Review Article Sleep disorders in multiple sclerosis and their relationship to fatigue Christian Veauthier a,⇑ , Friedemann Paul b,c a Centre Hospitalier de Belfort-Montbéliard, Department of Neurology, 2, rue du Docteur Flamand, 25209 Montbéliard, France b NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité University Medicine Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany c Experimental and Clinical Multiple Sclerosis Research Center, Department of Neurology, Charité University Medicine Berlin, Germany article info Article history: Received 26 March 2013 Received in revised form 14 August 2013 Accepted 20 August 2013 Available online xxxx Keywords: Multiple sclerosis related fatigue Periodic limb movement disorder Restless legs syndrome Insomnia Nocturia Sleep-related breathing disorders Modified Fatigue Impact Scale Fatigue Severity Scale abstract Treatment of multiple sclerosis (MS)–related fatigue is still a challenging task, given that no proven therapies exist and its mechanisms are not known. Our review highlights the relationship between MS-related fatigue and sleep disorders (SD). Although many studies suggest a higher overall prevalence of SD in MS, there are no valid and robust data to confirm this hypothesis until now except for restless legs syndrome (RLS): the prevalence of RLS in MS patients—especially in those with severe pyramidal and sensory disability—seems to be four times higher than in controls subjects. RLS is sometimes difficult to distinguish from spasticity and in case of doubt, probatory dopaminergic therapy or polysomnographic (PSG) investigations may be helpful. Nocturia may impact MS-related fatigue and should be considered. The treatment of underlying SD led to an improvement of MS-related fatigue. From a scientific point of view, SD should be examined in all studies investigating MS-related fatigue and be considered as a rel- evant confounder. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction Multiple sclerosis (MS) is a chronic inflammatory and neurode- generative disease of the central nervous system with multifacto- rial etiopathogenesis, predominantly affecting young adults [1–4]. More than 80% of MS patients complain of fatigue and approximately one out of four view fatigue as the most burden- some symptom of the illness [5]. The mechanism of MS-related fatigue is not known [6,7]; the fatigue is a major reason for early retirement in MS [8] and no specific successful treatment options currently exist [7,9,10]. Several studies reported a relationship between the severity of fatigue on the one hand and other clinical findings, such as depres- sion [11–13], cognitive deficits [14], disability [13,15], disease course [15,16], sleep disorders (SD) [17–19], as well as radiologic features (high lesion load and brain atrophy, abnormal cervical cord function [20–23]) and medication (disease-modifying thera- pies [24] and symptomatic treatment [7,10]), on the other. Owing to different methodologic approaches and the use of various fati- gue scales with different cutoffs, it is difficult to summarize these findings in brief. In 2010, Brass et al. [25] reviewed SD in MS with particular interest in narcolepsy, sleep-related breathing disorders (SRBD), and rapid eye movement sleep behavior disorder (RBD), while Krupp et al. reviewed MS-related fatigue in general [26]. The aim of our review was to provide an overview on SD and MS-related fatigue to provide a practical and feasible approach for sleep specialists and neurologists. 2. Methods A PubMed database search last accessed on February 14th, 2013 was conducted using the terms sleep disorders AND multiple sclerosis (285 articles), insomnia AND multiple sclerosis (75 arti- cles), restless legs syndrome AND multiple sclerosis (34 articles), and nocturia AND multiple sclerosis (27 articles). After reading the abstracts, only relevant English-language articles were read (96 articles). 3. History of fatigue as medical condition Fatigue was first described in a medical context in 1857. The French physician Duchesne [27] chose it as a central theme in the ‘‘Disease of the Railroaders’’ (‘‘we have to acknowledge that 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.08.791 ⇑ Corresponding author. Address: Centre Hospitalier de Belfort-Montbéliard (CHBM), 2, rue du Dr Flamand, 25209 Montbéliard, France. Tel.: +33 6 80 75 60 30; fax: +49 3212 28 28 668. E-mail address: cveauthier@web.de (C. Veauthier). Sleep Medicine xxx (2013) xxx–xxx Contents lists available at ScienceDirect Sleep Medicine journal homepage: www.elsevier.com/locate/sleep Please cite this article in press as: Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med (2013), http:// dx.doi.org/10.1016/j.sleep.2013.08.791