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Fatigue, which may be defined as an overwhelming sense of tiredness, lack of energy, and feelings of exhaustion in excess of what might be expected for the associated level of activity, is thought to be the most common and perhaps the most disabling symptom in MS. Fatigue must be distinguished from depression, although not infrequently these two conditions coexist and aggravate each other. Practical issues such as a poor sleep pattern resulting from painful spasms or nocturia also need to be considered. Attempts have been made to distinguish the different types of fatigue in MS, for example, that which follows activity, chronic fatigue, and fatigue associated with a clinical relapse. The underlying mechanisms remain unclear. A range of measures from generic to disease-specific are currently available to evaluate this difficult symptom, some of which are shown in Table 4-1.
Fatigue management programmes are the mainstay in the management of this symptom—identifying fatigue as a relevant and disabling symptom, and examining daily routine to determine how best to minimize its impact, including energy conservation and work simplification techniques. A graded exercise programme has been advocated, although there are limited data to support its usefulness. A study that evaluated the role of aerobic exercise, while showing benefit in maximum aerobic capacity and isometric muscle strength, did not show an effect on fatigue as measured by the Fatigue Impact Scale. However, two recent studies decreased fatigue, a secondary outcome, as measured by the Short Form-36 (SF-36) with exercise.
Medication for Fatigue
Three oral agents, amantadine, an antiviral agent that also has anti-parkinsonian effects, pemoline, a CNS stimulant, and modafinil, an agent effective in narcolepsy, have been studied in the management of fatigue. A small, cross-over, randomized, control trial of amantadine showed that it had a significant effect on fatigue in relation to placebo. In contrast, a small, randomized, cross-over trial of 40 patients comparing pemoline and placebo showed no significant effect from pemoline, which was poorly tolerated in 25 percent of patients.
Table 4-1: Levels of Measurement and Examples of Generic and MS-Specific Measures
| Table 4-1: Levels of Measurement and Examples of Generic and MS-Specific Measures | | | Outcome Measures | | Term | Definition | Generic | MS-Specific | | Impairment | Clinical signs/symptoms resulting from nervous system damage | | Functional system of EDSS
MS Functional Composite Scale (T25, FW, 9PH, PASAT) | | Disability | Limitations on activities of daily living from neurological impairment | Barthel Index (BI)
Functional Independence Measure/Functional Assessment Measure (FIM/FAM) | Guy's Neurological Disability Scale (GNDS)
MS Impairment Scale (MSIS) | Handicap
(Participation) | Social and environmental consequences from impairment and disability | London Handicap Scale (LHS) | Environmental Status Scale (ESS) | | Health-related quality of Life (Qol) | The satisfaction that people have with health related dimensions of life, from their own perspective | Short Form-36 (SF-36)
Nottingham Health Profile
Sickness Impact Profile | MS Impact Scale, MS Walking Scale,MSQol54*, Functional Assessment of MS Qol Instrument (FAMS)*, MS Qol Inventory (MSQLI)*, Functional Assessment of MS | | Emotional well-being | | General Health Questionnaire | | | Symptoms e.g., fatigue | Overwhelming sense of tiredness or exhaustion in excess of what might be expected from level of activity | Fatigue Impact Scale
Fatigue Severity Scale | MS-Specific Fatigue Scale | | Spasticity | Velocity dependent increase in tonic stretch reflex | Ashworth Scale | MS Spasticity Scale (MSSS-88) | | * Developed from existing scales |
In the most comprehensive study to date, pemoline and amantadine were compared with placebo. The placebo group received advice on fatigue management. A range of outcome measures, including the generic Fatigue Severity Scale and the six-item MS-Specific Fatigue Scale, was used.
Amantadine showed a benefit over placebo in the MS Specific Fatigue Scale but not the Fatigue Severity Scale. No benefit was seen with pemoline. On the basis of this study, the authors suggested that amantadine should be the first-line medication for use in MS-related fatigue, although they did caution that a placebo response from either agent is a strong possibility. More recently, encouraging results have been reported from the use of modafinil. In a single-blind crossover study of 72 patients with MS, significant benefit was seen with both 200 mg and 400 mg doses with no added benefit from the higher dose and no serious side effects.
Another agent that holds some promise, although it has never been comprehensively evaluated in fatigue, is the potassium channel blocker 4-aminopyridine. This drug was comprehensively evaluated in a randomized, placebo-controlled, double-blind, cross-over study involving 70 patients with MS. A significant effect on the Expanded Disability Status Scale (EDSS) was seen in the treated group, although side effects, which included paresthesias, dizziness, and gait instability, were common. Longer follow-up has suggested that it may be useful in fatigue, although the occasional occurrence of an epileptic seizure (usually associated with high levels) remains a concern. A recent double-blind, placebo-controlled, randomized, crossover trial involving 54 patients with progressive MS only showed an effect on the Fatigue Severity Scale in those with high serum levels of 4-AP. A number of small studies of 3-4 diaminopyridine have also suggested some potential benefit. Epileptic seizures can also result from these therapies. It has also been suggested that the disease modifying agents may improve fatigue most notably glatiramer acetate, though this remains to be proven.
A comprehensive strategy is contained within the evidence based guidelines on fatigue management produced by the MSCCPG.
In the view of the Committee, fatigue remains one of the most disabling symptoms in MS, and drug therapy plays a relatively minor role in comparison to more practical approaches to its management.
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