The Learner

Do we need to include cognition as a treatment target in multiple sclerosis?

In every clinic, I do patients with MS complain of cognitive symptoms. Either it is increasing forgetfulness, difficult multi-tasking, the inability to learn and use a new technology or cognitive fatigue.

Case study: One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was recently forced to take early retirement because of her MS. She had been interferon-beta-1b for 12 years but had stopped treatment about 7 years ago when she had moved to London. Her MRI showed a highish lesion load and severe brain atrophy. She had had a few relapses on interferon-beta in the early years, but her neurologist decided to leave her on interferon-beta. Back then this was normal practice; we didn’t expect interferon-beta to render you relapse-free. Interferons were only meant to reduced attack rates by about a third and severe attacks, i.e. those requiring steroids and/or hospital admission, by about a half. The only alternative when this patient was having relapses on interferon-beta was glatiramer acetate; please remember this was pre-natalizumab era. Apart from her cognitive problems, this patient had mild unsteadiness of gait, but this had not affected her walking distance and she was still able to do yoga several times per week. To help with her unemployment insurance claim I requested a formal neuropsychological assessment and she was documented to have profound cognitive deficits across multiple domains. The conclusion based on these tests was that she would never be able to have meaningful employment again; at least not in the knowledge economy When I took a detailed history it was clear that she had had progressive cognitive impairment over at least 7-10 years. In other words, she had secondary progressive MS manifesting as progressive dementia.

You must not underestimate the impact MS has on cognition. Cognitive problems can be there from the start; approximately a quarter of people with a radiologically isolated syndrome (RIS) or asymptomatic MS already have cognitive impairment. The proportion with cognitive impairment just gets higher the longer you have the disease. What is driving cognitive impairment is almost certainly grey matter pathology, both in the cortex and deep grey matter, which is not detected with our current monitoring tools.

In the analysis below, of the pivotal phase 3 fingolimod trials, we showed that not being able to improve on the Paced Auditory Serial Addition Test (PASAT) at baseline predicted a worse outcome. The PASAT is a very sensitive cognitive test that used to part of the battery we called the MS Functional Composite (MSFC). The PASAT is not very nice to do and has now been replaced by the SDMT (symbol digital modality test).

When you start doing cognitive screening tests such as the PASAT and SDMT you tend to improve the scores due to a learning effect. We hypothesised that pwMS who couldn’t learn i.e. were unable to improve their PASAT scores at baseline would do worse. This is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo. Poor learners were older, had a higher disability score at baseline, smaller brains and higher lesions volumes on MRI; i.e. they had reduced cognitive reserve. The depressing point about this analysis was that even the poor learners on fingolimod did badly; it was if they were already primed to do badly and that starting a DMT had a limited impact on the outcome. Active MS in the past had primed their brains to continue deteriorating; previous damage or a new type of MS lesion, possibly SELs (slowly expanding lesions) was driving their worsening.

The message here is that it is very important to prevent the ravages of MS by treating as early and effectively as possible. In some pwMS, this is easy because you present early before too much damage has accrued. In others, you may have longer asymptomatic periods during which you have already acquired a lot of damage. Regardless of what group you are in, you need to seriously consider getting on top of your MS disease activity as soon as possible to prevent further damage.

It is clear from the Sormani meta-analysis (article 2 below) that you do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions) and those that reduce brain volume loss the most. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly those that ‘normalise’ brain volume loss.

This study also raises the question about whether or not we should be monitoring cognition in routine clinical practice? This topic is a hot potato and gets discussed and debated all the time. At the moment I think most neurologists don’t agree with doing routine cognitive testing, because of the lack of evidence in terms of treatments that impact on cognition. This, however, may change when siponimod gets licensed. It is clear in the siponimod trial that siponimod delayed cognitive worsening compared to placebo. The following is the siponimod data that was presented at the AAN and EAN last year.

I believe that everyone with MS should have the option of monitoring their own cognition. If your cognition is improving and/or is stable that is good news. If, however, cognition is worsening then a frank discussion needs to be had about why it is getting worse and can anything be done about it. There are many reasons why pwMS may have worsening cognition and some of these are treatable. This is why we have developed an online cognitive test, which we are currently validating, to allow self-monitoring of cognition. If you had access to the test would you use it?

Article 1

Sormani et al. Learning ability correlates with brain atrophy and disability progression in RRMS. J Neurol Neurosurg Psychiatry. 2019 Jan;90(1):38-43.

OBJECTIVE: To assess the prognostic value of practice effect on Paced Auditory Serial Addition Test (PASAT) in multiple sclerosis.

METHODS: We compared screening (day -14) and baseline (day 0) PASAT scores of 1009 patients from the FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS) trial. We grouped patients into high and low learners if their PASAT score change was above or below the median change in their screening PASAT quartile group. We used Wilcoxon test to compare baseline disease characteristics between high and low learners, and multiple regression models to assess the respective impact of learning ability, baseline normalised brain volume and treatment on brain volume loss and 6-month confirmed disability progression over 2 years.

RESULTS: The mean PASAT score at screening was 45.38, increasing on average by 3.18 from day -14 to day 0. High learners were younger (p=0.003), had lower Expanded Disability Status Scale score (p=0.031), higher brain volume (p<0.001) and lower T2 lesion volume (p=0.009) at baseline. Learning status was not significantly associated with disability progression (HR=0.953, p=0.779), when adjusting for baseline normalised brain volume, screening PASAT score and treatment arm. However, the effect of fingolimod on disability progression was more pronounced in high learners (HR=0.396, p<0.001) than in low learners (HR=0.798, p=0.351; p for interaction=0.05). Brain volume loss at month 24 tended to be higher in low learners (0.17%, p=0.058), after adjusting for the same covariates.

CONCLUSIONS: Short-term practice effects on PASAT are related to brain volume, disease severity and age and have clinically meaningful prognostic implications. High learners benefited more from fingolimod treatment.

Article 2

Sormani et al. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9.

OBJECTIVE: To evaluate the extent to which treatment effect on brain atrophy is able to mediate, at the trial level, the treatment effect on disability progression in relapsing-remitting multiple sclerosis (RRMS).

METHODS: We collected all published randomized clinical trials in RRMS lasting at least 2 years and including as endpoints disability progression (defined as 6 or 3 months confirmed 1-point increase on the Expanded Disability Status Scale), active magnetic resonance imaging (MRI) lesions (defined as new/enlarging T2 lesions), and brain atrophy (defined as change in brain volume between month 24 and month 6-12). Treatment effects were expressed as relative reductions. A linear regression, weighted for trial size and duration, was used to assess the relationship between the treatment effects on MRI markers and on disability progression.

RESULTS: Thirteen trials including >13,500 RRMS patients were included in the meta-analysis. Treatment effects on disability progression were correlated with treatment effects both on brain atrophy (R(2)  = 0.48, p = 0.001) and on active MRI lesions (R(2)  = 0.61, p < 0.001). When the effects on both MRI endpoints were included in a multivariate model, the correlation was higher (R(2)  = 0.75, p < 0.001), and both variables were retained as independently related to the treatment effect on disability progression.

INTERPRETATION: In RRMS, the treatment effect on brain atrophy is correlated with the effect on disability progression over 2 years. This effect is independent of the effect of active MRI lesions on disability; the 2 MRI measures predict the treatment effect on disability more closely when used in combination.

CoI: multiple

32 thoughts on “The Learner”

  1. You said in your last post that natalizumab buys time to think and plan for a long term treatment.
    Why buy time if time is brain (i.e. brain will shrink during that time)?
    Surely a defeatist approach?

    1. But natalizumab is one of our most effective DMTs and it is reversible. You can literally start it with days or weeks of diagnosis and the make a decision about longterm treatment plans. I have little doubt in short-term head-2-head studies, using rebaselining with NEDA as the outcome, natalizumab will be the top rung in terms of efficacy. You need to read our posts on #AttackMS (formerly called #BrainAttack).


      1. Then how long would the average MSer need to be on natalizumab before exploring an alternative high efficacy solution caeteris paribus all other factors? 2 ys, 4 ys, 6ys…?
        Any optimisation exercise surely comes with time stamp after which one is better off switch for optimal results,

      2. If they turn out to be JCV positive 6-12 months should sufficient to allow them to make their minds up on what to do next. If they are JCV-ve they can potentially stay on natalizumab.

      3. “I also have a hypothesis that starting natalizumab early may alter the biology of MS, i.e. it prevents the maturation of the B-cell and plasma cell response with the CNS and it may actually disrupt the plasma cell niche.”

        Is this still valid? If so, is it being looked into?
        Would the same be said of Lemtrada/HSCT?

      4. Yes, this hypothesis is still valid and we would like to explore it as part of DrK’s #AttackMS trial. We are hoping to get some supporting data in place to at least get a trial started.

  2. Yes I’d self-test. I’m getting a bit worried about having opted for Tecfidera 4 years ago with the more recent posts about brain volume on the blog. I’m relapse and MRI activity clear but I’m also very fond of my brain. Whilst I’m doing everything I can to exercise and maintain brain health, I’m still worried I am not as cognitively quick as I was but have never had a test so I can’t prove this objectively.

    1. As I have said before the results on brain volume loss are average effects and you may turn out to be DMF responder. However, to know the latter we need to be monitoring your disease in much more detail, for example, to exclude smouldering MS.

  3. Prof G are the EXPAND cognitive results meaningful? Will the regulators allow you to include them in label? If not, that are simply a curiosity for academics to mull over.

    1. Yes, they are significant. An improvement of 4 points on the SDMT is clinically meaningful, i.e. is backed up with improved quality of life. Slide 5 shows you that over 41% of patients on the active drug, compared to 30% on placebo, improved. The placebo improvements could be due to learning effects and spontaneous recovery of cognition, but it does tell you that not everything is necessarily downhill. On the flip side trial subjects were much likely to have a clinically significant drop in cognition compared to siponimod treated subjects.

    2. Re: “If not, that are simply a curiosity for academics to mull over.”

      Definitely not an academic curiosity; this is people with MS’ cognition we are talking about. The problem with the world of MS is they only see MS via EDSS-blinkers. In my opinion, the cognitive loss in MS is a much bigger, and ignored problem compared to mobility. This is why I have tried to rebrand MS a preventable dementia.

  4. Wondering if anyone else with MS has noticed increasing difficulties holding conversations with people; not only do I personally find it utterly exhausting but I struggle to find the right words and so easily forget names. The many challenges of daily life – physical and mental – are certainly becoming harder to cope with as the disease worsens. I would certainly use your online cognitive test when it becomes available.

    1. Yes, conversations are exhausting. This was one of the msib reasons that I took early retirement from my job as a university professor (in the U.K.).
      I would certainly take an online test – my neurologist never has this discussion with me, and I would welcome it.

  5. Yes I would self monitor. I am functioning highly enough to be able to conceal my cognitive decline and appear articulate- but my thoughtful pauses to seem wisely contemplative are concealing my scrambling for the elusive word (or name) I want.
    I had full neuropsychological assessment soon after diagnosis; it was sadly apparent what had already been destroyed. The good news is following all brain health guides and on fingo as soon as diagnosed, when repeated there was significant improvement.
    That was 4 years ago though; I would like to self monitor as realistically it will probably start changing without detection unless actively measuring..

  6. I would quite happily do an online cognitive test but I do not need a cognitive test to show that my abilities are dwindling. My memory is vanishing, ability to do Sudoku and its even affecting my sense of humour. Worst of all is the reduction in power of concentration. On the upside I have learnt new skills, running my own website as well as being an active and busy service user.
    Medical retirement has forced to look at what I can still do and want to do So whilst MS has effectively deleted a part of my life. Other ares that were dormant have been discovered, I just hope that MS does not affect that part of my cognition.

  7. Regarding problems with cognition, concentration, extreme fatigue, multi-tasking etc – surely people with MS should be regularly monitored to test if they are still safe to drive and safe to work if they’re using potentially hazardous tools or machinery, for example; or responsible for other people’s welfare such as being in charge of children or working in healthcare, handing out drugs to patients?

    1. Yes, if you have MS you have to renew your driving license via the DVLA every 3 years; the assessment of cognition for driving, however, is very superficial.

      1. When you study any drug in advanced MS the treatment effect is small or modest; this is the nature of having to play around with pathways when there is little reserve to show a treatment effect. In addition, some of the treatment effects are due to a recovery of function, which also fails with age and loss of reserve.

  8. Prof G the siponimod results are very encouraging, but how much of the cognitive impairment in someone with MS is reversible?

    1. The answer to this question is in slide 5. I have also written an MSARD Editorial on exactly this subject. Cognitive deficits are like motor deficits; they can improve. This is why MSers need to use it or lose it, i.e. engage in cognitive rehab if they have defined deficits.

  9. I would use it and I would also like to utilise validated online cognitive training

    I’m aware that the Brief International Cognitive Assessment for MS produced by Dawn Langdon et al is being validated internationally e.g. adopted and recommended by the American Academy of Neurology. Awaiting completion of the validation process here in the UK.

    BICAMS has been used in interventions studies, I understand, including one that demonstrated cognitive rehabilitation via use of computer at home.

    Thanks for working on providing PwMS with a validated test that we can use for ourselves. I do hope it can be closely followed with provision of validated online brain training.

    1. I did approach Biogen to put their well-validated processing speed test online, but they said no for two reasons. One had to do with IP. The other concerned empowering patients with data on their cognition with which to harass their neurologists. Some people are not convinced the wider MS community is ready for this.

  10. I would absolutely use it. I am still with a CIS (spinal cord) diagnosis (with 10+ T2 brain lesions, but no contrast used so DIT not demonstrated, radiologically at least). But am mid second relapse, with further c-spine lesions seen on most recent MRI, so diagnosis may be changed shortly.
    I feel I have suffered some cognitive decline over the last 2 years (at least), and symptoms seem worse during relapse, but there seems to be nothing by way of evaluative tool and little interest in patient-reported cognitive difficulties, especially prior to diagnosis (and I do wonder how much of it might be related to the stress of CIS uncertainty). So I’d really welcome an online tool for self-monitoring.

    1. The neuropsychologists are not keen on you self-monitoring; then you may be putting them out of a job.

      1. I see! Well as a relatively ignorant CISer who’s been secretly hoping for a couple of years that I might be in the small % of people for whom it’s a one-off, I was none too aware of the existence of these experts! I’d be very happy to see one if it were an option. But options prior to MS diagnosis seem few and far between (and maybe cognitive assessment is not considered necessary by many neurologists in such early stages..?)

  11. Thank you for another great post!

    It seems to me that BVL testing is fuzzy (at best – no protocols and very subjective.
    Does BVL shrinkage correlate well with blood CSF? Can we use blood tests today in decision making ro do we have to rely on the radiologist’s naked eye?

    Thanks again,


  12. Yes, I would self test too. I’ve noticed my own decline and was tested. Still, fell into the “normal”category, but I felt like I was failing. . Are there any online programs that are promoted ?
    My Neuro has never mentioned anything about this, and it was my PT who suggested he testing.
    Thanks again for another great post. Albeit a bit depressing .

  13. Please excuse me if i say sth inappropriate, i know the inmense effort/dedication that is behind finding a drug candidate and going through all appropriate testing/safey/regulation . But we shouldn’t push sth with moderate effect that does not stop ms. We are wasting time and that is sth we patients don’t have. Maybe we should change strategy. I know noone knows the cause of ms but i believe nothing suitable will be found until the cause is foumd. I have got my eyes hoping for EBV.

Leave a Reply

%d bloggers like this: