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

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

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.

Keywords: Multiple sclerosis, Fatigue, Neuroinflammation, Neurodegeneration, Cytokine mediated sickness behavior, Axonal loss, Brain atrophy.

1. Introduction

1.1. General definition and pathophysiological considerations on fatigue in patients with Multiple sclerosis (MS)

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], and [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.
gr1

Fig. 1 Classification and etiology of fatigue in MS.

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.

2. 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], and [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], and [10].

Since fatigue is a purely subjective symptom, its diagnosis and evaluation are associated with difficulties. The self-perception of fatigue may vary considerably between patients and over time in single individuals. Fatigue cannot be objectified by any diagnostic procedure so far. Since a diagnostic “gold standard” is not available for fatigue, the sensitivity and specificity of the test procedures used so far cannot be judged with certainty, but can at best be estimated through comparisons with control groups. Two of the most common instruments for measuring fatigue in clinical practice and in studies are the Fatigue Severity Scale (FSS) and the modified Fatigue Impact Scale (MFIS) [11] and [12]. Both scores have considerable limitations: The FSS is only capable of indicating physical fatigue. The MFIS consists of subscales for physical, cognitive and psychosocial fatigue, but does not allow grading of the severity of the symptom or the determination of clinical limit values for the individual subscales. A recent method which tries to overcome these weaknesses is the Fatigue Scale for Motor and Cognitive Functions (FSMC [10]). It can be used to differentiate the severity of the total fatigue as well as the sub-domains of cognitive and motor functions. It is strongly recommended to implement preliminary depression and anxiety diagnostics into the MS-fatigue workup, e.g., the Hospital Anxiety and Depression Scale, which is easy to apply and is less time-consuming (HADS [13] and [14]).

Due to strong overlapping and coincidence with depression, sleep disturbances and cognitive decline a clear diagnostic attribution of reported fatigue symptoms remains challenging. This holds also true for the recorded imaging correlatives of fatigue. Different definitions of fatigue are often at the root of the numerous MRI-based studies. Hence, patients who might exhibit completely different forms of fatigue and different pathogenesis were and are examined in many studies as if they were part of a homogeneous group, which might explain the large number of inconsistent findings (Table 1). However, even if the problem of inhomogeneous patient populations was to be resolved, the problem that neither conventional nor advanced MRI techniques would be able to reflect the entire extent of MS-related damage would remain [15].

Table 1 Studies investigating the association of fatigue with neuroinflammation and adaptive neuroplastic reorganization and neurodegeneration.

Signs of CNS-autoimmunity Study protocol Pathology measure Fatigue measure Association with fatigue MS-type Patient number Reference
Cumulative localized, focal lesions of gray and white matter Single Gd +-enhanced MRI-scanning 1 — Lesions in defined anatomical regions, both supra and infratentorial
2 — Brain atrophy
CIS-FATIGUE [132] 1 — None
2 — None
26 RRMS
19 SPMS
45 (72% MSF) [32]
Cumulative localized, focal lesions of gray and white matter of brain and spinal cord Single Gd +-enhanced MRI-scanning; motor evoked potentials 1 — Lesions in defined anatomical regions, only supratentorial
2 — Alterations of central motor latencies
FSS 1 — Yes (frontal and parietal lobes, trigonum)
2 — None
RRMS 30 (“non-disabled”), 15 MSF, 15 MS0 fatigue [133]
White matter lesion and gray matter atrophy Native MRI-scanning, voxel-based morphometry 1 — Cumulative lesion load
2 — Localized white matter lesions
3 — Gray matter atrophy
MFIS 1 — Yes
2 — Yes (right parietotemporal, left frontal)
3 — Yes (frontal)
CIS, RRMS, SPMS, PPMS 60 MS, 20 HC [42]
Cumulative lesion load and atrophy Native MRI-scanning, automated measuring and calculations 1 — Cumulative lesion load
2 — Gray matter atrophy
3 — White matter atrophy
FSS 1 — Yes
2 — Yes
3 — Yes
RRMS 222 (“low disability”) [35]
Cumulative lesion load, cortical and subcortical gray matter atrophy Native MRI-scanning 1 — Thalamic and basal ganglia volume
2 — Cortical thickness
3 — Normal appearing white matter volume
4 — T2-lesion volume
MFIS 1 — None
2 — Yes (only posterior parietal lobe)
3 — None
4 — None
RRMS
SPMS
24 MS, 24 HC [37]
cortical and subcortical gray matter atrophy Native MRI-scanning 1 — Cortical atrophy
2 — Subcortical atrophy
FSS
MFIS
1 — Yes (superior frontal, inferior parietal)
2 — Yes (striatum, thalamus)
RRMS 71 MSF
81 MS0
[39]
Lesions and atrophy of gray and white matter Native MRI-scanning with voxel based morphometry, pattern analysis 1 — Pattern of lesion distribution
2 — White matter atrophy
3 — Gray matter atrophy — combined depression and fatigue
4 — Gray matter atrophy — specific for fatigue
FSS 1 — None
2 — None
3 — Yes (parts of frontal, parietal, occipital lobes)
4 — None
RRMS,
SPMS,
PPMS
123 MS
91 HC
[38]
Lesions and atrophy of gray and white matter MRI with statistical morphometry, combined with positron-emission-tomography 1 — Clusters of reduced gray matter density
2 — Clusters of reduced glucose metabolization
EMIF-SEP 1 — Yes (both frontal lobes, left parietal and temporal lobe)
2 — Yes (basal ganglia)
RRMS 17 MS [134]
Lesions and atrophy of gray and white matter MRI with automated morphometry and volume quantification 1 — Global alteration of cortical thickness and volume
2 — Areas of reduced cortical volume
FSS 1 — None
2 — Yes (right frontal and central regions)
RRMS 61 MS
61 HC
[36]
Lesions and atrophy of gray and white matter MRI with automated morphometry and volume quantification 1 — Cortical gray matter volume
2 — Subcortical gray matter volume
FSS 1 — None (after adjusting for EDSS)
2 — Yes (accumbens, caudate nucleus)
RRMS 49 MS and 30 controls [135]
White and gray matter atrophy Tensor based morphometry 1 — Global atrophy
2 — Lesion load
3 — Localized atrophy
FSS 1 — None
2 — None
3 — Yes (11 clusters of atrophy, most in regions associated with attentional control)
RRMS 17 with, 17 w/o fatigue [136]
Damaged basal ganglia connectivity Resting state fMRI
Diffusion-tensor-imaging
Voxel-based morphometry
1 — White matter density
2 — Gray matter density
3 — White matter integrity
4 — Gray matter integrity
5 — Basal ganglia volume
6 — Functional basal ganglia connectivity
FSS 1 — None
2 — None
3 — None
4 — None
5 — None
6 — Yes
RRMS 44 MS, 20 controls [137]
Cortical and subcortical activation patterns fMRI during motor tasks 1 — Increased activation
2 — Decreased activation
FSS 1 — Yes: cingulate motor area
2 — Yes: cerebellum, operculum, precuneus, thalamus, frontal gyrus
RRMS 15 MSF, 14 MS0 [54]
Thalamic damage Diffusion-tensor-imaging
Voxel-based morphometry, tract-based spatial statistics
1 — Total lesion volume
2 — Altered thalamic fractional anisotropy and
Mean diffusivity
FSMC 1 — None
2 — Yes
RRMS 38 MSF, 41 MS0, 40 HC [51]
Disturbed blood brain barrier Three serial MRI scans over 3 months with triple-dose delayed scanning 1 — Number and volume of Gd + -enhancing lesions
2 — changes in activity over time
FSS 1 — None
2 — None
RRMS 11 irrespective of fatigue [138]
Diffuse axonal damage MR-spectroscopy 1 — N-acetyl–aspartate–creatine ratio FSS 1 — Yes RRMS and SPMS 73 MS [139]
Diffuse axonal damage MR-spectroscopy 1 — N-acetyl–aspartate (NAA)
2 — Choline (Cho) 3–myoinositol
(creatine ratios)
FSS
MFIS
1 — None
2 — None
3 — None
RRMS 32 MS 43 HC [140]
Cortical and subcortical dysfunction FDG-PET 1 — Global CMRGlu
2 — Altered prefrontal, basal ganglia and cerebellar CMRGlu
FSS 1 — None
2 — Yes
RRMS 19 MSF
16 MS0
16 HC
[55]

MSF — MS patients with fatigue, MS0 — MS patients without fatigue, HC — healthy controls; FDG-PET — 18F-fluorodeoxyglucose positron emission tomography; and CMRGlu: Cerebral metabolic rate for glucose utilization.

3. 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 substantially to the understanding of fatigue.

3.1. Demyelination

The focal inflammatory demyelination is still, pathomorphologically, the most comprehensible element of MS pathology. In addition to the potentially reversible loss in myelin and oligodendrocytes, a significant and irreversible structural damage and loss in axons has been shown to take place within these focal lesions [16] and [17]. In contrast to earlier views, it has become clear that the disease process is not restricted to the discrete lesions seen in routine MRI or as plaques in post mortem studies. Instead, over the course of the disease, there are pathological changes irrespective of the focal inflammation in areas seemingly unaffected when looked at in routine imaging studies — the so-called normal appearing white matter[18]. Furthermore, the longstanding idea that demyelination may be limited to the white matter has been revised by the discovery of widespread pathological changes in the gray matter of the cerebral cortex and the cerebellum [19], [20], [21], and [22]. Finally, the cellular and humoral patterns within active lesions do not only convert within the temporal sequence of acute inflammation, degeneration and regeneration, but are also differing principally between individual patients [23].

3.2. Axonal damage

Awareness of axonal damage caused by MS has a history of up to 100 years [24]. However, much less attention has been put on its causes, course and extent than on those for demyelination [25]. Based on the consideration that the loss of myelin sheaths results in an interruption of the transmission of excitement, a compensatory overexpression of sodium and calcium channels with a following excitotoxicity was, among other factors, suggested as a non-immunological cause for the destruction of axons [26]. Other potential pathophysiological processes have been examined mainly in animal models and in vitro. Examples include the influences of oxidative stress and mitochondrial dysfunctions, humoral factors as well as direct damage by CD8-positive T lymphocytes [27], [28], [29], and [30].

4. 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], and [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 MS. In principle, four different hypotheses are currently discussed:

  • 1. The structural units of the cerebral cortex form vertically oriented “cortical columns”, which isolate themselves horizontally against each other through a dynamic lateral inhibition. Axonal degeneration induces changes in the functional behavior of the affected cortex areas depending on the distribution pattern of the affected inputs and outputs of these columns. In patients with relapsing MS, a correlation was found between particularly cortically accentuated cerebral atrophy as a marker for axonal loss and the occurrence of fatigue [35], [36], and [37]. Correlations with the occurrence of fatigue were found for different damage locations. Examples include lesions of fronto-frontal, fronto-occipital, fronto-limbic, and fronto-striatal tract systems of the left as well as damages to parieto-temporal areas of the right cerebral hemisphere [38], [39], [40], [41], [42], and [43]. Functional imaging data suggests that it is less the alteration of distinct tract systems than the complex adjustment processes of cortical reorganization that must be considered to be the actual cause of fatigue. As a result of loss in the fastest and most direct connections between individual cortical regions, increasingly more cortical areas are integrated into the completion of motor or cognitive tasks as a means of compensation. This adaptive process reduces the cortical information processing capacity, increases metabolic requirements and recovery needs [44]. In addition to functional changes at the cortical level, altered processes in the spinal cord also seem to be related to the development of fatigue [45].
  • 2. The localized damage to the ascending tracts of the brain stem, the Locus coeruleus and the nonspecific thalamic nuclei, lead to a reduction in the activation of the cerebral cortex. It is generally accepted that lesions in this functional system — referred to as “ascending reticular activating system” (ARAS) or ERTAS (“extended reticulo-thalamic activating system”) exert negative effects on the degree of alertness (“arousal”) and complex cognitive functions [46]. They are, however, neither specific for fatigue nor a sufficient condition for its development [9] and [47].
  • 3. Lesions in motor tract systems are clearly linked to quick fatigability when carrying out physical activities [48]. Changes in the activation of spinal motor neurons are, however, not just simple disturbances of recruitability due to alterations of descending tracts, but are also caused by disturbances in the physiological inhibition of the central activation networks. This applies especially to superficially less affected patients with respect to motor functions [49] and [50].
  • 4. Lesions in the area of the hypothalamus with corresponding neuroendocrine dysfunctions influence (circadian) endocrinal rhythms. They are discussed separately in the next section owing to their complex interaction with the activity of the primary disease.

The pathomorphological aspects mentioned here form interesting approaches to an explanation of particular aspects of primary MS fatigue, but cannot sufficiently explain the complexity of the clinical presentation. This raises the question of whether MS fatigue is not more likely the result of a complex network problem, which is caused by the fact that the integrity of the relevant communication paths is destroyed. In a recent study it was shown that patients with cognitive fatigue primarily presented alterations in the thalamus in terms of reduced fractional anisotropy and increased mean diffusivity [51]. Keeping in mind that the thalamus is a structure highly involved in cognitive processing but also in controlling the amount of activation passing to the cerebral cortex, the hypothesis of fatigue being the result of a subcortico-cortical network problem becomes realistic. Going one step further, just as in the case of cognition, it may further be assumed that fatigue is the result of a breakdown in a master network (“rich club hub”) [52] and [53]. If this master network is damaged, the individual network modules can still function, but the supraregional exchange from subcortical to cortical structures would no longer be possible. Former functional imaging studies applying fMRI or PET already pointed into the direction of a subcortico-cortical problem involving basal ganglia and thalamus [54] and [55]. Thalamic atrophy can occur even at an early stage of the disease, and increased volume depletion might be one factor responsible for the collapse of the master network [56]. A recent study reported decreased thalamic volume accompanied by increased functional connectivity as well as increased mean diffusivity in MS patients with cognitive impairment [61]. Whether these alterations which primarily point to a maladaptation also trigger the occurrence of fatigue has still to be shown.

5. 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], and [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] and [68]). From basic and clinical experience it is known for a long time that inflammation goes along with anorexia, fever and behavioral changes that are very similar to those seen in fatigue. Pathophysiological concepts that link inflammation to fatigue have first been stated in the context of this “cytokine-induced sickness behavior” observed in animal experiments [62] and [63]: Briefly, macrophages residing in peripheral organs, vagal nerve sheaths, the circumventricular organs or the choroid plexus release cytokines like IL-1 which then binds to receptors that are either located on neurons or on endothelial cells. Endothelial IL-1-receptors cause the activation of prostaglandin synthesis. The binding of these prostaglandins, namely PGE2, to neurons in medial preoptic and periventricular regions then leads to fever and an increased activity of the hypothalamus–pituitary axis but are not related to behavioral changes [64] and [65].

Neuronal receptors for IL-1 are mainly located at two different sites:

  • peripheral axons of the vagal nerve terminating in the parabrachial nucleus which sends projections to the central amygdala [66]
  • central neurons in the area postrema that likewise project to the central amygdala via the parabrachial nucleus [69] and [70]

Both pathways form parallel connections for signals originating in immune cells and ending in limbic brain structures where they can exert effects on motivation and behavior. Peripheral IL-1-sensitive axons form a fast route for the transmission of inflammatory signals to the CNS, whereas the central neurons sense IL-1 that is produced by macrophages inside the brain, supposedly in the choroid plexus and in the vicinity of the circumventricular organs, where the blood brain barrier is leaky under physiological conditions. This second route therefore is dependent on diffusion of IL-1 and has therefore been subsumed together with the endothelium dependent part of the IL-1-signaling as the “slow humoral pathway”. Although the contribution that each of this pathways gives to the phenomenon of fatigue is not fully known. Animal experiments have given some evidence for the importance of the neuronal route of the slow humoral pathway. After intraventricular application of an IL-1-antagonist, a peripheral inflammatory stimulus (LPS or IL-1) did no longer induce the behavioral alterations that were observed under control conditions [71].

Independently from the question which of the above pathways and mechanisms may be the most relevant in the pathophysiology of MS-related fatigue, it is of critical importance to notice that the signaling mechanisms studied so far are almost entirely paracrine (e.g., between macrophages in nerve sheaths that produce IL-1 acting on axons) or locally organized to minimize the distance of diffusion for IL-1 (e.g., macrophages in circumventricular organs). Cytokine concentrations can therefore be expected to be increased only locally and not in the systemic circulation. Immune cells found in peripheral blood may be tested to quantify their capacity to produce cytokines, but there is no guarantee that the functional state of these cells represents the one of those residing at the locations that are critical for the transmission of inflammatory signals to the CNS.

This complexity may explain why empirical studies that have been conducted to test the hypothesis that inflammation itself is associated with fatigue have yielded rather contradictory results for MS (but also in other immune mediated diseases except rheumatoid arthritis, see Table 2) as will be outlined below:

  • Interleukin-2 and its receptor were not elevated in RRMS patients with relevant fatigue when compared to healthy controls [72].
  • C-reactive protein, neopterin and ICAM-1, three laboratory markers of inflammation, do correlate with disease activity but not with fatigue severity in MS patients [73] and [74].
  • Immune cells of MS patients with fatigue release significantly less IFN-gamma upon being subjected to a nonspecific stimulation than the cells of MS patients without fatigue. TNF-alpha and IL-10 production did not differ between both groups [75].
  • The concentration of TNF-alpha mRNA has been shown to be positively correlated to the presence of fatigue in MS patients in one study [76].
  • TNF-alpha and IFN-gamma were found to be significantly increased in fatigued vs. non-fatigued MS patients when estimated using an ELISA in a whole-blood-cytokine-stimulation approach [77].
  • In contradiction to this finding, a study that compared the concentrations of multiple cytokines between fatigued and non-fatigued MS-patients using an elaborated statistical methodology and adjustments for important confounding factors found only IL-6 to be modestly correlated with the presence of fatigue [78].
  • Fatigue worsens during acute relapses of MS or may even be the sole clinical presentation of a relapse [79] and [80]. Without any doubt, proinflammatory cytokines play a critical role in local CNS-inflammation, but only scarce data exists regarding their concentrations in peripheral blood during acute relapses. TNF-alpha has been shown to be increased in subjects with acute relapses when compared to control [81]. This study did, however, not measure fatigue. To our best knowledge, no study has yet provided empirical data to support the hypothesis that elevated cytokine concentrations are responsible for accentuated fatigue during relapses.

Table 2 Cytokines that have been studied with respect to the correlation of their plasma levels with fatigue occurring in the course of different diseases. source: The table summarizes data from [71], [72], [82], [141], [142], [143], [144], [145], [146], [147], [148], [149], [150], [151], [152], [153], [154], and [155].

Marker MS CFS RA SLE Sjögren's syndrome
TNF-alpha 0 0 +/− 0 0
Interferon-g 0 0 + No data No data
Interferon-a 0 No data No data 0 No data
IL-1b 0 + + 0 0
IL-2 0 0 No data 0 0
IL-6 + + + 0 0
IL-10 0 0 No data 0 0
IL-10 mRNA + No data No data No data
Oxidative stress 0 + No data No data 0

The results of studies using whole blood stimulatory capacity are discussed in the text.

Besides chronic daytime tiredness, which might be considered to be at least partially an analogue of “sickness behavior” related to inflammatory signals affecting the CNS, another component of fatigue in MS patients is pathological exhaustibility. The data regarding the mechanisms of this phenomenon in MS-patients is rather scarce. In patients with chronic fatigue syndrome (CFS), the immunological response to exercise has been shown to be altered when compared to healthy controls. There is more oxidative stress, an increased complement activation and an increase in gene expression for IL-10 and TLR-4 in the post-exercise phase, which altogether might explain the post-exercise malaise which is a hallmark of CFS [82] and [83]. The results of exercise studies in patients with MS-fatigue focusing on immune-effects are in partial contradiction to the results obtained in CFS:

  • In a small study with 11 control subjects and 11 MS-patients, the changes in IL-6, TNF-alpha and IFN-gamma induced by a single bout of exercise were not differing. Over eight weeks of training, the resting levels of IL-6 decreased in both groups whereas TNF-alpha and IFN-gamma were increased only in the MS-group. This study did, however, not give any information regarding fatigue scores of patients [84].
  • Immune cells in blood samples from MS patients with fatigue, when compared to healthy control groups, showed increased concentrations of adrenoreceptor mRNA after physical exertion, whereas mRNA levels for TLR4 and IL-10 were decreased. In contrast to patients with non-MS-related chronic fatigue syndrome (CFS) who showed increases in the expression of P2X4-receptors, no increase in metabolite receptor expression was seen in patients with MS-fatigue [85].
  • Two studies report on changes in cytokine levels induced by training, but these data offer only limited information since there were no healthy controls and fatigue was not estimated in both studies: MS-patients taking part in a combined exercise training program had decreased levels of IL-17 and IFN-gamma after eight-weeks [86]. IL-4, IL-10, CRP and IFN-gamma, but not TNF-alpha, IL-2 and IL-6 were significantly reduced by resistance training in a small sample of MS-patients [87].
  • Treatment with interferon-beta has little or no effect on cytokine responses to progressive resistance training [88].

Taken together, the existing data on cytokines and fatigue in MS does not allow the conclusion that cytokines or other biomolecules released in the course of inflammation are central elements in the evolution of fatigue in MS-patients. In the future, studies on the detailed effects of locally produced mediators might contribute to a better understanding of immune mediated fatigue. A promising example is the increasing knowledge on the effects of inflammatory mediators on the expression of genes that are involved in cellular circadian clock networks as it might give rise for an explanation for both sleep disorders and daytime sleepiness in MS [89], [90], and [91].

6. 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] and [94]. From a theoretical point, this may lead to a decrease or an increase in the release of corticotropin releasing hormone and ACTH, depending on the degree to which stimulatory or inhibitory projections of the hypothalamic–pituitary network are lesioned. Empirical data points towards a stimulatory net effect with an impaired negative feedback loop of the HPA-axis in the majority of cases [95]. An elevation of cortisol and ACTH levels in plasma and a hypertrophy of the adrenal cortex have been demonstrated in MS patients [96] and [97]. Nevertheless, the studies addressing the relation between fatigue and HPA alterations have partly given contradictory results:

  • In patients with a non-MS related adult CFS, a hypofunctional HPA-axis is found and correlates with fatigue severity [98]
  • Heesen et al. found an increased prevalence of HPA-overactivity in patients with progressive forms of MS, but not in RRMS. Signs of increased HPA-activity were clearly correlated with cognitive impairment and physical disability, but only weakly with depression and fatigue [77] and [99].
  • A positive correlation between fatigue severity, ACTH levels and other signs of an increased activity of the HPA-axis was seen in a sample of patients with RRMS. The most prominent correlations with endocrine parameters were seen for daytime tiredness and asthenia, but fatigue-independent cognitive dysfunction correlated as well [100].
  • In patients with relapsing–remitting MS, the increase of cortisol physiologically occurring after awakening (cortisol awakening response, CAR) seems to be increased. Fatigue intensity is positively correlated with CAR and negatively with basal cortisol levels [101].

Taken together, these findings underline the distinctive character of endocrine changes accompanying MS and MS fatigue when compared to CFS. A correlation of increased HPA-activity with MS-fatigue seems to exist, although it is less clear than the one with cognitive dysfunction.

7. 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 tiredness. When subjects suffering from an urge incontinence try to counteract these limitations in everyday life by reducing their fluid intake, this may even worsen their constitution [102].

In fact, it has been argued that secondary fatigue is the dominant contributor to the overall phenomenon of MS-fatigue since the correlation with disease severity is weaker than that with sleep disturbance or depression [103]. Impaired autonomic regulation of cardiovascular functions seems to contribute to an impaired physical performance in a relevant number of patients [106]. Since all these disorders in MS are – in close analogy to fatigue in MS – related to both organic brain damage and psychosocial factors, the interrelation of fatigue and disturbed sleep underlines the shortcomings of the strict conceptual dichotomy between primary and secondary fatigue.

Regardless of these considerations, tiredness and limitations in capability as an expression of adverse drug reactions which occur frequently with some immunotherapeutic agents or drugs used for symptomatic therapy of spasticity and paresthesia may clearly be attributed to secondary fatigue.

Emotional adjustment disorders and cognitive changes that limit the drive for action and motivation can also result in fatigue. In particular, the high lifetime prevalence of depressive disorders in MS patients is still an underestimated problem in terms of patient care [104]. Recent imaging studies indicate an overlap of the cerebral lesion patterns seen in depression and fatigue such that neither the organic brain level nor the psychosocial level may be ignored during the causal classification of the symptoms [36] and [105].

8. 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 the progression of disability by arresting the immune process underlying MS. Fatigue may thus be either prevented, kept from worsening or, if it resulted from cytokines formed in the course of neuroinflammation, even be ameliorated. Conversely, a substance that leads to increased cytokine release or malaise in the course of its action may transiently worsen preexisting or even induce new fatigue in formerly unaffected subjects. The literature offers examples for each of these scenarios:

  • Studies investigating the effects of treatment with interferon beta preparations on fatigue symptoms found only minor changes. After three years of treatment, fatigue levels were unchanged in a group of RRMS patients treated with interferon beta-1a [107]. A recent study found that deterioration of fatigue occurring in the course of IFN-beta treatment is an indicator of clinical non-responsiveness and is correlated with the presence of neutralizing antibodies against interferon beta [108]. Interferon beta may also worsen or induce fatigue for a restricted time (few hours up to one day) after injection, which has been attributed to negative effects on sleep and increases in IL-6-levels that can be observed within that period of time [109] and [110].
  • Glatiramer acetate has been shown to improve fatigue sustainably in naïve RRMS patients. The improvement in fatigue was correlated to an improved health-related quality of life [111], [112], and [113].
  • One trial investigating the effect of switching treatment from interferon to glatiramer acetate found that significantly less fatigue was reported after switching from interferon to glatiramer acetate than vice versa [114]. In another study, fatigue was found to improve significantly more in naïve patients treated with glatiramer acetate than it did in those treated with interferon beta [115].
  • Patients treated with the monoclonal antibody Natalizumab have been reported to be less fatigued than those on interferon of glatiramer acetate [116]. Putzki et al. were able to show a slight improvement in the fatigue scores after a 6-month therapy with Natalizumab in a longitudinal study [117]. In a clinical study on 195 MS patients, a clinically relevant improvement in the fatigue was proven after one year of treatment with Natalizumab and was related to improvements in sleep and depression [118] and [119]. There have, however, also been reports of fatigue occurring as an adverse event with natalizumab treatment [120]. A possible reason for a transient deterioration in fatigue symptoms with the administration of Natalizumab is seen in an increased release of TNF-alpha under the therapy [121].
  • Episodes of fatigue have been reported as adverse events of the oral immunotherapeutic agent fingolimod (FTY720) occurring in 19% of patients in the initial phase II study [122]. Nevertheless, a positive long term effect on cognitive functions and fatigue was suspected already at that time and finally ascertained in later studies, including an improvement of fatigue severity after changing from interferon beta or glatiramer acetate to fingolimod [123], [124], and [125].
  • Fatigue has been observed as an adverse effect in the initial phase IIb-study on fumaric acid [126]. In a subsequent study, there were no differences in fatigue incidence between placebo and treatment groups [127].
  • Patients treated with a low dose (7 mg) of Teriflunomide show slightly more favorable fatigue scores as compared to patients under IFN-beta 1a; with the currently recommended dose of 14 mg daily, studies showed no difference from the IFN-beta therapy. Again, treatment related fatigue was one of the most frequently reported adverse events [128] and [129].
  • Patients treated with alemtuzumab were compared during the CARE-MS II study and showed a reduction in the fatigue scores as compared to patients undergoing treatment with interferon-beta-1a [130].
  • The anthracycline mitoxantrone has been reported to have no significant effect on fatigue [131].

9. 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 been identified to be linked with MS fatigue involve clusters in distinct regions of frontal and parietotemporal lobes as well as thalamus and basal ganglia. Besides the advances in explaining the behavioral and perceptual changes by reorganization of the CNS, the role of the ongoing immune process itself is still not well defined. Whereas data on laboratory markers of fatigue is not conclusive, a growing body of evidence supporting a role of the active autoimmunity comes from the data on modern immunotherapeutics that effectively and sustainably lead to stabilization and amelioration of fatigue in parallel to their dampening effects on the neuroinflammatory process.

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

relapsing–remitting MS

SLE

systemic lupus erythematodes

TNF

tumor necrosis factor

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 stabilization and amelioration of fatigue in parallel to their dampening effects on the neuroinflammatory process.

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Footnotes

a University of Rostock, Department of Physiology, Germany

b Cogito Center for Applied Neurocognition and Neuropsychological Research, Düsseldorf, Germany

c University of Rostock, Department of Neurology, Division of Neuroimmunology, Germany

Corresponding author at: Oscar-Langendorff-Institut für Physiologie, Universitätsmedizin Rostock, Gertrudenstraße 9, 18057 Rostock, Germany. Tel.: + 49 381 494 8006; fax: + 49 381 494 8002.


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    dsc_0787_400x400.jpg Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College,...
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