Fatigue In Multiple Sclerosis

Fatigue is a common disabling symptom of Multiple Sclerosis (MS). It is often considered a state of exhaustion distinct from depressed mood or physical weakness.

Fatigue can be assessed by either self-report scales or performance-based measures; however, neither method captures all features of Fatigue. Fatigue in MS frequently leads to unemployment.

It is associated with a sense of loss of control over one's environment, low positive affect, Psychological distress and Neurological impairment.

To date there is no reproducible NeuroImaging marker or biological correlate that has been identified.

Proposed pathological mechanisms of Fatigue in MS include Neuronal factors such as: dysfunction of PreMotor, Limbic, Basal Ganglia or HypoThalamic Areas; disruption of the NeuroEndrocrine Axis leading to low arousal; alteration in Serotoninergic Pathways; changes in NeuroTransmitter levels; and altered CNS functioning caused by a disruption of the Immune Response.

Treatment of Fatigue is best approached in a multidisciplinary fashion that incorporates NonPharmacological interventions as well as medication.

Amantadine and Modafinil are among the most commonly used medications for Fatigue associated with MS. Both medications have been studied with positive results in controlled clinical trials.

Additional research towards measurement and pathogenesis of Fatigue will hopefully lead to improved therapies.

Objectives
To determine the impact of personality characteristics on feelings of Fatigue in Multiple Sclerosis (MS) patients and to compare the results with the impact of bodily impairment.

Patients And Methods
Eighty patients with Definite MS (mean age 38.5 +/- 9.0 years, 62 females) were surveyed using questionnaires assessing Fatigue experience and personality traits (German Freiburg Personality Inventory-Revised; FPI-R) and by clinical examination assessing the Expanded Disability Status Scale.

Results
Increased levels of "Neuroticism", and "excitability" and decreased levels of "Extraversion" were found to relate independent of Fatigue scores (0.21 < beta < 0.52; 0.05 < P < 0.0001).

The impact of these personality traits on Fatigue (partial R2 ranging up to 0.32; 0.02 < P < 0.0001) was much higher than the impact of physical impairment (partial R2 ranging up to 0.04; not significant).

Conclusion
Our results support a psychological model of Fatigue in MS.

FPI-R-items over-weighted Somatic sources of the Fatigue syndrome in MS and may specifically relate to Fatigue experience in chronical disorders.

Although Fatigue is a common and troublesome symptom of Multiple Sclerosis (MS), its pathogenesis is poorly understood.

In this study, we used functional Magnetic Resonance Imaging (fMRI) to test whether a different pattern of movement-associated Cortical and SubCortical activations might contribute to the development of Fatigue in patients with MS.

We obtained fMRI during the execution of a simple motor task with completely normally functioning hands from 15 MS patients with Fatigue (F), 14 MS patients without Fatigue (NF), and 15 sex- and age-matched healthy volunteers.

F and NF MS patients were also matched for major clinical and MRI variables. FMRI data were analyzed using statistical parametric mapping.

In all patients, severity of Fatigue was rated using the Fatigue Severity Scale (FSS). Compared to healthy subjects, MS patients showed more significant activations of the:

1. ContraLateral Primary SomatoMotor Cortex
2. ContraLateral Ascending Limb of the Sylvian Fissure
3. ContraLateral IntraParietal Sulcus (IPS)
4. ContraLateral Supplementary Motor Area
5. IpsiLateral and ContraLateral Cingulate Motor Area (CMA)

Compared to F MS patients, NF patients showed more significant activations of the IpsiLateral Cerebellar Hemisphere, the IpsiLateral Rolandic Operculum, the IpsiLateral PreCuneus, the ContraLateral Thalamus, and the ContraLateral Middle Frontal Gyrus.

In contrast, F MS patients had a more significant activation of the ContraLateral CMA.

Significant inverse correlations were found between FSS scores and relative activations of the ContraLateral IPS (r = -0.63), IpsiLateral Rolandic Operculum (r = -0.61), and Thalamus (r = -0.62).

This study provides additional evidence that Fatigue in MS is related to impaired interactions between functionally related Cortical and SubCortical Areas.

It also suggests that fMRI might be a valuable tool to monitor the efficacy of treatment aimed at reducing MS-related Fatigue.

(c)2002 Elsevier Science (USA).

Fatigue is a very common symptom of Multiple Sclerosis (MS). Theoretically, Fatigue may be related to NeuroModulation by soluble products of the AutoImmune process or by disruption of Central Nervous System Pathways necessary for sustained activity, but little empirical evidence supports these possibilities.

Amantadine, Pemoline, and Modafanil improved Fatigue in placebo-controlled clinical trials, but these studies all had significant limitations.

Difficulty measuring Fatigue has impeded studies of its characteristics, mechanisms, and therapeutics. Most studies have relied on self-report questionnaires.

These may be inappropriate, however, because they can be easily confounded by other symptoms of MS, they are entirely subjective, and they require patients to make difficult retrospective assessments.

Studies of Fatigue would be improved by including measures of more rigorously defined, quantifiable components of Fatigue.

For example, motor Fatigue can be measured as the decline in strength during sustained muscle contractions.

Cognitive Fatigue can be measured as the analogous decline in Cognitive performance during tasks requiring Sustained Attention.

Lassitude is defined as a subjective sense of reduced energy, and it can be measured with the use of a visual analog diary.

These measures provide reproducible results and demonstrate significant differences between MS patients and healthy controls.

Dividing Fatigue into these components can provide objective assessments that are less likely to be confounded by other symptoms of MS, such as Weakness, Spasticity, Cognitive Impairment, and Depressed Mood.

Background
Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants.

Results of a placebo-controlled study showed it to improve Fatigue in Multiple Sclerosis (MS) at a dose of 200 mg daily, but not at a dose of 400 mg daily.

Objective
To establish the efficacy, safety and appropriate dose of Modafinil in the treatment of Fatigue and sleepiness in patients with Multiple Sclerosis.

Method
A total of 50 patients diagnosed with MS (mean age 40.4 +/- 10.3 years, 30 females/20 males; MS type: 36 Relapsing/Remitting, 1 Primary/Progressive, 13 Secondary/Progressive; mean disability level 3.8 +/- 1.5 on the Kurtzke EDSS) and complaining of chronic Fatigue were enrolled in a prospective 3-month, two-center, open-label study.

Efficacy was evaluated with the Fatigue Severity Scale (FSS, score range 0-42), the Epworth Sleepiness Scale (ESS, score range 0-24) and by subjective patient appraisal of change of Fatigue, quality of life and overall satisfaction with treatment.

Adverse effects (AEs) were recorded throughout the study. Treatment was started with a single daily dose of 100 mg in all patients.

In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg.

Results
Three patients discontinued Modafinil because of AEs (nervousness, dizziness).

Two patients (4 %) were treated with 50 mg, 25 (50 %) with 100 mg, 21 (42 %) with 200 mg and 2 (4 %) with 300 mg daily.

No patient required 400 mg daily. Mean FSS scores were 30.3 +/- 8.5 at baseline and 25.4 +/- 3.7 at 3 months (p < 0.0001).

Mean ESS scores were 9.7 +/- 3.9 at baseline and 4.9 +/- 2.9 at 3 months (p < 0.0001). Self-appraisal of change of Fatigue showed clear improvement in 41 patients (87.2 %), some improvement in 4 (8.5 %) and no change in 2 (4.3 %).

Overall clinical condition was clearly improved in 43 patients (91.5 %), somewhat improved in 1 patient (2.1 %), and unchanged in 3 patients (6.4 %). No patient reported worsening of overall clinical condition.

Conclusions
Treatment with Modafinil significantly improves Fatigue and sleepiness and is well tolerated by patients with MS.

Unlike the higher dose regimen required in Narcolepsy, a low-dose regimen of Modafinil is effective in MS.

Objective
To assess the efficacy and safety of Modafinil for the treatment of Fatigue in Multiple Sclerosis (MS).

Methods
Patients aged 18-65 years with a diagnosis of MS, a stable disability level < or = 6 on the Kurtzke Extended Disability Status Scale (EDSS).

And a mean score > 4 on the Fatigue Severity Scale (FSS) were eligible for the 9 week, single blind, phase 2, two center study.

Exclusion criteria included a diagnosis of Narcolepsy, Sleep Apnea, or clinically significant major systemic disease and recent use of medications affecting Fatigue.

All patients, who remained blinded for the treatment regimen, received placebo during weeks 1-2, 200 mg/day Modafinil during weeks 3-4, 400 mg/day Modafinil during weeks 5-6, and placebo during weeks 7-9. Safety was evaluated by unblinded investigators.

Efficacy was evaluated by self rating scales, using the FSS, the Modified Fatigue Impact Scale (MFIS), a Visual Analogue Scale for Fatigue (VAS-F), and the Epworth Sleepiness Scale (ESS). Adverse events were recorded.

Results
Seventy two patients (MS type: 74% Relapsing/Remitting; 7% Primary/Progressive; 19% Secondary/Progressive) received treatment.

After treatment with 200 mg/day Modafinil for 2 weeks, a significant improvement in Fatigue versus placebo run in was demonstrated.

Mean scores after treatment with 200 mg/day Modafinil were: FSS, 4.7 versus 5.5 for placebo (p< 0.001); MFIS, 37.7 versus 44.7 (p< 0.001); and VAS-F, 5.4 versus 4.5 (p=0.003).

Fatigue scores for 400 mg/day Modafinil were not significantly improved versus placebo run in.

Mean ESS scores were significantly improved (p< 0.001) with 200 mg/day Modafinil (7.2) and 400 mg/day (7.0) versus the score at baseline (9.5).

Serious adverse events were not found at either dose. The most common adverse events were Headache, Nausea, and Asthenia. Sixty five patients (90%) completed the study.

Conclusions
These data suggest that 200 mg/day Modafinil significantly improves Fatigue and is well tolerated in patients with MS.

Comment in:
1. J Neurol NeuroSurg Psychiatry. 2002 Feb;72(2):150

Objectives
The aim was to measure changes in walking patterns and self rated Fatigue in people with Multiple Sclerosis (MS) compared with age matched control subjects, from the morning to the afternoon within a single day.

Methods
Fourteen patients with MS and the same number of matched control subjects performed four 10 m gait trials at their preferred walking speed at 10 00 am and then again at 3 00 pm on the same day.

Gait speed, stride length, cadence, and the percentage of the gait cycle spent in double limb support were measured using a foot switch stride analyzer.

Patients with MS also self rated their Fatigue levels in the morning and afternoon using an 11 point scale.

Results
Compared with control subjects, patients walked very slowly, with reduced stride length and around twice as much variability in gait performance.

Although self rated Fatigue significantly increased from the morning to the afternoon, walking patterns remained consistent in both groups over the course of the day.

Conclusions
These findings imply that mechanisms controlling locomotion are separate from those regulating perceived Fatigue.

Objective measures of performance, rather than self report, should be used to monitor change in patients with Multiple Sclerosis.

Background
Modafinil is a unique wake-promoting agent that is chemically distinct from traditional stimulants. Results of a placebo-controlled study showed it to improve Fatigue in Multiple Sclerosis (MS) at a dose of 200 mg daily, but not at a dose of 400 mg daily.

Objective
To establish the efficacy, safety and appropriate dose of Modafinil in the treatment of Fatigue and sleepiness in patients with Multiple Sclerosis.

Method
A total of 50 patients diagnosed with MS (mean age 40.4 ± 10.3 years, 30 females/20 males; MS type: 36 Relapsing/Remitting, 1 Primary/Progressive, 13 Secondary/Progressive; mean disability level 3.8 ± 1.5 on the Kurtzke EDSS) and complaining of chronic Fatigue were enrolled in a prospective 3-month, two-center, open-label study.

Efficacy was evaluated with the Fatigue Severity Scale (FSS, score range 0-42), the Epworth Sleepiness Scale (ESS, score range 0-24) and by subjective patient appraisal of change of Fatigue, quality of life and overall satisfaction with treatment.

Adverse effects (AEs) were recorded throughout the study. Treatment was started with a single daily dose of 100 mg in all patients. In non-responders the dose was increased by 100 mg increments up to a maximum daily dose of 400 mg.

Results
Three patients discontinued Modafinil because of AEs (Nervousness, Dizziness). Two patients (4 %) were treated with 50 mg, 25 (50 %) with 100 mg, 21 (42 %) with 200 mg and 2 (4 %) with 300 mg daily. No patient required 400 mg daily.

Mean FSS scores were 30.3 ± 8.5 at baseline and 25.4 ± 3.7 at 3 months (p < 0.0001). Mean ESS scores were 9.7 ± 3.9 at baseline and 4.9 ± 2.9 at 3 months (p < 0.0001).

Self-appraisal of change of Fatigue showed clear improvement in 41 patients (87.2 %), some improvement in 4 (8.5 %) and no change in 2 (4.3 %).

Overall clinical condition was clearly improved in 43 patients (91.5 %), somewhat improved in 1 patient (2.1 %), and unchanged in 3 patients (6.4 %). No patient reported worsening of overall clinical condition.

Conclusions
Treatment with Modafinil significantly improves Fatigue and sleepiness and is well tolerated by patients with MS. Unlike the higher dose regimen required in Narcolepsy, a low-dose regimen of Modafinil is effective in MS.

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 Positron-Emission Tomography and correlations between Fatigue and Magnetic Resonance Imaging lesion burden support this hypothesis.

Some recent studies also suggest that ProInflammatory Cytokines contribute to the sense of tiredness.

No specific treatments are available. Management strategies include medications, exercise, and behavioral therapy; in most cases a combined approach is appropriate.

Although different factors are probably involved in the Etiology of Fatigue in Multiple Sclerosis patients, no definite mechanism has been proposed.

We have proposed that Fatigue is a complex symptom that includes three clinical different entities (Asthenia, Fatigability and Worsening of symptoms with effort).

The goal of this study is to demonstrate if there is a peculiar mechanism for each of the different varieties of Fatigue. A control sample of 155 patients (105 women, 50 men) with clinically definite MS was studied.

Fatigue was measured using the Fatigue Descriptive Scale (FDS) and the Fatigue Severity Scale (FSS). Treatment, Depression, Anxiety, Sleep and Cellular Immune status were studied too.

Fatigue was a symptom in 118 patients (76.13%); 26 patients (22.03%) described it as asthenia (Fatigue at rest); 85 patients (72.03%) as Fatigability (Fatigue with exercise), and seven patients (5.9%) as worsening of symptoms.

The severity of Pyramidal involvement was significantly more severe in patients suffering from Fatigue; some Immunological parameters were associated with Fatigue as well.

The discriminant analysis of the data shows that some of the ImmunoActivation parameters are associated with Asthenia (F=21.5, P< 0.001), and Pyramidal Tract involvement is associated with Fatigability (F=10.5, P< 0.001).

Sleep Disorders, Anxiety and Depression were linked with Fatigue in a few patients. No relationship with treatment was proven.

In conclusion, Fatigue in MS seems to be a heterogeneous entity. Asthenia and Fatigability may be different clinical entities.

Certain Immunoactivation parameters correlate with the presence of Asthenia while Pyramidal involvement is associated with Fatigability.

Fatigue is a prominent disabling symptom in a variety of medical and Neurologic disorders.

To facilitate research in this area, we developed a Fatigue Severity Scale, subjected it to tests of internal consistency and validity, and used it to compare Fatigue in two chronic conditions: Systemic Lupus Erythematosus and Multiple Sclerosis.

Administration of the Fatigue Severity Scale to 25 patients with Multiple Sclerosis, 29 patients with Systemic Lupus Erythematosus, and 20 healthy adults revealed that the Fatigue Severity Scale was internally consistent.

Correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in Fatigue over time.

Fatigue had a greater deleterious impact on daily living in patients with Multiple Sclerosis and Systemic Lupus Erythematosus compared with controls.

The results further showed that Fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate Fatigue that accompanies Multiple Sclerosis from Fatigue that accompanies Systemic Lupus Erythematosus.

This study demonstrates:

1. The clinical and research applications of a scale that measures Fatigue severity and
2. Helps to identify features that distinguish Fatigue between two chronic medical disorders

Background
As a symptom of Multiple Sclerosis (MS), Fatigue is difficult to manage because of its unknown etiology, the lack of efficacy of the drugs tested to date and the absence of consensus about which would be the ideal measure to assess Fatigue.

Objective
Our aim was to assess the frequency of Fatigue in a sample of MS patients and healthy controls (HC) using two Fatigue Scales.

The Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS) with physical, Cognitive and Psychosocial subscales.

We also studied the relationship Fatigue has with Depression, disability and Interferon-ß.

Methods
Three hundred and fifty-four individuals (231 MS patients and 123 HC) were included in this cross-sectional study.

Fatigue was assessed using the FSS and MFIS. Depression was measured by the Beck Depression Inventory (BDI), and disability by the Expanded Disability Status Scale (EDSS).

A status of Fatigue was considered when the FSS > or =5, of Non-Fatigue when the FSS < or =4, and scores between 4.1 and 4.9 were considered doubtful Fatigue cases.

Results
Fifty-five percent of MS patients and 13% of HC were fatigued. The global MFIS score positively correlated with the FSS in MS and HC (r =0.68 for MS and r =0.59 for HC, p < 0.0001).

Nonetheless, the MFIS physical subscale showed the strongest correlation score with the FSS (r =0.75, p < 0.0001).

In addition, a prediction analysis showed the physical MFIS subscale to be the only independent predictor of FSS score (p < 0.0001), suggesting other aspects of Fatigue, as Cognition and PsychoSocial functions, may be explored by the FSS to a lesser extent.

Depression also correlated with Fatigue (r =0.48 for the FSS and r =0.7 for the MFIS, p < 0.0001) and, although EDSS correlated with Fatigue as well, the scores decreased after correcting for Depression.

Interferon-ß showed no relationship with Fatigue.

Conclusions
Fatigue is a frequent symptom found in MS patients and clearly related with Depression. Each Fatigue Scale correlates with one another, indicating that they are measuring similar constructs.

Nevertheless, spheres of Fatigue as Cognition and PsychoSocial functions are probably better measured by the MFIS, although this hypothesis will need to be confirmed with appropriate Psychometrical testing.