The problem with the classifiers these algorithms are based on is that they are all flawed and not underpinned by biology. Is it not time for a change?
Yes, I understand the semantics. Very well actually.
I have had an ongoing argument with my neurologist for the past fifteen years: I keep telling him that I'm getting worse, and he keeps telling me that the medication(s) is(are) working and that I just need to do 'x/y/z.' (more exercise, etc) Except that x/y/z is only for maintenance, not reversal/betterment of disability, stopping or slowing of progression, and obviously a condemnation of the current DMT. I believe that my neurologist's arrogance partially blinded him to the fact that his overreliance on radiological evidence in spite of all the other evidence of PIRA (progression independent of relapse activity). He would tell me that I am doing well when obviously I wasn't, and that I was the newest/most advanced medication available, and there was nothing else when I would tell him that it wasn't working and I was still progressing. Then he would show me my MRIs and tell me, "see... you are stable." It didn't comport with what I was experiencing, and what my research was explaining to me. He also kept telling me that I didn't understand what I was explaining to him about what I was researching and learning. I didn't know what to think anymore, and I didn't know if it was gaslighting or if I was just really mistaken from ignorance.
So yes, Prof G, it is time for a fundamental and comprehensive change in the understanding of multiple sclerosis, especially in the theories around staging.
Thanks. Your explanations are straightforward and relatively easy to follow. Shocking to now learn (I was diagnosed with secondary progressive MS in 2019) that the classifications are a construct of the pharmaceutical industry and the FDA. Frankly, looking at my MS doctor’s chart/graph of the different stages, it was never clear to me how they reached the diagnosis. It makes more sense to me that there is a cause (SAW, perhaps) of my worsening (since 2019, my ability to walk is much reduced despite having no new lesions).
I’d like to ask you about what appears to be a research breakthrough by researchers at Ohio State University (Benjamin Segal, MD) on coaxing bone marrow cells to produce pro-regenerative cells that can help damaged nerve cells survive and perhaps regrow.
Re your newsletter: I would like to know if you understand the semantics and arguments in this newsletter and whether this has relevance to you as someone with MS.
I came here to comment to let you know how much I appreciated this article. I am the mother of a daughter with MS--she is aged 22 now, presenting symptom was ON at age 18, 1 mo.
Yes, I definitely understand the semantics and arguments in this newsletter and appreciate the explanation that makes sense to the average citizens such as myself. The framework in which you have classified (or suggested to declassify) makes total sense and my non-medical/non-research brain totally agrees. Thank you so much for sharing and I read all your newsletters.
I find the most interesting statement in this piece to be this: “I keep repeating these points because you can have MS and not develop smouldering disease. I suspect what is happening in this situation is that your immune system finds and eliminates the cause of MS, which prevents the subsequent development of smouldering disease.”
This needs to be tested ie a therapy which eliminates the cause of MS, or a therapy which enhances the immune system of MSers so that it can eliminate the cause of MS. Is there anything in the pipeline which offer hope in this regard eg Car T cell therapy, anti-virals……? Or are we still at the standard “ten years away” position?
Why would CD19 CAR T Therapy be better than say hitting the patient with Cladribine as well as a B-Cell depleter at the same time? Thought being to deplete B-Memory cells in the CNS with Cladribine while also having Anti-CD20 in the periphery to keep the B-Cells from reinfiltrating the CNS.
We are not sure if enough cladribine gets into the CNS and plasmablasts and plasma cells seem to be resistant to cladribine. In comparison, CD19-targeted CAR-T-cells expand in number in the body and go everywhere and also kill plasmablasts. This is why they are used as rescue therapy in patients with lymphoma in who anti-CD20 therapy fails.
Thank you for the explanation. The B-cells will then repopulate and eventually be infected through interaction with infected mucosal cells. Indeed this might buy a decade or longer, but a permanent fix? The underlying genetics of poor EBV control by the CD8+ T-cells haven't been changed. Then again, if one needs a "reset" every once in a while, this might be cheaper and of less risk to the patient than current highly effective treatments. Do you have a possible timeline of when we might see CAR T Therapy?
Possibly a difficult question for you to answer politically so I won't be offended if you let it go through to the keeper, to use cricket parlance, but is there an obvious reason why these approaches aren't put to trial?
Eg:
1/Refusal to accept your definion of MS pathology.
2/Lack of financial incentives for pharma
From what I've read there seems to be a widespread acceptance of EBV's potential role in MS pathology.
This was a very interesting post to read. I want to say thank you for posting it. Your explanations are always straight forward and it frustrates me on your or our behalf that your messages are not being heard and listened too.
I feel as someone that was diagnosed with ParsPlanitis in SA at 12. It was not known at the time it had a link to MS. 38 years later I know that MS doesn't stop going. From my own perspective every day even if you exercise and look after diet etc, you still have aches, pains, varying energy levels etc. I try to focus on being alive to live another day.
In my mind MS simply hibernates or regenerates to reinfect and cause lesions again. From my reading there are estimated to be around a million people suffering with MS globally. As you say there are more people confirmed to have MS after they passed.
I was interested to read that MS treatments started around 1993. For the record, I am grateful that I have treatment options today. I say what MS did to people in years prior and it was like watching MS taking shots at a fish in a barrel.
I personally believe that if things are not working, they should change as the labels in this case are not fit for purpose. The education system is a good example of this. It started being developed in a world that looks nothing like 2024. Why are we not changing it to keep up with the times or society needs.
While the Classifiers look logical to me, I wonder who actually writes and approves their use? Do any have MS and really know if they are fit for purpose or not?
I read a paper on ScientificAmerican.com that Exxon Knew about Climate Change almost 40 years ago (1977). Exxon chose to ignore it and we are living with their decisions today. Or Hiram S. Maxim in 1884, made the first automatic machine gun in the United States.
To answer your question. If I understand the semantics and arguments in this newsletter and whether this has relevance to you as someone with MS. I try the best I am able too. It has always felt to me that people who don't have MS or have walked a mile in my shoes are making decisions about my (or our) collective futures.
I apologise if this post may have offended anyone, it was not my intention.
No offense taken!! Yes, lottery for Betaseron (interferon beta 1-b) in 1993. When I was formally diagnosed in 1995, Avonex (betaseron 1-a) was marketed aggressively in 90s. I’m in the states. There’s money in them hills!! (I mean, DMTs….)
Thank you for this excellent newsletter. The current classifications can seem confusing. I have been on Tysabri for 13 yrs and have had neida for all that time. . My neuro suggested stopping Tysabri to see if my disease is now inactive as he suspects.
But, I have been getting worse in the past couple of years or so - fatigue, grip and walking. I have so far insisted I wish to continue with treatment. I believe stopping would be a terrible idea as I believe it is certainly helping me. I think I will ask him about his views on smouldering MS at my next consult but I suspect I know what he’ll say sadly.
Probably the most important thing you've written. However, you will need to keep repeating it as those classifications have been swallowed with a religious zeal.
The essence of your argument is sound and the flaws important to rectify as labels influence thinking.. Even the disease name Multiple Sclerosis is anachronistic and unhelpful to everyone involved with it today, having been based on post mortem observations produced in the 19th century, when medical support didn't exist. In neurorehab practice, through long-term follow-ups over years, the observation-based neurology-determined classifications were known to be impractical for managing patients, but provided some structure for neurologists, however useful/misleading that may have been. I welcome a biologically-based classification system, if it would be deemed to properly inform drug treatments, usefully guide other clinical inputs or give greater prognostic support to patients, and so very much welcome your initiative to raise this
Completely understand and agree with the uselessness of still widely used sub-types (RRMS, etc.). Interesting argument/hypothesis about how/why those subtypes were promulgated (orphan disease funding, etc.). Not sure whether all would agree with your hypothesis but doesn't matter. *COMPLETELY AGREE* that many with NEIDA will get worse, in some cases, sadly, much, much, much worse. I have experienced that first-hand with someone who has had access to and tried numerous DMTs deemed most effective, and whose non-medical habits/approaches towards trying to manage/slow progression have been exemplary. NOTHING MEDICAL OR NON-MEDICAL HAS WORKED. And MRI evidence of focal inflammation always was underwhelming, even early in her disease course, and ceased long ago. TWO QUESTIONS: First, you say that you would prefer MS status (have/not have) to be determined using "a biological definition of MS". Just what do you propose as the "biological definition"? Can it be verified prior to post-mortem pathological investigation? Second, how is the condition of "smoldering worsening" determined? Is determination of that condition entirely clinical, at least for someone who meets the "biological definition" of MS? "They're getting worse despite doing everything they should be doing, ergo, smouldering worsening"; is that how it would work? Is that helpful?
Re: how is the condition "smoldering worsening" determined.
We have just had a paper accepted by the Annals of Neurology on this topic. Smouldering MS can be detected using a combination of clinical and different biomarkers (imaging and body fluid). I will let you know when the article is published. It will be open access.
In the US, many DMTs are only for people with "highly active MS," but that has no actual definition, so the insurance companies can just deny it. Thus leading to the really messed-up explanation that they would like to see more brain damage before approving the DMT that your doctor is recommending to prevent brain damage. (I did eventually get it, but it was super stressful.)
And the discussion of what types of relapse "count" makes no sense to me. I've had symptoms before I could get an MRI, and active lesions on MRI with no symptoms. Both seem bad!
What I've been thinking of is that in order to get DMTs approved, back in the day, the FDA and pharma company worked together to game the system. That got the first DMT, interferon-beta-1b, approved under the Orphan Drug Act.
I don't think that was wrong. It demonstrated that the whole concept of DMTs was valid, and more/better drugs were pursued and released. It brought us from _no_ treatments for MS, to something that helped a lot of people, and a _process_ that helped even more! I don't know what would have happened if the FDA hadn't done that -- the US isn't the only country in the world, after all -- but it definitely seems to have helped. And I really don't know the state of knowledge back then; it seems likely that the distinctions were at least more plausible, even if (we think) we've learned better.
However -- that still means that the system was gamed, and doesn't reflect the clinical, biological, or scientific reality. That initial tilt continues to alter how MS is perceived and treated. I think it is important to un-game the system.
Seeing RIS/CIS/RRMS/SPMS/PPMS as all the same disease, which present differently based on the amount of neurological and other reserves we have, but are the same process underneath, makes a lot of sense to me. It also simplifies how I think of my own treatment and self-management: instead of wittering off after this diet or exercise or meditation program or whatever, I can think in terms of "building/restoring my reserves."
I think I just described MS as a dual control model, with separate disease and reserve processes. I'll have to think about that.
Rachael, did not know it was Orphan Drug Act. Just advocating for ourselves is a wear out. I swear, that’s what will take me out. There is no coordination of care where I am and I am too exhausted to do all of this. Cheers!!
This all makes sense to me. But then the question is how do you biologically determine MS yes or MS no? It seems like we would need biomarkers such as NfL but my understanding is NfL is nonspecific for MS. I often wonder, as someone who is still undiagnosed due to lack of radiological evidence but experiences exactly smoldering associated worsening, can someone start off with basically no inflammation? Can you have entirely PIRA or worsening with NEIDA from the get go? If so, people like me lose big because we waste a lot of time waiting for our slowing expanding lesions to become visible when I already know something is horribly wrong. What test will biologically determine that I have MS before it shows up on MRI and half my spinal cord has been chewed through?
The statement 'You can have MS and not develop smouldering disease' gives me some semblance of hope as it resonates with my personal situation. My MRIs have remained stable since my diagnosis.
Tweaks have been made to my lifestyle in terms of increased exercise, diet and medication, and so far things have been pretty good for the ;last 5 years.
Thanks for your efforts they're always enlightening and it clearly explains the contradictions in our healthcare. I've presented with MS since 2012 and often thought the DX was labelling for the convenience of treatment paths rather than the patient. You've helped me understand my MS and certainly the Smouldering aspect.
I do understand what you are saying but I think you miss an essential point. It is possible to have smouldering MS and inflammation at the same time. I was diagnosed because of double vision in 1995 but I am convinced that my MS started in 1972 when I had a significant bladder incident.
I had a good digestive system, no accidents or problems emptying my bowels until 2016, twenty years after my diagnosis. I started to be constipated and ate cooked prunes to ease the problem. Now I have to do anal irrigation because of severed constipation.
I noticed my walking started to get a bit wobbly in 2000 and by 2014 I could not walk unaided and must use a mobility scooter outdoors and a walking frame in the house. This all started over 25 years after I believed I had my first MS symptom.
I could go on and on. I will add that I know of people diagnosed several years after me who are more disabled than I am and those diagnosed before me who can still look after a big garden.
I consider MS to be a spectrum disease like Autism which is a spectrum disorder. I have no medical expertise but MS can gradually have a greater and greater impact on a person’s life and there are numerous ways that a person’s life can be affected.
I have taken an idea that you sort of expressed several years ago and maybe I have refined it very slightly. I think it can be used to define the overall level of disability without getting into the nitty gritty of individual disabilities.
Does this make sense? Obviously it is subjective rather than objective but it does allow the severity of the disease to be identified, Cancer has 4 stages, maybe MS warrants 10. What do you think?
Once you have MS it can develop and affect you in so many ways, both physically and mentally. By allocating a grade or number to it people can see get an idea of the severity. Yes it is approximate and subjective but it is an idea which EDSS fails to do. Your initials such as EIDA or SAW do not indicate the severity of the disease. There are many levels of disability caused by SAW but no indication of how much it affects a person's quality of life. Just a thought.
Re: "It is possible to have smouldering MS and inflammation at the same time."
Yes, in my diagram, this group is EIDA/SAW, i.e. pwMS, who have recent evidence of inflammatory disease activity and recent evidence of smouldering-associated worsening.
Thank you for sharing that smoldering MS can be evident through disease activity and yet not show up on an MRI. I have had approximately 8 attacks that seem to be from the same lesion (cause similar issues - numb forearm, MS hug in upper arm, numb hand(s) and numb feet etc) and haven’t shown up on an MRI. You can see the lesion on the MRI, but it doesn’t light up and the size hasn’t changed. Smoldering MS, ‘attacks’ every 3-8 months. It’s a relief to hear that my neurologist now knows about smoldering MS - next stop, a treatment? Hopefully.
Thank you Professor your explanation is crystal clear. It is also no surprise to read this.
One question I have - being SP with no new lesions but a body that’s degenerating - is how can I obtain alemtuzumab? Before it’s too late? Which neuro will let me have this given my MRI has not changed?
I was RRMS until I asked about stem cell therapy and was then told I am SP! Call me a cynic but never having been given a DMT I am now very concerned that I need better MS care.
If you have been labelled as having SPMS it is a one-way street. The only therapies licensed for active SPMS in the UK are interferon-beta-1b (Betaferon / Extavia) and siponimod (Mayzent). Have you read the following?
I just read it but am a bit confused given your explanation of the origins of ms classification.
I asked around 10 years ago when the NHS just started stem cell transplants. I was referred to Hammersmith to discuss and then told no due to no change in an MRI taken then compared to 2005 when I was diagnosed.
Am I reading this wrong? I am asking about alemtuzumab given the acceptance there is likely smouldering ms type activity?
Despite my take on things, the MHRA, EMA, and NHS still use the current classifications system (CIS, RRMS, active SPMS, inactive SPMS, active PPMS and inactive PPMS). Therefore if you have active SPMS you are only eligible for interferon-beta-1b and siponimod. If you have inactive SPMS, you are not eligible for any DMT using the current treatment algorithm. In comparison, alemtuzumab is only available for people with rapidly evolving severe MS.
I’m so sorry I hope I don’t seem rude. It’s just a very difficult time - my mobility has taken a nosedive. I seem to be the only person with ms who has never been given any ms medication and reading MS Selfie I feel I’ve missed out on something that could have helped
Welcome to the club. Mine MS started in 1972 and diagnosed in 1996. Either the drugs did not exist or my MS not aggressive enough to meet requirements to receive medication. I only get symptom management drugs
Patrick, same time frame as I am. I states, the interferons were aggressively marketed and prescribed. I was on and off different drugs, but mainly on interferon beta for approx 20 years.
Your situation seems very similar to my wife’s. No treatment, no proper diagnosis (well not one that has been communicated to her). Getting worse and nothing happens argh!
Yes, I understand the semantics. Very well actually.
I have had an ongoing argument with my neurologist for the past fifteen years: I keep telling him that I'm getting worse, and he keeps telling me that the medication(s) is(are) working and that I just need to do 'x/y/z.' (more exercise, etc) Except that x/y/z is only for maintenance, not reversal/betterment of disability, stopping or slowing of progression, and obviously a condemnation of the current DMT. I believe that my neurologist's arrogance partially blinded him to the fact that his overreliance on radiological evidence in spite of all the other evidence of PIRA (progression independent of relapse activity). He would tell me that I am doing well when obviously I wasn't, and that I was the newest/most advanced medication available, and there was nothing else when I would tell him that it wasn't working and I was still progressing. Then he would show me my MRIs and tell me, "see... you are stable." It didn't comport with what I was experiencing, and what my research was explaining to me. He also kept telling me that I didn't understand what I was explaining to him about what I was researching and learning. I didn't know what to think anymore, and I didn't know if it was gaslighting or if I was just really mistaken from ignorance.
So yes, Prof G, it is time for a fundamental and comprehensive change in the understanding of multiple sclerosis, especially in the theories around staging.
Dear Christopher, that’s so awful. 15 years is a long time. I get it.
Thanks. Your explanations are straightforward and relatively easy to follow. Shocking to now learn (I was diagnosed with secondary progressive MS in 2019) that the classifications are a construct of the pharmaceutical industry and the FDA. Frankly, looking at my MS doctor’s chart/graph of the different stages, it was never clear to me how they reached the diagnosis. It makes more sense to me that there is a cause (SAW, perhaps) of my worsening (since 2019, my ability to walk is much reduced despite having no new lesions).
I’d like to ask you about what appears to be a research breakthrough by researchers at Ohio State University (Benjamin Segal, MD) on coaxing bone marrow cells to produce pro-regenerative cells that can help damaged nerve cells survive and perhaps regrow.
Thank you.
Re your newsletter: I would like to know if you understand the semantics and arguments in this newsletter and whether this has relevance to you as someone with MS.
I came here to comment to let you know how much I appreciated this article. I am the mother of a daughter with MS--she is aged 22 now, presenting symptom was ON at age 18, 1 mo.
Yes, I definitely understand the semantics and arguments in this newsletter and appreciate the explanation that makes sense to the average citizens such as myself. The framework in which you have classified (or suggested to declassify) makes total sense and my non-medical/non-research brain totally agrees. Thank you so much for sharing and I read all your newsletters.
I find the most interesting statement in this piece to be this: “I keep repeating these points because you can have MS and not develop smouldering disease. I suspect what is happening in this situation is that your immune system finds and eliminates the cause of MS, which prevents the subsequent development of smouldering disease.”
This needs to be tested ie a therapy which eliminates the cause of MS, or a therapy which enhances the immune system of MSers so that it can eliminate the cause of MS. Is there anything in the pipeline which offer hope in this regard eg Car T cell therapy, anti-virals……? Or are we still at the standard “ten years away” position?
Spot on. CD19 CAR T-cells and EBV antivirals & immunotherapies are the things upper most in my mind.
Why would CD19 CAR T Therapy be better than say hitting the patient with Cladribine as well as a B-Cell depleter at the same time? Thought being to deplete B-Memory cells in the CNS with Cladribine while also having Anti-CD20 in the periphery to keep the B-Cells from reinfiltrating the CNS.
We are not sure if enough cladribine gets into the CNS and plasmablasts and plasma cells seem to be resistant to cladribine. In comparison, CD19-targeted CAR-T-cells expand in number in the body and go everywhere and also kill plasmablasts. This is why they are used as rescue therapy in patients with lymphoma in who anti-CD20 therapy fails.
Thank you for the explanation. The B-cells will then repopulate and eventually be infected through interaction with infected mucosal cells. Indeed this might buy a decade or longer, but a permanent fix? The underlying genetics of poor EBV control by the CD8+ T-cells haven't been changed. Then again, if one needs a "reset" every once in a while, this might be cheaper and of less risk to the patient than current highly effective treatments. Do you have a possible timeline of when we might see CAR T Therapy?
I will have to do a separate newsletter on how we think EBV drive MS disease activity. It is not simple and far from being well established.
Possibly a difficult question for you to answer politically so I won't be offended if you let it go through to the keeper, to use cricket parlance, but is there an obvious reason why these approaches aren't put to trial?
Eg:
1/Refusal to accept your definion of MS pathology.
2/Lack of financial incentives for pharma
From what I've read there seems to be a widespread acceptance of EBV's potential role in MS pathology.
If there’s a lack of financial incentive, well….hmmm. Btw, how’s the shoulder??
The mighty dollar rules us all unfortunately.
3 weeks post op, shoulder is mending well and my symptoms have quietened down. Thanks for asking.
This was a very interesting post to read. I want to say thank you for posting it. Your explanations are always straight forward and it frustrates me on your or our behalf that your messages are not being heard and listened too.
I feel as someone that was diagnosed with ParsPlanitis in SA at 12. It was not known at the time it had a link to MS. 38 years later I know that MS doesn't stop going. From my own perspective every day even if you exercise and look after diet etc, you still have aches, pains, varying energy levels etc. I try to focus on being alive to live another day.
In my mind MS simply hibernates or regenerates to reinfect and cause lesions again. From my reading there are estimated to be around a million people suffering with MS globally. As you say there are more people confirmed to have MS after they passed.
I was interested to read that MS treatments started around 1993. For the record, I am grateful that I have treatment options today. I say what MS did to people in years prior and it was like watching MS taking shots at a fish in a barrel.
I personally believe that if things are not working, they should change as the labels in this case are not fit for purpose. The education system is a good example of this. It started being developed in a world that looks nothing like 2024. Why are we not changing it to keep up with the times or society needs.
While the Classifiers look logical to me, I wonder who actually writes and approves their use? Do any have MS and really know if they are fit for purpose or not?
I read a paper on ScientificAmerican.com that Exxon Knew about Climate Change almost 40 years ago (1977). Exxon chose to ignore it and we are living with their decisions today. Or Hiram S. Maxim in 1884, made the first automatic machine gun in the United States.
To answer your question. If I understand the semantics and arguments in this newsletter and whether this has relevance to you as someone with MS. I try the best I am able too. It has always felt to me that people who don't have MS or have walked a mile in my shoes are making decisions about my (or our) collective futures.
I apologise if this post may have offended anyone, it was not my intention.
Thank you for reading and I hope it helps.
No offense taken!! Yes, lottery for Betaseron (interferon beta 1-b) in 1993. When I was formally diagnosed in 1995, Avonex (betaseron 1-a) was marketed aggressively in 90s. I’m in the states. There’s money in them hills!! (I mean, DMTs….)
Thank you for this excellent newsletter. The current classifications can seem confusing. I have been on Tysabri for 13 yrs and have had neida for all that time. . My neuro suggested stopping Tysabri to see if my disease is now inactive as he suspects.
But, I have been getting worse in the past couple of years or so - fatigue, grip and walking. I have so far insisted I wish to continue with treatment. I believe stopping would be a terrible idea as I believe it is certainly helping me. I think I will ask him about his views on smouldering MS at my next consult but I suspect I know what he’ll say sadly.
Probably the most important thing you've written. However, you will need to keep repeating it as those classifications have been swallowed with a religious zeal.
That’s such a great way to put it: religious zeal. I personally all of those classifications are whacked out, but that’s just my opinion.,
The essence of your argument is sound and the flaws important to rectify as labels influence thinking.. Even the disease name Multiple Sclerosis is anachronistic and unhelpful to everyone involved with it today, having been based on post mortem observations produced in the 19th century, when medical support didn't exist. In neurorehab practice, through long-term follow-ups over years, the observation-based neurology-determined classifications were known to be impractical for managing patients, but provided some structure for neurologists, however useful/misleading that may have been. I welcome a biologically-based classification system, if it would be deemed to properly inform drug treatments, usefully guide other clinical inputs or give greater prognostic support to patients, and so very much welcome your initiative to raise this
Thanks for explaining this Prof G, important stuff and definitely relevant to someone living with MS.
Completely understand and agree with the uselessness of still widely used sub-types (RRMS, etc.). Interesting argument/hypothesis about how/why those subtypes were promulgated (orphan disease funding, etc.). Not sure whether all would agree with your hypothesis but doesn't matter. *COMPLETELY AGREE* that many with NEIDA will get worse, in some cases, sadly, much, much, much worse. I have experienced that first-hand with someone who has had access to and tried numerous DMTs deemed most effective, and whose non-medical habits/approaches towards trying to manage/slow progression have been exemplary. NOTHING MEDICAL OR NON-MEDICAL HAS WORKED. And MRI evidence of focal inflammation always was underwhelming, even early in her disease course, and ceased long ago. TWO QUESTIONS: First, you say that you would prefer MS status (have/not have) to be determined using "a biological definition of MS". Just what do you propose as the "biological definition"? Can it be verified prior to post-mortem pathological investigation? Second, how is the condition of "smoldering worsening" determined? Is determination of that condition entirely clinical, at least for someone who meets the "biological definition" of MS? "They're getting worse despite doing everything they should be doing, ergo, smouldering worsening"; is that how it would work? Is that helpful?
Re: how is the condition "smoldering worsening" determined.
We have just had a paper accepted by the Annals of Neurology on this topic. Smouldering MS can be detected using a combination of clinical and different biomarkers (imaging and body fluid). I will let you know when the article is published. It will be open access.
Re: "biological definition" - I am in the process of writing an article on this. I will do a MS-Selfie Newsletter in due course on this topic.
It's absolutely time for a change.
In the US, many DMTs are only for people with "highly active MS," but that has no actual definition, so the insurance companies can just deny it. Thus leading to the really messed-up explanation that they would like to see more brain damage before approving the DMT that your doctor is recommending to prevent brain damage. (I did eventually get it, but it was super stressful.)
And the discussion of what types of relapse "count" makes no sense to me. I've had symptoms before I could get an MRI, and active lesions on MRI with no symptoms. Both seem bad!
What I've been thinking of is that in order to get DMTs approved, back in the day, the FDA and pharma company worked together to game the system. That got the first DMT, interferon-beta-1b, approved under the Orphan Drug Act.
I don't think that was wrong. It demonstrated that the whole concept of DMTs was valid, and more/better drugs were pursued and released. It brought us from _no_ treatments for MS, to something that helped a lot of people, and a _process_ that helped even more! I don't know what would have happened if the FDA hadn't done that -- the US isn't the only country in the world, after all -- but it definitely seems to have helped. And I really don't know the state of knowledge back then; it seems likely that the distinctions were at least more plausible, even if (we think) we've learned better.
However -- that still means that the system was gamed, and doesn't reflect the clinical, biological, or scientific reality. That initial tilt continues to alter how MS is perceived and treated. I think it is important to un-game the system.
Seeing RIS/CIS/RRMS/SPMS/PPMS as all the same disease, which present differently based on the amount of neurological and other reserves we have, but are the same process underneath, makes a lot of sense to me. It also simplifies how I think of my own treatment and self-management: instead of wittering off after this diet or exercise or meditation program or whatever, I can think in terms of "building/restoring my reserves."
I think I just described MS as a dual control model, with separate disease and reserve processes. I'll have to think about that.
Rachael, did not know it was Orphan Drug Act. Just advocating for ourselves is a wear out. I swear, that’s what will take me out. There is no coordination of care where I am and I am too exhausted to do all of this. Cheers!!
This all makes sense to me. But then the question is how do you biologically determine MS yes or MS no? It seems like we would need biomarkers such as NfL but my understanding is NfL is nonspecific for MS. I often wonder, as someone who is still undiagnosed due to lack of radiological evidence but experiences exactly smoldering associated worsening, can someone start off with basically no inflammation? Can you have entirely PIRA or worsening with NEIDA from the get go? If so, people like me lose big because we waste a lot of time waiting for our slowing expanding lesions to become visible when I already know something is horribly wrong. What test will biologically determine that I have MS before it shows up on MRI and half my spinal cord has been chewed through?
The statement 'You can have MS and not develop smouldering disease' gives me some semblance of hope as it resonates with my personal situation. My MRIs have remained stable since my diagnosis.
Tweaks have been made to my lifestyle in terms of increased exercise, diet and medication, and so far things have been pretty good for the ;last 5 years.
Thanks for your efforts they're always enlightening and it clearly explains the contradictions in our healthcare. I've presented with MS since 2012 and often thought the DX was labelling for the convenience of treatment paths rather than the patient. You've helped me understand my MS and certainly the Smouldering aspect.
Hello ProfG,
I do understand what you are saying but I think you miss an essential point. It is possible to have smouldering MS and inflammation at the same time. I was diagnosed because of double vision in 1995 but I am convinced that my MS started in 1972 when I had a significant bladder incident.
I had a good digestive system, no accidents or problems emptying my bowels until 2016, twenty years after my diagnosis. I started to be constipated and ate cooked prunes to ease the problem. Now I have to do anal irrigation because of severed constipation.
I noticed my walking started to get a bit wobbly in 2000 and by 2014 I could not walk unaided and must use a mobility scooter outdoors and a walking frame in the house. This all started over 25 years after I believed I had my first MS symptom.
I could go on and on. I will add that I know of people diagnosed several years after me who are more disabled than I am and those diagnosed before me who can still look after a big garden.
I consider MS to be a spectrum disease like Autism which is a spectrum disorder. I have no medical expertise but MS can gradually have a greater and greater impact on a person’s life and there are numerous ways that a person’s life can be affected.
I have taken an idea that you sort of expressed several years ago and maybe I have refined it very slightly. I think it can be used to define the overall level of disability without getting into the nitty gritty of individual disabilities.
Does this make sense? Obviously it is subjective rather than objective but it does allow the severity of the disease to be identified, Cancer has 4 stages, maybe MS warrants 10. What do you think?
Re: "I consider MS to be a spectrum disease like Autism which is a spectrum disorder. "
Yes and no. Either you have MS or you don't have MS. The spectrum is how it manifests clinically.
Once you have MS it can develop and affect you in so many ways, both physically and mentally. By allocating a grade or number to it people can see get an idea of the severity. Yes it is approximate and subjective but it is an idea which EDSS fails to do. Your initials such as EIDA or SAW do not indicate the severity of the disease. There are many levels of disability caused by SAW but no indication of how much it affects a person's quality of life. Just a thought.
Re: "It is possible to have smouldering MS and inflammation at the same time."
Yes, in my diagram, this group is EIDA/SAW, i.e. pwMS, who have recent evidence of inflammatory disease activity and recent evidence of smouldering-associated worsening.
Thank you for sharing that smoldering MS can be evident through disease activity and yet not show up on an MRI. I have had approximately 8 attacks that seem to be from the same lesion (cause similar issues - numb forearm, MS hug in upper arm, numb hand(s) and numb feet etc) and haven’t shown up on an MRI. You can see the lesion on the MRI, but it doesn’t light up and the size hasn’t changed. Smoldering MS, ‘attacks’ every 3-8 months. It’s a relief to hear that my neurologist now knows about smoldering MS - next stop, a treatment? Hopefully.
Yes!! We are very similar. Looks easy (bright!!) for a long number of years. Then I hit +/- year 2018, and it was all downhill with neida status.
Thank you Professor your explanation is crystal clear. It is also no surprise to read this.
One question I have - being SP with no new lesions but a body that’s degenerating - is how can I obtain alemtuzumab? Before it’s too late? Which neuro will let me have this given my MRI has not changed?
I was RRMS until I asked about stem cell therapy and was then told I am SP! Call me a cynic but never having been given a DMT I am now very concerned that I need better MS care.
Please advise. With thanks
H
If you have been labelled as having SPMS it is a one-way street. The only therapies licensed for active SPMS in the UK are interferon-beta-1b (Betaferon / Extavia) and siponimod (Mayzent). Have you read the following?
https://gavingiovannoni.substack.com/p/ahsct-who-should-have-access
I just read it but am a bit confused given your explanation of the origins of ms classification.
I asked around 10 years ago when the NHS just started stem cell transplants. I was referred to Hammersmith to discuss and then told no due to no change in an MRI taken then compared to 2005 when I was diagnosed.
Am I reading this wrong? I am asking about alemtuzumab given the acceptance there is likely smouldering ms type activity?
Despite my take on things, the MHRA, EMA, and NHS still use the current classifications system (CIS, RRMS, active SPMS, inactive SPMS, active PPMS and inactive PPMS). Therefore if you have active SPMS you are only eligible for interferon-beta-1b and siponimod. If you have inactive SPMS, you are not eligible for any DMT using the current treatment algorithm. In comparison, alemtuzumab is only available for people with rapidly evolving severe MS.
Please see: https://gavingiovannoni.substack.com/p/alemtuzumab
I’m so sorry I hope I don’t seem rude. It’s just a very difficult time - my mobility has taken a nosedive. I seem to be the only person with ms who has never been given any ms medication and reading MS Selfie I feel I’ve missed out on something that could have helped
Sorry to hear this.
I too have never been considered eligible for DMD despite having rrms diagnosis. Awareness of worsening issues is scary.
Welcome to the club. Mine MS started in 1972 and diagnosed in 1996. Either the drugs did not exist or my MS not aggressive enough to meet requirements to receive medication. I only get symptom management drugs
Patrick, same time frame as I am. I states, the interferons were aggressively marketed and prescribed. I was on and off different drugs, but mainly on interferon beta for approx 20 years.
I wasn't offered anything until 7 years after first symptoms. The local neurologist didn't believe in the medication.
I should add that I only received treatment after moving to a different city and a different health board
Oh that’s interesting Tiff. I hope it’s helping you now
Your situation seems very similar to my wife’s. No treatment, no proper diagnosis (well not one that has been communicated to her). Getting worse and nothing happens argh!