Classification of progressive MS


Typically the onset of disease progression in MS is ‘silent’ and differs from person to person. Not surprisingly, attempts at defining at least clinically has not been an exact science.

In a letter to Annals of Neurology Gil-Perotin et al. (Valencia) ask an important question, whether progression during the relapsing phase of MS is the same as in secondary progression (refer to MS-EPIC Team Silent Progression in Disease Activity-Free Relapsing Multiple Sclerosis. Ann Neurol. 2019; 00:1-14), or is there what is called bout onset progressive MS (BOPMS, includes single attack progressive MS and progressive MS after RRMS onset) where pre- and post-progression relapses accelerate time to progressive disease (refer to Mateo Paz Soldan Relapses and disability accumulation in progressive multiple sclerosis. Neurology 2015; 84(1): 81–88).

In biological terms the first is the pure progressive model defined by brain volume loss, whilst the latter is the focal inflammatory model (defined by T1/T2 lesion volumes). If you focus on this, by definition there is neuro-axonal loss (defined by neurofilament release) during both processes; so the two are not disparate in occurrence i.e. at least superficially; progressive MS pathophysiologically (disordered physiological processes associated with disease or injury) is the one and same disease process. However, the temporal process of neuro-axonal loss may differ, owing to differences in the underlying pathobiology (mechanisms of disease), and this is what we don’t know. Is the focal inflammatory model therefore, purely synaptic damage, whilst brain volume loss is the loss of large myelinated axons? And, where and how does regeneration and neuroplasticity fit into all of this?

If we re-think progressive MS along these lines, we will have a better understanding of the changes occurring at a clinical level.

If you disagree, then I’d like to hear your view point.

About the author

Neuro Doc Gnanapavan


  • Honestly? As someone with MS, I have no idea.

    I’ve had MS since I was a teenager, so paediatric MS, but no one would believe me so I was misdiagnosed as mentally ill with Chronic Fatigue Syndrome for decades.

    During that time, I honestly couldn’t tell you when I had ‘relapses’. I was never aware of them. I was severely disabled the entire time. I did go up and down, but not to any degree I would have called a relapse or remission.

    There was that time I went blind, and repeated episodes of numbness. Were they relapses? I still have no idea.

    When I eventually gave up on the NHS, diagnosed myself, went private, had my first ever MRI scan, and was proved right about everything, I was then told that my MS was by that point inactive, and they wouldn’t give me any treatment.

    But because the NHS had spent many years refusing to let me see a neurologist or have any neurological tests, there was no record or MRI scans up until then, and I’d been on no treatments.

    Then they did my second ever MRI, found activity, and put me on Plegridy, which made me even more ill.

    If I had been braver, I would have said no, I want Lemtrada. I did then try for HSCT, but they said no. They did then say I could have Lemtrada, but I couldn’t manage it as an outpatient with my disabilities and while I was trying to find a way they’d let me do it they restricted it.

    I’ve lived with MS for decades with no treatment for the disease, or the symptoms, or support. I’m used to having to try and survive on my own. I haven’t adapted to reporting symptoms to MS nurses, even if I had the energy, which I don’t. And I still have no idea when I have relapses.

    The local neurologist, having met me twice, told me I was going into secondary progressive. That was a few months after being diagnosed with relapsing remitting. And almost 30 years into being severely disabled by MS.

    To be honest, primary progressive seems closest to my experience. But I guess like anything else in life, nothing entirely fits, and one just has to accept the closest definition. And its all social constructs, so it may change, they may name another category of MS that fits me better.

    However, I will fight any attempt to change my diagnosis from relapsing remitting, because I already can’t access the top treatments and that would make it even harder.

    I still have no real concept of relapses, remissions, or secondary progressive. Do I feel significantly worse than I have since I was an adolescent? No. And given that there are no MRI scans to look back on, I don’t know how a neurologist who doesn’t even know me came to that conclusion. I am now losing the use of my right side. Is that the beginning of the end, or just another stop along this long journey that will at least improve? No idea.

    I know I desperately want Lemtrada or HSCT, because they seem to be my best bet to slow my MS. I already have ‘significant cerebral atrophy’, and Lemtrada seems to be the best treatment to slow that down. And, honestly, I just want to succeed at managing it, and for the NHS to finally give a damn about me.

    And it’s all so subjective. What counts as a relapse? I’m autistic and traumatised, I didn’t even know to tell them. How often are they going to give me MRI scans to look for new activity? Why doesn’t the NHS care that it’s entirely their fault I haven’t tried and failed more DMT’s?

    But they’re saying no to everything now. And I’ve told them that if they don’t let me access treatment, I’m going to go to a suicide clinic on mainland Europe.

    I realise this is no academic help. But MS isn’t academic to me. It’s my life. And this is my personal experience.

    • Jay,

      What a heart-wrenching email. I suffer from MS as well and I’m from the US so our health system is quite different than yours, but hearing your story and feeling your frustration with your NHS and its reluctance to provide you the treatment that you need is maddening. Hopefully someone at Barts will step up and offer some advice on how you can get out of the quagmire that you are stuck in.

      Good luck to you.

    • Hello Jay, sorry to hear your story. As you’ve pointed out clearly the clinical disease course is very ambiguous and open to different interpretations by different people. Delays in diagnosis are not uncommon, primarily driven by bottlenecking to see a neurologist in the current health service. Unfortunately, as this is a blog we cannot advice on individual cases. However, most neurologists and those at Barts Health will review for second opinions to re-evaluate disease activity. Please consider these options. We have also highlighted, new clinical trials targeting progressive MS: MS-STAT2 (UCL), sub-cut Cladribine (Barts Health), Ixazomib (Barts Health), that are additional options. Take care, NDG

      • Thank you very much for replying.

        At this point, my diagnosis is still relapsing remitting, as far as I’m aware,

        I did do what you’ve suggested, I asked for a second opinion. I asked to see ‘the best MS neurologist in the country.’

        I got referred to Prof G and have seen them once so far. I’m anxiously awaiting another appointment.

        The best the neurologist here will let me have is a possibility of Mavenclad. I was offered Lemtrada, I even had the chest x-ray and blood tests. But now they won’t let me have it because it’s been restricted. HSCT was never on the table.

        I’m sure that some people have their MS diagnosis delayed because of lack of neurologists. But that is 100% not what happened to me. The NHS didn’t delay diagnosing me, they would never have diagnosed me.

        They didn’t believe me. They wouldn’t let me see a neurologist. I wasn’t on a long waiting list, I couldn’t get a referral, I got turned down over and over.

        I tried numerous GP’s at numerous practices. The last GP I tried said there was ‘no clinic reason’ to refer me to a neurologist.

        I then gave up on the NHS, having diagnosed myself, had a battle to even get a private referral to a neurologist, but got one, paid to see a neurologist, and was proved right about everything.

        Literally a few seconds on google diagnoses my MS. If one puts in ‘fatigue, pain, numbness, optic neuritis’, google outright says ‘Multiple Sclerosis’ followed by page after page of links to nothing but MS.

        It’s not that hard to diagnose me. I did it.

        But the NHS made the choice to not test me for anything physical because they made the decision that I was making it all up because they had decided it was all in my head. They didn’t let me see a neurologist and do neurological tests to back-up what they thought. They had the irrational illness beliefs that I was wrongly accused of.

        I had MS undiagnosed for almost 30 years, and the NHS were just a cult convincing me I wasn’t sick and it was all my fault.

        I went blind from Optic Neuritis years before they misdiagnosed me with Chronic Fatigue Syndrome and years after that I got myself the correct diagnosis of MS.

        And now? The NHS doesn’t care that it destroyed my life. It wouldn’t even make reasonable adjustments so I could have Lemtrada.

        Honestly, all my hopes are resting on Barts. We’ll see what they’ll let me have…

        Meanwhile I’m joining Dignitas, for if all else fails.

        I know I sound bitter, it’s only because I am. But thank you for replying, and take care too.

        • Hello Jay, your feelings are justified, but you also sound like a fighter to me. I hope that fight doesn’t leave you and the Barts team is able to offer you a treatment. Best, NDG.

  • It has been demonstrated that patients with RRMS and SPMS have
    antibodies directed towards oligodendrocyte precursor cell lines, but only the
    SPMS patients had antibodies directed towards a neuronal cell line.49 This
    supports the idea that the concept of epitope spreading is important in MS.

    What is secondary progressive disease?
    From a clinical point of view SPMS is a loss of function that occurs slowly
    and gradually over years or even decades. Relapses tend to be absent or
    mild. SPMS cannot be treated successfully,25 and therapy can at best achieve
    slowing of deterioration.26 From an imaging standpoint, SPMS is
    characterized by axonal damage and increasing atrophy of the brain and
    spinal cord.27 This axonal damage can be measured in the CSF of MS
    patients as increased levels of neurofilament.

    Joachim Burman

    uppsala universitet

    Ps:This “colective cyborg” is saying (once again ) that relapse are independen of long term disability
    Whats your take on that?


  • This has been answered before…DMT control focal inflammation but do little for the long term smoldering inflammation that leads to diffuse brain atrophy and progressive disease. Reason newly diagnosed forego DMT for hsct.

    Long‐term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing–remitting MS.

    .The appearance of silent progression during the RRMS phase and its association with brain atrophy suggest that the same process that underlies SPMS likely begins far earlier than is generally recognized and support a unitary view of MS biology, with both focal and diffuse tissue destructive components, and with inflammation and neurodegeneration occurring throughout the disease spectrum.

    Moreover, as relapses and focal white matter lesions are brought under excellent control by disease‐modifying therapies for RRMS, the effectiveness of these agents against silent progression is likely to represent a key determinant of their relative value.



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