The single most common and the single most disabling symptom of MS is fatigue. Because it is an invisible symptom, it can lead to reactive depression: To the outside world, the person "looks so good" that it is often misunderstood what they can actually do. Managing fatigue begins with looking for medical and situational issues that may be contributing to fatigue. This includes, but is not limited to, thyroid disease, infections, heart disease, temperature aberrations, mononucleosis, and other causes. After these have been remedied, fatigue may be divided into five distinct types.

Type 1 is called normal fatigue. It is the fatigue seen in all persons when energy has been expended beyond capability. If one works hard, fatigue is likely. It is treated with understanding and ovation for the hard work. People with MS are not fragile, and they will not break because they worked hard. If they want to work to the point of fatigue, so be it. Occupational therapists, teaching activities of daily living using energy conservation can be very helpful in managing this type of fatigue.

Type 2 is neuromuscular fatigue or short-circuiting fatigue. It occurs when a demyelinated (or otherwise injured) axon is asked to fire frequently until a conduction block occurs. This person walks fairly well for a block, then limps for a block, then is unable to move for the last block. This fatigue is treated with rest stops that allow the nerve to recoup some function. A graded exercise program may allow for increased endurance over time, but it must be slow in its application.

Type 3 is the fatigue of deconditioning. If one is "out of shape" and asks the body to perform, it fails. This is true in both normal persons and patients with MS. This fatigue responds to getting back into condition.

Type 4 is fatigue associated with depression. If one is not sleeping well, eating well, and is feeling depressed, fatigue results. This type of fatigue must be recognized to be treated appropriately with counseling and antidepressant medication.

Type 5 is lassitude or MS-related fatigue. The most common and the hardest to understand fatigue, this variety presents as tiredness to the point of needing an hour of sleep. It occurs spontaneously and disables significantly. It is unrelated to depression or disease severity. It is likely neurochemical in origin, because neurochemicals such as amantidine and modafinil are helpful in its management. The specific serotonin reup-take inhibitors (e.g., fluoxetine) also may be helpful, even in the absence of depression. The neurochemistry for this type of fatigue has never been specifically worked out, but positron emission tomography (PET) scanning shows metabolic differences between those with this type of fatigue and those without it.

An algorithm for fatigue begins with its recognition. Elimination of other inciting causes, such as depression, infection, metabolic disease, and the like, separates out the other causes of fatigue from those fatigues associated directly with MS. Only then can proper management take place.

■ Five types of fatigue are found in MS: normal fatigue, neuromuscular fatigue, deconditioning fatigue, the fatigue of depression, and MS-related fatigue (lassitude).

■ Medications used to treat fatigue include amantidine (MS-related fatigue), modafinil (MS-related fatigue), pemoline (MS-related fatigue), fluoxetine (MS-related fatigue and the fatigue of depression), and 4-aminopyridine (neuromuscular fatigue).

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