Neurofilaments have it – the story behind smouldering MS


Recently, smouldering MS or chronically active MS lesions have become an entirely new entity in disease progression. They are characterized by a rim of activated microglia/macrophages in both RRMS and progressive MS and are linked to more aggressive disease. These lesions are visible on a type of MRI called susceptibility-based imaging and individuals with MS can have 0, 1-3, or ≥4 of these lesions. Whether the number of these lesions are associated with neuroaxonal damage is unknown, and measuring NfL (neurofilament light chain levels) in these individuals may go some way to answering this.

In a multi-center study originating from Basel they did exactly this. The investigators found that ≥2 smouldering lesions (PRL, paramagnetic rim lesions) was linked to higher levels of serum NfL (see figure below) in both RRMS and progressive MS without acute disease activity. This was independent of age, T2 lesion load (number of MS lesions on the MRI), and treatment. Those with greater than ≥2 smouldering lesions had a serum NfL level above the 80th percentile. Moreover, even though there were a greater number of T2 lesion in those with ≥2 smouldering lesions, the number and volume of T2 lesions didn’t relate to measured serum NfL level – which makes me wonder what T2 lesions on an MRI actually depict at a pathological level? I don’t think of T2 lesion measures in MRI as a nonentity, but that static correlations are probably not representative of the evolving T2 lesions in the MS brain.

Figure: Paramagnetic rim lesions strongly and uniquely predict serum neurofilament light levels. (A) Estimated effects of T2-lesion load, MS subtype, EDSS, oral and very-high-efficacy DMT, and the presence of ≥2 PRL, as compared to 0–1 PRL, on age-corrected sNfL percentile levels. (B) The same model is shown using a 3-group PRL categorization (0, 1–3, and ≥4 PRL). Platform DMT are glatiramer acetate and interferon beta-1a/b; oral DMT, teri-flunomide, dimethyl fumarate, and fingolimod; very-high-efficacy DMT: ocrelizumab, rituximab, natalizumab, mitoxantrone.

The only reservation I have about this work is that I have always considered NfL to be a bulk marker of neuronal damage, and for it to be sensitive to focal damage from these lesions all the way to the blood is stretching matters. However, having said this more work is needed in different cohorts to test this hypothesis.


Neurology. 2021 Jun 4;10.1212/WNL.0000000000012326. doi: 10.1212/WNL.0000000000012326. Online ahead of print.

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis

Pietro Maggi Jens Kuhle Sabine SchädelinFranziska van der Meer Matthias Weigel Riccardo Galbusera Amandine Mathias Po-Jui Lu Reza Rahmanzadeh Pascal Benkert Francesco La Rosa Meritxell Bach Cuadra Pascal SatiMarie Théaudin Caroline Pot Vincent van Pesch David Leppert Christine Stadelmann Ludwig Kappos Renaud Du PasquierDaniel S Reich Martina Absinta Cristina Granziera

Objective: To assess whether chronic white matter inflammation in multiple sclerosis (MS) patients – as detected in-vivo by paramagnetic rim MRI lesions (PRL) – is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuro-axonal damage.

Methods: In 118 MS patients with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathological evaluation was performed in 25 MS lesions from 20 additional autopsy MS patients.

Results: In univariable analyses, participants with ≥2 PRL (“PRL ≥2”, n=43) compared to those with ≤1 PRL (“PRL 0-1,” n=75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p<0.001) and higher MS disease severity scale (MSSS median, 4.3 and 2.4; p=0.003). In multivariable analyses, sNfL percentile levels were higher in PRL ≥2 cases (βadd: 16.3; 95% CI: 4.6-28.0; p<0.01), whereas disease-modifying treatment (DMT), EDSS, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRL (n=30; βadd: 30.4; 95% CI, 15.6-45.2; p<0.01). Subsequent multivariable analysis revealed that PRL ≥2 cases had also higher MSSS (βadd: 1.1; 95% CI, 0.3-1.9; p<0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p=0.004 and p=0.0002, respectively).

Interpretation: Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in non-acute MS patients, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.

About the author

Neuro Doc Gnanapavan


  • Thanks for the post.

    When trials begin (eg Sizomus) testing drugs to tackle smouldering MS, what are going to be the best markers of success eg normalising NfL levels, getting rid of OCBs, or seeing no SELs on MRI scans (I’m assuming SELs can be picked up by MRI)?

    “smouldering MS or chronically active MS lesions have become an entirely new entity in disease progression. They are characterized by a rim of activated microglia/macrophages”. Do we have any idea what is activating the microglia/macrophages? How do we know that they aren’t doing what they should be doing ie cleaning up dead / dying material?

    • Hi SID,
      Of course this is about smart trial design based on multi-parameter biomarker designs: 1) outcome oriented, 2) treatment targeted. NfL will be outcome oriented, whilst OCBs treatment targeted, for example.
      I suspect it is a bit of both, oxidative damage but also microglia/macrophages walling off the disease process and clearing up some of the debris. It would be nice to understand this before marching into it with new drugs!

    • Hi John,
      NfL (CSF) test has been part of routine care for years across Europe. In Canada, Ontario offers the test. We have received samples from USA, South America, Saudi Arabia. If you would like the test performed you need to speak to your neurologist. If you’re in the UK and are having difficulty accessing the test the London Independent is a private hospital that also sends us samples.

      • Ah right, I thought it was sort of new, and it was still in its infancy for the clinic. I know drugs trials now test the levels.



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