Slip-sliding away – do I have secondary progressive MS?

S

Barts-MS rose-tinted-odometer – zero stars

We have been running a campaign that #MS_is_1_not_2_or_3_diseases for sometime. This is based on the biology of MS and not what we see clinically. The pathology that underpins so-called progressive MS is the loss of axons, loss of neurons and loss of synapses, which are the chemical connections between neurons. All three of these processes begin very early in the so-called asymptomatic stage of MS. What dictates whether or not we see the effects of these subtle changes depends on how much we stress the neurological system concerned and how much resilience, or reserve, this system has to handle the stress.

A good example is a marathon runner with MS who develops a dropped foot after running for about an hour at race pace. A year earlier he would only notice that symptoms towards the end of the marathon. Does this marathon runner have SPMS? If this runner had not stressed his motor pathway with vigorous competitive exercise the issue of whether or not he has SPMS would not arise. In other words, the question of SPMS would only arise when his dropped foot would impact on normal activities of daily living, for example walking, which may have only occurred in 10 years time if he had not been a runner. 

What this anecdote tells us that the diagnosis of SPMS is a moving target and depends on what system, or systems, MS has shredded, how you use that system and how much reserve is left in that system to compensate for the damage. We know progressive cognitive dysfunction is the driver of early unemployment in so-called knowledge jobs. Why aren’t these patients being labelled as having SPMS? That is because neurologists, first and foremost, view MS as a physically disabling disease rather than a cognitively disabling disease. This needs to change; #ThinkCognition

The diagnosis of SPMS is therefore in the eye of the beholder. In my eyes, progressive MS is present from the beginning of the disease. Trying to identify a point in time when you can be diagnosed with SPMS is futile and to discuss transitioning MS is a misnomer. Neurologists think we are smart when we classify our patients as having relapsing-remitting MS, or relapsing SPMS, or non-relapsing SPMS. Let me tell you this is a fallacy. 

For example, I am doing a relapse assessment on a patient later today who was thought to have non-relapsing SPMS. Four weeks ago she went off her legs with new-onset weakness in her good leg. Her MS nurse said this is likely to be progressive MS and asked her to sit it out. Over the last few weeks, she has been recovering function in that leg and has started to mobilise again. Based on her history it is likely she has had a relapse. I am seeing her, to document the likely relapse, to assess whether or not she needs a course of steroids and to counsel her about her future treatment options. At present, she is not on any DMT having completed two courses of off-label cladribine several years ago. 

The problem the MS community faces is that we view MS through clinical and MRI spectacles and we don’t think about the biology of the disease. If we took a biological approach to MS all MS would be labelled as being inflammatory, all MS would be active and all MS would progressive. Based on this thinking all people with MS would need to be offered treatment with a combination therapy approach and treated holistically. 

The following study below describes the development of a new HCP-completed questionnaire to support HCP-patient interactions in evaluating disease transition or progression to SPMS. Using a prompt like this in clinical practice will almost certainly lead to an earlier label change in the notes, i.e. SPMS being diagnosed earlier. Will this help the patient? In the UK once you are labelled as having SPMS you are meant to stop DMTs. Would things change if NICE approved siponimod for the treatment of active SPMS under the NHS? If siponimod was green-lighted by NICE the SPMS label had better be ‘active-SPMS’ and not ‘inactive-SPMS’. The latter label would make the patient ineligible for treatment. 

Another problem around the corner is that what happens if you now are now labelled as active-SPMS and start on siponimod and you then have to stop taking it because of lack of efficacy, poor tolerance or an adverse event?  Will we be able to relabel the patient as having relapsing MS and put them back on a DMT that is licensed for relapsing MS? I call this flip-flopping and it happens all the time in clinical practice. However, it is likely that NHS England will put in place systems to prevent this from happening. My solution is to get rid of labels and let the neurologist and the patient decide on what treatment they want. 

I think all the licensed treatment for MS, including HSCT, work in patients with active MS but have very little impact on smouldering disease. Smouldering MS is really the next frontier in the management of MS. 

I hope the above demonstrates the folly of our ways. We need to call-out MS for what it is; an inflammatory neurodegenerative disease from the outset. Our guiding treatment principle should be to diagnose and treat MS early and effectively to prevent end-organ damage. Our therapeutic aim should be to maximise brain health for the duration of our patients’ lives. Anything less would be doing them a disservice. 

Ziemssen et al. A mixed methods approach towards understanding key disease characteristics associated with the progression from RRMS to SPMS: Physicians’ and patients’ views. Mult Scler Relat Disord. 2019 Nov 18;38:101861. doi: 10.1016/j.msard.2019.101861.

OBJECTIVES: The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) evolves over time and it can be challenging for physicians to identify progression early. Typically, SPMS is diagnosed retrospectively with a significant delay, based on a history of gradual worsening, independent of relapses, following an initial relapsing-remitting disease course. As such, SPMS is often associated with a considerable period of diagnostic uncertainty. This study aimed to explore and characterize key symptoms and impacts associated with transitioning from RRMS to SPMS and inform the content for a tool to support evaluation of early subtle signs suggestive of progressive disease.

METHODS: The qualitative study involved 60-min, face-to-face, concept elicitation (CE) interviews with 32 patients with MS (US = 16 and Germany = 16); and 30-min, telephone, CE interviews with 16 neurologists (US = 8 and Germany = 8). Multivariate analysis on data from a real-world observational study of 3294 MS patients assessed the differences between early-RRMS and early-SPMS, and identified factors that were significant drivers of this difference. These studies informed selection of the key variables to be included in a pilot tool. Sixteen physicians used the pilot tool, presented as a paper questionnaire, with a sample of patients whom they suspected were progressing to SPMS (n ≥ 5). Following this, the physicians participated in a 30-min cognitive debriefing (CD) interview to evaluate the relevance and usefulness of the tool. Qualitative analysis of all anonymized, verbatim transcripts was performed using thematic analysis.

RESULTS: Patients and physicians reported signs that indicated progression to SPMS including gradual worsening of symptoms, lack of clear recovery, increased severity and presence of new symptoms. No specific symptoms definitively indicated progression to SPMS, however a number of potential symptoms associated with progression were identified by SPMS patients and physicians, including worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Quality of life domains reported to be more severely impacted in SPMS than MS in general included: physical activity, work, daily activities, emotional and social functioning. Multivariate analysis of the observational study data identified several variables strongly associated with progression to SPMS including, requirement of assistance in daily living, presence of motor symptoms, presence of ataxia/coordination symptoms, and unemployment. Physicians reported that items included in the tool were easy to understand and relevant. Physicians also reported that there is an unmet need for a tool to help identify signs of SPMS progression and so the tool would be useful in clinical practice.

CONCLUSIONS: This was the first stage of development of a novel, validated, physician-completed tool to support physician-patient interactions in evaluating signs indicative of disease progression to SPMS. Qualitative and quantitative methods (involving physician and patients) were used to determine tool content. The usefulness and unmet need for such a tool in clinical practice was confirmed via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm and validate the tool so that it can be reliably implemented in clinical practice.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

17 comments

  • Perhaps just using the terms ‘stable’ and ‘worsening’ would be more effective, with descriptors withing each to aid definition.

  • It’s a pity the MSologists waste so much time coming up with different terminology for the disease or names for the perceived different stages. They have used positive terms like “advanced” and “progressive” for the grim stages of MS!

    “Smouldering MS is really the next frontier in the management of MS.” My interpretation of this is fill your boots young MSologists, you will be kept busy with research / papers for decades to come. It’s taken 50 years to work out that relapses and focal inflammation are not the real MS.

    2019 has been a crap year for MSers who follow this blog. We now know MS is one disease not three or four, we now know that we are progressive from the start, we now know that the real disease is smouldering (although no treatments are currently available to treat the smouldering MS), we now know that combination treatments are needed (although the treatment to add to an anti-inflammatory is not yet available).

    Let’s hope that in the 2020s some MSologist will have the guts to do the research which leads to treatments to address the real MS. Too long has been spent pontificating about terminology, too long navel gazing, too long doing experiments on rodents who can’t get MS, too long debunking dogma or putting forward one hypothesis after another.

    Fingers crossed for 2020. I’m confident that somewhere on this little island there’s a researcher who’s going to produce something which will radically change the future of people with MS. All MSers want the same thing – not to become more disabled – we’ve been let down so far.

    • As the blog says the “Good and Bad Research news” but that’s for your summation.

      It seems that you have been learning by following the blog so we are doing our job OK.

      However science is putting one hypothesis after another

      ProfG may do his as he doesn’t get a proper Christmas break.

      As for what’s happening.on this island, the MS Society has been focussing on smouldering MS for some times as has the other MS societies the progressive MS alliance put out a call for projects just a couple of weeks ago.

      However, I will say again as I have been saying for years already, until the trial design can show a responsive change in a reasonable amount of time it doesn’t matter what science finds as it will go nowhere quickly. I have become a grumpy old mouse.

      Let’s hope that the new decade brings progress

      • At least with a Tory Government with a big majority and Brexit nearly sorted we can look forward to a brighter future. Please thank Welsh Mouse and his Welsh compatriots for helping deliver the new government.

        Have a good Christmas.

        PS Prof G could donate a bottle of Krug champagne and some Fortnum and Masons mince pies to the Whitechapel food banks.

    • Like you, I have MS. There seem to be a lot of posts that are vexatious in nature, and this is one example. Like you also, I want a cure and I don’t want to become more disabled. Time is indeed brain. However, I’m not sure if you understand just what is involved in the research process and progress. It’s not at all helpful to acuse people of failure or letting you down. It smacks of having absolutely no understanding and I will apologise to the Barts-MS Team on your behalf. Merry Christmas.

  • Prof g in your marathon runner example how would this new presence if earlier drop foot change your treatment? For example if he were already on high efficacy dmd (ocrevus or tysabri) for relapses would you switch? Add on? I imagine he would not be happy with no change given he has clear evidence of the shredder continuing to shred

    • RE: “…if he were already on high efficacy dmd (ocrevus or tysabri) for relapses would you switch? Add on? ”

      We would do an MRI with Gd and an LP to see if he raised neurofilament levels. If there was signs of activity (new or enhancing lesions and/or a raised NFL level) we would offer a switch/escalate. If there was no evidence of activity then would want to offer a trial to test an add-on neuroprotective/remyelinaton therapy.

      • If evidence of activity what do you switch to as “escalation” from ocrevus? And for those of us not in the uk what can we do as patients to seek out add ins for neuroprotection? My wish for 2020 is that the medical profession starts pushing us to treat more aggressively so that we don’t have to be so pushy and have to become experts ourselves. It is exhausting to be so proactive while living with this and trying to live our own lives too.

        • Be pushy or go under! It definitely applies in the U.K. too!
          It took 5 years before my doctor was prepared to refer me to a neurologist, despite recommendations to him from the first physiotherapist he sent me to. 5 years of decline, and £ thousands on private physio, pilates, orthotic insoles, osteopaths, who at least watched me walking! (The doctor not, because that takes time.)

  • Some people think, want, or would like, that ms was :

    Black/white
    Yes /no
    One disease

    Etc

    I remember Dr Burt saying some years ago that when he was in is twenties

    Every thing was black or white
    But now there´s more “grey areas”

    Guess some people never grow old

    🙂

    Obrigado

  • How invaluable this blog is. I used to have to wait for my consultation once a year to ask a couple of questions about: causes, diet, possible treatments, new medications, HSCT, etc., only to be told: “We don’t know “ or “People are different “ or even “Don’t worry about those things, leave it to us”. I said to one consultant that what was needed was a team of neurologists who actually had the condition themselves. From reading the various blogs over the last year, even the super scientific, I feel more confident and clear- headed about what I can do myself, less concerned about treatments or medications that are unobtainable for reasons I can now understand. Thank you!

  • How would I ask to participate in a demyelination trial? My next appointment is in July: do I have to wait till then? I am an ex runner and karateka, have had an MRI and LP, show NEDA ( but am 73) -would I qualify?

    • Hope you don’t go on a demyelinating trial a remyelination trial is what you want.

      As for the remyelinating trials in UK I am sure they will.be announced in 2020. Your egilibilty depends on the entry criteria

  • “may have only occurred in 10 years time if he had not been a runner” —
    – Does that mean the person would have done better to avoid marathons?

    More generally, should we try to avoid stressing our systems? For example, with stressful jobs or extreme exercise

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives