How important is your brain volume?

H

Barts-MS rose-tinted-odometer: ★★★★(A blue sky and sunflower yellow Tuesday; #87CEEB #ffda03)

I bang on about treating-2-target beyond NEIDA (no evident inflammatory disease activity) and targeting the end-organ, i.e. to try and normalise brain volume loss (BVL). The aim is to get pwMS to old age with a healthy brain so that they can age normally. Who wants to be at risk of premature ageing and being demented earlier than you have to be?

When it comes to  BVL, not all DMTs are made equal. At the top of the ladder are HSCT and alemtuzumab, then natalizumab. Behind these come the anti-CD20 therapies, the S1P modulators, cladribine, teriflunomide and the also-rans.

In the smallish real-life study below pwMS who have been on natalizumab for at least 2 years appear to lose brain volume at a similar rate as normal controls. I wonder what would happen over a longer period of time? Natalizumab is very effective but it does not necessarily get on top of smouldering MS, so some patients will be doing better than others. Don’t be lulled into a sense of security by the average effect; 50% of people do worse than average (median) and 50% of people do better than average (median).

Please be aware that BVL is complicated with many physiological (day-2-day), biological (age), disease factors(duration, level of disability, lesion load, comorbidities) and other Influences (e.g. genomic factors) affecting the brain volume and rate of BVL. Despite BVL not being assessed in routine clinical practice, it is one of the metrics that need to be taken into account when choosing your DMT. Just maybe BVL should be the most important factor to consider in terms of efficacy?  What do you think? 

Yes, the volume of your brain predicts disability outcomes, cognition and how well you will do in old age.

Alvarez et al. Brain atrophy rates in patients with multiple sclerosis on long term natalizumab resembles healthy controls. Mult Scler Relat Disord. 2021 Jul 24;55:103170. 

Background: Clinically stable multiple sclerosis (MS) patients often have negligible inflammatory MRI changes. Brain atrophy may provide insight into subclinical disease progression. The objective was to compare brain atrophy rates in stable patients on long term natalizumab treatment vs. age and gender matched healthy non-MS controls (HC) prospectively over two-years examining brain volume, cognition, and patient reported outcomes (PROs).

Methods: MS patients treated with natalizumab for a minimum of 2 years, age 18-60 were recruited and compared with age- and gender-matched healthy controls (HC). Both groups were followed prospectively to obtain two years of consecutive magnetic resonance imaging, clinical and PRO data. Baseline normalized brain volume (NBV), yearly T2 lesion volume (T2LV), and percent brain volume change (PBVC) were measured using SIENAX, JIM 6.0, and SIENA respectively. Neuropsychological tests from the MACFIMS battery were selected to optimize assessments for impairments in the domains of information processing speed and memory. Patient reported outcomes (PROs) for domains of physical, mental and social quality of life were evaluated using the NeuroQol short forms.

Results: Forty-eight natalizumab and 62 HC completed all study visits. At baseline, unadjusted mean NBV (natalizumab=1508.80cm (Popescu et al., 2013) vs. HC=1539.23cm (Popescu et al., 2013); p=0.033) and median baseline T2LV (natalizumab=1724.62mm (Popescu et al., 2013) vs. HC=44.20mm (Popescu et al., 2013); p=<0.0001) were different. The mean PBVC at year 2, adjusted for gender and baseline age was -0.57% (CI: 0.7620, -0.3716) for natalizumab and -0.50% (-0.7208, -0.2831) for HC, but the difference between groups was not statistically significant (0.073%; p=0.62). Over the 2-year period, HC demonstrated mild improvements in some cognitive tests vs. natalizumab subjects. However, PROs were similar between the two groups.

Conclusion: Stable MS patients on natalizumab have similar brain volume loss as people who do not have MS, suggesting normalization of brain atrophy.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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.

31 comments

  • Would you say cladribine has better or worse brain atrophy data than anti-CD20 (or not enough information to say)? And would you say ocrelizumab is better at slowing brain atrophy than rituximab and ofatumumab (because of being higher-dose)?

  • Do you think molecules such as ALA or Ibudilast or similar, that seam to lower the rate of brain volume loss will make a difference to disability outcomes?

    If it’s proves the case that they significantly slow brain volume loss, is it actually slowing MS? or just brain volume loss, or may MS still progress at the same rate despite slower brain atrophy?

    • Re: Do you think molecules such as ALA or Ibudilast or similar, that seam to lower the rate of brain volume loss will make a difference to disability outcomes?

      I don’t know which is why we need phase 3 double-blind controlled randomised studies.

    • Re: “If it proves the case that they significantly slow brain volume loss, is it actually slowing MS? ”

      I think this has been proven with long-term follow-up studies, i.e. accelerated BVL correlates with poor outcome and slowing it down is associated with better outcomes. This is why many pragmatic real-life trials are using BVL as their intermediate outcome measure, e.g. DELIVER-MS.

  • HOW IMPORTANT IS YOUR BRAIN VOLUME?

    Do you expect any MSers to say “not very”?

    Neuros should be stressing the importance and putting patients on the most effective treatments to reduce brain volume loss.

    What process causes most BVL? Focal inflammation (relapses) or smouldering MS?

    Please can you do a post on how treatment approaches might develop in the next 5-10 years. I feel great strides have been made with 1/2 the disease, but the other 1/2 (progression) is still not being treated. As a result, we still see patients needing wheelchairs and getting very disabled, despite the success at addressing relapses.

    • “As a result, we still see patients needing wheelchairs and getting very disabled, despite the success at addressing relapses.”

      Apparently relapses are not the real ms…yet that’s all they treat at Barts:

      PROF G
      October 17, 2019 at 11:16 am
      “In our centre, if you don’t have evidence of inflammatory disease activity you are not eligible for DMTs; this includes licensed and off-label DMTs and HSCT. Why should we have different criteria for HSCT; it is simply a more potent IRT.”

      • Yes, that is all we treat because that is how the drugs are licensed and paid for by NHS England. Because relapse and MRI activity are not the real MS does not mean they should be ignored. They are the immune system’s response to the cause of the disease so you still need to suppress them. The corollary is not necessarily correct, i.e. if you are NEIDA (no evident inflammatory disease activity) doesn’t mean your MS is under control. Many patients who are NEIDA still get worse with ongoing brain volume loss etc. this is what we refer to as smouldering MS. What we now need are treatments that go beyond NEIDA and target smouldering MS. Sadly at present we don’t have any treatments to treat smouldering MS.

        • Prof G,

          “if you are NEIDA (no evident inflammatory disease activity) doesn’t mean your MS is under control.”

          “Sadly at present we don’t have any treatments to treat smouldering MS.”

          Both killer statements for those with MS. Many of us bought in to the treat relapses early and hard with an IRT (and took the risks which came with the approach), yet years later we are told that relapses aren’t the disease! Then we are informed that the anti-CD20 drugs don’t have much impact on BVL! Whatever MSers do – there is always a sting in the tail! We needed an MS Tsar to coordinate research focused on the real MS. What we got was hundreds of teams chasing the low hanging fruit (drugs to reduce relapses) or tin pot studies of neuro-protective agents which came to nothing eg MS Smsrt. If you want a template of how to understand a disease and develop treatments to effectively address it, it isn’t MS.

          • RE: ““Sadly at present, we don’t have any treatments to treat smouldering MS.”

            We don’t have pharmaceuticals, but we have lifestyle and wellness interventions; diet, sleep, exercise, etc. The problem nobody thinks of these as being disease-modifying when they are.

    • Re: What process causes most BVL? Focal inflammation (relapses) or smouldering MS?

      We think both and some of the smouldering processes are set up by focal inflammation.

  • Isn’t it more accurate that 50% of people do better, and 50% do worse than the median? An average doesn’t necessarily mean an equal amount will be above and below.

    • Yes, you are correct. The correct term is median. However, if the data is normally distributed the mean and mean are very close to each other.

    • I don’t think any DMT will…. 1.)stop your rrms from eventually turning progressive or
      2.) do an effective job at brain volume loss….lesson learned is get hsct…not alemtuz..or
      cladribine…way to early to risk your life on those.

      This was the latest…Rituximab is worse on brain volume than interferon beta which was
      the first DMT in 1993…so many thought interferon was a cure they had lotteries to distribute it.

      PROF G
      July 4, 2021 at 3:13 pm
      “We just heard from Frederik Piehl at our MS meeting that in their Swedish cohort the brain volume loss on rituximab was greater than the interferon-beta treated comparator group. The BVL data in general on anti-CD20 therapies is very disappointing. Anti-CD20 may be good at stopping relapses and MRI activity but is not that effective at stopping smouldering pathology or the real MS.”

      This was the first news that anti-CD20 is not effective therapy to stop ms progression..2016
      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221476/

      https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221476/bin/ACN3-4-46-g001.jpg

  • Is there any protocol to measure any bvl in a clinical practice? My neuro says bvl is great on a population level; but can’t be used on a personal level.

    • Yes, your neuro is correct. However, seeing what happens over years is important. A lot of scanners now come with propriety software that allows one to measure BVL or the images need to be processed separately offline.

  • Prof. G – In response to your inquiry….I still believe BVL is not ready for clinical use, given that a simple variable such as drinking a bottle of water before the MRI can affect the outcome.

    On days I get a T3 MRI performed, I always try to be very cognizant of my liquid intake/outtake during the 24hrs leading up to the procedure. Plus, having the procedure done at the same US based university hospital, with a dedicated radiologist specializing in MS, also helps 😉

    I have found that BVL is best viewed over time, rather than at a point in time. In addition, as with most aspects of managing MS, I believe it is imperative that base line levels are measured for as many areas as possible at the time of diagnosis, which would include BVL and cognition.

    At this time, BVL is good to know, but for me is limited in it’s usefulness as a factor in determining the efficacy of a DMT. I am more inclined to focus on improved brain fog data than BVL when looking at a potential DMT.

    I am not going to pick a DMT purely on BVL data. If I did, then I probably would not have chosen CLAD after I had breakthrough disease activity and adverse reactions to OCR then TERI. (And before someone comments, yes I am aware of the positive BVL data associated with ALEM and HSCT over CLAD)

    If a DMT is shown to also reduce BVL, that is an added benefit I am open to recognize. However, it is not on the top of my list…….at least not yet.

    • I am not talking about individual BVL changes regarding DMTs, but what happens at a group level.

      Clad’s BVL data is very good in the CIS cohort so it depends on age and disease duration.

      • “I am not talking about individual BVL changes regarding DMTs, but what happens at a group level.”…….I agree that my individual BVL trend may not be as relevant to others as it is to me; however, I still feel that even if the group level data shows a greater impact on BVL, I am personally not inclined to focus on that specific group level data point when making a DMT decision.

  • Please don’t use light blue writing on bright yellow background – that’s too much for anybody’s brain volume and eye sight! Thanks 🙂

  • even if natalizumab is so good, it still has to be stopped after a shorter or longer time because of the pml risk.

  • You mentioned in one of your comments ‘we have lifestyle and wellness interventions; diet, sleep, exercise, etc.’

    I keep as active as possible and to the best of my ability. I have a routine in my life with regular sleep, healthy diet but not OMS and try to do everything in the kitchen. They make me feel better but the ‘best of my ability’ is continually getting worse, ie my MS continues to advance.

    Its not easy to remain optimistic.

    • Patrick,

      My experience follows yours. I am a poster child for brain health matters, compulsive reader, good sleep, BP in the ideal zone, never smoked, took IRT… but walking now much slower and worsening. I suspect MS always wins in the end. It’s a biological disease – probably a virus in the CNS which kicks off smouldering MS and the external immune system sometimes wades in.

      I’m not convinced withe the exercise is neuroprotective case. In my 20s and 30s I ran 8k twice a week, circuit trying every Wednesday, lots of cycling. I was diagnosed in my late 30s with RRMS and the experts tell me that you should exercise! My 22 stone neighbour who is a smoker got T2 diabetes, but his doctors give him tablets. He can walk faster and longer than me and I’m half his weight.

      I think the MSologists play the exercise, diet, sleep, crossword puzzles because once relapses subside and the real MS (smouldering MS / progression) reveals itself, there’s nothing they can give us.

      • I would say the reason you have gone SPMS is that you weren’t diagnosed/treated early enough and have burned through all your neurological reserve. HSCT might still be able to prevent further deterioration.

        • When I was diagnosed with RRMS in 1996 there was nothing, n o drugs, no advice not even an MS nurse. Just ‘come back in 6 months time’.
          I am an optimistic person but SPMS follows RRMS like night follows day and smouldering MS is there when diagnosed with RRMS.
          As an aside I suspect that HSCT only works 100% if the patient is treated as soon as MS strikes so smouldering MS is there from the get-go or soon after

          • “As an aside I suspect that HSCT only works 100% if the patient is treated as soon as MS strikes so smouldering MS is there from the get-go or soon after”

            If smolderring ms is there from the beginning…then why do people in rr not show any walking disability until they transition to spms…and from that point it can take only 6 months or 3..4..or..5 years till edss 7.0.

            Many people stop their progression with hsct…after long term ms… Heard of people getting hsct in Sweden at first 2 years of diagnosis and failing it and they tell them it happens in 20% of the patients.

        • “I would say the reason you have gone SPMS is that you weren’t diagnosed/treated early enough and have burned through all your neurological reserve. ”

          Plenty of people are diagnosed early and put on DMT….but their yearly brain loss is around 1% because they didn’t get HSCT…only useless DMT’s…and spms results.

          The disease is more complex than just neurological reserve.
          Some people turn spms in first 5 years after diagnosis….They
          huge neurological reserve and yet high edss.

          Sandi Selvi was early spms and edss 6.5 and many symptoms
          when she was first the hsct in u.s. in 1999. Her neurological reserve allowed her to get back to low edss 2…hsct stopped any future progression and so she can still play 20 years later.
          Her book is 10 years old…and still no hsct. Outrageous.

          Does lack of neuroogical reserve drive progression in ppms..?
          Don’t think so.

          https://www.amazon.com/Stem-Cell-Transplant-Recovery-Story/dp/1936214105

          • >Plenty of people are diagnosed early and put on DMT….but their yearly brain loss is around 1% because they didn’t get HSCT…only useless DMT’s…and spms results.

            I mean, I think the data from phase III clinical trials simply proves you wrong. Alemtuzumab and natalizumab both bring BVL to way down below 1%, on average. Conversely, there are people who get HSCT and become symptom-free but then four, five, six years later have all their symptoms return and start progressing again.

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