Sleep Medicine 15 (2014) 5–14

Contents lists available at ScienceDirect

Sleep Medicine journal homepage: www.elsevier.com/locate/sleep

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 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 b

a r t i c l e

i n f o

Article history: Received 26 March 2013 Received in revised form 14 August 2013 Accepted 20 August 2013 Available online 15 November 2013 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

a b s t r a c t 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 relevant confounder. Ó 2013 Elsevier B.V. All rights reserved.

1. Introduction Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system with multifactorial 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 burdensome 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 depression [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 therapies [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 articles), 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

⇑ 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: [email protected] (C. Veauthier). 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.08.791

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

6

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

this medical condition exists even when we call it so far only fatigue’’). In the English scientific literature, the term fatigue began to appear late in the 19th century as ‘‘fatigue of sight’’ [28], and ‘‘mental fatigue’’ in school children [29], as well as in an electrophysiologic and cell physiologic context in basic research [30– 33]. In 1912 Lee [34] applied this cell physiologic concept from basic research to workers (‘‘Fatigue is a physical phenomenon, a lessened power of work, which has as its basis certain metabolic phenomena’’). Fatigue in MS was described by Klenner [35] for the first time in 1949. To define chronic fatigue syndrome, Holmes et al. [36] published a working definition of chronic fatigue syndrome with two major criteria and eight minor criteria in 1988, replaced soon after in 1994 by the criteria of Fukuda et al. [37]. 4. History of MS-related fatigue In 1988 Krupp et al. [5] published their seminal work on fatigue in MS [5], and a year later they published the unidimensional Fatigue Severity Scale (FSS) comparing 25 patients with MS, 29 patients with systemic lupus erythematosus, and 20 healthy adults [38]. Today the most common definition of MS-related fatigue is that of the MS Council [7], which defines fatigue as a ‘‘subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities.’’ This definition means that scales are not a prerequisite for a diagnosis of fatigue and that fatigue is not only a burdensome symptom of MS, but also has a substantial negative impact on patients’ quality of life (QoL). Nevertheless, the MS Council proposed a scale to monitor fatigue and to investigate the interference with activities known as the Modified Fatigue Impact Scale (MFIS) [7]. Notwithstanding, scales also are needed for research purposes. 5. History of MS fatigue scales The Short-Form Health Survey (SF-36), or Health Status Questionnaire, is a measure of health status of the general population [39]. After adding nine MS-specific measures to the SF-36, a new questionnaire called the 54-item Multiple Sclerosis QoL Inventory (MSQLI) [39] was created for the specific context of MS. To investigate the impact of MS-related fatigue, a shorter version of the MSQLI has been validated in 85 MS patients and 20 patients with mild hypertension called the Fatigue Impact Scale (FIS) (40 items) [40]. However, because a 40-item scale is still time consuming in clinical routine, the MFIS [7] was created. Nonetheless, the MFIS is the second most important MS fatigue scale after the FSS used to determine the impact of fatigue on daily life. Table 1 provides an overview of all scales cited in our review. 6. History of fatigue in SD First, we have to distinguish between sleepiness and fatigue: sleepiness includes the propensity to fall asleep and often is associated with an effort to avoid sleeping, whereas fatigue is not necessarily associated with sleep pressure. Sleepiness can be measured with objective tests (e.g., multiple sleep latency test [83], multiple sleep wakefulness test [84], pupillography [85], driving simulator [86]), though fatigue can be measured in clinical practice only with self-report measures. Fatigue also can be indirectly measured by neuropsychologic tests [87] and seems to be related to oculomotor parameters [88]; however, these tests can be influenced by cognitive impairment, depression, and other confounders. We also have to distinguish between occasional fatigue in healthy subjects and permanent fatigue in SD patients [89], though

a clear distinction between fatigue and tiredness remains challenging. The International Classification of Sleep Disorders, second edition (ICSD-2) [90], also mentions ‘‘exhaustion’’ as a minimal criterion of sleep apnea and there are no objective findings to differentiate fatigue from exhaustion. SD can cause sleepiness [90] in addition to fatigue, tiredness, and exhaustion [37]. Hossain et al. [91] investigated 283 SD patients referred to a sleep laboratory for various indications and 64% of these reported fatigue without overlap of sleepiness measured with the Epworth Sleepiness-Scale (ESS) [70]. In contrast to the high percentage of fatigued patients, the percentage of referral for fatigue was only 4%. This low percentage means that fatigue seems to be underrecognized as important consequence of untreated SD. Bailes et al. [92] compared patients with SRBD and healthy controls (HC) using self-report measures of sleepiness and fatigue with a classification in several subgroups (high fatigue/high sleepiness, high fatigue/low sleepiness, low fatigue/high sleepiness, and low fatigue/low sleepiness). In their study, highly fatigued but not sleepy individuals had similar levels of apnea severity compared with high sleepiness patients without fatigue. However, groups with high fatigue ‘‘tended to report diminished quality of life and less adaptive psychological functioning.’’ This finding indicated that ‘‘fatigue was associated with more severe dysfunction than high sleepiness’’ [92]. Fatigue should be considered as a serious problem from a sleep medicine point of view. 7. Studies investigating sleep in MS patients In 1994, Tachibana et al. [93] described SD in approximately 50% of their MS patients. Ferini-Strambi et al. [94] investigated sleep in 25 MS patients without mood disorders vs 25 HC and found a significantly reduced sleep efficiency with more arousals and more frequent periodic limb movements (PLM) (36% vs 8%). In addition, MS patients with PLM had higher infratentorial lesion loads (cerebellum and brainstem) on magnetic resonance imaging. Merlino et al. [95] reported that approximately half of MS patients were poor sleepers and that SD were more frequent in patients with pain and in those with higher scores on the Expanded Disability Status Scale [96]. In another study [97] higher Pittsburgh Sleep Quality Index (PSQI) values [47] were associated with higher fatigue scores. 8. Insomnia and MS According to the International Classification of Diseases 10th edition (ICD-10) (1992) [98] of the World Health Organization, the ICSD-2 (2005) [90], and the Diagnostic and Statistical Manual, fourth edition-text revision (2000) (DSM-IV-TR) [99] of the American Psychiatric Association, insomnia is defined as the incapability to initiate sleep, or as disrupted sleep or early morning awakenings. However, there are differences between these classification systems (Table 2). Sleep complaints in general are common in the general population [100], but only 6% of the general population fulfill the DSM-IV-TR criteria [100]. To our knowledge, there are no studies to date investigating insomnia in MS patients according to ICD-10 or DSM-IV-TR criteria and only one cross-sectional study [17] using ICSD-2 criteria, which reported insomnia in 25% of MS patients. Studies investigating insomnia in MS are listed in Table 3. Tachibana et al. [93] reported SD in 15 out of 28 consecutive MS patients (spasms or discomfort in the legs [n = 8], insomnia [n = 3], habitual snoring [n = 4], nocturia [n = 1], sleep apnea [n = 2]). Fleming and Pollak [19] cited the study by Tachibana et al. [93], describing insomnia in 40% of MS patients as another term for SD causing disturbed

Table 1 Validation studies of questionnaires cited in our review. Authors

Insomnia MOS-SS

Created by Hays and Stewart Hays and Stewart [41] Hays et al. [42] Lau et al. [43] Rejas et al. [44] Viala-Danten et al. [45] Allen et al. [46]

Pittsburgh Sleep Quality Index

Doi et al. [50] Fictenberg et al. [51] Shochat et al. [52] Quality of life MSQLI-54

Created by Vickrey et al. [53]

3445 (chronic illness) 1184 (neuropathic pain; HC)1 363 (overactive bladder) 603 (neuropathic pain) 512 (neuropathic pain and diabetes mellitus) 551 (RLS)

91 (depression, insomnia, HC) 18 (older adults) 473 (transplantation, cancer, women with benign breast problems) 174 (insomnia, psychiatric disorders) 91 (traumatic brain injury) 511 (patients from 2 sleep clinics and HC)

Internal consistency Cronbach a

Test– retest r

Convergent validity

Discriminant validity

6 subscales: sleep disturbance (initiation, maintenance, quantity), perceived sleep adequacy, somnolence, awaken short of breath or headache, snoring, and sleep quantity during past 4 weeks

12 items averaged 11 items rated from 1– 5 or 6 Reverse scoring and transforming linearly to a common metric Range, 0–100; no cutoff (quantity of sleep is scored as hours slept per night) Out of the 24 items, only the 19 selfassessed items were measured (transformation of each of the 7 subscales to a 4-point Likert scale 0–3) Total score 3  7 = 21; range, 0–21; cutoff >5

Average 0.84 (0.63– 0.87) lowest range: somnolence

0.79–0.91 (P < .001) [44]

Correlation with the RLS overall quality of life score (r = 0.40) and changes in MOS-SS were responsive to improvements in RLS severity [46]

Significant differences in patients with sleep disorders (neuropathic pain, overactive bladder) compared with the general US population [42,43]

0.46–0.85

0.65–0.84

Correlation with insomnia confirmed by polysomnography (sleep latency and duration) Fictenberg et al. [51]: good correlation with DSM-IV, sensitivity 100%

Significant differences between inpatients (sleep-clinic) (PSQI, 7.3) and healthy adults (PSQI, 3.5) (P < .001) [52]

7 subscales: sleep quality, latency, duration, sleep disturbances, efficiency, medication use, and daytime dysfunction. (further by the bed partner: snoring, apnea, movement, confusion, agitation)

0.70–0.78 0.77 (0.11–0.95) 0.72

0.57–0.82

12: SF-36 supplemented by 9 symptom-specific measures (fatigue, pain, bladder function, bowel function, emotional status, perceived cognitive function, visual function, sexual satisfaction, and social relationships)

54 items: 52 items in 2 summary scores: physical and mental health; reverse scoring with scoring key (yes/ no and 3-point until 10-point Likert scale) and 2 single-item measures No overall summary score is used. No cutoff

SF-36 [39]: total: 0.89– 0.95 subscales: 0.75–0.94 (except social functioning)

0.66–0.96 [53]

SF-36 physical/mental components correlated with SIP dimensions [54] (physical [r = 0.62]/psychosocial [r = 0.51]) Visual impairment moderately correlated with objective measures

Overlap between MFIS and MSQLI values (r > .30) showing a moderate correlation with fatigue. Good discrimination from HC (physical subscale)

Created by Krupp et al.: Krupp et al. [38]

74 (MS, HC, SLE)

Fatigue severity No subscale, unidimensional

For MS: 0.81 for SLE: 0.89 for HC: 0.88

r = 0.84, (P < .01)

Good correlation with fatigue rated on VAS (r = 0.68; P < .001)

Good discrimination from HC but overlap with depression (r = 0.40, P < .001)

Created by Fisk et al. [40]

105 (MS, mild hypertension)

3 subscales: cognitive, physical, and psychosocial

9 items averaged, rated 1–7 describing the degree of agreement Range, 1.0–7.0; cutoff P4.6 (some studies 5.0) Sum of 40 items, rated 0–4; range, 0–160; no cutoff

Good correlation between FIS values and self-reported fatigue/SIP [54] values.

Significant difference between fatigued MS patients and patients with hypertension.

Fischer et al. [39]

FIS

Items number, scoring range (min–max); cutoff

300 (MS)

2

Fatigue FSS

Subscales assessed parameters

>0.93

/

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

Created by Buysse et al. Buysse et al. [47] Gentili et al. [48] Carpenter and Andrykowski [49]

Patients n (disease)

(continued on next page)

7

8

Table 1 (continued)

Modified FIS (MFIS)

Patients n (disease)

Subscales assessed parameters

Items number, scoring range (min–max); cutoff

Internal consistency Cronbach a

Test– retest r

Convergent validity

Discriminant validity

Created: MS Council [7]

Created during development of MSQLI 151 (MS) 68 (MS, HC) 1271 (MS)

3 subscales: psychosocial fatigue, physical fatigue, and cognitive fatigue

Sum of the 21 items, rated 0–4; range 0–84 No cutoff described in the original article [6] Different cutoff used: 38 or 45 [16,55,121]

>0.93

Good correlation with FSS (physical subscale r = 0.77; cognitive r = 0.55). Moderate correlation with VAS values (r = 0.47)

Good discrimination from HC but overlap with pain (r = 0.60), depression (r = 0.70) [57], and sleep disorders [17]

1469 (cancer and chronic fatigue patients, HC) 783 (chronic fatigue patients, chronically unwell patients and HC)

5 subscales, measuring fatigue severity and impact: general, mental and physical fatigue, reduced activity, and reduced motivation

>0.80 (0.53–0.93) total score: 0.93 subscales: 0.71–0.83

Correlation with VAS: general fatigue r = 0.77 physical fatigue r = 0.70 reduced activity r = 0.61 reduced motivation r = 0.56 mental fatigue r = 0.23

Good discrimination from HC Significant correlation with anxiety (r = 0.40– 0.52) and depression (r = 0.61–0.77)

74 (MS, HC, SLE)

Fatigue severity

20 items, each subscale 4 items 7point Likert scale (1995) modified to 5point Likert scale (1996) Range, each subscale 0–20 No cutoff; some items worded in a positive/ negative direction 100-mm line: at the left end of the scale: not tired at all; right end: extremely tired No cutoff

Total: 0.85 Physical: 0.73 Cogn.: 0.88 Psychosocial:0.81 /

Good correlation with FSS (r = 0.47, P < .05) [38]

No correlation with EDSS, depression [4]. Good discrimination between fatigued and healthy adults (5.7 vs 3.0; P < .001)

Sum of the 21 items, rated 0–3. Range, 0– 63; no arbitrary cutoff but usually healthy volunteers 21 20 items rated from 0– 3 Items are summed Range, 0–60; cutoff P16

>0.83

r = 0.60– 0.75

Construct validity by integration of DSM-III criteria Good correlation with Geriatric Depression Scale (r = 0.59)

Moderate correlation with self-perceived cognitive difficulties. Overlap with fatigue (r = 0.70) and sleepiness (ESS) (r = 0.85) [67]

MS: 0.90 general population: 0.85–0.93

0.45–0.70

Good correlation with other valid self-report depressions scales and clinical interview ratings of depression (r = 0.49.0.61)

Good discrimination from HC, low correlation (r = 0.19–0.26) with medication, aggression; moderate correlation with anxiety (r = 0.44– 0.71)

Flachenecker et al. [55] Kos et al. [56] Amtmann et al. [57]

Multidimensional Fatigue Inventory (MFI-20)

Created by Smets et al.: Smets et al. [58] Smets et al. [59] Lin et al. [60]

100-mm visual analog scale

Krupp et al. [38] Brunier and Graydon [61] Flachenecker et al. [55] Beiske et al. [62] Kos et al. [63]

Depression Beck Depression Inventoryamended/ revised (BDIIA, BDI-II)

Center for Epidemiologic StudiesDepression Scale in MS (CES-D)

Created by Beck and Steer [64] Jo et al. [65] Lovera et al. [66]

Created by Radloff et al. [68] Verdier-Taillefer et al. [69]

2729 (volunteers >60 y) 39 (MS)

2346 (MS, general practice, HC)

Cognitive, affective, somatic, and vegetative symptoms of depression

No subscale but 4 factors: depressed affect, positive affect, somatic complaints, or retarded activity; interpersonal relationships

/

/

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

Authors

Table 1 (continued)

Sleepiness Epworth Sleepiness Scale (ESS)

Patients n (disease)

Subscales assessed parameters

Items number, scoring range (min–max); cutoff

Internal consistency Cronbach a

Test– retest r

Convergent validity

Discriminant validity

Created by: Johns [70]

180 (OSAS, narcolepsy, hypersomnia, HC) 141 (OSAS, healthy medical students) 225 (OSAS, narcolepsy, PLMD, hypersomnia) 141 (OSAS) Letter to the editor and reply by Johns 226 (OSAS) 344 (sleep-clinic-patients, HC) 2259 (individuals >65 y without PSG, prospective study of psychiatric disorders)3

Sleep propensity

8 items rated from 0–3 Range, 0–24; cutoff P10

Healthy controls: r = 0.73 obstructive sleep apnea: r = 0.88

r = 0.82 (healthy controls)

Correlation with the Functional Outcomes of Sleep Questionnaire, OSAS, narcolepsy, and hypersomnia. Inconsistent findings about relationship with sleep apnea severity and sleep latency (MSLT)

In HC and in patients with snoring, insomnia, and PLMD; ESS values were not significantly increased. Tsuno et al. [77]3: correlation with lifetime prevalence of (hypo) manic episodes, male gender, snoring

Johns [71] Olson et al. [72] Chervin [73] Chervin and Aldrich [74] Fong et al. [75] Izci et al. [76] Tsuno et al. [77]

Abbreviations: MOS-SS, Medical Outcomes Study Sleep Scale; RLS, restless legs syndrome; HC, healthy controls; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; DSM-III, Diagnostic and Statistical Manual of Mental Disorders, third edition; MS, multiple sclerosis; SLE, systemic lupus erythematosus; SIP, Sickness Impact Profile; MSQLI, MS Quality of Life Inventory; OSAS, obstructive sleep apnea syndrome; ESS, Excessive Sleepiness Scale; EDSS, Expanded Disability Status Scale; y, years; PLMD, periodic limb movement disorder; PSG, polysomnography; SF-36, the Short-Form Health Survey or ‘‘Health Status Questionnaire’’ [39]; FSS, Fatigue Severity Scale; FIS, Fatigue Impact Scale. Please note that the 5-item Insomnia Severity Index [81] and the 8-item Athens Insomnia scale [82] also are validated self-assessment tools for insomnia with high consistency, reliability, and external validity; however, these questionnaires have not yet been used in the specific context of MS until today. In sum, the cited scales showed in most cases a good internal consistency, a good test–retest reliability and a good convergent validity. As regards the discrimination between healthy controls on the one hand and sleepy/fatigued/ depressed or sleep-disturbed patients on the other, the above mentioned scales have good discriminative capacities, although they do not differentiate very well fatigue/sleepiness from depression. 1 In a representative sample of 1011 US adults, measures were made by telephone, whereas the MOS-SS was self-administered at baseline and 8 weeks after baseline to 173 adults who had postherpetic (neuropathic) pain for at least 3 months and were randomized to placebo or pregabalin as part of a clinical trial [42]. 2 Please do not confuse the MSQLI-54 with the MSQLI (a longer 138-items version with 10 different questionnaires) [78]. 3 Tsuno et al. [77] did not perform polysomnographies. The higher ESS values in men could be in line with the higher prevalence of OSAS in the general population [79]. Nevertheless the fact that lifetime episodes of mania and hypomania which were independently associated with excessive daytime sleepiness measured with the ESS after controlling for confounding variables remains relevant. Olson et al. [72] found a weak univariate relationship between depression scores and ESS values in their study (r = 0.23; P = .0006) but without multivariate analysis. The fact that continuous positive airway pressure therapy improves depression [80] argues instead for a relationship between OSAS and depression.

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

Authors

9

10

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

Table 2 Minimal criteria to diagnose insomnia.

Incapability to initiate sleep Disrupted sleep Early morning awakenings Nonrestorative sleep Reduced daytime functioning or fatigue and tiredness Duration Nights/week Only nonorganic etiology

DSM IV TR

ICD-10

ICSD-2

x x x x x P1 month Not specified x

x x x No criteria No criteria Considerable period of time P3 x

x x x x x P1 month Not specified Different types of insomnia*

Abbreviations: DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, fourth edition-Text Revision; ICD-10, International Classification of Diseases, 10th edition; ICSD2, International Classification of Sleep Disorders, second edition. * The ICSD-2 classifies insomnia in acute, psychophysiologic, paradoxical, idiopathic insomnia and insomnia due to mental disorders, drug abuse, medical conditions, among others. In the DSM-III or DSM-IV-TR, and ICD-10, insomnia is defined as nonorganic insomnia.

Table 3 Studies investigating insomnia in multiple sclerosis patients. Authors Pokryszko-Dragan et al. [101] Stanton et al. [102]

Bamer et al. [103] Tachibana et al. [93] Veauthier et al. [17]

Number of patients 100 60

1063 28 66

Results Sleep complaints in 49% of patients (nonvalidated sleep questionnaire) Sleep diaries for 1 week: - 42% of patients had an incapability of initiating sleep (>30 min) at least two nights per week. - 53% of patients had disrupted sleep at least two nights per week. - Nocturia was the most common cause of disrupted nights (72.5%)* Using the Medical Outcomes Study Sleep Scale [64] moderate or severe sleep problems in 33.1%. 3 patients had nonorganic insomnia 25% of patients had insomnia according ICSD-2 criteria

Abbreviations: min, minutes; ICSD-2, International Classification of Sleep Disorders, second edition. In sum, aside from the study by Veauthier et al. [17] there is no other study investigating the prevalence of nonorganic insomnia in MS patients applying the diagnostic criteria of ICD-10, ICSD-2, or DSM-III/DSM-IV. * The authors mentioned the number of disrupted nights (episodes) caused by nocturia, but the number of patients with nocturia was not mentioned.

sleep; however, only three patients (10.7%) had insomnia in that study [93]. We must distinguish between insomnia and disturbed sleep in general. In sum, the prevalence of insomnia in MS seems to be higher than in the general population, but the lack of studies comparing HC with MS patients using the ICD-10, ICSD-2, or DSM-III or IV-TR criteria is a methodical limitation. In clinical practice insomnia is a clinical diagnosis (ICSD-2) and polysomnographic (PSG) investigations are recommended in cases of therapy resistance or when other SD are suspected [104]. 9. MS and nocturia Nocturia leads to disturbed sleep and is frequent in the general population: one-third of individuals reported nocturia at least three nights per week and one-fourth reported episodes almost every night [105–109]. Prevalence of nocturia increases with age; episodes have been reported in more than half of adults older than the age of 55 years and in more than three-fourths of adults older than 65 years [108]. QoL significantly decreases in individuals with nocturia and the impact on QoL was greatest with at least two episodes per night [107–111]. Neurogenic bladder affects up to 80% of patients with MS [112] and overactive bladder symptom scores are associated with decreased QoL [113]. Only 43.3% of patients with moderate to severe overactive bladder symptoms were evaluated by urology and only 51% were treated with an anticholinergic medication, which is significantly underused [113]. Sleep problems by nocturia are reported by some authors in the context of MS [93,102], but there are no studies investigating the impact of nocturia on MS fatigue to date.

10. MS and pain, RLS and PLMD In a large Italian epidemiologic survey [114], the prevalence of RLS in MS was 19%, particularly in patients with severe pyramidal and sensory disability and in only 4.2% in control subjects. RLS had a significant impact on sleep quality. Miri et al. [115] reported a RLS prevalence of 27.8% in a cross-sectional survey of 205 consecutive MS patients. In a large cross-sectional study (65,544 women of the Nurses’ Health Study II cohort without diabetes mellitus, arthritis, and pregnancy aged 41–58 years) [116], the prevalence of moderate to severe RLS was significantly higher in MS patients (15.5/9.9%) than in HC (6.4/2.6%); even after adjustment for potential confounders including other SD, MS was associated with a high risk for having RLS (odds ratio, 2.72). Pain often is a comorbid condition to MS-related fatigue but is confounded by depression and medication for treating pain or pain-induced SD [117]. We must distinguish between pain in the context of RLS and pain without RLS due to other reasons. In a recent PSG cross-sectional survey of 66 MS patients [17], only one patient (1.5%) had SD caused by nocturnal pain without RLS, whereas moderate to severe RLS was found in 12% of patients. Until now, there are no valid and robust data about the impact of SD, which are caused by pain (not pain in general) on MS-related fatigue. Regarding periodic limb movement disorder (PLMD), the abovementioned PSG cross-sectional survey [17] showed that 23% of patients had moderate to severe PLMD without pain or RLS. In sum data from different countries have consistently shown that RLS more frequently occurs in MS than in the general population. RLS is prone to be underdiagnosed in MS, as symptoms may be attributed to comorbid spasticity. Therefore, RLS should be considered with a low level of suspicion, and probatory

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

dopaminergic therapy may be helpful when there is doubt of a definite diagnosis. Accordingly, PLMD seems to be frequent in MS. The recent Clinical Practice Guidelines of the American Academy of Sleep Medicine [118] do not recommend pharmacologic therapies in PLMD without RLS. The Guidelines recommended that ‘‘clinical judgment must be used in any pharmacologic intervention in PLMD’’ [118].

11. Actigraphic and PSG investigations in MS Kaynak et al. [119] compared PSG parameters such as oxygen desaturation index or apnea–hypopnea index (AHI) per hour in fatigued vs nonfatigued MS patients without any significant difference, but no individual diagnosis of relevant SD leading to daytime fatigue was made. In a small case-control study using actigraphy, Attarian et al. [120] found disturbed sleep or circadian rhythm abnormality in 12 out of 15 fatigued vs only 3 out of 15 nonfatigued MS patients and in none of the HC (one patient with sleep-state misperception insomnia). Veauthier et al. [17] investigated the frequency of SD in unselected MS patients using two home-based overnight PSG assessments and compared the frequency of SD in fatigued vs nonfatigued MS patients. They found a highly significant relationship between MFIS and FSS scores and the presence of SD; in contrast, there was no significant relationship between ESS values and MS-related fatigue. However, sleepiness is not the same as fatigue, and it is not surprising that fatigue scales display sleep-related fatigue better than the ESS. However, many studies use the ESS as a screening tool for SD [121], and it is important to acknowledge that there are patients who feel fatigued unrelated to sleepiness [91,122]. Of the 66 patients who underwent PSG in this study [17], 74% had a relevant SD (SRBD in 12.1%; RLS, moderate to severe PLMD, or leg pain in 36.4%; moderate to severe insomnia and inadequate sleep hygiene in 25.75%; and no relevant SD in 25.75%). To avoid false conclusions with respect to mild SD as possible causes of tiredness, nocturia, mild insomnia, mild PLMD, and SRBD with an AHI 34 or PSQI >5), and they recommended the combination of the MFIS and the PSQI as a screening instrument for SD in MS. Kaminska et al. [18] investigated 62 MS patients and 32 HC using PSG and found obstructive sleep apnea (OSA) in 36 MS patients (58%) and 15 HC (49%). Fatigue (FSS P5) was associated with OSA and a respiratory effort–related arousal in MS, but not in control subjects. When OSA was diagnosed only by the AHI and oxygen desaturation index, only 7 out of 62 MS patients (11%) had OSA, similar to the 12% in the study by Veauthier et al. [17]. In the study of Veauthier et al., all SRBD patients had more than 10 desaturation-related hypopneas or apneas per hour). Both groups discussed the different scoring criteria as a possible explanation of the different prevalence of SRBD [124,125].

11

The Montreal Group published follow-up data [126] from 56 patients of their original cohort of OSA patients [18] after sleep medical treatment. In the meantime, the authors also have diagnosed other SD, including RLS, insomnia, RBD, narcolepsy, and somnambulism. Interestingly and in contrast to the studies by Ferini-Strambi et al. [53] and Veauthier et al. [17], there were no patients with PLMD. The Montreal Group [126] found that the FSS values significantly decreased from a mean of 5.11 to 4.49 in MS patients with sleep medical treatment, the decrease was nonsignificant in untreated SD from 5.37 to 5.09. In contrast, FSS scores increased in patients without SD from 4.82 to 5.22. Beyond that, patients treated with continuous positive airway pressure also showed an improvement in depression scores. The authors concluded that treatment of SD may improve fatigue and other clinical outcomes in MS. These results were confirmed by a follow-up study from Veauthier et al. [127] of their original cohort [17]; here, MS-related fatigue improved after treating SD in patients with adequate compliance. 12. Fatigue and other SD Several cases of narcolepsy-like syndromes and hypersomnia in MS with partial response to prednisone therapy have been reported [128–130]. Until today, there are no data on the prevalence of these SD in MS and no studies on a possible relationship with fatigue. Moreover, two different studies investigating hypocretin-1 levels in fatigued MS patients showed inconsistent findings. Whereas Papuc´ et al. [131] found decreased hypocretin-1 cerebrospinal fluid levels, Constantinescu et al. [132] found normal hypocretin-1 cerebrospinal fluid levels in 34 consecutive MS patients compared to patients with other inflammatory (n = 24) or noninflammatory (n = 42) neurologic diseases. Magnetic resonance imaging studies [133] and postmortem investigations [134] showed an unexpectedly high incidence of active lesions in the hypothalamus, and it is possible that they may have impacted sleep–wake cycles, hypothalamic functioning, and fatigue. Plazzi and Montagna [135] described a patient with a steroid-responsive RBD as the initial presentation of MS, but there are no studies to our knowledge investigating the relationship between MS fatigue and RBD, nocturnal epilepsy, somnambulism, and other parasomnias. 13. Future research directions First, it would be desirable to create more sensitive and specific questionnaires for SD in the context of MS-related fatigue to screen patients who may require further sleep medical investigations. Second, we currently do not know why RLS prevalence is four times higher in MS than in the general population [114]. MS patients often exhibit regional grey-matter volume loss in the thalamus [136,137], which also seems to be involved in the etiology of idiopathic RLS [138]. Moreover, MS patients often present spinal cord lesions [139,140]. Patients with spinal cord injury often show PLM [141]. Thus it would be interesting to investigate these anatomic pathways in MS patients with RLS. Third, we need a better sleep medical understanding of the etiology of fatigue caused by SD. What drives fatigue? Guilleminault et al. [142] found a relationship between sleep instability and fatigue in patients with upper airway resistance syndrome using cyclic alternating pattern. Until today, there are no studies investigating the microstructure of sleep using cyclic alternating pattern in the specific context of MS-related fatigue. 14. Conclusion We do not have exact data on the overall prevalence of SD in MS patients compared with the general population, but RLS is more

12

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

frequent in MS patients. MS patients presenting spasticity with unpleasant sensation in the legs at night or difficulty in initiating sleep should be systematically asked if the discomfort is relieved by movement of the limbs. In indefinite cases, the iron storage protein ferritin also should be examined [143] and a probatory dopaminergic treatment should be considered. PSG investigations can help to distinguish between pain and spasticity and RLS [17,144]. Nocturia seems to be an underlying condition for MS-related fatigue in some cases, but studies investigating this relationship are lacking to date; however, it is important to consequently treat nocturia in the context of fatigue. The treatment of OSA with continuous positive airway pressure therapy may not only improve MS-related fatigue but also depression. Insomnia is a clinical diagnosis and can be treated without PSG. However, admission to a sleep laboratory should be considered in patients with MS-related fatigue without metabolic reasons for fatigue or without response to previous therapies presenting MFIS values higher than 34 or PSQI values higher than five. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2013.08.791.

References [1] Sinnecker T, Mittelstaedt P, Dörr J, et al. Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 2012;69:739–45. [2] Borisow N, Döring A, Pfueller CF, et al. Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy. EPMA J 2012;3:9. [3] Goodin DS. The causal cascade to multiple sclerosis: a model for MS pathogenesis. PLoS One 2009;4:e4565. [4] Pfueller CF, Brandt AU, Schubert F, et al. Metabolic changes in the visual cortex are linked to retinal nerve fiber layer thinning in multiple sclerosis. PLoS One 2011;6:e18019. [5] Krupp LB, Alvarez LA, LaRocca NG, et al. Fatigue in multiple sclerosis. Arch Neurol 1988;45:435–7. [6] Döring A, Pfueller CF, Paul F, et al. Exercise in multiple sclerosis—an integral component of disease management. EPMA J 2012;3:2. [7] Multiple sclerosis council for clinical practice guidelines. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington (DC): Paralyzed Veterans of America; 1998. [8] Simmons RD, Tribe KL, McDonald EA. Living with multiple sclerosis: longitudinal changes in employment and the importance of symptom management. Neurology 2010;257:926–36. [9] Paul F, Veauthier C. Fatigue in multiple sclerosis: a diagnostic and therapeutic challenge. Expert Opin Pharmacother 2012;13:791–3. [10] Brañas P, Jordan R, Fry-Smith A, et al. Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess 2000;4:1–61. [11] Greim B, Benecke R, Zettl UK. Qualitative and quantitative assessment of fatigue in multiple sclerosis. J Neurol 2007;254(Suppl. 2):S58–64. [12] Bakshi R, Shaikh ZA, Miletich RS, et al. Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler 2000;6:181–5. [13] Patrick E, Christodoulou C, Krupp LB. New York State MS Consortium. Longitudinal correlates of fatigue in multiple sclerosis. Mult Scler 2009;15:258–61. [14] Weinges-Evers N, Brandt AU, Bock M, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler 2010;16:1134–40. [15] Merkelbach S, Schulz H, Kölmel HW, et al. Fatigue, sleepiness, and physical activity in patients with multiple sclerosis. J Neurol 2011;258:74–9. [16] Colosimo C, Millefiorini E, Grasso MG, et al. Fatigue in MS is associated with specific clinical features. Acta Neurol Scand 1995;92:353–5. [17] Veauthier C, Radbruch H, Gaede G, et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler 2011;17:613–22. [18] Kaminska M, Kimoff RJ, Benedetti A, et al. Obstructive sleep apnea is associated with fatigue in multiple sclerosis. Mult Scler 2012;18:1159–69. [19] Fleming WE, Pollak CP. Sleep disorders in multiple sclerosis. Semin Neurol 2005;25:64–8. [20] Pellicano C, Gallo A, Li X, et al. Relationship of cortical atrophy to fatigue in patients with multiple sclerosis. Arch Neurol 2010;67:447–53.

[21] Sepulcre J, Masdeu JC, Goñi J, et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler 2009;15:337–44. [22] Rocca MA, Absinta M, Valsasina P, et al. Abnormal cervical cord function contributes to fatigue in multiple sclerosis. Mult Scler 2012;18(11): 1552–9. [23] Bomboi G, Ikonomidou VN, Pellegrini S, et al. Quality and quantity of diffuse and focal white matter disease and cognitive disability of patients with multiple sclerosis. J Neuroimaging 2011;21:e57–63. [24] Metz LM, Patten SB, Archibald CJ, et al. The effect of immunomodulatory treatment on multiple sclerosis fatigue. J Neurol Neurosurg Psychiatry 2004;75:1045–7. [25] Brass SD, Duquette P, Proulx-Therrien J, et al. Sleep disorders in patients with multiple sclerosis. Sleep Med Rev 2010;14:121–9. [26] Krupp LB, Serafin DJ, Christodoulou C. Multiple sclerosis-associated fatigue. Expert Rev Neurother 2010;10:1437–47. [27] Duchesne EA. Des chemins de fer et de leur influence sur la santé des mécaniciens et des chauffeurs. Paris: Bachelier, Imprimeur-Librairie de l’Ecole Polytechnique et du Bureau des Longitudes; 1857. p. 183–5. [28] Fatigue of sights, [no authors listed]. Science 1889;13:41. [29] Thorndike E. The mental fatigue due to school work. Science 1899;9:862–4. [30] Brodie TG. Fatigue in non-medullated nerves. J Physiol 1902;28:181–200. [31] Fletcher WM. The osmotic properties of muscle, and their modifications in fatigue and rigor. J Physiol 1904;30:414–38. [32] Levy AG. A further research into fatigue of the central nervous system when caused by electrical stimulation. J Physiol 1902;28:1–13. [33] Levy AG. An attempt to estimate fatigue of the cerebral cortex when caused by electrical excitation. J Physiol 1901;26:210–28. [34] Lee FS. The effects of temperature and humidity on fatigue. Am J Public Health 1912;2:863–70. [35] Klenner FR. Fatigue, normal and pathological, with special consideration of myasthenia gravis and multiple sclerosis. South Med Surg 1949;111:273–7. [36] Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988;108:387–9. [37] Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953–9. [38] Krupp LB, LaRocca NG, Muir-Nash J, et al. The fatigue severity scale. Arch Neurol 1989;46:1121–3. [39] Fischer JS, LaRocca NG, Miller DM, et al. Recent developments in the assessment of quality of life in multiple sclerosis. Mult Scler 1999;5:251–9. [40] Fisk JD, Ritvo PG, Ross L, et al. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis 1994;18(suppl 1):S79–83. [41] Hays R, Stewart A. Sleep measures. In: Stewart A, Ware J, editors. Measuring functioning and well-being: the medical outcomes study approach. Durham (NC): Duke University Press; 1992. p. 235–9. [42] Hays RD, Martin SA, Sesti AM, et al. Psychometric properties of the Medical Outcomes Study Sleep measure. Sleep Med 2005;6:41–4. [43] Lau DT, Morlock RJ, Hill CD. Psychometric evaluation of the medical outcomes study-sleep scale in persons with overactive bladder. Clin Ther 2006;28:2119–32. [44] Rejas J, Ribera MV, Ruiz M, et al. Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain. Eur J Pain 2007;11:329–40. [45] Viala-Danten M, Martin S, Guillemin I, et al. Evaluation of the reliability and validity of the Medical Outcomes Study sleep scale in patients with painful diabetic peripheral neuropathy during an international clinical trial. Health Qual Life Outcomes 2008;6:113. [46] Allen RP, Kosinski M, Hill-Zabala CE, et al. Psychometric evaluation and tests of validity of the Medical Outcomes Study 12-item Sleep Scale (MOS sleep). Sleep Med 2009;10:531–9. [47] Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193–213. [48] Gentili A, Weiner DK, Kuchibhatla M, et al. Test-retest reliability of the Pittsburgh sleep quality index in nursing home residents. J Am Geriatr Soc 1995;43:1317–8. [49] Carpenter JS, Andrykowski MA. Psychometric evaluation of the Pittsburgh Sleep Quality Index. J Psychosom Res 1998;45:5–13. [50] Doi Y, Minowa M, Uchiyama M, et al. Psychometric assessment of subjective sleep quality using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI-J) in psychiatric disordered and control subjects. Psychiatry Res 2000;97:165–72. [51] Fictenberg NL, Putnam SH, Mann NR, et al. Insomnia screening in postacute traumatic brain injury: utility and validity of the Pittsburgh Sleep Quality Index. Am J Phys Med Rehabil 2001;80:339–45. [52] Shochat T, Tzischinsky O, Oksenberg A, et al. Validation of the Pittsburgh Sleep Quality Index Hebrew translation (PSQI-H) in a sleep clinic sample. Isr Med Assoc J 2007;9:853–6. [53] Vickrey BG, Hays RD, Harooni R, et al. A health-related quality of life measure for multiple sclerosis. Qual Life Res 1995;4:187–206. [54] Bergner M, Bobbitt RA, Carter WB, et al. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981;19:787–805. [55] Flachenecker P, Kümpfel T, Kallmann B, et al. Fatigue in multiple sclerosis: a comparison of different rating scales. Mult Scler 2002;8:523–6.

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14 [56] Kos D, Nagels G, D’Hooghe MB, et al. A rapid screening tool for fatigue impact in multiple sclerosis. BMC Neurol 2006;17(6):27. [57] Amtmann D, Bamer AM, Noonan V, et al. Comparison of the psychometric properties of two fatigue scales in multiple sclerosis. Rehabil Psychol 2012;57:159–66. [58] Smets EM, Garssen B, Bonke B, et al. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39:315–25. [59] Smets EM, Garssen B, Cull A, et al. Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy. Br J Cancer 1996;73:241–5. [60] Lin JM, Brimmer DJ, Maloney EM, et al. Further validation of the Multidimensional Fatigue Inventory in a US adult population sample. Popul Health Metr 2009;15(7):18. [61] Brunier G, Graydon J. A comparison of two methods of measuring fatigue in patients on chronic haemodialysis: visual analogue vs Likert scale. Int J Nurs Stud 1996;33:338–48. [62] Beiske AG, Naess H, Aarseth JH, et al. Health-related quality of life in secondary progressive multiple sclerosis. Mult Scler 2007;13:386–92. [63] Kos D, Kerckhofs E, Nagels G, et al. Origin of fatigue in multiple sclerosis: review of the literature. Neurorehabil Neural Repair 2008;22:91–100 [published online ahead of print April 4, 2007]. [64] Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol 1984;40:1365–7. [65] Jo SA, Park MH, Jo I, et al. Usefulness of Beck Depression Inventory (BDI) in the Korean elderly population. Int J Geriatr Psychiatry 2007;22:218–23. [66] Lovera J, Bagert B, Smoot KH, et al. Correlations of perceived deficits questionnaire of Multiple Sclerosis Quality of Life Inventory with Beck Depression Inventory and neuropsychological tests. J Rehabil Res Dev 2006;43:73–82. [67] Chellappa SL, Araújo JF. Excessive daytime sleepiness in patients with depressive disorder. Rev Bras Psiquiatr 2006;28:126–9 [published online ahead of print June 26, 2006]. [68] Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas 1977;1:385–401. [69] Verdier-Taillefer MH, Gourlet V, Fuhrer R, et al. Psychometric properties of the Center for Epidemiologic Studies-Depression scale in multiple sclerosis. Neuroepidemiology 2001;20:262–7. [70] Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14(6):540–5. [71] Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992;15:376–81. [72] Olson LG, Cole MF, Ambrogetti A. Correlations among Epworth Sleepiness Scale scores, multiple sleep latency tests and psychological symptoms. J Sleep Res 1998;7:248–53. [73] Chervin RD. The multiple sleep latency test and Epworth sleepiness scale in the assessment of daytime sleepiness. J Sleep Res 2000;9:399–401. [74] Chervin RD, Aldrich MS. The Epworth Sleepiness Scale may not reflect objective measures of sleepiness or sleep apnea. Neurology 1999;52:125–31. [75] Fong SY, Ho CK, Wing YK. Comparing MSLT and ESS in the measurement of excessive daytime sleepiness in obstructive sleep apnoea syndrome. J Psychosom Res 2005;58:55–60. [76] Izci B, Ardic S, Firat H, et al. Reliability and validity studies of the Turkish version of the Epworth Sleepiness Scale. Sleep Breath 2008;12:161–8. [77] Tsuno N, Jaussent I, Dauvilliers Y, et al. Determinants of excessive daytime sleepiness in a French community-dwelling elderly population. J Sleep Res 2007;16:364–71. [78] Ritvo PG, Fischer JS, Miller DM, et al. Multiple Sclerosis Quality of Life Inventory (MSQLI): a user’s manual. New York (NY): National Multiple Sclerosis Society; 1997. [79] Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230–5. [80] Schwartz J, Karatinos G. For individuals with obstructive sleep apnea, institution of CPAP therapy is associated with an amelioration of symptoms of depression which is sustained long term. J Clin Sleep Med 2007;3:631–5. [81] Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297–307. [82] Soldatos CR, Dikeos DG, Paparrigopoulos TJ. The diagnostic validity of the Athens Insomnia Scale. J Psychosom Res 2003;55:263–7. [83] Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519–24. [84] Doghramji K, Mitler MM, Sangal RB, et al. A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997;103:554–62. [85] Wilhelm B, Wilhelm H, Lüdtke H, et al. Pupillographic assessment of sleepiness in sleep deprived healthy subjects. Sleep 1998;21:258–65. [86] Anund A, Kecklund G, Kircher A, et al. The effects of driving situation on sleepiness indicators after sleep loss: a driving simulator study. Health 2009;47:393–401. [87] Anderson C, Horne JA. Sleepiness enhances distraction during a monotonous task. Sleep 2006;29:573–6. [88] Finke C, Pech LM, Sömmer C, et al. Dynamics of saccade parameters in multiple sclerosis patients with fatigue. J Neurol 2012;259:2656–63.

13

[89] Lee KA, Hicks G, Nino-Murcia G. Validity and reliability of a scale to assess fatigue. Psychiatry Res 1991;36:291–8. [90] American Academy of Sleep Medicine (AASM). International classification of sleep disorders. 2nd ed. Westchester (IL): American Academy of Sleep Medicine; 2005. [91] Hossain JL, Ahmad P, Reinish LW, et al. Subjective fatigue and subjective sleepiness: two independent consequences of sleep disorders? J Sleep Res 2005;14:245–53. [92] Bailes S, Libman E, Baltzan M, et al. Fatigue: the forgotten symptom of sleep apnea. J Psychosom Res 2011;70:346–54. [93] Tachibana N, Howard RS, Hirsch NP, et al. Sleep problems in multiple sclerosis. Eur Neurol 1994;34:320–3. [94] Ferini-Strambi L, Filippi M, Martinelli V, et al. Nocturnal sleep study in multiple sclerosis: correlations with clinical and brain magnetic resonance imaging findings. J Neurol Sci 1994;125:194–7. [95] Merlino G, Fratticci L, Lenchig C, et al. Prevalence of ‘poor sleep’ among patients with multiple sclerosis: an independent predictor of mental and physical status. Sleep Med 2009;10:26–34. [96] Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444–52. [97] Bøe Lunde HM, Aae TF, Indrevåg W, et al. Poor sleep in patients with multiple sclerosis. PLoS One 2012;7(11):e49996 [published online ahead of print November 14, 2012]. [98] World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: World Health Organization; 1992. [99] American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition. Washington (DC): American Psychiatric Association; 1994. [100] Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6:97–111. [101] Pokryszko-Dragan A, Bilin´ska M, Gruszka E, et al. Sleep disturbances in patients with multiple sclerosis. Neurol Sci 2013;34:1291–6 [published online ahead of print October 30,2012]. [102] Stanton BR, Barnes F, Silber E. Sleep and fatigue in multiple sclerosis. Mult Scler 2006;12:481–6. [103] Bamer AM, Johnson KL, Amtmann D, et al. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler 2008;14:1127–30. [104] Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4:487–504. [105] Ohayon MM. Nocturnal awakenings and comorbid disorders in the American general population. J Psychiatr Res 2008;43:48–54. [106] Bliwise DL, Foley DJ, Vitiello MV, et al. Nocturia and disturbed sleep in the elderly. Sleep Med 2009;10:540–8. [107] Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardisation of terminology in nocturia: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:179–83. [108] Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect of nocturia on sleep. Sleep Med Rev 2011;15:91–7. [109] Yu HJ, Chen FY, Huang PC, et al. Impact of nocturia on symptomspecific quality of life among community-dwelling adults aged 40 years and older. Urology 2006;67:713–8. [110] Fiske J, Scarpero HM, Xue X, et al. Degree of bother caused by nocturia in women. Neurourol Urodyn 2004;23:130–3. [111] Kobelt G, Borgstrom F, Mattiasson A. Productivity, vitality and utility in a group of healthy professionally active individuals with nocturia. BJU Int 2003;91:190–5. [112] Valiquette G, Herbert J, Maede-D’Alisera P. Desmopressin in the management of nocturia in patients with multiple sclerosis. A double-blind, crossover trial. Arch Neurol 1996;53:1270–5. [113] Mahajan ST, Patel PB, Marrie RA. Under treatment of overactive bladder symptoms in patients with multiple sclerosis: an ancillary analysis of the NARCOMS Patient Registry. J Urol 2010;183:1432–7. [114] Manconi M, Ferini-Strambi L, Filippi M, The Italian REMS Study Group. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS Study. Sleep 2008;31:944–52. [115] Miri S, Rohani M, Sahraian MA, et al. Restless legs syndrome in Iranian patients with multiple sclerosis. Neurol Sci 2013;34:1105–8 [published online ahead of print September 9, 2012]. [116] Li Y, Munger KL, Batool-Anwar S, et al. Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women. Neurology 2012;78:1500–6. [117] O’Connor AB, Schwid SR, Herrmann DN, et al. Pain associated with multiple sclerosis: systematic review and proposed classification. Pain 2008;137:96–111. [118] Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039–62. [119] Kaynak H, Altintasß A, Kaynak D, et al. Fatigue and sleep disturbance in multiple sclerosis. Eur J Neurol 2006;13:1333–9. [120] Attarian HP, Brown KM, Duntley SP, et al. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch Neurol 2004; 61:525–8.

14

C. Veauthier, F. Paul / Sleep Medicine 15 (2014) 5–14

[121] Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64:1139–43. [122] Lichstein KL, Means MK, Noe SL, et al. Fatigue and sleep disorders. Behav Res Ther 1997;35:733–40. [123] Veauthier C, Paul F. Fatigue in multiple sclerosis: which patient should be referred to a sleep specialist? Mult Scler 2012;18:248–9. [124] Veauthier C, Blau A, Paul F. ‘Obstructive sleep apnea is associated with fatigue in multiple sclerosis’ by Kaminska et al.. Mult Scler 2013;19:372–3 [published online ahead of print April 18, 2012]. [125] Kaminska M, Kimoff R, Trojan D. Reply: ‘obstructive sleep apnea is associated with fatigue in multiple sclerosis’ by Kaminska et al.. Mult Scler 2013;19(3):374–5 [published online ahead of print May 4, 2012]. [126] Côté I, Trojan D, Kaminska M, et al. Impact of sleep disorder treatment on fatigue in multiple sclerosis. Mult Scler 2013;19:480–9 [published online ahead of print August 22, 2012]. [127] Veauthier C, Gaede G, Radbruch H, et al. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin Neurol Neurosurg 2013;115:1826–30 [published online ahead of print June 13, 2010]. [128] Wang CY, Kawashima H, Takami T, et al. A case of multiple sclerosis with initial symptoms of narcolepsy. No To Hattatsu 1998;30:300–6 [In Japanese]. [129] Iseki K, Mezaki T, Oka Y, et al. Hypersomnia in MS. Neurology 2002;59:2006–7. [130] Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005;9:269–310. [131] Papuc´ E, Stelmasiak Z, Grieb P, et al. CSF hypocretin-1 concentrations correlate with the level of fatigue in multiple sclerosis patients. Neurosci Lett 2010;19(474):9–12. [132] Constantinescu CS, Niepel G, Patterson M, et al. Orexin A (hypocretin-1) levels are not reduced while cocaine/amphetamine regulated transcript levels are increased in the cerebrospinal fluid of patients with multiple sclerosis: no correlation with fatigue and sleepiness. J Neurol Sci 2011;15(307):127–31. [133] Huitinga I, De Groot CJ, Van der Valk P, et al. Hypothalamic lesions in multiple sclerosis. J Neuropathol Exp Neurol 2001;60:1208–18.

[134] Huitinga I, Erkut ZA, van Beurden D, et al. Impaired hypothalamus–pituitary– adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions. Ann Neurol 2004;55:37–45. [135] Plazzi G, Montagna P. Remitting REM sleep behavior disorder as the initial sign of multiple sclerosis. Sleep Med 2002;3:437–9. [136] Benedict RH, Hulst HE, Bergsland N, et al. Clinical significance of atrophy and white matter mean diffusivity within the thalamus of multiple sclerosis patients. Mult Scler 2013;19:1378–84 [published online ahead of print March 4, 2013]. [137] Lansley J, Mataix-Cols D, Grau M, et al. Localized grey matter atrophy in Multiple Sclerosis: a meta-analysis of voxel-based morphometry studies and associations with functional disability. Neurosci Biobehav Rev 2013;37:819–30 [published online ahead of print March 18, 2013]. [138] Rizzo G, Tonon C, Testa C, et al. Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome. Brain 2012;135(pt 12):3712–20. [139] Nair G, Absinta M, Reich DS. Optimized T1-MPRAGE sequence for better visualization of spinal cord multiple sclerosis lesions at 3T. AJNR Am J Neuroradiol 2013;34(11):2215–22 [published online ahead of print June 13, 2013]. [140] Klawiter EC, Xu J, Naismith RT, et al. Increased radial diffusivity in spinal cord lesions in neuromyelitis optica compared with multiple sclerosis. Mult Scler 2012;18:1259–68. [141] Telles SC, Alves RC, Chadi G. Periodic limb movements during sleep and restless legs syndrome in patients with ASIA A spinal cord injury. J Neurol Sci 2011;303:119–23. [142] Guilleminault C, Lopes MC, Hagen CC, da Rosa A. The cyclic alternating pattern demonstrates increased sleep instability and correlates with fatigue and sleepiness in adults with upper airway resistance syndrome. Sleep 2007;30:641–7. [143] Allen RP. Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome. Am J Med 2007;120(Suppl. 1):S13–21. [144] Allen RP, Improving RLS. Diagnosis and severity assessment: polysomnography, actigraphy and RLS-sleep log. Sleep Med 2007;8(Suppl. 2):S13–8.