pathologically identify MS lesions with smoldering
    inflammation at the lesion edge, remyelination failure, and
    often ongoing axonal degeneration.1-10
    • However, the long-term effects of rim persistence at the lesion
    level in vivo (e.g., slow expansion) and at the patient level (e.g.
    disability accrual) are still uncertain

    Persistent inflammation at the lesion edge is not only a major barrier for remyelination, but can exert ongoing damage to the
    surrounding tissue.
    ü Long-term lesion evolution (dichotomy):
    • rim+ lesions tend to remain stable or expand over time;
    • rim- lesions tend to shrink over time11
    ü Rim+ lesions = more likely to be destructive (higher 7T T1 values) -> in line with impaired early lesion repair8

    From actrims dont know if 2019 or 2020

    Nice post

    • It’s the future of MRI in MS – expect to see more and more on it this year with longer follow up.

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