A sequence of losses

Prof G has the MS community go it wrong?

In this week’s NEJM there is an insightful perspective by Louise Aronson on ageing and driving.

Aronson. Don’t Ruin My Life — Aging and Driving in the 21st Century. N Engl J Med 2019; 380:705-707.

Louise quotes the American poet Donald Hall, who explains in Essays After Eighty how life is irrevocably and excruciatingly changed when a person must let go of their car: “For years I drove slowly and cautiously, but when I was eighty I had two accidents. I stopped driving before I killed somebody, and now when I shop or see a doctor, someone has to drive me. …Old age is a ceremony of losses.”

Although this refers to old age the same can be said for someone with MS. MS is a sequence of losses. Does it have to be this like this? I hope not, but to get to this position we need to go beyond NEDA.  

I am running one of our Barts-MS teaching programmes this week in which a case was presented by one of the delegates. The lady, who is in her early thirties, has a diagnosis of relapsing MS and is NEDA, off therapy for 5 years, i.e. no relapses and no new T2 lesions. However, when you look at her sequential MRIs next to each other it is clear that she has progressive brain volume loss. She has NEDA-3, but clearly, something else is happening to her brain. I suggested to the neurologist looking after this patient to interrogate her in detail, i.e. to measure her brain volume, send her for cognitive testing, arrange for a more objective interrogation of her neurological functioning and to do a lumbar puncture to assess if she has inflammation and ongoing damage as measured by CSF neurofilament levels. In other words, don’t rely on what we have now to assess her MS disease activity.

The problem we have is that we have created a beast called NEDA and the wider MS community now think evident disease activity or EDA (relapses and focal MRI activity) is MS. EDA is obviously not MS. It is clear that EDA in untreated patients is a very poor predictor of outcome. IF EDA was MS it would predict outcome regardless of being treated or not. In other words, EDA fails one of Prentice’s criteria for being a surrogate marker of MS.

Despite writing frequently on the topic that MS is not due to relapses and/or focal MRI activity the dogma seems to stick. I have arguably helped create NEDA as a treatment target and have been responsible for some of its stickiness as a treatment target. Can I admit I am wrong? NEDA is a useful construct, but it is now becoming a barrier to treating MS properly.

If I was a behavioural psychologist I would be referring to NEDA as the new cognitive bias. We need to shift our worldview of MS away from an MRI worldview. What we should be doing is creating a biological worldview of MS and asking what is happening in the ‘field‘ or the brains of people with MS. We have to explain why end-organ damage is ongoing despite switching off focal inflammatory activity. What is driving SELs (slowly expanding lesions), the subpial cortical lesion, grey matter atrophy and the accelerated brain volume loss? If we don’t then MS will remain a sequence of losses.

28 thoughts on “A sequence of losses”

  1. Out of curiosity- is this person still eligible for treatment if they wanted it as there ms is technically inactive?

  2. What would be your advice in this particular case, knowing that high efficacy DMTs are not capable of halting end organ damage? HSCT?

    1. The data suggests that your are wrong in your assumptions early treatment with high efficacy DMT moves atrophy rates in to normal aging

      1. But this lady is not on a DMT and seems to be inactive. How can you be recommending a treatment when she is inactive?

      2. Yes, under the NHS you are correct. We could an LP and measure her CSF NFL levels and if raised we can offer her off-label cladribine.

      3. “The data suggests that your are wrong in your assumptions early treatment with high efficacy DMT moves atrophy rates in to normal aging”
        With this opinion you are officially included in the dinosaur category.
        It seems Cladribine can hurt healthy brains too.

    2. This patient would not be eligible for HSCT either. Do you think HSCT would normalise her brain volume loss? If it did it would explain a lot about the pathogenesis of MS.

      I suspect this patients brain is stuffed full of microscopic areas of damage and inflammation. In particular areas of antibody binding, complement activation and microglial activation. There will be active neuroaxonal loss, synaptic pruning and loss and gliosis. There may even be a few T cells around, but I bet you the CD8+ T-cells would be dominant.

  3. As someone who reads this blog for a long long time, I have to say that I didn’t get an impression that you promoted NEDA (NEDA3) as the end goal. NEDA3 was (still is!) useful in the time where majority of Neuros were (are?) quite happy to subscribe CRABS and do a wait-and-see-its-probably-a-benign-desease-oh-its-not-oh-well-thats-life approach. It empowers pwMS with moving away from “few new holes in MRI are normal for MS” recommendation. So if NEDA3 is now the replacement of old wait-and-see approach, that’s a step forward in my book.

    It just means that we all need to talk about beyond NEDA3: biomarkers, NfLs, BVL, etc until we are blue in the face. And I hope that soon we’ll do a step forward again 🙂

    Keep up the good work.

  4. Morning.
    Please can you share the comparative data – rough percentages are fine – regarding ‘normal’ brain atrophy the one sees in ageing with healthy individuals and that experienced by someone with MS?
    I appreciate there are many subtle distinctions and it can be endlessly parsed. But…it is a rough idea that I am after. Is it, say, 20% worse with MS than normal.
    I am just trying to understand better the seriousness of the brain atrophy discussion.
    As a patient I have raised this several times to try and understand and the Q has been batted away with reference to different MRI machines, different diagnostic software versions, both of which make a comparison of past scans impossible regarding the measurement of brain volume and any changes, and, I suspect, that this hasn’t long been looked for as a specific thing.
    Thank you.

    1. Bottom line is that short-term brain volume loss (BVL) measurements in individual patients are useless unless they are extreme, for example, a loss of more than 1% per annum. The latter is necessary to overcome physiological and technical variations in the measurement. If you are losing 1% BVL per annum you are in serious trouble. The other issue is age-related brain atrophy, i.e. as you get older you lose more brain. MS may exacerbate the age-related changes as it triggers early ageing mechanisms. The following paper tries to set limits for accepted BVL in normal controls. However, I have a problem with this as the normal rate of BVL are dependent on many lifestyle and other factors that may be modifiable, for example, smoking, excessive alcohol intake, lack of exercise, etc. In other words, there are healthy agers, unhealthy agers and super-healthy agers. At a personal level, I would want to be a super-healthy ager whether or not I had MS. Nevertheless, there are not many DMTs that reduce your BVL to less than 0.3% per annum (see previous posts on this topic).

      Opfer et al. Estimates of age-dependent cutoffs for pathological brain volume loss using SIENA/FSL-a longitudinal brain volumetry study in healthy adults. Neurobiol Aging. 2018 May;65:1-6.

      Brain volume loss (BVL) has gained increasing interest for monitoring tissue damage in neurodegenerative diseases including multiple sclerosis (MS). In this longitudinal study, 117 healthy participants (age range 37.3-82.6 years) received at least 2 magnetic resonance imaging examinations. BVL (in %) was determined with the Structural Image Evaluation using Normalisation of Atrophy/FMRIB Software Library and annualized. Mean BVL per year was 0.15%, 0.30%, 0.46%, and 0.61% at ages 45, 55, 65, and 75 years, respectively. The corresponding BVL per year values of the age-dependent 95th percentiles were 0.52%, 0.77%, 1.05% and 1.45%. Pathological BVL can be assumed if an individual BVL per year exceeds these thresholds for a given age. The mean BVL per year determined in this longitudinal study was consistent with results from a cross-sectional study that was published recently. The cut-off for a pathological BVL per year at the age of 45 years (0.52%) was consistent with the cut-off suggested previously to distinguish between physiological and pathological BVL in MS patients. Different cut-off values, however, need to be considered when interpreting BVL assessed in cohorts of higher ages.

      1. Thank you, I appreciate the effort. My father, in his eighties and no MS, will be delighted by this. He maintains great fitness and loves reading and cryptic crosswords, all so, in his words, ‘he doesn’t go ga-ga’.

  5. Until the root cause and pathology of MS is properly understood, I think any talk of cure or NEDA is just chasing mirages. I think those presenting with PPMS at a young age may hold a lot of clues… The body’s inflammatory response is very damaging, and also a distraction in terms of research effort.

    1. I agree; I think the inflammatory response in MS is similar to that which occurs in leprosy and other disorders. Lepromatous leprosy is PPMS and tuberculoid leprosy is RRMS. This is a hypothesis a formulated back in 1993 and have briefly discussed it in the past. It does not change my position that I doubt MS the disease is due to the focal inflammation per se. The focal inflammation is in response to the cause of MS.

  6. Thank you for your reasoned arguements re. NEDA-3 & it’s relationship to presentations of MS but as you argue it’s not MS. I can’t but agree with the questions you post at the end of the post with regard to finding answers to the ‘story of losses’ that MS of whatever form is, what we need to be doing.

    Thank you

    Mary MS survivor of 40+ years

  7. Did you see the paper in Nature today?

    1. Lodygin D, Hermann M, Schweingruber N, gel-Koch CFX, Watanabe T, Schlosser C, et al. β-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration. Nature. Springer US; 2019 Feb 20;:1–33.

    and the “News and Views”…

    1. Pappalardo JL, Hafler DA. Multiple sclerosis enters a grey area. Nature. 2019 Feb 20;476:214–2.

    Seems like you might be ahead of your time…. Makes sense re T cells needing to be targeted. I think another obvious target of HSCT and Alemtuzumab are cells of myeloid origin. It would be interesting to see long term effects of prolonged fasting as this appears to have an effect on lymphocyte populations leading to reconstitution….

    1. Longo VD, Cortellino S. Enhancing Stem Cell Transplantation with “Nutri-technology”. Stem Cell. Elsevier Inc; 2016 Dec 1;19(6):681–2.

    1. Thanks for this. The more I read about intermittent fasting and ketogenic diets the keener I am in exploring these as a potential complementary treatment for MS. Please note complementary and not alternative. Diet is just one of the many things we can do to optimise MS outcomes.

      1. Of course, especially considering that there actually are good therapies out there now and time is brain.

        I am on day 5 of a 5 day FMD, will be interesting to see how it makes me feel.

        But the evidence regarding other measures of health, potential for long-term health, and self-reported wellness are promising,

  8. re myeloid cells…

    1. Mundt S, Mrdjen D, Utz SG, Greter M, Schreiner B, Becher B. Conventional DCs sample and present myelin antigens in the healthy CNS and allow parenchymal T cell entry to initiate neuroinflammation. Sci Immunol. Science Immunology; 2019 Jan 25;4(31):eaau8380.

    DCs express CD52

  9. Natalizumab, Alemtuzumab, etc. already proved that MS more than relapses and MRI activity… MS also means a sub-acute brain inflammation too. Hit hard early, switch the infl. off and finally preserve brain volume.

  10. Well how is EDA not MS? Does a patient with 5 relapses and 20 contrast enhancing lesions at diagnosis have the same prognosis as a patient with 3 lesions and 1 relapse if they both receive treatment and achieve NEDA right away. The problem is we don’t diagnose early and achieve NEDa; many patients have more than 20 t2 lesions at diagnosis, the innate immunity in the brain is already activated by the amount of EDA inflammation. You don’t stop it with NEDA but you stop further triggering. What data say that NEDA in untreated patients is not a prognostic marker?
    NEDA is not the whole answer but a big step forward. Next with today’s methods is early diagnosis. People with atypical sciatica should go to neurologist, not to physiotherapists with symptoms getting better after a myelitis and accumulate more lesions until diagnosis. Third is to find drugs against SEL, impaired demyelination, neurodegeneration, but first or in parallel achieve NEDA, also since we already have the tools.

    1. The point is not to be satisfied with NEDA-3. Getting there is a start, but we have to go beyond, i.e. beyond smouldering MS.

  11. I can only comment from the perspective of a person with MS. I want to step away from the whys and wherefore of these various definitions which are made up, evolve and then superceded over time.

    I find this debate incredibly frustrating. Bear with me for a brief background first of all…..I was diagnosed at the age of 48 with RRMS, rapidly transitioned to SPMS and an edss of 6.5. I had no idea before a big relapse (despite family history) that this was brewing and within 18 months I went from apparently healthy, running my own business, working more than full time to wheelchair user, many days stuck in bed through fatigue and unable to work.

    With hindsight there were many missed opportunities to note that something was wrong: EBV +ve bloods twice – aged 19 and again 3 years later; repeated respiratory infections; persistent fatigue; self resolving double vision; extreme lumbar back pain requiring facet joint injections; odd sensory symptoms; regular clumsy falls; vocal chord problems; long term depression; increasing emotional liability; strange blood results with persistently raised ESR. Even in the middle of a huge relapse which left me barely able to walk, unable to hold a pen and completely numb from the waist down, a GP sent me away with a virtual pat on the head, telling me it was “probably stress”.

    So to to get to the point,

    – individually and in isolation my issues were dealt with one by one or just ignored. medical records need to be more joined up to give a summarised and analysed timeline to give a better chance of getting an early diagnosis and facilitating highly effective treatment early. Even The nhs access app could be a lot better in this regard – the basis is in place, it just needs improving. To quote a cliche, Some joined up thinking is needed.

    – NEDA or EDA, lesions, atrophy, black holes or whatever – it’s too late. Focus on early diagnosis and early treatment.

    – Stop treating the illness and start treating the person. I can tell you that pre HSCT I could feel the active inflammation in my body. Never had active lesions and I maintain my view that lesions are a nonsense measure of disease activity, they are just another symptom. MRIs also depend on the machine, the radiographer and the interpretation so can not be consistent.

    Some really different thinking would be refreshing and I think the place to start is with those of us who live with MS – Every. Single. Day.

    So this is my challenge, talk to people with MS, find trends that give clues, look for ways to achieve early diagnosis. The lab and drug trials are not the only way to tackle research.

    PS And if on the way you can figure out how to sort out helping my mitochondria to function better so that my cells can actually be refuelled with energy, that would be great. Now that it’s too late and the damage is done, the fatigue is a killer ! Thanks 😏🤞

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