Becoming an MS outlier: the manual


MS outliers are pwMS that are different from all other people diagnosed with the disease. Being an outlier could go both ways. Some pwMS develop significant disability very short after being diagnosed while others live with the disease for decades and are still out and about. The problem is we cannot reliably predict the disability trajectory of pwMS at diagnosis. Observations in big groups of untreated pwMS have shown that male gender and older age at onset might be unmodifiable negative prognostic factors. Modifiable lifestyle factors such as smoking and obesity have also been associated with a more aggressive disease course.  It’s no rocket science that people who are smoking and obese also very often do not sufficiently exercise. However, the ‘exercise’ factor has often been neglected in observational cohorts or experimental research. 


Fortunately, Brian Lozinski and V Wee Yong have summarised what we do know about the effects of exercise on the MS brain in an enlightening review. 

  • The highlights of the review in the animal model of MS: 

In a pivotal study, the spinal cords of mice were exposed to lysolecithin which causes acute toxic demyelination after which the brain repair mechanisms (= oligodendrocyte precursor cells) become active and induce remyelination. In these mice, running wheel activity (= a treadmill for mice) activated the PPAR gamma co-activator-1α (PGC1α) within oligodendrocyte progenitor cells and increased the number of remyelinated axons, along with thicker myelin sheaths, compared to sedentary controls.  Furthermore, the therapeutic effect of exercise was facilitated by a remyelinating drug, clemastine. In mice following the “MedXercise” protocol (running wheel + clemastine), there were more surviving axons after lysolecithin demyelination compared to exercise or clemastine alone groups. 

In addition, many other studies in MS animal models showed that exercise reduces clinical severity scores, renders immune cells less pro-inflammatory and improves the integrity of the blood-brain-barrier allowing for less pro-inflammatory cells to invade the brain. Potentially the timing of exercise could be important, with exercising soon after a demyelinating event having more impact in terms of remyelination than weeks later. 

  • The highlights of the review in pwMS: 

The evidence in humans is more indirect and does not involve remyelinating agents. In healthy individuals, there was a compelling association between piano practice and the integrity of the white matter tracts translating into more high level performances. In pwMS, several studies documented an impact of exercise on MRI measures. For example, a 24-week randomised controlled cross-over trial comparing progressive resistance training (= e.g. lifting weights) and self-guided physical activity with no training showed that brain volume change differed between groups and there were higher absolute cortical thickness values in several brain regions in the exercise group. There was no consensus among the different studies regarding the type of exercise and the benefits of exercise are most likely transient if the program is not maintained. 

In summary, we need more human data to link exercise, brain function and repair. Moreover, it would be very interesting to know how pwMS on treatments such as ocrelizumab do vs. pwMS on ocrelizumab + an exercising program. Of note, all this emerging evidence comes on top of the fact that exercise has been clearly linked with less fatigue, less depression and anxiety, better cognition and higher mobility, and thus becoming an MS outlier in the most positive sense. The official advise for pwMS is to engage in 150-300 minutes of medium-vigourous exercise per week (i.e. increased respiratory rate and perspiring). As we all know from last week, the doorstep mile is the most difficult one. For anyone struggling to metaphorically get out of the door, I wanted to add the following advice:

  • Do something you like to do
  • Create a facilitating micro-environment: Put exercising in your agenda? Schedule exercising the day beforehand? Put your hiking shoes already next to the door? Rise and shine in a new sports outfit? For people working from home: Feel free to wear your sports outfit all-day long until you take the doorstep mile (some sports gear looks very professional during zoom meetings ;-))
  • Multitask: Watching your favourite Netflix show is definitely compatible with exercising on a stationary bike? Running with an audiobook (warning: only if you wear bone-conducting headphones!) Hiking and listening to your favourite podcast? Taking one stop earlier on the subway to work and walk the remainder of the trajectory? Commuting by bike?
  • Make it social: Tell other people about your ambitions, you will notice you get a lot of support and some people might even join! 

And remember: we are all outliers, and that’s a good thing!

Twitter: @SmetsIde

Exercise and the brain in multiple sclerosis

Brian M Lozinski 1, V Wee Yong 1Affiliations expand

  • PMID: 33124511
  • DOI: 10.1177/1352458520969099


While people with multiple sclerosis (PwMS) historically were advised to avoid physical activity to reduce symptoms such as fatigue, they are now encouraged to remain active and to enlist in programs of exercise. However, despite an extensive current literature that exercise not only increases physical well-being but also their cognition and mental health, many PwMS are not meeting recommended levels of exercise. Here, we emphasize the impact and mechanisms of exercise on functional and structural changes to the brain, including improved connectome, neuroprotection, neurogenesis, oligodendrogenesis, and remyelination. We review evidence from animal models of multiple sclerosis (MS) that exercise protects and repairs the brain, and provide supportive data from clinical studies of PwMS. We introduce the concept of MedXercise, where exercise provides a brain milieu particularly conducive for a brain regenerative medication to act upon. The emphasis on exercise improving brain functions and repair should incentivize PwMS to remain physically active.

Keywords: Exercise; magnetic resonance imaging; neuroprotection; oligodendrocytes; remyelination; repair.

About the author

Ide Smets


  • Well the stroke doc allready should know this

    And agressive exercise soon after the insult

    High-intensity step training boosts stroke survivors’ walking skills

    Our study suggests that stroke patients can perform higher intensity walking exercises and more difficult tasks than previously thought possible. We need to move beyond traditional, low-intensity rehabilitation to challenge the nervous and cardiovascular systems so patients can improve function and perform better in the real world.

    The researchers found:

    Survivors in both the high-intensity, variable training and high-intensity, forward walking groups walked faster and farther than the low-intensity, variable training group.

    For all walking outcomes, 57% to 80% of participants in the high-intensity groups had important clinical gains, while only 9% to 31% of participants did so following low-intensity training.

    High-intensity variable training also resulted in improved dynamic balance while walking and improved balance confidence.

    Look at the video

    Rehabilitation that allows walking practice without challenging the nervous system doesn’t do enough to make a statistical or clinically significant difference in a patient’s recovery after a stroke,” Hornby said

    Challenged the nervous system

    • It’s definitely true that the stroke field has far better data on the usefulness of rehabilitation, and that in MS there is still a lot of work to do. Again, this study highlights that it’s not only about recovery of the disability but also about training other healthy muscles that need to compensate.

    • Absolutely, and ideally for pwMS that experience issues with balance. It is also very often used in rehabilitation of people with a spinal cord injury.

  • So I was right to run London Marathon with diplopia? (yes I could only see 1m in front of me and I couldn’t see any of my supporters, but I’d done all that training…)

    The relapse before that I remember going out for a long run with numb feet. They felt better by the time I got home (numb again the next day though).

    And every other relapse I did my best to keep active and by the end of each day I always felt so much better. Though I struggled to run in a straight line with optic neuritis. And when I had nystagmus I missed a course split in a trail race and ended up running 21km instead of the 15km I’d decided to switch to before the race. I also tripped and fell in that race.

    I’ve also kept working and not taken a day off during any relapse. I sort of decided that if it happened again (and now I’m on a permanent contract and eligible for sick leave) I would take sick leave. But maybe it’s better not to?

    • You sound really persistent, and congratulations on the London marathon!

      Overall, I don’t think there is any harm in taking time off work when you have a relapse. It is indeed important that you stay active even when having a new disability, but not necessarily at the same pace as before. Taking time off work also allows to invest in focused physiotherapy, and taking a jumpstart in terms of recovery – mentally and physically.

      • Fortunately my employment situation is a lot more secure than it was before my diagnosis! But when you’re crossing your fingers for a contract to be renewed is not the best time to say “by the way, some times I get all kinds of weird symptoms, no I haven’t been diagnosed with anything, no I’m not a hypochondriac, yes I really want to keep this job”

        • No I agree. Sick leave is a relative luxury, and not everyone has his/her career sorted before the MS diagnosis. Although this should not be the case in an ideal world, it’s naive to assume it would not influence an employer’s HR policy.

  • That’s really interesting. I started running (jogging) not long after diagnosis, probably because I didn’t want to think about not being able to do something in the future. I feel lucky that I’m still able to exercise and have more recently found a friendly local triathlon club. My current go-to is Zwift. It’s taking up space in the house but I can hop on really easily. Bike racing virtually on a turbo trainer set up has pushed me much harder than I have ever had the motivation to do before. Even better is I can do it in a team which provides added peer pressure to go faster! I do have the ‘use it or lose it’ fear.

    • Happy to hear you joined team Zwift. I assume you know every bend of Box Hill by now 🙂 It’s always good to have a little bit of fear, keeps you going. It’s really impressive how many people have engaged with indoor cycling because of Zwift. I feel it has become the healthy variant of online gaming.

      • 😀. I am now a WTRL Team Time Trial addict and have just signed for the next Zwift racing league. It has been a brilliant find through lockdown. I’m looking forward to finding out how it has made a difference in real life too – once I remember to brake, steer etc!!

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