3. Effect of the quality of sleep in multiple sclerosis

Sleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes [8] and can contribute to the depression, pain and fatigue symptoms that are commonly seen in MS patients, which are often disabling [3, 9, 10].

#### 3.1. Fatigue

Fatigue is defined as a subjective lack of physical or mental energy perceived by the patients or their caregivers which interferes with desired activities of daily living and it is the most frequent symptom in MS [18].

Between 80 and 97% [6] of patients report chronic fatigue, and more than 33% of patients rate this symptom as the most disabling [34–36].

The study occasionally needs to be completed with ultrasound studies, urodynamics, MRI and

Hygienic measures such as reduced fluid intake at the end of the evening and frequently going to the bathroom during the day can help. Adequate treatment of co-morbid conditions such as diabetes mellitus, congestive heart failure or sleep apnea requires direct intervention for

Anticholinergics, mirabegron, a-blockers, 5-a reductase inhibitors, oral phosphodiester-ase-5 inhibitors, desmopressin, diuretics, sleep-promoting agents and phytotherapy are used to treat urinary problems [33]. Half of MS patients with moderate to severe overactive bladder symp-

Antimuscarinic drugs (Solifenacin), the most appropriate treatment for OAB, inhibited bladder stimulation may originate a decrease of drive to the brain stem, improve urination urgency and frequency and effectively reduce involuntary contractions and increase bladder capacity in patients with storage symptoms. The night time dosing of antimuscarinic drugs may

Antidiuretic therapy using clinician-directed dose titration has been reported to be more effective than placebo in terms of reduced nocturnal voiding frequency and duration of

Nocturia severity improvement contributes to overall improvements in health-related quality

The impact of treatment for nocturia in MS fatigue is unknown [18]. Non-pharmacological therapies such as cognitive behavioral therapy for nocturia (CBT-N) act on the abovementioned perpetuating factors. Sleep restriction entails reducing the excessive time in bed (a common

Sleep disturbances have been associated with increased risk of mortality, cardiac disease, obesity and diabetes [8] and can contribute to the depression, pain and fatigue symptoms that

Fatigue is defined as a subjective lack of physical or mental energy perceived by the patients or their caregivers which interferes with desired activities of daily living and it is the most

Interventions targeting nocturia may potentially improve sleep quality [31].

urinary sediment to identify LUTD or OAB problems.

toms are treated with an anticholinergic medication [18].

improve tolerance compared to daytime dosing [32].

occurrence in insomnia) and thereby improves sleep efficiency.

3. Effect of the quality of sleep in multiple sclerosis

are commonly seen in MS patients, which are often disabling [3, 9, 10].

2.4.4.2. Management

176 Neuroplasticity - Insights of Neural Reorganization

improvement nocturia.

undisturbed sleep [33].

of life [33].

3.1. Fatigue

frequent symptom in MS [18].

Fatigue may occur at any stage of the disease and can even precede MS onset by several years. Fatigue affects the social and professional capabilities of patients, is a major reason for early retirement, reduced employment and is considered to be one of the main causes of impaired quality of life among MS patients, regardless of depression or disability [18].

Fatigue starts early in the morning and increases during the day. The perception of fatigue is exacerbated with environmental temperature and humidity [25], with age, [36] greater EDSS, mental or physical activity, infections and food ingestion [37].

Fatigue also deteriorates cognitive domains, such as information processing, memory and attention, [35] and it has significant socioeconomic consequences, including loss of work hours and in some instances, loss of employment, as well as family relationships and leisure time [36].

Fatigue is a symptom in MS patients and may have multi-factorial causes such as immunologic abnormalities (pro-inflammatory cytokines such as INF-α), endocrine influences (cortisol and dehydroepiandrosterone (DHEA)), axonal loss, altered patterns of cerebral activation, sleep disorders (RLS, chronic insomnia, sleep-disordered breathing and altered sleep microstructure), depression and medications used to treat MS symptoms or immunomodulatory and immunosuppressive treatments [7, 38, 39].

"Primary" fatigue is related to the pathological changes of the disease itself, and results from a spectrum where one pole is the inability to generate the force required to perform the task due to a failure of force production at the muscle level "peripheral fatigue"; and the other pole is the inability to sustain the required neural drive to muscle because of supraspinal, spinal and even peripheral nerve contribution "central fatigue."

"Central fatigue" can be the result of both cognitive and physical exertion and can reflect either a subjective sensation (fatigue) or an objective change in performance (fatigability) [37]. Dopamine imbalance plays a major role in developing fatigue. Central fatigue is a failure of the nonmotor functions of the basal ganglia.

The subjective feeling of fatigue is related to inflammation and increased levels of cytokines such as interleukin-1 (IL-1), IL-6 and TNF-alpha [40].

"Secondary" fatigue attributed to mimicking symptoms, co-morbid sleep, irritable bowel syndrome, migraine, mood disorders, depression and anxiety and medication side effects [36, 37]. Persons with secondary fatigue report greater levels of fatigue than those with isolated primary fatigue [36].

There is a great variability in MS lesions from extensive areas of destruction during MS attacks, healing processes of and neuroplasticity. The clinical manifestations of fatigue do not seem to exclusively depend on the structural damage, but rather on the balance between restorative and inflammatory/degenerative processes and the rupture of the neural network [37].

In this respect, there is evidence that supports these hypotheses, linking fatigue with structural or functional abnormalities (atrophy in the thalamus, corpus callosum, cortical gray matter regions: superior frontal and inferior parietal gyrus, parietal lobe) within various brain networks (the cortico-subcortical circuit as a substrate for MS fatigue and the involvement of a "fronto-striatal network"), greater activation of the premotor area ipsilateral to the movement with functional MRI (fMRI), decreased N-acetylaspartate-creatine ratio (NAA/Cr) as a marker of axonal dysfunction. Resting-state fMRI studies show changes in functional connectivity (FC) of the basal ganglia including reward processing and motivation. In addition to motor functions, the abovementioned aspects are involved in the pathophysiology of fatigue [18].

Hygienic measures such as energy conservation programs, specific rehabilitation interventions physical (endurance, resistance, aerobic and combined training), aquatic therapy, cooling therapies, Tai chi, stretching, mindfulness-based interventions, yoga, acupuncture, progressive muscle relaxation and sleep hygiene advice (dependent on the nature of the sleep disorder) are

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 179

Adequate treatment of co-morbid conditions such as diabetes mellitus, congestive heart failure, obesity, sleep apnea and other sleep disorders, depression and anxiety with pharmacological, psychological, behavioral and educational interventions is recommended [40, 41]. Pharmacological interventions for fatigue that are effective for reducing fatigue in patients with MS include amantadine, pemoline, prokarin (1 pilot study, side effects not reported), modafinil and pemoline combined with aspirin are efficacious for reducing fatigue in patients with multiple sclerosis. Carnitine has a discreet effectiveness. In general, the risk benefit of the drugs used for fatigue makes their recommendation be evaluated in each patient, highlighting them to the amantadine [37, 41]. Aminopyridines and coenzyme Q10 have an effect on fatigue

Nowadays, non-invasive brain stimulation (NIBS) techniques are gaining interest in the treat-

Promotion of health behaviors such as quitting smoking, physical activity (a high level of physical activity was borderline significantly associated with a decrease in co-morbidity) [42] and healthy eating may prevent some co-morbidities which were slow to show improvement

Cognitive impairment is a frequent feature of MS affecting up to 65% of patients [43] at both

MS negatively affects several aspects of cognitive functions, including attention, information processing [46], learning and memory, executive function and visuospatial abilities [47], having an important impact on quality of life [48], employment status [49], daily functioning,

Several factors have a negative influence on cognition in MS patients, such as depression [53], fatigue and sleep disturbances. Proper sleep is important for memory consolidation [54], and sleep deprivation has been related to impaired functioning in various cognitive domains [55]. Sleep disturbance causes a decrease in sustained attention [56], interferes with information processing and executive functioning [52]. Sleep disturbed patients reported higher levels of

OSA and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function (as reflected by response inhibition), attention, processing speed

Excessive daytime sleepiness can lead to poor attention, poor memory, mood disturbances and

the earlier and later stages of the disease [44] and it tends to worsen over time [45].

more effective than pharmacological interventions [41].

in fatigue after the intervention, but they are effective [36].

independence [50] and participation in social activities [51, 52].

subjective cognitive problems compared to patients with normal sleep [52].

by improving nerve conduction.

ment of MS fatigue [37].

and working memory [52].

increased risk of accidents [29].

3.2. Cognition

#### 3.1.1. Diagnostic approach

Patients with MS report being fatigued very often, sometimes it is just the feeling of lack of energy but in others it interferes with their work or their daily life. There are tools that help quantify the degree of fatigue which are described below.

Severity Scale (FSS): is a self-administered questionnaire with nine items (questions) investigating the severity of fatigue in different situations during the previous week. Grading of each item ranges from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement and the final score represents the mean value of the 9 items. A total score of less than 36 suggests that you may not be suffering from fatigue [24].

Modified Fatigue Impact Scale (MFIS): The full-length MFIS consists of 21 items (total score 0– 84, 38 as a cutoff to discriminate fatigued from non-fatigued individuals) while the abbreviated version has 5 items (0–20.). The abbreviated version can be used if time is limited but the fulllength version has the advantage of generating physical, cognitive and psychosocial functioning subscales. The MFIS is one of the components of the MS quality life inventory [37].

MS patients, regardless of their fatigue level, have a significantly high frequency of RLS, higher Epworth sleepiness scale (ESS) scores, and higher PSQI scores. The time in bed, wake time after sleep onset %, total arousal index, limb movement arousal index and periodic limb movement arousal index are abnormal. The sleep efficiency index and sleep continuity index are lower in fatigued MS patients than non-fatigued MS patients. The PSQI results also suggest more disrupted sleep in fatigued MS patients. For all of the reasons above, quality of sleep studies should be performed with fatigued MS patients.

Once the patient has been identified with fatigue, it is necessary to investigate whether other co-morbidities are present (depression, anxiety, sleep disturbance, diabetes, heart disease, obesity, anemia, thyroid disease and nocturnal urinary disorders), what factors influence perpetuating fatigue and what situations can be modified in their lifestyle [6].

#### 3.1.2. Management

Interventions targeting fatigue may potentially improve sleep quality and quality of life [31].

Pharmacological interventions are also reviewed and if there is evidence that a drug is involved in fatigue, it should be suppressed or the dose decreased [18]. Disease-modifying treatments (DMTs) are generally used to reduce relapses and progression and they occasionally cause an increase in fatigue, and in these circumstances it is important to change the medication for another DMTs [40].

Hygienic measures such as energy conservation programs, specific rehabilitation interventions physical (endurance, resistance, aerobic and combined training), aquatic therapy, cooling therapies, Tai chi, stretching, mindfulness-based interventions, yoga, acupuncture, progressive muscle relaxation and sleep hygiene advice (dependent on the nature of the sleep disorder) are more effective than pharmacological interventions [41].

Adequate treatment of co-morbid conditions such as diabetes mellitus, congestive heart failure, obesity, sleep apnea and other sleep disorders, depression and anxiety with pharmacological, psychological, behavioral and educational interventions is recommended [40, 41]. Pharmacological interventions for fatigue that are effective for reducing fatigue in patients with MS include amantadine, pemoline, prokarin (1 pilot study, side effects not reported), modafinil and pemoline combined with aspirin are efficacious for reducing fatigue in patients with multiple sclerosis. Carnitine has a discreet effectiveness. In general, the risk benefit of the drugs used for fatigue makes their recommendation be evaluated in each patient, highlighting them to the amantadine [37, 41]. Aminopyridines and coenzyme Q10 have an effect on fatigue by improving nerve conduction.

Nowadays, non-invasive brain stimulation (NIBS) techniques are gaining interest in the treatment of MS fatigue [37].

Promotion of health behaviors such as quitting smoking, physical activity (a high level of physical activity was borderline significantly associated with a decrease in co-morbidity) [42] and healthy eating may prevent some co-morbidities which were slow to show improvement in fatigue after the intervention, but they are effective [36].

### 3.2. Cognition

regions: superior frontal and inferior parietal gyrus, parietal lobe) within various brain networks (the cortico-subcortical circuit as a substrate for MS fatigue and the involvement of a "fronto-striatal network"), greater activation of the premotor area ipsilateral to the movement with functional MRI (fMRI), decreased N-acetylaspartate-creatine ratio (NAA/Cr) as a marker of axonal dysfunction. Resting-state fMRI studies show changes in functional connectivity (FC) of the basal ganglia including reward processing and motivation. In addition to motor func-

Patients with MS report being fatigued very often, sometimes it is just the feeling of lack of energy but in others it interferes with their work or their daily life. There are tools that help

Severity Scale (FSS): is a self-administered questionnaire with nine items (questions) investigating the severity of fatigue in different situations during the previous week. Grading of each item ranges from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement and the final score represents the mean value of the 9 items. A total score of less than 36 suggests that

Modified Fatigue Impact Scale (MFIS): The full-length MFIS consists of 21 items (total score 0– 84, 38 as a cutoff to discriminate fatigued from non-fatigued individuals) while the abbreviated version has 5 items (0–20.). The abbreviated version can be used if time is limited but the fulllength version has the advantage of generating physical, cognitive and psychosocial function-

MS patients, regardless of their fatigue level, have a significantly high frequency of RLS, higher Epworth sleepiness scale (ESS) scores, and higher PSQI scores. The time in bed, wake time after sleep onset %, total arousal index, limb movement arousal index and periodic limb movement arousal index are abnormal. The sleep efficiency index and sleep continuity index are lower in fatigued MS patients than non-fatigued MS patients. The PSQI results also suggest more disrupted sleep in fatigued MS patients. For all of the reasons above, quality of sleep

Once the patient has been identified with fatigue, it is necessary to investigate whether other co-morbidities are present (depression, anxiety, sleep disturbance, diabetes, heart disease, obesity, anemia, thyroid disease and nocturnal urinary disorders), what factors influence

Interventions targeting fatigue may potentially improve sleep quality and quality of life [31]. Pharmacological interventions are also reviewed and if there is evidence that a drug is involved in fatigue, it should be suppressed or the dose decreased [18]. Disease-modifying treatments (DMTs) are generally used to reduce relapses and progression and they occasionally cause an increase in fatigue, and in these circumstances it is important to change the medication for

perpetuating fatigue and what situations can be modified in their lifestyle [6].

ing subscales. The MFIS is one of the components of the MS quality life inventory [37].

tions, the abovementioned aspects are involved in the pathophysiology of fatigue [18].

quantify the degree of fatigue which are described below.

studies should be performed with fatigued MS patients.

you may not be suffering from fatigue [24].

3.1.1. Diagnostic approach

178 Neuroplasticity - Insights of Neural Reorganization

3.1.2. Management

another DMTs [40].

Cognitive impairment is a frequent feature of MS affecting up to 65% of patients [43] at both the earlier and later stages of the disease [44] and it tends to worsen over time [45].

MS negatively affects several aspects of cognitive functions, including attention, information processing [46], learning and memory, executive function and visuospatial abilities [47], having an important impact on quality of life [48], employment status [49], daily functioning, independence [50] and participation in social activities [51, 52].

Several factors have a negative influence on cognition in MS patients, such as depression [53], fatigue and sleep disturbances. Proper sleep is important for memory consolidation [54], and sleep deprivation has been related to impaired functioning in various cognitive domains [55].

Sleep disturbance causes a decrease in sustained attention [56], interferes with information processing and executive functioning [52]. Sleep disturbed patients reported higher levels of subjective cognitive problems compared to patients with normal sleep [52].

OSA and sleep disturbance are significantly associated with diminished visual memory, verbal memory, executive function (as reflected by response inhibition), attention, processing speed and working memory [52].

Excessive daytime sleepiness can lead to poor attention, poor memory, mood disturbances and increased risk of accidents [29].

In subjects with insomnia, a functional magnetic resonance imaging (fMRI) showed hypoactivation of the medial and inferior prefrontal areas during a cognitive task, in relation to the control subjects, which returned to normal values after treatment. Insomnia or superficial sleep produces less activation of the hippocampus and less connectivity is observed in the thalamus than in the control subjects. Damage to the hippocampus and thalamus (e.g., lesions and atrophy) in MS is associated with worse cognition. In controls, both regions may be related to sleep and cognition [52].

Patients with fatigue should organize daily routine and workloads. The physician also needs to improve the efficiency of information processing and working memory in these patients

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 181

Anxiety, depression, difficulty in sleeping and fatigue may have an impact on cognitive problems. If a person with MS experiences these symptoms and has problems with memory and cognition, they need to be provided with assessment and treatment (occupational thera-

The concept of mental toughness (MT) has recently been recognized for its psychological importance not just in coping with stress but also for its association with increased physical activity (PA), and for its impact on both stress and objective sleep quality. MT consists of four key factors such as control (of own life and emotions), commitment, challenge and confidence (in own abilities and in other people); thus covering a range of cognitive-emotional processes closely involved in coping with stress, emotions, unexpected events and social setting [62].

Patients who suffer from problematic sleep and/or fatigue (with or without anxiety) may be

Depression is a mental illness that causes feelings of sadness and loss of hope, changes in sleeping and eating habits, loss of interest in your usual activities and pains that have no

A trans-diagnostic approach to symptoms may be more effective than targeting each symptom separately, such as depression treatment or pain treatment alone. Trans-diagnostic models explain how multiple co-morbid symptoms or disorders develop rather than create disorder

A trans-diagnostic treatment is an intervention that targets a range of diagnoses or problems through the use of treatment strategies targeting psychological processes that are common across disorders. It may be useful to consider all five factors such as depression, pain, anxiety, sleep and fatigue in designing a treatment plan. Treatments for the constellation of biopsychosocial con-

The beneficial effects on depression of CBT targeting insomnia highlight a need for a comprehensive assessment of multiple concerns such as depression, anxiety, sleep problems or fatigue

The mechanism by which sleep disorders trigger an acute MS relapse might be multi-factorial. Normal sleeping plays an important role in maintaining the normal function of the immune

when treating people with MS who report higher levels of pain [63].

3.4. Trigger for an acute multiple sclerosis exacerbation

more likely to experience higher depressive symptoms [63].

with fatigue [40].

3.3. Depression

physical explanation.

3.3.2. Management

3.3.1. Diagnostic approach

or symptom specific models [63].

cerns affecting many people living with MS.

pist and neuropsychologist).

MS patients performed worse on all cognitive tests compared to controls. MS patients had less normalized gray matter (GM) volume, normalized white matter (WM) volume, hippocampal volume and thalamic volume. The hippocampus and thalamus showed increased functional connectivity (FC) in patients compared to controls, but lower FC was observed in patients with sleep disturbances (32%) [52].

#### 3.2.1. Diagnostic approach

Neuropsychological manifestations can even be detected in patients during early stages of the disease. The Brief Repeatable Battery-Neuropsychology (BRB-N) [57] test was developed as a short and sensitive test to identify disturbances of cognitive domains in MS patients. The BRB-N has become the most widely used neuropsychological battery for MS, [58] and it is now being applied in clinical trials to monitor cognitive changes.

Different cognitive impairment criteria have been used: <1.0 SD, <1.5 SD and <2.0 SD in one, two or three subtests of the battery, respectively [59, 60].

#### 3.2.2. Management

Strategies to optimize sleep could improve cognitive function in patients with MS.

In the case of insomnia, relaxation techniques such as autogenic training or progressive muscle relaxation can help the patient fall asleep earlier and have a longer sleep. But they do not improve sleep, so it has no sleep recovery effect. Behavioral therapies can improve sleep, but not prolong it. A combination of relaxation techniques and behavior therapy could be the most appropriate therapy for certain sleep disorders.

The general strategies for insomnia treatment include aspects of sleep hygiene such as extensions of night time in bed and frequent naps during the day. Pharmacological treatment is usually administered with stimulants such as amphetamines, methylphenidates, pemoline and modafinil [61].

As regards sleep hygiene, it is often necessary to make some lifestyle changes such as dinner should not be too late, nor too spicy or copious, maintain a regular sleep schedule, do not spend too much time in bed other than bedtime, do not drink caffeinated beverages such as coffee, black tea or cola, or caffeine medications, 4–6 hours before bedtime, do not smoke before going to bed or during the night, try to get enough rest and darken the bedroom, ventilate the bedroom, the temperature should not exceed 18, do not do any physically demanding sport immediately before sleep because otherwise it will stimulate too much circulation, do not drink alcohol before going to bed or avoid sleeping too much during the day.

Patients with fatigue should organize daily routine and workloads. The physician also needs to improve the efficiency of information processing and working memory in these patients with fatigue [40].

Anxiety, depression, difficulty in sleeping and fatigue may have an impact on cognitive problems. If a person with MS experiences these symptoms and has problems with memory and cognition, they need to be provided with assessment and treatment (occupational therapist and neuropsychologist).

The concept of mental toughness (MT) has recently been recognized for its psychological importance not just in coping with stress but also for its association with increased physical activity (PA), and for its impact on both stress and objective sleep quality. MT consists of four key factors such as control (of own life and emotions), commitment, challenge and confidence (in own abilities and in other people); thus covering a range of cognitive-emotional processes closely involved in coping with stress, emotions, unexpected events and social setting [62].

#### 3.3. Depression

In subjects with insomnia, a functional magnetic resonance imaging (fMRI) showed hypoactivation of the medial and inferior prefrontal areas during a cognitive task, in relation to the control subjects, which returned to normal values after treatment. Insomnia or superficial sleep produces less activation of the hippocampus and less connectivity is observed in the thalamus than in the control subjects. Damage to the hippocampus and thalamus (e.g., lesions and atrophy) in MS is associated with worse cognition. In controls, both regions may

MS patients performed worse on all cognitive tests compared to controls. MS patients had less normalized gray matter (GM) volume, normalized white matter (WM) volume, hippocampal volume and thalamic volume. The hippocampus and thalamus showed increased functional connectivity (FC) in patients compared to controls, but lower FC was observed in patients with

Neuropsychological manifestations can even be detected in patients during early stages of the disease. The Brief Repeatable Battery-Neuropsychology (BRB-N) [57] test was developed as a short and sensitive test to identify disturbances of cognitive domains in MS patients. The BRB-N has become the most widely used neuropsychological battery for MS, [58] and it is now

Different cognitive impairment criteria have been used: <1.0 SD, <1.5 SD and <2.0 SD in one,

In the case of insomnia, relaxation techniques such as autogenic training or progressive muscle relaxation can help the patient fall asleep earlier and have a longer sleep. But they do not improve sleep, so it has no sleep recovery effect. Behavioral therapies can improve sleep, but not prolong it. A combination of relaxation techniques and behavior therapy could be the most

The general strategies for insomnia treatment include aspects of sleep hygiene such as extensions of night time in bed and frequent naps during the day. Pharmacological treatment is usually administered with stimulants such as amphetamines, methylphenidates, pemoline and

As regards sleep hygiene, it is often necessary to make some lifestyle changes such as dinner should not be too late, nor too spicy or copious, maintain a regular sleep schedule, do not spend too much time in bed other than bedtime, do not drink caffeinated beverages such as coffee, black tea or cola, or caffeine medications, 4–6 hours before bedtime, do not smoke before going to bed or during the night, try to get enough rest and darken the bedroom, ventilate the bedroom, the temperature should not exceed 18, do not do any physically demanding sport immediately before sleep because otherwise it will stimulate too much circulation, do not drink

alcohol before going to bed or avoid sleeping too much during the day.

Strategies to optimize sleep could improve cognitive function in patients with MS.

be related to sleep and cognition [52].

180 Neuroplasticity - Insights of Neural Reorganization

being applied in clinical trials to monitor cognitive changes.

two or three subtests of the battery, respectively [59, 60].

appropriate therapy for certain sleep disorders.

sleep disturbances (32%) [52].

3.2.1. Diagnostic approach

3.2.2. Management

modafinil [61].

Patients who suffer from problematic sleep and/or fatigue (with or without anxiety) may be more likely to experience higher depressive symptoms [63].

Depression is a mental illness that causes feelings of sadness and loss of hope, changes in sleeping and eating habits, loss of interest in your usual activities and pains that have no physical explanation.

#### 3.3.1. Diagnostic approach

A trans-diagnostic approach to symptoms may be more effective than targeting each symptom separately, such as depression treatment or pain treatment alone. Trans-diagnostic models explain how multiple co-morbid symptoms or disorders develop rather than create disorder or symptom specific models [63].

#### 3.3.2. Management

A trans-diagnostic treatment is an intervention that targets a range of diagnoses or problems through the use of treatment strategies targeting psychological processes that are common across disorders. It may be useful to consider all five factors such as depression, pain, anxiety, sleep and fatigue in designing a treatment plan. Treatments for the constellation of biopsychosocial concerns affecting many people living with MS.

The beneficial effects on depression of CBT targeting insomnia highlight a need for a comprehensive assessment of multiple concerns such as depression, anxiety, sleep problems or fatigue when treating people with MS who report higher levels of pain [63].

#### 3.4. Trigger for an acute multiple sclerosis exacerbation

The mechanism by which sleep disorders trigger an acute MS relapse might be multi-factorial. Normal sleeping plays an important role in maintaining the normal function of the immune system. Various studies have shown that sleep disorders are associated with elevated serum levels of pro-inflammatory cytokines and markers of oxidative stress [15].

Co-morbidities can negatively impact sleep in MS patients, which can, in turn, lead to a

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 183

Patients with sleep disorders are at risk of co-occurrence of other problems like vascular diseases, obesity and diabetes that would threaten the health of patients in the long term [17]. Circadian disruptions occur in shift workers and appear to contribute to hypertension, diabetes, breast cancer, lung cancer and elevated prostate-specific antigen. Shift work entails changes in diet, exercise and tobacco use, which can confound circadian rhythm and sleep disturbance studies [65].

Narcolepsy is classified as a chronic sleep disorder associated with sleep attacks and other features attributed to abnormalities of rapid eye movement sleep, such as hypnagogic/hypnopompic hallucinations, cataplexy, sleep paralysis and disrupted nocturnal sleep. The usual PSG features include a mean sleep latency of less than or equal to 8 minutes and two or more sleep onset rapid eye movement periods [6]. There is a high variability in the prevalence across different geographic areas, which is thought to be related to differences between the populations and

Narcolepsy is estimated to affect 0.02–0.05% of the general population, the overall prevalence

Narcolepsy type 1(immune-mediated loss of hypocretin-secreting cells in the lateral hypothalamus) [6, 10] is characterized by the presence of cataplexy (a reliable clinical marker for

The secondary causes of narcolepsy show that MS is the fourth most common cause of narcolepsy after inherited disorders, CNS tumors and brain injury, and it has been found that

In terms of genetics, 95% of narcoleptic patients and 50–60% of MS patients are positive for DR2 haplotype. The human leukocyte antigen (HLA) 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 labeling for most autoimmune diseases. This relationship suggests that similar autoimmune factors may be at work in the development of each disorder and might be partially

The aforementioned findings merit further attention given the potential impact of sleep disor-

A diagnosis of narcolepsy requires PSG and CSF hypocretin assays (only performed at a few

worsening of symptoms, especially fatigue and pain.

of narcolepsy among persons with MS is unknown [6, 10].

Narcolepsy type 2: normal hypocretin levels [6, 10].

There are two subtypes of primary narcolepsy which are described below.

hypocretin deficiency) and hypocretin deficiency in CSF (<110 pg./dl).

12% of the cases of secondary narcolepsy were due to MS [6, 10, 66].

responsible for symptoms of fatigue and sleepiness [6, 10, 67].

ders on the health and quality of life of MS patients [10].

4.1. Narcolepsy

current study methods [10].

4.1.1. Diagnostic approach

academic institutions).

The circadian regulation of cytokine output produces a daily rhythm in the inflammatory profile, with a pro-inflammatory state occurring at night. Disrupted sleep can interfere with this pattern leading to prolonged periods of inflammation throughout the day, thereby exacerbating symptoms. Furthermore, the circadian rhythmicity of key components of the immune system has been shown to be dysregulated in MS patients [64].

The central circadian pacemaker, located in the hypothalamic suprachiasmatic nuclei, is responsible for regulating the timing and expression of various circadian rhythms [65].

Sleep dysfunction and disruption in the circadian system alter the synchrony between these transcriptional and translational feedback loops, resulting in increased cellular permeability, which is thought to be an important underlying mechanism for initiating the inflammatory cascades causing a disease flare. In addition, the presence of pro-inflammatory cytokines has been proven to suppress the activity of circadian genes [65].

Melatonin is produced by the pineal gland that regulates circadian and seasonal rhythms. Secretion of melatonin is suppressed during daylight and enhanced during the night, promotes sleep by reducing sleep latency, decreasing wake time and increasing overall sleep quality [65].

Melatonin promotes anti-inflammatory states: it inhibits nitric oxide production, nuclear factor-κB activation and tumor necrosis factor- α, it reduces COX-2 expression and matrix metalloproteinase activity (modulating apoptosis) [65].

Circadian sleep disorders are common in MS patients and could be linked to a disruption in melatonin production, which is important in sleep-wake cycle regulation. Melatonin helps dampen the overactive immune system and low levels are associated with relapse [64].

According to studies on an animal model, sleep deprivation is associated with an accelerated autoantibody production rate and increases oxidative stress (toxic effect on oligodendrocytes causing oligodendrocyte death and myelin damage). Chronic sleep deprivation breaks down blood-brain barrier (BBB) thereby increasing permeability [15].

Sleep disorders also result in an elevated serum concentration of interleukin-6 (IL-6), which further activates polyclonal B cells and triggers an autoimmune reaction. The serum concentration of IL-6 is significantly associated with the number of relapses in female patients with relapsing-remitting multiple sclerosis (RRMS) [15]. In the study of Sahraian et al. [15], the group in relapse had worse scores of global PSIQI for the previous month than remission group (87.5% were poor quality sleepers). Age, gender, EDSS and disease duration did not associate with sleep quality in either group.
