Clinical ReviewSleep disorders in patients with multiple sclerosis
Introduction
Multiple sclerosis (MS) is a chronic central nervous system autoimmune demyelinating disease that most commonly affects people between the ages of 20 and 50 years, with a worldwide prevalence of approximately 2.5 million people.1 The disease is characterized by relapsing and remitting neurological symptoms, such as weakness, numbness, vertigo, cognitive changes and blindness, leading long term to physical disability.
Though often unrecognized, sleep disorders are seen in the MS population at higher frequency than the general population, with estimates ranging from 25% to 54% based on small series of patients.2, 3, 4, 5, *6, *7 Sleep disorders such as insomnia, sleep disordered breathing, circadian rhythm disorder, restless legs syndrome (RLS), narcolepsy and rapid eye movement (REM) sleep behavior disorder have all been reported in the MS population. These findings merit further attention given the potential impact of sleep disorders on the health and quality of life in individuals living with MS.4, *6 Sleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes,8, 9, 10, 11 and can contribute to depression, pain and fatigue – symptoms that are commonly seen in MS patients, and that are often disabling.2, 3, 4, 5, *6, *7
The goal of the review is to review our current knowledge of sleep disorders in the MS population. In addition to examining specific sleep disorders, we will discuss the additional features specific to MS that may contribute to sleep disruption. We aim to raise awareness of sleep disorders in the MS population, with the ultimate goal of providing guidance concerning diagnosis and treatment. We discuss the intricate relationship between sleep and the immune system with respect to MS, and close with recommendations for further research.
Section snippets
Narcolepsy
Narcolepsy is classified as a chronic sleep disorder associated with sleep attacks and other features attributed to abnormalities of REM sleep, such as hypnagogic/hypnopompic hallucinations, cataplexy, sleep paralysis, and disrupted nocturnal sleep.12 The usual polysomnographic features include a mean sleep latency of less than or equal to eight minutes and two or more sleep onset rapid eye movement periods (SOREMPs). There is a large variability in the prevalence across different geographic
Sleep disordered breathing
Patients with sleep disordered breathing may present with sleepiness, nocturnal apneas, choking episodes, and snoring, with polysomnographic evidence of five or more apneas or hypopneas per hour. When the apneas are associated with respiratory effort, the term obstructive apnea is used, and when there is lack of respiratory effort, central apnea is used. In patients with both central and obstructive apneas, central sleep apnea is diagnosed when > 50% of the events are central.12 Patients with
REM sleep behavior disorder
REM sleep behavior disorder (RBD) is a parasomnia whereby the patient exhibits injurious or disruptive behavior in REM sleep, and is associated with increased EMG tone on submental or limb leads in REM sleep.12 Patients often lack the muscle atonia that normally accompanies REM sleep, and will act out dreams with kicking, punching, choking, and leaving the bed. RBD often takes on a violent theme, and has been reported to lead to injury of bed partners.
The overall prevalence of RBD is between
Circadian rhythm disorders
Circadian rhythm disorders (CRD) can occur from a mismatch between the internal interval and the external environment regarding the timing and duration of sleep. CRD often leads to complaints of insomnia, excessive daytime sleepiness or both, resulting in work, school, or social impairment. Patients may present with advanced sleep phase, delayed sleep phase, irregular sleep-wake rhythm or a free running sleep-wake rhythm.12
The prevalence of CRD in the general population is unknown. The
Restless legs syndrome
The restless legs syndrome (RLS), as described by Ekbom50, is a disorder with sensory and motor components. The International Restless Legs Syndrome Study Group (IRLSSG) established four clinical criteria defining RLS: 1) an urge to move, usually due to uncomfortable sensation in the legs with, 2) the urge in the legs improves with movement of the legs, 3) symptoms worsen at rest, 4) symptoms often worsen in the evening. When severe, RLS disrupts sleep, causing excessive daytime sleepiness,
Insomnia
Insomnia occurs when patients, despite adequate opportunity, have trouble with sleep initiation (initial insomnia), sleep maintenance (middle insomnia), or arising earlier than desired (terminal insomnia). According to the International Classification of Sleep Disorders-2, at least one daytime impairment symptom from insomnia must be present, including: “fatigue, mood disturbances, social and occupational problems, daytime sleepiness, loss of energy, proneness for accidents, memory impairment,
The link between cytokines, sleep and multiple sclerosis
Independent of sleep disorders, there is clear evidence that sleep and the immune system interact with each other. This interplay exists in health, in infections, and in autoimmune diseases like MS.70, 71 Cytokines are the link between sleep and the immune system. These proteins serve as chemical messengers, and help regulate sleep. The pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1), and interleukin-6 (IL-6) are the most studied cytokines in health
Sleep and medications used in MS
In addition to comorbid sleep disorders, disease modifying and symptomatic therapies commonly used in MS may also affect sleep, by causing either insomnia or hypersomnia. Those MS medications that are more commonly associated with sleep disturbances are summarized in Table 2.
Sleepiness and fatigue in MS
Fatigue is the most common symptom associated with MS. Differentiating this organic fatigue from excessive daytime sleepiness due to an underlying sleep disorder can be challenging.3, 5, *6, 85
MS fatigue is defined as a “subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual or desired activities.” The fatigue associated with MS often occurs early in the morning, is aggravated by heat and humidity, and worsens as the day
Directions and issues for future research
While an association between MS and various sleep disorders has been established, the prevalence and strength of the associations has not yet been determined on a large-scale level. The current study limitations are due to the small numbers of subjects, selection bias, and often a lack of objective reports or polysomnographic data. Large-scale evaluations are therefore needed to define the extent to which sleep disorders affect the MS population. Further research needs to be pursued to
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