Pharmacologic Therapy for Multiple Sclerosis–Related Fatigue

Fatigue is the most common symptom of multiple sclerosis and is perhaps the symptom with the most devastating impact on patient well-being. It is reported by 75% to 95% of individuals, and more than half describe it as the worst symptom of the disease. The mechanisms underlying the development of fatigue remain unclear; although fatigue is believed to be a primary symptom of MS (ie, related to the demyelinating processes of the disease), fatigue may also occur secondarily to factors such as sleep disturbances, depression, or the effects of medications. The highly variable presentation of MS and the number of agents used for disease modification and symptom management make it important for potential contributors to MS-related fatigue to be identified and managed appropriately. If fatigue continues despite elimination or adequate management of secondary causes, pharmacologic therapy may be required. Several agents have been reported to improve MS-related fatigue; however, only three have been investigated in controlled trials. Amantadine has been studied in several small controlled trials, and appears to be effective in one quarter to one third of those with mild-to-moderate fatigue. It has shown efficacy on a number of scales, including the Visual Analog Scale for Fatigue (VAS-F) and the MS-Specific Fatigue Scale (MS-FS). The central nervous system (CNS) stimulant pemoline has demonstrated limited benefit in clinical trials and is often poorly tolerated, especially in higher doses. Recently, the wake-promoting agent modafinil has been shown to significantly improve MS-related fatigue on a number of commonly used fatigue assessment scales, including the Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS).

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Fatigue Is Associated with Poor Sleep in People with Multiple Sclerosis and Cognitive Impairment

Multiple Sclerosis International ◽

10.1155/2014/872732 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 5

Author(s):

Michelle H. Cameron ◽

Vanessa Peterson ◽

Eilis A. Boudreau ◽

Ashley Downs ◽

Jesus Lovera ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cognitive Impairment ◽

Sleep Quality ◽

Cross Sectional Study ◽

Poor Sleep ◽

Common Symptom ◽

Cross Sectional ◽

Impact Scale ◽

Quality Sleep ◽

Fatigue Severity

Background. Fatigue is the most common symptom in people with multiple sclerosis (MS). Poor sleep also occurs in this population.Objective. The objective of this study was to determine the relationship between fatigue and sleep quality in people with MS and cognitive impairment.Method. This cross-sectional study assessed relationships among fatigue, assessed with the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), sleep quality assessed with the Pittsburg Sleep Quality Index (PSQI), and demographics in 121 people with MS and cognitive impairment.Results. Fatigue was significantly correlated with poor sleep quality (MFIS:F=15.60,P<0.01; FSS:F=12.09,P<0.01). FSS scores were also significantly correlated with the PSQI subscore for daytime dysfunction and MFIS scores were significantly correlated with disability, age, and the PSQI subscores for sleep quality, sleep duration, and daytime dysfunction.Conclusions. This study demonstrates a relationship between fatigue and sleep quality in individuals with MS and cognitive impairment.

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Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis–related fatigue

Multiple Sclerosis Journal ◽

10.1177/1352458520936226 ◽

2020 ◽

pp. 135245852093622

Author(s):

Kathryn C Fitzgerald ◽

Bridget Morris ◽

Aurash Soroosh ◽

Alexandra Balshi ◽

Dermot Maher ◽

...

Keyword(s):

Multiple Sclerosis ◽

Low Dose ◽

Controlled Trial ◽

Common Symptom ◽

Double Blind ◽

Mixed Effect ◽

Ketamine Infusion ◽

Impact Scale ◽

Post Infusion ◽

Fatigue Severity

Background: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. Objective: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. Methods: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. Results: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (−0.10 point; 95% confidence interval (CI): −0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (−5.2 points; 95% CI: −10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (−13.5 point; 95% CI: −25.0, −1.98; p = 0.04). Conclusions: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

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Relationship between Fatigue and Physical Activity in a Polish Cohort of Multiple Sclerosis Patients

Medicina ◽

10.3390/medicina56120726 ◽

2020 ◽

Vol 56 (12) ◽

pp. 726

Author(s):

Michalina Rzepka ◽

Mateusz Toś ◽

Michał Boroń ◽

Katarzyna Gibas ◽

Ewa Krzystanek

Keyword(s):

Physical Activity ◽

Multiple Sclerosis ◽

Severe Depression ◽

Neurological Impairment ◽

Common Symptom ◽

Metabolic Equivalents ◽

Impact Scale ◽

Relapsing Remitting ◽

Fatigue Severity ◽

Multiple Sclerosis Patients

Background and objectives: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS). It can be defined as a subjective lack of physical and mental energy. The aim of this study was to evaluate the frequency and severity of fatigue in patients with MS and its relationship with overall physical activity and disease-related disability. Materials and Methods: The study included 100 patients with a clinical relapsing-remitting form of MS. Patients with severe depression were excluded. Neurological impairment was rated using the Expanded Disability Status Scale (EDSS). Fatigue was assessed using the Modified Fatigue Impact Scale (MFIS) and the Fatigue Severity Scale (FSS), with FSS scores greater than 36 indicating patients with fatigue. Physical activity was evaluated with the International Physical Activity Questionnaire (IPAQ) and categorized on three levels: low, moderate, and high, using standard metabolic equivalents (MET). Results: The average FSS and MFIS scores were (mean ± SD) 31.3 ± 15.2 and 30.1 ± 17.0, respectively. The mean EDSS score was 2.5 ± 1.5. 42%. Patients were classified as fatigued based on FSS. Fatigued patients had higher mean EDSS scores than non-fatigued (3.0 ± 1.6 vs. 2.2 ± 1.4, respectively, p = 0.002). Low, moderate, and high levels of physical activity were reported in 35%, 20%, and 45% of patients, respectively. Higher scores of fatigue in FSS and MFIS were inversely correlated with the intensity of physical activity (r = −0.38, p < 0.001 and r = −0.33, p < 0.001, respectively). Conclusions: In patients with MS, fatigue is a common symptom. Patients with lower physical activity and greater MS-related disability have a higher severity of fatigue, which negatively affects cognitive, psychosocial, and physical functioning.

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Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters

Multiple Sclerosis Journal ◽

10.1191/1352458502ms839oa ◽

2002 ◽

Vol 8 (6) ◽

pp. 523-526 ◽

Cited By ~ 338

Author(s):

P Flachenecker ◽

T Kümpfel ◽

B Kallmann ◽

M Gottschalk ◽

O Grauer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Physical Disability ◽

Rating Scales ◽

Disease Duration ◽

Correlation Coefficients ◽

Clinical Activity ◽

Impact Scale ◽

Fatigue Severity ◽

Underlying Mechanisms ◽

Definition Of

Objectives: Fatigue is one of the most common, yet poorly defined, disabling symptoms in patients with multiple sclerosis (MS). To delineate more clearly the frequency and type of fatigue, we first compared four widely used fatigue scales in consecutive MS patients. Secondly, to further clarify the nature of fatigue, we investigated its relation to physical disability, course of the disease, immunotherapy, and depression. Patients and Methods: Between February and September 2000, 151 consecutive MS patients entering our outpatient clinic (94 relapsing-remitting, 50 secondary progressive, and 7 primary progressive patients; mean age 29.0-7.3 years, mean disease duration 9.9-6.7 years, median EDSS 3.5) filled in a standardized questionnaire including four fatigue scales - Fatigue Severity Scale (FSS), MS-specific FSS (MFSS), Modified Fatigue Impact Scale (MFIS), and Visual Analogue Scale (VAS). Patients were included in the ‘MS-related fatigue group’ (MS-F) when they stated in the questionnaire that fatigue: 1) is one of their three most disabling symptoms; 2) occurs daily or on most of the days; and 3) limits their activities at home or at work. Patients fulfilling none of these criteria were classified as ‘MS-related nonfatigue group’ (MS-NF). Depression was measured by Beck’s Depression Inventory (BDI). Results: Although all scales showed significant differences between MS-F and MS-NF, correlation between these scales was, at best, moderate (correlation coefficients ranging from 0.06 to 0.56). The most discriminative scales were FSS and MFIS, showing no overlap of the 10th and 90th percentiles for the MS-F and MS-NF groups, with cut-off values of 4.6 and 38, respectively. Depression (BDI≥18) was present in 24 of 148 patients who filled in the BDI (16%). FSS was significantly correlated with physical disability (r =0.33, p <0.0001) and BDI (r =0.41, p<0.0001), but not with age, disease duration, clinical activity, and treatment with interferon-b. In multivariate analysis, however, only BDI independently predicted fatigue. Conclusions: The association of fatigue and depression suggests that there might be either common underlying mechanisms or interdependence by a cause-and-effect relationship that requires further investigation. The weak correlation within various fatigue scales is best explained by the fact that fatigue is a multidimensional symptom and, therefore, the available tests measure and weight different aspects of fatigue. Our findings underline the necessity for a more exact definition of fatigue and the development of more valid tools if these are to be used to evaluate treatments.

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Reduction in Fatigue Symptoms Following the Administration of Nutritional Supplements in Patients with Multiple Sclerosis

Medical Sciences ◽

10.3390/medsci9030052 ◽

2021 ◽

Vol 9 (3) ◽

pp. 52

Author(s):

Pasquale Ferorelli ◽

Francesco Antonelli ◽

Anna Shevchenko ◽

Carlo Mischiati ◽

Manfred Doepp ◽

...

Keyword(s):

Multiple Sclerosis ◽

Dietary Supplements ◽

Nutritional Supplements ◽

Therapeutic Interventions ◽

Inflammatory Parameters ◽

Impact Scale ◽

Fatigue Severity ◽

The Individual ◽

Two Parameters ◽

The Impact

Despite recent advances in immune-modulatory drugs, pharmacological therapies have been proven ineffective in severe presentations of multiple sclerosis (MS), including secondary progressive MS. At present, therapeutic interventions’ performance is primarily focused on ameliorating symptoms to improve the patient’s quality of life (QOL). Among complementary treatments, nutrition has been considered a decisive factor to control symptoms and enhance the wellness of MS patients. Although no special diets are associated with MS, the impact of diet and dietary supplements on the course of progressive forms of the disease has been studied during the last few years. Fatigue is among the most common and disabling symptoms reported by MS patients. Fatigue has been defined in the Multiple Sclerosis Council for Clinical Practice Guidelines (MSCCPG, 1998) as a “subjective lack of physical and/or mental energy that the individual perceives as an interference with habitual and desired activities”. This study aimed to compare the psychometric functioning of the “Fatigue Severity Scale” (FSS) and the “Modified Fatigue Impact Scale” (MFIS) in our sample of people with MS. Specifically, during chronic treatment, the change in these two parameters with two vitamin-rich dietary supplements (Citozym® and Ergozym®) was evaluated. The impact of these nutritional supplements revealed differences in antioxidant and anti-inflammatory parameters among the volunteers in the treatment group, with a subsequent improvement in fatigue. In conclusion, the results obtained have confirmed the effectiveness of complementary nutritional therapies, evaluated essentially based on hematological biomarkers, through which it is possible to act on disability to improve the QOL of MS patients.

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Fatigue after a first attack of suspected multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458517709348 ◽

2017 ◽

Vol 24 (7) ◽

pp. 974-981 ◽

Cited By ~ 3

Author(s):

Roos M van der Vuurst de Vries ◽

Jan JA van den Dorpel ◽

Julia Y Mescheriakova ◽

Tessel F Runia ◽

Naghmeh Jafari ◽

...

Keyword(s):

Multiple Sclerosis ◽

Depression Scale ◽

Common Symptom ◽

Disability Status ◽

Definite Multiple Sclerosis ◽

Fatigue Severity ◽

Clinically Definite Multiple Sclerosis ◽

In Cis

Background: Fatigue is reported by more than 75% of multiple sclerosis (MS) patients. In an earlier study, we showed that fatigue is not only a common symptom in patients at time of clinically isolated syndrome (CIS; fatigued 46%) but also predicts subsequent diagnosis of clinically definite multiple sclerosis (CDMS). The course of fatigue after CIS is unknown. Objective: We aimed to explore the long-term course of fatigue after CIS. Methods: In this study, 235 CIS patients, aged 18–50 years, were prospectively followed. Patients filled in the Krupp’s Fatigue Severity Scale (FSS) and the Hospital Anxiety and Depression Scale (HADS) at baseline and annually. After reaching CDMS diagnosis, Expanded Disability Status Scale (EDSS) was obtained annually. Mixed-effects models were used to analyse longitudinal FSS measurements. Results: Fatigue at baseline was an independent predictor for CDMS diagnosis (hazard ratio (HR): 2.6, 95% confidence interval (CI): 1.6–4.4). The evolution of FSS was the same in CIS patients who remained monophasic and patients who were diagnosed with CDMS during follow-up. However, FSS increased by 0.86 units after reaching CDMS diagnosis ( p = 0.01). After this increase, the FSS course remained unaltered ( p = 0.44). Conclusion: Fatigue, which is often present at time of CIS, probably persists over time and increases after a second attack.

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Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment

Multiple Sclerosis Journal ◽

10.1191/1352458504ms1051oa ◽

2004 ◽

Vol 10 (4) ◽

pp. 462-468 ◽

Cited By ~ 48

Author(s):

Alfredo Romani ◽

Roberto Bergamaschi ◽

Elisa Candeloro ◽

Enrico Alfonsi ◽

Roberto Callieco ◽

...

Keyword(s):

Multiple Sclerosis ◽

Test Scores ◽

Rating Scale ◽

Symptomatic Treatment ◽

Cognitive Test ◽

Treatment Groups ◽

Impact Scale ◽

Relapsing Remitting ◽

Fatigue Severity ◽

Relapsing Remitting Multiple Sclerosis

Sixty relapsing-remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck’s Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.

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A longitudinal study on effects of a six-week course for energy conservation for multiple sclerosis patients

Multiple Sclerosis Journal ◽

10.1177/1352458507084649 ◽

2008 ◽

Vol 14 (4) ◽

pp. 500-505 ◽

Cited By ~ 38

Author(s):

C. Sauter ◽

K. Zebenholzer ◽

J. Hisakawa ◽

J. Zeitlhofer ◽

K. Vass

Keyword(s):

Multiple Sclerosis ◽

Sleep Quality ◽

Energy Conservation ◽

Fatigue Severity Scale ◽

Severity Scale ◽

Fatigue Management ◽

Impact Scale ◽

Fatigue Severity ◽

Fatigue Impact Scale

Objective Fatigue management and energy conservation are effective strategies to minimize fatigue in multiple sclerosis (MS). Sustained results have not yet been reported. Methods A fatigue management course was provided for 32 MS patients. They were tested prior to, directly after participation in the course and in a 7—9 month follow-up with the Fatigue Severity Scale, the MS-specific Fatigue Scale, the Modified Fatigue Impact Scale (MFIS), the Pittsburgh Sleep Quality Index and a self-rating scale for depression. The Expanded Disability Status Score (EDSS) and the MS functional composite (MSFC) were evaluated before and after participation in the course. Results The total score and the Cognitive and Physical subscores of the MFIS showed significant improvements on both points of time. Scores in the Fatigue Severity Scale, MS-specific Fatigue Scale and Psychosocial Fatigue Impact Scale did not improve significantly. MS functional composite and EDSS remained unchanged after six weeks of course participation. Subjective sleep quality improved directly after participation in the course and after 7—9 months. The depression score decreased significantly to a normal level at the end of training and in the 7—9 month follow-up. Conclusion Fatigue management enables MS patients to cope with their fatigue and energy more effectively. Follow-up evaluations showed stable results after 7—9 months. Multiple Sclerosis 2008; 14: 500—505. http://msj.sagepub.com

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Associations Between Fatigue and Disability, Functional Mobility, Depression, and Quality of Life in People with Multiple Sclerosis

International Journal of MS Care ◽

10.7224/1537-2073.2015-013 ◽

2016 ◽

Vol 18 (2) ◽

pp. 71-77 ◽

Cited By ~ 27

Author(s):

Hina Garg ◽

Steffani Bush ◽

Eduard Gappmaier

Keyword(s):

Quality Of Life ◽

Multiple Sclerosis ◽

Functional Mobility ◽

Common Symptom ◽

Timed Up And Go ◽

Predominant Symptom ◽

Impact Scale ◽

Scale Scores ◽

Study Participants

Background: Fatigue is a common symptom in people with multiple sclerosis (MS), but its associations with disability, functional mobility, depression, and quality of life (QOL) remain unclear. We aimed to determine the associations between different levels of fatigue and disability, functional mobility, depression, and physical and mental QOL in people with MS. Methods: Eighty-nine individuals with MS (mean [SD] disease duration = 13.6 [9.8] years, mean [SD] Expanded Disability Status Scale [EDSS] score = 5.3 [1.5]) and no concurrent relapses were retrospectively analyzed. Participants were divided into two groups based on five-item Modified Fatigue Impact Scale (MFIS-5) scores: group LF (n = 32, MFIS-5 score ≤10 [low levels of fatigue]) and group HF (n = 57, MFIS-5 score >10 [high levels of fatigue]). Results: Sixty-four percent of the sample reported high levels of fatigue. Compared with group LF, group HF demonstrated significantly (P < .05) greater impairments in the Timed Up and Go test, Activities-specific Balance Confidence scale, and 12-item Multiple Sclerosis Walking Scale scores; depression; and QOL but not in the EDSS scores, which were not significantly different between groups. Conclusions: Fatigue was found to be a predominant symptom in the study participants. Individuals reporting higher levels of fatigue concomitantly exhibited greater impairments in functional mobility, depression, and physical and mental QOL. Disability was not found to be related to level of fatigue. These findings can be important for appropriate assessment and management of individuals with MS with fatigue.

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Mindfulness-based interventions for mental well-being among people with multiple sclerosis: a systematic review and meta-analysis of randomised controlled trials

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-320165 ◽

2019 ◽

Vol 90 (9) ◽

pp. 1051-1058 ◽

Cited By ~ 10

Author(s):

Robert Simpson ◽

Sharon Simpson ◽

Nitish Ramparsad ◽

Margaret Lawrence ◽

Jo Booth ◽

...

Keyword(s):

Multiple Sclerosis ◽

Systematic Review ◽

Randomised Controlled Trials ◽

Meta Analysis ◽

Treatment Options ◽

Well Being ◽

Controlled Trials ◽

Medical Subject Headings ◽

Randomised Controlled ◽

Mental Well Being

ObjectiveImpairment of mental well-being (anxiety, depression, stress) is common among people with multiple sclerosis (PwMS). Treatment options are limited, particularly for anxiety. The aim of this study was to update our previous systematic review (2014) and evaluate via meta-analysis the efficacy of mindfulness-based interventions (MBIs) for improving mental well-being in PwMS.MethodsSystematic searches for eligible randomised controlled trials (RCTs) were carried out in seven major databases (November 2017, July 2018), using medical subject headings and key words. Studies were screened, data extracted, quality appraised and analysed by two independent reviewers, using predefined criteria. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Mental well-being was the primary outcome. Random effects model meta-analysis was performed, with effect size reported as standardised mean difference (SMD).ResultsTwelve RCTs including 744 PwMS were eligible for inclusion in the systematic review, eight had data extractable for meta-analysis; n=635. Ethnicity, socioeconomic status, comorbidity and disability were inconsistently reported. MBIs varied from manualised to tailored versions, lasting 6–9 weeks, delivered individually and via groups, both in person and online. Overall SMD for mental well-being (eight studies) was 0.40 (0.28–0.53), p<0.01, I2=28%; against active comparators only (three studies) SMD was 0.17 (0.01–0.32), p<0.05, I2 =0%. Only three adverse events were reported.ConclusionsMBIs are effective at improving mental well-being in PwMS. More research is needed regarding optimal delivery method, cost-effectiveness and comparative-effectiveness.PROSPERO registration numberCRD42018093171.

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