Why I’m no longer talking to pwMS about wheelchairs

W

When newly diagnosed pwMS enter a clinic room, they have read up about MS and are often focused on the daunting idea of ending up in a wheelchair or having to use a zimmer frame. From natural history cohorts before disease-modifying treatments (DMTs) were introduced, we know that for an untreated pwMS it takes a median 11.4 years to reach EDSS 4/not being able to walk unrestricted anymore, 23 years to reach EDSS 6/walking with a cane and 33 years to reach EDSS of 7/having to use a wheelchair. There is consistent evidence that our army of DMTs impacts on these hard disability endpoints, and delays them with several years. This is undeniably good news. However, what happens in two decades from now might not be what drives your life choices today and tomorrow.  

This study of De Meo et al. performed extensive cognitive assessments among 1,212 pwMS and 196 healthy controls. This allowed them to delineate five different cognitive phenotypes: 

  1. Preserved cognition
  2. Mild verbal memory or semantic fluency: This means your use of language becomes more restricted, your brain has to spend more energy on accessing less frequently used words. 
  3. Severe executive/attention: This means you have difficulties multitasking. In practice, this means that cooking while keeping an eye on your offspring, putting laundry in the washing machine and answering a text might become very demanding. Similarly, also following conversations with multiple people at once might become tiresome. 
  4. Mild multidomain: PwMS underachieving on all cognitive tests. Next to verbal memory and attention, there are also difficulties with visuo-spatial memory (i.e. difficulties with the board game ‘memory’) and cognitive inhibition which is your mind’s ability to tune out stimuli that are irrelevant to the task at hand.
  5. Severe multi-domain: cfr. Mild multi-domain but more pronounced. 

Most striking is the frequency of these phenotypes among pwMS, and especially among – so called –  “early RRMS” i.e. less than 5 years from symptom onset – and thus not diagnosis. In ‘early RRMS’, only 25% had preserved cognition, 38% had mild verbal memory or semantic fluency deficits, 14% had mild multi-domain deficits, 11% severe–executive/attention and 12% severe–multidomain deficits. The picture becomes more sombre in individuals with a longer disease duration where only 5% (SPMS) and 7% (PPMS) had preserved cognition. 

https://www.vectorstock.com/royalty-free-vector/brain-fist-logo-design-vector-33853267

In the beginning of the disease, pwMS often do not realise that MS-related cognitive deficits will be much more fundamental in how the disease impacts on their life than not being able to run. Cognitive impairment is one of the most important reasons for unemployment early in the disease course, with about 54% of pwMS with an EDSS <3 (i.e. pwMS that still have an unrestricted walking range) being unemployed in Europe. In many work environments, solutions can be found for physical disabilities (e.g. flexible hours to avoid busy commute, working from home one or two days a week, private transport to work, …) but bypassing cognitive disabilities is much more challenging. In practice, it often involves cutting back on working hours. Not being able to work, unwillingly affects your self-confidence, reduces common ground with many individuals from your social network and puts your disease at the center stage of your life. 

At this point, it is unfortunately not possible to systematically categorise pwMS according to one of these cognitive subtypes in clinics. A cognitive test battery to determine cognitive status easily takes two to three hours to complete, and systematically repeating this examination over time as a monitoring tool is not realistic. Moreover, underperforming on a cognitive test has no clear consequences for your DMT management. This means that the effect of DMTs on the preservation or slowing down of cognitive deficits is not well studied. If an individual would have a lower score on a verbal memory test one year after a baseline measurement, we do not know whether a change in DMT would impact on preserving verbal function in the future. 

The reason we do not have this information is because most DMT clinical trials have focused on relapse rate reductions and EDSS as primary endpoints. These are legitimate endpoints in MS but it is not necessarily what will determine whether you can stay at work and be integrated in society. Therefore, we need to know how and to what extent DMTs impact on cognitive decline: the cognitive efficacy. Hopefully, the mildly encouraging data on cognition in the siponimod trial will set the scene for more and better. 

Twitter: @SmetsIde

Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

JAMA Neurol 2021 Apr 1;78(4):414-425. doi: 10.1001/jamaneurol.2020.4920.

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis

Ermelinda De Meo 1 2 3, Emilio Portaccio 4 5, Antonio Giorgio 6, Luis Ruano 7 8, Benedetta Goretti 3, Claudia Niccolai 5, Francesco Patti 9, Clara Grazia Chisari 9, Paolo Gallo 10, Paola Grossi 11, Angelo Ghezzi 12, Marco Roscio 12, Flavia Mattioli 13, Chiara Stampatori 13, Marta Simone 14, Rosa Gemma Viterbo 14, Raffaello Bonacchi 1 2 15, Maria A Rocca 1 15, Nicola De Stefano 6, Massimo Filippi 1 2 15 16, Maria Pia Amato 3 5

  • PMID: 33393981
  • PMCID: PMC7783596 (available on 2022-01-04)
  • DOI: 10.1001/jamaneurol.2020.4920

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, setting, and participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main outcomes and measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus. Conclusions and relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies.

About the author

Ide Smets

27 comments

  • Beautifully put. I’ve just been trying and failing to explain this to an insurance company who have denied my claim (but in fairness, they didn’t want to listen anyway)

  • I am so pleased this is being highlighted, it’s the only reason I am not driving or working and contributes enormously to my avoidance of socialising, and inevitably adds to anxiety and depression.

  • Ide,

    Thanks for your post.

    “for an untreated pwMS it takes a median 11.4 years to reach EDSS 4/not being able to walk unrestricted anymore, 23 years to reach EDSS 6/walking with a cane and 33 years to reach EDSS of 7/having to use a wheelchair.” I’ve never believed these data. They make MS look very benign.

    Do any neuros tell their newly diagnosed MS patients that they are unlikely to need a wheelchair for 33 years even if they don’t take any treatment? I know plenty of MSers using wheelchairs in their 30s and 40s. I wonder how much difference DMTs, particularly the highly effective give DMTs, are making to these endpoints?

    • I totally agree that these kind of numbers give a false sense of security, for HCP and pwMS. And the fact that clinical trials only use EDSS-deducted endpoints only adds to this safety illusion. The numbers are median values, meaning that 50% of pwMS will reach these endpoints sooner than 11/23/33 years.

      We don’t know to what extent DMTs delay the milestones yet. Moreover, it has become more difficult to assess this as pwMS are diagnosed earlier anno 2021 – given the prospect of treatment – compared to 20 years ago when most of the natural history data were collected. Based on the studies I have read, I expect the hard EDSS 4 endpoint to be delayed with about 4-6 years. This is because a lot of the damage has already been done at diagnosis, which is essentially an arbitrary timepoint in an individual’s disease course.

    • When I saw the title of this blog, I was looking forward to reading something positive for a change – the opposite happened, content depressing.
      However, my neurologist tells me that looking for the right word is part of the natural ageing process, he finds the same himself, but I am only 53, not that old, nor does he have a MS diagnosis.

      • Agreed, it is pretty depressing. It seems to suggest that even with the most effective DMT or any new treatment approaches that are found the course has already been set pre-diagnosis. Hopefully future pwMS will do better but not much for anyone already diagnosed

        • MS is like an onion – you keep peeling the layers and it gets worse and worse. Physical disability is bad enough, but MS is the gift that keeps giving – cognitive issues! I still think we are in the dark ages with understanding what this disease is and how to treat it. Nightmare disease which I would wish on my worst enemy. Gladly exchange it for any other “auto-immune” disease or a cancer which gives you a fighting chance.

          • I guess it’s a common theme among any neurological disease whether it’s auto-immune, degenerative, vascular,.. The impact of the damage is always much more extensive than the lesion location or size suggests.

        • That is only partially true. DMTs are absolutely disease modifying. But if we keep looking at remote disability endpoints rather than the cognitive endpoints, we will never find out to what extent DMTs affect cognition – and this is what matters in the semi short term.

      • “…my neurologist tells me that looking for the right word is part of the natural ageing process, he finds the same himself, but I am only 53, not that old, nor does he have a MS diagnosis.”

        I used to have a vocabulary that was out the roof, but no more. Oh those lovely lovely words are still in there, but accessing them in under a minute or more? Not usually, no. So, yes, it’s depressing. But it becomes enraging when our cognitive problems are brushed off by docs as “normal aging”. In fairness, I don’t suppose there is much they can actually do about the problems, but they don’t have to always try to make it seem like everyone else is dealing with the same thing, so what we’re dealing with (usually far younger than we should be) is something the doc “gets” (hint: he doesn’t) and is just something that needs to be sucked up. Like pwMS need lectures on how to suck it up? We could give whole master-level courses in that, amirite?

  • Apologies, but you have to remember: we can have conversations about optimal endpoints now because we finally have a whole range of DMTs now. The time had come to shift focus towards the real disability endpoint that matter. Personally, I do think DMTs affect cognition positively. But nobody knows how to integrate that knowledge in practice.

    It’s always difficult to distinguish age-related cognitive decline from MS. The best way to understand where you are cognitively would be to have a cognitive test battery, which compares your performance to performance of peers with the same age.

    • ‘It’s always difficult to distinguish age-related cognitive decline from ms.’

      Not necessarily from the patient perspective. After one particular relapse (muedullary?) my cognition was damaged severely, and only partially recovered. The 5 minute chat I had with a therapist at the time found no cognition damage because I concentrated and could remember a word from the beginning of our conversation, but the tasks I could no longer manage such as reading out my credit card number over the phone were life changing. After a hospital visit I was mentally exhausted and drove out the hospital and turned the wrong way into a dual carriageway. Looking back I can see that I was tired and couldn’t process all the sensory information. It is frustrating when doctors want to blame such marked and sudden cognitive changes on age because they don’t have the means to see what is really happening.

      • Agree, especially if it all appears after a relapse. I agree that brushing memory symptoms away as age-related is an insult to many pwMS who have to deal with these symptoms on a daily basis. But on the other hand, it’s also important not to overinterpret as age, mood, drugs (for example bladder meds) and fatigue are important confounders with also a not directly MS related negative effect on cognition. Most important is to communicate this line of thought, and to be honest about the fact that indeed it could be ms-related but not immediately modifiable. Unless we start having outcome data on this!

        • And to always consider referral for cognitive rehab which is essentially about learning to cope with these deficits rather than real rehab but incredibly helpful for many.

  • It sounds to me that the MS clinicians need to redefine and re-evaluate the EDSS. Too much emphasis is placed on walking as opposed to other metrics. Cognitive deficiencies are as important as physical deficiencies. When it comes to lesions it is all about location.

      • Thank you for including these endpoints on walking. I have never received something so clear from any of my neuros over the years (I was diagnosed in 2001 and have PPMS). Can you provide a reference for the disability endpoints? I would like to read the journal article on PubMed. You mention that your times are medians. And is this regardless of MS type? (I realize that the construct of MS types is somewhat arbitrary)

        To my neuro’s credit, I have had discussions with him based on the Roxburgh scale/Global Multiple Sclerosis Severity Scores (MSSS), but it always takes me while to decipher that grid/scale. Are the times a reference to that research?

        As an aside, regarding measures and endpoints, I will say that the 25 foot time walked in clinic is such a bad measure for me; I have no problem generating a time that has not varied much over the years; however, if you could see my worsening drop foot, swing gait/hitching, or measured the time from a sit to a stand, the true progression would be seen. I realize something objective needs to get measured.

        I do appreciate your point about the drugs and whether they impact cognition. I have been fortunate that I have maintained a high level job in healthcare administration full time. Cognitive impacts of the disease and the effects of fatigue are huge concerns for me.

        • Hi John,

          The endpoints on walking come from the following article:

          https://www.nejm.org/doi/full/10.1056/nejm200011163432001

          The numbers I cite are for RRMS. For PPMS, the picture is less optimistic: 0.0, 7.1, and 13.4 years for EDSS 4/6/7, respectively.

          The reference of the Roxburgh scale:

          https://pubmed.ncbi.nlm.nih.gov/15824338/

          Thanks for the input on the 25FWT. It illustrates that the majority the scales we use are insensitive to subtle damage.

          Cognition and fatigue influence quality of life more than ever while so many pwMS are not informed these symptoms are a part of the disease. This definitely needs to change.

      • “Absolutely!”

        Sorry…absolutely not edss is most important…
        because as it rises problems w/bowell/bladder/
        blood clots/high blood pressure/weight/and stroke
        increase and lifespan is reduced to very few years
        as one goes from paraplegic to quadraplegic.
        Are you unaware of this..?

        • Not sure where you are coming from…

          EDSS is by far not granular enough and it’s overwhelmingly driven by walking.

          • “and it’s overwhelmingly driven by walking.”

            Because that’s most important thing to overall health…if you can’t walk your weight increases…you can develop blood clots and high blood pressure…all things that increase
            mortality severely.

  • Thank you Ide for a great post. It’s good to know that such a difficult subject is open to discussion.
    Sadly this may have to remain the elephant in the room for many of us, for a number of reasons. We don’t want to flag up to the DVLA that there are times when we don’t know which way is up. We don’t want our solicitors to know what when we sign documents that we may not be able to understand them. We don’t want to sign Power of Attorney documents for relatives who are elders when we are less mentally able than they are. We don’t want to present our Neurologists with yet another issue than they can do nothing about. We don’t want our EDSS to record the true terror and chaos of our mental lives. And on and on…
    Karen your post made me laugh as you highlight as once again we are expected to ‘suck it up’

    • How true. Until there is some help for cognitive decline, what is the point in cataloguing it for an individual? It simply leads to depression . We find our own ways of dealing with it .

  • Thank you Dr Smets. I have to say, as an old newspaper type, that I’d be inclined to chide your headline writer (who might well be you, I suppose). Your commentary is about a shift in emphasis, not a plan to swear off wheelchair talk.

    It’s certainly good practice to flag the potential for cognitive issues to arise. As with physical symptoms, early therapy to address these seems advisable, as there are well-validated methods of coping.

    However, as you point out, median values don’t tell the whole story. Distribution along axes is always instructive. I’ll go out on a fairly solid limb and predict that a combination of age, years since onset and area of lesion concentration will correlate well with cognition status and gross motor disability. Someone in their 20s who was diagnosed eight years ago and has primarily brain lesions will suffer from cognition problems well before lower-limb disability, whereas someone in their fifties with onset just three years ago whose spine shows fairy lights on MRI will log a time-to-wheelchair much shorter than the median.

    The whole picture should be shared with patients, subject to their desire for information and ability to absorb it.

    Thanks again for this stimulating post.

  • Luckily I had the multi-hour battery of cognitive tests performed shortly after being diagnosed. I say lucky, as my health insurance covers the cost and the MS center offers the tests as part of their standard care. This also means it can be routinely performed over time.

    I highly encourage all newly diagnosed to have these tests performed. However, I completely understand the concerns and reservations some pwms have around the possible stigma associated with the test and results.

    Nevertheless, I wanted a baseline of my cognitive abilities at the time of diagnosis. This baseline assessment has become an extremely valuable piece of data. For example, I was diagnosed at 38yr old, three years later EDSS between a 5-6 and cognitive phenotype between 2-3, given the definitions stated above. All the DMTs I have used are considered high efficacy and I was turned down for the aHsct clinical trial….and do not have an extra $50k sitting under my couch.

    Most recent cognitive assessment showed I had declined to “average” in a few of the metrics, meaning I was previously “above average” so without having the baseline test, I would not have had the clinical evidence of the slight decline….other than the obvious symptoms I was experiencing in my day to day life.

    I recently started a new DMT, so if my next cognitive assessment shows I improved back up to “above average”, then maybe I could correlate the improvement to the new DMT since my brain is still relatively young.

    Great post and discussion Ide.

  • Happy to hear that some centres have these cognitive policies in place. Irrespective of the DMT effect, it’s very valuable info in terms of awareness. Would be great if we would have the resources to do this in our centre.

  • There are many ways to reflect on things…I had graduated with a PhD in Psychology and was licensed, so I could do therapy too. I got my dream job working as an Organizational Consultant, assessing organizational functioning. I was diagnosed before graduating. This was all back in the early 90’s. Point #1- When my first employer discriminated against me, made up some stuff about me and fired me, I sued successfully. There was no data back then about cognitive deficits of MSr’s. They would have sucked it up, and maybe they would have been right, that I should have told them about my MS during my job interviews. Point #2- After this, a few years later, I taught several courses at community colleges, and it did indeed become more difficult than it had been earlier when I taught a few times. Interviewing employees to come up with organizational trends, teaching psychology with active and interesting discussions, or doing effective therapy does indeed require being able to access and juggle so many facts, past and present, and then present points quickly in an intriguing and persuadable manner. Can you imagine doing therapy, and your client commits suicide, and his heirs find out you have MS and suggest you should have known? Maybe they’d be right? In the 90’s I thought, “Well, at least I’ll be able to think and get paid for it”. Boy, was I wrong.

By Ide Smets

Translate

Categories

Recent Posts

Recent Comments

Archives