How soon does the shredder begin to shred?

Barts-MS rose-tinted-odometer: zero-★s

She was only 26-years and she couldn’t understand why she was falling behind her peers at work. She started working at an ultra-competitive law firm after finishing as one at the top of her peer group at Oxford. She was clearly the best-performing intern in the 2017 intake, which is why she was kept on after her internship. However, things were now going wrong. She was suffering from chronic fatigue, forgetfulness and she simply couldn’t juggle the complex tasks she was being expected to working for more than one client at a time. This job was a high-octane one and you were expected to perform at the level. Her poor performance and increasing list of mistakes had resulted in one performance review already. What should she do?

The back story to this young lawyer is her identical twin sister had been diagnosed with MS at the age of 18, shortly after completing her A-levels. Her sister had decided to delay going to university because of being diagnosed with MS. The odds are this young lawyer had asymptomatic MS and her fatigue and cognition problems are linked to smouldering MS. Do you think she should seek a neurological opinion? She is aware that her lifetime risk of being diagnosed with MS is about 30%.

Do you think she should seek a neurological opinion?

I have made the case that the real MS is not relapses and/or focal MRI activity, but smouldering MS. The real question is when do the pathological processes that drive smouldering MS begin? In this study on asymptomatic MS (radiologically-isolated syndrome or RIS) a third of them already have cognitive impairment and two-thirds had lesions with paramagnetic rims (PRL), i.e. a rim of hot microglia. These so-called PRLs are the precursor to the dreaded SELs (slowly-expanding lesions) that are so unresponsive to our current treatments and responsible for so much damage in MS. 

So what are the implications of this study for MS? 

  1. MS begins long before your first attack.
  2. Smouldering MS, formerly known as progressive MS, also begins long before your first attack.
  3. PRLs and SELs, one of the substrates for smouldering MS, are part of MS pathology from very early in the disease course; possibly the beginning.
  4. Cognitive impairment and end-organ damage begin very early in the course of MS.
  5. We need to change our diagnostic criteria to allow MS to be diagnosed very early on, in this case in the so-called asymptomatic phase of the disease. By using PRLs and the central vein sign (CVS) we are likely to improve the sensitivity and specificity of the diagnostic criteria. So what are we waiting for?

We clearly need a new treatment paradigm to tackle smouldering MS. The current anti-inflammatory monotherapy model of treating MS is unlikely to work. We need combination therapies ASAP. To achieve the latter we are going to have to get Big Pharma and the regulators to innovate quickly and intelligently. 

Oh et al. Cognitive impairment, the central vein sign, and paramagnetic rim lesions in RIS. Mult Scler. 2021 Mar 23:13524585211002097.

Objective: The central vein sign (CVS) and “paramagnetic rim lesions” (PRL) are emerging imaging biomarkers in multiple sclerosis (MS) reflecting perivenular demyelination and chronic, smoldering inflammation. The objective of this study was to assess relationships between cognitive impairment (CI) and the CVS and PRL in radiologically isolated syndrome (RIS).

Methods: Twenty-seven adults with RIS underwent 3.0 T MRI of the brain and cervical spinal cord (SC) and cognitive assessment using the minimal assessment of cognitive function in MS battery. The CVS and PRL were assessed in white-matter lesions (WMLs) on T2*-weighted segmented echo-planar magnitude and phase images. Multivariable linear regression evaluated relationships between CI and MRI measures.

Results: Global CI was present in 9 (33%) participants with processing speed and visual memory most frequently affected. Most participants (93%) had ⩾ 40% CVS + WML (a threshold distinguishing MS from other WM disorders); 63% demonstrated PRL. Linear regression revealed that CVS + WML predicted performance on verbal memory(β =-0.024, p = 0.03) while PRL predicted performance on verbal memory (β = -0.040, p = 0.04) and processing speed (β = -0.039, p = 0.03).

Conclusions: CI is common in RIS and is associated with markers of perivenular demyelination and chronic inflammation in WML, such as CVS + WML and PRL. A prospective follow-up of this cohort will ascertain the importance of CI, CVS, and PRL as risk factors for conversion from RIS to MS.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

25 thoughts on “How soon does the shredder begin to shred?”

  1. I would agree she should seek an opinion from a neurologist and presumably it would occur to her to do so because of her sister’s diagnosis. But what happens when someone has such an experience and has no relative or close friend who has MS, doesn’t even know anything about it, except, perhaps, that it exists? A visit to a GP might come to mind but a GP is likely to leap to the idea that the patient could have MS. Surely this is why most people don’t get a diagnosis or even close to one until the disease has already caused quite a lot of damage? I am not sure how smouldering MS is tackled early on unless for some unusual reason the individual is very aware of neurological conditions?

    1. My experience was that I was accused of being a hypochondriac by my GP who refused a neurology referral. He didn’t even bother with neurological examination, just put it down to “stress” and being a hypochondriac.
      I went over his head and went private (following a neurological exam by a family member former-GP). The private neurologist then forwarded his diagnosis back to my GP.
      My GP then refused to refer me to an NHS MS specialist as I’d chosen to go over his head and go private, so I should stay in the private system.
      It took 3 years and a brain-stem lesion while my GP was on holiday for his locum to over-rule him and get me seen on the NHS. After that, it’s been fine but arguably by then a LOT of the damage had been done at least in “time = brain” terms.

      1. Weirdly Simon, my story is so similar…. my symptoms were chalked up to being neurotic and stressed while in grad school. And cognitive to stress I guess? It was years later that a significant brain stem lesion while my neuro was on vacation that got everyone’s attention. (But in my Case my dedicated neuro came to my rescue from his holiday). The lesion’s rim stayed glowing for upwards to a yr, afterwards despite a lot of steroids. “Smouldering” he called it, but No one has ever suggested it meant anything other than what was clinically obvious physically.

    2. This. So much this. My suspicion: doubly so for males (not saying medicine in general does a particularly good job for women).
      It was depression, pinched nerves, burnout (it probably was at some point), stress, post SSRI sexual dysfunction, your physically ok so eat healthy and do sport, whatever for years.
      Including two separate neuros (!) testing for carpal tunnel…

      1. Yep, me too… carpal tunnel, trapped nerve, bulging disc, difficult labour causing toileting issues…. couldn’t find my nose on my face when a private apt suggested an mri….

  2. Happy Easter Prof G. I need another outline of smouldering MS (or a pointer to the blog where you explained it). I obviously wasn’t paying attention when you first explained. Not cog fog, as my visual memory (as described above by Oh et al) must be at the 99th percentile. I recognise alumni from behind after 50 years, I’m that good. Trouble is they don’t recognise me!

  3. zero stars eh? hmmm…

    I know I started to get cognitive “slow down” in my late teens. I put it down to “student lifestyle” and “smoking pot”… First “actual” episode when I was 25 by which point I was struggling to hold down a job as a computer programmer due to concentration problems and poor attitude (aka cognitive decline and mental health problems, both probably MS).

    I disagree with zero stars. It’s zero stars if the medical community chooses to ignore all this information about CI / CVS / PRL / RIS etc.

    To solve any problem you must first admit there is a problem to be solved. This paper and this case study do exactly that. So for me – it’s one star. You identify and highlight the problem. This is massively important.

    Now they need to come up with a protocol for addressing these early signs.

    When a young person shows up at A&E with numbness or tingling or chest pains they do tests to make sure the patient doesn’t have heart problems – just to make sure. This needs to be the same thing. When people start to struggle cognitively at a relatively very early age, they should be made to get a high-res MRI to look for the smouldering pattern. Even if you can’t stick them straight on a DMT they should be told:

    1.) There is a slim possibility that you might have the early signs of an autoimmune demyelinating disease, the most famous and scary of which is MS but there are others – and what’s important is what you do next.
    2.) Regardless of whether it is MS or not, there is a bunch of stuff you must do to delay / prevent and possibly even reverse it:
    a) diet and lifestyle changes
    b) exercise and weight maintenance
    c) vitamin D – 2000 iu / day minimum from now on in.
    d) keeping an eye on it in case it gets worse.
    3.) In most people it doesn’t get worse.
    In people with MS if it does get worse, in most people it doesn’t get much worse.
    In people with MS where it DOES get much worse, if we are watchful now and monitor it and clobber it aggressively and early (at the appropriate time) we can delay it, so it doesn’t get much worse.

    Time is both your friend and your enemy. We caught it early. You have time, as a patient, to shift the odds in your favour. But time is also your enemy because it’s degenerative in teeny tiny gradual ways you won’t even notice. Time is brain. The more you (as a patient) do now to put those fires out, the less damage it can do and the less you’ll notice it 10, 15, 20 years down the line.

    In the olden days, we didn’t know any of the stuff we know now and people got very disabled with MS – but these days we have so many weapons in our armoury that it’s a completely different prospect, almost a completely different disease – and it’s something that can be controlled rather than something that just has to be managed. We wouldn’t be having this conversation now. We’d be having it in 10 or 15 years when you already had significant, irreversible – and preventable – MS damage. And you would probably already start to be experiencing all the horrible symptoms you see when you look up MS on Google which is probably exactly what you’re gonna do when we finish this conversation. As well as miracle cures (most of which don’t work) and medical cures (some of which do work).

    These days, because of these early detection methods and early treatment regimes, many people are thriving with MS just as if they didn’t have it at all or only had it a bit. It’s best to know early and prevent the irreversible damage rather than try to live with that damage. Because that then lets you continue your life “as normal” – to help prevent and alleviate any early symptoms and allow you to live a completely “normal” life, with a great quality of life, “with the condition” – and with the condition controlled.

    And yeah you guys need to come up with some more treatments too 😉 but you’re on that anyways.

  4. One of the problems with measuring cognitive impairment is you don’t have a baseline. When I flagged I was having issues, I was taken through some activities to see if I qualified for treatment in a local study. Unfortunately one of the tests was mathematical – mental maths. As a Cambridge maths graduate who had spent the last few years volunteering to support year 6 children with their maths (which is very much based on mental maths) I was counted as not impaired – unsurprisingly with my background, impaired (for me) I scored better than the majority of the population.
    The other test was word related. As someone who had noticed a drop in their ability to remember suitable words, I was doing a lot of word puzzles to assist. Again I didn’t show as impaired (enough). But I knew I was.
    Cognitive impairment is relative. We need help as we start to struggle, not waiting until we are more impaired than the majority of the population / so impaired that we can’t do things/ do our jobs.
    The biggest issue I have found has been in the loss of vocabulary, and ability to multi-task / juggle different things at the same time. As a (part-time) working mother, they are skills that are critical to my life.
    There needs to be a way of assessing cognitive impairment on diagnosis and regularly afterwards. If we are only deteriorating with age – that would be reassuring to know. If we are deteriorating faster, then we need assistance to slow the decline.

    1. This is so important.

      When we measure cognitive impairment for heaven’s sake why measure it against the “average”? That’s a crap measurement – so arbitrary and so inaccurate. Our cognitive impairment has to be measured against what we USED to be able to do. We can’t go down the route of being aggressive against the physical manifestations of MS but then say, “hey it’s ok if MS turns you from an eloquent Cambridge grad into a semi-literate moron because that’s the “average” of the population”.

      The baseline has to be that people who don’t have MS or similar conditions, over a period of 5 years, under 50 or under 60, will not experience any cognitive decline that they notice themselves. In fact, ageing brings cognitive decline but it’s not something you notice, it’s programmed in, if you like.

      So it is THAT which must be the baseline. If you suddenly find your vocabulary shrinking (compared to what it was) or your ability to reason / your logical abilities, or your ability to conceptualise and abstract – dropping markedly below what it was just very recently – then that is an important measurement.

      Otherwise we’re not comparing like with like. It’s a bit like telling someone with crumbling discs in their back being told, “well we won’t treat you until you’re shorter than the average height” – fine if you started out at just-above-average height, rather less suitable for a 7 foot basketball player…

      I disagree slightly with, “There needs to be a way of assessing cognitive impairment on diagnosis and regularly afterwards”

      All thing being equal, there needs to be a way of using a fast decline in cognitive abilities as a warning signal that all is not right. Cognition is a very important marker in its own right and shouldn’t just be an add-on at the end. I am sure I speak for many of us who would be far more inconvenienced through (please excuse the turn of phrase) losing our marbles than our ability to run 100 metres, for example…

    2. I agree but with a qualification… cognitive impairment is relative UNLESS you are comparing it to the abilities required to keep a high octane high cognitive based job, like the young woman Prof. G writes about above. In my personal experience, if EDSS is low, there is little medical validation at first, and no good employment solutions. My experience is that Human Resources is not interested in hiring someone who is considered “over qualified” and is viewed as desperate for applying for such position. And Professional jobs aren’t often available part time. My hope is that changes made to work places during the pandemic will open up more permanent opportunities part time and remotely to MSers, and other disabled individuals. I think there is a need to study underemployment/ unemployment of MSers, and document corresponding EDSS, cognitive, and fatigue impairment. Such data would help MSers by identifying obstacles to employment as well as supporting need to redefine when someone with MS is unable to work.

  5. We need clinicians doing the combination studies before pharma jumps in… pharma will wait for a round of drug to go before investing in the new one unless competitors are already there in the rush.
    Unfortunately there are not enough doctors doing trials but hopefully those that are doing trials will finally get there 🙂
    This is one of the reasons I read the blog!

  6. Is it a capability of all MRI machines and MS specialists in the country to detect and confirm PRL and SEL? It is not something that is ever discussed at appointments. I was told I had non-specific lesions in my brain, which led to delays with my diagnosis as it was considered in the borderlands of normal for a 32 year old. Not sure what the difference is

  7. Hello Doctor. This is what motivates my attorney brother- Truth in the face of harmful ignorance. I wonder what her motivation is? Often, in personality and clinical psychology, things are linked that way- what you see as a trait or tendency in others, often lurks first in yourself. So your 26 year old could be finding it difficult to do with herself, what she does best with others. You ask us, by way of finally seeking a neurological opinion that she has been resisting, if she should be seeking the truth behind her difficulties. I focus here more on the “truth” option..

    So from what I read here and in other locations, and from my experience, there are not really any truly effective long term options for your 26 year old. Ocrevus? First off, I believe it is standard care, to tell and encourage the truth, even when there are no options (I’d have to look that up). 2nd, I believe (again with the same degree of certainty), that people prefer brute honesty given in a gentle but effective manner. Based on 1 & 2, I’d have to say tell her to seek the neurological opinion she has been resisting. .

    Personally myself, we all (in our Men’s Group) thought that Betaseron was the final answer to MS back in the later 90’s). We wouldn’t be getting any worse, we thought. And also so, it seemed, thought our doctors. And I (it seemed), wasn’t getting any worse, so I “drank the cool-aid”. I would have preferred info, sometime prior to 2020, that such wasn’t true, that being on a DMT did not solve your problem (probably). If I had gotten that info earlier, I would have been more prepared for what might come. But that’s “the rub”. You don’t want someone to be less “at will” in deciding how they want their life to unfold, as being less “motivated” may affect the outcome. So perhaps- don’t see a neurologist for a while?

    Many many people in the MS blogs still routinely report, advise and accept that DMTs stop MS. Being on a DMT is the “end-all” for RRMS people.

    But I still go with total honesty and/or seeking it out, until someone can prove differently. Get to the neurologist as soon as possible!

  8. Without knowing what causes or drives MS, we will probably never know when it begins. Who knows it may move something simple that’s being overlooked.

    What ever it is, it’s effect on the brain start well before a white matter lesions, it may come with other symptoms, symptoms that go un noticed and just become ‘normality’

    – anxiety
    – mild depression
    – easily stressed
    – occasional sensation, numbness tingling etc

    If your young and go to the doctors with an issue, 9/10 you just get dismissed due to your age, unless it’s a serious issue

    MS just seams like a disease that no one wants to approach or tackle, it’s not at the forefront of doctors minds, ibuprofen and paracetamol is the go to approach and on your way.

    Natural treatment are the best we have to tackle MS progression so far, doing your own research on brain health and putting it into practice and pushing yourself todo it.

    Hopefully treatments like BTK inhibitors will address part of the issue of smouldering MS progression. But as the macrophages it targets also are vital to brain health, who knows.

    1. John, you may be right, the answer to MS may be simple, and right in front of us ! I stopped worrying about the cause, however the cause keeps hitting me in the head (I seem to hit my head more often, like yesterday when I was working on my boat engine, I turn my head quickly, then boom, hit my head temple on engine manifold, bam, nothing to do with pollution but one of my many MS issues). My MS cause or Theory has increased over time and cannot be pushed to the side is POLLUTION. Man-made and natural pollution has increased over time since the the 1800’s. Also, Stress is a problem we created is involved, gene traits, and a virus may be part of the equation. However, Pollution may be the smoking gun, the Pollution is all around us, i.e. Nuclear testing created a blanket of nuclear isotopes spread over the globe, radiation related pollution from nuclear testing, accidents and war, the nuclear waste is larger problem then the experts will admit per 2013 WSJ article. I discovered the USA blew off 2 more underground nuclear tests near my home in 1961 and 1967. Agriculture pollution, which includes herbicides, insecticides, fertilizers damaged the land, crops, and humans. Industrial pollution from all sources, War pollution, Auto pollution, coal power plants, and on and on. Man has clearly poisoned the planet. Why would our over active immune system attack oneself, the obvious answer is pollution that induces the immure system to attack. P The MS cause is possibly piggybacked by opportunistic virus (HBV), stress, poor diet, lack of natural vitamin D, poor sleep duration, and the gene trait link cannot be forgotten. I believe we should ALL be on the clean planet train, prevent pollution from being ingested, inhaled, absorbed subcutaneously, and etc should be our top goal. Clean water should also be one of our top goals as well, the yearly water report is a wake up call, all water is contaminated with chemicals and organisms not meant for immunocompromised, elderly, and babies or anyone. Obviously, drinking unclean water is not healthy, no matter what level of PPM of poison or organisms, any level of poison is a red flag in drinking water, Organisma work optimally with pure H20 vs drinking 100’s of man made and natural chemicals with a shot of protozoa/pharmaceutical pollution to keep us healthy, NOT.

      1. There has been a lot of change in the last century, maybe to much for the human body to handle, we have lost touch with the real world it seams

        Pollution has got to be a factor, I understand living near a busy road increases your chance of MS and people living in the country side is lower, it’s all around us, lowering your body’s load to pollution has to be a good thing, but some cannot be avoided.

        I used to drink a lot of fizzy pop out of a can, I wish I didn’t now, I’ve always been healthy I look at the risk factors of MS and I have non and pollution isn’t mentioned so much as a risk factor. Maybe it was the aluminium in the can, the acids, the additives the sweaters.

        I also think we’re not as kind to out gut
        -processed foods
        -to clean
        -preservatives in foods
        -pesticides and herbicides
        -generally lower fibre in our diets
        -poor sleep
        -lack of nutrition in the soil
        -high carb diets

        Modern life is hard on our systems and maybe that’s what’s driving the rise in auto immune conditions around the globe, I totally agree

  9. I notice no indication of cognitive impairment, but significant disability progression in mobility. I am NEDA and assume the cause of degeneration is SEL(s), but have no way of knowing. I do believe it would be helpful to know, because the mind can do wonders, especially when there seems to be no cognitive impairment!

    1. Curious Peter, how old are you, what is your job, and how long have you had MS? How can you be sure you don’t have cognitive impairment, one cannot judge oneself well in my opinion, brain decline can be subjective, including the brain testing as well. When I am very tired or not sleeping well, my issues spike, then reverse after rest and sleep. I have pushed my brain my entire life, may be my saving grace or not.

      1. I am nearly 75, I am an artist (painter), my symptoms go back to 2008, my diagnosis was in 2013. Because I have no other diversions, I read and draw and paint every day. Most reading is art history and literature, and my attention span is greater than formerly. I read many texts in German, also poetry in Spanish and Italian, and have taught myself the basics of Portuguese, to enjoy more the poems of Alberto Caeiro. I read footnotes and introductions to monographs on artists I am interested in. I read books on natural history. This is not to obtain any credit or recognition in the world, neither is my work being exhibited anywhere.I work, think and challenge myself because that is what I have trained myself to do as an artist. I would admit to a degree of decline in stamina after 12 hours of struggling with mobility, but not to cognitive impairment.

  10. Who does HSCT and Alemtuzumab buck the trend? Given in the first 5 years of MS they cure the condition? If smouldering MS isnrhe real MS, shouldn’t it continue even after alem and HSCT? Also you post implies not matter what treatment we take the natural course of MS cannot be changed!

    1. In September 2003 a young woman fell ill. It began with a facial palsy, soon
      followed by weakness in a leg, pronounced fatigue and loss of vision. A
      diagnosis of multiple sclerosis was made. Although these symptoms got
      better, others more ominous took their place. She became paralyzed from the
      waist down and her bladder stopped working. She got treatment and again
      she got better for a while. However, this was just a short respite and by
      spring she was completely paralyzed.
      She was transferred to the University Hospital. At the darkest hour, she
      was offered a novel treatment. Hematopoietic stem cell transplantation. With
      little to lose and everything to gain, she accepted. None could have guessed
      at the outcome.
      A few days into procedure, she was able move her toes again, for the first
      time in two months. Rapid improvement followed. Some weeks after
      discharge, she could walk with a stroller. After three months she could walk
      unaided. After one year she was working part-time.
      Ten years later, she is living a normal life. She works full-time. She is the
      mother of two healthy children. She has no treatment. She has not had any
      Is she cured from multiple sclerosis?

      1. I suspect she may be cured. It is clear that alemtuzumab and HSCT (and possibly cladribine) seem to cure a proportion of pwMS. Why? How? What is the target? What separates the ‘curative treatments’ from the rest seems to be activity against both T and B cells.

      2. That we use the word “cured” and MS in same sentence, is remarkable. I hope very much this is true.
        I gleamed from paper that absence of tissue damage was measured by lack of presence of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein in spinal fluid. Would measurement of these biomarkers help determine tissue damage in other DMTs? Does their presence show shredding ? Am I pragmatic to no longer seek my own cure and just want to stop the shred and progression?

  11. Prof G and Team,
    Barts MS Blog is a brilliant, unique resource for a person pwMS in US.
    Concept of shredding and stripping well describes my situation.
    15 years MS (Hopkins, Queen Sq, Anne Rowling Clinic, Brighams and Weill Cornell)
    Low lesion count but shredding for me is fatigue/pain spiral.
    C suite job coming to early disability.
    Tysabri works best by far but PML risk is high. No other DMD s close.
    What other DMD’s have similar function; sealing blood/brain barrier?
    Zeposia?? Siponimod? What else has closest function?
    Thanks for pointers (not med advice I know.
    Your blog posts are so eclectic and help us
    pwMS focus on HOW TO BE versus WHAT TO DO.
    Thank you

  12. Just going on my own experience here…I was referred to specialists in the NHS in 3 different areas (rheumatology, cardiology and dermatology) over the course of 7 years for unexplained symptoms, but which included fatigue and pins & needles in my hands. To every specialist I saw, I mentioned that my aunt has MS and asked if my symptoms could be related…at times I was laughed at for even suggesting it, as the genetic element was not even a faint consideration.

    Does more awareness need to be given to other specialists in the NHS, and to GPs of potential genetic links in MS, and if they have a patient presenting with unexplained symptoms and who have a family history of MS (even if it’s quite distance) to just refer the said patient to neurology?

    On a separate note, I see some similarities to the story of the lawyer…I worked in the City in a high pressured environment, and struggled to keep up with my peers…to the extent that I’ve had 3 extensive career breaks/sickness absences before my mid 30s. And it’s only in the most recent one that I’ve finally realised why I have had such difficulties for so long and had an MS diagnosis.

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