March 7, 2019 | News | Living with MS

Why MS fatigue?

Fatigue is the most common symptom of multiple sclerosis, with about 85% of people affected by it (Stuke and colleagues. J Neurol 2009;256:1932-1935). Fatigue is one of the ‘invisible symptoms’ of MS – unseen by others (“You look so well”), hard to describe, a drag on your daily activities, and difficult to relieve even with rest periods and naps. There are a few treatments for MS fatigue, but they are often ineffective. In part, this is because fatigue isn’t well-defined and its underlying mechanisms are poorly understood, so it’s hard to target it effectively with a medication.

MS fatigue has been described “an overwhelming sense of tiredness” (Induruwa and colleagues. J Neurol Sci 2012;323:9-15), and “lack of motivation to…engage in high effort performance” (Dantzer and colleagues. Trends Neurosci 2014;37:39-46). These definitions are really quite different – the first emphasizing the physical, the second the psychological – pointing to a fuzziness in how fatigue is viewed. In fact, MS fatigue is both: there is an impact on actual physical performance (called ‘fatigability’), which can be detected on tests of physical or mental performance; as well as an impact on a person’s perceptions of fatigue. People’s subjective experience with fatigue is more difficult for researchers to measure. This doesn’t mean that fatigue is “all in the head”. But it does suggest that there is a complex interaction between psychological and physical factors that are contributing to a sense of fatigue.

There are many theories about the causes of MS fatigue but few hard answers. The three main areas of research have looked at structural changes in the brain caused by inflammatory lesions; immune mechanisms that promote inflammation and alter brain function; and cognitive aspects and how the brain monitors itself (called ‘metacognition’).

Structural changes: MS is characterized by the development of MS lesions in the white matter and grey matter of the brain, as well as a more diffuse inflammation throughout the central nervous system. These lesions may impair connections or slow communications between different brain regions. It has been difficult to show that this damage directly causes fatigue, although it can cause MS symptoms (such as difficulty walking) that contribute to fatigue. Recent studies have looked at whether lesions in specific brain regions impair the brain’s biochemical processes. For example, neurons produce a protein called orexin, which regulates vigilance and attention. Orexin levels are low in conditions such as narcolepsy, in which people find it difficult to remain awake. Some studies have found that orexin levels are low in people with MS fatigue (Papuc and colleagues. Neurosci Lett 2010;474:9-12), while other studies haven’t found a connection (Constantinescu and colleagues. J Neurol Sci 2011;307:127-131).

Another theory holds that the inflammation and neurodegeneration associated with MS force the brain to change how it performs its tasks. The workload normally performed by a specific part of the brain may be redistributed over several areas, much like office tasks may be shared by several co-workers if a key person calls in sick. Imaging studies have shown that in performing a task, people with MS may need to recruit more areas of the brain to compensate for areas where there is impairment (Filippi and colleagues. Neuroimage 2002;15:559-567; Tartaglia and colleagues. Eur J Neurol 2008;15:413-419). This means that it requires more mental effort to accomplish a task, which can lead to fatigue.

Immune changes: The activated immune response seen in MS triggers changes in the brain that affect nerve function. Also affected are neurotransmitters that regulate mood (e.g. serotonin) and motivation (e.g. dopamine) – both of which can have an impact on a person’s feelings of fatigue. Low levels of serotonin have been linked to depression (many antidepressants boost serotonin in the brain). Dopamine is part of the brain’s “reward” system and is key to feeling motivated (it’s also released when you smoke, take illicit drugs, gamble and compulsively shop). In the context of MS fatigue, altered dopamine function may leave you unmotivated and feeling that everything requires too much effort.

One interesting area of research involves a substance called kynurenine, which is involved in the metabolism of tryptophan (the precursor to various neurotransmitters and often taken as a supplement). Kynurenine is broken down to toxic metabolites that promote inflammation in the brain. Inflammation in turn degrades tryptophan, which diminishes the body’s ability to synthesize serotonin and dopamine. The unwelcome effects of kynurenine, such as feelings of depression and stress, can be offset by exercise, which converts kynurenine into a form that can’t enter the brain (Agudelo and colleagues. Cell 2014;159:33-45).

Cognitive changes: The structural and functional changes mentioned above may contribute both to the physical aspects of fatigue (doing something is more difficult), and to the psychological aspects of fatigue (feeling weary, unmotivated and overwhelmed when faced with a task). Also important is ‘metacognition’ – which means “thinking about your thinking”. As we perform tasks, part of our brain is thinking about our performance – can we do it, how well is it being done, how hard is the task, and are we in control of the process? Our brains are able to monitor how well our body is functioning. If the brain perceives that the body is ill, a person may be left feeling too sick and tired to complete a task. An altered inner perception of bodily states has been reported in MS (Salamone and colleagues. Hum Brain Mapp 2018;39:4743-4754). A sense of fatigue can then arise if the brain’s internal assessment decides that the expected rewards (of continuing or completing a task) aren’t worth the effort (McMorris and colleagues. Neurosci Biobehav Rev 2018;93:93-107).

The many theories show that fatigue is a complicated syndrome – both a cause and consequence of other problems common in MS, such as physical challenges with daily tasks, problems with thinking and planning, depression and anxiety. In the ideal world, a specific cause of fatigue could be identified and treated in an individualized way, but that isn’t possible at the moment. This means that coping with MS fatigue will need to be a process of trial and error. Some people may benefit from scheduling tasks when fatigue is less severe (such as in the morning), taking a half-hour nap in the afternoon or enlisting the help of loved ones to do some of the chores. Others may feel a boost with regular exercise and a healthier lifestyle. And some may benefit from medications that treat underlying depression/anxiety or boost energy levels. Perhaps the best starting point is to talk to your neurologist and MS nurse so they can work with you to devise the best solutions to improve your MS fatigue.

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