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:

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

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