Association of a deficit of arousal with fatigue in multiple sclerosis: effect of
modafinil.
Author(s): Niepel G(1), Bibani RH, Vilisaar J, Langley RW, Bradshaw CM, Szabadi E,
Constantinescu CS.
Affiliation(s): Author information:
(1)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.
Publication date & source: 2013, Neuropharmacology. , 64:380-8
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'.
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