Longitudinal determinants of employment status in people with relapsing-remitting multiple sclerosis.

Purpose: To investigate longitudinal relationships between employment status and disease-related, (neuro)psychological, and work-related factors in people with multiple sclerosis (MS). Methods: 170 employed people with MS underwent yearly neurological and neuropsychological examinations to assess MS-related disability and cognitive functioning. Additionally, they completed yearly questionnaires assessing depression, anxiety, fatigue, cognitive complaints, workplace support and coping. Multilevel models for change were fitted to examine progression of these factors over three years, and to assess possible relationships with change in employment status. Results: People with a deteriorated employment status after three years reported more depression (p=0.009), a higher impact of fatigue (p<0.001), more cognitive complaints (p<0.001) and less workplace support (p=0.001) at baseline than people with a stable employment status. There were no differences in progression over time of the examined variables between people with a stable or deteriorated employment status. Conclusion: More depression, a higher impact of fatigue, more cognitive complaints and less workplace support are predictive of a deteriorated employment status after three years in individuals with MS. How these factors progress over time is not different between those with a stable or deteriorated employment. MS-related disability, anxiety, objective cognition and coping were not related to a deterioration in employment status.

Personality traits are not associated with changes in employment status over 3 years in persons with multiple sclerosis.

Previous research discovered a protective effect of higher conscientiousness against a 3-year deterioration in employment status in persons with multiple sclerosis (pwMS). To replicate these findings, we used data from a multicentre prospective cohort study where 145 employed pwMS completed questionnaires, neurological and neuropsychological examinations at baseline and after 3 years. A 3-year deterioration in employment status was reported in 31.0%. We observed no differences in personality, demographics or clinical characteristics between pwMS with deteriorated or stable employment status. These null findings may be partly explained by the classification of deteriorated employment status, which does not reflect Dutch labour conditions.

Subjective cognitive impairment is related to work status in people with multiple sclerosis.

Background: Unemployment is common among people with multiple sclerosis (pwMS) and has been associated with subjective cognitive difficulties, specifically in memory, attention, and executive functioning. However, longitudinal research on subjective cognitive difficulties and employment is scarce. Objective: We investigated whether subjective cognitive impairment (SCI), based on the clinical cut-off score of the MS Neuropsychological Screening Questionnaire (MSNQ), was associated with work status and negative work events (NWE) at baseline and after 2 years. Moreover, we investigated whether four MSNQ subdomains were related to work status and NWE. Methods: 287 participants (77.4% female, median age = 42 years) completed questionnaires on subjective cognitive functioning, depression, anxiety, and fatigue, and completed the Symbol Digit Modalities Test (SDMT). After baseline comparisons, logistic regression analyses were performed, with work status and NWE at baseline, and employment change and NWE change within 2 years after baseline as dependent variables. Independent variables included SCI and the MSNQ domains. Covariates anxiety, depression, fatigue, and SDMT were added. Results: SCI, depression and anxiety were associated with work status (Nagelkerke R 2 = .286), but only SCI was associated with employment change (Nagelkerke R 2 = .164). No predictors were associated with NWE at baseline or follow-up. In addition, no MSNQ subdomain was related to work status, employment change or NWE. Conclusion: Unemployed pwMS and pwMS with a deteriorated work status reported more cognitive difficulties after 2 years than employed pwMS or pwMS with a stable work status. In addition, depression, and anxiety were associated with work status.

MSmonitor-plus program and video calling care (MPVC) for multidisciplinary care and self-management in multiple sclerosis: study protocol of a single-center randomized, parallel-group, open label, non-inferiority trial.

BACKGROUND: We designed a new multi-modal version of the MSmonitor, called the MSmonitor-Plus and Video calling Care (MPVC), a self-management and education program with e-health interventions that combines frequent use of specific questionnaires with video calling in treating multiple sclerosis (MS) patients. OBJECTIVE: To assess the effectiveness, cost-effectiveness and feasibility of MPVC compared to care as usual (CAU), with the goal of achieving equal or better quality of life for MS patients and their partners/informal caregivers. Our hypothesis is that by using MPVC, monitoring will become more efficient, that patients' self-efficacy, quality of life, and adherence to treatment will improve, and that they will be able to live their lives more autonomously. METHODS: A randomized, parallel-group, open label, non-inferiority trial will be conducted to compare MPVC with CAU in MS patients and their partners/informal caregivers. A total of 208 patients will be included with follow-up measurements for 2 years (at baseline and every 3 months). One hundred four patients will be randomized to MPVC and 104 patients to CAU. Partners/informal caregivers of both groups will be asked to participate. The study will consist of three parts: 1) a clinical effectiveness study, 2) an economic evaluation, and 3) a process evaluation. The primary outcome relates to equal or improved disease-specific physical and mental quality of life of the MS patients. Secondary outcomes relate to self-efficacy, efficiency, cost-effectiveness, autonomy, satisfaction with the care provided, and quality of life of partners/informal caregivers. DISCUSSION: The idea behind using MPVC is that MS patients will gain more insight into the individual course of the disease and get a better grip on their symptoms. This knowledge should increase their autonomy, give patients more control of their condition and enable them to better and proactively interact with health care professionals. As the consulting process becomes more efficient with the use of MPVC, MS-related problems could be detected earlier, enabling earlier multidisciplinary care, treatment or modification of the treatment. This could have a positive effect on the quality of life for both the MS patient and his/her partner/informal caregiver, reducing health and social costs. TRIAL REGISTRATION: NCT05242731 Clinical Trials.gov. Date of registration: 16 February 2022 retrospectively registered.

Work difficulties in people with multiple sclerosis: The role of anxiety, depression and coping.

Background: Symptoms of anxiety and depression affect the daily life of people with multiple sclerosis (MS). This study examined work difficulties and their relationship with anxiety, depression and coping style in people with MS. Methods: 219 employed people with MS (median age = 43 years, 79% female) completed questionnaires on anxiety, depression, coping style, demographics and work difficulties, and underwent a neurological examination. Two regression analyses were performed with work difficulties as the dependent variable and either anxiety or depression as continuous independent variables. Coping style, age, gender, educational level, MS-related disability and disease duration were added as additional predictors, as well as interaction terms between coping style and either symptoms of depression or anxiety. Results: A significant model was found (F (10,205) = 13.14, p < 0.001, R 2 = 0.39) in which anxiety, emotion- and avoidance-oriented coping and MS-related disability were positively related to work difficulties. The analysis of depression resulted in a significant model (F (10,205) = 14.98, p < 0.001, R 2 = 0.42) in which depression, emotion- and avoidance-oriented coping and MS-related disability were positively related to work difficulties. None of the interaction effects were significant. Conclusions: Work difficulties were positively related to anxiety, depression, emotion- and avoidance-oriented coping and MS-related disability in workers with MS.

Adherence to dietary guidelines is associated with better physical and mental quality of life: results from a cross-sectional survey among 728 Dutch MS patients.

BACKGROUND: A healthy diet has been associated with less symptoms or progression of disease in multiple sclerosis (MS). However, whether specific diets are needed, or general healthy diet recommendations are sufficient is unknown. OBJECTIVE: To investigate the association between diet quality, use of diets, and quality of life (QoL) in men and women with MS. METHODS: Diet quality was measured with the Dutch Healthy Diet-index, which measures adherence to the Dutch Guidelines for a Healthy Diet. QoL was assessed with the MSQoL-54 questionnaire. A total of 728 people were included (623 women, 105 men). Multiple linear regression, stratified for gender, was used to analyse the data. RESULTS: In women with MS, an association was found between diet quality and both physical and mental QoL after adjusting for several confounders (Physical Health Composite Score (ß=0.410; P=0.001); Mental Health Composite Score (ß=0.462; P=0.002)). Similar results were less pronounced in men. Subjects following a specific diet had higher diet quality and QoL than subjects not following a diet. CONCLUSION: Adherence to the Dutch dietary guidelines is associated with better physical and mental QoL, especially in women. Following an MS-specific diet may help to adhere to these guidelines.

Self-reported occupational functioning in persons with relapsing-remitting multiple sclerosis: Does personality matter?

BACKGROUND: Multiple sclerosis (MS) poses a major threat to sustainable employability. Identifying conditions and factors that promote work participation is of great importance. Our objective was to explore the contribution of personality traits in explaining occupational functioning in MS. METHODS: 241 participants with relapsing-remitting MS (78% female, median age: 42.0 years, median EDSS: 2.0) and 60 healthy controls (70% female, median age: 45.0 years) underwent neuropsychological and neurological examinations and completed questionnaires. Multivariate logistic and linear regression analyses were conducted to examine relations between personality traits and self-reported occupational functioning, while accounting for known correlates. RESULTS: Personality traits were not associated with self-reported occupational functioning when correcting for known correlates. A higher impact of fatigue (B = -0.05, p = .005 and B = -0.04, p = .009) and depression (B = -0.22, p = .008 and B = -0.21, p = .01) were associated with no paid job (R2 = 0.13) and considering to reduce work hours (R2 = 0.12). A higher impact of fatigue (B = -0.05, p = .008, ß = 0.46, p = .001 and ß = -0.36, p = .001) was associated with absenteeism from work (R2 = 0.15), more presenteeism (R2 = 0.35) and lower work ability (R2 = 0.25). A higher impact of fatigue (ß = 0.46, p = .001) and anxiety (ß = 0.25, p = .001) were associated with more work difficulties (R2 = 0.54). CONCLUSION: Personality traits did not explain additional variance in self-reported occupational functioning in persons with relapsing-remitting MS with mild disability. The impact of fatigue was the main and most consistent correlate of occupational functioning, often combined with depression or anxiety. Total explained variance of the models was limited, emphasizing the need to additionally examine other (contextual) factors when considering occupational challenges in MS.

Patient decision aid based on multi-criteria decision analysis for disease-modifying drugs for multiple sclerosis: prototype development.

BACKGROUND: Since decision making about treatment with disease-modifying drugs (DMDs) for multiple sclerosis (MS) is preference sensitive, shared decision making between patient and healthcare professional should take place. Patient decision aids could support this shared decision making process by providing information about the disease and the treatment options, to elicit the patient's preference and to support patients and healthcare professionals in discussing these preferences and matching them with a treatment. Therefore, a prototype of a patient decision aid for MS patients in the Netherlands-based on the principles of multi-criteria decision analysis (MCDA) -was developed, following the recommendations of the International Patient Decision Aid Standards. MCDA was chosen as it might reduce cognitive burden of considering treatment options and matching patient preferences with the treatment options. RESULTS: After determining the scope to include DMDs labelled for relapsing-remitting MS and clinically isolated syndrome, users' informational needs were assessed using focus groups (N = 19 patients) and best-worst scaling surveys with patients (N = 185), neurologists and nurses (N = 60) to determine which information about DMDs should be included in the patient decision aid. Next, an online format and computer-based delivery of the patient decision aid was chosen to enable embedding of MCDA. A literature review was conducting to collect evidence on the effectiveness and burden of use of the DMDs. A prototype was developed next, and alpha testing to evaluate its comprehensibility and usability with in total thirteen patients and four healthcare professionals identified several issues regarding content and framing, methods for weighting importance of criteria in the MCDA structure, and the presentation of the conclusions of the patient decision aid ranking the treatment options according to the patient's preferences. Adaptations were made accordingly, but verification of the rankings provided, validation of the patient decision aid, evaluation of the feasibility of implementation and assessing its value for supporting shared decision making should be addressed in further development of the patient decision aid. CONCLUSION: This paper aimed to provide more transparency regarding the developmental process of an MCDA-based patient decision aid for treatment decisions for MS and the challenges faced during this process. Issues identified in the prototype were resolved as much as possible, though some issues remain. Further development is needed to overcome these issues before beta pilot testing with patients and healthcare professionals at the point of clinical decision-making can take place to ultimately enable making conclusions about the value of the MCDA-based patient decision aid for MS patients, healthcare professionals and the quality of care.

Empathy in multiple sclerosis--Correlates with cognitive, psychological and occupational functioning.

BACKGROUND: Recent studies report deficits in social cognition in individuals with multiple sclerosis (MS). Social cognitive skills such as empathy are important for adequate social and occupational functioning. Our objectives are: (1) to examine whether empathy differs between individuals with MS and healthy controls, (2) to examine relations between empathy and cognitive, psychological and occupational functioning. METHODS: 278 individuals with MS (relapsing-remitting subtype) and 128 healthy controls from the MS@Work study participated in this investigation. The participants completed questionnaires about demographics, cognitive, psychological and occupational functioning, and underwent neurological and neuropsychological examinations. Mann-Whitney U-tests were used to examine group differences in empathy. Pearson and Spearman rank correlation analyses were used to examine relations between empathy and the other measures. RESULTS: Empathy did not differ between individuals with MS and healthy controls. In individuals with MS, higher empathy was correlated with a higher educational level (X2(df) = 13.2(2), p = 0.001), better verbal learning (r = 0.20, p = 0.001), less symptoms of depression (r=-0.21, p = 0.001), higher extraversion (r = 0.25, p ≤ 0.001), agreeableness (r = 0.55, p ≤ 0.001) and conscientiousness (r = 0.27, p ≤ 0.001) and better occupational functioning in terms of work scheduling and output demands (r = 0.23, p = 0.002) and less cognitive/psychological work barriers (r = -0.21, p = 0.001). In healthy controls, higher empathy was correlated with less symptoms of depression (r = -0.34, p ≤ 0.001), less fatigue (r = -0.37, p ≤ 0.001), higher agreeableness (r = 0.59, p ≤ 0.001) and better occupational functioning in terms of work ability as compared to lifetime best (r = 0.28, p = 0.001) and less cognitive/psychological work barriers (r = -0.34, p ≤ 0.001). Empathy did not differ between unemployed and employed individuals with MS or healthy controls. CONCLUSION: Empathy did not differ between individuals with MS and healthy controls. Within both investigated groups, higher empathy was weakly to moderately correlated with less symptoms of depression, higher agreeableness and better occupational functioning. We also found unique correlations for empathy within the investigated groups. Longitudinal studies are needed to further examine social cognition in relation to cognitive, psychological and occupational functioning in both individuals with MS and healthy controls. It would be particularly interesting to concurrently examine changes in the brain network involved with social cognition.

Caregiver strain among life partners of persons with mild disability due to relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disorder of the central nervous system with an unpredictable disease course. Life partners often become caregivers, which can be both rewarding and challenging, as the caregiver's physical and mental health is often negatively affected. Previous studies on caregiver strain focused on caregivers of persons with MS with relatively high disability levels, while caregiver strain may already be experienced by life partners living with mildly disabled persons with MS. OBJECTIVE: The current study examines factors associated with caregiver strain in life partners of persons with mild disability due to relapsing-remitting MS. METHODS: We included 173 persons with relapsing-remitting MS (79% female; mean age 42.8 years; 90% employed; median EDSS 2.0) and their life partners. The life partners completed questionnaires on caregiver strain and neuropsychiatric and cognitive functioning of the person with MS. The persons with MS completed questionnaires about demographics, fatigue, personality, physical, cognitive and neuropsychiatric functioning, and underwent neuropsychological and neurological examinations. A linear regression analysis was conducted to examine predictors of caregiver strain. RESULTS: 24% of the life partners experienced above average levels of caregiver strain. A multivariate linear regression analysis revealed that a higher age of the person with MS (ß = 0.16, p = 0.04), more physical disability (ß = 0.17 p = 0.04), more cognitive and neuropsychiatric problems of the person with MS as reported by the life partner (ß = 0.33, p = 0.001) and higher severity of neuropsychiatric symptoms as reported by the life partner (ß = 0.32, p = 0.001) were associated with higher caregiver strain (R2 = 0.49). CONCLUSION: Higher caregiver strain in life partners of persons with mild disability due to relapsing-remitting MS was primarily associated with cognitive and neuropsychiatric problems of the person with MS.

The capability set for work - correlates of sustainable employability in workers with multiple sclerosis.

BACKGROUND: The aim of this study was to examine whether work capabilities differ between workers with Multiple Sclerosis (MS) and workers from the general population. The second aim was to investigate whether the capability set was related to work and health outcomes. METHODS: A total of 163 workers with MS from the MS@Work study and 163 workers from the general population were matched for gender, age, educational level and working hours. All participants completed online questionnaires on demographics, health and work functioning. The Capability Set for Work Questionnaire was used to explore whether a set of seven work values is considered valuable (A), is enabled in the work context (B), and can be achieved by the individual (C). When all three criteria are met a work value can be considered part of the individual's 'capability set'. RESULTS: Group differences and relationships with work and health outcomes were examined. Despite lower physical work functioning (U = 4250, p = 0.001), lower work ability (U = 10591, p = 0.006) and worse self-reported health (U = 9091, p ≤ 0.001) workers with MS had a larger capability set (U = 9649, p ≤ 0.001) than the general population. In workers with MS, a larger capability set was associated with better flexible work functioning (r = 0.30), work ability (r = 0.25), self-rated health (r = 0.25); and with less absenteeism (r = - 0.26), presenteeism (r = - 0.31), cognitive/neuropsychiatric impairment (r = - 0.35), depression (r = - 0.43), anxiety (r = - 0.31) and fatigue (r = - 0.34). CONCLUSIONS: Workers with MS have a larger capability set than workers from the general population. In workers with MS a larger capability set was associated with better work and health outcomes. TRIAL REGISTRATION: This observational study is registered under NL43098.008.12: 'Voorspellers van arbeidsparticipatie bij mensen met relapsing-remitting Multiple Sclerose'. The study is registered at the Dutch CCMO register ( https://www.toetsingonline.nl ). This study is approved by the METC Brabant, 12 February 2014. First participants are enrolled 1st of March 2014.

[Clinical drug profiles: an instrument to improve shared decision-making]. / Klinische geneesmiddelprofielen.

Doctors and patients are increasingly choosing treatment options by means of the shared decision-making process. However, human decisions are subject to cognitive bias, i.e. systematic and predictable errors in probability estimation and information synthesis. Decision-making may also be hampered by incomplete information. Clinical Drug Profiles (CDPs) aim to provide up-to-date, evidence-based and independent information about drug characteristics that are relevant to doctors and patients alike in the context of shared decision-making. They contain information about mechanisms of action, mode and frequency of administration, clinical efficacy, therapeutic effectiveness, side effects, persistence and adherence, and safety monitoring. CDPs are to be made freely available on the internet, thus enabling doctors and patients to obtain drug-specific information on potential benefits and risks, before or during the decision-making process. In addition, the patient can make a subjective appraisal of the chances of success and the risk of side effects. In all, CDPs increase the likelihood that two major conditions of successful shared decision-making are met: minimisation of cognitive bias and complete information.

Coping strategies in relation to negative work events and accommodations in employed multiple sclerosis patients.

BACKGROUND: Job loss is common in multiple sclerosis (MS) and is known to exert a negative effect on quality of life. The process leading up to job loss typically includes negative work events, productivity losses and a need for accommodations. By using active coping strategies job loss may be prevented or delayed. OBJECTIVE: Our goal was to examine negative work events and accommodations in relation to coping strategies in employed relapsing-remitting MS patients. METHODS: Ninety-seven MS patients (77% females; 21-59 years old) completed questionnaires concerning the patient's work situation, coping strategies, demographics, physical, psychological and cognitive functioning. Forward binary logistic regression analyses were conducted to examine coping strategies and other (disease) characteristics predictive of reported negative work events and accommodations. RESULTS: Nineteen per cent of the employed MS patients reported one or more negative work events, associated with a higher use of emotion-oriented coping and more absenteeism. Seventy-three per cent reported using one or more work accommodations, associated with a higher educational level and more presenteeism. MS patients reporting physical changes to the workplace employed more emotion-oriented coping, while flexible scheduling was associated with task-oriented coping. CONCLUSION: Emotion-oriented and task-oriented coping strategies are associated with negative work events and the use of accommodations.

Cognitive impairment in multiple sclerosis.

Cognitive impairment occurs in 40-65% of multiple sclerosis (MS) patients, typically involving complex attention, information processing speed, (episodic) memory and executive functions. It is seen in the subclinical radiologically isolated syndrome, clinically isolated syndrome, and all phases of clinical MS. In pediatric-onset MS cognition is frequently impaired and worsens relatively rapidly. Cognitive impairment often affects personal life and vocational status. Depression, anxiety and fatigue aggravate symptoms, whereas cognitive reserve partially protects. Cognitive dysfunction correlates to brain magnetic resonance imaging (MRI) lesion volumes and (regional) atrophy, and degree of and increase in MRI abnormalities predict further worsening. Experimental MRI indicates a crucial role for (focal) cortical lesions and atrophy, abnormal cortical integrity, and early changes in normal appearing brain tissue. Functional MRI suggests compensatory reorganization and adaptation changes in neural activities. Screening tools are the Brief Repeatable Neuropsychological Battery, Symbol Digit Modalities Test and Audio Recorded Cognitive Screen. The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MS) is used for formal neuropsychological evaluation. What constitutes a clinically relevant change and how to optimally monitor cognition are issues to be settled. In relapsing-remitting MS timely and adequate disease modifying drug treatment may stabilize or possibly improve cognition. There is no evidence-based symptomatic drug treatment, nor are there optimal non-pharmacological approaches. Leisure activities enhance cognitive reserve. Cognitive rehabilitation in MS patients is still in its infancy. Cognitive behavioral therapy, exercise, and education programs are promising psychosocial interventions to improve coping and lessen cognitive symptoms.

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.

OBJECTIVE: To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. MATERIALS AND METHODS: We studied 80 patients with relapsing-remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. RESULTS: CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 +/- 0.21; SPMS, 0.10 +/- 0.15; controls, 0.021 +/- 0.020), but not in PPMS (0.061 +/- 0.052). CTTS index was higher in MS patients with elevated MNC or CSF-restricted oligoclonal IgG bands than in MS patients without these CSF findings. CONCLUSIONS: CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.

Neuromyelitis optica with clinical and histopathological involvement of the brain.

Diagnostic criteria for neuromyelitis optica (NMO) state that there should be no active disease outside the optic nerves and spinal cord. However, several cases have been described with symptomatic brain involvement. We describe an autopsy case of a patient with NMO and symptomatic involvement of the brain. The histopathology of the brain lesions is typical for NMO, with extensive macrophage infiltration, including perivascular accumulation of large numbers of eosinophils. This is the first case that clearly shows that in NMO, the histopathology of the brain lesions is identical to that of the lesions in the optic nerves and spinal cord.

No effect of intravenous immunoglobulins on cytokine-producing lymphocytes in secondary progressive multiple sclerosis.

Intravenous immunoglobulins (IVIG) have been effective in reducing multiple sclerosis (MS) disease activity and improving disability scores. However, the mechanism by which this beneficial effect is achieved remains unclear. An effect of IVIG on pro- and anti-inflammatory cytokines which are thought to play a role in the disease process - has been postulated in a number of animal and ex vivo studies. Hence, we performed a study on 34 patients with secondary progressive (SP) MS being treated with monthly IVIG or placebo for two years according to the protocol of the ESIMS study. Clinical outcome measures and cytokine production (interferon gamma, tumour necrosis factor alpha, interleukin-4 and -10) were recorded in all patients and compared with respect to the treatment group. Against our expectations, IVIG did not reduce the relapse rate or the progression of disability or cytokine production. Our data argue against an enduring immunomodulating effect of IVIG, at least in SPMS.

The role of helplessness as mediator between neurological disability, emotional instability, experienced fatigue and depression in patients with multiple sclerosis.

The aim of this study was to test, in patients with multiple sclerosis (MS), whether the concept of helplessness might improve the understanding of the relationship between disease severity (neurological impairment) and personality characteristics (emotional instability) on one hand, and depressive mood and fatigue severity on the other hand. Data pertain to 89 patients with a definite diagnosis of MS (Expanded Disability Status Scale [EDSS] ratings: 1-8). Helplessness, fatigue severity, depressive mood and emotional instability were rated with validated questionnaires. Model testing revealed that more neurological impairment and more emotional instability were associated with more helplessness, while higher levels of helplessness were associated with more fatigue and depressive mood. The initially observed direct relationship between EDSS and fatigue disappeared. Emotional instability also had a direct significant relationship with depressive mood, and depressive mood had only a small relationship with fatigue severity. The results indicated that helplessness affected both depressive mood and fatigue severity and that fatigue was not merely a symptom of depressive mood. The correlation between neurological impairment and fatigue severity was largely explained by the mediating effect of helplessness. These findings suggest that MS patients troubled by disabling fatigue might benefit from a psychological intervention targeting unfavourable illness cognitions.