title: Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil.
abstract: Multiple sclerosis (MS) is a multifocal demyelinating disease of the central nervous system, leading to chronic disability. Fatigue is a common and distressing symptom of MS which is unrelated to its clinical form, stage of development, the degree of disability, or the lesion load on magnetic resonance imaging. Fatigue in MS is associated with excessive daytime sleepiness and autonomic dysfunction. Recently it has been reported that the wakefulness-promoting drug modafinil may relieve fatigue in MS patients and ameliorate the associated cognitive difficulties. However, it is not clear to what extent the anti-fatigue effect of modafinil may be related to its alerting and sympathetic activating effects. We addressed this question by comparing three groups of subjects, MS patients with fatigue, MS patients without fatigue and healthy controls, matched for age and sex, on measures of alertness (self-ratings on the Epworth and Stanford Sleepiness Scales and on a battery of visual analogue scales; critical flicker fusion frequency; Pupillographic Sleepiness Test; choice reaction time) and autonomic function (systolic and diastolic blood pressure, heart rate, pupil diameter), and by examining the effect of a single dose (200 mg) of modafinil on these measures. MS patients with fatigue, compared with healthy controls, had reduced level of alertness on all the tests used; MS patients without fatigue did not differ from healthy controls. MS patients with fatigue had a reduced level of cardiovascular sympathetic activation compared to the other two groups. Modafinil displayed alerting and sympathomimetic effects in all three groups of subjects. As fatigue in MS is associated with reduced levels of alertness and sympathetic activity, modafinil may exert its anti-fatigue effect in MS by correcting these deficiencies. The anti-fatigue effect of modafinil may reflect the activation of the noradrenergic locus coeruleus (LC), since there is evidence that this wakefulness-promoting nucleus is damaged in MS, and that modafinil, probably via the dopaminergic system, can stimulate the LC. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Division of Academic Clinical Neurology, School of Clinical Sciences, University of Nottingham and Nottingham University Hospital Trust, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom.
authors: Graham
authors: G
authors: Niepel
authors: Rashid H
authors: RH
authors: Bibani
authors: Janek
authors: J
authors: Vilisaar
authors: Robert W
authors: RW
authors: Langley
authors: Christopher M
authors: CM
authors: Bradshaw
authors: Elemer
authors: E
authors: Szabadi
authors: Cris S
authors: CS
authors: Constantinescu
mesh_terms: D000328:Adult; D001143:Arousal / Q000187:drug effects; D001341:Autonomic Nervous System / Q000187:drug effects; D001559:Benzhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D002317:Cardiovascular Agents / Q000009:adverse effects / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000009:adverse effects / Q000627:therapeutic use; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005221:Fatigue / Q000209:etiology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D018697:Nootropic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D011597:Psychomotor Performance / Q000187:drug effects; D012894:Sleep Stages / Q000187:drug effects; D012893:Sleep Wake Disorders / Q000209:etiology / Q000517:prevention & control*; D013564:Sympathetic Nervous System / Q000187:drug effects; D013566:Sympathomimetics / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D001559:Benzhydryl Compounds; D002317:Cardiovascular Agents; D000697:Central Nervous System Stimulants; D018697:Nootropic Agents; D013566:Sympathomimetics; D000077408:Modafinil