Why is the concept of MS being a progressive disease from the outset so hard to get a across the wider MS community? #ClinicSpeak #ThinkHand
Why don’t potent anti-inflammatory DMTs switch off worsening of disability? They do, but the extent to which they do depends on how much pre-existing damage there is in a particular pathway. The more damage that accumulates, the fewer healthy neurons and axons there are to repair the pathway, the less likely that pathway will flat-line or improve. In all likelihood disability continues to worsen because of the amount of inflammatory damage accumulated in the past. This is why there is therapeutic lag, i.e. you will only see slowing down of worsening, or flat-lining, occurring in the future once the delayed neuronal and axonal loss has run its course. The timing is length-dependent, in other words the longer the axon the more vulnerable it is to multiple hits and because of its metabolic load it degenerates first. This is why we see the ‘clinically-apparent’ progressive phase of MS start in the bladder and legs and only much later it involves the arms and hands and then later speech and swallowing. These observations underpin our #ThinkHand campaign to make the MS community focus on trying to preserve hand and arm function in people with more advanced MS.
The other issue that needs to be kept in mind is that premature ageing may underlie some of the delayed worsening of disability we see in pwMS. Reserve capacity protects us from age-related neurodegeneration, which is a fact of life. Speak to anyone older than 50 and they are acutely aware of their nervous system beginning to fail; reduced memory, slower reflexes, poor balance, etc. If you shred your reserve, which is what MS does, then the ageing curve is shifted left and age-related worsening of disability starts much earlier. Unfortunately, we don’t have any anti-ageing drugs at present, except for well-known lifestyle factors and preventing, or treating, so called comorbidities (other diseases) that accelerate ageing.
The following are some of the slides that I presented at the Roche satellite symposium at the EAN 2017 in Amsterdam. The purpose of the presentation was to get these concepts across. I hope the slides are self explanatory? If not, I would be willing to do a webinar (Google Hangout) to explain them and to answer any of your questions.
Why don’t potent anti-inflammatory DMTs switch off worsening of disability? They do, but the extent to which they do depends on how much pre-existing damage there is in a particular pathway. The more damage that accumulates, the fewer healthy neurons and axons there are to repair the pathway, the less likely that pathway will flat-line or improve. In all likelihood disability continues to worsen because of the amount of inflammatory damage accumulated in the past. This is why there is therapeutic lag, i.e. you will only see slowing down of worsening, or flat-lining, occurring in the future once the delayed neuronal and axonal loss has run its course. The timing is length-dependent, in other words the longer the axon the more vulnerable it is to multiple hits and because of its metabolic load it degenerates first. This is why we see the ‘clinically-apparent’ progressive phase of MS start in the bladder and legs and only much later it involves the arms and hands and then later speech and swallowing. These observations underpin our #ThinkHand campaign to make the MS community focus on trying to preserve hand and arm function in people with more advanced MS.
The other issue that needs to be kept in mind is that premature ageing may underlie some of the delayed worsening of disability we see in pwMS. Reserve capacity protects us from age-related neurodegeneration, which is a fact of life. Speak to anyone older than 50 and they are acutely aware of their nervous system beginning to fail; reduced memory, slower reflexes, poor balance, etc. If you shred your reserve, which is what MS does, then the ageing curve is shifted left and age-related worsening of disability starts much earlier. Unfortunately, we don’t have any anti-ageing drugs at present, except for well-known lifestyle factors and preventing, or treating, so called comorbidities (other diseases) that accelerate ageing.
The following are some of the slides that I presented at the Roche satellite symposium at the EAN 2017 in Amsterdam. The purpose of the presentation was to get these concepts across. I hope the slides are self explanatory? If not, I would be willing to do a webinar (Google Hangout) to explain them and to answer any of your questions.
If you buy into the above concepts then we need your support to make the widerMS community aware that in all likelihood ocrelizumab will not be made available to treat PPMS under the NHS and therefore access to the drug will be inequitable. The latter is a serious problem, undermining the founding principles f socialist healthcare and makes me very angry.
Thank you.
CoI: multiple
For the last 50 years the experts told us that it took c.10-15 years before the disease (RRMS) became progressive (neuro-degenerative). They also told us that there were two phase – inflammatory phase followed by a progressive / neuro-degenerative phase (with a tiny bit of overlap). So it's going to take a while for the idea that the progressive / neuro-degenerative phase is there from the outset. For the last 50 years various neuros have been awarded prizes for their work in understanding MS. Much of this work was about MS being a T cell disease, MS being a two stage disease. Perhaps these prizes and the money that went with them should be given back as MS is quite a different disease to the disease described by these experts (who were clearly were clearly wrong).
:-). Wonder if we'll get a prize
I doubt it. MS is a research area where the game is to come up with a theory and another research group shoots down the theory. It's kept a lot of MS researchers employed for a very long time. The pyramid graphic looks great but we never get off first base (a bit like Mouse Doctor and his first girlfriend in Yorkshire). Mouse may get a prize for vermin control as he's personally killed off more mice than Rentokill. May be for best ponytail for a 55 year old. Prof G may get an award for services to destroying the ozone from his million miles a year flying habit. I've no idea what Neil Kinnock mouse actually does. The Blog itself does deserve a prize with a special award to Mouse for all his hard work. AofTW.
"In all likelihood disability continues to worsen because of the amount of inflammatory damage accumulated in the past."Another explanation is that disability is rather independent of inflammation.The problem is that you can't really prove which explanation holds by using drugs:1. No drug can ever switch off inflammation completely, so you can always argue that inflammation drives disability.2. Since CNS resides in closed compartments of fixed volume (skull & vertebral column), inflammation exerts pressure to nearby axons, which in turn malfunction. This can be perceived as disability worsening that responds to anti-inflammatory drugs.The means you use to explore the origin of MS (handling of immune responses) are unable to discriminate whether inflammation causes disability, or runs in parallel with it. Dealing with MS by virtue of immunology alone, prevents you from testing the other possible explanation which is kept beyond reach.If ones vocabulary contains the word "witchcraft", he may end up burning witches.
A lot of compounds that have immense potential for neurorestoration also happen to feed ongoing inflammatory reactions, which has IMO made it hard to study their use for MS until recently. Now we have strong anti-inflammatory drugs (like Alemtuzumab or preferably HSCT) we can experiment with neuroprotection/neuroregeneration on top of that without being hassled by ongoing inflammation which stuffs everything up.My suggestion is to look at administration of neutrophic factors like NGF, BDNF and maybe VEGF. My concern with VEGF is that it promotes BBB permeability but if inflammation has been switched off that might not be a big problem (would be interested in comment here).
But this is not the only theory, is it? What about MS being primarily about progression, from the beginning, which is made worse by the immune system's reaction to the damage? And this length dependent axon thing doesn't ring entirely true with me, my experience of MS. At least, I think it is only a part of the story. I think the level of immune system complexity and development in different areas is what is most important.
Drugs like Alemtuzumab work far too well in early RRMS for MS not to be primarily an immune mediated disease.Also, almost every single gene we've so far discovered that is associated with MS is an immune system related gene.PPMS is the puzzling case. It often presents with very little obvious focal inflammation, yet damage progresses much faster than in most obviously inflammatory RRMS cases. Does this support the hypothesis MS isn't primarily an immune disease? Not really, because if the immune system is only reacting to damage that is occurring then RRMS should be worse than PPMS.
It may be that in pwPPMS their neurons may be more susceptible to damage than others. A similar phenomenon has been described in recovery from a stroke though genetic analysis seems to be scarce.
I have PPMS, and I have often had the impression that RRMS is in some ways worse, that in some people, the unhelpful immune system reactions are of a greater magnitude, whilst in others, the neurodegeneration plays – in relative terms – a greater role. I am not convinced that progression is not the primary damage at all. I worry about too much being based on – this sounds rude, but it's not meant to be – half-baked / pet theories.
"..if the immune system is only reacting to damage that is occurring then RRMS should be worse than PPMS."Not all immune systems are made the same. Some react more, some less. Also, the inflicted CNS areas vary between patients. Last but not least, the relapse phase can be severely debilitating, yet transient.RRMS, PPMS are outdated terms of purely clinical origin. They reflect nothing of the underlying mechanisms involved. Their initial purpose was to group similar patients for drug trials. A better approach would be the differentiation between cerebral and spinal MS. Maybe the blog MDs would agree that the spinal cord has far less placticity than the brain, and that spinal damage is not always accompanied by evident inflammation.Roughly speaking, one could say that RRMS has profound cerebral involvement, whereas PPMS is mostly spinal.
A similar phenomenon has been described in recovery from a stroke though genetic analysis seems to be scarceGreat point why isn´t the immune system doing the same thing in stroke injury (aseptic inflammation)as it does in Ms?
"aseptic inflammation"The Immune Response to Acute Focal Cerebral Ischemia and Associated Post-stroke Immunodepression: A Focused Reviewhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173797/"It is currently well established that the immune system is activated in response to transient or focal cerebral ischemia. This acute immune activation occurs in response to damage, and injury, to components of the neurovascular unit and is mediated by the innate and adaptive arms of the immune response. The initial immune activation is rapid, occurs via the innate immune response and leads to inflammation. The inflammatory mediators produced during the innate immune response in turn lead to recruitment of inflammatory cells and the production of more inflammatory mediators that result in activation of the adaptive immune response."Stroke (AIS) and MS are much more alike than most people think.
Great point …Say someone recover from a mild stroke.Why then are´nt they developing lessions and relapses,seen in ms? You have to had genetic factor in there?Thanks Luis
It's a different sort of event and is self-limiting. Those getting a stroke are also usually well past the typical age of developing MS though interestingly those stroke patients with systemic inflammation tend to have a poorer outcome.
"Why then are´nt they developing lessions and relapses,seen in ms?"The answer is straightforward, but requires courage:In MS, as in stroke, the immune system is reacting normally to tissue injury inflicted by something way above the cell scale.
No, the imune system behaves normally in the case of stroke (in the vast majority of cases that is) but abnormally in the case of MS.
Neurogenic inflammationMagnesium deficiency causes neurogenic inflammation in a rat model
MD2, but the mystery is why PPMS has so little obvious inflammation compared to RRMS. We know it isn't just RRMS + poor recovery, it's completely different in a number of ways. My pet theory (you'll hate me here Hmm) is that PPMS is actually SPMS wherein all the early damage from the disease was subclinical and in areas where MRIs can't detect inflammation easily. But it's probably a lot more complicated than this.MD2, what's your pet theory as to PPMS? If PPMS didn't exist MS would be a fairly easy disease. But it does exist, and that complicates everything. It can't be just normal MS plus poor recovery. That doesn't explain the lack of relapses, the often marked lack of any type of ongoing inflammatory activity, or the existence of RPMS.I was reading Wheelchair Kamikaze's blog and his "PPMS" features a remarkable absence of oligoclonal bands (!!).
Yes, there is little in the way of "obvious" inflammation ie lesions that than can be detected by MRI but it is probable from what I can deduce that there is a significant level of activated microglia which won't be detected by MRI, which will produce low-level grumbling long-lived inflammation that is also neurotoxic in the long term. We've seen huge numbers of activated microglia in the spinal cords of our chronic progressive EAE mice which have stopped having overt relapses. So my guess might be that PPMS might be primarly a problem of excessive microglial activity leading to neurotoxicity, which correlates with the progression of RRMS to SPMS where relapses are much less common and again the activated microglia are again chiefly responsible. So to sum up maybe PPMS reflects an overactive microglial response to initial damage, which is slower to develop in SPMS.
Sounds interesting/convincing to me, MD2. And these microglia won't be knocked out by current DMTs, will they?
No current DMTs won't, though I've been pondering for years given that aspirin could downregulate activated microglia but we'd need a trial to prove it and as there's no money to be made off aspirin it's unlikely to happen.
Aspirin is for Alzheimers:"Epidemiological reports suggest that the use of nonsteroidal anti-inflammatory drugs, such as aspirin, can prevent the onset of Alzheimer’s — although only if their use is initiated well before any signs of the disorder begin to show up in older people, Andreasson said. “Once you have any whiff of memory loss, these drugs have no effect,” she said." http://med.stanford.edu/news/all-news/2014/12/blocking-receptor-in-brains-immune-cells-counters-alzheimers.html
"And these microglia won't be knocked out by current DMTs, will they?"No..drugs can't penetrate the CNS..useless. There areimmune therapies derived from oncology but only in trials now.Get rid of CNS B cells(EBV)and maybe you plug the dam and stop macrophages,autoantibodies,NK cells, and microglia."In progressive MS, accumulation of B cells, T cells, and follicular dendritic cells can form in the meninges.21,22 These aggregates are linked to microglial activation," http://www.roche.com/research_and_development/what_we_are_working_on/neuroscience/ms/bcellsandms/see_the_clinical_connection.htm
Cladribine crosses the blood:brain barrier.Just sayin' 😉
"Aspirin is for Alzheimers" Rather more than just Alzheimer's I think, prophylactic in the case of Alzheimer's and probably Parkinson's but I think something like aspirin certainly could have an effect on slowing neurodegeneration in MS. I'd love to see a trial but as I said funding for this would have to be independent of pharma as there's no money to be made.
To Adam Bombhttp://multiple-sclerosis-research.blogspot.com/2016/01/the-special-one-cladribine-acting-in-cns.html
Would, in your opinion MD2, ibuprofen have the same effect as aspirin?
Re: OCB-negative PPMS. I think it is a different disease.
No..drugs can't penetrate the CNSThe reported CNS penetration of thiotepa and busulfan is both >80%, while that of cyclophosphamide is 20–30%.22 The excellent CNS penetration of the TBC regimen is in opposition to that of agents in the BEAM regimen, where CNS penetration of BCNU is 15–70%, etoposide is <5%, Ara-C is 6–22%, and melphalan is 10%.22 Although BCNU and Ara-C do penetrate into the CNS to some degree, the doses of these agents in BEAM are not particularly high relative to their maximal doses without ASCThttp://www.nature.com/bmt/journal/v31/n8/full/1703917a.html
MD2, how are activated microglia detected in vivo?
Crowdfunding for an aspirin trial? Or ibuprofen? Ibuprofen interests me… When I first presented with my first PPMS symptoms – "cramps" down one side of my upper body and face – I had bad period pain too. The GP put me on strong ibuprofen for a while. Maybe she really did me a favour…
Activated microglia are imaged with things like radioactive TSO using fMRI
The small underpowered trial of testosterone for MS showed a return to normal levels of activated microglia IIRC. Why? Because it protected nerves from damage so the microglia didn't need to be activated any more to clean up the damage.
In the comments above you mentioned other types of damage to the CNS; it would be very insightful if we could find evidence of the 10% progressive damage in the CNS in another area of medicine. So is it that we haven't looked hard enough or that it doesn't exist?
Prof G I vote for you doing a hangout.
Very interesting discussions. I saw my online moniker "Wheelchair Kamikaze" mentioned earlier, in relation to my "PPMS" being marked by an absence of O-bands.Just wanted to add that my "PPMS" also manifested as hemiparesis, i.e. my entire right side was effected first (starting with a slight weakness in my right knee), and now my right arm and leg are essentially totally paralyzed, with the muscles quite atrophied. For a long time my left side was left completely unscathed. Unfortunately, my left side is now severely weakened as well, 14 years after my diagnosis (I'd actually been exhibiting symptoms for 5-6 years prior).In addition to the lack of O-bands, it seems my disabilities all stem from a big, juicy lesions right at the juncture of my spinal cord and brain stem. I only have one other lesion, a very small one in the right periventricular. These lesions have not changed one iota, nor been joined by any others, since my first MRI images over 14 years ago.I also have widespread endocrine dysfunction (probably caused by some sort of autoimmune action attacking my pituitary), along with some other atypical weirdness.My neuro did an experiment, injecting my CSF into a mouse, to compare it to other mice which had been injected with the CSF of RRMS, SPMS, and PPMS patients. My mouse did not exhibit the patterns seen in the other injected mice. My critter did, though, exhibit many clusters of activated microglia in the CNS.All this is to say that my "PPMS" is likely not PPMS at all, which is why I refer to my disease on my blog most often as Creeping Paralysis.My neuro and I have agreed to call my disease PPMS, but in my case the acronym stands for the "Peculiar Paralysis of Marc Stecker". At least I can have a good chuckle while my body continues in self-destruct mode…Anybody out there care to offer some conjecture as to what it is I might actually be suffering from? All opinions would be met with overabundant gratefulness. As well as any ideas on how to shut down those activated microglia. Aspirin?Sorry about making this comment all about me, but I thought it might be interesting to introduce what has been called "Atypical PPMS" by almost all of the doctors who have examined me (including the neuroimmunology team at the NIH) into this conversation. Not all MS patients fit the predefined definitions. Perhaps we are not MS patients at all, and perhaps they were more or less out there than people realize…
IMO (MD2 will disagree with me) the microglia are activated because they need to be. They are cleaning up the debris from the chronic neurological damage going on. They are activated whenever nerves have been or are being damaged.You said that all your disabilities stem from your two focal lesions, but this is something that would need to be verified. Maybe it would be worth tracking spinal cord and brain atrophy.
WK I look after two patients exactly like you. One with a slowly expanding lesion in the upper cervical cord and the other with a progressive myelopathy. Both are OCB-ve. Both are very disabled and getting worse. For want of a better description I have labelled the first as having atypical PPMS and the second as an idiopathic myelitis.
"IMO (MD2 will disagree with me) the microglia are activated because they need to be. They are cleaning up the debris from the chronic neurological damage going on. They are activated whenever nerves have been or are being damaged."I wouldn't disagree with that, initially they may be activated as a result of inflammatory lesions and nerve damage and will phagocytose debris, however and this is the important point in many cases they remain activated long after the initial lesion has resolved and in my opinion this low level slow burn inflammation is contributing to disease progression. The same progress is fingered in Alzheimer's and Parkinson's too.
Just adding so that I will be notified of replies.
Correcting some typos:…one big, juicy lesion right at the juncture of my brainstem and spinal cord…… and perhaps there are more of us out there than people realize.Sorry about those, lack of proofreading in conjunction with using voice recognition software…
Nice post Wk keep up the good workLuis
Just thought to throw this in, following my comments about ibuprofen – I have been warned by medics to whom I've mentioned my penchant for this painkiller that long term use of ibuprofen increases hypertention and weakens the heart. And hypertention and a weak heart will worsen progression I gather. So no free lunch. And I hear about professional rugby players etc. who regularly use common painkillers and end up with serious issues like kidney problems, on dialyses for life etc. (Disappointed not to have MD's opinion on ibuprofen vs. aspirin. Even though neither can be taken long term safely…)
People have been taking low-dose aspirin (enteric-coated 75 mg) as an anti-clotting agent) safely for decades, we're not talking the huge doses ingested by sportsmen/women. From what I've read ibuprofen is not effective for the application we're talking about here.Hope you're no longer disappointed.
No – quite the opposite – thank you MD2! Many thanks.
Thanks MD2 I've been tempted to start taking low dose aspirin on a more regular basis. However having received the first round of Alemtuzumab I've test results showing low platelet levels, so I think I'm correct that it wouldn't be a good idea, at least for the time being??Your professional opinion will be appreciated. Indeed the potential interaction with other DMTs maybe of interest to others, so anything you can share will be good.
Hi FiI'm not a clinician but yes having a low platelet count (hopefully not a sign of alemtuzumab-related ITP) would mean taking aspirin is definitely NOT a good idea.
MD says it better than me
Appreciate so much the prompt reply! Glad once again as a lay person I've an accurate handle on things and that the Bart's team are always so helpful in clarification and/or confirmation. Pleased to say that no I'm not at point of ITP concern. My neuro has reassured me and I'm sensibly checking myself out on a daily basis for signs and symptoms.Thanks again!
You're welcome Fi, hope everything continues to go well.