Fatigue in multiple sclerosis — A brief review

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Abstract

Fatigue is the most common and debilitating symptom in multiple sclerosis (MS) and is believed to be distinctly different from fatigue seen in other chronic conditions. It can affect a patient's mood, sleep and have a detrimental effect on their quality of life. In the recent years much literature has emerged in an attempt to elucidate the potential causes and treatment of this common symptom. This review article aims to examine the most recent theories on the pathophysiology of fatigue in MS as well as its association with sleep and depression. We describe the pharmacological and non-pharmacological approaches to its treatment and propose a multidisciplinary, patient enabled and individualised manner to the management of fatigue in MS.

Introduction

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Focal neurological symptoms caused by acute and chronic inflammation include loss or alteration of sensation (numbness, paraesthesiae), of motor function (typically spastic paresis or complete paralysis), visual symptoms such as blurred vision or transient blindness, disturbance of conjugate eye movements, bladder and bowel dysfunction and cognitive impairment. MS is considered the most important non-traumatic cause of neurological disability in young adults. It affects females more often than men (2–3:1) and typically requires lifelong medical and rehabilitative care.

The most frequent symptom reported by patients with MS is fatigue, which is reported to affect between 50% and 80% of patients [1], [2]. For many, it is the most disabling and chronic symptom [3]. Fatigue is a very subjective feeling and this has led to many controversies in its definition. The UK Multiple Sclerosis Society defines MS fatigue as “an overwhelming sense of tiredness for no apparent reason.” Krupp, in 2003, stated that the word fatigue is, at the same time tremendously meaningful and terribly imprecise; describing it as an overwhelming sense of tiredness that is out of proportion to “normal” tiredness. She goes on to explain that many terms such as malaise, asthenia and weakness are often used interchangeably with fatigue and highlights the necessity for accurate assessment of such a subjective symptom [4].

A medical definition of fatigue in MS was proposed by Mills and Young in 2007 as a “reversible, motor and cognitive impairment with reduced motivation and desire to rest, either appearing spontaneously or brought on by mental or physical activity, humidity, acute infection and food ingestion. It can occur at anytime but is usually worse in the afternoon. In MS, fatigue can be daily, has usually been present for years and has greater severity than any premorbid fatigue” [5].

It seems that the fatigue experienced by patients with MS is distinct from the fatigue seen in healthy individuals or those with other diseases [6] and clearly carries a major physical and psychological burden, especially when completing everyday tasks [7], [8]. Fatigue is more frequently seen in primary and secondary progressive MS compared to patients with relapsing remitting disease [7], [9]. It appears to be worse during the second part of the day [5], [6], [7], [10], [11] and is often worsened by heat or hot humid environments [12], [13], [14]. Patients often find that the effort required to perform a particular action is disproportionately high [7] and the effect it has on their quality of life is detrimental on finances, employment, self-esteem and identity [15], [16].

The Mills and Young study served to further highlight the variance in patient descriptions of fatigue. Such accounts varied from being a lack of motivation, physical and mental exhaustion and increased mental effort, even when doing pre-learned tasks [5]. In other studies, patients have described feeling detached from their surrounding environment [6], [17].

An accurate measurement of fatigue is useful to help guide clinicians towards the best treatment strategies for each patient. Table 1 describes the most commonly used scales when measuring fatigue [18], [19], [20], [21], [22], [23], [24]. These are mainly self-report questionnaires, not intent on diagnosis but are instead tools with which patients can highlight, as well as understand, their most important health concerns. Unfortunately, many of the widely used scales are not specific to MS and are also used in other diseases such as chronic fatigue syndrome. One of the most commonly used self-report scales, the Fatigue Severity Scale (FSS), was looked at by Valko et al. [25]. They found that the FSS had a high test–retest consistency as well as good correlation with visual analogue scale (VAS) results, reflecting its ability to guide patients and doctors towards appropriate and individualised treatments [25].

Partly due to lack of consensus on a precise definition, fatigue in MS and its causes remain incompletely understood. It is complex and multifactorial. The aims of this review article will be to summarise the available evidence on the pathophysiology of fatigue in MS, explore its links with altered sleep and depression as well as to describe the current treatment options available. We selected research and review articles among those identified by a PubMed search using “Multiple Sclerosis AND Fatigue” as keywords.

Section snippets

Pathophysiology

Despite the clinical significance of fatigue in MS, its pathophysiology is still not completely understood. Much of the research has been investigating the role of proinflammatory cytokines, central nervous system lesion load, cerebral quantitative imaging abnormalities and patterns of cerebral activation, endocrine influences and axonal injury.

Depression and fatigue

Psychiatric symptoms such as depression are widely recognised to be a common symptom in MS. Patten et al. reported an annual prevalence rate of 26% in their study in 2003 [53]. Fatigue is common to both depression and MS and even though a relationship between fatigue and depression has been suspected, the existence of a correlation has not been proven and is likely to be complex and multifactorial.

Kroencke et al. suggested that fatigue and depression were highly correlated and that depressed

Sleep disorders

Individuals with MS have significantly more difficulties in sleeping than the general population [61] and research suggests that around 50% of MS patients report sleeping problems [61], [62]. These can include problems in initiating sleep as well as increased awakenings throughout the night from disease related factors such as pain, muscle spasms, periodic limb movements, nocturia and anxiety [62], [63]. Sleep disorders in MS are important to address as they can potentially exacerbate other MS

Demographics

There have been many inconsistencies when exploring a relationship between demographic factors and fatigue in MS. Tedeschi et al. suggested that higher levels of education and female sex may play a protective role towards fatigue [37]. However in other studies, age and race have been found to have no association with fatigue in MS [18], [77] and many suggest no significant difference in mean fatigue estimates between the sexes [21].

Treatment

Improving fatigue is an important treatment goal for patients with MS [78] yet the exact method in which treatment should be provided has proved elusive. Obstacles include the poorly understood pathogenesis, difficulties in accurate measurements of fatigue in MS and in the choice of optimal pharmacological delivery of drugs to the CNS [3]. Both pharmacological and non pharmacological strategies have been explored.

Non-pharmacological approaches include aerobic exercise programmes, energy

Conclusion

The main aim of our review article was to summarise key aspects of the current thinking on fatigue in MS. The pathogenesis of the fatigue experienced by MS patients is not fully understood and we have highlighted some of the hypotheses currently being looked into.

As suggested by previous work [9], although MS-related fatigue is quite distinct from depression, the latter was one of few predictors of the development of fatigue in a population of MS patients studied at baseline and after 1-year

Conflict of interest

The authors declare no conflicts of interest.

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