Grey matter, matters

G

How big is your grey matter iceberg? 

As you are aware, MS is an iceberg, with most of the MS disease activity and resultant damage being hidden. The study below expands the concept of the MS iceberg to the cerebral cortex or grey matter. Most lesions (~80%) found at post-mortem in the grey matter are not detected using specialised MR imaging. Please note that post-mortem MRI imaging in more standardised than that which happens in clinical practice and I suspect even more lesions will be missed in real-life. 

Is this study important? You bet. We know that these grey matter lesions are associated with cognitive impairment, loss of brain volume and in particular progressive grey matter atrophy and are associated with poor longterm outcome and reduced quality of life. 

Do you want to know what your true MS disease burden is? Based on this data and other studies it looks as if MRI is not the best way of doing this. I suspect a better marker will be ‘deep phenotyping’, i.e. interrogating the function of your nervous system using stress tests to see how you perform. Knowing you have cognitive impairments, for example, slow cognitive reaction times, difficulty with concentration and attention, poor memory or other specific deficits may be more meaningful to you. Or not? I say ‘or not’ as not all pwMS want to know that have cognitive impairment; they argue if nothing can be done about it is best to ignore it. This is called the ‘ostrich syndrome’.

Knowing you have cognitive deficits will allow you to take specific actions to address the problem and to potentially make important real-life decisions about your future. It also allows your HCP to take action to address some medical issues that are linked to cognitive impairment, i.e. poor adherence to treatments, physical accidents and comorbid depression and anxiety to name a few. One could argue that pwMS who have cognitive impairment should be put on a high-risk register for more proactive management and care.

It is clear that the burden of MS is not only physical but cognitive as well. This is another reason to diagnose, treat and manage MS effectively and as early as possible to prevent end-organ damage and preserve your grey matter. Can I please remind you that no all DMTs are made equal when it comes to preserving brain volume or grey matter.

This post reminds me of an infographic I put together about 5 years ago called ‘Grey Matter, Matters’, which I used to support a campaign I started to redefine MS as a ‘preventable dementia’.

Do you agree with me?

Piet M Bouman et al. Histopathology-validated recommendations for cortical lesion imaging in multiple sclerosis. Brain. 2020 Aug 21;awaa233. doi: 10.1093/brain/awaa233.

Cortical demyelinating lesions are clinically important in multiple sclerosis, but notoriously difficult to visualize with MRI. At clinical field strengths, double inversion recovery MRI is most sensitive, but still only detects 18% of all histopathologically validated cortical lesions. More recently, phase-sensitive inversion recovery was suggested to have a higher sensitivity than double inversion recovery, although this claim was not histopathologically validated. Therefore, this retrospective study aimed to provide clarity on this matter by identifying which MRI sequence best detects histopathologically-validated cortical lesions at clinical field strength, by comparing sensitivity and specificity of the thus far most commonly used MRI sequences, which are T2, fluid-attenuated inversion recovery (FLAIR), double inversion recovery and phase-sensitive inversion recovery. Post-mortem MRI was performed on non-fixed coronal hemispheric brain slices of 23 patients with progressive multiple sclerosis directly after autopsy, at 3 T, using T1 and proton-density/T2-weighted, as well as FLAIR, double inversion recovery and phase-sensitive inversion recovery sequences. A total of 93 cortical tissue blocks were sampled from these slices. Blinded to histopathology, all MRI sequences were consensus scored for cortical lesions. Subsequently, tissue samples were stained for proteolipid protein (myelin) and scored for cortical lesion types I-IV (mixed grey matter/white matter, intracortical, subpial and cortex-spanning lesions, respectively). MRI scores were compared to histopathological scores to calculate sensitivity and specificity per sequence. Next, a retrospective (unblinded) scoring was performed to explore maximum scoring potential per sequence. Histopathologically, 224 cortical lesions were detected, of which the majority were subpial. In a mixed model, sensitivity of T1, proton-density/T2, FLAIR, double inversion recovery and phase-sensitive inversion recovery was 8.9%, 5.4%, 5.4%, 22.8% and 23.7%, respectively (20, 12, 12, 51 and 53 cortical lesions). Specificity of the prospective scoring was 80.0%, 75.0%, 80.0%, 91.1% and 88.3%. Sensitivity and specificity did not significantly differ between double inversion recovery and phase-sensitive inversion recovery, while phase-sensitive inversion recovery identified more lesions than double inversion recovery upon retrospective analysis (126 versus 95; P < 0.001). We conclude that, at 3 T, double inversion recovery and phase-sensitive inversion recovery sequences outperform conventional sequences T1, proton-density/T2 and FLAIR. While their overall sensitivity does not exceed 25%, double inversion recovery and phase-sensitive inversion recovery are highly pathologically specific when using existing scoring criteria and their use is recommended for optimal cortical lesion assessment in multiple sclerosis.

Keywords: cortical lesions; double inversion recovery; multiple sclerosis; phase-sensitive inversion recovery; post-mortem imaging.

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.

38 comments

  • Thanks for highlighting this. I have hardly any physical symptoms but suffered burnout from work due to the stress of trying to work in a high pressure environment with cognitive impairment. Going to. NeuroPsychologist was key to understand my impairment and intact abilities to help me make life and work decisions. Ignoring cognitive impairment leads to anxiety and depression which makes your cognition worse.
    But getting the right support can help you rehabilitate along with early effective treatment.

  • About time a neurologist spoke the truth regards grey matter. I had damage in grey matter picked up on my first mri 20 years ago. The neuro said it didn’t really matter.
    I’ve recently had another unchanged mri. However it doesn’t match my struggle with memory and concentration. The brain exhaustion. My young adult children recognise it and worth I’ll get dementia like my father and other relatives. I know I won’t be taken seriously if I raise this this medics. So I plod on knowing, only able to skim read, and getting things muddled up.

    • “The neuro said it didn’t really matter.” Perhaps they said that with treatment in mind, which around that time was still dominated by steroids; interferons & glatiramer had just become available to pwMS in the UK.
      It tells you something about the collective memory of the MS community when it needs to be reminded on a regular basis that grey matter damage exists given its been described for >100 years, e.g. by Otto Marburg (https://twitter.com/KlausSchmierer/status/762925314582384640).

      • hit Nail on head!!! Just like Helpet, I was told about 20 yrs ago that my gray matter damage on MRI didn’t matter, which I interpreted as not supportive or consistent with an MS diagnosis, and not relevant to my symptoms. In more recent yrs, Radiologists occasionally on MRI summaries describe my white matter lesions placement as consistent with MS and then remark that there are grey matter lesions. My attention, focus, recall are all affected, but I’m usually told how good my MRI looks. yAY! So yes, Dr G, please keep reminding the MS community about gray matter damage, using whatever tools, slides, etc you desire.

      • I wasn’t offered steroids. He said that we have a vast amount of grey matter, hence it wasn’t significant and didn’t matter. You always remember what you are told on diagnosis. I had no knowledge of MS then. If I were told now my response would be totally different.

  • Timely article but as MS docs we knew this ages ago; rubbing salt into the wounds is the 7T magnet approval by the FDA in the USA in 2017 or thereabouts which simply puts patients and docs who use this magnet strength MRI to scan brains at a DISTINCT advantage in deciphering sub-pial lesions where the action resides. And meanwhile as this aspect of science has taken off, across the globe (and even in the USA), most Universities ONLY have 3T and some perhaps, even 1.5 T. Given this disparity, state and Federal Government(s) ought to promote ‘uniformity’ by pumping in money to those Universities that LACK a 7T to make it a level playing field. Lest, the person who speaks the 7T language sounds like he/she is speaking Latin or Greek to the folks who deal with 3T.

    And as data builds and new avenues develop, the gulf will become ever more yawning. Regardless of histological findings and or physical symptoms of patients, a basic requirement is that everyone is looking at the same data.

    • There is a 7T unit nearby but as far as I can tell it is not regularly used for MS diagnostics – should I push to get a scan there?

      What difference does it really make?

    • Am I missing something about value of 7T to Msers who are alive? I ran to the first 3T mri in my US state. Believing, or hoping, it would lead to a better understanding and treatment than a 1T or 1.5T. And to vindicate me to my doctors of my daily struggles with this disease. It created more heat in body and marginally better images. But different facilities and programs prevent overlay comparison with prior images. There is no standard recognized algorithm for measuring brain atrophy or its structures. The increased magnet strength did not change my treatment or give “proof” of level of my daily challenges. I understand 7T doesn’t image lower half of brain well, so while it may help identify signs of MS for diagnosis, it isn’t going to be belpful to me to manage MS. Managing it requires acknowledgement, true acknowledgement, by doctors, employers, long term disability insurers, family, and friends the breadth of symptoms of this x@$^#@ disease. No image, 7T or otherwise, is going to translate to societial empathy or help for a MSer. MSers need slides to be made to educate or remind everyone else what this disease is. Rehtorical query, based on the above slide statistics, how many MSers are dropped by their LTD insurers early in disease and how many of those MSers were able to be gainfully employed afterwards? Neuros need to be able to appreciate and define an MSers disability level clinically. An mri image has limited use for managing MS, especially spms.

  • Prof G,

    If you ever think about a career change, please don’t consider light entertainment or comedy. My aunt died in her late 40s of MS so I know what it does (bed bound, divorced, dementia). When I was diagnosed 10+ years ago I had to listen to the neuro describing MS as autoimmune and how some people had a benign course (I knew that MS was more akin to Parkinson’s, MND (light) ie it was a neurodegenerative disease).

    The scale of MS is mind boggling (for the patient). Every bodily function is potentially under threat. Every aspect of our lives will eventually be changed (for the worse – whatever the happy clappy MSers say). I love the MSers who say “I’ve got MS, but MS hasn’t got me” or those in the electric wheelchairs with thumbs in the air and a big smile on their face as they appear on an MS society website!We need to be honest with ourselves.

    MS is a bastard disease. But listing out all the things it does and the collateral damage (divorce, job loss, social isolation) isn’t particularly helpful. It might be academically interesting to refer to MS as a dementia (with a claim that it is preventable), but how would you feel if you were 19 years old to be told this?

    Throughout the Covid crisis every Tom, Dick and Harry appearing on the news has called for “clarity”. Instead of producing slides setting out every dreadful thing MS does, I’d like to see a couple of slides setting out what every MSer must do. You say that “not all DMTs are made equal when it comes to preserving brain volume or grey matter.” So which ones should we be using? I’d like clarity on that. And why would a neuro be prescribing DMTs that are less effective in preserving brain volume or grey matter?

    When I took my car to the garage the mechanic explained to me why it wasn’t running properly and ran through various technical problems with the engine management system. After 10 mins of listening I nodded politely. In reality I had no interest in the technical issues as I didn’t have a clue what the mechanic was talking about. In my mind I was just thinking “get on a fix the bloody thing”. I now feel the same way about MSologists. I don’t care about T cells, B cells, hot microglia, smouldering MS, EBV…. I just want the neuro to prescribe the most effective treatment to preserve my brain and spinal cord. Am I (and newly diagnosed MSers) asking too much?

    • You’re not.! MS patients already live with a great deal of fear. I’ve sat in a room of 25+ MSers, myself a newly diagnosed patient, and only one was in a wheelchair, and 2 were using walking aids. I’ve already been told by my neurologist that the course of MS is difficult to predict. I take my DMT and am doing everything I can to keep myself healthy and strong. The absolute last thing I need is a fatalistic slide show.

      To the author: You want to know why depression and anxiety are so prevalent with MS? Re-read this piece and watch the slideshow again. Now imagine this is talking about *your* life. No research study needed, no medical degree required: take away hope, and what do you have left?

      • Jennifer,

        I’m in complete agreement with you. I’m fed up with the slides telling me I’ll die 8 years before the average, that I’ll lose my job, get divorced…. These observations don’t help me a jot. I’ve not got my head in the sand, I just think that after 50 years of MS research we should be in a better position – like most cancer research. We need to stop praising neuros, MSologists and MS researchers and start asking why we aren’t being offered the most highly effective treatment from the get go ie we shouldn’t have to beg for it. We need to be more critical, more demanding etc. At my first neuro appointment there were two patients with advanced MS slumped in wheelchairs with little function left. That was in 2007ish. I couldn’t believe my eyes. Surely we are entitled to a bit more hope in 2020 – therapy to stop progression, therapy to repair some deficits (even partially). It’s the dearth of ambition that makes me so angry. My first drug reduced relapses by 30%, my second drug reduced relapses by c.75%. Then they tell me relapses aren’t the real disease! You couldn’t make it up.

        • I agree with you both. I don’t think this blog is always good for patients. It feels like they forget real human with MS are here, looking for information. I purposely didn’t look at the slide show because I knew what was coming and came to the comments instead. Preventable dementia? Gee, thanks.

    • RE: “You say that “not all DMTs are made equal when it comes to preserving brain volume or grey matter.” So which ones should we be using?”

      If you are up for the risk, HSCT or alemtuzumab has the best data in relation to brain volume loss.

  • yet in the uk there is never a rush to treat people with ms i recently moved hospital to see a specialist as the hospital i was at uses elevation in treatment where as i asked for induction therapy there looked confused when i asked which told me nope time to change neuro. if pwms arent going to be treated in a timely manner what hope do we have anyway ? throw us on the scrap? lemtrada and hsct have been shown to lower annualised brain volume loss and halt progression when used early so why are these third line treatments if a patient chooses to take the risk ? what else do we have to look forward to ? slide 7? i would rather take my chances with a risky treatment than that.

  • I’m not really keen on redefining MS as ‘preventable dementia’. In what sense is it preventable? I eat mainly fish and vegetables, have never smoked, and run 60km a week, yet I still got MS, and I don’t see how I can stop it now. What DMDs/lifestyle changes should we be making to prevent this particular dementia then? Because it doesn’t seem possible to me.

    • I agree with many of the comments above. Not sure how brain loss can be minimised in pwMS unless diagnosis is faster, which relies on most of us finding a GP who is knowledgeable and actually gives a toss. Support for MSers is fairly woeful given what we have to cope with. And slide 7, what a cracker! Think I’ll go find the happy clappers.

      • Are you all the same people?

        It’s just a post. By one man. He’s done loads of other ones, you can read them here. Some of them are really positive.

        • I agree, Anonymous. What is this? Pile on the Barts Team Day? You don’t HAVE to read the blog.

          We all know that MS is a shitty disease, but I’ve learned far more from this site than I have been told by any of the neurologists I’ve seen (who have, no joke, told me precisely nothing about MS), and as far as I’m concerned, knowledge is power. And the amount of input that the team gives above and beyond their regular work is incredible.

          I was happy to be put on Copaxone when I was diagnosed last year as I didn’t understand about the processes taking place in my body and what the different DMTs did. I was handed 4 bits of paper and told to choose one. With what I’ve learned on here I am now going to keep talking to my neurologist about more effective drugs until he listens. If he doesn’t, I’ll go to someone else. At least I will have tried.

          Sid, it would be great if we were put on the more effective DMTs from diagnosis and I don’t understand why there is such opposition to it – I would also be prepared to take the risks, but constantly having a go at the people who are sharing and explaining the research so that we can make informed decisions is not the way to go. You’re preaching to the converted. And being more critical and demanding? I think you’re doing a pretty good job of that already 😉 If you want someone to shout at, I’ll give you the number of my neurologist. He refuses to discuss induction therapy with me and told me to go and get a 2nd opinion but that they would agree with him anyway.

          I don’t want to be patronising but have you tried channeling your frustration in a different direction? I don’t know – writing to your MP or the EMA, starting a petition, taking part in a clinical trial or something? As you can see from the comments, you would have support. I have no idea whether it would achieve anything, but it might make you feel a bit better…

          • I feel those slides at the end(with older and maybe only data) are mainly responsible for eliciting such response from some of the readers. Regarding grey matter, ProfG has been informing us about it for a while. More and more data seems to align with his hypothesis. Thank you for educating us Prof

  • Really hope some PwMS who check out the slides are able to use it to fuel their determination to seek better treatment and support. Though I suspect a larger number will quite simply be frightened.

    Again, for me, this is another post where I think it would raise it to another level if it pointed people in the right directions – there’s a whole heap of info and advice on this site, if people know where to look.

    Plain fact is all of us with MS have to educate ourselves, advocate for ourselves and facilitate our well-being for ourselves.
    I had a five minute call with my neuro during lockdown and she’s gonna touch base with me again in a years time. Also haven’t heard from my MS nurse for 6 months – over to me then!

    This is why I find this site a life-saver and access it everyday.
    This is why others could benefit to by, as I say, some more pointing in the right direction – over to you ProfG.

  • Why this kind of lesions can’t be seen? Too small? Not adequate mri sequences?

    Regarding why we are not put on high efficacy DMTs at diagnosis I would say that this is a combination of drug and drug associated costs, side effects and the way they are perceived by neuros and finally to the use drugs are authorized for. This is disappointing but shifting this view requires a community joint effort from neurologists and patients.

    I have been lucky I was offered a high efficacy DMT first line because of the number and position of my lesions. I tried to push for alemtuzumab but the neuro was against it for the side effects.

    • As far as the slides go, I view it that myself, or someone close to me could develop another life threatening disease. Indeed, since my diagnose 20 years ago, when I was terrified of the future, I’ve lost younger friends to cancer, MND and accidents. I’d say stop dwelling on worst scenarios, live each day your best way, yes fight this disease as best you can, we all know worse case MS scenarios, but there are people that also live a reasonable life. I’m not a “ happy clappy MSer”. I just try not to think like a victim.

  • I’m glad I read the comments before I looked at the slides – I think I’ll give them a miss now! I’m depressed enough with the resurgence of covid and living in an ‘area of concern’ 😕

    Prof G please can I ask – your MS Selfie site with the table with DMT covid risk, has it changed recently? Specifically regarding anti CD20 and shielding advice?

  • Suggestion to the Barts Team: Add a disclosure to each post indicating the target audience. Obviously all the posts are relevant to individuals with MS; however, some posts seem more targeted to researchers, doctors, or the pharmaceutical companies (we know they read this blog). Adding a disclosure may help some people calm down! Might I suggest a target audience for today’s post…..”old school neuro’s”. Then again, given their egos, there is no way they would take the time to read this blog.

    On a side note, “happy clappers”…..really Sid. Other than the bullshit PR the MS societies push, no one is f@#king happy they have MS! Some of us would just rather focus on positivity than live in the pits of frustration, anger, and negativity. Does it make me angry I went 10 years before I was diagnosed? What about my first line high efficacy DMT failing? How about no one willing to order anti-drug antibody test? My doctors scoffing at my IRT approach? Being 38 but feeling like I am 80? Excruciating pain every day? Not knowing what problem or symptom today will bring? Having to use a cane? Having this disease chip away at my core every f@#king day? YES I am angry!!! I just choose to focus on what I still have not what I have or will lose. We all know the end result and how this is going to play out for most us, why make it a shitty ride. Yes we want progress, a cure, compassion. One of the most important lessons I learned in the military….suck it up the f@#k up and keep pushing forward. The Barts team is just trying to provide us with all the info, how one interprets and reacts to the info is up to each individual.

    • Totally agree with Tom. A red flag on depressing posts about smouldering MS and our journey to misery may be helpful. But then, who are we kidding? Were probably going to read it anyway. I actually think I am becoming a little but obsMSessed at the moment and should probably take a step back. Whilst the blog is hugely helpful and a great resource (free access to the top neuro in the UK and his team when our own nueros are so inaccessible and basically telling us to tough it out) some of the advice we simply cannot act upon, which causes frustration, stress, the feeling that there is more that we could do. Notwithstanding the slow diagnosis, i should be relatively pleased with my high efficacy maintenance therapy but instead I am looking at the cost of a trip to Russia or Mexico. I probably wouldn’t be without reading the blog but then…..I would be lulling myself in to a false sense of security 🤦 So please keep providing us with the knowledge but maybe with the odd word of warning. I would be interested to know how many neuros actually read the blog themselves. I would like to ask my first one if he did (now retired) but I think I already know the answer

      • OK grim stuff for us all to confront. Grey matter on the slab.

        What can we do? Hope for a cure or stay of execution – then support team Bart and their like (with all their foibles).
        Also we can follow the brainhealth or ageing well advice (tip from an oldie – it works for me).

        But in the spirit of timorous optimism can I suggest Prof G and assorted docs that you stop calling it (dead) grey matter? Its pink, surely, full of blood vessels mixing in with everything else. And there is your connection to brain health for all to see. Might even suggest new routes for treatments.
        OK, not a new idea but give it a try.
        THINK PINK!
        and good luck.

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