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Managing fatigue: clinical correlates, assessment procedures and therapeutic strategies.

Introduction

Fatigue is estimated to affect 75 to 95% of patients with multiple sclerosis (MS). For 50 to 60% of these, fatigue is one of the most incapacitating symptoms (1,2) and one of the major reasons for social and occupational problems. Fatigue can be present at all stages of the disease, (3) is often even a symptom of disease onset (4) and may persist throughout the disease course. The knowledge about its presence and substantial impact on quality of life is disproportionate to the knowledge about the symptom itself. The pathophysiology is still unknown although several suggestions have been made. It was assumed that peripheral abnormalities provoke fatigue due to a decrease in maximal voluntary force (5,6) and lower muscle force during repetitive peripheral nerve stimulation (6). On the other hand, central abnormalities such as demyelination and axonal damage in the reticular formation, (7,8) disturbed metabolism in the basal ganglia and the frontal cortex (9) as well as brain atrophy (10,11) are also discussed. Though some immune-related factors (12,13) and neuroendocrine abnormalities (14) are also thought to contribute to fatigue they nevertheless do not fully explain the entire symptom-complexity. Existing evidence so far supports a multicausal aetiology of MS fatigue with a strong contribution of central factors. Further, taking into account data from imaging studies in chronic fatigue syndrome and patients with MS (8,9,15) it can be assumed that fatigue is not an uni-dimensional phenomenon which is focused on physical symptoms, but consists in addition of a cognitive component. Changes in the frontal and temporal cortex as well as in the basal ganglia and thalamus have been reported to be present in patients with fatigue. Although cognitive fatigue was not assessed explicitly in these studies, the authors conclude that the observed abnormalities belong to circuits highly involved in cognitive processing.

Relation to Clinical Variables

Disability

It is still unclear whether fatigue is directly related to neurological disability. While several studies found positive correlations between these two variables, (16-18) others found only weak or no significant relationship. (1,19-21) Considering that fatigue and disability may already be present at the very early stages of MS4 leads to the assumption that it and disability are originally independent components of the disease. However, since most of the studies exploring the association between fatigue and disability rely on the Expanded Disability Status Scale (EDSS) the relationship between these dimensions remains still unclear. In fact, EDSS is a scale that reflects primarily physical impairment (e.g. bladder dysfunction) while disability reflects the influence of the latter with respect to everyday functioning (e.g. vocational difficulties due to sleep disturbances). Thus, since the precision of the EDSS is poor for some descriptors relevant to fatigue and since the EDSS composite measure fails adequately to account for gradual changes in fatigue, a lack of statistical association between EDSS and fatigue measures does not necessarily imply functional independence of these phenomena.

With increasing disability and disease duration other co-morbid factors which are key features of several symptoms at the same time might be responsible for some of the positive correlations.

Disease Duration

Similar to disability, disease duration is only a weak predictor for fatigue pathology. Since fatigue is reported to be already present before clinical manifestation or at the onset of other disease symptoms, (1,18) it might be argued that the duration of being affected by a neuroinflammatory and neurodegenerative disease seems not to account for developing fatigue symptoms.

Disease Course

Several studies report a significant correlation between disease course and fatigue. Patients with a progressive course, both primary and secondary, seem to be more affected by fatigue symptoms than those with a relapsing-remitting course. (17,18,20) On the other hand, it has to be considered that some symptoms which might accentuate fatigue in their own might be overrepresented in the progressive courses.

Depression and Cognition

While depression is found to negatively influence self-perception of fatigue, (22) patients often experience it in the absence of depression or a low mood. (19) The conflicting results on the relationship between fatigue and cognition might in part be explained by the adopted study-designs (cross-sectional versus longitudinal approaches, small sample-size). In a recent, combined retrospective-cross-sectional/ longitudinal design based on 465/69 patients respectively, there was no significant relationship between cognitive measures and fatigue, while self-reported fatigue was found to correlate with self-reported depression. (22)

Relation to MRI Parameters

Structural and Functional Imaging

Magnetic resonance imaging (MRI) is a sensitive method in the diagnostic process of MS. It is therefore reasonable to look for a relation between fatigue pathology and MRI parameters. A study on cognitive impairment and depression in MS found a direct relation between brain-stem MRI lesions and fatigue. (23) Another study by Bakshi et al (24) of 71 MS patients, could not find any relation between regional or global MRI abnormalities and fatigue pathology. This finding is in accordance with several other studies (25-27) suggesting that conventional magnetic resonance imaging (MRI) does not allow insights into the microscopic pathological alterations that might cause fatigue. Accordingly, early studies focusing on global brain atrophy and fatigue failed to find any relation between these variables, (24,27) whilst more recent studies report a relation between brain atrophy and fatigue. (10,11,28,29) The study by Marrie et al (28) could demonstrate that atrophy and fatigue were unrelated during the first 2 years of evaluation, but showed a strong link when the time interval was extended to 8 years. More precisely, an increase in fatigue during the first 2 years was associated with a decrease in Brain Parenchymal Fraction (BPF) over 8 years, suggesting that fatigue pathology might be a predictor for the development of atrophy in the long run.

More advanced imaging techniques such as magnetization transfer, MR spectroscopy, diffusion tensor imaging (DTI) functional MRI (fMRI) and positron emission tomography (PET) may provide a better approach to find a relationship between brain changes and fatigue. Disappointingly, MTR and DTI were not able to differentiate fatigued from non-fatigued MS patients (30) indicating that the amount of damaged fibres as well as the extent and severity of normal appearing brain tissue (NABT) pathology are not contributing to fatigue. In contrast, proton MR spectroscopy showed a statistically linear inverse correlation between the Fatigue Severity Scale (FSS) scores and N-acetylaspartate-creatine (NAA/Cr) ratio (31) when the spectroscopic region of interest (ROI) was located over the corpus callosum including cortico-spinal tracts as well as frontal, parietal, and occipital white matter regions. The choline-creatine (Cho/Cr) ratio did not differ between the low- and high-fatigued groups of patients. As NAA is directly found in neurons, (32) alterations in concentration can be interpreted as changes in neuronal integrity. Consequently, a low NAA concentration in the white matter may be related to axonal damage or even loss. (33) Taking into account the abovementioned results, it can be argued that fatigue might be related to axonal damage.

Functional imaging studies with PET and MRI in patients with fatigue are still rare, but data already available show alterations in activation patterns. (9,15) Hypometabolism in the frontal cortex and the basal ganglia was reported by Roelcke et al (9) in a PET study. Accordingly, studying motor function by fMRI, Filippi et al (15) showed a dysfunction of corticosubcortical circuits with involvement of the thalamus in MS patients with motor fatigue. Whether those changes can also be observed when studying cognitive fatigue has still to be evaluated. From the two functional imaging studies published so far, it can be concluded that at least physical fatigue is expressed by a decrease in functional brain activation where especially subcortical areas such as basal ganglia and thalamus play an essential role. These results also fit with electrophysiological data on MS fatigue (34) where event-related synchronization and desynchronization of the 18 to 22 Hz frequency bands were altered over frontal brain regions in fatigued compared with non-fatigued MS-patients. At present, DTI has not been used frequently to find correlates to fatigue pathology. The only existing study, by Codella et al (30) reports no differences in mean diffusivity and fractional anisotropy between fatigued and non-fatigued MS patients.

Assessment

Neurological Interview and Patient Reports

The content of fatigue reports relies mostly on subjective feelings, and is often experienced by MS patients as a phenomenon that involves physical as well as cognitive and social domains. It is perceived as a loss of energy, causing restrictions of professional, familial and social activities. The problems in assessing fatigue arise from the fact that it extends over a wide range of symptoms covering different organic and endocrine systems also influencing activities of daily living and social interaction. This might explain why many patients at the beginning of feeling exhausted are overstrained in clearly distinguishing fatigue from other disease factors, which in turn, points to the necessity of the treating physician to directly ask for those symptoms. Moreover, professionals have to determine whether the symptoms then reported by the patient constitute a new onset of fatigue or whether it represents an increase in the basal fatigue level. Further, it is important to detect whether some signs or the whole symptomatology constitutes or precedes the manifestation of a new relapse or whether the fatigue symptoms accompany progression of disability due to MS. The regular neurological follow-up of MS patients will help to differentiate the causes of fatigue, to identify factors that can induce or worsen fatigue, and to exclude treatable factors that are not directly related to MS. Aggravating conditions comprise thyroid dysfunction, anaemia or even low iron load especially in women, infectious disorders, exposure to heat, adverse events of medications as well as psychosocial stress. Drugs commonly used in MS for the management of disease symptoms may increase fatigue, including antispasticity agents, anticonvulsants, benzodiazepines, analgesics, beta-blockers, tricyclic antidepressants, as well as immunomodulators.

Fatigue Diaries

It is crucial for the thorough diagnosis of a disease symptom that is not clinically apparent, to gain further information by patients' self reports. Thus, diaries might be a helpful additional source to get more precise information about the symptoms' course throughout the day. Depending on the focus of the diary, the patient can record the onset and duration of the experienced symptoms, their frequency and variation during the day, the subjective experienced level of fatigue as well as related changes in behaviour and emotional state enriched by personal comments. (35)

Finally, a diary provides a structure of the symptoms' occurrence or absence over a defined period of time and can thereby support the patients' understanding of their individual pattern of fatigue, hence facilitating symptom management. However, diaries are not recommended as first choice in the clinical routine to decide whether a patient has fatigue or not. In this context, fatigue scales/questionnaires are much more economic and should be the method of choice in combination with the neurological interview.

Fatigue Scales

In the past 20 years, a remarkable number of scales aiming to assess different aspects of fatigue have been developed (see Table 1). The reason for the multiplicity of fatigue-assessment procedures lies in the complexity of the symptom itself. Thus, while some scales are aimed to assess the multidimensional facets of fatigue other scales have their focus on some domain-specific symptoms (e.g. motor performance or muscle strength).

Finally, the number of existing fatigue scales might simply reflect the disagreement in the community of MS-professionals about the question which aspects a valid fatigue scale should focus on. Besides, most of the existing scales suffer from methodological limitations leading to a general dissatisfaction and provoking the idea of developing new and even better scales. This might be one of the main reasons for the publication of eight scales within 3 years during the period 1993-1996).

From a methodological point of view, a fatigue scale should display what a patient really experiences, should be as short as possible to avoid an induction of fatigue by the length and complexity of the scale itself. Moreover, it should include clearly formulated items, differentiate between the fatigued and non-fatigued MS-patients and healthy controls respectively, and should enable to differentiate between cognitive and motor fatigue. These requirements should then be assessed in a comprehensive validation procedure considering essential external and internal criteria. Although these prerequisites are not fulfilled by the majority of developed fatigue scales and even not by the most widely used instruments - the FSS, (36) and the MFIS, (35)--the two latter scales are nevertheless the most often applied instruments to assess fatigue in clinical trials. To overcome the methodological limitations mentioned, a recently developed questionnaire, the Fatigue Scale for Motor and Cognitive Functions (FSMC) (37) underwent such comprehensive validation procedure to provide reliable assessment of fatigue in the future.

Managing Fatigue

For the management of fatigue, several pharmacological and non-pharmacological options are available, although it has to be underlined that at present no specific 'gold-standard' treatment exists. Thus, the final decision on which treatment option will be applied is taken by the treating physician on their own clinical experience.

Pharmacological approaches to treat MS-related fatigue comprise: amantadine, pemoline, fampridine and modafinil. Amantadine, has monoaminergic, cholinergic and also glutaminergic effects and has shown moderate efficacy (38,39) although its tolerability is poorly documented and good-quality, randomized, controlled trials are needed. (40) Most of the controlled trials conducted thus far have been parallel-arms and crossovers comparing amantadine with other substances, thus reaching only Level II evidence according to the accepted quality criteria of clinical trials. Modafinil has a1-adrenergic properties and has shown a significant efficacy for both cognitive as well as motor aspects of MS fatigue. (41-44) However, over 9 weeks, in a single-blind, one-arm, placebo-controlled Phase-II study, substantial placebo effects on fatigue, sleepiness and depression occurred in MS without significant benefits greater than placebo. (43) Moreover, in a somewhat better designed 5-week, double-blind, placebo-controlled study including a total of 115 patients there was no substantial difference in favour of modafinil as measured by the MFIS. (45) Level II-3 evidence for beneficial effects of the dopaminergic agent pemoline has been shown in a single-arm, randomized, placebo-controlled, 8-week crossover trial including 46 patients reporting excellent or good relief of fatigue in 46.3% of the participants (46) or in a parallel trial, together with amantadine. (16) Nevertheless, pertinent efficacy has still to be proven, since the clinical trials conducted thus far, bear some methodological flaws. (47)

For 4-aminopyridine (4-AP) documentation of fatigue improvement is still scarce. (48) A randomized, controlled, dose-titration trial using a timed-release formulation of 4-AP (fampridine-SR), showed some improvement in walking speed and lower limb strength. Side-effects included dizziness, insomnia, numbness and tingling; at the higher doses, two subjects had seizures. (49) Alhough this study meets Level I-evidence criteria there was no significant improvement on MSFC or fatigue-related measures.

Although there is little methodological evidence supporting the use of antidepressants for the fatigue caused by MS the use of selective serotonine inhibitors (SSRIs) or reversible inhibitors of MAO-A (RIMAs) may be of benefit in some individuals. Taken together, for each substance discussed so far, there is only a limited amount of studies that meet pertinent criteria of evidence-based medicine (EBM). Regardless of some beneficial drug effects, it has to be underlined that an effective, specific, fatigue treatment is still missing and drugs used thus far have caused numerous side-effects.

Within the domain of non-pharmacological approaches, cooling therapy might be one option primarily for patients suffering from Uthoff's phenomenon, where the conduction blockade can be decreased by cold. In one study, significant modest improvements by this method were described. (50) A more recent study investigated the effectiveness of an advanced lightweight cooling-garment and showed significant functional improvement in thermosensitive MS patients. (51) In addition, yoga and physical exercise are alternative strategies for improving fatigue symptoms, (52) although evidence-based data for this is scarce. Nevertheless, cognitive behavioural therapy should accompany any therapeutic approach for the treatment of fatigue since most patients have to learn to restructure their everyday life, including sufficient intervals of resting and relaxation. The acquisition of helpful coping strategies might finally enhance efficacy of the chosen therapy.

Conclusion

Fatigue in MS is a serious symptom with widely obscure pathophysiology. Since the underlying mechanisms provoking it are still unknown, reliable assessment is crucial to provide clarity for patients and relatives, hence giving the opportunity to plan individual activities. Finally, an individual appropriate treatment strategy has to be chosen, comprising both pharmacological and nonpharmacological approaches. Future studies will elucidate if the different aspects of fatigue need differentiated treatment regimens.

Key Points

* The majority of patients with multiple sclerosis experiences fatigue

* Fatigue negatively impact on quality of life being a major reason for early retirement and unemployment

* Reliable assessment of fatigue is difficult

* Both pharmacological and non-pharmacological therapeutic strategies are available to treat fatigue, but a 'gold-standard' treatment is needed

Received: 10 December 2009

Accepted: 3 February 2010

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IK Penner [1,2], P Calabrese [1,2]

[1.] Department of Cognitive Psychology and Methodology, University of Basel, Switzerland;

[2.] Department of Neurology, University Hospital Basel, Switzerland

Address for Correspondence

PD Iris-Katharina Penner

Department of Cognitive Psychology and Methodology, University of Basel, Missionsstr. 60/62, 4055 Basel/Switzerland

Tel: +41 612 673 525

Fax: +41 612 673 526

E-mail: ik.penner@unibas.ch
Table 1: Fatigue scales developed between the
years 1989 and 2006

* FSS (Fatigue Severity Scale, Krupp et al, 1989)

* FAI (Fatigue Assessment Instrument, Schwartz et al,
1993)

* FRS (Fatigue Rating Scale, Chalder et al, 1993)

* FIS (Fatigue Impact Scale, Fisk et al, 1994)

* MFI (Multidimensional Fatigue Inventory, Smets et al,
1995)

* MS-FSS (MS-Specific Fatigue-Severity Scale, Krupp
et al, 1995)

* MAF (Multidimensional Assessment of Fatigue,
Schwartz et al, 1996)

* CIS (Checklist of Individual Strength, Vercoulen
et al, 1996)

* FAMS (Functional Assessment of Multiple Sclerosis,
Cella et al, 1996)

* MFIS (Modified Fatigue Impact Scale, MS Council,
1998)

* FDS (Fatigue Descriptive Scale, Iriarte et al, 1999)

* WEIMuS (Wurzburger Erschopfungsinventar bei MS,
Flachenecker et al, 2006)
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Author:Penner, I.K.; Calabrese, P.
Publication:The International MS Journal
Article Type:Report
Geographic Code:4EXSI
Date:Mar 1, 2010
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