How we define fatigue remains as controversial today as it did 40 years ago: “True fatigue and....tiredness are plainly different.”¹. Fatigue is more than tiredness and has recently been referred to as “pathological exhaustion”.² In this context the term “pathological” would, for example, classify the physical fatigue which athletes experience as part of voluntary effort as being abnormal. Fatigue must therefore surely be a normal phenomenon—a subjective feeling of tiredness or exhaustion which could refer to both physical (motor activities) and mental (cognitive or emotional) processes. Fatigue is only pathological if it is disabling—that is, if it affects a person’s social, physical, and occupational wellbeing. For lack of a better definition the Centres for Disease Control and Prevention (CDC) defines “profound fatigue” and by implication “pathological fatigue” in the context of the chronic fatigue syndrome (CFS) as fatigue that “is not improved by bed rest and that may be worsened by physical or mental activity”.³ This definition appropriately excludes exercise induced or temperature dependent conduction block, a form of physical fatigue which occurs in subjects with demyelinating disease.

Approximately 80% of subjects with multiple sclerosis (MS) have pathological fatigue and in half these cases …