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Symptom Management
Focus On Fatigue In Multiple Sclerosis


In providing care to people affected by multiple sclerosis (MS), there are three general areas of therapeutic intervention presently recognized: symptomatic therapies, treatments of clinical attacks or exacerbations (often represented as 'exasperations' by the patient), and the currently used immunomodulatory agents to alter the course of the disease.

Immunomodulatory agents have been referred to as the 'ABC' drugs, because they include the interferons, Avonex® and Betaseron®, and the random copolymer, Copaxone®. Various factors influence the choice of which agent is prescribed, including convenience, efficacy and side-effect profiles. In general, these agents can reduce the frequency of attacks, the accumulation of new lesions, and the progression of disability in this disease. Unfortunately, they are not perfect, and exacerbations may still occur, as well as variable symptoms from day to day.

The treatment of exacerbations continues to focus on the short-term use of steroids or their precursor, adrenocorticotrophic hormone (ACTH), which is available now as the synthetic molecule, cosyntropin. Such treatments are somewhat limited by a number of issues, which include immediate manifestations such as fluctuations in blood sugar, potassium levels, fluid retention and blood pressure, as well as longer term considerations, such as the risk of avascular necrosis from repeated use, particularly in those who are relatively immobile, and the potential for limited responsiveness.

In contrast, symptomatic treatments continue to play an important role in improving the day-to-day care of people with MS by addressing various symptoms that affect the quality of life and cause a greater level of disability if left unattended. The most frequent complaint in MS is fatigue. This has been attributed to a variety of potential causes, such as depression, overexertion, heat sensitivity, altered sleeping patterns, axonal dysfunction and a generalized lassitude. In truth, each of these factors may play a role, and therefore, the approach must be multifaceted, rather than hoping for a single effective modality.

Depression in MS is common. This clinical symptom reflects the presence, and is the clinical correlate, of white-matter lesions observed in the brain on the cerebral magnetic resonance imaging. The degree of depression documented is in direct proportion to the extent of white-matter lesions in the brain. This has been repeatedly shown by a number of investigative teams, the most widely recognized being the one led by Stephen Rao in Milwaukee. Although depression can contribute to the intensity of fatigue in MS, antidepressants do not always resolve the problem.

Overexertion has been recognized as a factor in the fatigue of MS as well. Individuals try to maintain their level of performance on a par with their activity levels before MS, they and are more likely to overdo activities in the course of their day. Simply resting a bit and pacing the activities during the day will go a long way to reducing this burden. Unfortunately, there may be practical issues that limit the ability to cut back, and the health care team must be sensitive to and supportive of these considerations. For example, asking a single, working mom to 'cut back' may not be reasonable.

Heat sensitivity is a common problem in a demyelinating disease like MS. Air conditioning is mandatory. Keeping the core body temperature down is the most useful way to alleviate heat-related fatigue. To accomplish this, I often suggest that the individual increase their intake of ice-cold liquids. The drawback to this suggestion is the impact on the bladder, as the patient already is experiencing urinary urgency and frequency. Nevertheless, a compromise can be achieved if the individual is aware of the impact of raised core body temperature on their performance level, and they can make an educated choice as to when they will increase their ice-cold fluid intake.

Altered sleeping patterns may play a prominent role in the daytime fatigue observed in people with MS. There are several factors that may contribute to this association. There is the potential for overlap between narcolepsy and MS because both disorders are associated with the DR2 locus. Common sleep disorders, such as sleep apnea, also occur in MS, especially in people who have gained weight because of decreased physical activity due to their MS. Periodic leg movements in sleep are also common in MS and can alter the normal sleep architecture, leading to more daytime fatigue. A detailed history addressing these issues is warranted. If necessary, sleep studies should be performed to investigate these potential problems further. Successful treatment of these issues requires awareness of their potential role in the bigger picture of managing symptomatic MS.

Axonal dysfunction in MS occurs from a variety of mechanisms. It reflects slowing of conduction in the demyelinated nerve fiber segment, redistribution of potassium channels along the newly exposed demyelinated nerve fiber segment, and frank destruction of nerve fibers by inflammation associated with the demyelinated lesion. Slowed conduction in demyelinated fibers is sometimes transient, because it improves, albeit imperfectly, with even limited degrees of remyelination, which may occur four to six weeks after the demyelinating lesion forms.

Redistribution of potassium channels has been addressed by Floyd Davis. He found the utility of 4-aminopyridine (4-AP) in blocking these potassium channels, consequently improving conduction in demyelinated fibers. Steroid use also accomplishes this, in part, but cannot be sustained because of problems with long-term use. Destruction of nerve fibers can be restricted by limiting lesions, which is being accomplished with the continued use of the immunomodulatory agents for the treatment of MS and the judicious use of steroids for limiting the extent of acute attacks.

The generalized lassitude occurring in MS has been more difficult to treat. It may reflect a biochemical change in neurotransmitter release in the brain as a consequence of demyelination or alterations in axonal function, or as a consequence of circulating inflammatory mediators in MS, such as elevated levels of tumor necrosis factor (TNF).

Various agents have empirically been tried to alleviate fatigue in MS. Amantadine, at a dose of 100 milligrams up to three times daily, has been used with limited success, reducing fatigue in as many as one-third of people on whom it was tried. However, it also may make people feel more tired.

Stimulants such as pemoline, methylphenidate and amphetamines, which have become more commonly used in neurology because of their role in treating attention deficit disorder (ADD), have been used as well. There is concern with their use because of the perception of potential for hepatotoxicity (pemoline) and abuse (methylphenidate and amphetamines). There is a place for these agents in treating this common problem, but there clearly is a need for a better-tolerated agent with less potential for abuse. The recent introduction of modafenil for the treatment of narcolepsy and excessive daytime sleepiness may fulfill this need.

Modafenil has been available in Europe for a number of years and is now available in the United States for the Food and Drug Administration-approved indications of treating narcolepsy and excessive daytime sleepiness. In off-label use, it has been used in people with MS who have fatigue and have been treated with one of the other agents without clinical benefit. The dosage used has been a 200-milligram tablet that is broken in half, with one half taken on arising, and the second half taken before 1 p.m., to avoid altering the ability to fall asleep later that day. In some, it is necessary to use a full 200-milligram dose at the same time intervals for effectiveness. There is, in general, a more uniform response of increased alertness without jitteriness. Further studies will be needed to determine the efficacy and utility of this agent for the fatigue problem of MS.

In people with MS who have fatigue that is resistant to all forms of drug therapy and who have an overwhelming sense of fatigue, I have tried plasmapheresis empirically. This is based on the rationale that circulating cytokines are contributing to their fatigue level. This treatment has often been used in conjunction with the nighttime administration of cosyntropin, 1 milligram over six hours per day for 10 days, with plasma exchange of 2 to 3 liters every other day.

The treatment of fatigue is an important component of the overall care of the person affected by MS, both physically and psychologically. It is often an invisible symptom, with no outward sign of its presence, and may, therefore, be misconstrued as lack of effort on the part of the patient. Controlling fatigue can help restore a 'can do' attitude on the part of individuals with MS, helping them to become victors rather than allowing them to be victims. As can be appreciated from the discussion of the many possible contributing factors associated with this problem, it often requires a multifaceted treatment approach. As our understanding of the basis for the different components of fatigue increases and becomes better understood, hopefully, so will our ability to treat this pervasive problem in MS.


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