smouldering MS – Page 3 – Prof G's MS Blog Archive

Do you want a cure?

MSers want a cure. However, even if we have an MS cure in hand we may not prevent or reverse progressive disease. How can this be?

Focal inflammation damages nerves in two ways. It can shred and destroy nerve fibres as part of the initial inflammatory stage (acute neurodegeneration) or it can damage nerves and leave them functioning, but the resulting damage primes them to die off in the future; I call this delayed neurodegeneration.

The mechanisms that result in delayed neurodegeneration of nerves or smouldering MS are many and include innate immunity (hot microglia), energy deficits (mitochondrial dysfunction), excitotoxicity (calcium overload), free radicals (oxygen and nitrogen radicals), premature ageing, intrathecal plasma cell production of pathogenic autoantibodies, etc.

Clearly, anti-inflammatory drugs that prevent new lesions formation, such as natalizumab, alemtuzumab and ocrelizumab, will not be able to prevent the delayed neurodegeneration from previous inflammatory lesions. What has happened in the past has happened; i.e. the water under the bridge analogy. So if you have relapsing MS and have had a lot of inflammatory activity in the past that have damaged many nerve fibres, even if you go onto a highly effective DMT that renders you NEDA, it is not going to prevent the ongoing loss of nerve fibres that are primed to die off from previous inflammation in the future. This is why did the PROXIMUS trial and are promoting the OXO trial; add-on neuroprotective drug to try and modify the delayed die-off of neurons and axons.

What protects you from entering the clinically-apparent secondary progressive phase of the disease is reserve capacity, i.e. the surviving healthy nerve fibres in nerve pathways keep you functioning normally. I suspect that MSers, who have been treated with highly-effective DMTs and have now become secondary progressive, had a low reserve capacity and a large number of damaged nerve fibres that had been primed to die off in the future. In other words, they were treated with DMTs too late to prevent SPMS. This is why we keep pushing the message ‘early effective treatment’ is the only way to prevent secondary progressive MS.

There are two conclusions to be drawn from these observations; (1) it is best to have your MS treated effectively early in the disease course to maximise your reserve capacity, and (2) we need additional add-on neuroprotective therapies to target the delayed neurodegenerative processes referred to above. The latter includes avoiding or reversing factors that prematurely age the nervous system.

The ageing hypothesis of progressive MS is a major factor that underpins our Brain Health campaign, which targets non-specific factors that have been associated with more rapid progression in MS (smoking, co-morbidities, lack of exercise, infections, etc.).

So unless you are rendered NEDA early in the course of your disease it may not prevent you from entering the progressive phase of the disease, i.e. it will not be the panacea you want. In addition, our licensed DMTs don’t kill long-lived plasma cells that continue to make intrathecal (within the CNS) antibodies that my drive progressive MS. The exception may be natalizumab. There are several reports of MSers on natalizumab losing their OCBs (oligoclonal bands or antibody bands). It now emerges that plasma cells live in a ‘niche’ or home and that to keep them in the niche they use the VCAM-1-VLA-4 adhesion molecule interaction. Natalizumab disrupts this interaction and hence it is plausible that natalizumab may reduce the life expectancy of intrathecal (inside the CNS) plasma cells. If this proves to be the case natalizumab may still have the edge on the other DMTs in this regard.

To target plasma cells, which are long-lived, we will need add-on therapies. This is high on our list of priorities and we are starting the SIZOMUS trial to test a therapy for myeloma (malignant plasma cells) in MS. Can we scrub the MS brain free of plasma cells?

CoI: multiple

Inactive MS; does it exist?

I had an interesting discussion with some like-minded colleagues recently about active and inactive MS. We seemed to agree on what active MS is, be it in the relapsing or progressive phases of MS. However, we couldn’t really agree on what inactive MS is. Take this following case scenario; many said he was inactive, but others felt he had active MS and should have his treatment switched. Would you agree?

When you look at post-mortem studies of people dying with endstage MS they all have active inflammation within their brains. Active inflammation refers to both adaptive (memory responses) and innate (hard-wired) immune responses. MSers at death still have T-cells, B-cells and plasma cells in their brains in addition to astrocyte and microglial activation.

If we extrapolate these pathological findings to life then all MSers have active MS. What is the solution in terms of forming a common nomenclature? Surely MS is a biological disease rather than a clinical disease? If this is the case we need to come up with a biological classification system to describe active and inactive MS.

On reflection, I think we need to get rid of the terms active and inactive and describe what we mean pathologically using metrics. For example,

This patient has evidence of ongoing focal inflammation (relapses, new and/or enlarging T2 lesions and/or Gd-enhancing lesions and/or raised CSF NFL levels) in the last 12 or 24 months.
This patient has no evidence of ongoing focal inflammation in the last 24 months but has worsening disability (physical and/or cognitive) and evidence of smouldering MS with increased brain/spinal cord atrophy and/or an increasing T1 black volume.
This patient has no evidence of ongoing focal inflammation in the last 24 months, is stable clinically (physical and cognitive) and has no evidence of smouldering MS, i.e. no increased brain/spinal cord atrophy and a stable T1 black volume.

I suspect that we will have very few MSers in category 3, simply because with an MS-centric view of the world we are forgetting that MSers are human and will age and will get comorbidities. Therefore, how do we include ageing and comorbidities, which affect these biomarkers, into this classification system? In addition, none of our metrics is black-and-white so there is scope for miss-classification. What is clear that if you take this approach then MS is one, and not two or three, diseases. A person with PPMS with new lesions will be treated in the same way as someone in the relapsing-remitting phase of the disease. Do you have a problem with this?

Thoughts, please?

CoI: multiple

Old age; how is it going to affect me?

Is ageing a disease? It is if you have MS.

We have been making the argument for moving our treatment target in MS to focus on old age; i.e. how do we your HCPs get you to old age with enough brain to deal with the ravages of age-related cognitive impairment?

It is clear that your brain and cognitive reserves are what protects you from the ‘normal age-related neuronal drop-out’, which occurs as part of normal life. We know that MS shreds both brain (size) and cognitive (synapses) reserve and hence it should bring forward age-related cognitive impairment in MSers. The latter was a hypothesis, but the study below shows it is not necessarily a hypothesis anymore. In summary, older MSers are more likely to be cognitively impaired (77%) compared to younger MSers (43%). The challenge is to prevent this. How? Early effective treatment to stop the shredder and to make sure we tackle smouldering MS.

Do you need any more evidence? Please ask your neurologist if you have NEDA is there any evidence of smouldering MS? He/She may want to know what smouldering MS is. You can then tell them it is what is happening at the bottom of the treatment pyramid that is out of sight of our routine monitoring. This is the reason why you need to self-monitor and if you are getting worse you need to ask what can be done about it.

Branco et al. Aging with multiple sclerosis: prevalence and profile of cognitive impairment. Neurol Sci. 2019 Apr 23. doi: 10.1007/s10072-019-03875-7.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group.

OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients.

METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains.

RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70).

CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

CoI: multiple

Why is everyone drinking anti-CD20 kool-aid?

Prof G will ocrelizumab and rituximab prevent SPMS?

Just back from the COMBAT-MS stakeholders meeting in Pasadena with the Kaiser (Kaiser Foundation Research Institute) and Swedish (Karolinska Institute) trial teams, PCORI (Patient-Centered Outcomes Research Institute) and many brave an wonderful people with MS and their families.

The COMBAT-MS study (NCT03193866) is recruiting well and is on schedule to deliver very important comparative data on the effectiveness of rituximab in real-life. The full title of the study is ‘COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient’s Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis’. In short, COMBAT-MS will be comparing Rituximab with Natalizumab, Fingolimod, Alemtuzumab, Interferon-beta, Glatiramer acetate and Dimethyl Fumarate. Because the use of alemtuzumab seems to be quite limited in Sweden, with the majority of patients going onto rituximab, the study will not have enough power to compare rituximab with alemtuzumab. This a great pity because the real question I have is how does anti-CD20 therapy compare to our top-guns, i.e. alemtuzumab and HSCT. This question is becoming a priority for me.

We had a comprehensive safety update from the COMBAT-MS trial team, which will be presented later this year. However, the safety profile of rituximab is broadly in keeping with what is seen in rheumatology, with a few interesting exceptions. However, the overall safety profile will help with the adoption of rituximab as a treatment of MS in resource-poor environments.

I included in my presentation on why I think anti-CD20 is not good enough to treat MS in the long term and why we need to think beyond NEDA. I presented data, mainly from ocrelizumab, that shows MS continues to smoulder away on ocrelizumab despite patients being NEDA. The response to the data was what we are seeing was simply secondary progressive MS. Yes and no. It may be a secondary progressive disease, but the pathology driving smouldering MS (microglial activation, slowly expanding lesions, subpial cortical lesions, intrathecal immunoglobulin production, demyelination, mitochondrial toxicity and energy failure, oxidative damage, delayed axonal loss, synaptic pruning, premature ageing, etc.) are all present at the very earliest stages of the disease, even the asymptomatic stage of the disease, i.e. radiologically isolated syndromes. This is why I don’t think SPMS really exists and why MS is one and not two or three diseases.

The construct that MS has distinct phases, an early inflammatory and a delayed degenerative phase, is artificial and comes from the Pharma industry’s need to get interferon-beta licensed under the orphan drug act, i.e. MS had to have a prevalence of fewer than 200,000 affected people for the orphan drug act to apply. The only way to get the numbers down to less than 200,000 was to salami-slice up MS into three diseases, i.e. RRMS, SPMS and PPMS. Later on, a fourth category, CIS (clinically isolated syndrome) was added. However, CIS has largely disappeared as a category because of diagnostic creep and the earlier diagnosis of MS with the evolving definition of MS based on the newer versions of the McDonald criteria. Having looked hard I can find no scientific justification for making SPMS a different disease.

In my opinion, smouldering MS and the pathologies driving it do not seem to be anti-CD20 responsive. If they were then we would see a much better impact of anti-CD20 on brain volume loss, disease improvement and the slowly expanding lesion. What does this mean for people with MS? It means that anti-CD20 therapies may be a good platform to start on but you will require additional add-on therapies to stop smouldering MS. Can I please urge you to re-read Stephen Hauser’s case report below. You may argue that one swallow doesn’t make a summer, but Stephen Hauser implied two year’s ago in a response to a question at ECTRIMS that anti-CD20 was not the panacea everyone wants it to be and that a lot of his long-term rituximab-treated patients were now secondary progressive, i.e. they had smouldering MS.

The concept of smouldering MS is a difficult one for people in the field to grasp. Why? It is because NEDA-3 has become de-facto what defines MS. We need to move beyond what we can see and measure and focus on end-organ markers of disease activity, i.e. whole brain and regional or grey matter volumes, the expanding MS lesions, neurofilament levels and more sensitive clinical outcomes. An EDSS view of the world is simply too narrow. We need to look at cognition, visual function and more sensitive functional tests of different neuronal systems. One of the attendees was horrified when I said that the best thing that could happen to the field is if we could automate the neurological examination using a validated technology platform. The idea of using a neurologist to assess eye movements and balance, when it can be done so much better with eye tracking systems and balance sensors, shocked this individual. Bring on the robots and maybe our worldview of MS, in particular, smouldering MS, would change.

I was also able to deliver good news about our WHO Essential Medicine List (EML) application that includes ocrelizumab as one of the three drugs and rituximab as a suitable replacement for ocrelizumab if access to ocrelizumab is a problem. If our EML application is successful this will allow us to pressurise governments to prioritise the treatment of MS in low prevalence countries. I explained to the group that what had started out for me as an ‘Essential Off-label DMT list’ in 2014, may become an official WHO-backed Essential DMT list in 2019. I am holding thumbs we get MS onto the EML, it needs to be there for many reasons.

I also covered in my talk alternative hypotheses, i.e. that MS may be due to a virus and that our current world-view of MS being an autoimmune disease driven by T and B-cells may be wrong. I briefly presented the B-cell-EBV hypothesis and our proposed EBV vaccination trial. I stressed that we need to use anti-CD20 as a tool to explore the EBV hypothesis and the good news is that Fredrik Piehl is going to explore EBV biomarkers as part of the COMBAT-MS study.

I used my lecture to represent my ‘marginal gains’ philosophy as it applies to treating MS and how we need to manage MS holistically and focus on the small things that may make a big difference to MS outcomes in the future. This is only the second time that I have presented this concept to my peer group, but it is something that still needs work to make it sticky.

The following are my slides from the meeting, which you can download from my slide sharing site.

I would like to thank PCORI and the Kaiser team for including me in this study and for your wonderful hospitality. I have little doubt that the COMBAT-MS study is going to help change the way the MS community treats MS globally. I would also like to thank the MSers who attended and spoke at the meeting; you are are the reason why we are doing what we do.

von Büdingen et al. Onset of secondary progressive MS after long-term rituximab therapy – a case report. Ann Clin Transl Neurol. 2016 Dec 20;4(1):46-52.

A patient with relapsing multiple sclerosis (RMS) was treated with a standard immunomodulatory therapy, but due to ongoing disease activity was switched to rituximab. Relapses ceased, but secondary progressive MS (SPMS) eventually appeared, associated with new focal spinal cord white matter lesions. Cerebrospinal fluid (CSF) showed persistent oligoclonal bands (OCB) and clonally related B cells in CSF and peripheral blood. The treatment escalation approach failed to prevent evolution to SPMS, raising the question of whether initiation of B-cell depleting therapy at the time of RMS diagnosis should be tested to more effectively address the immune pathology leading to SPMS.

CoI: multiple

Beyond the B-cell

Do we have the right cell target in MS? Yes and no; we need a multicellular approach.

Recently the attention in MS has been on the B-cell as if it was the holy grail of MS treatments. It is not.

In several posts, over the last few weeks, I have made the case that the B-cell is important, probably as an antigen presenting cell, but it is not the ‘be all and end all’ of MS treatments. It is clear that rebound post-natalizumab is driven my B-cells and the positive data on the first BTK inhibitor would indicate that the B-cells are working via the B-cell receptor on antigen presentation. If only we knew what these antigens were we would have a much better handle on the cause of MS.

I know this science stuff is hard, but it is important. At the end of the day, the nut and bolts of MS must be molecular; molecules mean treatment targets and potentially more focused and hopefully better and safer treatments in the future.

I have stressed that simply targeting B-cells in both the periphery and central nervous system will not be enough to effectively treat MS in the long-term. When we look at end-organ damage markers in pwMS who are on B-cell therapies they have ongoing brain volume loss, albeit at a lower rate, and enlarging lesions (T1 black holes), which are both indicative of ongoing smouldering MS. So what do we need to do? I have provided circumstantial evidence that NIRTs (non-selective immune reconstitution therapies) have a slight edge on the B-cell therapies and this may be because they are also targeting T-cells. The latter, however, comes at a price of greater adverse events in relation to immunosuppression. The proportion of MSers on NIRTs who experience disability improvement seems higher when compared to the anti-B cell agents, which indicates that NIRTs are doing something else over and above their effect on the B-cell compartment. However, based on their overall safety profile it is unlikely that the NIRTs (alemtuzumab & HSCT) will be a therapeutic strategy that the wider MS community will adopt with vigour. Although from comments on this blog there is an informed group of MSers who feel hard done by because their HCPs won’t offer them the option of using NIRTs first-line, i.e. very early in the course of their disease when they have the most to gain from these therapies.

Is there anything else we can do to improve on the profile of B-cell therapies to make them better? Yes, I think there is. Targeting the plasma cell,in addition to the B-cell. Data on plasma cells goes back decades and surprisingly the plasma cell has never been a major therapeutic target in MS. John Prineas, one of my MS heroes, has always stressed the importance of the plasma cell in MS. His paper below from 1978 documents just how enriched the brains of MSers are with this population of cells. What is often not stressed is that the biology of plasma cells is so so different to the B-cell, which opens up new therapeutic targets that are quite different to those in the T and B cell compartments. More on this topic another time.

You are aware of the recent publication showing that about 55% of Polish MSers treated with intravenous cladribine lost their oligoclonal bands 10 or more years after treatment and if they did lose their OCBs they tended to have lower EDSS scores. We have known for years that MSers, with either relapse-onset or primary progressive diseases, who don’t have OCBs do better. There is also evidence from biomarker and pathology studies that the OCBs may be driving several of the disease processes that have been linked to advanced or progressive MS, i.e. microglial activation and grey matter pathology. Based on these observations, we hypothesise that OCBs are very likely to be pathogenic in MS, which is why we are embarking a research programme to try and target the plasma cells within the CNS of MSers. Do you think we are crazy?

To get a handle on the plasma cell we are going to have to study what happens in the spinal fluid. There are simply too many plasma cells in the periphery which will drown out any signal from the CNS. To participate in the studies we are planning we will have to perform serial, annual, lumbar punctures or spinal taps to see if our add-on therapy is killing and/or reducing the number of plasma cells in your brain and spinal cords. The good news is that we have de-risked the lumbar puncture with the use of atraumatic needles and screening. I never thought I would be saying this but most of our patients don’t mind having LPs, particularly when they understand the reason behind the LP. CSF neurofilament levels are now part of our prognostic profile of MSers at baseline and we are increasingly using them to assess response, or lack of response, to treatment. So if you want to be treated and treated-2-target beyond NEDA, and beyond the B-cell, then having an LP is important.

We hope our proposed plasma cells studies will lead to a mindset that goes beyond the B-cell to target some of the mechanisms that are responsible for smouldering MS.

Prineas & Wright. Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest. 1978 Apr;38(4):409-21.

Perivascular cells in CNS tissue from six multiple sclerosis (MS) patients and a patient with motor neuron disease were examined by light and electron microscopy. Lymph node tissue from one MS patient was also examined. CNS perivascular macrophages in both MA and motor neuron disease were found to closely resemble free macrophages elsewhere in the body except that they often contained unusually large primary lysosomes. Cytoplasmic inclusions consisting of membrane-bound stacks of curved linear profiles, presumed to be a product of myelin degradation, were constantly observed in microglia in MS plaques but were rarely observed in perivascular macrophages in the same area. Unidentified cylindrical bodies were observed within cysternae of rough endoplasmic reticulum in some lymph node cells. Quantitative studies of the perivascular cell population in one MS case revealed, in histologically normal white matter 260 lymphocytes and 178 plasma cells per cubic millimeter of fresh tissue. Typical chronic plaque tissue without obvious inflammatory cell cuffing contained 1772 plasma cells per cubic millimeter of fresh tissue. No plasma cells were observed in the CNS in motor neuron disease. The results of this study suggest that perivascular macrophages in the CNS represent a specialized population of monocyte-derived free macrophages, that these cells differ functionally from microglial cells, and that the digestion of myelin breakdown products in MS requires the participation of both cell types. The results also suggest that in some chronic MS cases there is a large, permanent population of CNS plasma cells that persists, like the elevated cerebrospinal fluid IgG level in this disease, for the life of the patient, that these cells, rather than inflammatory cells in fresh lesions, are the major source of this raised IgG, and that the existence of such a population of cells may indicate the continuing expression of antigens in chronic MS lesions in the absence of fresh lesion formation.

The next generation

Training the next generation of MSologists is one of my priorities.

I helped arrange and teach on the Pan-London Calman Specialist Registrar (SpR) teaching day yesterday. It was great to see so many young trainee neurologists attending; thank you. And to the speakers for giving up their time to teach and inspire the next generation of neurologists to become MSologists; thank you.

I hope you all enjoyed the day the following is the programme.

Neuro-Calman-MS-programme-16th-Jan-2019-gg3

I was impressed by the level of engagement of the audience. I was particularly happy with an insight from one of the trainees who suggested we should be managing MS they way rheumatologists manage RA; i.e. early and aggressively. This was music to my ears. I have been pushing the treat-2-target RA paradigm for MS for several years now. The only difference is that our treatment targets have gradually become more ambitious as we have moved from NEDA-1 (relapses) to NEDA-3 (MRI activity) to preventing end-organ damage as measured with MRI (normalising the rate of brain volume loss or NEDA-4) and normalising CSF and blood neurofilament levels (NEDA-5) and beyond. What I mean by beyond is that our ultimate aim is to cure people of having MS and to allow them to get to old age with as much brain as possible. Is this too ambitious?

The following is my presentation from yesterday that can be downloaded from my slideshare site.

At the end of my session, we got into a lively debate about whether or not everyone with MS needs to be treated. Obviously not, based on my presentation only people with active MS are eligible for treatment. Those who have inactive MS cannot be treated under current NHS England guidelines and if they remain inactive they will hopefully end-up having benign MS. Surely the aim of our treatments is to convert everyone with MS into having inactive MS that will hopefully turn out to be benign MS after 25-30 years of follow-up. What we did not cover in this mini-debate is what is active MS? Should it include smouldering MS?

If any of the trainees are reading this post can I please recommend that you read the following posts I have recently done and to bookmark my MS-Selfie site that is still under development.

Posts of potential interest:

Smouldering MS: does it exist?

… by taking an MRI-centric view of MS we may have lulled ourselves into a false sense of security. … an MRI worldview of MS has framed, and continues to frame, our perspective of MS and has created a cognitive bias.

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?