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?