Do you know your neurofilament level?

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In my opinion, if the latter half of the 21st century in MS was defined by something it was the realization that neurofilament levels introduce clarity into individual disease courses that was not possible with clinical descriptors or MRI alone.

The days of wandering what your MS is going to be like in the future may well be over as new tools such as neurofilaments become more readily available.

This letter published in the Journal of Internal Medicine demonstrates that blood neurofilament levels followed-up by 13.5 years (on average 6.2 years) were associated with loss in cortical volume (surface of the brain) despite stable T1 lesion volumes (essentially areas of hypointensity on MRI brain scans in MS – please see slide below).

Previously, a limited analysis of the fingolimod data (Phase 3 study) demonstrated that the effect of fingolimod on lowering neurofilament levels captured 60% of its effect on brain volume loss, whilst active lesions only captured 45%.

Multiple Sclerosis Disease Overview & Current Management Strategies - ppt  download
From slide player published by Jaidyn Steves

Having said all of this, this evidence for blood neurofilaments is based on a group effect. In this letter the authors point out that “NfL levels were around 50 times higher in CSF compared with plasma (median plasma NfL levels [IQR]: 12.1 pg/mL [8.4–18.5], median CSF NfL levels [IQR]: 665 pg/mL [375.2–1347.2])“. Spot CSF NfL levels therefore remain the more informative test in deciphering who is highly active compared to blood neurofilaments. However, this may change as we learn more about individual fluctuations in blood neurofilament.

Letter

J Intern Med. 2021 Apr 19. doi: 10.1111/joim.13286. Online ahead of print.

Neurofilament light chain as a marker for cortical atrophy in multiple sclerosis without radiological signs of disease activity

B V IneichenT MoridiE EwingR Ouellette A ManouchehriniaL Stawiarz D FerreiraS J MuehlboeckJ KuhleE WestmanD Leppert J Hillert T Olsson I Kockum F Piehl T Granberg

Dear Editor,
Neurofilament light chain (NfL) appears to reflect nerve-damaging inflammatory disease activity and neuroaxonal degeneration in multiple sclerosis (MS) . However, to what degree NfL can provide additional information not conveyed by magnetic resonance imaging (MRI) monitoring is less clear. Hence, it is still a matter of debate whether NfL mainly reflects ongoing focal neuroaxonal damage or whether it also can be used to assess diffuse, smouldering neurodegeneration for which both clinical MRI monitoring and conventional MRI monitoring have low sensitivity. Resolving this issue would help to understand the potential added value of assessing NfL in clinical practice and whether plasma NfL measurements can sub-stitute for more invasive CSF sampling. The objective of this study was to investigate the relationship between plasma and CSF NfL concentrations and imaging measures, as well as with volumetric changes in strategic brain structures, in a well-characterised incident MS cohort with long-term
prospective follow-up.

Disclaimer: Please note that the opinions expressed here are those of the author NDG and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary University of London.

About the author

Neuro Doc Gnanapavan

23 comments

    • Blood neurofilaments are currently mainly in research because it’s still not possible to say what the variations in it are at an individual level. The only centre that I’m aware that has started using them is University of Ottawa, Canada. I’m hoping that this would be sorted out over the next year in most MS centres.

  • NDG,

    Thanks for your post.

    As a layman, my questions are:

    what do NfL levels tell us about what MS is ie is it one disease (as some suggest) and what drives the damage;

    are NFL levels reflecting smouldering disease (which Prof G suggests is the real MS) or the immune response (focal inflammation) [or both];

    are some treatments showing a better impact on reducing NfL levels ie they are having more impact at reducing the damage to brain / spinal cord cells?

    Are NfL levels being used in trials of potential neuro-protective therapies eg simvastin, Alpha Lipoic Acid?

    Thanks.

    PS apologies for the number of questions – the dog wanted a walk at 6am and on my return I looked at the Blog and saw a post that isn’t Covid related. NFL testing looks a promising area.

    • Hi Sid,

      NFL reflects both inflammation and neurodegeneration (this includes smouldering MS). By lowering this you are effectively reducing the damage (if you get rid of the inflammation you also reduce the damage to the underlying neurones).
      Definitely the MS-STAT study will be measuring this, as I know Tom the research fellow has done this analysis numerous times. I don’t know about lipoic acid though.

        • Yes the same. Not surprisingly the most highly active treatments reduce NfL by most.
          You may have already seen Dr Schmierer is doing a study called CLADRIPLAS at RLH where elevated NFL qualifies you for s/c cladribine?
          In some hospitals – I have heard a trial of rituximab being given with elevated levels.

          • An Ocrevus trial reported at the AAN where NfL is one of the measures being used to assess effectiveness.

            https://index.mirasmart.com/AAN2021/PDFfiles/AAN2021-002261.html

            “At the start of the ENSEMBLE study, most participants had higher-than-normal levels of a protein called neurofilament light (NfL) in their blood, which is indicative of damage to the nervous system. After a year of treatment, patients’ NfL levels were mostly within the range that is seen in the general population.”

        • No one knows exactly what is causing the damage in MS after memory B-cells are wiped out. ENSEMBLE data will help to establish an understanding of if B-cells are wiped out early, how much of the smoldering process will be controlled. The data looks very promising to me at year 1, I hope at year 5, 10 and 20 they will look the same or even better. I see the smoldering process as a process slowly accelerate before B-cells are wiped (hit the break), and then it slows down.

  • I had mine done via LP. It said slightly raised / moderate disease activity. Honestly, I had no idea what that meant or what to reference it against.
    Once you’ve had NFL measured from LP is it possible to get it checked via blood in the future rather than constant LPs (not fun)?

    • Hopefully that would be the idea. As the CSF is the closest fluid next to the brain it would be most reflective of what is happening in the brain. So if there are doubts about the blood level it will need to be re-checked. The initial CSF reading is used to see what the risk of progression is and the correct/appropriate treatment is considered.

  • I had a Kappa Light Chain free serum test and got a result of 10.3 mg/L. The reference range was 3.3-19.4 mg/L.
    I am so confused as all of the research articles use different units of measurement so I still do not know where I stand. Any input?

    • Hi RA,
      Kappa Light Chain’s are a different test entirely and look at a specific portion of the antibody that is produced by immune cells – very different neurofilaments which are neuronal proteins. Kappa light chains are used to monitor a condition called multiple myeloma that produce vast quantities of antibodies, but can be elevated in MS (mostly in the CSF though) as those with MS can also produce elevated quantities of antibodies.

        • It is called neurofilament test (if this is what your question is about?) If you live in Europe, the Karolinska, Basel, and Gothenburg all provide these routinely as part of their clinical practice.

  • The neurologist I see annually dismissed neurofilament tests when I asked him about them last year. He said they were a way for the London hospitals (the only place the analysis can be performed??) to make money and the results would not help him to change his treatment plan (which, in my case, with inactive secondary progressive MS is to prescribe nothing) so what was the point in knowing if brain loss was occurring over time.

    • I’m sorry to hear that, two years ago at ECTRIMS at the meeting round up as the biggest recent development in the field of MS. Every MS clinical trial coming out is performing CSF and/or blood neurofilaments. Unfortunately, not everyone is a convert (I refer to the adoption curve in Technology, which is worth reading about).

    • It’s pretty well-established that anti-inflammatories modify all stages and types of the disease. Even interferon-beta modifies progressive ms if you monitor for a long enough period of time. If your neurologist isn’t prescribing you anything you should consider finding a new neurologist.

      • “It’s pretty well-established that anti-inflammatories modify all stages and types of the disease.”

        It is…?
        Why then did prof G post that Barts treats only if there are signs of active inflammation…And that they view all DMT and HSCT as active only against inflammation and if they can’t find any then they can’t offer any treatment.

  • Hopefully NfL in the blood will be used as a bio marker in MS, which is much needed. This along with higher T MRI and OCT can provide a better picture of what is going on besides conventional MRI. Thanks

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