Elsevier

Autoimmunity Reviews

Volume 15, Issue 3, March 2016, Pages 210-220
Autoimmunity Reviews

Review
Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration

https://doi.org/10.1016/j.autrev.2015.11.005Get rights and content

Abstract

Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue.

Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics on MS-fatigue.

Introduction

Multiple sclerosis is an immune mediated disease of the central nervous system (CNS). Chronic neuroinflammation and neurodegeneration are the pathomorphological hallmarks of the disease and give rise to a great variety of clinical symptoms, of which fatigue is one of the most frequent and disabling [1], [2], [3]. Due to the high variability of the clinical presentation, it has been proposed to consider fatigue as a complex symptom composed of the three main components

  • ▪

    Asthenia/daytime tiredness,

  • ▪

    Pathological exhaustibility and

  • ▪

    Worsening of symptoms due to stress [4].

From a pathogenetic point of view, a distinction can be drawn between primary and secondary fatigue [5]:

  • •

    Primary fatigue is caused by the MS-pathology itself. This includes fatigue which a) shows a correlative to the lesion localization and is triggered by loss in connectivity between cortical and subcortical structures, b) is caused by mediators and cytokines that are released within the scope of the immune-mediated inflammation, or c) is caused by neuroendocrine dysfunctions as a result of lesions in central regulatory regions as is depicted in Fig. 1.

  • •

    Fatigue that results from impaired motor function, coincident accompanying diseases, pain or side effects of drugs is attributed to secondary fatigue. Secondary fatigue is not an alternative diagnosis but may rather coexist with primary fatigue in the same patient.

The distinction between primary and secondary fatigue is important from a theoretical perspective and may help practitioners as a guidance for the diagnostic process and treatment. Nevertheless, it may almost be impossible to pinpoint the role of these components in an individual patient who exhibits both primary and secondary fatigue at the same time [5]. Furthermore, the relative importance of the different mechanisms underlying primary fatigue is largely unknown due to the fact that most studies have concentrated either on biomarkers and patterns of inflammation or on functional reorganization and adaptive changes in the CNS of affected patients. The aim of this work is to compile the existing knowledge on the contribution of the different components of the autoimmune process to fatigue in patients suffering from MS.

Section snippets

MS-fatigue as a prominent symptom of CNS autoimmunity

The prevalence of fatigue is already high when other first symptoms of MS manifest; it can increase up to 85% in the first year of the disease and reach up to 95% as the disease progresses [3], [6], [7]. Unlike other symptoms of MS such as paresis or paresthesia, the clinical assessment of fatigue is considerably more difficult, which has led to a high degree of inconsistency in the existing epidemiological and therapeutic studies [8], [9], [10].

Since fatigue is a purely subjective symptom, its

Immunopathology and pathomorphological changes in MS

The relation between “fatigue” and the CNS damage caused by MS is not as straight as it is for other symptoms like motor weakness or visual disturbances which we are able to explain by distinct, circumscript lesions. As will be outlined further, fatigue reflects rather a cumulative CNS damage that is acquired in the course of MS. Therefore, the increasing knowledge on the diverse and complex pathomorphology of MS and the mechanisms of the underlying immune responses has contributed

Pathomorphological damage patterns and fatigue in MS

The severity of MS fatigue does not correlate with the cumulative lesion load or imaging signs of the present disease activity seen in standard clinical MRI [31], [32], [33]. Instead of their mere existence, it is rather the localization of the lesions (mainly prefrontal, temporal and thalamic) that determines the development and manifestation type of MS fatigue [34]. Table 1 summarizes the findings of studies on the correlation between imaging signs of immune mediated CNS damage and fatigue in

Cytokines, inflammation and MS-fatigue

Fatigue symptoms that resemble those seen in MS occur during chronic infections, systemic autoimmune diseases or malignant tumors (for reviews see [57], [58], [59], [60]). The common factor of all those diseases is that they are accompanied by chronic inflammation which is reflected by a complex pattern of changes in biochemical and molecular biomarkers in blood and cerebrospinal fluid (recent reviews are given in [67], [68]). From basic and clinical experience it is known for a long time that

Neuroendocrine disorders in MS

Dysfunctions of the hypothalamus and corresponding vegetative–emotional changes are prevalent among MS patients. Since alterations of endocrine may interfere with immune functions, they may either be considered as a possible cause or a consequence of the immunological process of the disease [92].

On the basis of existing data, it can be assumed that in MS patients, dysfunctions in the regulation of the hypothalamus-pituitary adrenal-gland axis occur due to hypothalamic lesions [93], [94]. From a

Beyond central damage: secondary fatigue in MS patients

Besides the immunological disease process and its effects on the functioning of the CNS, fatigue may also be caused by numerous other factors such as adverse effects of medications, other MS-symptoms or diseases coinciding with MS which interfere with the patients' physical or mental strength and capacity. For example, many patients with bladder dysfunction suffer from a frequent urge to urinate at night. As a consequence, their sleep pattern is disturbed, which leads to increased daytime

Therapeutical implications

The stabilization of the progression of MS and the effective symptomatic management of existing impairments are central concerns of patient care. In particular, due to the fact that a significant increase in symptom-free or low-symptom life years can be achieved with a consistent immunomodulatory therapy, it is becoming more and more important to gain an accurate knowledge of the potential risks and benefits of the prescribed substances.

Immunotherapeutic treatment has the goal to slow or hold

Conclusion

Fatigue is a frequent and debilitating symptom of MS. As its clinical presentation is highly variable, it seems likely that the same applies to its pathophysiology. Diffuse cortical damage, circumscribed lesions and compensatory neuroplasticity can be seen in the CNS of all MS patients to different extents. Imaging studies have shown that immune mediated CNS and the development of fatigue are not linked by a simple correlation of lesion load and symptom severity. The lesion patterns that have

Abbreviations

    CMRGlu

    Cerebral metabolic rate for glucose utilization

    CNS

    Central Nervous Systems

    EMIF-SEP

    Échelle Modifiée Impact de la Fatigue — Sclèrose en Plaques

    FDG-PET

    18F-fluorodeoxyglucose positron emission tomography

    FSMC

    Fatigue Scale for Motor and Cognitive Functions

    FSS

    Fatigue Severity Scale

    HADS

    Hospital Anxiety and Depression Scale

    HC

    healthy controls

    IL

    interleukin

    MFIS

    modified Fatigue Impact Scale

    MS

    Multiple sclerosis

    MS0

    MS patients without fatigue

    MSF

    MS patients with fatigue

    RA

    rheumatoid arthritis

    RRMS

Conflicts of interest

The authors declare that they have no competing interest in connection with this paper.

Take-home messages

  • •

    Fatigue is frequent and debilitating with a highly variable clinical presentation.

  • •

    The pathophysiology of MS-fatigue is thus also variable and consists of a combination of:

    • ○

      Diffuse cortical damage, circumscribed lesions and compensatory neuroplasticity

    • ○

      Lesion clusters in distinct regions of frontal and parietotemporal lobes as well as thalamus and basal ganglia

  • •

    Chemical mediators of inflammation could not be proven unequivocally to be related to MS-fatigue.

  • •

    Modern immunotherapeutics lead to

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