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.
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.
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.
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.
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.
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