Despite therapeutic suppression of relapses, people with MS often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity". Do you agree?
1 'New' or 'enlarging T2 lesions' ought to be QUANTIFIED, no longer is it enough to say something has worsened or not, based on 'observations'. We need objectivity. Of course we do NOT use available technology to characterize VOLUME loss.
Most smoldering associated worsening is seemingly 'patient-driven' and therefore hugely subjective.
2 Why don't we simply accept the notion that the disease is relentlessly progressive, and whether it's defined under PIRA or SAW, or any other metric, the worsening is relentless over time and that DMTs have minimal or no role in the process ? This is probably true in about 70% of all MS patients, and whether it is reported or not by the patients themselves, one can look at the data and arrive at this conclusion. We honestly do not need more 'evidence' do we ? This could be true for MOST neurodegenerative disorders !!
3 Based on metrics such as reduced exercise endurance, exercise induced symptoms (aka Uhthoff's), worsening of fatigue, and generalized 'worsening', almost every single patient with multiple sclerosis can be considered to be worse from when they began the treatment. And if you consider Parkinson's or Alzheimer's I am sure the parallels are eerily similar.
4 We do not even test for cognitive function (no uniform, OP-based testing) in MS and certainly have zero consensus on the characterization of cortical lesions. Folks who have access to 7T magnets have reaped the benefit of such technology by producing gobs of publications with almost zero utility for most university-based clinics across the USA who do NOT have such fancy toys, let alone Europe. It is a mismatch at many different levels. It is like you have a GM cricket bat while mine is from some lumberyard, fashioned as one (cricketing analogy - you are from SA and I am from India, so we get this).
“Why don't we simply accept the notion that the disease is relentlessly progressive, and whether it's defined under PIRA or SAW, or any other metric, the worsening is relentless over time and that DMTs have minimal or no role in the process ?”
For MSers this must be considered a sad day. 20 years ago (when I was diagnosed) MS was an autoimmune / inflammatory disease which went into “remission” for RRMSers. We were also sold a line that the most powerful DMTs could turn off relapses and shut the disease down. 20 years later and we’re back to square one. MS is a progressive / neurodegenerative disease from the start and stopping relapses / focal inflammation has little impact long term - the unrelenting tissue damage / neurodegeneration continues. And there are no treatments to stop it! Good news for MS researchers - certainly another 20 annual ECTRIMS conferences to go. You wonder what’s been achieved in the first 40!
When you look at progress in MS over a 2-5 year timeline little happens, but over decades an enormous amount has changed. I think we know a lot more now than we did in the past. The insights into smouldering MS are probably not new. Prof. George Ebers was making the case for SAW 30 years ago, but the MS community ignored him. Sometimes ideas need to mature before the larger community are prepared to accept them. Let's hope the MS community accept SAW.
Never sure what “MS community” means! Surely any half decent neuro can see deterioration in their MS patients over time, regardless of what DMT they are on. Researchers picked the low hanging fruit - relapses. And pharma cashed in. Progression (SPMS / PPMS) was too difficult so researchers ducked out (bar a few underpowered studies). I like the way we are ‘hoping’ for the MS community to accept SAW. MSers have to live with the reality of SAW everyday.
We’ll have to agree to disagree on the amount of progress made in MS research. I find stories like this heartbreaking:
You are kind of where I am on this, and I just posted a comment that has a similar flavor. I feel as if someday--in the who knows how distant future--real answers (and therapeutic solutions) to the questions we really care about are going to come from outside MS-focused research, per se.
Suppose as a patient I could get 7T scans, what would it help? There is at least one 7T machine in the city where I live but I really doubt it would do me any good whatsoever....
A 7T scan will let you and your neurologist to see much more detail, i.e. paramagnetic rims lesions, cortical lesions, etc. and may be identify many more small lesions that would be missed on the conventional scan. But it would not really change clinical decision making very much.
I have secondary Progressive ms, I agree with the smouldering ms ,it’s quietly taking more of my functions away I haven’t had any relapses, but in the past 6 years, , I’ve lost the motor function in my left leg and foot, but haven’t been able to walk far in that time and now can’t walk at all, but thankfully so far my arms are still working , I love following your page as the neurologists I’ve seen, say there’s nothing to help me now
I don’t know if you mean overwhelm. We have no one where I live to coordinate services. My fatigue is so great right now, I’m at my wit’s end, but it’s another medical issue. I wish I had energy because there is no assistance..
Even if one has a less-than-rudimentary understanding of the immune system—which I do—scanning this article, it appears that there are so many potential elements of the immune system possibly implicated in progression that it will take decades to sort it out. It took decades to figure out that MS was a B-cell mediated disease and to develop relatively crude B-cell therapies for tamping down focal inflammation. It’s difficult to be optimistic.
Re: " It took decades to figure out that MS was a B-cell mediated disease and to develop relatively crude B-cell therapies for tamping down focal inflammation. It’s difficult to be optimistic."
Are you sure MS is a B-cell mediated disease? The evidence suggest the contrary. My take on why B-cell targeted therapies work in MS is that they are targeting EBV. In addition, most of the B-cell therapies don't scrub the B-cells and plasma cells from the CNS compartment, which explains why they are not that good at tackling SAW.
Thank you for sharing this with us. The paper notes that “…early in the disease course, among subjects with no walking impairment, transient exercise-induced neurological deficit (eg, foot drop) or early fatigability are commonly reported.”. Can I please ask if this how progression in MS typically manifests in the early stages?
I am 3 years post diagnosis. I have no obvious walking impairment on a neurological exam, but following a spinal cord relapse I experience exercise induced leg weakness and unnaturally poor muscle endurance. Unfortunately these things are not picked up on a typical neurological exam.
This is all based on my own experience. I believe the initial RRMS attack is highly affected by inflammation which subsides and symptoms therefore improve. (we know that.) Damage and scarring of nerves occurs, which can produce symptoms on top, to which the sufferer may make adjustments given new alternative nerve connections, repair of some lost myelin, and use of alternative ability making up for the old ones lost (we know all that). This is where I was from about 2000 to 2016, after initial light (1990) and relative severe and complicated numerous symptoms through 1995). Then I went back seemingly to about normal for 20 years.
I believe the initial repair of myelin breaks down with time, along with loss of some alternative ability, leading to what is perceived as SAW (at least for me). Worsening symptoms included bladder function and walking skills. Add to this all, other walking problems not MS, but probably brought on over time by deficits in motor skills caused by MS (peronial neuropathy). PTTD for example, brought about after a lifetime with flat feet but no symptomology, I was a fast runner in HS. Painful toe nails for example due to MS clonus combined with increased reflexes. I have had no new MRI detected lesions since 1996 except for in 2000, on my spine during a temporary switch from Betaseron to Avonex for 9 months [seemingly a bad idea]). I did do Ocrevus for a couple years, but at 62 years, Covid put the K-Bosh on that one. Now I’ll just stick with Alpha Lipoic Acid and Simvastatin.
So I am still stuck on the idea that my MS at present is minimal. When you get to my age (66) and have been where I have, you can expect stuff unrelated to MS to accumulate with your MS and it’s tuff to keep up with. People newly diagnosed try their darnedest to get back to believing everything is OK, and when they discover for themselves it isn’t, they are devastated, perhaps again. I made it generally in one piece, and even though most of my treatment was “CRAB” medicine, I believe it kept me in one piece. We have to go back to basics. I am not going to live forever. At some point, even with the best of health, life becomes a pain in the ass. But most of us would still rather live it. So I’ll plow ahead as best I can and try to do something meaningful as long as I can.
The Consensus is quite detailed and beyond my expertise although I read a fair chunk of it. This and the consensus are a great status report but could upset a few. I usually vote to tell the truth. Seems like aHSCT is the way to go for now if you are young enough at the very beginning. Deal with this stuff when you have to.
Tom, as usual, you hit all the high notes. I’ve got more fish to fry at this point than MS. Plus, I find looking backward is, uh, unproductive? (Former gymnast, now without balance. Sometimes, you just gotta laugh…)
Very interesting but where does that leave me as newly diagnosed (although had symptoms for 4 years!) and no new lesions on mri but a positive lp? My worsening has been put down to smouldering disease! Should I push to go on an immunosuppressive dmt that at my age of 58 could be of little benefit and put me at risk of serious infections? Many thanks.
great news that smouldering ms is maybe going to be considered more seriously.
thankyou!
3 questions please:
1. will this change approach to dmts?
should patients with new diagnoses start on dmts, then swap to smouldering treatment?
or?
2. there are so many of us late / undertreated on DMTs. but most neurologists just seem interested in the new / recent diagnoses. Its - surely- easier?
but where do the rest of us fit in? nowhere important, it seems.
(the reason ive only recently gone for dmts (after 30ish years) is that i always thought dmts treated mri results more than disability.)
3. multimorbidity
im sure its not only me who has more than an ms diagnosis
its very disappointing that those other parts of us are still ignored
eg im just not sure if im more smouldering - and/or struggling with my non-ms diagnoses
Yes, that is the aim of the paper, i.e. to get the MS community and regulators to change the development paradigm so we have DMTs that primarily target SAW.
Not sure they are being ignored. One of the drivers of SAW are comorbidities (infections, HTension, diabetes, sedentary behaviour, poor sleep, etc.), which is why I such a big proponent of the holistic management of MS and the marginal gains philosophy.
Re: "2. there are so many of us late / undertreated on DMTs. but most neurologists just seem interested in the new / recent diagnoses. Its - surely- easier?"
In my opinion it is never too late to treat MS. Even in the terminal phase of the disease you can do things to improve QoL and make things easier for pwMS and their families.
Gotta say I’ve often aspired to be classified as ‘smouldering’, so I for one, a laywoman with PPMS, am delighted by the terminology you are developing!
Totally agree. Current practice is to look at the scar, and not the injury underneath. Well, they call it active or no, but the injury is under the scar. That's what needs to be treated, and so far our only treatment is shutting down the immune system. Which they won't do at my age, 66. So I'm stuck with a poor left side, spasms they can't control (6 drugs later), and a wheelchair for my future. Keep preaching, doc, maybe they will wake up
I’m not a scientist I don’t have the jargon. However, for me as a woman going through perimenopause it gets me thinking why do women fair better than men. Why when pregnant women with MS feel amazing. Why is it women who have went through menopause talk in groups about symptoms worsening. Estrogen and progesterone have flat lined. HRT has become more mainstream talk in the media more than Iv ever seen it. More women are going on estrogen and will and can stay on HRT forever.
I would love to see how this will affect long term decline. Or if keeping estrogen helps.
I agree with you. There is already evidence that HRT and oestrogens help MS. Unfortunately, the evidence base is not class 1, which would lead to a change in prescribing behaviour. Saying this, I encourage all post-menopausal women with MS to consider HRT unless there is a contra-indication to HRT.
Where do you stand on HRT (Test supplementation really) for men? Despite a truckload of calories and a fair bit of sport I keep losing weight and muscle mass.
Good reads, and I agree, being an old smoulderer, that the concept of smouldering/SAW etc being *the* real disease makes complete sense to me. I say this because consider the time and brain lost just getting a diagnosis, and time is brain! As I’ve said before, as a high functioning person who is now losing it, I have never had any tests for comparison to measure cognitive function. With that, I defer to Tom’s cogent comment, whose MS journey has been very similar to mine. Even though cyclophosphamide was difficult to take for chemotherapy, I know I had a huge remission of MS. (And I also had a great 20+ years.) So I agree. Were I younger at this point, I’d also be looking at stem cell. I also have the issue that as I age, MS is melting into the stew of comorbidities. So we plod on and find something each day. Thanks for bringing this to us.
Gavin, what would you advise someone recently diagnosed with PPMS?
I saw you previously state that if you were diagnosed with MS you’d get HSCT. Would that be true if you developed progressing symptoms? Would you sink your life savings into pursuing HSCT route ASAP or prioritise living your best life while you have the luxury of mobility? The prospect of debt, the risks of the treatment and recovery and then seeing no net gain in terms of halting progression of disability versus taking the holiday of a lifetime and hoping for a breakthrough in remyelimation is the gamble I’m facing. I’d be grateful for your thoughts.
Great piece of work. 'Lotsa' questions.
1 'New' or 'enlarging T2 lesions' ought to be QUANTIFIED, no longer is it enough to say something has worsened or not, based on 'observations'. We need objectivity. Of course we do NOT use available technology to characterize VOLUME loss.
Most smoldering associated worsening is seemingly 'patient-driven' and therefore hugely subjective.
2 Why don't we simply accept the notion that the disease is relentlessly progressive, and whether it's defined under PIRA or SAW, or any other metric, the worsening is relentless over time and that DMTs have minimal or no role in the process ? This is probably true in about 70% of all MS patients, and whether it is reported or not by the patients themselves, one can look at the data and arrive at this conclusion. We honestly do not need more 'evidence' do we ? This could be true for MOST neurodegenerative disorders !!
3 Based on metrics such as reduced exercise endurance, exercise induced symptoms (aka Uhthoff's), worsening of fatigue, and generalized 'worsening', almost every single patient with multiple sclerosis can be considered to be worse from when they began the treatment. And if you consider Parkinson's or Alzheimer's I am sure the parallels are eerily similar.
4 We do not even test for cognitive function (no uniform, OP-based testing) in MS and certainly have zero consensus on the characterization of cortical lesions. Folks who have access to 7T magnets have reaped the benefit of such technology by producing gobs of publications with almost zero utility for most university-based clinics across the USA who do NOT have such fancy toys, let alone Europe. It is a mismatch at many different levels. It is like you have a GM cricket bat while mine is from some lumberyard, fashioned as one (cricketing analogy - you are from SA and I am from India, so we get this).
Jagannadha Avasarala
U of Kentucky Medical Center
Lexington, KY
“Why don't we simply accept the notion that the disease is relentlessly progressive, and whether it's defined under PIRA or SAW, or any other metric, the worsening is relentless over time and that DMTs have minimal or no role in the process ?”
For MSers this must be considered a sad day. 20 years ago (when I was diagnosed) MS was an autoimmune / inflammatory disease which went into “remission” for RRMSers. We were also sold a line that the most powerful DMTs could turn off relapses and shut the disease down. 20 years later and we’re back to square one. MS is a progressive / neurodegenerative disease from the start and stopping relapses / focal inflammation has little impact long term - the unrelenting tissue damage / neurodegeneration continues. And there are no treatments to stop it! Good news for MS researchers - certainly another 20 annual ECTRIMS conferences to go. You wonder what’s been achieved in the first 40!
When you look at progress in MS over a 2-5 year timeline little happens, but over decades an enormous amount has changed. I think we know a lot more now than we did in the past. The insights into smouldering MS are probably not new. Prof. George Ebers was making the case for SAW 30 years ago, but the MS community ignored him. Sometimes ideas need to mature before the larger community are prepared to accept them. Let's hope the MS community accept SAW.
Never sure what “MS community” means! Surely any half decent neuro can see deterioration in their MS patients over time, regardless of what DMT they are on. Researchers picked the low hanging fruit - relapses. And pharma cashed in. Progression (SPMS / PPMS) was too difficult so researchers ducked out (bar a few underpowered studies). I like the way we are ‘hoping’ for the MS community to accept SAW. MSers have to live with the reality of SAW everyday.
We’ll have to agree to disagree on the amount of progress made in MS research. I find stories like this heartbreaking:
https://mstrust.org.uk/news/stories/advanced-ms-23-years-old-my-story
You are kind of where I am on this, and I just posted a comment that has a similar flavor. I feel as if someday--in the who knows how distant future--real answers (and therapeutic solutions) to the questions we really care about are going to come from outside MS-focused research, per se.
Suppose as a patient I could get 7T scans, what would it help? There is at least one 7T machine in the city where I live but I really doubt it would do me any good whatsoever....
I would like an answer to this Q, as I am getting a 7 Tesla scan in December.
A 7T scan will let you and your neurologist to see much more detail, i.e. paramagnetic rims lesions, cortical lesions, etc. and may be identify many more small lesions that would be missed on the conventional scan. But it would not really change clinical decision making very much.
Thank you! Helpful
I have secondary Progressive ms, I agree with the smouldering ms ,it’s quietly taking more of my functions away I haven’t had any relapses, but in the past 6 years, , I’ve lost the motor function in my left leg and foot, but haven’t been able to walk far in that time and now can’t walk at all, but thankfully so far my arms are still working , I love following your page as the neurologists I’ve seen, say there’s nothing to help me now
Re: "there’s nothing to help me now"
There are always marginal gains to be had from managing MS holistically. Have you read the following newsletters?
https://gavingiovannoni.substack.com/p/aan-2023-what-is-the-greatest-unmet?utm_source=publication-search
https://gavingiovannoni.substack.com/p/brain-health-how-important-is-it?utm_source=publication-search
'Marginal gains' are, by definition, marginal.
Not when you add them all together, which is why you need to do them all to see the difference.
I don’t know if you mean overwhelm. We have no one where I live to coordinate services. My fatigue is so great right now, I’m at my wit’s end, but it’s another medical issue. I wish I had energy because there is no assistance..
Even if one has a less-than-rudimentary understanding of the immune system—which I do—scanning this article, it appears that there are so many potential elements of the immune system possibly implicated in progression that it will take decades to sort it out. It took decades to figure out that MS was a B-cell mediated disease and to develop relatively crude B-cell therapies for tamping down focal inflammation. It’s difficult to be optimistic.
Re: " It took decades to figure out that MS was a B-cell mediated disease and to develop relatively crude B-cell therapies for tamping down focal inflammation. It’s difficult to be optimistic."
Are you sure MS is a B-cell mediated disease? The evidence suggest the contrary. My take on why B-cell targeted therapies work in MS is that they are targeting EBV. In addition, most of the B-cell therapies don't scrub the B-cells and plasma cells from the CNS compartment, which explains why they are not that good at tackling SAW.
Thank you for sharing this with us. The paper notes that “…early in the disease course, among subjects with no walking impairment, transient exercise-induced neurological deficit (eg, foot drop) or early fatigability are commonly reported.”. Can I please ask if this how progression in MS typically manifests in the early stages?
I am 3 years post diagnosis. I have no obvious walking impairment on a neurological exam, but following a spinal cord relapse I experience exercise induced leg weakness and unnaturally poor muscle endurance. Unfortunately these things are not picked up on a typical neurological exam.
This is all based on my own experience. I believe the initial RRMS attack is highly affected by inflammation which subsides and symptoms therefore improve. (we know that.) Damage and scarring of nerves occurs, which can produce symptoms on top, to which the sufferer may make adjustments given new alternative nerve connections, repair of some lost myelin, and use of alternative ability making up for the old ones lost (we know all that). This is where I was from about 2000 to 2016, after initial light (1990) and relative severe and complicated numerous symptoms through 1995). Then I went back seemingly to about normal for 20 years.
I believe the initial repair of myelin breaks down with time, along with loss of some alternative ability, leading to what is perceived as SAW (at least for me). Worsening symptoms included bladder function and walking skills. Add to this all, other walking problems not MS, but probably brought on over time by deficits in motor skills caused by MS (peronial neuropathy). PTTD for example, brought about after a lifetime with flat feet but no symptomology, I was a fast runner in HS. Painful toe nails for example due to MS clonus combined with increased reflexes. I have had no new MRI detected lesions since 1996 except for in 2000, on my spine during a temporary switch from Betaseron to Avonex for 9 months [seemingly a bad idea]). I did do Ocrevus for a couple years, but at 62 years, Covid put the K-Bosh on that one. Now I’ll just stick with Alpha Lipoic Acid and Simvastatin.
So I am still stuck on the idea that my MS at present is minimal. When you get to my age (66) and have been where I have, you can expect stuff unrelated to MS to accumulate with your MS and it’s tuff to keep up with. People newly diagnosed try their darnedest to get back to believing everything is OK, and when they discover for themselves it isn’t, they are devastated, perhaps again. I made it generally in one piece, and even though most of my treatment was “CRAB” medicine, I believe it kept me in one piece. We have to go back to basics. I am not going to live forever. At some point, even with the best of health, life becomes a pain in the ass. But most of us would still rather live it. So I’ll plow ahead as best I can and try to do something meaningful as long as I can.
The Consensus is quite detailed and beyond my expertise although I read a fair chunk of it. This and the consensus are a great status report but could upset a few. I usually vote to tell the truth. Seems like aHSCT is the way to go for now if you are young enough at the very beginning. Deal with this stuff when you have to.
Tom, as usual, you hit all the high notes. I’ve got more fish to fry at this point than MS. Plus, I find looking backward is, uh, unproductive? (Former gymnast, now without balance. Sometimes, you just gotta laugh…)
That has a funny twist.
Very interesting but where does that leave me as newly diagnosed (although had symptoms for 4 years!) and no new lesions on mri but a positive lp? My worsening has been put down to smouldering disease! Should I push to go on an immunosuppressive dmt that at my age of 58 could be of little benefit and put me at risk of serious infections? Many thanks.
great news that smouldering ms is maybe going to be considered more seriously.
thankyou!
3 questions please:
1. will this change approach to dmts?
should patients with new diagnoses start on dmts, then swap to smouldering treatment?
or?
2. there are so many of us late / undertreated on DMTs. but most neurologists just seem interested in the new / recent diagnoses. Its - surely- easier?
but where do the rest of us fit in? nowhere important, it seems.
(the reason ive only recently gone for dmts (after 30ish years) is that i always thought dmts treated mri results more than disability.)
3. multimorbidity
im sure its not only me who has more than an ms diagnosis
its very disappointing that those other parts of us are still ignored
eg im just not sure if im more smouldering - and/or struggling with my non-ms diagnoses
Re: "1. will this change approach to dmts?"
Yes, that is the aim of the paper, i.e. to get the MS community and regulators to change the development paradigm so we have DMTs that primarily target SAW.
Re: "3. multimorbidity"
Not sure they are being ignored. One of the drivers of SAW are comorbidities (infections, HTension, diabetes, sedentary behaviour, poor sleep, etc.), which is why I such a big proponent of the holistic management of MS and the marginal gains philosophy.
Re: "2. there are so many of us late / undertreated on DMTs. but most neurologists just seem interested in the new / recent diagnoses. Its - surely- easier?"
In my opinion it is never too late to treat MS. Even in the terminal phase of the disease you can do things to improve QoL and make things easier for pwMS and their families.
Yes, I have more than MS, and it’s beginning to be more difficult to parse this out. I hear you.
Thank you.
Gotta say I’ve often aspired to be classified as ‘smouldering’, so I for one, a laywoman with PPMS, am delighted by the terminology you are developing!
Totally agree. Current practice is to look at the scar, and not the injury underneath. Well, they call it active or no, but the injury is under the scar. That's what needs to be treated, and so far our only treatment is shutting down the immune system. Which they won't do at my age, 66. So I'm stuck with a poor left side, spasms they can't control (6 drugs later), and a wheelchair for my future. Keep preaching, doc, maybe they will wake up
I’m not a scientist I don’t have the jargon. However, for me as a woman going through perimenopause it gets me thinking why do women fair better than men. Why when pregnant women with MS feel amazing. Why is it women who have went through menopause talk in groups about symptoms worsening. Estrogen and progesterone have flat lined. HRT has become more mainstream talk in the media more than Iv ever seen it. More women are going on estrogen and will and can stay on HRT forever.
I would love to see how this will affect long term decline. Or if keeping estrogen helps.
I agree with you. There is already evidence that HRT and oestrogens help MS. Unfortunately, the evidence base is not class 1, which would lead to a change in prescribing behaviour. Saying this, I encourage all post-menopausal women with MS to consider HRT unless there is a contra-indication to HRT.
Where do you stand on HRT (Test supplementation really) for men? Despite a truckload of calories and a fair bit of sport I keep losing weight and muscle mass.
I need to find an open minded endo...
Re: "Where do you stand on HRT (Test supplementation really) for men?"
Please read:
https://gavingiovannoni.substack.com/p/q-and-a-40-should-i-take-testosterone
Good reads, and I agree, being an old smoulderer, that the concept of smouldering/SAW etc being *the* real disease makes complete sense to me. I say this because consider the time and brain lost just getting a diagnosis, and time is brain! As I’ve said before, as a high functioning person who is now losing it, I have never had any tests for comparison to measure cognitive function. With that, I defer to Tom’s cogent comment, whose MS journey has been very similar to mine. Even though cyclophosphamide was difficult to take for chemotherapy, I know I had a huge remission of MS. (And I also had a great 20+ years.) So I agree. Were I younger at this point, I’d also be looking at stem cell. I also have the issue that as I age, MS is melting into the stew of comorbidities. So we plod on and find something each day. Thanks for bringing this to us.
Gavin, what would you advise someone recently diagnosed with PPMS?
I saw you previously state that if you were diagnosed with MS you’d get HSCT. Would that be true if you developed progressing symptoms? Would you sink your life savings into pursuing HSCT route ASAP or prioritise living your best life while you have the luxury of mobility? The prospect of debt, the risks of the treatment and recovery and then seeing no net gain in terms of halting progression of disability versus taking the holiday of a lifetime and hoping for a breakthrough in remyelimation is the gamble I’m facing. I’d be grateful for your thoughts.