I have recently posted on why you can have MS and have a normal MRI or a very low lesion load. I made the point that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip of the tip of the iceberg and that most of MS pathology is hidden from view with conventional MRI. To capture this pathology we need to use unconventional imaging techniques or look at end-organ damage markers, i.e. whole brain, or preferably grey matter, volume loss or atrophy. Another option is serial CSF or possibly peripheral blood neurofilament levels. At least the end-organ damage markers will capture the end-result of MS pathology; the loss of neurones and axons.
In another recent blog post, I explained how someone with MS can still be deteriorating despite being NEDA (no evident disease activity). The NEDA here is referring to focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind this worsening despite being NEDA could be driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is modifiable by our current DMTs. Therefore I think we should reserve the term smouldering MS to this process, i.e. one that is modifiable by current DMTs.
The really important question this raises is when you treat someone a DMT and they become NEDA how do you know they don’t have smouldering MS and would benefit from being escalated to a more effective DMT? One commentator asked specifically about cladribine.
‘If a patient was treated with cladribine and was rendered relapse and MRI activity free how can we be sure that this patient did not have smouldering MS?’
This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. We may then be able to answer this question. However, this won’t necessarily tell us if escalating people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab will result in them doing better than them simply waiting for their smouldering MS to become overtly active MS before making a switch in their treatment.
A point has been made that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease. I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT in particular with alemtuzumab or HSCT appear to be in very longterm remission and may even be cured of their MS (please read my previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree with you and this is why I have proposed doing a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence.
What this post is telling me is that by taking an MRI-centric view of MS we may have lulled ourselves into a false sense of security. In other words, an MRI worldview of MS has framed, and continues to frame, our perspective of MS and has created a cognitive bias. Dare I call it an MRIscopic bias?
What is the point of looking for smouldering MS if you can’t do anything about it? You can’t escalate treatment under current treatment guidelines so why bother.
Why bother about anything? If we want to maximise lifelong brain health then we have to switch the shredder off. Why would you want to leave the shredder active if can at least try and switch it off
testing123.
ProfG
I can’t see the anonymous option
Just enter anonymous as your name and post.
A must read for all neurologists. This is were we are today. We are treating relapses, not MS. We need to look closer to innate activation for neurotoxicity and neurodegeneration. We know so little at the moment.
However, are NFL levels capable of detecting this kind of neurodegeneration?
We also need to understand why relapses and lesions stop expressing at a certain point. Noone ask this question. It probably hides useful answers. Biotin can cause relapses to PPMS patients. Is it because it lessens neurotoxicity? We need to know.
Your statement on biotin caught my attention Anon, then I found this:
http://n.neurology.org/content/90/15_Supplement/P5.348
Would be grateful for Prof G or MD’s opinion.
I am aware of this report and the potential of biotin to increase disease activity. However, these are small numbers and will need to be confirmed in large studies. It is interesting that biotin, a potential remyelinating agent, may increase MS disease activity. I wonder if this is a class effect and that all remyelinating agents will do the same. We have always maintained that there is little logic in promoting remyelination in the absence of an effective anti-inflammatory agent to prevent recurrence of the autoimmune attack against the new myelin.
But if remyelination could cause MS activity to increase why then Glatiramer Acetate (Copaxone) wouldn’t do the same, since it relies on a composition of amino acid copolymers that would mimic the composition of the myelin sheath ?!
And if remyelination would increase MS activity, what would this mean, that myelin is the “target antigen” of autoimmunity in MS?!
As for the text, I also think about it, how to know if I’m indeed NEDA even the pictures of the MRI exam showing nothing. I still look at the CSF analysis as indispensable, I’m trying to convince my neuro that I do to check for the presence or not of neurofilaments. But it’s very difficult to discuss this with doctors, they are the specialist, we até patients, so there is a very “thin” line between who determines the path to be followed in the treatment …
GA is anti-inflammatory and will reduce or prevent a new ‘autoimmune attacks’ on the new myelin.
You should be able to ask the doctor what your options are for treatment. Be in charge of the thin line. Best.
” I wonder if this is a class effect and that all remyelinating agents will do the same.”
If it is myelin the target of MS.
They have been trying for many years to find that antibody to myelin to no avail. PPMS patients did not have a response to their myelin before.
Is myelin causal or related?
Could it be that certain HERVs are activated causing both an innate
https://www.ncbi.nlm.nih.gov/pubmed/26068187
and an adaptive immune response and we are targeting only the adaptive one?
That the attacks of the adaptive are towards HERVs and not myelin?
And the innate keeps working to eliminate HERVs and it accomlishes so when it reaches PMS but to reach that goal it has created such a neurotoxicity that is destructive to the brain? A similar theory has been proposed for Alz. after all the failed attempts to target amyloid b plaques.
We are seeing the tree and lose the forest.
https://www.ncbi.nlm.nih.gov/pubmed/29307292
Very interesting. Surely, if this effect – of triggering relapse activity – is corroborated, it says something important about MS pathology. But the effect may have nothing to do with myelin itself, but rather some other component, molecule or cell involved in the complex biochemistry of repair?
Perhaps this is one of the things that set people like me wPPMS apart – failure of repair?
Perhaps biotin’s (side) effects help elucidate repair and relapse processes one day. But it may still not reveal much about what triggers MS damage in the first place…
Hi, I started taking biotin last spring/early summer (for menopausal hair loss) and since summer I feel that I my ms has got worse,particularly my legs,I have just read this piece about biotin ! Does this mean that the biotin could poss have made my ms worse and not the heatwave that we suffered last summer ! .
I am not a dr but it I doubt it. It needs a tremendous amounts of Biotin to have any effect on MS. Also, relapses can be good news for PMS.
Anon, you state “Also, relapses can be good news for PMS.”
May I ask where you obtained this information / impression?
It does not fit with my experience at all.
Or many others
Progressive patients with active inflammation (relapses) have better outcomes to treatment, both DMTs and HSCT. Also, activity can make them eligible for DMTs that otherwise would not be able to get. Of course relapses should not be left untreated and should be prevented.
Looks like I may have crossed onto the other side:-)
I do not have access to the full text of this paper:
https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25463?af=R
Can someone from Team G post the results subset per treatment (Sample size and Number of conversions to SPMS)?
Thank you
Do you take private patients ? Who think they might have MS?
As a second opinion?
ProfG does not do private practise
Ben Turner does
I implore people to stop using private healthcare: it’s killing the NHS