I understand your feelings. The problem for us, as patients, is that due to the continued dissemination of outdated ideas, research cannot shift in the right direction. And I don’t know what we can do about this to help to spread the knowledge about the smouldering MS, as proactive patients are often seen as troublemakers, much like anyone who challenges the official mindset. It has always been like that...
I don't have a medical background, but I can say that I agree with you, and makes more sense to me that the real MS is smoldering MS.
This sentence: "relapses and focal MRI activity are MS, i.e. they are the disease and that suppressing relapses and MRI activity is what we aim to achieve with our DMTs" - this is what my neuro told me and assured me that I would be fine on B cell depleators.
Fast forward 6 years, I am not fine, despite having no actual relapses or new MRI spots, my EDSS is now 4 (I started with 1)
I applaud your theory that ppms is a label given to those diagnosed later in life. I was diagnosed with ppms at age 43. I believe I've had the condition since my very early twenties. I was told I had depression and treated like I was an attention seeking hypochondriac despite the fact I had extreme fatigue and kept fainting and other symptoms I won't go in to. I was a student nurse and couldn't take it easy. It made me push my body and I always felt pathetic, clumsy and worthless.
I believe a very bad case of Tonsillitis where I lost 10kg in a week, weight I couldn't afford to lose, and made me so weak I could hardly stand was the trigger that kicked it up a gear and led to diagnosis.
This would make me wonder if any infection could push the immune system and escalate it like they think EBV does.
Tend to agree with you and have wondered for years why general thinking seemed to be that like some infectious disease, MS had one causative organism. Why not think about it in the same way as we think of cancer? Sometimes it’s possible to say that e.g it’s very likely that someone’s lung cancer was caused by the smoke of many cigarettes, but sometimes there is no obvious cause and perhaps it’s simply that some people’s lung cells are prone to react easily to foreign bodies.- smoke, dust, or whatever.
In my case when I was a child I had pretty bad Meningitis and brain inflammation ( in hospital for two weeks). Who knows if that has any link to my MS
Same with me, plus two hospital stays with severe strep throat prior to spinal meningitis at 20. (MS at 30). But female cousin also has MS without those illnesses. I smoked, she didn't. Our courses are about the same, mild to moderate. Me betaseron 23 years, her, oral steriods for 20 years. No one else in the family, though good records were not kept in Italy or the US in the 30's and 40's.
I have not had a scooby, since my MRI has always been clear and I have been symptom-free before and since diagnosis over 6 years ago. I would argue that I have not had any noticeable relapses. Or perhaps I am just a hardy lass from the north of England.
If you asked my last Neurologist, he would tell you I am a 'difficult patient' because I have some clue as to what is going on and the latest MS research findings. My new Neurologist seems more approachable. But, after one phone call of 7 mins. Then, in one face-to-face meeting of 10 minutes, it isn't easy to build a meaningful relationship.
I think I have smoldering MS and that's fine with me. Exercise, diet, sleep hygiene, and meditation seem to be keeping me on the right track for now. The only noticeable difference is my motor fatigue when walking. It's manageable but is in slow decline.
Since I do not qualify for any treatment according to the NICE guidelines there is not much the NHS will do for me. I am too healthy apparently which I am thankful for.
In other news, my Neurologist does not want to see me for two years! Then, the NHS schedules an appointment for me next March. Go figure...? It would be lovely for someone to have a proper conversation about my MS journey to give me some hope for the future. I have to make do with foraging for information. Thank god for MS Selfie. Long may it reign.
That is unfortunate. Even though you are not feeling the effects from multiple sclerosis very much, it is still doing its thing and tearing down neurons and axons In the central nervous system, little by little, and it's a big question whether it will or will not stop in any person. Although I sometimes sound like a harbinger of grief, my core belief is that there is a great deal of hope, and in the short term as well as the long term. The biggest problem in this being the interminable process of digging through massive piles of information to find what is pertinent and applicable to me and my situation--same for everyone else, I think. It's like medical archeology, and it's exhausting as well as sometimes defeating.
It’s some 18 years since my diagnosis and long before I had heard of smouldering lesions I found myself puzzled by the concept of RRMS, PPMS, SPMS I.e the idea that somehow or another there were different types of MS and that RRMS developed into SPMS. It just didn’t make sense to me. Many many moons ago I gained a PhD in plant biology- pathology and although I have little or no knowledge or experience in the world of human biology and disease the idea that a disease could somehow develop into something slightly different which couldn’t be treated seemed ‘weird’. My take on MS was that something causes my immune system to attack areas of my CNS and that , in my then thoughts, natural ‘wear and tear’ wore down those weakened areas . Or, a bit like a mouth ulcer, or leg ulcer, once you get an inflamed area it can remain troublesome for many years and can get worse.
A few years ago I was really, really pleased to come across your thinking about smouldering lesions all of which makes total sense to me. The alternative is to believe that there is some sort of strange mystery to MS and the way in which our body responds to inflammatory attacks , morphing from one form to another each of which requires different treatments.
My challenge these days is is to support the health of my CNS and, like any other part of my body and physiology, help it to repair and rejuvenate as much as possible ( at age 70 this is becoming an increasing challenge).
Perhaps the most interesting point in your piece was this:
“This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib.”
Those experiencing progression (worsening disability) from smouldering MS would welcome a halt in the worsening (disability improvement is the icing on the cake).
In reality, patients can’t affect the slowness of neuros / MS researchers at embracing new insights into the disease. MS patients experiencing worsening disability caused by smouldering MS can only wait until treatment options become available. I suspect tolebrutinib will be the first available, then Car-T cell therapy and someway down the track anti-virals. Which of these is likely to have the most impact on smouldering MS? Your Black Swan seems to have flown south for the winter - will we ever see it appear?
I concur. I would like more investigation into EBV as the trigger, can you imagine if we had EBV vaccines and it did the same for MS as the vaccines have done for cervical cancers? we need more focus on the basic cause and processes that follow rather than the end result, the lesion formation.
And on a personal note, I would like to see some form of treatment that is safe to take when cancer is an issue, a real challenge as all DMT is based on immune suppression or immune modulation
I think, as usual, you are correct. DMT, no new lesions, progression of symptoms (without relapse). If I look back over my 64 years, from age 30 I had symptoms, culminating at age 54 with a massive attack. Well the damage is done by that point. No MRI from 54 to 61 when I had worsening symptoms but no relapses. On DMT For 3 years but continue to get progressive symptoms in same area. Not sure what the DMT is meant to be doing?? I just keep investigating my options but it’s a postcode lottery and my age excludes me from some avenues of treatment.
I was diagnosed with relapsing remitting MS in 2020. I have never had a relapse as far as I know and yet my disability has progressed from EDSS of 4 to 6. My neurologist explained to me that without diagnosing RRMS I would not be able to have any DMTs and luckily I have been on the Gemini trial ( teriflunomide) and am about to transfer to tolebrutinib. Smouldering MS is the only explanation that matches my experience.
That is true. It is confusing, but if you talk to your doctor he or she will explain that it's for your best interest to be able to get on medication, otherwise everything is working against you including the establishment. My doctor was the same way, and it was very confusing to me until I asked him about it and he explained that if he did not designate me as RRMS that my choices for a DMT would be very limited. And this is in the United States. I believe if your Kurtzke score is as high as yours you are probably in secondary progressive multiple sclerosis, but I could be wrong. Mine was 6.5 a couple of years after dx (diagnosis), and the second opinion doctor, with no skin in the game, told me I was already secondary progressive (no pun intended). I also have never had a strictly defined relapse (that I know of), and it still confuses the heck out of me to this day.
Thank you Gavin, so appreciate you fighting the status quo! I was diagnosed in 2021 age 44 with RMS, (I’m on Natalizumab) apart from sensory, some neuropathic pain and intermittent jet lag like fatigue I’m doing well. However a recent MRI, although stable, showed my brain volume and white matter volume is on the first percentile- I wasn’t that surprised as I kept pointing the atrophy out to my neurologists, but it is rather confronting. I do wonder what the future holds and if I’m on the right DMT but my neurologist is pleased with the stable MRI and that’s where the conversation stops!
Hi Jane, that must have been so confronting, and really tough when your neurologist isn't interested in continuing the conversation. There do seem to be some DMTs that are better at normalizing brain volume atrophy than others, but that won't do you much good without your neuro's cooperation. I just wanted to mention in case you hadn't heard of it, that a 2 year study with participants taking 1200mg of alpha lipoic acid once a day (another study suggested that you do have to take it that way rather than split the dose for it to help) had a massive impact on brain atrophy rates, with three times normal in the placebo group (-0.65 a year), to pretty much normal levels (-0.21 a year) in the group taking the alpha lipoic acid. The study link is here if you're interested in learning more: https://pmc.ncbi.nlm.nih.gov/articles/PMC5489387/
Yes, mine is very much the same as Ms Kershaw. As I have mentioned before, I do indeed believe that smouldering MS is the disease. End of the discussion. And at my age 70+, there are no options. I have begun PT for pwMS, stroke etc, but once again, it was far too aggressive and exacerbated spasticity and vertigo. It will be interesting to see the results of the MRI which I finally got. Vertigo, aside from other symptoms), has been more difficult than anything. Prof G, I thoroughly agree with you, and always have and I really do tire of getting that jaundiced eye when I query a doctor re smoldering MS..particularly when I’ve taken a dive to a EDSS 6. Thanks for this…
All of your points make a lot of sense, and it's perplexing why other doctors would overlook the relevance and feasibility of this hypothesis.
"If you have an MS relapse or attack in one particular area of the brain or spinal cord, you are more likely to have subsequent attacks in this area. Something locally in a specific anatomical area triggers recurrent attacks in the same site." In a way this reminds me of Alfred Knudson's two-hit system. I originally heard it described in a symposium in 1990 where I was running the sound equipment. At the time I didn't really understand biology or cancer very well, but over the years I've come to understand the concept a lot better. This also makes sense relating to tissue insults... in that being injured it is much more likely that the area will incur injury again more so than anywhere around it or elsewhere, mostly because of disturbances in the microenvironment, but that's not a given either. Exasperating, isn't it?
Of course you are right. The uncomfortable mystery of the 'cause' of MS persists and it is particularly within the events occurring in primary progressive tissues that the toxic 'cause' will be found. Could you comment on 'Anti-CD20 Therapies in Drug -Naive Patients with primary progressive MS: A multicenter Real life Study. Hay et al Neurology Oct 22 2024.
Most of the patients were treated with rituximab, which is not as effective as ocrelizumab in terms of deep B-cell depletion, and the doses vary, so it is very hard to interpret. What it confirms is that anti-CD20 therapy, in particular rituximab, is not that effective in PPMS. We know that already from the ORATORIO PPMS study. What we need are CNS penetrant drugs to scrub the brain clean of B-cells.
Makes complete sense Dr. G. It does make me wonder what I should do being someone diagnosed with PPMS but no disability. It sounds like I should actually be on teriflunomide given i have hypogammaglobulinemia. Personally I'd rather take subcutaneous cladribine and hit this before I experience disability. But that would involve my neurologist going off label.
Seems completely obvious from my patient perspective! Especially when you add the observable disease progression with escalation treatment vs starting with highly effective DMT’s immediately.
After slowly progressing for years, I had my first focal inflammation in 16 years when I ran out of the immune protection from estrogen in the contraceptive I take for perimenopause symptoms. n=1, but you cannot convince me that’s not been smouldering.
I understand your feelings. The problem for us, as patients, is that due to the continued dissemination of outdated ideas, research cannot shift in the right direction. And I don’t know what we can do about this to help to spread the knowledge about the smouldering MS, as proactive patients are often seen as troublemakers, much like anyone who challenges the official mindset. It has always been like that...
I don't have a medical background, but I can say that I agree with you, and makes more sense to me that the real MS is smoldering MS.
This sentence: "relapses and focal MRI activity are MS, i.e. they are the disease and that suppressing relapses and MRI activity is what we aim to achieve with our DMTs" - this is what my neuro told me and assured me that I would be fine on B cell depleators.
Fast forward 6 years, I am not fine, despite having no actual relapses or new MRI spots, my EDSS is now 4 (I started with 1)
Me too! In 18 years no new lesions but my EDSS is now 4-5 but started with 1
Hi Belma, yes! It is the disease…I believe also. 💕
I applaud your theory that ppms is a label given to those diagnosed later in life. I was diagnosed with ppms at age 43. I believe I've had the condition since my very early twenties. I was told I had depression and treated like I was an attention seeking hypochondriac despite the fact I had extreme fatigue and kept fainting and other symptoms I won't go in to. I was a student nurse and couldn't take it easy. It made me push my body and I always felt pathetic, clumsy and worthless.
I believe a very bad case of Tonsillitis where I lost 10kg in a week, weight I couldn't afford to lose, and made me so weak I could hardly stand was the trigger that kicked it up a gear and led to diagnosis.
This would make me wonder if any infection could push the immune system and escalate it like they think EBV does.
Tend to agree with you and have wondered for years why general thinking seemed to be that like some infectious disease, MS had one causative organism. Why not think about it in the same way as we think of cancer? Sometimes it’s possible to say that e.g it’s very likely that someone’s lung cancer was caused by the smoke of many cigarettes, but sometimes there is no obvious cause and perhaps it’s simply that some people’s lung cells are prone to react easily to foreign bodies.- smoke, dust, or whatever.
In my case when I was a child I had pretty bad Meningitis and brain inflammation ( in hospital for two weeks). Who knows if that has any link to my MS
Same with me, plus two hospital stays with severe strep throat prior to spinal meningitis at 20. (MS at 30). But female cousin also has MS without those illnesses. I smoked, she didn't. Our courses are about the same, mild to moderate. Me betaseron 23 years, her, oral steriods for 20 years. No one else in the family, though good records were not kept in Italy or the US in the 30's and 40's.
I have not had a scooby, since my MRI has always been clear and I have been symptom-free before and since diagnosis over 6 years ago. I would argue that I have not had any noticeable relapses. Or perhaps I am just a hardy lass from the north of England.
If you asked my last Neurologist, he would tell you I am a 'difficult patient' because I have some clue as to what is going on and the latest MS research findings. My new Neurologist seems more approachable. But, after one phone call of 7 mins. Then, in one face-to-face meeting of 10 minutes, it isn't easy to build a meaningful relationship.
I think I have smoldering MS and that's fine with me. Exercise, diet, sleep hygiene, and meditation seem to be keeping me on the right track for now. The only noticeable difference is my motor fatigue when walking. It's manageable but is in slow decline.
Since I do not qualify for any treatment according to the NICE guidelines there is not much the NHS will do for me. I am too healthy apparently which I am thankful for.
In other news, my Neurologist does not want to see me for two years! Then, the NHS schedules an appointment for me next March. Go figure...? It would be lovely for someone to have a proper conversation about my MS journey to give me some hope for the future. I have to make do with foraging for information. Thank god for MS Selfie. Long may it reign.
Xx
That is unfortunate. Even though you are not feeling the effects from multiple sclerosis very much, it is still doing its thing and tearing down neurons and axons In the central nervous system, little by little, and it's a big question whether it will or will not stop in any person. Although I sometimes sound like a harbinger of grief, my core belief is that there is a great deal of hope, and in the short term as well as the long term. The biggest problem in this being the interminable process of digging through massive piles of information to find what is pertinent and applicable to me and my situation--same for everyone else, I think. It's like medical archeology, and it's exhausting as well as sometimes defeating.
That may be the case but I continue. I think having a mostly happy disposition helps. Xx
Christopher you do an amazing amount of research!
It’s some 18 years since my diagnosis and long before I had heard of smouldering lesions I found myself puzzled by the concept of RRMS, PPMS, SPMS I.e the idea that somehow or another there were different types of MS and that RRMS developed into SPMS. It just didn’t make sense to me. Many many moons ago I gained a PhD in plant biology- pathology and although I have little or no knowledge or experience in the world of human biology and disease the idea that a disease could somehow develop into something slightly different which couldn’t be treated seemed ‘weird’. My take on MS was that something causes my immune system to attack areas of my CNS and that , in my then thoughts, natural ‘wear and tear’ wore down those weakened areas . Or, a bit like a mouth ulcer, or leg ulcer, once you get an inflamed area it can remain troublesome for many years and can get worse.
A few years ago I was really, really pleased to come across your thinking about smouldering lesions all of which makes total sense to me. The alternative is to believe that there is some sort of strange mystery to MS and the way in which our body responds to inflammatory attacks , morphing from one form to another each of which requires different treatments.
My challenge these days is is to support the health of my CNS and, like any other part of my body and physiology, help it to repair and rejuvenate as much as possible ( at age 70 this is becoming an increasing challenge).
Perhaps the most interesting point in your piece was this:
“This treatment effect on smouldering MS was seen in the relapsing (Gemini 1&2 trials) and non-relapsing SPMS trials (Hercules trial). Subjects in the Hercules trial were also more likely to have significant disability improvement, with a trend in the relapsing or Gemini trials. The disability improvement data is critical and tells us that something is happening centrally to promote recovery of function in subjects on tolebrutinib.”
Those experiencing progression (worsening disability) from smouldering MS would welcome a halt in the worsening (disability improvement is the icing on the cake).
In reality, patients can’t affect the slowness of neuros / MS researchers at embracing new insights into the disease. MS patients experiencing worsening disability caused by smouldering MS can only wait until treatment options become available. I suspect tolebrutinib will be the first available, then Car-T cell therapy and someway down the track anti-virals. Which of these is likely to have the most impact on smouldering MS? Your Black Swan seems to have flown south for the winter - will we ever see it appear?
It's being eaten for Christmas ;-)
:D LOL!
I concur. I would like more investigation into EBV as the trigger, can you imagine if we had EBV vaccines and it did the same for MS as the vaccines have done for cervical cancers? we need more focus on the basic cause and processes that follow rather than the end result, the lesion formation.
And on a personal note, I would like to see some form of treatment that is safe to take when cancer is an issue, a real challenge as all DMT is based on immune suppression or immune modulation
Absolutely!
I think, as usual, you are correct. DMT, no new lesions, progression of symptoms (without relapse). If I look back over my 64 years, from age 30 I had symptoms, culminating at age 54 with a massive attack. Well the damage is done by that point. No MRI from 54 to 61 when I had worsening symptoms but no relapses. On DMT For 3 years but continue to get progressive symptoms in same area. Not sure what the DMT is meant to be doing?? I just keep investigating my options but it’s a postcode lottery and my age excludes me from some avenues of treatment.
I was diagnosed with relapsing remitting MS in 2020. I have never had a relapse as far as I know and yet my disability has progressed from EDSS of 4 to 6. My neurologist explained to me that without diagnosing RRMS I would not be able to have any DMTs and luckily I have been on the Gemini trial ( teriflunomide) and am about to transfer to tolebrutinib. Smouldering MS is the only explanation that matches my experience.
That is true. It is confusing, but if you talk to your doctor he or she will explain that it's for your best interest to be able to get on medication, otherwise everything is working against you including the establishment. My doctor was the same way, and it was very confusing to me until I asked him about it and he explained that if he did not designate me as RRMS that my choices for a DMT would be very limited. And this is in the United States. I believe if your Kurtzke score is as high as yours you are probably in secondary progressive multiple sclerosis, but I could be wrong. Mine was 6.5 a couple of years after dx (diagnosis), and the second opinion doctor, with no skin in the game, told me I was already secondary progressive (no pun intended). I also have never had a strictly defined relapse (that I know of), and it still confuses the heck out of me to this day.
Thank you Gavin, so appreciate you fighting the status quo! I was diagnosed in 2021 age 44 with RMS, (I’m on Natalizumab) apart from sensory, some neuropathic pain and intermittent jet lag like fatigue I’m doing well. However a recent MRI, although stable, showed my brain volume and white matter volume is on the first percentile- I wasn’t that surprised as I kept pointing the atrophy out to my neurologists, but it is rather confronting. I do wonder what the future holds and if I’m on the right DMT but my neurologist is pleased with the stable MRI and that’s where the conversation stops!
Hi Jane, that must have been so confronting, and really tough when your neurologist isn't interested in continuing the conversation. There do seem to be some DMTs that are better at normalizing brain volume atrophy than others, but that won't do you much good without your neuro's cooperation. I just wanted to mention in case you hadn't heard of it, that a 2 year study with participants taking 1200mg of alpha lipoic acid once a day (another study suggested that you do have to take it that way rather than split the dose for it to help) had a massive impact on brain atrophy rates, with three times normal in the placebo group (-0.65 a year), to pretty much normal levels (-0.21 a year) in the group taking the alpha lipoic acid. The study link is here if you're interested in learning more: https://pmc.ncbi.nlm.nih.gov/articles/PMC5489387/
Thank you so much Sea Field, really appreciate the information. I will certainly be talking to my GP about taking it. Really appreciate your response.
Yes, mine is very much the same as Ms Kershaw. As I have mentioned before, I do indeed believe that smouldering MS is the disease. End of the discussion. And at my age 70+, there are no options. I have begun PT for pwMS, stroke etc, but once again, it was far too aggressive and exacerbated spasticity and vertigo. It will be interesting to see the results of the MRI which I finally got. Vertigo, aside from other symptoms), has been more difficult than anything. Prof G, I thoroughly agree with you, and always have and I really do tire of getting that jaundiced eye when I query a doctor re smoldering MS..particularly when I’ve taken a dive to a EDSS 6. Thanks for this…
All of your points make a lot of sense, and it's perplexing why other doctors would overlook the relevance and feasibility of this hypothesis.
"If you have an MS relapse or attack in one particular area of the brain or spinal cord, you are more likely to have subsequent attacks in this area. Something locally in a specific anatomical area triggers recurrent attacks in the same site." In a way this reminds me of Alfred Knudson's two-hit system. I originally heard it described in a symposium in 1990 where I was running the sound equipment. At the time I didn't really understand biology or cancer very well, but over the years I've come to understand the concept a lot better. This also makes sense relating to tissue insults... in that being injured it is much more likely that the area will incur injury again more so than anywhere around it or elsewhere, mostly because of disturbances in the microenvironment, but that's not a given either. Exasperating, isn't it?
Absolutely totally agree with you .
Of course you are right. The uncomfortable mystery of the 'cause' of MS persists and it is particularly within the events occurring in primary progressive tissues that the toxic 'cause' will be found. Could you comment on 'Anti-CD20 Therapies in Drug -Naive Patients with primary progressive MS: A multicenter Real life Study. Hay et al Neurology Oct 22 2024.
Most of the patients were treated with rituximab, which is not as effective as ocrelizumab in terms of deep B-cell depletion, and the doses vary, so it is very hard to interpret. What it confirms is that anti-CD20 therapy, in particular rituximab, is not that effective in PPMS. We know that already from the ORATORIO PPMS study. What we need are CNS penetrant drugs to scrub the brain clean of B-cells.
Makes complete sense Dr. G. It does make me wonder what I should do being someone diagnosed with PPMS but no disability. It sounds like I should actually be on teriflunomide given i have hypogammaglobulinemia. Personally I'd rather take subcutaneous cladribine and hit this before I experience disability. But that would involve my neurologist going off label.
Seems completely obvious from my patient perspective! Especially when you add the observable disease progression with escalation treatment vs starting with highly effective DMT’s immediately.
After slowly progressing for years, I had my first focal inflammation in 16 years when I ran out of the immune protection from estrogen in the contraceptive I take for perimenopause symptoms. n=1, but you cannot convince me that’s not been smouldering.