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Volume 12 No. 06
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Scientific Investigations

Low Prevalence of Sleep Disorders in Demyelinating Disease in a Northern Tenerife Population

http://dx.doi.org/10.5664/jcsm.5874

Montserrat González-Platas, PhD1; Javier González-Platas, PhD2; Moises Bermúdez-Hernández, BS1; Maria Yaiza Pérez-Martín, PhD1; Cristina Croissier-Elías, BS1; Pedro Javier Pérez-Lorensu, BS1
1Department of Neurology, Hospital Universitario de Canarias, Spain; 2Faculty of Mathematics and Physics, University of La Laguna, Campus Anchieta, La Laguna, Spain

ABSTRACT

Study Objectives:

Sleep disorders are seen in patients with demyelinating disease (DD) more often than in the general population. Combination of physical and psychological factors such as pain, spasms, nocturia, depression, anxiety, or medication effects could contribute to sleep disruption. Frequently, these disturbances have a major impact on health and quality of life of patients. The aim of this study was to estimate the prevalence of sleep disorders in patients seen in the DD consultation.

Methods:

240 patients; mean age 43 years, 187 women; 163 patients with multiple sclerosis (MS): 144 relapsing-remitting, 19 progressive forms, 36 clinically isolated syndrome, 26 radiological isolated syndrome, and 15 patients with others DD. All participants completed questionnaires: Pittsburgh, Epworth, and Stanford scales, indirect symptoms of RLS and Obstructive Sleep Apnea, Fatigue Severity Scale, and Multiple Sclerosis Quality of Life-54.

Results:

Moderate/severe insomnia 12.5%, OSA 5.8%, RLS 9.6% (confirmed 3 cases), narcolepsy 0, fatigue (> 4) 24.6%. Physical QoL 66.6 ± 19.6, Mental QoL 66.1 ± 21.9. Patients with an established diagnosis showed higher scores on insomnia compared to the group of CIS and RIS (F = 3.85; p = 0.023), no differences were in the other parameters. Fatigue showed high correlation with insomnia (r = 0.443; p < 0.001), RLS (r = 0.513; p < 0.001), and sleepiness (r = 0.211; p = 0.001). None of the variables included in the regression model were shown to be predictors of Physical and Mental QoL.

Conclusions:

A high percentage of our sample sleeps well. Emphasize the low prevalence of sleep disorders (insomnia, fatigue, RLS, etc). We detected an overestimation in the RLS questionnaire and the low QoL recorded.

Citation:

González-Platas M, González-Platas J, Bermúdez-Hernández M, Pérez-Martín MY, Croissier-Elías C, Pérez-Lorensu PJ. Low prevalence of sleep disorders in demyelinating disease in a northern tenerife population. J Clin Sleep Med 2016;12(6):805–811.


INTRODUCTION

Multiple sclerosis (MS) is the main cause of a chronic traumatic disability among young adults (between 20 and 50 years of age) with neurological disorder. MS is an inflammatory autoimmune disease of the central nervous system (CNS) resulting in myelin destruction and axonal degeneration in the brain and spinal cord.

Eighty percent of patients present a relapsing-remitting sub-type, characterised by clearly defined episodes of neurological dysfunction (relapses) separated by periods of relative clinical stability (remissions). In the majority of untreated cases, relapsing-remitting MS evolves into a secondary-progressive phase during which the subject experiences a gradual, insidious deterioration, usually in the form of paraparesis, hemiparesis, or dementia. A primary-progressive subtype occurs in a smaller percentage of patients, characterised by a slow deterioration in neurologic function from onset, without distinct relapses.

The clinical manifestations of MS are provoked by multifocal demyelination and damage to axons in multiple neurological functional systems; these are known as deficit symptoms (or negative symptoms). Other manifestations of MS, such as neuropathic pain and paroxysmal phenomena, are derived from functionally inappropriate axonal responses, which are known as positive symptoms.

BRIEF SUMMARY

Current Knowledge/Study Rationale: Our goal was to indentify the presence of sleep problems in the study population with the objective to refer the patients to a specialist in sleep disorders for their treatment. We endeavored to confirm that sleep disorders are as prevalent as those described in the literature to determine if the measuring instruments used are useful for its detection.

Study Impact: There is a significant the low prevalence of sleep disorders in the population in our study compared with other studies. This illustrates the importance of avoiding biases in the selection of the sample and to not specifically select those patients having explicit complaints of sleep problems.

The frequency of sleep disturbances in MS and their impact on the patients' quality of life are unknown. The few studies published on this subject report that sleep disturbances are more prevalent among MS patients than in the general population, ranging from 25% to 54% according to the patient series analyzed.13

Sleep disorders during the course of MS may be secondary to numerous symptoms arising from the disease itself or can be primary with a common biological link. In either of the two cases, a bidirectional relationship exists between these comorbid conditions.4

Insomnia, restless legs syndrome (RLS), respiratory disorders during sleep and narcolepsy are the more frequent sleep disturbances associated with MS.

Insomnia

Insomnia, or sleeplessness, is an inability to fall asleep or to stay asleep as long as desired. Insomnia is described as a complaint of prolonged sleep onset latency, disturbance of sleep maintenance, or the experience of non-refreshing sleep. Patients with insomnia may complain of difficulty falling asleep, difficulty staying asleep, or waking up sooner than desired. Episodic insomnia can usually be traced to an acute psychological stressor or an environmental change. Chronic insomnia may be related to a combination of factors including depression, poor sleep hygiene, learned sleeplessness, sleep-disordered breathing, nocturia, medications, or extrinsic factors such as noise.5

Patients with MS face a high risk of insomnia of around 40%.1,6 Awakening too early in the morning is the most common symptom (58%).7 Primary symptoms of MS which can be associated with insomnia are neurogenic bladder (nocturia), spasticity, sexual dysfunction, neuropathic pain, paroxysmal phenomena, depression and anxiety, whereas insomnia affects daytime activities, because of fatigue, mood disturbances, attention, concentration and memory impairment.4

Restless Legs Syndrome

The 4 main criteria for diagnosis of restless legs syndrome (RLS) are: (1) unpleasant sensations in the legs; (2) worsening of the symptoms during rest; (3) relief of the symptoms by movement; and (4) exacerbation of the symptoms in the evening or at night.8

Most RLS patients (80% to 90%) have periodic leg movements (PLM) during sleep. They can cause arousals or micro-arousals leading to non-refreshing sleep, daytime sleepiness, and fatigue. The prevalence of RLS in MS patients and the general population is 19% vs. 4.2%, respectively, as reported in the main multicenter study.1014

RLS should always be considered in MS patients complaining of insomnia or excessive daytime sleepiness. However, differentiating RLS from other sensory and motor symptoms of MS can be difficult, as MS patients frequently suffer from spasms, dysesthesias, paresthesias and spasticity in the legs, which worsen with immobility.15

Predictive factors for RLS in MS patients include: older age, longer disease duration, progressive primary forms, greater disability (as measured by the EDSS scale), especially in the pyramidal and sensory subscales and shaking of the legs before onset of sleep.16 Furthermore, RLS symptoms are more severe when associated with MS than when not associated with MS.

RLS is a common finding in MS and correlates with cervical cord damage. Primary RLS is a genetic form of RLS with autosomal dominant transmission.17 RLS is frequently secondary to numerous physiological or pathological conditions, many of which are associated with iron deficiency, including anemia, renal failure, pregnancy, diabetes, rheumatoid arthritis, neuropathies, myelopathies, Parkinson disease and spinocerebellar ataxia. Furthermore, RLS has also been linked to the use of certain drugs, including dopaminergic antagonists, antidepressants, and lithium.18

Respiratory Disorders during Sleep

Sleep-disordered breathing is characterised by episodes of nocturnal hypopnea and apnea resulting in a reduction or a cessation of airflow in the upper airway. Apnea and hypopnea may be caused by a collapse of the tissues and muscles in the pharynx (obstructive apnea/hypopnea) or a failure in the medullary respiratory signal (central apnea/hypopnea). These apnea and hypopnea episodes may lead to nocturnal hypoxemia, frequent awakenings, and daytime somnolence. Patients with sleep-disordered breathing may complain of “fatigue,” decreased concentration, mood changes, erectile dysfunction, nocturia and mood changes—all of which are complaints similar to those experienced in MS.19

The prevalence of obstructive sleep apnoea in patients with MS is not higher than in the general population and should be considered in this patient population in the evaluation of symptoms of daytime somnolence, increased fatigue, and non-refreshing sleep.5

Obstructive sleep apnea (OSA) is one of the most common respiratory disorders, affecting 2% of women and 4% of men of adults. Central sleep apnoea (CSA) is rare, and the prevalence is unclear in the general population. The coexistence of OSA or CSA and MS has been described in the literature.1,20

Narcolepsy

Narcolepsy is classified as a chronic sleep disorder associated with sleep attacks and other features attributed to abnormalities of REM (rapid eyes movements) sleep, such as hypnagogic/ hypnopompic hallucinations, cataplexy, sleep paralysis, and disrupted nocturnal sleep. The usual polysomnographic features include a mean sleep latency ≤ 8 min and ≥ 2 sleep onset REM periods (SOREMPs). There is a high variability in the prevalence across different geographic areas, which is thought to be related to differences between the populations and current study methods.

A study on the secondary causes of narcolepsy reports that MS is the fourth most common cause of narcolepsy after inherited disorders, CNS tumors and brain injury, and found that 12% of the cases of secondary narcolepsy were due to MS.21 In terms of genetics, 95% of narcoleptic patients and 50% to 60% of MS patients are positive for the DR2 haplotype. The human leukocyte antigen DQB1*0602, a known genetic risk factor for narcolepsy, also influences the presence and severity of MS. Therefore, both diseases are closely related to the same genes of the human leukocyte antigen (HLA) system, which is the basis for the labelling of most autoimmune diseases. This relationship suggests that similar autoimmune factors may be at work in the development of each disorder and might be partially responsible for symptoms of fatigue and sleepiness.22

Fatigue

Fatigue is defined as the lack of physical or mental energy perceived by the patients or their care givers which interferes with activities of daily living and it is the most frequent symptom in MS. Between 80% to 97% of patients report chronic fatigue, and more than 33% of patients rate this symptom as the most disabling.23,24 Fatigue typically starts early in the morning and increases during the day. Environmental temperature and humidity exacerbate the perception of fatigue.25

Fatigue is considered to be one of the main causes of impaired quality of life among MS patients, regardless of depression or disability. Fatigue also deteriorates cognitive domains, such as information processing, memory and attention,24 and it has significant socioeconomic consequences, including loss of work hours and in some instances, loss of employment.

Fatigue in MS patients may have multifactorial causes: proinflammatory cytokines (INF-α), endocrine influences (cortisol, DHEA), axonal loss, altered patterns of cerebral activation, sleep disorders (RLS, chronic insomnia, sleep-disordered breathing) and medications used to treat MS symptoms or immunomodulatory and immunosuppressive treatments. Altered sleep microstructure, which is reflected in indicators such as the number of spontaneous arousals per hour and the index of interruptions, has been related to the presence of fatigue.26

In addition to immunologic abnormalities, MS is associated with an increased prevalence of other conditions contributing to fatigue, including depression and several sleep disorders.4,27

MS patients, regardless of their level of fatigue, have a significantly high frequency of RLS, higher Epworth Sleepiness Scale scores, and higher Pittsburgh Sleep Quality Index scores. The time in bed, wake time after sleep onset %, total arousal index, limb movement arousal index, and periodic limb movement arousal index were also higher in MS patients than healthy controls. The sleep efficiency index and sleep continuity index are lower in fatigued MS patients than non-fatigued MS patients. The Pittsburgh Sleep Quality Index results also suggest more disrupted sleep in fatigued MS patients. There were no group differences in sleep stage percentages, apnea/ hypopnea indices, or minimum oxygen saturations. Depression symptoms also correlated with fatigue in the study by Kaynak et al.28

The aforementioned findings merit further attention given the potential impact of sleep disorders on the health and quality of life of MS patients. Sleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes29 and can contribute to the depression, pain and fatigue symptoms that are commonly seen in MS patients, which are often disabling.2,28

The aim of this study is to investigate the prevalence of sleep disturbance in patients with demyelinating disease (DD) and whether DD clinical symptoms are associated with sleep disturbance.

METHODS

This study was carried out in accordance with the Declaration of Helsinki and was approved by the Local Ethics Committee. After a detailed explanation of the study, all subjects provided written informed consent.

Patients diagnosed with the following pathologies were included in the study: radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS), and other demyelinating disease (DD). Radiologically isolated syndrome (RIS) affects patients who have incidental brain MRI abnormalities suggestive of MS, but without any sign or symptom attributable to the disease.

Clinically isolated syndrome (CIS) involves CNS demyelination occurring in the optic nerve, brain stem, or spinal cord, or any 2 or all 3 of these areas, and which is not attributable to other diseases.30

Relapsing-remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) were defined according to the revised McDonald criteria 2010 and reporting neither attacks nor steroid use during the month before the interview was held.

Other demyelinating disease (DD): different from MS but which were attended to in our consulting service.

All patients selected were in our Multiple Sclerosis Database and were contacted by telephone. The patients who consented to participate in the study completed the following questionnaires between April and November 2012: Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), Grade severity with the IRLS Rating Scale, Krupp's Fatigue Severity Scale (FSS) and Multiple Sclerosis Quality of Life-54 (MSQOL-54). A further 10 questions designed to identify the presence of obstructive sleep apnea syndrome (OSA) were also used.

The following patient data were collected: age, gender, age at onset of DD, first symptoms, disease duration, frequency of attacks, family history of MS, existence of other diseases, past brainstem or spinal cord relapse and drug intake (related to MS) of patients were also recorded.

A neurological examination of all the patients was carried out, and their disability was defined according to Kurtzke Expanded Disability Status Scale (EDSS) score and by using points for functional systems.31

MRI (magnetic resonance imaging) scans were retrospectively reviewed and the location of the lesions was recorded with special attention paid to the presence/absence of spinal cord, brainstem and basal ganglia lesions (MRI performed in the 6 months before or after the questionnaires).

The relationships between sleep disturbances, fatigue and quality of life were analyzed. Patients with abnormal scores were referred to a specialist in sleep disorders to confirm or rule out the presence of disease.

Statistical Analyses

Categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as means, standard deviations, medians and ranges (min-max). Normality was tested with the Kolmogorov-Smirnov test.

The comparison between groups for continuous variables was performed with the T test and the Mann Whitney U test was used for the comparison of categorical variables.

Pearson correlation analysis was used to investigate the relationships among quantitative variables. The regression model was used to find predictors.

Statistical analysis was performed with SPSS v. 17.0 (Chicago, IL). P values less than 0.05 were considered statistically significant.

RESULTS

The clinical and demographic characteristics of the patients are shown in Table 1. Two hundred forty of the 324 patients who came to the multiple sclerosis unit in our hospital participated in the study (74% of the total). There were no differences between participants and nonparticipants in age, disease duration, EDSS score, and type of disease, but there were differences in gender (there were more women than men).

Clinical and demographic characteristics of patients.

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Table 1

Clinical and demographic characteristics of patients.

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The study sample consisted of 187 women and 53 men with an average age of 43 years. RRMS was the most common diagnosis of the patients (59.6%) followed by CIS (15%), RIS (10.8%), other DD (6.3%), and SPMS and PPMS (5.8% and 2.1%, respectively). The mean disease duration was 9 years and the mean EDSS score mean was 2.16 (median 1.5).

Sleep disorders are shown in Table 2 (first column shows the results of the total sample and the second column shows the results of patients with MS and CIS but not RIS and other DD different from MS). Only 12.6% (30 out of 240) of the DD patients had moderate or severe insomnia. Sixteen patients (6.7%) suffered from sleepiness as defined by SSS score (more related with alertness) and 23 patients (9.6%) suffered from sleepiness as defined by ESS. RLS symptoms were reported in differing degrees by 72 patients (30%). The PSQI parameters show that the mean sleep time was approximately 450 minutes (around 7 h), and the sleep efficiency was 87.33%. No cases of OSA were detected.

Sleep disorder measurements using questionnaires.

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Table 2

Sleep disorder measurements using questionnaires.

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One hundred twenty-four patients scored within normal limits on all the sleep questionnaires. As regards the interactions found, the most frequent association was moderate insomnia and severe RLS or moderate RLS symptoms (12 and 5 patients, respectively); the other interactions were uncommon, and in fact, only one had an altered score in SSS, ESS, and reported severe RLS symptoms and subclinical insomnia. Conversely, the evaluation performed by the sleep disorders specialist showed a low confirmation with only 3 of 72 patients with a confirmed diagnostic of RLS.

Relationship between Sleep Variables

The Pearson correlation showed that higher scores on insomnia were associated with more RLS symptoms (r = 0.356; p < 0.001), higher ESS scores (r = 0.174; p = 0.007), and less sleep efficiency (r = −0.170; p = 0.009).

The RLS score showed a strong correlation with sleep latency and efficiency (r = 0.386 and r = −0.314; p < 0.001) and ESS score (r = 0.224; p < 0.001).

The SSS score showed no relationship with any other sleep parameter.

Relationship of Sleep Parameters with Age and Gender

No correlation was found between sleep questionnaires and age. As regards gender, men showed significantly higher SSS scores than women (F = 0.975; p = 0.005) and no other differences were found.

Relationship of Sleep Parameters with Clinical Variables

No differences associated with the type of disease were found. Disease duration was moderately related to the SSS score (r = 0.134; p = 0.038) but not to other sleep disorders. The presence of urinary problems (bladder EDSS score) was not associated with sleep variables (EDSS ignores the presence of nocturia). The EDSS score was moderately related to quality of sleep (r = −0.163; p = 0.012) and more specifically, the sensitive score on the EDSS scale was related to insomnia (r = 0.170; p = 0.008) and patients with spasticity (nightly spasms and anti-spastic medication) had a higher score on insomnia (F = 4.562; p = 0.033)

Radiological Variables

The presence of lesions in the target areas was observed in the radiology report so it is possible that these data regarding this are underestimated. The number of patients with lesions in the target areas is shown in Table 3.

Radiological parameters.

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Table 3

Radiological parameters.

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The patients with spinal cord lesions had higher insomnia scores (F = 13.256; p = 0.002) and severity of RL symptoms (F = 17.365; p = 0.032) than patients without these lesions. Brainstem lesion presence was not associated with any questionnaire result and the presence of basal ganglia lesions was associated with SSS (F = 1.030; p = 0.12).

Fatigue

Table 2 shows FSS scores. When using FSS 4 as the cutoff score, 59 (24.6%) patients were categorized as suffering from fatigue. Higher FSS scores were associated to EDSS (r = 0.191; p = 0.003) and disease duration (r = 0.171; p = 0.008).

The results regarding the differences in sleep disorders between patients suffering from fatigue and patients not suffering from fatigue are shown in Table 4. The fatigue group show more insomnia, RLS symptoms and latency and poorer efficiency and quality of sleep.

Fatigue and sleep parameters.

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Table 4

Fatigue and sleep parameters.

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EDSS

Three groups of patients were defined according to their EDSS scores. The mild disability group included patients with an EDSS ≤ 3, the moderate disability group included patients with an EDSS score > 3 and ≤ 6, and the severe disability group included patients with an EDSS score > 6.

The patients with severe disability reported poorer quality of sleep than patients with mild disability. No differences between the mild and moderate or between the moderate and severe disability groups were found in any of the sleep questionnaires.

Quality of Life (QOL)

Table 2 shows the results of quality of life as measured with the MSQOL-54.

All the variables in the sleep questionnaires and fatigue were included in the regression model in order to identify predictors of QOL. None of the variables proved to be predictors of physical or mental QOL. On the other hand, physical QOL correlated with fatigue (r = −0.133; p = 0.042) and RLS (r = −0.156; p = 0.016) and mental QOL correlated with quality of sleep (r = −0.136; p = 0.037), insomnia (r = −0.139; p = 0.0339), and RLS (r = −0.158; p = 0.015).

DISCUSSION

Firstly, it should be mentioned that this study was conducted in a demyelinating diseases medical unit, unlike other studies in the area, and did not exclusively include patients with definite diagnosis of MS (RIS and other DD patients were included).

One of the objectives of the present study was to help determine the frequency of sleep disorders among the population affected by DD. In this regard, the low prevalence of sleep disturbances found in the series in this study compared with the data found in the literature is noteworthy.5,32 The combination of two or more sleep disorders is also infrequent.

RLS is the most commonly referred to disorder in the study sample, although the low number of case confirmations by the sleep specialist suggests the low diagnostic accuracy of the test used. These data agree with those of Gómez-Choco et al., who reported that the RLS disorder in MS is not more frequent than in the general population.11

Only a small percentage of the patients in the study reported moderate to severe symptoms of insomnia. Sleepiness or drowsiness was very uncommon (less than 10% of the sample) and no cases of OSA were detected. Moreover, the patients in the study reported good sleep efficiency.

As regards insomnia, this may be related to poor sleep hygiene, medications, or learned sleeplessness in the general population, and some authors report that 40% of patients with MS have insomnia and consequently have difficulty initiating or maintaining sleep.1 Insomnia was related to sensitive symptoms (obtained from the EDSS score), spasticity, and presence of spinal cord lesions in the sample of the present study.

Sleepiness defined by the SSS was related to the disease duration and was present more often in men than women. The results are possibly related to a more “cognitive” component of sleepiness (mental fatigue), which may explain, in part, why its relationship with cognitive impairment is more common in men than in women with MS and sleepiness seems to be related to the duration of the disease.33

Fatigue, one of the most disabling deficits in MS patients, has been frequently associated with sleep distortions.34,35 In the present series, fatigue was associated with higher latency, poorer sleep efficiency, and symptoms of RLS in the IRLS Rating Scale. The aforementioned finding supports the idea that fatigue and abnormalities in the circadian sleep-wake rhythm frequently coexist.

Neurological disability, in the present study, is most commonly classified as a feature of mild to moderate disability (defined by Kurtzke scale). The quality of sleep was only associated with patients with severe disability as compared to mild disability, but may be associated with moderate symptoms due to the presence of important mobility problems. Sleep disturbances have recently been related with the EDSS score.36

Quality of life was associated with differential aspects depending on the physical and mental component. Thus, the physical QOL was associated with fatigue and RLS symptoms and mental QOL was associated with quality of sleep, insomnia and RLS. The aforementioned suggests that sleep disorders may impair the quality of life of patients with MS, which has been reported in other studies.36,37

It should be mentioned that the present study does not include factors such as the use of drugs or the presence of psychiatric disorders (anxiety or depression).

The count of injuries in target areas of sleep pathology in MRI was taken from the radiological report (not specifically addressed to these areas). It is possible that new conclusions would be drawn if the images were revised again.

In conclusion, the low prevalence of sleep disorders in the population of the present study compared with other studies is noteworthy, considering that the sample in this study was expanded to include demyelinating diseases other than multiple sclerosis and patients with RIS and there was no bias in the selection of subjects.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.

ABBREVIATIONS

CIS

clinically isolated syndrome

CNS

central nervous system

CSA

central sleep apnoea

DD

demyelinating disease

EDSS

Expanded Disability Status Scale

ESS

Epworth Sleepiness Scale

FSS

Fatigue Severity Scale

HLA

human leukocyte antigen

ISI

Insomnia Severity Index

MRI

magnetic resonance imaging

MS

multiple sclerosis

MSQOL-54

Multiple Sclerosis Quality of Life-54

OSA

obstructive sleep apnea

PPMS

primary progressive multiple sclerosis

PSQI

Pittsburgh Sleep Quality Index

QOL

quality of life

REM

rapid eyes movements

RIS

radiologically isolated syndrome

RLS

restless legs syndrome

RRMS

relapsing-remitting multiple sclerosis

SOREMPs

sleep onset REM periods

SPMS

secondary progressive multiple sclerosis

SSS

Stanford Sleepiness Scale

REFERENCES

1 

Tachibana N, Howard RS, Hirsch NP, Miller DH, Moseley IF, Fish D, authors. Sleep problems in multiple sclerosis. Eur Neurol. 1994;34:320–3. [PubMed]

2 

Merlino G, Fratticci L, Lenchig C, et al., authors. Prevalence of “poor sleep” among patients with multiple sclerosis: an independent predictor of mental and physical status. Sleep Med. 2009;10:26–34. [PubMed]

3 

Bamer AM, Johnson KL, Amtmann D, Kraft GH, authors. Prevalence of sleep problems in individuals with multiple sclerosis. Mult Scler. 2008;14:1127–30. [PubMed Central][PubMed]

4 

Caminero A, Bartolomé M, authors. Sleep disturbances in multiple sclerosis. J Neurol Sci. 2011;309:86–91. [PubMed]

5 

Fleming WE, Pollak CP, authors. Sleep disorders in multiple sclerosis. Semin Neurol. 2005;25:64–8. [PubMed]

6 

Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M, authors. Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults. J Clin Sleep Med. 2008;4:487–504. [PubMed Central][PubMed]

7 

Stanton BR, Barnes F, Silber E, authors. Sleep and fatigue in multiple sclerosis. Mult Scler. 2006;12:481–6. [PubMed]

8 

Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J, authors. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101–19. [PubMed]

9 

Ondo WG, author. Restless legs syndrome. Neurol Clin. 2009;27:779–99. vii. [PubMed]

10 

Auger C, Montplaisir J, Duquette P, authors. Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis. Neurology. 2005;65:1652–3. [PubMed]

11 

Gómez-Choco MJ, Iranzo A, Blanco Y, Graus F, Santamaria J, Saiz A, authors. Prevalence of restless legs syndrome and REM sleep behavior disorder in multiple sclerosis. Mult Scler. 2007;13:805–8. [PubMed]

12 

Manconi M, Ferini-Strambi L, Filippi M, et al., authors. multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS Study. Sleep. 2008;31:944–52. [PubMed Central][PubMed]

13 

Deriu M, Cossu G, Molari A, et al., authors. Restless legs syndrome in multiple sclerosis: a case-control study. Mov Disord. 2009;24:697–701. [PubMed]

14 

Högl B, Kiechl S, Willeit J, et al., authors. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology. 2005;64:1920–4. [PubMed]

15 

Crayton H, Heyman RA, Rossman HS, authors. A multimodal approach to managing the symptoms of multiple sclerosis. Neurology. 2004;63(11 Suppl 5):S12–18. [PubMed]

16 

Manconi M, Rocca MA, Ferini-Strambi L, et al., authors. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage. Mult Scler. 2008;14:86–93. [PubMed]

17 

Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G, authors. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003;126:1485–92. [PubMed]

18 

Trenkwalder C, Paulus W, authors. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol. 2010;6:337–46. [PubMed]

19 

Caples SM, Gami AS, Somers VK, authors. Obstructive sleep apnoea. Ann Intern Med. 2005;142:187–97. [PubMed]

20 

Ferini-Strambi L, Filippi M, Martinelli V, et al., authors. Nocturnal sleep study in multiple sclerosis: correlations with clinical and brain magnetic resonance imaging findings. J Neurol Sci. 1994;125:194–7. [PubMed]

21 

Nishino S, Kanbayashi T, authors. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev. 2005;9:269–310. [PubMed]

22 

Iseki K, Mezaki T, Oka Y, et al., authors. Hypersomnia in MS. Neurology. 2002;59:2006–7. [PubMed]

23 

Krupp L, author. Fatigue is intrinsic to multiple sclerosis (MS) and is the most commonly reported symptom of the disease. Mult Scler. 2006;12:367–8. [PubMed]

24 

Bakshi R, author. Fatigue associated with multiple sclerosis: diagnosis, impact and management. Mult Scler. 2003;9:219–27. [PubMed]

25 

Vucic S, Burke D, Kiernan MC, authors. Fatigue in multiple sclerosis: mechanisms and management. Clin Neurophysiol. 2010;121:809–17. [PubMed]

26 

Veauthier C, author. Younger age, female sex, and high number of awakenings and arousals predict fatigue in patients with sleep disorders: a retrospective polysomnographic observational study. Neuropsychiatr Dis Treat. 2013;9:1483–94. [PubMed Central][PubMed]

27 

Pokryszko-Dragan A, Bilińska M, Gruszka E, Biel Ł, Kamińska K, Konieczna K, authors. Sleep disturbances in patients with multiple sclerosis. Neurol Sci. 2013;34:1291–6. [PubMed Central][PubMed]

28 

Kaynak H, Altintaş A, Kaynak D, et al., authors. Fatigue and sleep disturbance in multiple sclerosis. Eur J Neurol. 2006;13:1333–9. [PubMed]

29 

Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR, authors. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry. 2002;59:131–6. [PubMed]

30 

Barkhof F, Filippi M, Miller DH, et al., authors. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain J Neurol. 1997;120(Pt 11):2059–69.

31 

Kurtzke JF, author. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–52. [PubMed]

32 

Brass SD, Li C-S, Auerbach S, authors. The underdiagnosis of sleep disorders in patients with multiple sclerosis. J Clin Sleep Med. 2014;10:1025–31. [PubMed Central][PubMed]

33 

Reuter F, Zaaraoui W, Crespy L, et al., authors. Frequency of cognitive impairment dramatically increases during the first 5 years of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2011;82:1157–9. [PubMed]

34 

Labuz-Roszak B, Kubicka-Bączyk K, Pierzchała K, Machowska-Majchrzak A, Skrzypek M, authors. Fatigue and its association with sleep disorders, depressive symptoms and anxiety in patients with multiple sclerosis. Neurol Neurochir Pol. 2012;46:309–17. [PubMed]

35 

Veauthier C, Paul F, authors. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med. 2014;15:5–14. [PubMed]

36 

Leonavicius R, Adomaitiene V, authors. Features of sleep disturbances in multiple sclerosis patients. Psychiatr Danub. 2014;26:249–55. [PubMed]

37 

Bøe Lunde HM, Aae TF, Indrevåg W, et al., authors. Poor sleep in patients with multiple sclerosis. PLoS One. 2012;7:e49996. [PubMed Central][PubMed]