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Multiple Sclerosis Centers of Excellence

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Fatigue and MS A Medical Perspective

Lauren Krupp MD, Professor of Neurology and Psychology
State University of New York at Stony Brook
James Hunziker, MSN, ARNP
VA Puget Sound Health Care System-Seattle

What is fatigue?
How is MS fatigue different?
How can fatigue be measured?
Is measuring fatigue important?
Is there a cause for fatigue in MS?
What are non-MS causes of fatigue?
How is fatigue treated?
Is depression linked to fatigue?
What medications can also cause fatigue?
What are non-pharmacological treatments for fatigue? 
What medications are effective in treating fatigue?
Conclusion
For Patients

The following article is an edited excerpt from the live VA satellite broadcast program on Fatigue and MS that aired in April 2005. The program was transcribed, reviewed and edited for the MS website by James Hunziker, MSN, ARNP, MS Center of Excellence, West.

Multiple sclerosis (MS) is a chronic neurological disease that affects an estimated 2.5 million people around the world. Symptoms of multiple sclerosis are numerous. They vary from person to person and for the same person over time. One of the most common and disabling symptoms is fatigue. MS fatigue, also called MS lassitude, can significantly interfere with a person's ability to function at home and at work, and it is a major reason why people with MS have to leave the workforce early. We need to understand MS fatigue and strategies for coping so people with MS can live active and fulfilling lives.

What is fatigue?

Fatigue in MS patients is defined as an overwhelming sense of tiredness, lack of energy, or a feeling of exhaustion. It is distinct from weakness, and it is different from depression. For those of us without MS, we can best relate to it as a feeling we have when we get the flu and we are just rather wiped out. Moreover, that is what people with MS have to experience almost every day.

Fatigue has been studied in cancer, infections like Lyme disease, multiple sclerosis (of course), post-surgery, Parkinson's disease, and systemic lupus erythematosus and other autoimmune diseases - but it is because of the research done in MS that we are able to understand fatigue in these other conditions.
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How is MS fatigue different?

Fatigue in MS is different from other diseases in that it is much more common. It is seen in about 80 to 90 percent of patients, and almost two-thirds of people with MS feel their fatigue on a daily basis. Fatigue in MS can also be made worse by heat. This symptom can actually predate other symptoms of MS.
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How can fatigue be measured?

There is a variety of different scales for measuring MS fatigue. The most commonly used scale is the Fatigue Severity Scale. Other scales are the Fatigue Impact Scale, the Fatigue Scale, the Profile of Mood States, and the Visual Analogue Measure. There are also scales for home use so patients (or their caregivers) can easily track and report changes. The home scales do have some drawbacks in that they are very subjective, and require a fair amount of insight on the part of the patient. (refer to the article on this website titled MS Self-report Questionnaires for the complete Fatigue Severity Scale)

An easier way of assessing fatigue is to take a more objective look at assessing fatigue by describing changes in function. This method focuses on changes in sustained functioning, sustained motor grip, or problems with sustained cognitive functioning and/or cognitive performance.
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Is measuring fatigue important?

An accurate measurement of fatigue is needed when deciding on the best treatment. The reason for this is what was found when studies were done looking at tests of attention and vigilance. When people with MS do these tests, they tend to deteriorate over a period in contrast to people without MS. When we look at studies of memory, the same thing happens. A person with MS cannot continue doing their memory tasks as well as somebody without MS. For example, someone without MS gets a chance to improve and learn from practice, and that does not seem to help the person with MS.
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Is there a cause for fatigue in MS?

We have looked at brain function using neurological measures and neuroimaging. These have helped us understand the basis for fatigue. Although we have not been able to find one specific location that we can point to which explains the fatigue of MS, we do know that there is not any association between where lesions lay, the number of lesions, and the severity of fatigue.

There are a number of neuroarousal studies that used neuroimaging techniques like MRI, CAT and PET scans. These studies found different parts of the brain lighting up when there's arousal happening or someone's paying attention and vigilant.

In addition, some of the newer techniques that have been applied in studies of fatigue in MS have shown some very interesting associations. Using a PET scan, people have seen that areas of glucose utilization are diminished in people with MS fatigue. Looking at MR spectroscopy, we've been able to show areas of axonal injury that seem to correlate with severe fatigue. Using T1 relaxation times, dysfunction in what would otherwise appear to be normal-appearing white matter seems to show up in those patients with more fatigue.
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What are non-MS causes of fatigue?

There are many other causes, including neuroendocrine and hypothalamic causes, motor system fatigue, and problems with the immune system. In terms of the motor causes, impaired drive from the motor cortex, decreased motor unit firing, inadequate motor unit recruitment, as well as impaired muscle metabolism all are important. In terms of the immune factors, we know that in MS (as well as in other diseases) when we use medications that are cytokines (like the interferons), many people report they have transient fatigue (or short-lived fatigue). Animal studies have shown that different cytokines when administered to animals can cause fatigue. There has been a range of different reasons to think cytokines are important in fatigue because other autoimmune diseases that are based on immune dysfunction also have fatigue as a component.

In terms of axonal injury, we know that atrophy, low NAA, changes in the normal-appearing white matter, all contribute. Among the neuroendocrine reasons for fatigue, we think of thyroid dysfunction. There have been varieties of abnormalities in the HPA axis in patients with MS that have been linked to fatigue. It's also likely that the effects of cytokines in MS on the HPA axis are contributing to impairments in cortisol and ACTH release.

Among the hypothalamic causes, the medication modafinil has helped a lot in understanding this mechanism. Modafinil is thought to work through non-dopaminergic pathways related to the hypothalamus. The fact that it works and that it has a positive effect on fatigue in MS makes us think that the hypothalamus does have role, as does the fact that the hypothalamus is connected with sleep disturbance and arousal.
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How is fatigue treated?

The first step in treating fatigue is developing specific treatment goals. The overarching goals are to reduce fatigue severity, reduce its impact, help patients reach their goals, develop an improved sense of control, and improve their quality of life. This is done by addressing those things that are cofactors for fatigue such as depression. If someone is depressed, that must be dealt with before addressing fatigue. If someone is in pain all the time, that will make the person tired; the pain must be treated first. If someone is inactive, deconditioned, or taking medications that are responsible for fatigue, each must be addressed to lessen the fatigue.
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Is depression linked to fatigue?

When a person is fatigued, how do you tell the difference between fatigue and the depression? This can be difficult to do, and must be dealt with first. No progress toward reducing fatigue will be made while severe depression is present. On the other hand, it's important to know that there are many people with MS that have fatigue and don't have depression. Therefore, it's important to do a thorough job of assessing these symptoms.

If in addition to treating depression pain is also being treated, it is likely that several medications will need to be used concurrently. To do this is, take a sequential approach to treatment and pick one condition at a time. Depression should be treated first, then address pain if it is still present. Always keep in mind when treating pain that nonpharmacologic methods like physical therapy, exercise, and helping with coping while someone's trying to battle their fatigue can be beneficial.
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What medications can also cause fatigue?

Are there medications that can make fatigue worse when you're treating MS? People with MS have many different symptoms that require medications. Some of these medications can interfere with fatigue, for example, antispasticity medications for stiffness or spasms.

Anticonvulsants can cause fatigue, and they're used frequently for neurologic pain. Antidepressants, benzodiazepines (used in treating periodic leg movement disorder or spasms), and medications used to improve bladder control can also have fatigue as a side effect. Interferon therapy (used with some patients) can also cause transient fatigue.
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What are non-pharmacological treatments for fatigue?

There are varieties of nonpharmacologic strategies that can be used. It's very important to educate patients and to reassure them that this is indeed part of the symptom, tell the family that they're not lazy. In addition, the VA system has really been a great help in programs such as these in terms of improving recognition of fatigue as a genuine MS symptom.

Other strategies include physical therapy and exercise. Cooling, sometimes using a cooling vest, for example, could be helpful since fatigue is made worse by heat. Other good strategies include encouraging patients to take rest periods, doing endurance training, getting a better handle on their sleep and, for those who are feeling a bit out of control, trying to provide some supportive therapy.
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What medications are effective in treating fatigue?

There are a number of different medications that have been used successfully when fatigue. One of the first was amantadine, which is actually an antiflu agent. This was discovered by accident. A physician in Canada (who happened to have MS) was taking amantadine for the flu noticed that while he was taking the medication his fatigue was less. This led to several research studies by the Canadian MS Society, which showed this was an effective treatment.

There has also been some work done with the medication pemoline, which is a CNS stimulant. This seems to help some people. We tend to not to use it much now because of its effect sometimes on the liver. Methylphenidate, or Ritalin, is a CNS stimulant that also has been tried. It can be helpful in some cases. The concern is that it may be addicting.

A very frequently used medication is modafinil, which was originally developed for narcolepsy but has been shown to be helpful. It has not been universally effective for all patients. A recent study showed that for some people it is not helpful.

Most recently, there has been some exciting work looking at aspirin, and that seems to have been providing some benefit.
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Conclusion

Well, the take-home message is that clinicians need to ask their patients about fatigue. It should be really on the forefront of their thoughts. We need to recognize that fatigue has multiple mechanisms and there are multiple cofactors, and as a result, the treatment should be multidisciplinary and involve multiple modalities.

Fatigue is real. It is something patients complain about and share with their family and providers. It is interfering with their quality of life. It can interfere with meeting responsibilities. Nevertheless, it can be treated. That is the main message for the clinician because often when we hear a patient complaining of fatigue, we feel rather helpless. However, there are many very simple and practical things that we can do that will help manage fatigue.
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For Patients

If you are experiencing fatigue, share your concerns with your provider. There are varieties of medications and rehabilitations strategies that are available through your local VA medical center that can address MS symptoms.

For a DVD of the entire satellite broadcast program send an email to Marsha.tarver@va.gov

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Last updated: September 2009