How we define fatigue remains as controversial today as it did 40 years ago: “True fatigue and....tiredness are plainly different.”¹. Fatigue is more than tiredness and has recently been referred to as “pathological exhaustion”.² In this context the term “pathological” would, for example, classify the physical fatigue which athletes experience as part of voluntary effort as being abnormal. Fatigue must therefore surely be a normal phenomenon—a subjective feeling of tiredness or exhaustion which could refer to both physical (motor activities) and mental (cognitive or emotional) processes. Fatigue is only pathological if it is disabling—that is, if it affects a person’s social, physical, and occupational wellbeing. For lack of a better definition the Centres for Disease Control and Prevention (CDC) defines “profound fatigue” and by implication “pathological fatigue” in the context of the chronic fatigue syndrome (CFS) as fatigue that “is not improved by bed rest and that may be worsened by physical or mental activity”.³ This definition appropriately excludes exercise induced or temperature dependent conduction block, a form of physical fatigue which occurs in subjects with demyelinating disease.

Approximately 80% of subjects with multiple sclerosis (MS) have pathological fatigue and in half these cases it is their most disabling symptom. In general, fatigue does not correlate with neurological impairment, physical disability, or the lesion load on conventional magnetic resonance imaging (MRI). In one study, subjects with “benign MS” had as much fatigue as those with non-benign MS.⁴ Rarely, MS may present initially as chronic fatigue. In more recent studies a relation has been demonstrated between altered cerebral activation patterns⁵ and the development of progressive brain atrophy⁶ and fatigue. In the latter study the development of progressive brain atrophy was independent of disability, mood, or other MRI findings.⁶ These observations question whether anatomical and physiological substrates underlie MS related fatigue.

One emerging hypothesis is that MS related fatigue is caused by ongoing inflammation. Fatigue that occurs as a result of acute infections can be reproduced by the administration of proinflammatory cytokines—for example, the type 1 interferons (α or β) or interleukin 2. The evolutionary benefits of fatigue in relation to systemic infection are obvious—in response to an infection the immune response triggers a behavioural response to maximise an animal’s chance of recovery and hence of survival. Thus it is not surprising that fatigue is such a prominent symptom in chronic diseases associated with systemic inflammation. In rheumatoid arthritis, a systemic inflammatory disease without obvious CNS pathology, levels of acute phase proteins correlate with fatigue.⁷ In MS, weak correlations between fatigue and markers of systemic inflammation have been reported.^4,8 Similarly, in this issue of the journal (see page 34–9), Heesen et al report a weak association between fatigue and the stimulated whole blood production of the proinflammatory cytokines tumour necrosis factor α (TNFα) and interferon γ (IFNγ).⁹ An important observation, however, is that MS related fatigue does not correlate with Gd enhancing lesions on MRI,^6,10 the most widely accepted marker of active inflammation in MS. These observations suggest that MS related fatigue is linked to peripheral rather than central inflammation. This may explain why treatment with IFNβ, a systemically administered cytokine that reduces MRI activity, is not associated with an improvement in fatigue scores.¹¹ How systemic inflammation induces fatigue is unknown, but the symptom may be mediated by proinflammatory cytokines, similar to the hypnotic effects of interleukin 1 and TNFα.¹²

Whether or not fatigue is a sensory percept is a moot point. Focal areas of the cerebral cortex or subcortical structures involved in the perception of fatigue have not been identified. On the other hand, fatigue and arousal may have a similar neuroanatomical basis. In arousal, subcortical systems integrate sensory and environmental information, which is processed and stimulates the cerebral cortex through the ascending reticular activating system. The latter hypothesis would explain how systemic inflammation induces fatigue.

An important caveat to the above observations and to the ongoing research into MS related fatigue is the lack of well validated outcome measures to quantify fatigue. The interpretation of fatigue by subjects responding to the most commonly used fatigue questionnaires may be context and disease specific. Work is therefore required to standardise the measurement of fatigue in MS and other conditions.

Uncertainties over the definition, pathogenesis, and measurement of MS related fatigue are clearly hampering the testing of specific therapeutic anti-fatigue strategies. There are, however, unproven strategies that could be tried to help ameliorate MS related fatigue. As fatigue appears to be related to mood and quality of life, it is important to address these issues at the outset. Similarly, it is important to exclude common medical conditions that could exacerbate fatigue—for example hypothyroidism—and to optimise the doses of drugs that are known to exacerbate fatigue. Non-pharmacological approaches for the specific management of fatigue include behavioural therapy, graded aerobic exercise programmes, energy conservation strategies, dietary advice, environmental cooling, and improvement in basic sleep hygiene. For subjects experiencing disabling fatigue, amantadine may be partially effective.¹³ Despite its widespread use, modafinil has yet to be shown to be effective in MS related fatigue.^14,15 Antidepressant drugs, particularly serotonin and the noradrenaline reuptake inhibitors, are widely used, with little or no evidence to support their effectiveness in MS related fatigue. The use of stimulants—such as amphetamines, methylphenidate, and pemoline (discontinued in the UK)—in MS related fatigue cannot be sanctioned in view of their unproven efficacy and potential side effects.

If the findings of Heesen et al prove to be correct then targeting inflammation may be the most effective anti-fatigue strategy in MS. Glatiramer acetate, which has an impact on MS relapses similar to IFNβ but which is not associated with the flu-like symptoms, appears to have a positive impact on MS related fatigue.¹¹ Nataluzimab, a selective adhesion molecule antagonist which reduces the relapse rate in MS by more than 50%, markedly improved the perception of wellbeing (a crude index that includes fatigue) compared with placebo.¹⁶

It is important that we, as health care workers, should recognise and understand the impact that MS related fatigue has on sufferers from MS, and be aware of the emerging evidence that at least a component of this complex symptom is linked to inflammatory disease activity and that strategies are emerging to manage fatigue more effectively.