ClinicSpeak: managing expectations in worsening MS

Should we ban the use of the term progressive in MS? #ClinicSpeak #MSBlog #MSResearch

“We are about to have ocrelizumab licensed for primary progressive MS. People with PPMS (pwPPMS) typically don’t have relapses, they get worse slowly and relentlessly. So if they go onto ocrelizumab that slows down ‘progression’, or the the rate of worsening, of disability how are they going to know if they are responding to ocrelizumab, or not? Do you think you will know if you are a responder if you continue to worsen, albeit more slowly? I suspect not. My survey from several years ago on this issue highlights the issue. Some pwPPMS are expecting to improve, or get back to normal, with an effective DMT for progressive MS. This is an unrealistic expectation. The ocrelizumab trial data suggests most pwPPMS will simply get worse more slowly. The question is will you notice a response?”

‘I can imagine the discussions that I am going to have with our patients.  

PwPPMS: ‘Prof G you told me this drug was going to help me. It is not; I am still getting worse. Last year I could manage to walk 200m and now I can’t do more than 50m and it exhausts me. I have also had to start using a wheelchair when I go out.’

Prof G: ‘I did warn you that you may not notice any dramatic effect. Although it is clear that you are worsening, you are probably getting worse more slowly than you would have if you were not on ocrelizumab.’

PwPPMS: ‘Is there anything that you measure to show me that it is working?’

Prof G: ‘We are monitoring you with an annual MRI scan and as you have seen there are no new lesions on your MRI therefore ocrelizumab is working it is stopping new lesions from developing.’

PwPPMS: ‘It is clear that the MRI is useless in PPMS; it may work for relapsing disease but my MRI is stable and despite this it is only a matter of time before I need a wheelchair.”

Prof G: ‘Are you prepared to have a lumbar puncture? We could measure your spinal fluid neurofilament levels to see if they are raised, but as we don’t have a baseline sample I wouldn’t be able to tell if the levels have dropped on ocrelizumab.’ 

PwMS: ‘Not sure I want a lumbar puncture; the last time I had one I had a terrible headache.’

Prof G: ‘We have changed our method of doing an LP and now use a atraumatic, or non-cutting, needle that reduces the chances of you getting a post-LP headache. We are also using ultrasound guidance which also minimise the risk of a painful LP.’


‘By the way I hate using the term progressive, or progressing, MS. By definition ‘progress’ means improvement. This is why the term worsening is so much better when describing what is happening in relation to disability. Do you think we can ban the lexicon ‘progressive’ from the field of MS and get away with it?’

CoI: multiple

17 thoughts on “ClinicSpeak: managing expectations in worsening MS”

  1. With the definition of "progression" given above it only needs a minor adjustment to be a good fit for progressive MS:"the process of developing gradually towards a more advanced state of loss of function!!!"Seriously tho Prof G – they are good points you raise – how can anyone tell whether they are deteriorating more slowly than they would have done without the drug. I suspect it might come down to a balancing act for each individual between side effects and the possible slowing of function loss, and will probably be based on guesswork.

  2. Not exactly a ringing endorsement for Tysabri. When are we going to realize that T and B cell therapies are not the answer for stopping MS? Surely there are clinicians and researchers who agree……..are you out there, somewhere?

    1. I think you'll find many many pwMS who have been in remission for YEARS after taking Alemtuzumab or other T or B cell treatments may beg to differ with you here.

    2. Yes I differ.Who knows whether or not anything is the ultimate answer. But consider this: three years on effective treatment, no relapses, no worsening, a lot of improvement.Perhaps I'm like the man in the old story, the one who fell from the top of the Empire State Building. From a window someone shouted 'How's it going?'The falling man shouted back 'So Far So Good!' Short-sighted perhaps, but one doesn't have a choice

  3. I progressed from EDSS 3.0 to 6.5 in 2 weeks following a burst appendix with peritonis. Nothing gradual about that.

    1. Team G – this can't be a coincidence. Do we know why a burst appendix would take the EDSS from 3.0 to 6.5 in two weeks?

    2. Speculating completely off the top of my head, it could be that a burst appendix would release a large amount of bacterial toxins such as lipolysaccharides (LPS)into the blood stream which can enter the brain and is a well known activator of microglia and so could worsen symptoms. The question is did the EDSS go down again after the infection/burst appendix was resolved or did it stay at 6.5?You see something similar in Alzheimers patients, where a bacterial infection can worsen symptoms during the infection but improves again after antibiotics and the infection is cleared.

    3. EDSS 3 to 6.5 in two weeks is probably a relapse causing inflammation and swelling leading to block of the nerves and causing severe symptoms. As the inflammation is removed then one would expect that the symptom to reverse but may not completely to normal because damage may be done.This is the basis for some of the magic cures e.g. with HSCT…it is called natural history of disease that attacks resolve.As MD2 says factors liberated after infection can cause cells to become more inflammatory and can cause attacks indeed in one of our models we use a toxin made by the whooping cough bacteria to trigger relapses so from mouse EDSS 0 to mouse EDSS 9 in 2-3days once the disease starts

    4. I have progressive MS (SPMS reclassified from PPMS although I have never had RRMS to my knowledge).EDSS has stayed at 6.5 for 17 months now so I guess that is the new paradigm for me. I agree with MD2 and I believe that the peritonitis has caused my MS to progress rapidly without any chance of remission. My neurologist described this as "the straw that broke the camels back".

    5. Sorry to hear that! Infections are the worst when it comes to this crappy disease! I guess there was no question of getting on corticosteroids because of the ongoing infection? Just wondering if that might have prevented some of the worsening?..

  4. Personally, I think all of these "just stick a spanner in the immune system" drugs are b——-. I don't think I would take Ocrelizumab for my slow PPMS.

    1. Totally agree! I'm actually wondering if they do not as a matter of fact promote progression on their own. I also do not understand why there is not more research (to my knowledge) into why stress is such a big factor mostly in triggering relapses but also in the worsening of the symptoms. As far as I understand, stress triggers the release of cortisol which acts as an immune suppressor. Then how can a drug based on the same basic mechanism help? Can someone explain that?

  5. When we look at Dr. G's treatment pyramid of MS (inflammation-neurodegeneration-remyelination-neurorestoration), Ocrelizumab addresses only 23% of 1/4 the treatment pyramid of MS (neurodegeneration). I suppose more if you account for the reduction of inflammation by this drug.Until researchers either find the cause preventing MS or start combining drugs addressing the different levels of disease, then any individual MS treatment is bound to fail. For example, Alemtuzumab, Tysabri, CRAB, BG-12, Aubagio, Gilenya, Ocrelizumab (inflammation) should be combined with Laquimod, Ibudilast, antiseizure meds, Ocrelizumab (neurodegeneration) and anti-Lingo, clemastine or RhigM22 (remyelination) with neuroprogenitor stem cells (neurorestoration). This will never happen during our lifetime for multiple reasons for which the number one reason is cost (or greed). By just treating each level of the disease independent of one another, as is done currently, all MS patients will continue to worsen.

    1. By the time all the studies are done it will be a long, long time. But on the bright side the companies supplying the DMTs will continue to reap their profits on the newly diagnosed.

    2. Find the master brick at the base of the pryramid and you can dispense with alot of the rest

  6. I think a lot of MSers are trying to do more than just DMDs and interested in the four-part treatment ideal. In addition to Tecfidera, for example, could take MitoQ, Vitamin D, SSRI or Tramadol, coffee, green tea, curcumin, etc. Although I am concerned about safety issues, many PPMS will try any combination therapy that seems promising and they can access. (Look at the self-helpers experimenting with biotin over the past year.) The problem is you can't do that with prescription drugs, only those options that will make money are put into trials, and these trials take too long.

    1. It's relatively hard to do yourself damage with coffee, green tea, biotin or vitamin D. And likewise, whilst they may play a part within a beneficial healthy lifestyle, they are not going to make any massive difference in isolation. Kind of like flapping at a chip pan fire with a bit of damp kitchen paper. AS MD said, we need the master brick. Not a whole dose of drugs that meddle with the end stages of the MS disease cascade. EBV??? Why, oh why is this research only getting underway now? Because it may yield the black swan which earns no cash, and spoil the pharmaceutical industry's fertile drug field?

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