Prof G what causes MS-related fatigue?

MS-related fatigue is complex, but I will try and keep it simple.

Fatigue is one of the most disabling symptoms pwMS suffer from. In over 50% of pwMS fatigue is the one symptom they would like to get rid of most. MS-related fatigue has several underlying mechanisms. For a short discussion on the major mechanisms…….

(1) Inflammation in the brain causes fatigue. This is due to inflammatory mediators or cytokines, in particular, interleukin-1 (IL-1) and TNF-alpha, which trigger sickness behaviour. Sickness behaviour is the behavioural response we have to inflammation, which forces us to rest and sleep so that our body can recover. This is what happens to you when you get a viral infection; in fact many of the pwMS I look after describe their fatigue as being similar to the fatigue they experience when they get flu. Sickness behaviour from an evolutionary perspective is well conserved and occurs in most animals. This type of fatigue needs to be managed by switching off ongoing inflammation in the brain. This is why so many pwMS who go onto highly-effective DMTs comeback saying ‘I feel so much better, my fatigue and/or brain fog has cleared’. Do you relate to this? This is why recent onset fatigue that can’t be explained by other factors (see below) may indicate MS disease activity. At present fatigue on its own does not constitute a relapse, but there are some of us who would disagree if we find subclinical/MRI or biomarker (neurofilament) evidence of a relapse.

(2) Another cause of fatigue is exercise related conduction block. This is when pwMS notice their legs getting weaker with exercise. We think this is due to demyelinated, or remyelinated axons, failing to conduct electrical impulses when they become exhausted. Exercise-induced fatigue is probably the same as temperature-related fatigue; a rise in body temperature also causes vulnerable axons to block and stop conducting. To deal with this type of fatigue we need therapies to promote remyelination and to increase conduction. These types of fatigue are treated by rest, cooling and possibly drugs such as fampridine that improve conduction. At the heart of this type of fatigue is localised EF (energy failure).

(3) The other cause of fatigue is neural plasticity. When the brain is damaged by MS other areas are co-opted to help take over, or supplement, the function of the damaged area. In other words, it takes more brain power to complete the same task that normal people do. This type of fatigue usually manifests as mental fatigue and is why pwMS have difficulty concentrating for prolonged periods of time. At present we have no specific treatment for this type of fatigue, but some patients find amantadine and modafinil helpful. In short, preventing the loss of brain power, or damage, in the first place should prevent this type of fatigue.

(4) Fatigue can also be related to so-called co-morbidities, or other diseases, that are related to MS. The big co-morbidities that cause fatigue that need to be screened for are:

  • Infection; we all get tired when we have infections; it triggers sickness behaviour 
  • An underactive thyroid gland or hypothyroidism; this is commoner in pwMS 
  • Poor sleep hygiene and/or sleep disorders; if you are not sleeping well you feel tired in the morning 
  • Obesity; when you are overweight it takes more energy to perform physical tasks 
  • Depression and anxiety; fatigue is a common symptom of depression and anxiety 
  • Side effects of drugs; in particular drugs that cause sedation and from DMTs. Anticholinergics and anti-spasticity drugs are sedating and blunt cognition and may worsen MS-related fatigue. Specific side effects, for example, the flu-like side effects from interferon-beta may make fatigue worse. 
  • Deconditioning; deconditioning is simply the term we use for being unfit. If you are unfit, performing a demanding physical task makes you tired. Deconditioning is treated with exercise, which paradoxically can reduce fatigue. 
  • Poor nutrition; some pwMS are anorexic and eat very poorly and hence have little energy as a result of this. Although this is quite rare I look after a few pwMS with this problem. Similarly, overnutrition may have the same effect. Some of the hormones your gut produce cause you to feel tired and want to sleep; i.e. the so-called siesta effect. Reducing the size of your meals and changing your eating behaviour may improve post-prandial (after eating fatigue). I have a few patients who avoid eating lunch for this reason. 

It is apparent from this discussion that fatigue in MS is more complex than you realise and needs a systematic approach to be treated and managed correctly. So be careful, or at least wary, when your neurologist simply wants to reach for the prescription pad to get you out of the consultation room. Like other MS-related problems, a holistic and systematic approach is needed to manage and treat MS-related fatigue correctly.

The following is a summary of the results of an old blog survey on the causes of fatigue.

CoI: multiple

8 thoughts on “Prof G what causes MS-related fatigue?”

  1. Thanks ProfG, very interesting. It seems that fatigue can accompany desease progression not caused only by inflammation. However, if you are proactive from the start, you might only need to hit inflammation related fatigue -while protecting from the rest causes at the same time, with high efficacy drugs, right? Tysabri, Ocrevus and Rituxan, Lemtrada and HSCT have all an impact on fatigue and this should also be a factor for choosing a DMT. Fatigue is a far neglected symptom in many diseases, showing the indifference of Pharma and doctors for quality of life. If you still breathe you are cool for them.

    1. Fatigue is a many headed monster; inflammation may be the biggest head, but you need to remember the other ones.

  2. I'm surprised only 1 person added menstrual period as a cause of fatigue on the survey. I would have thought it would be much higher number. But I guess it wasn't on the list of causes to tick.It's one of my main causes of fatigue. But I was anaemic years ago, so I have multi-vitamin with iron. It would be interesting to see the male and female ratio of who answered the survey.I wonder about iron build up in the brain and MS, with the iron tablets?

    1. Menstruation and ovulatory associated fatigue has not been studied in depth and needs more attention. There are many reasons why these physiological processes exacerbate MS-related fatigue.

  3. Thank you very much Prof G. That is both comprehensive and comprehensible and yet a succinct piece. I feel that I sort of knew all/most of it but had not put it all together so coherently.

  4. Hello!
    Reading this feels like finally being invited to the right club where everyone nods at you with that look of understanding. 🙂
    I could identify with the vast majority of types of fatigues, which again confirms that I’m not imagining things. For example when explaining to my doctor that, sometimes, Amantadine helps, and sometimes it doesn’t. I can see now that it will have helped with mental fatigue, but not the other types.

    I have a question that doesn’t seem to have been touched on (which may indicate that it’s a myth anyway): I seem to suffer from 3 weeks of continuous, debilitating fatigue paired with the symptoms of a very active MS (nerve pain, vibrating or hot body parts, mouth ulcers, the lot) about three times a year. I’ve only been diagnosed in 2017 (RRMS), so haven’t been able to establish a clear trend, but it appears to be in autumn and spring. Can season changes affect fatigue? Which group would this type fit in?
    Thanks so much!
    Karin (fatigued right now, 15 days and counting)

  5. Dear Prof. G.,
    you name inflammation in the first place as a cause for fatigue. Don’t you then find it astonishing that a recent study (Hakansson et al., MSARD, in press) did not find any correlation between fatigue and inflammatory markers in CSF?

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