Do we need a new hypothesis to tackle progressive MS? #MSBlog #MSResearch
The asynchronous progressive MS hypothesis; what is it? #MSBlog #MSResearch
“The MRI study below demonstrates that lesions on MRI in MSers with relapse-onset or primary progressive MS are identical. They interpret that these clinical sub-types as being the same disease. This supports all the other evidence that there is are no biological differences between relapse-onset MS (RRMS & SPMS) and PPMS. The pathology and genetics of the two subtypes are the same. Similarly, when MS occurs in families and the first sibling develops RRMS the second and third siblings may develop either RRMS, or PPMS, in proportion to their incidence in the population. PPMSers are therefore unlucky in that they don’t present with a relapse that allows them to be diagnosed earlier when their chances of responding to a treatment and benefiting are greater. But I remain hopeful that DMTs will help PPMSers for two reasons; firstly, I think there is a therapeutic lag and we simply need to do longer PPMS trials (please see previous post on this topic) and secondly, I think PPMS affects different functional systems asynchronously; i.e. the asynchronous progressive MS hypothesis.”
“What is the asynchronous progressive hypothesis? I have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the most wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts. The other systems (vision, motor system to the upper arms, sensory system, cognition, etc.) tend to be affected later by ‘overt’ progressive disease. I say overt because there is MRI evidence that the progressive component of MS is present from the start of the disease. The only reason we don’t see it clinically is because the nervous system can compensate. However, once the compensatory systems fail progressive MS ensues. This does mean that we may have different windows of opportunity to impact on these different systems. In other words there are multiple windows of therapeutic opportunity to act and we should therefor shift our focus in PPMSers on trying to delay the onset of progression in systems that are still not clinically affected. To do this we need to shift our focus away from the EDSS and use multi-dimensional outcome measures that focus on the importance of the other functional systems. This is what is currently happening as part of the Progressive MS Alliance (PMSA).”
Epub: Kuchling et al. Identical lesion morphology in primary progressive and relapsing-remitting MS -an ultrahigh field MRI study. Mult Scler. 2014 Apr.
Background: Potential differences between primary progressive (PP) and relapsing-remitting (RR) multiple sclerosis (MS) have been controversially discussed.
Objectives and methods: In this study, we compared lesion morphology and distribution in MSers with PPMS and RRMS (nine in each group) using 7 T MRI.
Results: We found that gray and white matter lesions in PPMS and RRMS MSers did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436).
Conclusions: Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI.
Another day and another nail in the coffin for those of us with MS. A couple of weeks ago we were told that progressuion e.g. nerve / axon loss is there from the start. Now we are told that RRMS and PPMS are the same disease (why did my neuro tell me that i was 'lucky' to be diagnosed with RRMS not PPMS?My prediction is that MS will be a primarily neuro-degenerative disease.This is a no-hoper disease from the start. Another hypothesis and more 'windows of opportunity' is more work for the MS researchers. Unfotunately it is bad news for those of us with the disease. Still no neuroprotective theraipies, still no repair therapies. I don't expect much change in the next decade, especially as the hypotheses keep coming (vit d and ebv seem to have gone quiet). Depressing, vile disease. Thank god for Dignitas.
I am not sure I see any new problem here. PPMS and RRMS are the same disease RRMS evolves into SPMS the processes of RRMS and PPMS/SPMS maybe and probably are different. Does RRMS condition the other or does PPMS/SPMS occur independently?. In EAE it is clear that the immune process conditions and latter and can also be superimposed upon the degenerative process once it takes hold. Stop the immune process early enough and you stop the degenerative process kicking in.Once it kicks in you may need to do more than just take an immune modulator that works to stop cells getting into the brain.There are lots of studies ongoing as you write some of them will turn up trumps
If you read this blog, there is no hope for repair because they only focus on immunosuppressive therapies. The tests done for progressive ms in the past were flawed from the beginning because the endpoints used were bad indicators of a drugs success. Because of this, more emphasis should be on the drugs mechanism of action. Unfortunately, clinicians only rely on the results of 2 year placebo controlled trials to determine what is effective and what is not. As msers you have to educate yourself and make your own decisions:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758287/
Anon, stop spreading negativity – you won't die of MS – I have MS and once you get to the wheelchair stage you actually can even welcome it as a mobility tool.
Anonymous May10, 3.52. Oh contraire, people do die from MS, but death is the least of the problems that come with MS. I'm glad for you that you are taking a more 'positive' stance in accepting MS (whatever works for an individual, may not work for someone else) but I feel it very dismissive and a tad blase to accuse the other poster of 'spreading negativity', just because s/he has a different opinion to you.
AnonymousSaturday, May 10, 2014 1:08:00 pm No, that's how it may appear at the moment but be reassured that our primary focus is on neuroprotective therapies. Results of which in MSers will start to be announced soon.
If PPMS is the same as RRMS then how are we to believe that new DMTs stop the progressive phase of the disease? No DMTs have proven to positively work on PP/SPMS. Progressive MS is the greatest unknown. It's mitochondrial failure, and no medicine can impact on that.
Until we have evidence, I won't believe it. I think there are reasonably good ideas of what is going on and as to no medicines impacting the mitochondrial problem I again think there are tools to address this also
Anon 11:28, I think you're right that he says PPMS and RRMS are the same. But I think he also said (and has been saying) something important about treating progressive disease. That is, highly effective DMTs might prove to be working on progressive disease if we looked longer than the typical 2-year trial.
What are the tools to address the mitochondrial problem? Why are we not given them, then? It's is absolutely dumbfounded you saying that mitochondrial failure is addressable because we've been told on this blog that it remains incurable, hence why PPMS has no treatments.Basically all I'm getting from this blog is suppositions, not facts. You claim you have a pretty good idea of what is going on but cannot explain the epidemiology of PPMS.RRMS and PPMS being the same goes to show that both are incurable and, in all reality, untreatable. This blog is clueless.
Wh are you not given them because Docs use evidence-based medicine and you need proof from trials .
Clueless …….read the blog there are pleny of ideas
Prof G,No thanks – no more hypptheses! Surely after 60 years of research the experts should have a good understanding of this disease? Looks like we are all progressive MSers now. And i was dreading the day my neuro was to tell me that I'd moved fron RRMS to SPMS. Now i don't have to worry – i've already made it. If we are all the same disease, what does it mean for your early highly effective treatment approach? If only neuros had focussed on neuroprotection years ago rather than the useless first line injectibles. So we must continue to wait and hope that treatments to slow or stop progression are on the way. Give past experience, don't hold your breath fellow MSers. Bad disease, bad research, bad outllook. Please just one positive story!
Speak for yourself. There are many people who are grateful for the first line therapies (me included) and the results of a two year trial that only looks at relapse rate (RRMS) or change in EDSS score (PPMS) have no real bearing on long term efficacy.Many of these drugs do show evidence of neuropotection, and the long term follow-up studies support this assumption.http://www.jhasim.com/files/articlefiles/pdf/asm_8_9p315-321-stuve.pdfNo drug is going to reverse damage that has already occurred regardless of how quickly it can suppress your immune system.
There's no doubt MS is a horrible disease and it makes it very easy to feel bitter about life.I think there are problems with the way medical research works – a lot of time, money and effort is put into piecemeal research projects that doctors have to do to advance in their career even if they have no interest in research. There's not necessarily a great deal of co-ordination of effort.There's no doubt that the state of understanding of MS feels like it's a lot poorer than it should be. If you take a step back though, overall we're no-where as advanced in our understanding of disease as is generally made out. There are still many many incurable diseases, many many poorly understood diseases, and many treatments that work, at least to some extent for poorly understood reasons.I think frustration is completely understandable, but I think that campaigning for better research and better access to currently available treatments is required. The problem is that MS can leave people with the disease too apathetic to do as much as they would otherwise like. I'm not sure that in my initial experience of the disease that I've seen the various MS charities be vocal or belligerent enough on MSer's behalf. Why is the access to treatment still so poor in the UK? Just like the researchers, are there too many charities all with their own aims to produce a more united, stronger response to the disease?
Prof G,I'm a recipient of alemtuzumab and, on MRI and clincial assessment (no relapses), currently am NEDA. Have i wasted my time? If we are all progressive, what else can I do. I don't know of any available treatments for progressive disease.
" have made the argument in the past that the neurological systems to be affected first by progressive MS are those that have the most wiring and hence more likely to be hit by multiple lesions; this is why the motor system to the legs, bladder and the cerebellar or balance system are typically affected first when progressive disease starts" Since the pathology of lesion is similar does this mean that the only difference between RRMS and PPMS is the location of the lesions? Sounds like MS and selling real estate are all about location, location, location.
Nice graphic, but what does it really mean? For the therapeutic windows, there aren't any therapies! I think what we have is a situation where all of us are experiencing progression and it's a downward slope (either slow or quick). Does this mean that the alemtuzumab experiment is doomed to fail? I felt quite hopeful the other week when you referred to the low number of alem patients who had moved to SP. I hate this disease.
Re: "The asynchronous progressive MS hypothesis."This hypothesis is not new and simply represents what we know already that in progressive MS different neurological systems get affected first and progress more quickly. What I am trying to do is make people realise that even in progressive MS there are other therapeutic aims. In other words we should continue to do clinical trials in progressive MS, but may be we should focus on other outcomes or at least outcome measures that are holistic and are not dominated by lower limb motor function and mobility. I am also trying to get Pharma to do longer studies; I really do think therapeutic lag is a real phenomenon and that we should be doing progressive trials of up to 5 years duration. Interestingly some very influential MS statisticians agree with me on this one. For those of you who despair that we don't discuss repair enough; unfortunately, we report on what is available. The fact there are so few posts on repair is that there is not much clinical activity going on right now on repair. Most of the activity in still in the pre-clinical phase.
Well put, Steve S at 4:45pm“Since the pathology of lesion is similar does this mean that the only difference between RRMS and PPMS is the location of the lesions? Sounds like MS and selling real estate are all about location, location, location.”I know that MS is different from person to person, but I think my MS stuffed up on reading the street maps and decided to go on its own road trip and arrange symptoms and lesions slightly differently to the Windows diagram above.2006 – Balance and dizziness problems started – told by ENT specialist in 2008 it was probably BPPV even though the symptoms did not match BPPV2007 onwards – problems with weakness in legs2008 – problems with loss of coordination and strength in legs2009 – getting odd little numb spots on fingers and toes, and fatigue decided to come and join the party2010 – all of the above getting bad enough to affect daily living to some extent. An ear infection resolved into classic BPPV. Soles of feet are frequently numb, and feel cold even if they are not cold to the touch.2011 – A nice little scintillating scotoma comes along to amuse me every so often.2012 –Balance is bad enough that I have to be careful not to fall over in the dark. Also developed new problems with fine motor coordination of hands for some activities (whoops – just started pouring the jug of water on the floor instead on into my glass………)Late 2012 – Bladder decides to become rather overactive, and I finally get to see a neurologist who tells me that its extremely unlike I have MS, tells me that I need MRI, nerve conduction and bloods tests etc, but sends me away without orders for any tests! This one also tells me that whatever it is, it is “terminal” – at least I was smart enough to realise that he meant to say “incurable”.Early 2013 – finally get to see Neurologist No 2 – he’s equally sure it’s not MS – I’m too old (mid-50s), and never had an identifiable acute relapse. MRI gets done about three weeks later in order to “rule out” MS – querying ischaemic blood flow problems. No nerve conduction or blood tests done. Mid 2013 – some minor cognition problems have developed – mostly lost words, and thought processes sometimes affected by a bit of mushy “baby food brain”.Five months later – get to see Neuro No 2 again – lots of lesions, including spinal. Yup – it’s MS!Now in late 2014 – can’t work full time due to fatigue, can’t “walk” more than 200m without needing to sit down, can’t sew or play music anymore, no gardening due to fatigue and un-cooperative legs.So – having copped everything so far except pain and optic neuritis it seems to me that even if there were suitable drugs available the curtains are probably already closed on most of my Therapeutic Windows!Is it any wonder that so many of us get fed up with what appears to be an obsession with “reducing relapse rates” and so many trials where the holy grail outcome seems to be a reduced Annualised Relapse Rate. If we are all progressing down that slippery slope of increasing disability, then maybe a change of focus in drug development and related clinical trials is rather overdue. At least then by the time the currently increasing number of people diagnosed with RRMS get to a stage where they no longer have relapses there might be some good meds around that don’t significantly increase your risk of getting some other deadly disease which can kill you, or make life a misery while you take them.
Hi there. How are you doing? Yep? That is the same old thing with me…………But I has 26 lesions and He still said I don't think so. 2 days later at a ms clinic with a female neuro and what else? Of course it is MS. Shortly SPMS, and now PPMS probable . Great and there is no drugs for you. It was like a Monty Python skit. I am a paranoid skeptic now…………..by choice. But it is still a beautiful day! Take care…THE QUESTION QUEEN.