Fatigue in MS – what we don’t know?


Fatigue in MS is a strange duck, on many levels obvious and frequently described by PwMS (80-90%), but one that lacks sound medical explanation and science doesn’t even know how to test it yet. I was sure that the fatigue in MS, particularly exercise induced fatigue, was somehow related to the conduction block caused by the demyelination in the long tracts (corticospinal tract). It would seem that I was wrong.

In a study testing this specifically, Mordillo-Mateos et al. (see abstract at the bottom) used a hand grip task to squeeze a hand dynamometer for two mins to induce fatigue, and measured post-exercise motor evoked potentials, MEP (a measure of the descending corticospinal tract drive) and conduction times (CMCT) in the long tracts to the arms, to see if there was any depression in the readings. Additionally, they also evaluated the electrical pulse arising from the activated muscle fibres in the target muscle supplied by the nerve (compound muscle action potential, CMAP). The findings were compared with controls who didn’t have MS.

Hand dynamometer

As expected, both MEP and CMCTs were smaller in the MS group than controls. The latter correlated with diminished maximal hand strength, i.e. the more prolonged the CMCT (corticopinal tract dysfunction) the less the maximal hand grip strength.

Following exercise, however, the MEP in the control group decreased immediately afterwards and then recovered slightly, while no changes were observed in the MS group (see figure below). The motor system fatigability (measured as a decrement in MEP as a percentage of the baseline value) was therefore larger in controls than the MS group. Similarly, the CMAP was decreased after exercise in the controls but not the MS group.

Normalized Motor Evoked Potentials in healthy subjects and MS patients at baseline and after fatiguing task. Error bars are standard deviations.

Both the MS group and the control group perceived a similar fatigue state of the executed task (i.e. the muscle effort produced during the handgrip task was somewhat hard irrespective of whether the person had MS). However, unlike in the control group where the fatigue was related to the task at hand, in the MS group the fatigue state was independent of the fatigue trait (i.e. MS group had higher perceived fatigue generally).

But, it would seem that the fatigue trait is independent of the corticospinal tract dysfunction, at least. One explanation for these findings is that in MS there is compensatory increase in central motor drive – previously reported by other researchers.

The problem of fatigue in MS may therefore be higher up, a result of the changes in brain connectivity, including reward and motivation brain circuits, as well as the re-organization that have taken place. So, exercise isn’t a bad thing, and possibly mindfulness programs can be tailored to tackle the brain fatigue.


Front Neurol. 2019 Apr 9;10:339. doi: 10.3389/fneur.2019.00339. eCollection 2019.
Fatigue in Multiple Sclerosis: General and Perceived Fatigue Does Not Depend on Corticospinal Tract Dysfunction.
Mordillo-Mateos L, Soto-Leon V, Torres-Pareja M, Peinado-Palomino D1, Mendoza-Laiz N3, Alonso-Bonilla C1, Dileone M4, Rotondi M5, Aguilar J6, Oliviero A1.

Background: Multiple sclerosis (MS) is an autoimmune disorder of the CNS in which inflammation, demyelination, and axonal damage of the central nervous system coexist. Fatigue is one of the most disabling symptoms in MS and little is known about the neurophysiological mechanisms involved. Methods: To give more mechanistic insight of fatigue in MS, we studied a cohort of 17 MS patients and a group of 16 age-matched healthy controls. Baseline Fatigue Severity Scales and Fatigue Rating were obtained from both groups to check the level of fatigue and to perform statistical correlations with fatigue-induced neurophysiologic changes. To induce fatigue we used a handgrip task. During the fatiguing task, we evaluated fatigue state (using a dynamometer) and after the task we evaluated the Borg Rating of Perceived Exertion Scale. Transcranial magnetic stimulation and peripheral electric stimulation were used to assess corticospinal tract and peripheral system functions before and after the task. Results: Clinically significant fatigue and central motor conduction time were greater in patients than in controls, while motor cortex excitability was decreased and maximal handgrip strength reduced in patients. Interestingly, fatigue state was positively correlated to perceived fatigue in controls but not in patients. Furthermore, in the presence of similar fatigue state over time, controls showed a significant fatigue-related reduction in motor evoked potential (a putative marker of central fatigue) whereas this effect was not seen in patients. Conclusions: in MS patients the pathogenesis of fatigue seems not driven by the mechanisms directly related to corticospinal function (that characterize fatigue in controls) but seems probably due to other “central abnormalities” upstream to primary motor cortex.

About the author

Neuro Doc Gnanapavan


  • Autoimmune disease symptoms
    The early symptoms of many autoimmune diseases are very similar, such as:

    achy muscles
    swelling and redness
    low-grade fever
    trouble concentrating
    numbness and tingling in the hands and feet
    hair loss
    skin rashes

    • So, the initial period is felt to be the result of cytokine release, giving rise to a flu-like response. But probably different mechanisms later on. The prevailing theory is that it’s a brain connectivity issue. This work also supports this theory.

  • I have the feeling that there are different types of fatigue going on in MS. The most pernicious is an extremely drained feeling I get if I push myself too hard over too many days. Eating and resting, sleeping don’t readily allow recovery from this feeling. I feel that this is some sort of metabolic problem.

    • As in my reply to Luis above, aside from cytokines people have researched problems in the hypothalamic pituitary axis (endocrine system hormonal system), but findings have been conflicting.

      • As I remember some time back from talking to some pwMS who were treated with Tysabri, the big thing that they noticed was their fatigue completely disappeared.

        • ” … some pwMS who were treated with Tysabri, the big thing that they noticed was their fatigue completely disappeared.”

          That statement is true, in this household, also. The biggest thing we notice now in having switched from Tysabri to Ocrevus approx. 2 years ago is the fatigue has returned.

          • Really sorry to hear that but it is scientifically really interesting as to why that should be.

  • When you (and others) describe fatigue, are you referring to how quickly muscles tire – prematurely? – when undertaking a repetitive exercise load?

    In order that I can use the correct terminology with my treatment team should I use a different term. For me: fatigue is that feeling of having a hot, damp and heavy blanket draped over me. I can do life but it is slower and more one-dimensional. I can’t do much complex thinking or reading. I plod through daily tasks at a slower speed.

    Would you refer to that differently? I can exercise and train, these days the effort expended is proportional to the hit described above that I feel afterwards. A higher price than I am accustomed to!

    Thoughts? Thank you.

    • I have PPMS and have just returned from my gym after exercise, completely fatigued. It’s a warm day today, however. In the winter months, the same exercise routine causes me nominal fatigue. The colder the temperature, the better it is.

    • Yes, so this is what this study is alluding. That the fatigue experienced in PwMS isn’t directly related to the muscle groups being exercised, as the long tracts seemed to ramped up. It is the way the brain is spending a lot of time and energy dealing with motor constructs, cognitive constructs (often people refer to this as cog fog).

  • I think the initial fatigue that accompanies any AD which derives from inflammation and is easier to modify, transforms into a more debilitating fatigue that is related with damage to brain synapses and it gets progressively more difficult to intervene. Patients who are early on highly effective treatment can return to a normal state of fatgiue, but the same does not apply to older patients. Early regulation of fatigue should be a therapeutic target in NEDA, that would exclude CRABS for this extra important reason.

  • One limitation that I see in the research on fatigue in MS is that it generally fails to distinguish between physical fatigue and cognitive fatigue. As someone with RRMS that experiences cognitive fatigue, but virtually no physical fatigue, I’ve found research on cognitive fatigue in the context of TBIs to be much more relevant to my symptoms and their treatment.

  • Fatigue in Multiple Sclerosis comes in different disguises.
    -waking up at night, more than once, contributes to be tired in daytime,
    -after eating breakfast, I can feel totally exhausted,
    -now a days I know when to announce “enough” in time during exercise to prevent total exhaustion, which can last a week,
    -some people give me energy, some drain my energy,
    -if I need to do something I know it is quicker to wait until I’m in the right frame of mind to do it, if I’m not in the right frame of mind I simply make to many mistakes.
    Living with MS is simply a daily tiring battle.

  • Aaan 201

    The results suggest that fatigue in MS is related to negative mood and inflammation. Damage to
    white matter tracts and cerebral atrophy may help explain fatigue in patients with more advanced disease, but we
    did not see this in our early cohort. We suspect that there may be different phenotypes of fatigue throughout the
    disease process and failure to consider this may explain why we’ve had difficulty determining what causes
    fatigue. Identification of phenotypes may lead to more targeted and effective treatments


  • Aan 2019


    The results suggest that fatigue in MS is related to negative mood and inflammation. Damage to
    white matter tracts and cerebral atrophy may help explain fatigue in patients with more advanced disease, but we
    did not see this in our early cohort. We suspect that there may be different phenotypes of fatigue throughout the
    disease process and failure to consider this may explain why we’ve had difficulty determining what causes
    fatigue. Identification of phenotypes may lead to more targeted and effective treatments.

  • One on fatigue and DMF, T cells and inflammation

    Immunophenotyping of Depression and Fatigue in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients Treated with Dimethyl Fumarate

    Results:There is a significant positive correlation between the depression and fatigue scores. Depressed patients had significantly lower number of T cells than those without depression. CD8+ Treg were shown to be significantly higher in depressed patients. HADS-D score also strongly correlated with both CD4+ and CD8+ Treg counts. Fatigue scores (FSS) had a significant positive correlation with the number of classical monocytes. Both CD4+ and CD8+ Tregs also positively correlated with FSS scores as well as the CD4+CD45RA-CD62L+ subpopulation.

    Conclusions:Our results show that depression and fatigue in MS patients treated with DMF are associated with an increased level of regulatory T cells, as previously shown in studies involving depressed patients without MS. This may be a result of the immune system compensating for the proinflammatory environment, which suggests that even in MS depressed and fatigued patients have a more inflammatory immune environment than those without the two symptoms.

  • Fatigue has always been my worst symptom, and for so many years it was severely debilitating. This had been the case no matter what DMT I had been using, including my favorite, Tysabri. However, what I have found to be greatly helpful is an intermittent fasting diet. Back in 2006, I had read an article about the potential benefits of fasting on MS symptoms and decided to create my own fast where I fasted every other day for awhile before easing up and fasting only once or twice per week. I also was watchful of my sugar, dairy, bread & red meat intake for weight loss purposes but then loosened-up quite a bit there, as well. For me, the fast completely improved my quality of life and changed the trajectory of it, as well. JSV



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