Aims It has been proposed that fatigue, a troublesome symptom of multiple sclerosis (MS), may be associated with sympathetic dysfunction. The wakefulness promoting drug modafinil, which has sympathomimetic effects, can reduce fatigue in MS. We examined whether MS fatigue is associated with sympathetic impairment and, if so, whether the sympathetic dysfunction is susceptible to modafinil.

Methods Three groups of subjects were recruited: 1. MS patients with fatigue (12 females, 5 males), 2. MS patients with no fatigue (5 females, 4 males), 3. healthy controls (5 females, 4 males). The subjects participated in two double-blind sessions (modafinil 200 mg, placebo). Tests included pupil diameter, blood pressure, heart rate, blood pressure response to isometric handgrip. Data were analysed with ANOVA; criterion p<0.05.

Results Baseline autonomic functions did not differ between the groups prior to treatment. However, an evoked sympathetic response (increase in diastolic blood pressure to isometric handgrip) indicated a deficit for Group 1: the frequency of a normal response, defined as an increase ¡Ý 16 mm Hg, in Group 1 (34%) was lower than that in Group 2 (67%; p<0.05) or Group 3 (59%; 0.05<p<0.1) (÷2 test). Modafinil increased blood pressure, heart rate and pupil diameter in all three groups, consistent with its sympathomimetic effects.

Conclusions MS patients with fatigue showed reduced sympathetic activation. Interestingly, MS patients with fatigue also show a reduced level of alertness, consistent with a close association between arousal and sympathetic activity.