When people meet someone with multiple sclerosis (MS), they often expect to see signs of muscle weakness or poor balance and coordination. MS is an autoimmune disease that affects the brain and spinal cord and produces a wide range of symptoms that come and go over time, causing varying degrees of disability. But people living with the disease say that one of their most debilitating symptoms is not visible to others. It's fatigue.

Fatigue affects up to 87 percent of people with MS, and about 40 percent say it is their most disabling symptom—and one that interferes with their work and social lives. Although the cause of MS-related fatigue is not fully understood, a study recently published in the Archives of Neurology found that nerve cell dysfunction is associated with fatigue in MS. This was determined by measuring nerve cell damage or loss with magnetic resonance spectroscopy (MRI). The extra work the brain has to do to compensate for this brain injury, the study authors write, results in a feeling of fatigue.

Below, Heidi Crayton, MD, co-director of the Multiple Sclerosis Center at Georgetown University Hospital in Washington, DC, discusses how people with MS can cope with fatigue.

Do most people with MS experience fatigue?
The majority of people with MS, regardless of their degree of disability, report that fatigue is huge symptom. And their fatigue is certainly not simple tiredness. It's whole-body washout. People describe feeling completely wrung out like a rag. It can be a physical as well as a mental fatigue; people are just incapable of performing at the level that they're used to. Lassitude is probably the closest word in the English language that comes close to MS fatigue.

Is there a way that fatigue is measured in MS?
Yes, when we try to objectively measure fatigue in clinical trials, we use several scales. They measure how much fatigue affects people's activities of daily living, the typical duration of their fatigue, and if it impacts them psychologically, physically, cognitively.

I think fatigue probably interferes more with daily living and one's ability to have a job than physical disability does. A workplace can make accommodations for someone's physical disability, but it's very difficult to make accommodations for somebody's cognitive deficits, which are often the result of fatigue. The ability to multitask goes down. Memory declines, and without those skills, sometimes it's very difficult to maintain a job. Fatigue also contributes to the loss of relationships.

Is fatigue often one of the first signs of MS?
Oftentimes people present very early on with fatigue as their sole symptom. I think it occurs a lot more frequently than we think because people are misdiagnosed with chronic fatigue syndrome or said to be distressed or working too hard. It's usually attributed to something else.

Is fatigue due to the disease process itself?
Yes, there is evidence that MS-related fatigue is associated with the disease process itself. There has been evidence for decreased blood sugar metabolism in certain areas of the brain in MS patients who experience fatigue. The recent study in the Archives of Neurology supports that theory. There was also evidence of nerve cell destruction in the brains of MS patients who suffered from fatigue. In the future, we may be able to use neuroprotective agents to prevent or slow this destruction to have a greater impact on the treatment of MS fatigue.

Does heat exacerbate fatigue?
Certainly most, though not all, MS patients report that their symptoms either worsen or they have a feeling of increased fatigue when they overheat. Heat slows down nerve conduction, and people with MS already have abnormal nerve conduction. Even as little as a half a degree increased body temperature can create problems, and that increase could be from fever, working out or environmental temperature increase.

How do you know if the fatigue is MS related?
People can experience fatigue as a relapse, or as an exacerbation, of MS, or they can just have it as an everyday baseline symptom that can be pretty steady. Or sometimes people have daily fatigue at a certain level that can then increase during the period of a flare-up or an exacerbation.

But fatigue, depression and cognitive deficits are so intimately related it's very difficult sometimes to sift out the primary problem. Most people who are fatigued experience cognitive problems. And depression can actually present as fatigue. So it can be very difficult to see if fatigue is the primary problem or whether a sleep disturbance due to depression is the primary problem or even if other medical non-MS related issues are to blame.

Sometimes people who have MS aren't always treated as if they have a whole body and may have other medical issues. We always have to make sure that the fatigue is not caused by some other medical problem, such as a thyroid condition, or medicines that they're taking for other conditions.

Why is fatigue often so hard for friends and family to understand?
Oftentimes fatigue doesn't correlate with physical disability, so it's something that people on the outside are not really able to observe. We often think of fatigue as being tiredness. So people might think: "Oh, why don't you just take a nap and get over it?" Unless you've really experienced true fatigue itself, it's very difficult to really understand what that concept means.

Is MS-related fatigue sometimes under-recognized by health professionals?
Most definitely; probably more so in women than in men. It's often attributed to overworking or to stress, so people get patted on the back and are told to take it easy and things will get better.

I think that the general primary care doc especially is not very attuned to the impact that fatigue plays with MS. But even some neurologists aren't attuned to it.

How can people living with MS manage fatigue?
I highly encourage vigorous physical activity, as long as people can tolerate it, which seems kind of counterintuitive. But getting people moving with exercise and getting some element of aerobic activity in their life is very important. For people who do become a little symptomatic if they overheat, I have them put cold towels around their neck or make sure that the room that they do their aerobics class in, or their gym, is air conditioned, or that they have a fan on them.

If people do become symptomatic after working out because they've overheated, immediately cooling their bodies down afterwards can quiet those symptoms. They can just get into a cool shower or put ice packs on their neck or their wrists.

The intensity of the exercise should be tailored to what a patient is able to do. If they have limited range of motion or they are very physically disabled, then we're talking about a totally different exercise program than one for somebody who has absolutely no problem with their arms or legs.

But even somebody who is confined to a wheelchair often has a lot of strength in their upper extremities, and you can still get your heart rate up by using your upper extremities. There are just some modifications that need to be made, but there is usually something that you can find that can help people out in terms of exercise.

Are there any other behavioral strategies for avoiding or minimizing fatigue?
If it's at all possible, I recommend that people incorporate a little bit of a rest time sometime in the afternoon. I think that really helps a lot with rejuvenating and increasing energy levels and decreasing fatigue for the remainder of the day.

Are there medications available to treat fatigue?
We have a few. The one that has probably been used the longest is amantadine. It's an antiviral medication, actually. We use it for many diseases, including Parkinson disease. Nobody knows the how amantadine works in terms of treating fatigue and not everyone experiences the full benefit of it.

Some people have used stimulants such as Ritalin, but psychostimulants often have unpleasant side effects of nervousness, anxiety and jitteriness, and insomnia, which can be a problem in ultimately exacerbating fatigue.

More recently, we've added modafinil, which is also called Provigil. It was originally Food and Drug Administration-approved for the sleeping disorder narcolepsy. There have been several studies that have shown its benefit in treating MS fatigue. It has many fewer side effects than other drugs, though a small percentage of people feel a little jitteriness from it. The most common side effects are headache and some appetite suppression.

What is your advice to someone who has MS and fatigue?
They should really be aggressive about having their fatigue treated. People often feel like fatigue is something that's in their control, and they sometimes don't even bring it up to their physician. But it's a real and sometimes very disabling symptom. It's not in their head. And there is really a lot that can be done for it.

Most of what we do for MS is to increase the quality of life. We don't have any cures for this disease right now, so our number-one goal is to slow down the progression of the disease process and to treat the symptoms—such as fatigue—that are getting in the way of somebody having a great quality of life.