The psychology of fatigue in patients with multiple sclerosis: A review

Fatigue is a frequent and disabling symptom in patients with multiple sclerosis (MS), but it is difficult to define and measure. Today, MS-related fatigue is not fully understood, and evidence related to explanatory pathophysiological factors are conflicting. Here, we evaluate the contribution of psychological factors to MS-related fatigue. Insight into the possible underlying psychological mechanisms might help us to develop adequate psychological interventions and to improve the overall management of fatigue. Conceptual issues and the relationships between MS-related fatigue and mood, anxiety, cognition, personality, and cognitive-behavioral factors are discussed, and the implications for clinical practice and research are presented.     

Neural correlates of cognitive fatigue in multiple sclerosis using functional MRI

Although fatigue is one of the major symptoms of persons with multiple sclerosis (MS), the behavioral and neural correlates are poorly understood. The present study utilized a novel approach to cognitive fatigue examining objective behavioral performance while simultaneously monitoring brain activity using fMRI. Fifteen persons with MS and 15 healthy controls were given 4 trials of a behavioral task assessing processing speed (mSDMT) during fMRI acquisition. It was hypothesized that individuals with MS would show an abnormal pattern of activity across time in specific brain areas previously hypothesized to subserve fatigue [Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci 2000;179:34-42]. Specifically, it was hypothesized that persons with MS would show a greater increase in cerebral activation across time during behavioral performance than that seen in healthy controls, which was interpreted as fatigue. No difference in performance accuracy on the mSDMT was observed, although the MS group was significantly slower than controls. Behavioral alterations indicative of fatigue in the MS group were associated with increased activation in the basal ganglia, frontal areas including superior, medial, middle and inferior regions, parietal regions (precuneus and cuneus), thalamus and the occipital lobes. These data provide direct support for the Chaudhuri and Behan model of "central" fatigue which hypothesizes a specific role of the "non-motor" functions of the basal ganglia.     

认知康复治疗在多发性硬化认知功能损害中的积极作用

目的 探讨认知康复治疗在多发性硬化(MS)认知功能损害中的积极作用。 方法 对广州医学院第二附属医院神经内科自2008年9月至2010年10月收治的40例MS存在认知功能损害的患者采用神经心理学测验方法系统评价神经行为认知状况、执行功能及整体认知功能,针对其出现的不同类型认知功能损害早期实行认知康复治疗策略,比较治疗前后患者各神经认知功能评分的差异。 结果 与认知康复治疗前相比,治疗后MS患者智能损害明显改善,神经行为认知状况中定向能力、专注能力、理解、语言、空间结构、记忆、判断等项目评分明显增高,执行功能相关量表评分明显增高,差异均有统计学意义(P＜0.05)。 结论 认知康复治疗能明显改善MS患者认知损害中智商、神经行为认知状况、执行功能的损害,对MS患者的生活状况改善有积极的意义。     

Effect of cannabinoids on spasticity and ataxia in multiple sclerosis

Summary The chronic motor handicaps of a 30-year-old multiple sclerosis patient acutely improved while he smoked a marihuana cigarette. This effect was quantitatively assessed by means of clinical rating, electromyographic investigation of the leg flexor reflexes and electromagnetic recording of the hand action tremor. It is concluded that cannabinoids may have powerful beneficial effects on both spasticity and ataxia that warrant further evaluation.Dedicated to Professor H.H. Kornhuber on the occasion of his 60th birthday     

多发性硬化患者认知改变与事件相关电位研究

目的研究多发性硬化(MS)患者认知功能障碍的发生情况,及其与事件相关电位(ERPs)的相关关系。方法对70例MS患者进行韦氏智力量表测查及ERPs检查。结果韦氏智力量表测试发现MS组全量表智商(FIQ)不正常者(<90分)的比率为40%(28/70),与正常组比较差异显著(P<0.01)。MS组N2、P300潜伏期明显延长,与对照组比较差异具有显著性(P<0.05)。脑或脑脊髓型及进展型MS患者P300潜伏期明显延长,P300波幅降低。病程与P300潜伏期呈显著正相关。言语量表智商(VIQ)、FIQ与P300潜伏期呈负相关,与P300波幅呈正相关;操作量表智商(PIQ)与P300波幅呈正相关。结论MS患者存在有认知障碍。ERPs检查对MS认知障碍的判断有一定参考意义。     

Impact of cognitive impairment on coping strategies in multiple sclerosis

Objectives: To assess the impact of cognitive impairment (CI) on coping strategies in multiple sclerosis (MS). Materials and methods: Sixty-three patients (40 women, 55 relapsing-remitting and 8 secondary progressive, age 42.6 ± 10.1 years, Expanded Disability Status Scale 2.2 ± 1.7) were assessed using the Coping Orientation for Problem Experiences-New Italian version Inventory, the Beck Depression Inventory and the Rao's Brief Repeatable Battery. Results: MS patients were less likely to use positive and problem-focused strategies, whereas avoiding strategies were adopted more frequently. Twenty-three (36.5%) cases were CI. We found no differences in the type of coping between CI and cognitively preserved patients. Scores on the Stroop test (beta = −0.91, p = 0.04) and on the Word List Generation (beta = 1.15, p = 0.04) were associated with poorer coping strategies. Conclusions: Our study suggests that cognitive functioning (in particular on sustained attention and aspects of executive function) must be considered in a comprehensive account of the factors contributing to successful coping in MS patients.     

Trajectory of fatigue severity in natalizumab treated multiple sclerosis patients

Fatigue is one of the most debilitating symptoms in multiple sclerosis (MS). The aim of this study was to observe the severity of MS associated fatigue in a community-based sample of natalizumab (ntz) treated patients over one year. In 48 relapsing remitting MS patients (mean age = 38.3 years) fatigue was longitudinally measured with the Modified Fatigue Impact Scale (MFIS) at two time points. The primary analysis of differences in MFIS was performed using non-parametric Wilcoxon test for dependent variables. Mean total MFIS Score increased significantly from 32.6 ± 20.9 to 49.1 ± 20.0 over the observation period of 12 months (p < 0.001). 83% of patients remained clinically disease activity free (no relapse, no progression in the Expanded Disability Status Scale, EDSS) over the observation period of one year. Age, gender, disease duration, spinal involvement, Gd-enhancement, depressive symptoms and EDSS had no influence on fatigue levels as measured with MFIS. Severity of fatigue symptoms during ntz treatment might increase despite very low disease activity.     

Polypharmacy in multiple sclerosis: Relationship with fatigue,perceived cognition,and objective cognitive performance

Objective

Patients with multiple sclerosis (MS) commonly use a variety of medications to slow disease progression, alleviate symptoms, and treat comorbid conditions. Polypharmacy has been linked to adverse outcomes in other patient groups, but has not been studied extensively in MS. We investigated the impact of polypharmacy on fatigue, objective neuropsychological performance, and subjective cognitive impairment in a sample of patients with MS.

Methods

MS patients (n = 85) completed a medication inventory, self-report questionnaires, and a battery of neurocognitive tests. MS patients with polypharmacy were compared to MS patients without polypharmacy, using multivariate analysis of covariance (MANCOVA).

Results

After controlling for disease characteristics, MS patients with polypharmacy (n = 28) exhibited prospective memory deficits and reported significantly more fatigue and subjective cognitive problems than MS patients without polypharmacy.

Conclusion

Clinicians and patients should carefully weigh the costs and benefits of prescribing multiple medications, as these may contribute to iatrogenic fatigue and cognitive problems in MS. Moreover, researchers should account for polypharmacy when conducting studies examining fatigue and cognition in MS.     

A longitudinal study on fatigue,depression, and their relation to neurocognition in multiple sclerosis

Aims: Fatigue and depression are two common syndromes in patients with multiple sclerosis (MS), but their inherent relation and causes are still under debate. Method: With a longitudinal design we analyzed their development over a period of one year and their relation to the clinical status, brain atrophy, and neurocognitive performance at the beginning of the study. Forty patients with relapsing-remitting MS were included and were assessed for fatigue and depressive mood, clinical status, neurocognitive performance, and brain parenchymal fraction. Results: Regression analyses showed that changes in fatigue are predicted by fatigue status and gait performance at Visit 1. Changes in depressive mood are predicted by executive functioning, memory performance, and depressive mood at Visit 1. Additional evidence for a dissociation between fatigue and depression was found when patient groups suffering at Visit 2 from fatigue or not and having a depressed mood or not were contrasted. Conclusion: We conclude that although fatigue and depressive mood share many features, they do not behave similarly in the course of relapsing-remitting MS. Our results fit the proposal that fatigue is a reversible syndrome similar to sickness behavior, and that depressive mood is at least partially related to neurodegeneration.     

Difficulties with emotion regulation in multiple sclerosis: Links to executive function,mood, and quality of life

Introduction: Little is known about the influence of multiple sclerosis (MS) on the regulation of emotion. The current study tested whether people with MS report more emotion regulation difficulties than healthy controls. The relationship between emotion regulation and other important variables (mood, quality of life, and executive function) was explored. Mediation models were used to further understand the links between emotion regulation, depressed mood, and executive function in MS. Method: A total of 31 people with MS and 31 controls completed the Difficulties in Emotion Regulation Scales and measures of executive function (fluency and a go/no-go task), mood (Hospital Anxiety and Depression Scales), and a multidimensional assessment of quality of life (World Health Organization Quality of Life, brief version). Results: People with MS reported experiencing more difficulties in emotion regulation than controls. Mediation analyses indicated that depression mediated the emotion regulation difficulties in MS, while executive dysfunction did not. Difficulties in emotion regulation predicted poorer psychological and social quality of life in MS, independent of problems with executive function. Conclusions: People with MS experience difficulties in emotion regulation, which predict poorer quality of life. These results indicate that emotional control skills should be investigated in further detail when considering interventions to enhance well-being in MS.     

Effect of seasonal fluctuation of ambient temperature on fatigue in multiple sclerosis patients living in Attica,Greece

Fatigue limits daily functioning of patients with multiple sclerosis (MS) and has a severe impact on their quality of life. Fatigue is considered a result of biological, psychological and environmental factors. This study investigated the effect of the ambient temperature on the levels of fatigue during each season of the year in MS patients and a healthy population. Forty-five MS patients and 42 healthy people matched for age and sex participated in the study. Measurement of fatigue was based on the Fatigue Severity Scale. Patients were asked which season they felt the worst fatigue. The measurements were conducted every 3 months in November, February, May and August on the last day of the month. MS patients (mean = 4.20, standard error [SE] = 0.22) exhibited a higher mean fatigue severity than the control group (mean = 2.68, SE = 0.22). MS patients did not present any significant differentiation in fatigue between seasons. However, the control group exhibited a tendency for fatigue severity to significantly increase in August, and actually experienced fatigue levels higher than the MS group during the last week of August. Significant fluctuation of fatigue was not observed in patients with MS. Patients may avoid worsening fatigue caused by climatic conditions with appropriate organization of their life routine.     

Magnetic resonance imaging and cognitive functioning in multiple sclerosis

Summary The relationship between cognitive impairment in multiple sclerosis and brain lesions seen on magnetic resonance imaging (MRI) was studied. Three groups of 11 patients with multiple sclerosis, matched for the variables of disability, duration of illness, age and sex, were included. On the basis of neuropsychological testing, the groups were seen to differ in their level of cognitive impairment. The first group showed no cognitive impairment, the second group a moderate, and the third group a serious cognitive impairment. These differences between the groups were reflected by MRI, which revealed more abnormalities in the groups with cognitive impairment compared with the group with normal cognitive function. However, by MRI it was not possible to distinguish between the groups with moderate and that with serious cognitive impairment.     

Fatigue in multiple sclerosis: Interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability

Although fatigue is a frequent complaint of patients with multiple sclerosis (MS), little is known about the origins of multiple-sclerosis-associated fatigue. Our primary focus was to study if the extent of cerebral abnormalities, as shown on magnetic resonance imaging (MRI), had any relation with the frequency and intensity of fatigue complaints of patients with a definite diagnosis of MS. Fatigue severity was rated by the patients with the use of a 2-week diary and a fatigue questionnaire, while conventional T1- and T2-weighted MRI provided several measures for cerebral abnormalities. In total, 72% of 45 patients reported to be seriously fatigued at least several times a week over the last 3-month period. Fatigue severity was not related to the total extent of cerebral abnormalities, or to MRI-based atrophy measures. Regional lesion load did not differ between fatigued and non-fatigued subjects. Although neurological disability, as measured by the Expanded Disability Status Scale (EDSS) and Neurological Rating Scale (NRS), did correlate significantly with most MRI measures, it showed no relation with fatigue severity. Neurological progression rates and number of exacerbations in the 2-year period prior to assessment were not significantly associated with the fatigue measures. Therefore, our findings suggest that differences in levels of self-reported fatigue in patients with multiple sclerosis cannot merely be explained by the degree of clinical disease activity, neurological disability or the extent of MRI abnormalities. These results are compared to other research findings and the possible role of alternative factors influencing fatigue in multiple sclerosis are discussed.     

Treatment of sleep disorders may improve fatigue in multiple sclerosis

Objective

In a previous polysomnographic cross-sectional study we found a significant relationship between sleep disorders and multiple sclerosis (MS) related fatigue. The purpose of this open follow-up observation was to compare the impact of treatment of sleep disorders on MS related fatigue measured with the Modified Fatigue Impact Scale (MFIS).

Methods

Non-randomized follow-up observation: treated versus untreated patients, subgroups according to compliance with sleep medical treatment recommendations (univariate, multivariate analysis, multiple logistic regression). 66 MS patients were followed after polysomnography, 49 patients with relevant sleep disorders and 17 without.

Results

Mean MFIS scores decreased from 41.2 to 26.2 (p = 0.025) in patients with good compliance (GC; n = 18), from 42.4 to 32.1 (p = 0.12) in patients with moderate compliance (MC; n = 12), and from 41.6 to 35.5 (p = 0.17) in non-compliant patients (NC; n = 17). Mean MFIS values increased in patients without sleep disorders from 22.9 to 25.4 (NSD; n = 12, p = 0.56). In multiple logistic regression, treatment of sleep disorders predicted decrease of MFIS-values (GC versus NSD odds ratio 13.4; p = 0.015; 95% confidence interval (CI) 1.7–107.2, MC versus NSD odds ratio 13.8; p = 0.028; 95% CI 1.3–143.3).

Conclusions

Sleep medical treatment may improve MS related fatigue when patients adhere to treatment recommendations.     

Stimulated peripheral production of interferon-gamma is related to fatigue and depression in multiple sclerosis

Objectives

The aim of the study was to evaluate the stimulated production of interferon-gamma (IFNγ) by peripheral CD3+CD4+ T lymphocytes in patients with multiple sclerosis (MS) with regard to the degree of fatigue, and to investigate relationships between immunological parameters, level of depression and clinical variables.

Methods

Forty MS patients (30 women, 10 men, aged 22–60 years): 20 fatigued and 20 non-fatigued were involved in the study. Fatigue was evaluated using the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS), depression level – using Beck Depression Inventory (BDI). Production of IFNγ by stimulated peripheral blood CD3+CD4+ T lymphocytes, assessed using flow cytometry, was compared between MS patients with different levels of fatigue and controls. Correlations were searched out between immunological findings and BDI, age, duration and course of MS, relapse rate, disability (assessed in Expanded Disability Status Scale – EDSS) and its progression.

Results

Stimulated production of IFNγ by CD3+CD4+ T lymphocytes was higher in severely fatigued patients in comparison with non-fatigued ones and controls, tended to correlate with FSS and MFIS, and correlated with BDI. No relationships were found between immunological findings and disease-related variables.

Conclusion

Stimulated production of IFNγ by peripheral CD3+CD4+ T lymphocytes is related to fatigue and depression in MS patients.     

The effect of tDCS on the fatigue in patients with multiple sclerosis: A systematic review of randomized controlled clinical trials

IntroductionFatigue is one of the most common disabling symptoms in patients with multiple sclerosis (MS) which is present in 75% of these patients and is usually associated with functional disabilities. According to the literature, there is no general agreement on the effectiveness of the existing treatments for fatigue in patients with MS. As transcranial direct current stimulation (tDCS) is a relatively new method in the treatment of fatigue symptoms in patients with MS, the purpose of this study was to systematically review published evidence conducted to assess the effects of tDCS on fatigue in patients with MS.Material & methodsA thorough literature search of published articles was conducted from 1996 to 2019 in different databases including PubMed, Science Direct, OVID, Google Scholar, Cochrane Library, Scopus, Embase, ProQuest and web of science with keywords of “tDCS”, “multiple Sclerosis” and “Fatigue”. Results yielded 1017 studies, which after excluding articles based on duplication and title and abstract, 8 of them were selected for review in this study.ResultsThe results from the literature revealed that six studies indicated positive effects of tDCS stimulation on fatigue reduction. In four studies stimulation was over the right dorsolateral prefrontal cortex (DLPFC); in three studies stimulation placed over the whole body’s primary somatosensory cortex (S1); and in one study stimulation applied over the posterior parietal cortex. In most studies, no serious side effects were reported.ConclusionMost studies revealed that tDCS can reduce the adverse effects of MS-related fatigue in particular cognitive type. As follow-ups were either absent or short period, as well as the application of treatment protocols and measurement instruments were different, it was very difficult to draw strong conclusion on the effects of tDCS in patients with MS. However, further large scale studies with long term follow-up are still recommended.     

Quality of life in patients with multiple sclerosis: the impact of fatigue and depression

Quality of Life (QOL) is impaired in multiple sclerosis (MS) in part due to physical disability. MS-associated fatigue (MSF) and depression (MSD) are common and treatable features of MS, which could also impact on QOL, independent of physical disability. We prospectively studied 60 consecutive patients with MS. QOL was assessed using Multiple Sclerosis Quality of Life (MSQOL)-54. Group differences in QOL scores were assessed after adjusting for Expanded Disability Status Scale (EDSS), Fatigue Severity Scale (FSS) and Hamilton Depression Inventory scores. MS patients were grouped into relapsing-remitting (RR) or secondary-progressive (SP), MSF (FSS> or =5) or MS-nonfatigue (MSNF) (FSS< or =4), and MSD or MS-nondepression (MSND). After accounting for disability and depression, fatigue was associated with impaired QOL with respect to health perception (p=0.03) and limitations due to physical dysfunction (p=0.008). After accounting for disability and fatigue, depression was associated with lower QOL with respect to health perception (p=0.02), sexual dysfunction (p=0.03), health distress (p=0.03), mental health (p=0.006), overall QOL (p=0.006), emotional dysfunction (p=0.04), and limitations due to emotional dysfunction (p=0.03). This study demonstrates that fatigue and depression are independently associated with impaired QOL in MS, after accounting for physical disability, suggesting that their recognition and treatment can potentially improve QOL.     

Aggressive course of cognitive impairment in multiple sclerosis: A new term for the management of patients

Multiple sclerosis (MS) can create different kinds of symptoms by involving different fields of the central nervous system. Cognitive impairment (CI) is one of the symptoms that can be caused by the onset of the disease and provide a change in the patient’s quality of life. Considering the course of the disease, CI usually worsens increasingly, and there is usually a severe CI in patients with end stage of MS. However, progressing CI can be so fast and severe in a few patients that it can disrupt the daily affairs of the individual. This paper plans to define the aggressive course of CIs in MS patients according to the reported cases. This definition explains that, the aggressive course of CI in MS patients happens in less than 5 years from the onset of the disease, and during this time, it causes dementia in the patient.     

Physiopathology and treatment of fatigue in multiple sclerosis

Fatigue is a common symptom of patients with multiple sclerosis (MS). It is reported by about one-third of patients, and for many fatigue is the most disabling symptom. Fatigue may be associated with motor disturbances and/or mood disorders, which makes it very difficult to determine whether the fatigue is an aspect of these features or a result per se of the disease. Although peripheral mechanisms have some role in the pathogenesis of fatigue, in MS there are clear indications that the more important role is played by “central” abnormalities. Neurophysiological studies have shown that fatigue does not depend on involvement of the pyramidal tracts and implicate impairment of volitional drive of the descending motor pathways as a physiopathological mechanism. Metabolic abnormalities of the frontal cortex and basal ganglia revealed by positronemission tomography and correlations between fatigue and magnetic resonance imaging lesion burden support this hypothesis. Some recent studies also suggest that pro-inflammatory cytokines contribute to the sense of tiredness. No specific treatments are available. Management strategies include medications, exercise, and behavioural therapy; in most cases a combined approach is appropritate. Received: 26 September 2000, Accepted: 28 September 2000