ClinicSpeak: NEDA-5

Should NEDA-5 be the new normal? #ClinicSpeak #MSBlog #MSResearch

“To make a difference to the way we treat and manage MS we need to remove our blinkers. I have already discussed the issue of the EDSS and how it has misshaped the field of MS and what we need to do to get away from an EDSS-centric view of disability. The next thing we need to do is reassess the role of the MRI in the management of MS. The other day I heard from a patient that their previous neurologist did not believe they had had a relapse as  their MRI did not show any new lesions. It is obvious to me that this particular neurologist had delegated clinical acumen and common sense to an MRI scanner. Of course you can have a relapse with an MRI that does not show new lesions. The resolution of an MRI scan is probably in the order of 4-5 mm and any lesion smaller than this will not be detected; a microscopic lesion in an eloquent site can cause a relapse that no MRI will detect. Then there is the issue of inter slice gap. The MRI is essentially a series of 2D images stacked together to create a pseudo-3D image. Clearly if the gap between these images is relatively large you could miss lesions between the slices. Finally, there is the problem with the MRI reader. It is very easy to miss new lesions and even with expert neuroradiologists the interrater agreement is far from 100%. In other words the MRI and the neuroradiologist are far from perfect.”

“Since we have starting measuring spinal fluid neurofilament levels it has become clear to me at how poor MRI is at measuring the impact of MS. Several patients have had stable MRI scans (NEDA-2), but feel they are not doing well or progressing. When we have performed a lumbar puncture on these patients to measure their CSF neurofilament light chain levels we find them to be raised. In other words MRI is missing some MS pathology. What we now need is a randomised clinical trials done in MSers with stable MRIs (no new or Gd-enhancing lesions) with raised CSF neurofilament levels to either escalate, or switch, DMTs and to compare their outcome to those who stay on their existing therapies. In other words to test the concept of NEDA-5; treat-2-target of normalising CSF neurofilament levels. It is clear that getting NEDA-4 into clinical practice is proving harder than one would have envisioned. There are simply too many problems with using brain atrophy in clinical practice.”

“May be we can leapfrog brain atrophy and simply target CSF neurofilament levels. Could this be our new normal? Thank you for rising to the challenge and responding to our survey on the concept of the new normal. the following are the preliminary results of the survey.”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • "Several patients have had stable MRI scans (NEDA-2), but feel they are not doing well or progressing."

    Therefore, lesion burden should not be an endpoint in clinical trials and all drugs out in the market should be re-evaluated.

  • Is there anyway of detecting neuro-filament levels in a simple blood test? Repeated LPs for disease monitoring is not a great prospect. Otherwise NEDA-5 sounds like a promising idea.

  • Didn't see that survey. What a strange term to obsess about – "normal". I find it hard to imagine anyone who has – for example – suffered perfectly natural PMS (as in pre-menstrual tension) feeling that striving for "normal" is anything but an academic endeavour. People are not robots. I wouldn't even describe my car as "normal" – who knows what bit will fall off next.

    • Then they are a load of old suits who have need to retire….
      Anyone one who thinks it is OK for disease to progress is doing a diservice for people in their care!

  • Another challenge for me is the length between relapses. I have had only 2 relapses within the last 5 years. I had one in March 2011 and then another one in March of 2015. When I do finally relapse I relapse badly. I was suspected of MS in 2011 (I am OCB negative,) but that wasn't confirmed until I relapsed in 2015. My EDSS is already at a 3 within 5 years, making my MS quite aggressive. The problem that I see is I won't know if a drug is even working until the 4 year market if the frequency of relapses stays constant.

    So in theory, I could have been in a 2 or 3 year clinical trial and the drug would have been considered a success. Without any treatment I am NEDA-3 anyways. Do they take this kind of information into account during these trials? In follow up studies it would show that the drug failed at the 4 year mark, but it still would have shown as a success as NEDA-3. So how in my case do I even know if a drug is even working, until I hit the 4 year mark. assuming relapses stay at the same frequency? How do clinical trials account for this? How rare is it to have a relapse rate as low as mine with no treatment?

    Any insight would be awesome. Thanks guys and keep up the good work.

  • I'm another example of my neurologist telling me i could not have possibly had a relapse as the MRI showed no evidence. I've had MS nearly 20 years,2 to 3 relapses a year before starting Tysabri and been stable with no evidence of relapse or activity for the last 5 (until now). I know my body and my MS and wish that my evidence of relapse held just as much weight. I think it's important in the overall management.
    Thank you for writing this blog as it had reassured me that an MRI is fallable and could well have missed something in this instance.

    • MR scans aren't fallible as such, it's just that the results generated have to be interpreted with care and the limitations of the technique borne in mind at all times. Cortical (grey matter) lesions pretty much can't be detected with standard clinical scanning and we know that 'normal appearing' white matter on standard sequences on MRI is very often abnormal when looking at the chemical make-up of the brain with more advanced techniques (though these are easier to apply when comparing large groups of normal people with those with MS than they are in a single person, just like when comparing brain volumes).

      So abnormal brain can absolutely be there without it being demonstrated on the images (or seen by the reading radiologist).

  • And yet we discount patients' wishes regarding aggressive treatment because they're not, at the particular time of the mri, showing new lesions….

By Prof G



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