Barts-MS rose-tinted-odometer – zero stars
Someone recently asked what is advanced MS? I suspect they have been getting frustrated with our use of this adjective without a clearer understanding of what it really means. To find out if you have advanced MS you need to put yourself through a battery of stress tests to find-out much reserve you have left to deal with MS and life in the future.
What is advanced MS is a very important topic and we at Barts-MS have tried not to define it using the EDSS as it entrenches the physically-disabling, particularly lower-limb function, worldview of MS.
Advanced MS is really when someone has lost reserve in a particular neuronal system and they are noticing worsening in that system that is impacting on their ability to function at a personal, social or occupational level and by inference is affecting their quality of life.
Using this definition someone can have advanced MS with very little physical disability. As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.
A software engineer with MS who depends on her cognitive skills for writing code, concentrating for prolonged periods of time and multitasking may find it very difficult-staying at the top of her game. She will notice much earlier her progressive cognitive loss based on her performance or lack of performance in her work. In comparison, a professional athlete may not necessarily notice early cognitive impairment but will be more susceptible to the effects of MS on their coordination and endurance, for example, the marathon runner with a dropped foot.
These examples are the two extremes, but they illustrate why we need stress tests of the nervous system to be able to ascertain how much reserve there is which will give us some idea how advanced MS is in a particular domain. One thing that is not done very well in MS clinics is cognition. Most MS centres don’t have the resources to monitor cognition properly. This needs to change (#ThinkCognition).
In almost every MS clinic I do I see patients who complain of cognitive symptoms; increasing forgetfulness, difficulty multi-tasking, the inability to learn and use a new technology or cognitive fatigue.
One of my high functioning patients, who worked in a large City law firm, simply could not keep up and was 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; this was in the 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 advanced (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 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.
Until recently we the MS community used the Paced Auditory Serial Addition Test (PASAT) for monitoring cognition in clinical trials. The PASAT is a measure of cognitive function that assesses auditory information processing speed and flexibility, as well as calculation ability. The PASAT is presented using audiotape or disk to ensure standardization in the rate of stimulus presentation. Single digits are presented every 3 seconds and you have to add each new digit to the one immediately prior to it. Shorter inter-stimulus intervals, e.g., 2 seconds or less have also been used with the PASAT but tend to increase the difficulty of the task. The PASAT is very difficult and requires multitasking; it is a very good cognitive stress test.
One of the reasons we dropped the PASAT test is because of its learning effect, when you do the PASAT test your scores improve because of so-called ‘learning’ or ‘practice’ effects. In reality this is a general phenomenon of most neurological stress tests; our nervous systems are wired for learning.
In the FREEDOMS 1 and 2 pivotal phase 3 fingolimod trials, we showed that not being able to improve on the PASAT at baseline predicted a worse outcome. We hypothesised that pwMS who couldn’t learn, i.e. were unable to improve their PASAT scores at baseline, would do worse and this is exactly what we found and we noted it regardless of treatment allocation; i.e. whether you were on fingolimod or placebo.
Not surprisingly, the 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 or resilience. In other words, they had more advanced MS. 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. In reality, their MS disease activity in the past had primed their brains to continue to deteriorate despite being on a DMT; previous damage or smouldering MS was now driving their disease worsening. This is why the treatment response on DMTs drop off with ageing and disease duration. Please note this applies to all DMTs, including HSCT.
It is important to prevent the ravages of MS by treating as early and effectively as possible. Some pwMS are luckier than others; i.e. you may present very early in the course of your MS before too much end-organ damage has accrued. In others, the asymptomatic period of the disease may be longer, during which time you acquire a lot of end-organ damage. Regardless of what group you are in, you still need to seriously consider getting on top of your MS disease activity as soon as possible to prevent any further damage.
It is clear from several data sources that on average pwMS do best on DMTs that have the greatest impact on inflammatory activity (new MRI lesions and relapses) and those that reduce brain volume loss. In reality, these are the high and very high efficacy DMTs. This is why flipping the pyramid and going for the most effective DMTs first-line is a very appealing treatment strategy; particularly the DMTs that ‘normalise’ brain volume loss.
This post illustrates why we should be monitoring cognition in routine MS clinical practice. Although this topic gets discussed and debated all the time 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, will change as data emerges that DMTs have positive effects on cognitive function, even in advanced MS. For example, siponimod has been shown to delay cognitive worsening compared to placebo in people with SPMS.
At Barts-MS we will continue to run our #ThinkCogniton campaign. By shifting the MS worldview from a physical one to a cognitive one we will hopefully get the MS community to manage MS more actively.
Maria Pia Sormani et al. Learning Ability Correlates With Brain Atrophy and Disability Progression in RRMS. J Neurol Neurosurg Psychiatry, 90 (1), 38-43 Jan 2019.
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.
CoI: multiple
What would be good to see, is research of a patient’s cognitive skills on medication and those without. Anyone doing a cognitive test is asked for their level of education ie. did you go to university?, but back in the day people could get a job that now needs a degree. I have friends that went onto further education with no illness that have difficulties remembering things. Give people the skills to cope with ageing memory decline, it’s not just MS and then maybe the world out there will employ us.
You are right it is not only, but MS-plus. The plus refers to ageing and all the other things that affect your brain health.
As someone with early onset, slow PPMS, I wish there was something more to offer than current DMTs taken earlier. In fact, a New Year’s resolution is to spend less time doing so. It does not help me. I’d rather spend my time reading and learning about something else.
Battery was going, missing a bit…
“…current DMTs taken earlier. I’m tired of reading about this. In fact…”
I agree. Rumination Syndrome is something that affects people with chronic diseases. They spend more and more time reading and researching their disease and this process then slowly takes over their life. I suspect some of our blog readers suffer from rumination syndrome.
It is fine to read occasionally and to keep yourself on top of developments, but to do it daily and for more than say 30 minutes a day is not good for you.
Please note the primary aim of this blog is to interpret and provide research news. And research is not always reproducible.
Thank you, Prof G. This confirmation and advice is very helpful. I would add that I do find this blog invaluable for being able to quickly and easily keep abreast of research, developments.
In some ways a very sad post. MS is like an onion – as we peel it back it gets worse and worse. My neurologist didn’t tell me 12 years ago that I might lose my marble because of MS (I haven’t yet). I feel for the lawyer lady as I’m in the same profession. Imagine losing your job at a relatively young age because of cognition issues! And the neuros are surprised when their MS patients experience depression! When the MSologists have finished documenting how bad MS is (I met someone the other day whose wife is quadriplegic because of MS) please can you focus on prevention, stopping accumulating disability and repair. These sort of posts are robbing people like me of hope and I wonder why I bother getting up every morning if my future is electric wheelchair, job loss, care home, early death. I’m guessing MSologists must have skin like Rhinos. I couldn’t dive a diagnosis, provide a list of every awful thing the shredder does and send them on their way. Surely job satisfaction for any doc is giving their patients some hope and getting some of them back to health and wellness!
RE: “Surely job satisfaction for any doc is giving their patients some hope and getting some of them back to health and wellness!”
Yes, but not false hope. It is clear that MS is undertreated globally. The new therapeutic nihilism is the passive treatment of MS. Hence the reason for our Brain Health initiative and our aggressive promoting of the ‘early effective’ treatment model. Without knowing the downsides of untreated or undertreated MS how are pwMS going to make informed decisions about their treatment?
Surely knowing the worst-case scenario allows you to better weigh-up the risks and benefits of treatments?
Please note each post I do comes with a health warning in the form of the Barts-MS rose-tinted-odometer score. This post came with zero stars.
So how would that fit in a tratment algo?
Take my case by way of example: responding well to natal, JCV-, low NFL. But noticeable cognitive decline (I forget all kind of things). Where to go from here?
But how old are you? If you are older than 35 years of age this could just be normal ageing or accelerated normal ageing if you have a lot of MS-related brain volume loss underlying things. The other question is could it be smouldering MS?
This is one questions we can’t answer at the moment using our standard metrics and forms part of the grant application we have put into the MS Society to try and answer. Can we include additional metrics and biomarkers into clinical practice that will allow us to measure and track smouldering MS and then to use these biomarkers as treatment response markers for the next generation of add-on therapies in MS?
If you want to do Barts-MS, and the MS community, a favour can you please ask the MS Society to fund research into smouldering MS as one of their priorities.
Good thinking, Doctor. As an old nurse assessor, I had to assess patients for Vermont Medicaid long term program care eligibility. We often saw the person at their home. Cognitive deficits were the hardest to assess. We sometimes heard from families. The patient wasn’t bathing or uncharacteristically disorganized, left a pot on the stove and forgot things, got lost. Sometimes subtle signs. It was detective work. One man seemed fine. In reality, his candy dish had cat food in it, and he snacked on it. These were mostly Dementia patients. But sometimes a person just couldn’t hold it all together. They were often aware. They often didn’t want us to know or couldn’t put into words they needed help. A teacher was so organized she nearly was denied. It’s sometimes more Focal. For me, the travel, daily grind and heavy decision making exhausted me. Holding it together. Fatigue multiplied the falling apart, the tethered thinking. I think assessment only at clinic visits misses so many signs. Even before home visits, cognitively impaired patients often got up early, covering any signs of falling apart, Pulled it together. Nobody wants to fail any test. Sometimes you can hold it together for a two hour visit. Then they often collapsed after I left, their cognitive reserve spent. This was the hardest type of patient to assess. I really think that a series of computer testing could capture more information. Even a game that required different areas of thinking. Then, over time, you would get more complete information. There are inherent difficulties in trying to measure cognitive function while you’re watching them. They may perform well, then go home and fall apart. If you knew the finer points of their cognitive function, disability qualifications might be easier for the patient and the assessor. I kept a journal of sick days, feelings on those days, how all my energy was spent at my job and nothing left when I got home from work. Fatigue has an impact on cognitive ability as well. It’s all so invisible on the outside.
Lack of reserve of cognitive resilience can cause fatigue. It takes so much more energy to complete a cognitive task when you have reduced reserve that it causes extreme mental fatigue.
So what comes first the fatigue or the cognitive impairment? Chicken or Egg? In my opinion, they are very closely related to each other and I suspect that early cognitive fatigue, provided you are not depressed or anxious, is related to cognition problems.
Prof G,
Don’t bring me problems, bring me solutions.
It’s 2020 next week – 195 years after Charcot was born. He must be turning in his grave.
I’m grateful for all the efforts made by Barts, but real breakthroughs are now needed (by MS researchers across the world). Those people diagnosed with MS in the 2020s should not have to face the same dreadful future (which Prof G has listed out many times) as those that have gone before. Think#stopsmoulderingMS.
Re: “Don’t bring me problems, bring me solutions.”
We have a whole programme of work planned to tackle smouldering MS under our MS Society Programme Grant application, including developing new treatments to target smouldering MS.
Prof G,
You’re the go-to guy for cheery news. I see from your twitter account that you say that all MSers get advanced MS if they live long enough. I better buy some more shares in Dignitas as they will see a big increase in business for MSers like me who aren’t prepared to face the double whammy of increasing physical disability and dementia. Sad, because I was really looking forward to a fulfilling retirement after a 35 year career.
F
PS in January could you post a teeny weeny positive post. Your relentless posting of how bad aMS has given me depression.
You have just pressed where it hurts! Ouch!
Truth is that G is an eternal hopeful, getting hit by a reality check like the rest of us.
Few years ago Tysabri showed the promise of a cure…until it didn’t. Same for alemtuzumab. Then Roche went awol regarding BVL and ocrel.
G gave up on the lot and famously stated around a year ago that if he had MS, he would go for HSCT to the surprise of some of his own colleagues…to finish this year with an HSCT reality check.
Where do we stand now: if you have already been diagnosed, or about to be: you’re screwed. The likes of G and that american youtube guy will buy you a few relapse free years (10 in my case and counting) but live your life to the fullest whilst saving your cash for later. Arrange for disabled access where you are and start your “war planning”. I have now come to terms that I will be disabled in the coming years at some point and am readying myself to embrace the challenge.
Happy new year everyone.
Re: “I have now come to terms that I will be disabled in the coming years at some point and am readying myself to embrace the challenge.”
May be not we are working on add-on treatments to tackle smouldering MS and to scrub the CNS clean of B and plasma cells, which may be driving smouldering MS.
Who knows this may be the year of the black swan and that anti-EBV CTL therapy comes of age and is shown not only to treat MS but to cure MS. Or maybe we simply need an add-on CNS penetrant antiviral agent to tackle smouldering MS.
There are many miles to go before I sleep!
Re: “all MSers get advanced MS”
What I am saying is that all pwMS will be hit by ageing mechanisms and it is our job to maximise brain health so that when they get to old age they can age as normally as possible. To accept anything less as a treatment target would be doing our patients a disservice.
Re: “You’re the go-to guy for cheery news. ”
We aim to comment on good, bad and other aspects of MS research. We want to keep you up to date with what’s going on in the world of MS research. As my posts come with a health warning you don’t have to read them.
I whole-heartedly support your endeavours to have the treatment pyramid flipped and can see the logic in sifting focus to cognition on this basis.
However, I’m also in agreement with ALF – test the hell outta someone and inform them their cognitive abilities are shot, resulting in a ravaged sense of themselves, then send em on their way – just perfect! Quality of life is enhanced not solely by what you can or cannot do physically or mentally but is about how you are in yourself psychologically, and self worth is right at the top of the pile! I hate to think that the lawyer, whilst benefitted with her insurance claim, may have had her sense of self destroyed, potentially resulting in severe depression. Sometimes knowledge is about what it does to you, not for you and for whose benefit is it knowing that cognition is shot with no provision available to assist?!
So, yes use cognitive testing to enhance the capacity to utilise the more effective DMTs otherwise don’t inflict it unless a) PwMS requests it b) it’s necessary to ensure the personal safety of the PwMS or c) when you know you can offer meaningful supportive provision.
Re: “However, I’m also in agreement with ALF – test the hell outta someone and inform them their cognitive abilities are shot, resulting in a ravaged sense of themselves, then send em on their way – just perfect!”
Cognitive testing is voluntary for this reason. We explain to pwMS this issue and let them make an informed decision. Sometimes knowing you have cognitive impairment is important it explains why you are not coping at work, it may prompt you to take early retirement or change careers, it may change your decision about education, i.e. not to that physics course. It also gives you prognostic information and may just be the factor that tips the decision in favour of HSCT as a treatment option. From an HCP perspective, it may be the factor that put you on our high-risk register so that we see you more often and provide you with different services, i.e. cognitive rehab, or a different fatigue management course. It may prompt us to not only try you on fampridine for your walking problems but for your cognitive issues as well. It may make you realise that those two driving accidents you had last year could be a consequence of your cognitive problems and weren’t just accidents; it may prompt you to stop driving. Since acknowledging that you have cognitive impairment and using your new aide memoir you have stopped missing your medications. Your family are also relieved in that it explains why you are so forgetful and they can change or adapt the way they interact with you; for example, they now send you calendar invites before they visit so that you get a reminder that they are coming the day before.
Or you have the option of putting your head in the sand! The latter is referred to as the Ostrich Syndrome.
Reassuring to hear that Barts is confident of offering cognitive testing meeting the three prerequisites that I listed. I’m confident of saying that this isn’t true of most centres. When I spoke about cognitive testing to the neurologist at the London centre that provided my Alem she acknowledged they had no resources. In fact they’d lost the one metal health nurse that had been in post. None of the other three neurologists I’ve seen/see have even mentioned cognition.
Not ostrich – just don’t want those I engage with, especially HCPs to make living as a PwMS worse.
Will add once again that I agree with the comments about the benefit of this site, even MDs capacity to make me laugh out loud is a valuable juxtaposition to having this sh***y disease.
Fingers crossed for more progress in treatment options – add ons etc.
Could it be fixed by any highly effective drug? (Before the age related downhill begins.)
(F.e. a pwMS switched from Gilenya to Lem. because her preg. plans. G works well, but her PASAT was 42. After 6mnths her PASAT was 59 /9hole, 500m were better as well/)
I have started self screening my EDSS with your software more than a year ago every month on the same date. I could do a selfscreen on cognition in the same way. It would take away the fear of not knowing where I stand. Excuse me for my English.
re the cog fog which really should be called broken brain as it’s far more apt.
Neuro psychologists can do tests on cognition, words, remembering etc can’t they?
I’ve recently had them done, are they only done if the patient keeps telling the consultant they are having problems speaking/thinking etc?
Sometimes I feel like my brain is on dial-up as opposed to broadband
I’m an endurance athlete with a demanding full time job…
It’s definitely affecting my job more than my athletic performance right now, despite a couple of falls this year (one of which was pure accident but the other involved tripping over my foot).
Your example of a software engineer made me shudder. I work as a software engineer. I learned to write code in high school and I absolutely loved it. Coding came n aturally to me and I decided to pursue it as a career. I felt very lucky to have found my calling. Then all of a sudden when I was in college, I wasn’t so good at it. It took me a long time to understand new concepts and struggled to get passing grades. I couldn’t understand what was wrong with me. My classmates got multiple job offers, I felt lucky that I got at least one offer, given how bad my grades were in graduate school. Then I was diagnosed with MS ten years later. As I slowly learned more about this disease, mostly through this blog, I wondered whether cognitive impairment in college was my first real symptom. Now this post confirms it.
I understand that you want to be able to monitor cognition better in pwms but surely by having an
Official cognition scale you could end up restricting drugs in a similar way to how the edss restricts drugs whereas at the moment anyone with only cognitive impairment regardless of its severity get offered the currently most effective drugs
Read it.. I don’t agree with your quote “As you are aware the initial impact of MS may be cognitive, which is probably the main driver of the high early unemployment rates we see in MS.”
There are other factors, I was lucky to have a very understanding director.. However other that worked in the office targeted ethnic minorities. Some where afraid they get by using your phone etc.. Like most they were existed out by the term restructuring.. 😳 Really. It was clear if you were not enthic with cancer treatment it is okay 👌 but educating ppl is another.
Ms does vary for everyone. One has to keep the mind and body healthy. I ve been on a special diet and herbal meds.. Touchwood my, legions have disappeared, I live a normal life no different then a able person, most have similar issues without having Ms? It would be interesting testing on both groups or stages to compare results.. Just helping.. I remember doing one last year, In a crazy noisey environment and I scored 138 points.
what I am saying it does cause brain fog for most Ms suffer but I’ve seen normal ppl at times just the same?
Professor if would be interesting to see how it effect people in groups and sectors you will be surprised like I was when I looked.
Regards