4. Co-morbidity condition

Co-morbidities have been shown to affect MS progression, time to initiation of the diseasemodifying therapy (DMT), as well as treatment compliance, which may be related to the increased mortality of these patients as compared to the general population.

Co-morbidities can negatively impact sleep in MS patients, which can, in turn, lead to a worsening of symptoms, especially fatigue and pain.

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].

#### 4.1. Narcolepsy

system. Various studies have shown that sleep disorders are associated with elevated serum

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

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

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

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

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

Co-morbidities have been shown to affect MS progression, time to initiation of the diseasemodifying therapy (DMT), as well as treatment compliance, which may be related to the

increased mortality of these patients as compared to the general population.

levels of pro-inflammatory cytokines and markers of oxidative stress [15].

system has been shown to be dysregulated in MS patients [64].

182 Neuroplasticity - Insights of Neural Reorganization

been proven to suppress the activity of circadian genes [65].

metalloproteinase activity (modulating apoptosis) [65].

blood-brain barrier (BBB) thereby increasing permeability [15].

associate with sleep quality in either group.

4. Co-morbidity condition

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 current study methods [10].

Narcolepsy is estimated to affect 0.02–0.05% of the general population, the overall prevalence of narcolepsy among persons with MS is unknown [6, 10].

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

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

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

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

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

The aforementioned findings merit further attention given the potential impact of sleep disorders on the health and quality of life of MS patients [10].

#### 4.1.1. Diagnostic approach

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

Narcolepsy cannot be established in the presence of concomitant OSA, insufficient sleep, shift work or another circadian sleep disorder [10].

increases with higher odds for disability and prior relapse and lower health-related quality

Central obesity, as defined by increased waist circumference, absolute waist circumference >102 cm in men and >88 cm in women or waist-hip ratio (the circumference of the waist divided by that of the hips) of >0.9 for men and >0.85 for women, is often indicative of metabolic syndrome, and is suggested to be a more potent risk factor (cardiovascular disease,

Patients who are overweight and obese are usually referred for diagnosis and management by a multidisciplinary team such as specialist nutritionist, physiotherapists, surgeons and neuro-

Gradual weight loss and gentle physical exercise and stretching are recommended. Small meals and small amounts of food, low in animal fats and fresh fruits. Bariatric surgery may

Co-morbidities have been shown to be associated with increased hospitalization, rate of progression to disability, decreased quality of life and increased mortality risk which is why they

Adverse health behavior including being overweight and obese, smoking and sedentary behavior are common in people with MS [42]. These behaviors can be modified and may significantly change the level of health. Health professionals should be focused on achieving

The therapeutic approach to multiple sclerosis involves pharmacological, rehabilitative, psychological, lifestyle modifying interventions, etc. These can be used independently or coordinated with each other with a holistic view. This approach involves changes in the structure of

Therapeutic options to treat MS relapses include oral glucocorticosteroids [70, 71] or their intravenous administration at a high dose as first line and therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) as second line treatments in glucocorticosteroids

5. Influence of the treatment of multiple sclerosis in sleep

unresponsive patients [72], corticotrophin injection and Acthar [73].

), waist circumference and waist-hip ratio.

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 185

Alzheimer's diseases and type 2 diabetes) than body mass index alone.

of life [42].

4.2.1. Diagnostic approach

4.2.2. Management

psychologists.

Weight, height, BMI = weight (kg)/height (m2

be necessary in severe cases of obesity.

these behavioral changes in patients with MS.

sleep, which are not always beneficial.

5.1. Treatment of relapses

have to be properly treated [42].

In such cases, adequate treatment of concomitant sleep disorders must be confirmed prior to the multiple sleep latency testing.

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].

It is necessary to perform MRI studies to rule out secondary causes of narcolepsy [6].

#### 4.1.2. Management

Patients with suspected narcolepsy are usually referred for diagnosis and management by sleep specialists: wake-promoting agents or stimulants may be used to increase wakefulness and vigilance.

Sodium oxybate (an endogenous metabolite of gamma-aminobutyric acid (GABA) may be used in selected cases.

REM-suppressing antidepressants may be useful for cataplexy and sleep paralysis.

In cases of secondary narcolepsy when new hypothalamic lesions are identified, a trial of highdose steroids should be considered [6].

#### 4.2. Overweight and obesity

Being overweight is having more body fat than is optimally healthy. The degree to which a person is overweight is generally described by the body mass index (BMI). Overweight is defined as a BMI above or equal to 25 and below 30.

Obesity is defined as a BMI over 30. The prevalence of overweight and obesity in patients with multiple sclerosis ranges from 19 to 55%. These differences are due to the distinct prevalence in the general population, differences in geographic origin, population type (military veterans or hospital users) and/or age group. It is notable that the American population has the highest numbers of obesity. Besides which, it is worth mentioning the different methodology used, including overweight with obesity in some studies [42, 68].

Spanish data (NARCOMS study) have shown that overweight people with MS had lower general and mental health scores compared to those with normal weight and found no differences in other quality of life scales of the SF-36 [69].

Depression levels were higher in the overweight versus normal weight MS Spanish patients. This finding is due to pathophysiological mechanisms common to both depression and obesity, given that chronic low-grade pro-inflammatory states can generate various abnormalities in different neural networks [69].

BMI was significantly related to levels of disability, with obese participants 1.4 times more likely to have moderate/severe disability while controlling for age, gender, time since diagnosis and number of co-morbidities. As the BMI increases, the number of co-morbidities increases with higher odds for disability and prior relapse and lower health-related quality of life [42].

Central obesity, as defined by increased waist circumference, absolute waist circumference >102 cm in men and >88 cm in women or waist-hip ratio (the circumference of the waist divided by that of the hips) of >0.9 for men and >0.85 for women, is often indicative of metabolic syndrome, and is suggested to be a more potent risk factor (cardiovascular disease, Alzheimer's diseases and type 2 diabetes) than body mass index alone.

#### 4.2.1. Diagnostic approach

Weight, height, BMI = weight (kg)/height (m2 ), waist circumference and waist-hip ratio.

#### 4.2.2. Management

Narcolepsy cannot be established in the presence of concomitant OSA, insufficient sleep, shift

In such cases, adequate treatment of concomitant sleep disorders must be confirmed prior to

The usual PSG features include a mean sleep latency of less than or equal to 8 minutes and two

Patients with suspected narcolepsy are usually referred for diagnosis and management by sleep specialists: wake-promoting agents or stimulants may be used to increase wakefulness

Sodium oxybate (an endogenous metabolite of gamma-aminobutyric acid (GABA) may be

In cases of secondary narcolepsy when new hypothalamic lesions are identified, a trial of high-

Being overweight is having more body fat than is optimally healthy. The degree to which a person is overweight is generally described by the body mass index (BMI). Overweight is

Obesity is defined as a BMI over 30. The prevalence of overweight and obesity in patients with multiple sclerosis ranges from 19 to 55%. These differences are due to the distinct prevalence in the general population, differences in geographic origin, population type (military veterans or hospital users) and/or age group. It is notable that the American population has the highest numbers of obesity. Besides which, it is worth mentioning the different methodology used,

Spanish data (NARCOMS study) have shown that overweight people with MS had lower general and mental health scores compared to those with normal weight and found no differ-

Depression levels were higher in the overweight versus normal weight MS Spanish patients. This finding is due to pathophysiological mechanisms common to both depression and obesity, given that chronic low-grade pro-inflammatory states can generate various abnormalities

BMI was significantly related to levels of disability, with obese participants 1.4 times more likely to have moderate/severe disability while controlling for age, gender, time since diagnosis and number of co-morbidities. As the BMI increases, the number of co-morbidities

It is necessary to perform MRI studies to rule out secondary causes of narcolepsy [6].

REM-suppressing antidepressants may be useful for cataplexy and sleep paralysis.

work or another circadian sleep disorder [10].

or more sleep onset rapid eye movement periods [6].

the multiple sleep latency testing.

184 Neuroplasticity - Insights of Neural Reorganization

4.1.2. Management

and vigilance.

used in selected cases.

dose steroids should be considered [6].

defined as a BMI above or equal to 25 and below 30.

including overweight with obesity in some studies [42, 68].

ences in other quality of life scales of the SF-36 [69].

in different neural networks [69].

4.2. Overweight and obesity

Patients who are overweight and obese are usually referred for diagnosis and management by a multidisciplinary team such as specialist nutritionist, physiotherapists, surgeons and neuropsychologists.

Gradual weight loss and gentle physical exercise and stretching are recommended. Small meals and small amounts of food, low in animal fats and fresh fruits. Bariatric surgery may be necessary in severe cases of obesity.

Co-morbidities have been shown to be associated with increased hospitalization, rate of progression to disability, decreased quality of life and increased mortality risk which is why they have to be properly treated [42].

Adverse health behavior including being overweight and obese, smoking and sedentary behavior are common in people with MS [42]. These behaviors can be modified and may significantly change the level of health. Health professionals should be focused on achieving these behavioral changes in patients with MS.
