I attended an online meeting yesterday and gave my usual talk on why the MS community needs to change its worldview from MS being a “clinico-radiological” entity to being a “biological disease”. There are many reasons for doing this but an alternative MS worldview will allow us to (1) diagnose MS earlier, (2) start treatment earlier, (3) define prevention strategies targeting very early MS or the at-risk, (4) stop MS being considered two or three diseases, (5) develop combination therapies for smouldering or the real MS and (6) to manage MS more holistically.
If we think about MS from a biological perspective rather than a clinical (relapses) or MRI (new lesion) perspective then we will not be lulled into a sense of false security that we are on top of this disease or be surprised when patients who are apparently disease-activity free become secondary progressive.
One of the participants and respected colleague asked me what will it take to get the MS community to accept the biological definition of MS and to move away from the clinico-radiological view of the disease. I tried to answer the question but failed horribly.
On reflecting on my inability to answer this question I realised that I have probably been trying to do this, i.e. redefine MS, for decades and have failed. My research, traditional communication channels (journals, congresses, etc.) and new media platforms (blogging, social media, etc) are clearly not working.
Maybe the solution is to create a parallel MS universe, i.e. set-up an alternative committee to redefine the disease. This ‘New MS Definition Committee’ would use sound philosophical principles to define MS, avoid the diagnostic tautology that underpins the McDonald criteria, and include definitions that are underpinned by biology. We can then retrospectively validate these criteria on existing data sets, refine the criteria (feedback loop) and then set-up prospective studies to validate the criteria. Yes, validate them, i.e. establish the sensitivity and specificity of the criteria and to then establish how they perform in high, intermediate and low prevalence regions of the world. What clinicians and researchers need to know is the positive and negative predictive value of the criteria in their clinics. You will be surprised by how much incorrect diagnoses or misclassifications affect research outcomes (more on this later).
This parallel MS Universe will have to include a different research and education agenda to challenge the current dogma. And will have to generate a few creative memes (infectious ideas) and policy to speed up adoption.
I wonder how many of my colleagues would want to join this parallel Universe? Is the status quo tenable? The motivation for doing this is to improve outcomes for people living with MS and to prevent the next generation of people getting MS.
CoI: nil
Prof G,
On a positive note, I watch lots of YouTube videos of interviews with MSologists and follow twitter feeds of a number of MSologists (I’ve had MS for almost 20 years) and I’ve noticed a definite shift in the last couple of years – many now openly acknowledge that MS is probably one disease and that relapses / MRI activity aren’t the real MS. You and others have done a good job in changing established mindsets – even among those I considered dinosaurs.
It’s a real shame that the MS conferences couldn’t take place this year as there is a momentum building behind this alternative view of MS. While changing the definition of MS will be important (MS as a biological disease), what’s really needed is a well evidenced paper on what factors / processes are behind smouldering MS and some potential therapies which will address these factors / processes.
From an MSers point of view, the change appears a major step backwards. Since the first injectable arrived in the mid 1990s we were told how lucky we were. As more therapies and more effective therapies have arrived we were told that it’s never been a better time to have MS. Our neuros were happy to tell us that we were NEDA (no relapses, no MRI activity). We eagerly waited for new therapies to protect, re-myelinated and perhaps restore. Now we hear a different message – relapses / MRI activity are pretty much irrelevant and that even the best anti-inflammatories are unlikely to address the underlying causes / processes which drive increasing disability. I’m not sure it’s the best time to have MS given that the old thinking has been turned on it’s head.
Thanks, Sid!
Re: “what’s really needed is a well evidenced paper on what factors / processes are behind smouldering MS and some potential therapies which will address these factors / processes.”
I am in the process of writing one with a group of like-minded colleagues.
This is great news ☺️
I took some time to watch recorded sessions at EAN 2020 online and I felt that neurologists are gradually buying into the concept of MS as one disease. Also some big pharma seem to start following this concept even if trials are still designed for the 3 MSs. To push forward this view I think that one good evidence is much stronger than several papers. I believe one of the most recent papers on Ocrelizumab and the PIRA (you are among authors) is another proof.
Then I think that the SIZOMUS study will provide additional strong evidence as people without OCB (cladribine and natalizumab studies) seem to do better even long term. My neuro told me that some people from the first cladribine study have been good for 10+ years like Rejdak paper, but we could not discuss this any further. We also need effective biomarkers to prove ongoing disease even in relapse free patients. Thanks a lot for all you and your team are doing for us.
Could you please link me to studies on cladribine and those who are OCB -ve? This intrigues me. I’ve been looking into the protective genetics in the OCB- population. And coincidentally am doing very well post year 1 after some early wrinkles.
https://pubmed.ncbi.nlm.nih.gov/30368223/
My relapse would disagree with you on on them being pretty much irrelevant with the residual damage it left. Whether it smoulders or flares, it’s all residual, building damage over time. Definitely the ‘real ms’ at the time.
Wow Sid, I’m speechless at such a positive comment!
In this case let’s hope normal service will not be resumed 😉
Prof G the Independent SAGE committee is a good analogy of what you are proposing to do.
When scientists and other experts realised that SAGE (The Scientific Advisory Group for Emergencies) was not providing UK government ministers and officials with evidence-based scientific advice and issues around transparency and political interference arose, they set-up a ‘parallel universe’, which has had a real impact.
https://www.independentsage.org/independent-sage/
Good luck!
I agree 200%. The people who wait years for a diagnosis due to small technicalities and accumulate so much disability – it’s a tragedy. Not to mention the medical gaslighting that occurs by neurologists saying “not ms” and dismissing a patient, over and over, until magically one day it is.
Sore spot. I know many people in this situation as I once was.
Smoulder, smoulder. And sometimes even fires.
I pray this changes. Thank you for your work.
KC-this is me..6 YEARS…textbook MS..abnormal neurological exam, diagnostic evidence of CNS involvement, everything ruled out, 30+ doctors, zero lesions …so adamant it’s not MS..but can’t tell me what it is. Progressively getting worse, gaslighted by a couple of Neuros …body is screaming louder than MRIs are detecting…it’s pure insanity!! I’m not smoldering, I’m burning into ashes.
From my point of view, the solution is to change the current “clinical types” for real types, like Tumefactive MS, anti-MOG MS (there are reports), anti-TNF MS (cases induced by adalimumab), CIDP and neurofascin associated MS, Myelocortical multiple sclerosis (some years ago there was a lot about it), etc
You presumably also need huge momentum from patients. This whole issue needs to be on everybody’s lips, the MS topic of the moment, so that every neurologist will expect to be questioned by every patient. I suppose it’s not as immediately compelling as – say – the CCSVI story, but when you consider how much traction that had, it does show that public opinion can challenge dogma. What can we do to get the ball rolling?
Thank you for your efforts on behalf of people with smoldering MS.
As someone who had relapses from 2000 until 2011 when I had my first negative MRI in Europe and then 6 years of symptoms with perfectly fine MRIs in Europe and in the USA on various levels of machines, it does my heart good to see this kind of understanding circulate.
Ironically, I had an MRI in 2017 that showed a ton of lesions in my spine, brain stem, and optic nerve, the tables flipped and the doctors were urgent that I start a DMT when previously they blamed me for having my symptoms without a supporting MRI as if it was my favorite pastime. Even more ironic, two years later, there is no trace of lesions and I am undiagnosed again (after having Ocrevus pushed hard). I look forward to more information about the holistic management of MS and the difference a healthy lifestyle can make.
The only difference now is that pre-MRI evidence I was gaslighted and now the same doctors openly admit that some patients don’t show MRI evidence until later. If they know this, why was I left to languish for so many years?
Reading this does shine hope into a dark corner of the world around MS. I hope for rapid adoption of this advanced understanding of a very complicated process.
Lesions seen in MS are symptomatic of an underlying and ongoing biological process. Patients (my wife included) continue to deteriorate with no new are expanding lesions. DMTs treat downstream effects. Until we know the causal agent (viral, bacterial, toxins), all we will get are more of the same immunosuppressant medications.
What if the immune system of MS patients are functioning as designed but are in fact attacking an unidentified pathogen (or pathogens with similar epitopes). Many viruses and bacteria are neurotrophic. How about we start seriously looking at them?
Hi Prof G, I concur with all the above, especially Sid comments. I too believe I have smouldering MS & my MRI & EDSS tests are not inline with my symptoms or disease progression. I have tried to raise this with my MS Neuro & team but I’ve not received any supporting dialogue or I think in some of the cases, total understanding. It took roughly 2 years to have onset of symptoms for me personally & then a further year before I actually got to see a Neuro – then various tests, including a very frightening lumbar puncture, whereby the pain I experienced, gives me nightmares! I digress, I think it will work ‘the parallel universe’ – it’ll be an amazing shift to try to get HCPs to start looking at ways now, to support their patients, especially newly diagnosed.
If the disease is taken back to GPs & Neuro teams to pull apart its onset, origin and help support those patients who are not showing enough activity on MRI or tests, for them to qualify for disease modifying therapies – giving a more boarder option & way to stop it getting to an unbearably, depressive & disabling worse.
Good luck with everything & keep doing what you do – 🙂
Dr. G, As a neurologist in the US, I’m convinced you’re absolutely correct about “The Real MS”. This is my view of your trying to “drain the swamp” of, i.e., the existing dogma of what MS is. The economically and historically powerful MS pharmaceutical companies have provided us, and our patients, better than expected, mainly peripheral > central, anti inflammatory DMT’s for the 10-15 years of the adaptive peripheral pathophysiology. You’re absolutely correct about The Real MS years before MS diagnosis and till the end of the MS patient’s life.. The DMT’s are highly profitable, highly expensive, and have excessively price escalated since the mid 1990’s. MS pharma, through orphan drug status, was able to get regulatory approval, and market their anti inflammatories, that measure what is easily measured: relapses( at 1 year ), new MRI activity( at 6 months ) and barely disability progression with the weak EDSS( 1950’s devised scale ) at 2 years.
1. Yes, I speak and advise for all MS pharma, which gives me the opportunity to teach patients and physicians about the disease.
2. Yes, I am compensated for my time and expertise, but that is not why I am out late at night, pre Covid, giving talks, or traveling, after seeing MS patients all day. I am time poor, like you, and these long MS days can be exhausting, but I will lose sleep and deplete what energy I have left at my older age to interact with anyone and everyone about the amazing and ever changing and evolving field of MS.
3. Yes, wealthy MS pharma companies have the financial means to get us providers, passionate about MS, together, preferably face to face, but now Virtually, to collaborate, exchange ideas, learn from each other and satisfy MS pharma’s questions on where we stand on MS in general, and their MS DMT’s. None of us can afford, or would financially, sacrificially, try to afford, all of these meeting venues.
So we, who are dedicated to our MS patients, and the very fluid and dynamic pathophysiologic and treatment field of MS, have to do a symbiotic dance with MS pharma for reasons mentioned.
I am on board with you and your intellectual superior power in the world of MS pathophysiology, but traditional, economically profitable conglomerates keep protecting the status quo which does not open it’s arms to a sandwich, or cocktail,( like in Oncology ) of treatments ( likely repurposed generic, non profitable medications ), on top of the antiinflammatories. Plus half the treatment in the hands of the MS patient is a healthy holistic lifestyle.
Respectfully, Clifford Reed