Advanced pwMS skills: Reading between the lesions!

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For many pwMS, the annual MRI scanning has become an anxiety-provoking routine. The goal is to compare the most recent MRI with the previous one. Similar to a sepia or black-and-white filter on your camera, we use different MRI filters to improve visualisation of certain brain structures. A T2-sequence is the MRI filter we use to visualise (new) MS lesions. If new lesions appear between scanning timepoints, this is an indication of MS disease activity. However, an active, currently inflamed lesion also lights up on the T1-sequence taken after injection of gadolinium contrast. This is what we call a contrast-enhancing lesion or CEL. 

The fact that new lesions can appear without pwMS experiencing new symptoms is daunting and confusing at the same time. Moreover, there will often be no more than one new and/or active lesion, making interpretation even more difficult: when mentally processing these findings, pwMS are often torn between “one is none” versus “my brain is on fire”. Based on the scan verdict, decisions need to be made about disease-modifying treatments: stopping, switching or continuing. This has implications for family planning, travel plans, vaccination response, infection risk etc. Therefore, it’s essential for pwMS to understand the significance of one or more new MS lesions. The following facts might be helpful when making up your mind. 

https://www.visitlimburg.be/nl/wat-te-doen/reading-between-lines-gijs-van-vaerenbergh-pit

Contrast-enhancing vs. non-enhancing new lesion? 

Contrast-enhancement of an inflamed lesion lasts for about 1 to maximum 6 weeks, which is a relatively short time window compared to the usual time between MRI scans. When the acute inflammation wanes, the CEL becomes a normal T2-weighted ‘new lesion’ and does not light up on the T1 sequence after contrast. In other words, if you have a CEL, you also automatically also have a new T2 lesion that will be visible long beyond the 6-week window.

Source: https://radiopaedia.org/

How often do new lesions appear?

In a study performing weekly MRI scans for 12 weeks in 5 relapsing, untreated pwMS who had a relapse in the preceding 6 months, there was on average 1.1 entirely new CEL per weekly MRI scan, and thus about 12 new CELs over the 12 week scanning period. In a cohort of 115 relapsing, untreated pwMS who had at least one CEL at study entry, there were on average 17 new CELs at 6 months follow-up. In a group of 66 relapsing, untreated pwMS who had no CEL at study entry, there were 13 CELs at 6 month follow-up. Similar numbers were reported for secondary progressive pwMS. All these data stem from ‘old-school’ MRIs with 1.5 tesla magnets, and the numbers might increase if they were repeated with our newer, higher resolution, 3 tesla MRIs. Some of these lesions might go unnoticed when performing MRI scans less frequently, especially when the lesions overlap with lesions that were already there, or if they are very small. It’s important to remember that once the contrast enhancement disappears, the T2-filter itself does not allow to distinguish between a lesion and a recently active lesion. 

Interestingly, the rate at which new lesions appear decreases as people get older. We believe that this has nothing to do with disease duration but is instead age-driven. The older you get, the less likely it becomes to exhibit signs of active inflammation. In a recent study, assessing the occurrence of CELs in untreated pwMS, 51% of <30 year old, 37% of 31-40y, 36% of 41-50y and 22% of 51-60 year old pwMS had contrast-enhancing lesions. As expected, but now also objectively demonstrated, similar frequencies were seen for people with progressive MS. The reason for this phenomenon is the natural ageing of the immune system leading to changes in lymphocyte function and development. 

How many lesions give rise to clinical symptoms?

It is expected that about one in ten new brain lesions leads to clinical symptoms. For the spinal cord, this is about one-third of new lesions. Three-quarters of clinical spinal cord relapses are associated with a new MRI lesion in a location appropriate to the symptoms, underscoring the fact that the biological basis of a relapse is almost always a new lesion. The reason that lesions can go unnoticed is partly because the majority of our brain is involved in the mere processing of information rather than hard-core functions such as vision, sensation and motor strength. These ‘soft’ brain regions do not have a direct impact on your daily functioning, and other areas can compensate for the part that is inflamed. Another reason might be that the part of the brain that is undergoing inflammation may not be sufficiently stunned to generate symptoms. 

Do lesions remain present forever? 

All T2-hyperintense lesions tend to persist over time. although they often shrink very slowly. This, however, does not exclude a lesion from remaining chronically active. About 15 to 20% of the CELs remain chronically inflamed after enhancement disappears and turn into slowly expanding lesions (SEL), which often have what’s known as a ‘paramagnetic iron rim’ that can be seen on MRI. Chronic active lesions are not highlighted with post-contrast T1 sequences because the gadolinium contrast tends not to leak out of the bloodstream in those areas, unlike in new active lesions. Instead, they are best seen with a very strong MRI magnet (7 tesla, not widely available in clinical practice yet) and different MRI filter (called ‘susceptibility sequences’), where they are called PRLs or ‘paramagnetic rim lesions’. (Paramagnetic is the term used when something in the brain, in this case iron, attracts the magnetic field created by the MRI system.) There is a lot of work going on to figure out how we can detect PRLs using MRI systems that are widely available in clinics.

To sum it all up, pwMS can have a non-enhancing lesion without paramagnetic rim, a non-enhancing lesion with paramagnetic rim and an enhancing lesion. The latter two lesion subtypes are considered ‘active’ lesions, and are associated with increases in neurofilament levels reflecting inflammation-driven damage to the nerve processes known as axons. 

Source: Absinta et al. JAMA Neurol. 2019;76(12):1474-1483

How many of the new lesions lead to permanent tissue loss? 

Tissue lost can be visualised best on a T1-sequence, even without gadolinium contrast. The colour of healthy brain tissue on T1 sequences is an intermediate level of grey. If active new lesions appear very dark on T1, it means there is demyelination, which is what happens to all MS lesions in the acute phase. However, when the dark signal remains very dark after the acute phase, it indicates there has been tissue loss: myelin has not repaired, and axons have died off because of the inflammation. Looking over all pwMS across the lifespan, about 2 of 3 lesions will remain dark, whereas the other third will recover most or all of their normal ‘grey’ intensity through the process of remyelination. However, this is very variable among pwMS, and for some people more than 2 out of three lesions might result into tissue loss whereas for others it’s less. The fact that MRI can detect lesion repair using T1 sequences means that we will have a good way of testing new medications that might help the brain remyelinate.

Source: https://radiopaedia.org/

Twitter: @SmetsIde @gavingiovannoni and @danielsaloreich

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and dr. Daniel Reich and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry, Barts Health NHS Trust or the United States National Institutes of Health.

The information in this blogpost is based on the following articles:

Koch et al. Neurology 2021;97:e1334-e1342. doi:10.1212/WNL.0000000000012603

Thorpe et al. Neurology 1996 Feb;46(2):373-8. doi: 10.1212/wnl.46.2.373

Giovannoni et al. Eur Neurol 2000;44:222–228 DOI: 10.1159/000008241

Sormani et al. JNNP 2001;70:494–499 doi: 10.1136/jnnp.70.4.494

Sethi et al. MSJ 2017 Mar;23(3):464-472. DOI: 10.1177/ 1352458516655403

Kolb et al. Annals of Neurology 2021;90:612–626 doi: 10.1002/ana.26194

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Ide Smets

23 comments

  • Few questions –
    1. Does prognosis correlate with the proportion of lesions ended up as tissue loss?
    2. Are proportion of lesions become tissue loss correlates with age?
    3. How much % of function loss (cognition and physical) are explained by lesion load?

    Thank you Ide

    • 1. Yes, but there are many more variables that weigh on prognosis. Also the mere number of T2 lesions, location of the lesions, timing of treatment initiation etc are important factors.
      2. Good question, I don’t think this known. If this is true, the lesser amount of inflammatory lesions at older age would be compensated by the higher rate of axonal damage.
      3. In a meta-analysis of 13 clinical trials the treatment effect on new/enlarging or enhancing lesions explained 61% of the effect on disability progression measured by EDSS, which is only the tip of the iceberg. So lesions do explain a large chunk of disability in MS.

      • Thank you Ide, meta-analysis of clinical trials to me only explains changes within a two-year interval. Is there analysis focus on longer-term outcomes – or do yu expect things will change when we look at long term progression?

        • There are also other more observational studies that show that lesion accrual in the first five years of an individual’s disease course is highly determinant of disability progression after 15 years.

    • Difficult question, and we don’t know exactly. One of the factors that might influence this ratio is your ability to demyelinate. This is where there’s definitely a window for remyelination therapies as they could potentially increase this ration from one in three to two in three for example.But they need to be administered in the acute phase, during the relapse, or otherwise the damage is done…

  • Are responses to DMT homogeneous across lesions? My current hospital does conduct MRI spine in addition to brain (in absence of symptoms) in those with spinal lesions. In addition, contrast-enhanced scans are not performed, so it is difficult to comment on whether NEDA is truly achieved. There is also no comment on brain volume and certainly not SELs. Whilst long-term impact of highly efficacious DMTs is not defined as yet; I’d really like to better understand how my disease is evolving (or not) and wondered if you feel strongly on any of the above. I fully understand limitation on resources, scanning departments etc. Perhaps I should pursue a 2nd opinion just to get these answers and all being well continue with my current plan which is funded by our wonderful NHS.

    • It sounds like a good policy from your hospital. If there are no new lesions, and you are clinically stable you are likely to be NEDA. It is not necessary to know about enhancement to define NEDA. It is true that the current clinically defined protocols miss out on some of the disease activity. On the other hand, DMTs most likely do not impact on SEL and individual measurements of brain volume are difficult to interpret – there are only informative at group level. So at this stage we can measure but not immediately act on these additional MRI parameters.

  • Thanks a lot!

    One question: If lesion only stay enhancing 1-6 weeks and then remain as new ‘regular’ T2 areas, why do we even bother with gadolinium (I am not too sure that doing gadolinium yearly is all that healthy, TBH)?

    • Gadolinium is most useful in the initial work-up, because at that moment there is no previous scan available that allows to give any indication on timing of the lesions. Afterwards, it’s mainly useful if people with MS have a high lesion load. Because then it’s not always easy to distinguish new T2 lesions from already exiting T2 lesions, especially as there is sometimes overlap between new and old.

  • Excellent post thank you 🙂
    A few thoughts:

    Re MRI, guess that in future
    a computer/machine/algorithm will be better at comparing between two scans than the human eye (ie radiologist)? As long as the MRI scans written in the same ‘language’?

    Wonder how many pwMS receive an annual MRI?

    Re age
    So dogma re stop MS dmts in older age groups is (generally) correct?

    Sad anecdotal story: a friend wSPMS age late 50s recently had an MRI to check if suitable for siponimod. Apparently neurologist said that as only one small lesion found on spinal cord it wasn’t worth starting treatment! Quite why neuro offered scan I don’t know, sounds like he’s ticked a box then tried to justify his lack of action.

    You’ve also answered another thing I’ve been unsure about:
    nfl (whether from peripheral blood or csf) cannot distinguish between SEL/PRL ‘slow burn’ active versus contrast lymphocyte active.

    Would you expect to see more nfl in RRMS during a relapse than in progressive MS?

    • I’m convinced that computer algorithms would do a better job at comparing scans over time. However, computer algorithms have difficulties with mechanical artifacts which are inherent to scanning on different scanners. These will always need interpretation from a radiologist.

      Older pwMS have less newer lesions but that does not mean no lesions. It’s definitely true that the balance between risks and benefits changes at older age, but that we should not consider treatment in older pwMS.

      Yes, I would expect to see more NfL in RRMS during a relapse.

  • What’s a better way to describe lesion load? Number of lesions & location or Volume (cubic mm) & location? Or they both tell stories?

    Say if someone has 10 small lesions and 20 tiny lesions, comparing to having just 10 lesions but higher volume, at similar locations, which one is likely to have a higher disease burden?

    • The most objective would definitely be lesion volume, and this is the measure that has been linked to disability accrual in most trials.
      So better to have 10 small ones than 4 big ones.

    • Yes, but not all black holes on T1 are permanent. Acute demyelination also results into black holes while this does not reflect permanent tissue damage.

  • Really informative post.
    I didn’t understand at the time (and still don’t) why my initial MRI scan after optic neuritis wasn’t with Gd enhancement (ordered via ophthalmologist). To my mind that could have potentially negated the lumber puncture and second MRI with Gd enhancement.

    • I guess this was more a screening kind of scan. Not all individuals with ON have or will develop MS, and by performing a blank MRI you have very valuable information about prognosis. But obviously when lesions are seen on this scan, there is definitely added value in gadolinium.

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