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 The problem for us, as patients, is that due to the continued dissemination of outdated ideas, research cannot shift in the right direction.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 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).
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.
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 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.
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.
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, I've been on it for 3 years and just researched that question- when and how to take? Best together and on empty stomach gets more into the blood, according to research on the question with 3 sample groups. Don't forget it should be R-ALA "R" is important. 66 yrs and stable, done with DMTs for 25 years. Don't know if or what worked or is working :-) We'll see about the ALA when the new study results come out.
Hi Tom, can you please share the research you found that indicating taking the R-ALA version is necessary? I didn't come across that info in the studies I read, and since it's a lot more expensive, it would be good to know either way.
From what I can find out, the double-blinded study I linked to above looking at brain atrophy used "R/S‐LA" which I believe is the synthetic version rather than the nonsynthetic R-ALA.
The last ALA study (NCT03161028) was listed as completed this past July (https://clinicaltrials.gov/study/NCT03161028?tab=results) but nothing has been submitted or drawn up reporting results that I can find. The supplement was never referred to as (R-…). Prior studies DID NOT use the R form as I had recalled, but I am a cheap person and would not have opted for a more expensive version for myself if not for good reason 3 years ago, so somewhere it was either being used or described as superior ???. But, I was wrong in that prior studies used 1200 mg Alpha Lipoic Acid which is sometimes only referred to as LA. Two sources call the recent study LAMPS, but the name actually is LAPMS with the number above. (see https://multiplesclerosisnewstoday.com/lipoic-acid-for-rrms/) The OCTOPUS study is using R/S Alpha Lipoic Acid, which is 50% "R" variety, I think?! You need to check all this stuff yourself and with your doctor if needed.
Hi Sea Field- I spent an hour trying to find it, but no success. I have checked it a few times and always it is R-ALA 600 mg x 2. I can 100% assure you that the R variety is what has and and is being used in the current studies. I have been taking it for 3 years, so my research goes back to then. It is not that I have been conned into believing that one thing is better than the other, I got it from write ups of the original studies. What I see currently appears to be a lot of careless writing by people who are not doing the studies. Yes, the R version is more expensive, but this is pretty important, isn't it? I get Immunovites NA R-Alpha Lipoic Acid from Amazon with 60 600mg capsules ea, about $100 for 3 bottles (3 mo.). I have no idea what is inside the capsule and am hoping for the best. I will stop as soon as the current study results come out showing no effect. I think the Octopus trial is in addition to another study which should be concluding sooner. I hate to say it, but "trust me". :-)
As I understand it R-ALA is more biologically available- easier for the body to absorb, so you can take less. Thank you for putting me on to ALA I just ordered some!
Don't think it can be less, still has to be 1200 mg daily. Beiber does mention R-ALA as better and that more is probably preferable, but he is talking diabetes. I'd try to find the original studies and copy them.
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.
Doctor- you are doing two things here- trying to point to the obvious and wondering why others don't see what you see. I'm not good with medically detailed minutia, but given the topic and the words which I believed I could no longer ignore, I doubled down to understand the things in the first part (but passed on your references- I'm too busy!). I can as a former practicing organizational psychologist, comment on the social aspects of the dilemma you face. Peer pressure is one of them, another is to understand how one gets their bread buttered. Sometimes you'll have to know someone very well, to understand what's going on with them, but it's always there to be found. (i.e. your KOL).
The ship has sailed on the MRI Lesion ship. It's easy to understand and do, and non-doc people understand too and are receptive and can repeat it. (Unfortunately, when the subsequent progression happens, that opens the door for all the other stuff.) The people who have invested their hope into a DMT do not want to hear that it might not or is not working and therefore search for those other answers when reality is telling them that it's not going as planned. Listening to your explanation then, may just seem more of the same.
You need to make the evidence voluminous and undeniable for your position. What you have put together is pretty good, but can you explain it simpler so that the average Joe or Josephine can understand and repeat it in a small amount of time? You need to formulate the best and easiest repeatable evidence for why things are not the way they seem, and produce that, lots of it, over and over and over again. Then establish the correctness of your opinion in the same way- the way things are. It must be undeniable. I know you are trying hard but brick walls are the hardest. Once you get the mind open, what do you do? If you were diagnosed with MS, were just average IQ Josephine, what would you need to understand to head in the most favorable direction? (I know you have a website for that!)? Remember, most of us are not nearly as smart as you and do not have a warehouse of data stored in our mind. Same with a newly licensed MS Specialist neurologist? Perhaps that 2nd question is more important.
I think I'll print out your essay and these replies and give it to my new just hired young neurologist MS expert at Penn State Health Hershey on my next visit in January. Not to correct or change him or my treatment, as we are just watching for now- I did my Betaseron already for 23 years plus 2 more of Ocrevus. I'm kind of stable.
OK, let me put out some thoughts; this won't be quick…
I understand by looking at the discussion of Tolebrutinib vs.Teriflunomide or Placebo that, as you state- "preliminary observations, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse MS outcomes." So (me, Tom) I am understanding that end organ damage is reduced with Tolebrutinib irrespective of the MRI / Lesion evidence. It is a new type of recognized positive outcome (and the study size was rather large, something like n= at least 200 up to 900 depending on how you count it?) The evidence from dose size of Ocrevus seems to raise the same question. Similar evidence in other studies needs to be highlighted, repeated and emphasized, if it is clear evidence and can be described as such. The fact that Sanofi has a smoldering MS website means one is no longer sticking their neck out too far when making the argument.
I have always been confused by the apparent correct logic of RAW, but the apparent worsening with PPMS which usually has no relapses. Here you have something that might explain that? Or am I just a novice looking at stuff he doesn't understand and shouldn't be talking about? Everybody is searching for one answer but here you have a combination of two, sometimes acting together (RRMS) and sometimes not (PPMS or naSPMS). So two answers from one "cause"- something in the "field".
The discussions about philosophy of science (Prentice) do not seem to me, to be something that one can easily hang their hat on like the "no new lesions" mantra. I wouldn't change your website over that.
I have no skin in this game… I am relatively stable and find that from my experience there are no longer things going on from SAW, RAW, PIRA (acronym phew!) or perhaps even Smoldering. But I always have been "touched" or disheartened with (what must be) the experience of PPMS- I was in the "Working Men's" self-help group (about 6 or 7 of us) in North Carolina in the mid 90's and we were all on Betaseron with the same (good) doc, and were doing well and had thought that with this new medicine we had the problem licked. Except for the one guy in a wheel chair with PPMS who had just recently gotten no where with a PT and was in the room crying. Always felt terrible about that. Seems the focus by your KOL is the same ol' same ol' as it was in 1995, and I read it all the time by MSr's ("no new lesions"), but it is a little clearer to me now how things can be connected. Genetic booby prizes influence different susceptibilities to different environmental factors which produce different specific immune responses, making for different appearing "types", but it is all one predictable process wherein lesions are more frequently but not always part of the process where smoldering usually occurs (???). So maybe things can start to turn?
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.
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 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).
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.
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 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.
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.
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, I've been on it for 3 years and just researched that question- when and how to take? Best together and on empty stomach gets more into the blood, according to research on the question with 3 sample groups. Don't forget it should be R-ALA "R" is important. 66 yrs and stable, done with DMTs for 25 years. Don't know if or what worked or is working :-) We'll see about the ALA when the new study results come out.
Hi Tom, can you please share the research you found that indicating taking the R-ALA version is necessary? I didn't come across that info in the studies I read, and since it's a lot more expensive, it would be good to know either way.
From what I can find out, the double-blinded study I linked to above looking at brain atrophy used "R/S‐LA" which I believe is the synthetic version rather than the nonsynthetic R-ALA.
The last ALA study (NCT03161028) was listed as completed this past July (https://clinicaltrials.gov/study/NCT03161028?tab=results) but nothing has been submitted or drawn up reporting results that I can find. The supplement was never referred to as (R-…). Prior studies DID NOT use the R form as I had recalled, but I am a cheap person and would not have opted for a more expensive version for myself if not for good reason 3 years ago, so somewhere it was either being used or described as superior ???. But, I was wrong in that prior studies used 1200 mg Alpha Lipoic Acid which is sometimes only referred to as LA. Two sources call the recent study LAMPS, but the name actually is LAPMS with the number above. (see https://multiplesclerosisnewstoday.com/lipoic-acid-for-rrms/) The OCTOPUS study is using R/S Alpha Lipoic Acid, which is 50% "R" variety, I think?! You need to check all this stuff yourself and with your doctor if needed.
Hi Sea Field- I spent an hour trying to find it, but no success. I have checked it a few times and always it is R-ALA 600 mg x 2. I can 100% assure you that the R variety is what has and and is being used in the current studies. I have been taking it for 3 years, so my research goes back to then. It is not that I have been conned into believing that one thing is better than the other, I got it from write ups of the original studies. What I see currently appears to be a lot of careless writing by people who are not doing the studies. Yes, the R version is more expensive, but this is pretty important, isn't it? I get Immunovites NA R-Alpha Lipoic Acid from Amazon with 60 600mg capsules ea, about $100 for 3 bottles (3 mo.). I have no idea what is inside the capsule and am hoping for the best. I will stop as soon as the current study results come out showing no effect. I think the Octopus trial is in addition to another study which should be concluding sooner. I hate to say it, but "trust me". :-)
https://youtu.be/-30sOmTe37s?si=4SiO69eNvfR64UKy. Watch from 3:34
As I understand it R-ALA is more biologically available- easier for the body to absorb, so you can take less. Thank you for putting me on to ALA I just ordered some!
Don't think it can be less, still has to be 1200 mg daily. Beiber does mention R-ALA as better and that more is probably preferable, but he is talking diabetes. I'd try to find the original studies and copy them.
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.
Doctor- you are doing two things here- trying to point to the obvious and wondering why others don't see what you see. I'm not good with medically detailed minutia, but given the topic and the words which I believed I could no longer ignore, I doubled down to understand the things in the first part (but passed on your references- I'm too busy!). I can as a former practicing organizational psychologist, comment on the social aspects of the dilemma you face. Peer pressure is one of them, another is to understand how one gets their bread buttered. Sometimes you'll have to know someone very well, to understand what's going on with them, but it's always there to be found. (i.e. your KOL).
The ship has sailed on the MRI Lesion ship. It's easy to understand and do, and non-doc people understand too and are receptive and can repeat it. (Unfortunately, when the subsequent progression happens, that opens the door for all the other stuff.) The people who have invested their hope into a DMT do not want to hear that it might not or is not working and therefore search for those other answers when reality is telling them that it's not going as planned. Listening to your explanation then, may just seem more of the same.
You need to make the evidence voluminous and undeniable for your position. What you have put together is pretty good, but can you explain it simpler so that the average Joe or Josephine can understand and repeat it in a small amount of time? You need to formulate the best and easiest repeatable evidence for why things are not the way they seem, and produce that, lots of it, over and over and over again. Then establish the correctness of your opinion in the same way- the way things are. It must be undeniable. I know you are trying hard but brick walls are the hardest. Once you get the mind open, what do you do? If you were diagnosed with MS, were just average IQ Josephine, what would you need to understand to head in the most favorable direction? (I know you have a website for that!)? Remember, most of us are not nearly as smart as you and do not have a warehouse of data stored in our mind. Same with a newly licensed MS Specialist neurologist? Perhaps that 2nd question is more important.
I think I'll print out your essay and these replies and give it to my new just hired young neurologist MS expert at Penn State Health Hershey on my next visit in January. Not to correct or change him or my treatment, as we are just watching for now- I did my Betaseron already for 23 years plus 2 more of Ocrevus. I'm kind of stable.
Does this make sense? Does it explain things in a simple way?
https://gavingiovannoni.substack.com/p/getting-worse
The topic is complex. Maybe I need a simple website to explain smouldering MS differently?
OK, let me put out some thoughts; this won't be quick…
I understand by looking at the discussion of Tolebrutinib vs.Teriflunomide or Placebo that, as you state- "preliminary observations, I suspect that in addition to fewer T2 lesions, tolebrutinib will also suppress the development of paramagnetic rim (PRLs) and slowly expanding lesions (SELs), both associated with worse MS outcomes." So (me, Tom) I am understanding that end organ damage is reduced with Tolebrutinib irrespective of the MRI / Lesion evidence. It is a new type of recognized positive outcome (and the study size was rather large, something like n= at least 200 up to 900 depending on how you count it?) The evidence from dose size of Ocrevus seems to raise the same question. Similar evidence in other studies needs to be highlighted, repeated and emphasized, if it is clear evidence and can be described as such. The fact that Sanofi has a smoldering MS website means one is no longer sticking their neck out too far when making the argument.
I have always been confused by the apparent correct logic of RAW, but the apparent worsening with PPMS which usually has no relapses. Here you have something that might explain that? Or am I just a novice looking at stuff he doesn't understand and shouldn't be talking about? Everybody is searching for one answer but here you have a combination of two, sometimes acting together (RRMS) and sometimes not (PPMS or naSPMS). So two answers from one "cause"- something in the "field".
The discussions about philosophy of science (Prentice) do not seem to me, to be something that one can easily hang their hat on like the "no new lesions" mantra. I wouldn't change your website over that.
I have no skin in this game… I am relatively stable and find that from my experience there are no longer things going on from SAW, RAW, PIRA (acronym phew!) or perhaps even Smoldering. But I always have been "touched" or disheartened with (what must be) the experience of PPMS- I was in the "Working Men's" self-help group (about 6 or 7 of us) in North Carolina in the mid 90's and we were all on Betaseron with the same (good) doc, and were doing well and had thought that with this new medicine we had the problem licked. Except for the one guy in a wheel chair with PPMS who had just recently gotten no where with a PT and was in the room crying. Always felt terrible about that. Seems the focus by your KOL is the same ol' same ol' as it was in 1995, and I read it all the time by MSr's ("no new lesions"), but it is a little clearer to me now how things can be connected. Genetic booby prizes influence different susceptibilities to different environmental factors which produce different specific immune responses, making for different appearing "types", but it is all one predictable process wherein lesions are more frequently but not always part of the process where smoldering usually occurs (???). So maybe things can start to turn?
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.