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Clinical Neurology and Neurosurgery 115S (2013) S82– S85

Contents lists available at ScienceDirect

Clinical Neurology and Neurosurgery

j o ur nal hom epage: www.elsev ier .com/ locate /c l ineuro

athophysiological background and clinical characteristics of sleepisorders in multiple sclerosis

arbara Baruna,b,∗

University Hospital Center Zagreb, Department of Neurology, Refferal Center for Demyelinating Diseases of the Central Nervous System, Zagreb, CroatiaSchool of Medicine, University of Zagreb, Department of Neurology, Zagreb, Croatia

r t i c l e i n f o

eywords:ultiple sclerosis

leep disordersarcolepsy

a b s t r a c t

Sleep disorders in multiple sclerosis (MS) are more common than in general population and are con-sidered to be one of the important etiological factors in development of fatigue, most common anddebilitating symptom of MS. Although almost all of the major subgroups of sleep disorders such as insom-

leep disorders breathingircadian rhythm disorders

nia, sleep disordered breathing, REM sleep behavior disorder, narcolepsy and restless legs syndrome havebeen described in the MS patients their higher prevalence in MS population than in healthy controls insome of the sleep disorders is not fully elucidated. Immunological background in disease developmentin both multiple sclerosis and sleep disorders have been proposed as possible common pathophysiologi-cal mechanism and recent findings of disrupted melatonin pathways in MS patients suggest multi-levelcausative mechanism of the development of sleep disorders in MS.

. Introduction

Multiple sclerosis (MS) is a chronic inflammatory disorder ofentral nervous system (CNS) affecting primarily young adults.rom the pathological standpoint it is characterized by inflamma-ion, which results in demyelination and axonal loss as a hallmarkf neurodegeneration. Etiology of MS is not yet completely elu-idated but it is considered to develop as a result of interplayetween hereditary and enviromental factors. Traditionally, MS isiewed as a T-cell driven immune disorder in which primary dys-egulation of peripheral immune responses leads to a CNS-directedutoimmune disease and inflammatory tissue injury which canlso trigger degenerative process, a pathological hallmark of clin-cal progression of neurological impairment. Besides T-cells therere other mediators of cell immunity such as macrophage, reactiveicroglia, NK cells, NK T cells, gamma/delta T cells and mediator of

ummoral immunity like antigen-specific CNS-reactive antibod-es, proinflammatory cytokines, nitric oxide and reactive oxygenpecies, leukotrienes, plasminogen activators and matrixmetalloroteinases (MMPs) [1] Symptoms and sings of MS depend on the

ocation of CNS affected [2] but fatigue is far most common symp-om of MS [3]. Fatigue in MS can be caused either by multipleclerosis per se or it can be result of other frequently encountered

∗ Correspondence to: University Department of Neurology, University Hospitalenter Zagreb, Kispaticeva 12, HR-10000 Zagreb, Croatia. Tel.: +385 12376033;ax: +385 12376033.

E-mail address: barbarabarun@gmail.com

303-8467/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.clineuro.2013.09.028

© 2013 Elsevier B.V. All rights reserved.

disturbances in MS such as depression, sleepiness, pain or due tovarious medication in the latter case it is usually called secondaryfatigue [4].

The exact pathophysiological mechanism of fatigue in CNS dis-orders is not clear but there are plethora of evidence that thereis an interplay between disturbed neurotransmitters equilibrium,immunological misbalance and deranged hypothalamic-pituitary-adrenal axis occurs in states of chronic stress and affects variouscerebral regions, especially limbic system [5,6]. Proinflammatorycytokines such as IL-1, IL-6 and TNF-alpha are abundantly releasedduring systemic inflammation. After entering CNS, usually throughcircumventricular organs, they act upon hypothalamic-pituitary-adrenal axis causing release of cortisol, noradrenaline, serotonineand dopamine [7,8] which results in fatigue, increased body tem-perature, sleepiness and loss of appetite. Sleep disturbances, whichare oftenly underrecognized, are common in MS. It is consideredthat between 25 and 54% of MS patients have sleep disorder [9–11].Given that sleep disorder heighten the risk of the heart disease, dia-betes, obesity, depression, pain and fatigue in MS they should becarefully sought in assessment of the MS patients.

2. Pathophysiological background of sleep disorders in MS

2.1. Immunology of sleep and MS

Traditional understanding that sleep is just lack of wakefulnesshas been challenged in the last half of the century and one of thecontemporary definitions of sleep states that sleep is a reversiblebehavioral state of perceptual disengagement from environment

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nd unresponsiveness to it [12]. Sleep consists of two phases, rapidye movement state (REM) characterized by muscle atonia causedy inhibition of spinal motor neurons by brainstem mechanisms,pisodes of rapid eye movements, EEG activation and dreamingnd non-REM state (NREM) divided into three stages (N1, N2 and3) which differ from each other and each from wakefulness inlearly defined behavioral and electroencephalographic features.t is difficult to define normal pattern of human sleep, especiallyn the grounds of sleep duration. The great number of factors likeolitional control, genetic determinants, duration of prior waken-ng and circadian rhythms determine sleep duration which highlyaries from person to person and from night to night but mostoung adults sleep 7.5 h a night on weekday nights and 8.5 h,n weekend nights [13]. Several brain region modulate sleep andake in humans. Brainstem histaminergic, serotoninergic, nora-renergic, cholinergic and dopaminergic neurons together withypothalamic orexinergic neurons are considered to be major wakeromoting brain regions [14] while preoptic area (POA) of theypothalamus is considered to have major role in promoting NREMleep. Both or these regions are under control of the suprachias-atic nucleus, which is major regulator of the circardian clock.Sleep is also largely influenced by several other biochemical

echanisms and various other neurochemical agents like proin-ammatory cytokines, adenosine, reactive oxygen species (ROS),rostaglandin D2, growth hormone–releasing hormone (GHRH)15]. It has been recognized that cytokines together with other hor-

onal and humoral agents influence sleep, acting either in sleepromoting or sleep inhibiting manner [16].

Both, central and systemic injection of IL-1 and TNF alpha causenhancement of delta waves in EEG and extends duration of NREMleep in all species test so far [17]. Association between these twoytokines and plethora of clinical conditions like fatigue, chronicnsomnia, influenza, rheumatic arthritis and alcoholism have beenescribed. TNF alpha is elevated in patients with chronic fatigueyndrome associated with MS, alcoholism, myocardial infarction,nfluenza, virus infections, rheumatoid arthritis, and sleep apnea18,19]. Presumably, IL-1 and TNF-alfa effectuate their somnogenicffect through activation of the nuclear factor kappa B (NFkB),denosin release, increased NO and PGD2 production [20]. Otherytokines as well like IL2, IL6, IL8, IL15, IL18, EGF, acidic fibroblastrowth factor, colony stimulating factor, and interferons are foundo induce NREM sleep while on the other hand IL1RA, IL4, IL10, IL13,nsulin-like growth factor, transforming growth factor beta and theoluble IL1 and TNF receptors are considered to inhibit NREM sleep20].

.2. Melatonin in sleep and in multiple sclerosis

As already mentioned, interplay between genetic and environ-ental factors is considered to cause pathological background inS [21]. Sunlight exposure, important for vitamin D and melatonin

ynthesis, is one of the environmental risk factors of MS which isased on the observation that prevalence of MS exhibits geograph-

cal latitude dependence with a latitude gradient showing lowerrevalence nearer the equator [22]. Although vitamin D was ini-ially an explanation for the latitude gradient [23] recent researchas suggested that sun exposure and vitamin D status may have

ndependent roles in the risk of MS [24]. Melatonin is a hormoneecreted by the pineal gland with circadian rhythmicity and isne of the major regulators of sleep-wake cycle [25]. In humans,

circadian clock center (pacemaker) is located in the hypothala-ic suprachiasmatic nucleus (SCN) and is crucial for maintaining

daily rhythm for numerous physiologic and metabolic functionsuch as sleep regulation, cytokine and hormone secretion. Disrup-ion of clock function impairs daily rhythm of various physiologicalunctions and could contribute to a number of chronic diseases

osurgery 115S (2013) S82– S85 S83

such as cancer [26], cardio-vascular disease [27], diabetes [28],Alzheimer’s disease [29] and autoimmune disorders [30]. Circa-dian abnormalities in MS have not been studied extensively buta study of MS patients with fatigue suggested disrupted circa-dian rhythm due to significant correlation between fatigue in MSpatients and abnormal sleep patterns [31]. Another study founda significantly higher cortisol awakening response (CAR) in MSpatients [32]. Also, a study investigating melatonin dysregulation,sleep, and fatigue in MS demonstrated significantly decreased lev-els of 6-sulphatoxy-melatonin (6-SMT) in urine of the treatmentnaive MS patients and disrupted circadian regulation of its secre-tion, which were increased with IFN-beta treatment, in associationwith improved fatigue [33]. A genetic study which investigated thesingle nucleotide polymorphisms (SNPs) of the genes coding forcritical enzymes and receptors involved in the melatonin pathwayin 193 MS patients and 397 healthy controls suggested dysregu-lation in melatonin pathways in the progressive subtypes of MS[34]. Additional evidences from animal studies of experimentalautoimmune encephalomyelitis (EAE) mice, an animal model ofMS, showed rhythmic disruption in heart rate and blood pressurein EAE [35], as well as altered clock gene expression and hormonalrhythms [36]. Chronotype is a preferred phase of an individual forthe timing of sleep, wakefulness and daily activities with some indi-viduals being preferentially so called morning types while othersso called evening types. It has been well established that chrono-types are influenced by the endogenous circadian system. Besidesthis synchronization of the endogenous circadian system and itsconsecutive influence, the chronotype is also under the influenceof environmental light and dark alteration and social time, whichbecome important with the introduction of a technical clock [37].

Given that there is evidence from the previous research for circa-dian rhythm impairment in MS, especially the melatonin pathwaywhich parallels sleep–wake cycle [38], that sleep disturbances inmultiple sclerosis are more prevalent than in general population[39] and that data on the prevalence of circadian rhythm sleep dis-orders has not been published so far, investigation of chrontypein MS patient might have important pathogenetical and clinicalimpact.

3. Sleep disorders in multiple sclerosis

Sleep disorders in the patients with MS are at higher frequencythan the general population and depending on the study they rangefrom 25% to 54% based on small series of patients [31,40–43]. Inthe large study [11], 504 MS patients were evaluated with thePittsburgh Sleep Quality Index (PSQI) [44]. 62% of the MS patientscompared with 32% of normal controls had poor sleep quality withinsomnia-type complaints. Sleep efficiency was markedly reducedin MS patients. Sleep quality, as well as depression, fatigue, and dis-ability, were correlated with quality of life. In another study in 15MS patients with fatigue, 15 MS patients without fatigue, and 15controls, all studied with actigraphy (measures body movementand has been correlated with sleep/wake cycles), an associationbetween MS fatigue and disrupted sleep or abnormal sleep cycleswas found [31]. Sleep disorders have been classified according tothe 2nd edition of the International classification of sleep disor-ders from 2005 [45] and major subgroups of sleep disorders havebeen described in multiple sclerosis. Insomnia is more frequent inpatients with multiple sclerosis (40%) than in general population(10–15%) [43] and it has been proposed that it has multifactorialetiology associated with MS per se like nocturia, spasticity, pain

and depression.

In a study of 28 MS patients investigating sleep disorder breath-ing; 15 MS patients reported sleep difficulties and underwentovernight oximetry. Of these, 3 showed O2 desaturation and

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nderwent PSG, which showed OSA in 2 patients. The authorsoncluded that sleep difficulties were common in MS, but that noc-urnal O2 insufficiency is rare [42]. In another study PSG resultsf 25 MS patients were compared to those of 25 normal con-rols. Patients had significantly reduced sleep efficiency (% totalleep time/time in bed), and increased nocturnal awakenings. Sleeprchitecture was otherwise similar in patients and controls. Threeatients had sleep disorders breathing (SDB) with AHI index of >546]. In a study that included 62 MS patients and 32 healthy controlsho where evaluated by overnight polisomnography, prevalence

f obstructive sleep apnea was 58% and 47%, respectively [47].uthors explained this high prevalence of OSA with using standardesearch criteria for scoring respiratory events [48]. The finding of

high prevalence of restless leg syndrome (RLS) by questionnairen MS patients compared to healthy controls has been confirmedn several studies [49–52] and they have been correlated with dis-ase duration, older age and cervical cord lesions. DistinguishingLS from other motor and sensory symptoms in MS can be dif-cult. Unlike leg discomfort encountered in RLS, which is worse

n evening, leg spasms, often seen in MS patients are worse onwakening and can occur at any time of the day.

There are also case series describing narcolepsy features [53]. study on the secondary causes of narcolepsy has revealed thatS is the fourth most common cause after inherited disorders, CNS

umors and brain injury; in this study, 12% of the cases of secondaryarcolepsy were due to MS [54] and it is also known that both dis-ases are related to human leukocyte antigen DQB1*0602 whichight suggest that similar autoimmune process may be important

n development of fatigue and sleepiness. Hypothalamic MS lesionsesulting in low CSF hypocretin levels have been described to causeypersomnia in affected patients [55].

There are case reports of REM sleep behavior disorder (RBD) inS patients suggested to be casued by the lesion in the proximity

f the penduculopontine nucleus [56] and they occured either asrst symptom of disease [57] or during the disease course [56]. Therevalence of RBD ranges from 0.38% to 0.5% [58]. RBD is a para-omnia characterized by loss of muscle atonia during REM sleep,onsecutive abnormal motor or verbal behaviors associated withnpleasant dreams [45]. A study that investigated prevalence ofBD in 135 MS patients and 118 healthy using RBD questionnaires

ound four (2.9%) MS patients and none of the healthy controlsaving RBD [59].

A circadian clock center (pacemaker) in humans is locatedn the hypothalamic suprachiasmatic nucleus (SCN) and is cru-ial for maintaining a daily rhythm for numerous physiologicnd metabolic functions such as sleep regulation, cytokine andormone secretion. Circadian rhythm disorders include advancedleep-phase syndrome, delayed sleep-phase syndrome, an irregularake–sleep rhythm, or free will wake–sleep rhythm [45]. Preva-

ence of circadian rhythm disorders in general population as wells in multiple sclerosis is not know although in previous researchhey have been connected with fatigue in MS. Conflicting resultsave been found in the studies performed to determine whetherS patients with fatigue have higher rates of circadian rhythm

isorders [31,60].

. Conclusion

Sleep disorders in multiple sclerosis (MS) are more commonhan in general population. More precisely, decreased sleep effi-iency on polysomnography correlated with fatigue, tiredness, and

ack of energy in MS patients compared to controls have beeneported [61]. Since several immunologic factors in serum haveeen implicated in devlopement of sleep disorders and sleepinessnd MS is proven to be characterized by immune abnormalities,

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notion that MS and sleep disorders share similar background seemsreasonable. However, sleep disorder should be seen separetely dueits different etiopatological grounds. Investigation of sleep disor-ders in multiple sclerosis is important, especially considering thefact that sleep disturbance largely contribute to developement offatigue, most common and debilitating symptom of MS. Takinginto consideration prevoisly published research in this field, fur-ther epidemiological studies using standardize subjective and/orobjective assasment tools are warranted in order to define preva-lence of certain sleep disorder in multiple sclerosis. Besides that,further evaluation of immunological and melatonin disruption inMS are needed.

Author’s contribution

Study concept and design, acquisition of data, analysis and inter-pretation of data, drafting of the manuscript, critical revision of themanuscript for important intellectual content and administrative,technical and material support was performed by Barun.

Conflict of interest statement

There is no conflict of interest.

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