2. Effect or influence of multiple sclerosis in sleep disorders

#### 2.1. Insomnia

The poor sleepers among patients with MS are more likely to report fatigue (one of the most frequent symptoms in MS) and pain (a co-morbid condition to MS-related fatigue but is confounded by depression and medication for treating pain or pain-induced sleep disor-

All the symptoms are intermixed, and it is not possible to discern the precipitating factor and the perpetuating factor. In this respect, sleepiness and fatigue may converge in some

Insomnia is present in mood disorders (depression and anxiety), restless leg syndrome (RLS), pain, nocturia and others [1]. RLS is also an important cause of pain in patients with MS. Sleep disorders may occur independently of demographic factors such as gender and clinicaldemographic factors. High psychological burden has been said to be independently associated with poor sleep patients with increased risk of co-morbid conditions such as heart disease, obesity and diabetes, which may have a profound impact on long-term health. The reverse

The frequency of sleep disturbances in MS and their impact on the patients' quality of life are unknown. The prevalence of sleep problems in the MS population ranges from 47 to 62%, with a higher prevalence in women [2–5]. Sex hormones and genetic mechanisms, psychosocial factors, certain physical factors that disrupt sleep, such as pain or bladder dysfunction may

Obstructive sleep apnea (OSA), RLS and chronic insomnia in particular are frequent problems in the MS population, and play a key role in the development of debilitating fatigue and other poor functional outcomes in MS. Yet, despite their impact, sleep disorders in MS remain critically under-recognized in most clinical settings. A recommended approach to the fatigued

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

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

Sleep disorders are under-recognized in persons with MS. These sleep disorders can contribute significantly to fatigue, other daytime dysfunction and poor quality of life. A systematic, practical approach that takes into account clinical features of MS is recommended to enhance recognition of these conditions and facilitate appropriate treatment. Clinicians caring for patients with MS should routinely screen for sleep disturbances and initiate diagnostic workups, if clinically

Sleep specialty referrals should be considered for management of conditions that require polysomnography (PSG) diagnosis, for complex patients who present a diagnostic challenge and for patients who do not respond to first-line treatments. Clinicians should also routinely

ask about sleep when forming a comprehensive care plan for patients with MS.

cases, a bidirectional relationship exists between these co-morbid conditions [7].

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

contribute to sleep differences between women and men [5].

der) [1].

situations [1].

indicated.

situation is also possible.

168 Neuroplasticity - Insights of Neural Reorganization

patient with MS is also highlighted [6].

Sleeplessness or insomnia 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 [10]. 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, drugs or extrinsic factors such as noise [6, 11].

Patients with MS face a high risk of insomnia of around 40% [6] compared to roughly 10–15% in the general population [12]. Awakening too early in the morning is the most common symptom (58%) [13].

Primary symptoms of MS that can condition the onset of insomnia are neurogenic bladder (nocturia), spasticity, sexual dysfunction, neuropathic pain, paroxysmal phenomena, depression and anxiety [7].

Insomnia affects daytime activities, because of fatigue, mood disturbances (depression and anxiety), attention, concentration and memory impairment [7]. Higher fatigue scores have also been found to correlate with insomnia, especially middle insomnia [13].

#### 2.1.1. Diagnostic approach

Patients with insomnia may complain of difficulty falling asleep, difficulty staying asleep or waking up sooner than desired [10]. There are screening tools to identify such patients.

The Pittsburgh Sleep Quality Index (PSQI) measures seven domains: subjective sleep quality, latency, duration, habitual efficiency, disturbances, use of sleep medication and daytime dysfunction over the last month. Each of these seven domains is self-rated by the individuals. The score of each question is based on a scale from 0 to 3, in which a score of 3 demonstrates the negative extreme on the Likert Scale. A global sum of 5 or greater indicates a poor sleeper (sensitivity of almost 100% for insomnia) [14, 15].

Insomnia Severity Index (ISI): a seven item questionnaire designed to assess the nature, severity, and impact of insomnia in adults. Scores >15 reflect moderate clinical insomnia. It is also a useful tool to monitor the effects of insomnia interventions [6].

Athens Insomnia Scale (AIS): a psychometric instrument designed for quantifying sleep difficulty. It consists of eight items: the first five pertain to sleep induction, awakenings during the night, final awakening, total sleep duration and sleep quality; while the last three refer to wellbeing, functioning capacity and sleepiness during the day. Either the entire eight-item scale (AIS-8) or the brief five-item version (AIS-5), which contains only the first five items, can be used. The score of each question is based on a scale from 0 to 3, where a score of 3 indicates the negative or normal extreme on the Likert Scale. A cut-off score of ≥6 on the AIS is used to establish the diagnosis of insomnia [16].

### 2.1.2. Management

After detecting insomnia, amelioration of any precipitating causes of insomnia is a cardinal step in its management. Medications or substances that may contribute to insomnia should be reduced or discontinued, if possible, there should be a check on which drugs the patient is taking (medications used to alleviate MS-related symptoms, including over-the-counter medications).

indicate adequate sleep hygiene and assess whether specific treatment is needed to improve

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 171

The four main criteria for diagnosis of RLS are: (1) unpleasant sensations in the legs; (2) worsening of the symptoms during rest; (3) relief of the symptoms by movement and (4)

The periodic limb movement disorder (PLMD) includes repetitive periodic shaking episodes lasting between 0.5 and 5 seconds that occur during sleep every 20–40 seconds; mainly in the

RLS and PLMD are motor disorders of sleep considered separate clinical entities, both conditions have the potential to cause disrupted sleep, share similar pathogenesis and have an increased

Most RLS patients (80–90%) 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 the general population ranges from 1 to 12% [20]. The prevalence of

Differentiating RLS from other sensory and motor symptoms of MS can be difficult, as MS patients frequently suffer from spasms, dysesthesia, paraesthesia and spasticity in the legs,

Predictive factors for RLS in MS patients include: older age, longer disease duration, progressive primary forms, greater disability as measured by the Expanded Disability Status Scale (EDSS), especially in the pyramidal and sensory subscales and shaking of the legs before onset of sleep [26]. Furthermore, RLS symptoms are more severe when associated with MS than

MS patients with RLS have more cervical cord lesions than those patients without RLS. These lesions possibly disrupt the ascending and descending pathways with cerebrospinal discon-

Primary RLS is a genetic form of RLS with autosomal dominant transmission [27]. Four genes have been associated with this syndrome [28] but no crossing over of those involved in MS

Pathogenesis of RLS and PRLS shows dysfunction of downstream dopaminergic pathways, namely diencephalospinal and reticulospinal pathways, that project to the spinal cord. These pathways, via dopaminergic transmission, are responsible for the suppression of sensory inputs and motor excitability, and are susceptible to damage from diseases affecting the spinal cord. Impaired iron metabolism is also thought to contribute to the pathogenesis of RLS, as

Certain medications used in the management of persons with MS, such as antiemetic drugs, antipsychotic dopamine antagonists, antidepressants and antihistamines can also cause or

iron is a cofactor for a rate-limiting step in the synthesis of dopamine [6, 10].

prevalence among persons with MS. PLMD also frequently occur in the absence of RLS.

RLS in MS patients is two to five times higher than in the general population [21–24].

exacerbation of the symptoms in the evening or at night [19].

daily performance.

2.3. Restless leg syndrome

legs, but sometimes in the arms.

which worsen with immobility [25].

when not associated with MS.

[10].

worsen RLS [6, 10].

nection leading to these symptoms [10].

Selective serotonin reuptake inhibitors, while helpful for depressive symptoms, may worsen insomnia.

Stimulants and wake-promoting agents, which are commonly used for fatigue, may interfere with sleep initiation if taken during the late afternoon or early evening hours.

Antihistamines, which are used as sleep aids by up to 25% of patients with MS, have the potential to worsen RLS, and thereby worsen sleep-onset insomnia [6].

Co-morbid symptoms must be identified and treated: neuropathic pain (tricyclic antidepressants and the α-2-δ ligand pregabalin), spasticity (baclofen or tizanidine) and urinary urgency (anticholinergics) [6].

Cognitive behavioral therapy (CBT) is an innovative psychotherapy approach. CBT treatment could reduce anxiety and depression by changing thoughts and beliefs and consequently reduce the symptoms of insomnia [6, 17].

Pharmacological therapies can be considered if more conservative strategies have been exhausted or are not fully effective: benzodiazepines, benzodiazepine agonists, melatonin receptor agonists and orexin receptor antagonists.

#### 2.2. Hypersomnia

Excessive daytime sleepiness (EDS)/excessive daytime drowsiness disrupt daily performance.

Hypersomnia may be due to acute thalamus injuries, mental disorders, especially depressive symptoms, sleep deprivation or as a consequence of received treatments.

#### 2.2.1. Diagnostic approach

The Epworth Sleepiness Scale (ESS) is a screening tool that assesses sleepiness and has eight items. ESS values equal to or greater than 10 indicate excessive daytime sleepiness (EDS), and in this case, patients should undergo polygraphy or PSG (screening for sleep apnea) [18].

All fatigued patients should be asked about sleepiness and fill in the Epworth Sleepiness Scale (ESS) as these are not always associated with sleepiness.

Magnetic resonance imaging (MRI) should be performed because of the need to identify structural lesions in the brain.

#### 2.2.2. Management

After detecting hypersomnia, the physician should check for any medications involved and withdraw them if possible, treat acute lesions of multiple sclerosis with corticosteroids, indicate adequate sleep hygiene and assess whether specific treatment is needed to improve daily performance.

#### 2.3. Restless leg syndrome

2.1.2. Management

170 Neuroplasticity - Insights of Neural Reorganization

insomnia.

(anticholinergics) [6].

2.2. Hypersomnia

2.2.1. Diagnostic approach

structural lesions in the brain.

2.2.2. Management

reduce the symptoms of insomnia [6, 17].

and orexin receptor antagonists.

After detecting insomnia, amelioration of any precipitating causes of insomnia is a cardinal step in its management. Medications or substances that may contribute to insomnia should be reduced or discontinued, if possible, there should be a check on which drugs the patient is taking (medications used to alleviate MS-related symptoms, including over-the-counter medications). Selective serotonin reuptake inhibitors, while helpful for depressive symptoms, may worsen

Stimulants and wake-promoting agents, which are commonly used for fatigue, may interfere

Antihistamines, which are used as sleep aids by up to 25% of patients with MS, have the

Co-morbid symptoms must be identified and treated: neuropathic pain (tricyclic antidepressants and the α-2-δ ligand pregabalin), spasticity (baclofen or tizanidine) and urinary urgency

Cognitive behavioral therapy (CBT) is an innovative psychotherapy approach. CBT treatment could reduce anxiety and depression by changing thoughts and beliefs and consequently

Pharmacological therapies can be considered if more conservative strategies have been exhausted or are not fully effective: benzodiazepines, benzodiazepine agonists, melatonin receptor agonists

Excessive daytime sleepiness (EDS)/excessive daytime drowsiness disrupt daily performance. Hypersomnia may be due to acute thalamus injuries, mental disorders, especially depressive

The Epworth Sleepiness Scale (ESS) is a screening tool that assesses sleepiness and has eight items. ESS values equal to or greater than 10 indicate excessive daytime sleepiness (EDS), and in this case, patients should undergo polygraphy or PSG (screening for sleep apnea) [18].

All fatigued patients should be asked about sleepiness and fill in the Epworth Sleepiness Scale

Magnetic resonance imaging (MRI) should be performed because of the need to identify

After detecting hypersomnia, the physician should check for any medications involved and withdraw them if possible, treat acute lesions of multiple sclerosis with corticosteroids,

with sleep initiation if taken during the late afternoon or early evening hours.

potential to worsen RLS, and thereby worsen sleep-onset insomnia [6].

symptoms, sleep deprivation or as a consequence of received treatments.

(ESS) as these are not always associated with sleepiness.

The four main criteria for diagnosis of 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 [19].

The periodic limb movement disorder (PLMD) includes repetitive periodic shaking episodes lasting between 0.5 and 5 seconds that occur during sleep every 20–40 seconds; mainly in the legs, but sometimes in the arms.

RLS and PLMD are motor disorders of sleep considered separate clinical entities, both conditions have the potential to cause disrupted sleep, share similar pathogenesis and have an increased prevalence among persons with MS. PLMD also frequently occur in the absence of RLS.

Most RLS patients (80–90%) 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 the general population ranges from 1 to 12% [20]. The prevalence of RLS in MS patients is two to five times higher than in the general population [21–24].

Differentiating RLS from other sensory and motor symptoms of MS can be difficult, as MS patients frequently suffer from spasms, dysesthesia, paraesthesia and spasticity in the legs, which worsen with immobility [25].

Predictive factors for RLS in MS patients include: older age, longer disease duration, progressive primary forms, greater disability as measured by the Expanded Disability Status Scale (EDSS), especially in the pyramidal and sensory subscales and shaking of the legs before onset of sleep [26]. Furthermore, RLS symptoms are more severe when associated with MS than when not associated with MS.

MS patients with RLS have more cervical cord lesions than those patients without RLS. These lesions possibly disrupt the ascending and descending pathways with cerebrospinal disconnection leading to these symptoms [10].

Primary RLS is a genetic form of RLS with autosomal dominant transmission [27]. Four genes have been associated with this syndrome [28] but no crossing over of those involved in MS [10].

Pathogenesis of RLS and PRLS shows dysfunction of downstream dopaminergic pathways, namely diencephalospinal and reticulospinal pathways, that project to the spinal cord. These pathways, via dopaminergic transmission, are responsible for the suppression of sensory inputs and motor excitability, and are susceptible to damage from diseases affecting the spinal cord. Impaired iron metabolism is also thought to contribute to the pathogenesis of RLS, as iron is a cofactor for a rate-limiting step in the synthesis of dopamine [6, 10].

Certain medications used in the management of persons with MS, such as antiemetic drugs, antipsychotic dopamine antagonists, antidepressants and antihistamines can also cause or worsen RLS [6, 10].

#### 2.3.1. Diagnostic approach

Many descriptors can be used by patients to describe the restless sensation, including creeping, crawling, itching, burning, tightening, tingling or pain.

Maintenance of upper airway patency during sleep requires an increase in pharyngeal tone that is primarily mediated by efferent motor output from cranial nerves X and XII to the palatal and genioglossus muscles, respectively. This process is largely influenced by afferent sensory input from pressure receptors in the upper airway, peripheral chemoreceptors in the aortic and carotid bodies, and brainstem respiratory generators. Pathophysiological processes that disrupt these tightly regulated brainstem pathways have the potential to impair nocturnal respiration. The medullary reticular formation is responsible for controlling automatic breathing

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 173

Causative factors include obesity, craniofacial abnormalities, enlarged tonsils, congestive heart

Such apnea and hypopnea episodes may lead to nocturnal hypoxemia, frequent awakenings and daytime somnolence. When the apneas are associated with respiratory effort, the term obstructive apnea is used, and central apnea is used when there is a lack of respiratory effort [10].

Central sleep apnea is diagnosed when more of 50% of the events are central in patients with

Obstructive sleep apnea is characterized by repeated episodes of upper airway obstruction and

The incidence of OSA in patients with MS is 2–21% and is one of the most common respiratory

Patients with MS who have a diagnosis of OSA and those at an elevated risk of OSA have increased fatigue and diminished quality life compared with undiagnosed or low-risk patients [6]. Sleepiness is primarily a result of acutely or chronically reduced sleep time, or poor sleep

Questions must be asked about symptoms of snoring, pauses in breathing witnessed by a bed partner, gasping or choking upon awakening, non-restorative sleep, excessive daytime hypersomnolence or fatigue, cognitive disturbances and nighttime awakenings, any of

Dysarthria or dysphagia, obesity, increased neck circumference, crowded oropharyngeal inlet,

The STOP-Bang questionnaire is a screening tool consisting of eight questions and measures that form the acronym snoring, tired, observed apnea, Blood Pressure-Body Mass Index, age, neck circumference and gender. Scores of 3 or higher indicate an elevated risk of OSA [6].

A full-night PSG is necessary to demonstrate the presence of obstructive respiratory events during sleep to confirm the diagnosis of OSA. These events may be partial (hypopneas) or

quality. Apnea severity may correlate with impaired cognition in MS [6].

retrognathia, or micrognathia are common physical exam findings [6].

which may arise in part from underlying OSA [6].

disease and degenerative central nervous system (CNS) disorders, to name a few [10].

during sleep [10].

both central and obstructive apneas.

2.4.2. Obstructive sleep apnea

hypoxia during sleep [6].

2.4.2.1. Diagnostic approach

disorders [10].

Symptoms of leg tightness relieved by voluntary movement suggest RLS, whereas involuntary spasms, even if a circadian component is endorsed, suggest spasticity. Rhythmic involuntary movements triggered by stretching or certain leg positions suggest clonus.

The Restless Legs Syndrome Diagnostic Index (RLS-DI) is a 10-item questionnaire. Scores range from 22 (no RLS) to +20 (definite RLS). A score of +11 yields 93.0% sensitivity and 96.1% specificity to accurately diagnose RLS [6].

Diagnosis of PLMD requires overnight PSG to assess for the presence of leg movements [6, 10].

The RLS Rating Scale is a useful tool to track treatment response and is a 10-item self-administered scale. Scores of 11–20 reflect moderate RLS.

#### 2.3.2. Management

Iron supplementation should be implemented for a ferritin level of less than 50 ng/ml.

Reduction or discontinuation of medications and substances that can cause or worsen RLS or PLMD (dopamine antagonists, lithium, selective serotonin reuptake inhibitors, serotoninnorepinephrine reuptake inhibitors, antihistamines, tricyclic antidepressants, alcohol, tobacco and caffeine) is recommended.

Dopamine agonists (pramipexole, ropinirole and rotigotine), and the α-2-δ ligand gabapentin and anticonvulsants are first-line treatments.

Benzodiazepines and opioid agents (oxycodone and methadone) are second line treatments.

Treatment for refractory RLS, or augmentation in response to dopaminergic therapy, is also likely to be optimized by sleep specialty care [6].

#### 2.4. Respiratory disorders during sleep

Sleep-disordered breathing is characterized by episodes of nocturnal hypopnea and apnea resulting in a reduction or a cessation of airflow in the upper airway.

Patients with sleep-disordered breathing may complain of "fatigue," decreased concentration, mood changes, erectile dysfunction, nocturia and mood changes, all these complaints are similar to those experienced in MS [29].

#### 2.4.1. Apnea and hypopnea

Apneas and hypopneas 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) [10].

Maintenance of upper airway patency during sleep requires an increase in pharyngeal tone that is primarily mediated by efferent motor output from cranial nerves X and XII to the palatal and genioglossus muscles, respectively. This process is largely influenced by afferent sensory input from pressure receptors in the upper airway, peripheral chemoreceptors in the aortic and carotid bodies, and brainstem respiratory generators. Pathophysiological processes that disrupt these tightly regulated brainstem pathways have the potential to impair nocturnal respiration. The medullary reticular formation is responsible for controlling automatic breathing during sleep [10].

Causative factors include obesity, craniofacial abnormalities, enlarged tonsils, congestive heart disease and degenerative central nervous system (CNS) disorders, to name a few [10].

Such apnea and hypopnea episodes may lead to nocturnal hypoxemia, frequent awakenings and daytime somnolence. When the apneas are associated with respiratory effort, the term obstructive apnea is used, and central apnea is used when there is a lack of respiratory effort [10].

Central sleep apnea is diagnosed when more of 50% of the events are central in patients with both central and obstructive apneas.

#### 2.4.2. Obstructive sleep apnea

2.3.1. Diagnostic approach

172 Neuroplasticity - Insights of Neural Reorganization

2.3.2. Management

and caffeine) is recommended.

crawling, itching, burning, tightening, tingling or pain.

96.1% specificity to accurately diagnose RLS [6].

scale. Scores of 11–20 reflect moderate RLS.

and anticonvulsants are first-line treatments.

likely to be optimized by sleep specialty care [6].

resulting in a reduction or a cessation of airflow in the upper airway.

2.4. Respiratory disorders during sleep

similar to those experienced in MS [29].

2.4.1. Apnea and hypopnea

hypopnea) [10].

Many descriptors can be used by patients to describe the restless sensation, including creeping,

Symptoms of leg tightness relieved by voluntary movement suggest RLS, whereas involuntary spasms, even if a circadian component is endorsed, suggest spasticity. Rhythmic involuntary

The Restless Legs Syndrome Diagnostic Index (RLS-DI) is a 10-item questionnaire. Scores range from 22 (no RLS) to +20 (definite RLS). A score of +11 yields 93.0% sensitivity and

Diagnosis of PLMD requires overnight PSG to assess for the presence of leg movements [6, 10]. The RLS Rating Scale is a useful tool to track treatment response and is a 10-item self-administered

Reduction or discontinuation of medications and substances that can cause or worsen RLS or PLMD (dopamine antagonists, lithium, selective serotonin reuptake inhibitors, serotoninnorepinephrine reuptake inhibitors, antihistamines, tricyclic antidepressants, alcohol, tobacco

Dopamine agonists (pramipexole, ropinirole and rotigotine), and the α-2-δ ligand gabapentin

Benzodiazepines and opioid agents (oxycodone and methadone) are second line treatments. Treatment for refractory RLS, or augmentation in response to dopaminergic therapy, is also

Sleep-disordered breathing is characterized by episodes of nocturnal hypopnea and apnea

Patients with sleep-disordered breathing may complain of "fatigue," decreased concentration, mood changes, erectile dysfunction, nocturia and mood changes, all these complaints are

Apneas and hypopneas 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/

Iron supplementation should be implemented for a ferritin level of less than 50 ng/ml.

movements triggered by stretching or certain leg positions suggest clonus.

Obstructive sleep apnea is characterized by repeated episodes of upper airway obstruction and hypoxia during sleep [6].

The incidence of OSA in patients with MS is 2–21% and is one of the most common respiratory disorders [10].

Patients with MS who have a diagnosis of OSA and those at an elevated risk of OSA have increased fatigue and diminished quality life compared with undiagnosed or low-risk patients [6].

Sleepiness is primarily a result of acutely or chronically reduced sleep time, or poor sleep quality. Apnea severity may correlate with impaired cognition in MS [6].

#### 2.4.2.1. Diagnostic approach

Questions must be asked about symptoms of snoring, pauses in breathing witnessed by a bed partner, gasping or choking upon awakening, non-restorative sleep, excessive daytime hypersomnolence or fatigue, cognitive disturbances and nighttime awakenings, any of which may arise in part from underlying OSA [6].

Dysarthria or dysphagia, obesity, increased neck circumference, crowded oropharyngeal inlet, retrognathia, or micrognathia are common physical exam findings [6].

The STOP-Bang questionnaire is a screening tool consisting of eight questions and measures that form the acronym snoring, tired, observed apnea, Blood Pressure-Body Mass Index, age, neck circumference and gender. Scores of 3 or higher indicate an elevated risk of OSA [6].

A full-night PSG is necessary to demonstrate the presence of obstructive respiratory events during sleep to confirm the diagnosis of OSA. These events may be partial (hypopneas) or complete (apneas), but must demonstrate evidence of a reduction in airflow during sleep, despite continued effort to breathe [6].

2.4.3.2. Management

recommended.

2.4.4. Nocturnal urinary disorders

frequency and nocturia [32]).

primarily due to sleep disruption.

2.4.4.1. Diagnostic approach

sion of the problem.

In the cases of central sleep apnea not symptomatic or central sleep apnea during sleepwake transition (20% of central sleep apnea cases resolve spontaneously) observation is

Sleep Disorders in Multiple Sclerosis http://dx.doi.org/10.5772/intechopen.72831 175

In other cases, PAP treatment, adaptive servo ventilation, oxygen, added dead space, carbon

Sleep disturbance is associated with outcomes such as increased risk of falls and mortality. Nocturia may both precipitate poor sleep and perpetuate insomnia (awakenings associated

Overactive bladder (OAB) syndrome is a condition that accompanies urgency (a significant factor for sleep disruption), with or without incontinence, frequently with increased daytime

Nocturia is defined by the International Continence Society as the complaint that an individual has to wake at night one or more times to void. It reflects the relationship between the amount of urine produced while asleep, and the storage by the bladder of urine received. Nocturia is a symptom rather than a disease and causative categories have been proposed and is the most

Nocturia can occur as part of lower urinary tract dysfunction (LUTD), notably in overactive bladder syndrome (OAB). Nocturia can also occur in association with other forms of LUTD,

Nocturia is due to nocturnal polyuria, a decreased nocturnal bladder capacity or a mixture of the two. Various duplicating factors for nocturia have been reported, including pathological conditions such as diabetes, LUTD, cardiovascular disease, primary sleep disorders and sleep apnea [32].

Nocturia is a feature of systemic conditions affecting water and salt balance, leading to excessive production of urine at all times (global polyuria) or primarily at night (nocturnal polyuria), so that nocturia can be a systemic symptom such as cardiovascular, endocrine and renal disease can

Nocturia can significantly influence quality of life, efficiency, vigor and awareness of health,

Asking how many times the patient wakes up at night because of nocturia, whether urinary urgency exists and the characteristics of urination, quantity of fluid intakes, physical exercise,

The use of specific questionnaires such as the PSQ, ISI and ASI for the diagnosis of insomnia or the ESS for the diurnal hypersomnia helps the physician to approach the functional repercus-

affect water and salt homeostasis, leading to an increased rate of urine production [33].

medication being taken, etc. is also necessary for the diagnosis of urinary problems.

dioxide inhalation and overdrive atrial pacing are needed.

with nocturia may themselves be perpetuating factors) [31].

common storage symptom in the general population [32].

such as bladder outlet obstruction or chronic pelvic pain syndrome [33].

### 2.4.2.2. Management

Management strategies for sleep-disordered breathing should take into account the patient's primary apnea subtype, apnea severity, co-morbidities and behaviors, and other MS-specific symptoms or limitations. Guidance by a sleep medicine physician is often helpful [6]. Discontinuation of medication, such as opiates, antispasmodics or CNS depressants medications [6].

Positive airway pressure (PAP) therapy is delivered by a mechanical device and mask to splint the upper airway open during sleep. Supplemental oxygen, bi-level PAP and adaptive servo ventilation are other improvements that these devices have [6].

Oral appliances work by repositioning the mandible in the anterior and inferior position [6]. By improving nocturnal oxygen saturation and sleep quality, PAP therapy effectively reduces fatigue and can be effective in the treatment of depression. This is especially important given the link between fatigue and depression in MS [6, 18].

Disease-modifying therapy use, in particular emerged as a strong predictor of reduced apnea severity, raising interesting possibilities about the role of local and/or systemic inflammation in OSA [6].

#### 2.4.3. Central sleep apnea

Central sleep apnea (CSA) is rare, and the prevalence is unclear in the general population. CSA involves repeated complete or partial reduction of airflow, caused by an intermittent lack of respiratory effort by failure in the medullary respiratory signal [10].

While the prevalence of CSA is less than that of OSA, patients with CNS disorders that affect pontine and medullary respiratory generators, including MS, may be at increased risk for this condition as well even nocturnal death (Ondine's curse) [6, 10].

CNS and brain stem-related nocturnal respiratory abnormalities such as central sleep apnea, paroxysmal hyperventilation, hypoventilation, respiratory muscle weakness and respiratory arrest have all been described and should be considered in this patient population in the evaluation of symptoms of daytime somnolence, increased fatigue and non-refreshing sleep [11].

#### 2.4.3.1. Diagnostic approach

In patients with symptoms of daytime somnolence, increased fatigue and non-refreshing sleep, the physician must ask about nocturnal respiratory abnormalities [11] and look for evidence of reduction in airflow in the absence of respiratory effort in an overnight PSG.

In patients with both central and obstructive apneas, central sleep apnea is diagnosed when more than 50% of the events are central. The coexistence of OSA or CSA and MS has been described by several authors [2, 10, 30].

### 2.4.3.2. Management

complete (apneas), but must demonstrate evidence of a reduction in airflow during sleep,

Management strategies for sleep-disordered breathing should take into account the patient's primary apnea subtype, apnea severity, co-morbidities and behaviors, and other MS-specific symptoms or limitations. Guidance by a sleep medicine physician is often helpful [6]. Discontinuation of medication, such as opiates, antispasmodics or CNS depressants medications [6]. Positive airway pressure (PAP) therapy is delivered by a mechanical device and mask to splint the upper airway open during sleep. Supplemental oxygen, bi-level PAP and adaptive servo

Oral appliances work by repositioning the mandible in the anterior and inferior position [6]. By improving nocturnal oxygen saturation and sleep quality, PAP therapy effectively reduces fatigue and can be effective in the treatment of depression. This is especially important given

Disease-modifying therapy use, in particular emerged as a strong predictor of reduced apnea severity, raising interesting possibilities about the role of local and/or systemic inflammation in

Central sleep apnea (CSA) is rare, and the prevalence is unclear in the general population. CSA involves repeated complete or partial reduction of airflow, caused by an intermittent lack of

While the prevalence of CSA is less than that of OSA, patients with CNS disorders that affect pontine and medullary respiratory generators, including MS, may be at increased risk for this

CNS and brain stem-related nocturnal respiratory abnormalities such as central sleep apnea, paroxysmal hyperventilation, hypoventilation, respiratory muscle weakness and respiratory arrest have all been described and should be considered in this patient population in the evaluation of symptoms of daytime somnolence, increased fatigue and non-refreshing

In patients with symptoms of daytime somnolence, increased fatigue and non-refreshing sleep, the physician must ask about nocturnal respiratory abnormalities [11] and look for evidence of

In patients with both central and obstructive apneas, central sleep apnea is diagnosed when more than 50% of the events are central. The coexistence of OSA or CSA and MS has been

reduction in airflow in the absence of respiratory effort in an overnight PSG.

despite continued effort to breathe [6].

174 Neuroplasticity - Insights of Neural Reorganization

ventilation are other improvements that these devices have [6].

respiratory effort by failure in the medullary respiratory signal [10].

condition as well even nocturnal death (Ondine's curse) [6, 10].

the link between fatigue and depression in MS [6, 18].

2.4.2.2. Management

OSA [6].

sleep [11].

2.4.3.1. Diagnostic approach

described by several authors [2, 10, 30].

2.4.3. Central sleep apnea

In the cases of central sleep apnea not symptomatic or central sleep apnea during sleepwake transition (20% of central sleep apnea cases resolve spontaneously) observation is recommended.

In other cases, PAP treatment, adaptive servo ventilation, oxygen, added dead space, carbon dioxide inhalation and overdrive atrial pacing are needed.

#### 2.4.4. Nocturnal urinary disorders

Sleep disturbance is associated with outcomes such as increased risk of falls and mortality. Nocturia may both precipitate poor sleep and perpetuate insomnia (awakenings associated with nocturia may themselves be perpetuating factors) [31].

Overactive bladder (OAB) syndrome is a condition that accompanies urgency (a significant factor for sleep disruption), with or without incontinence, frequently with increased daytime frequency and nocturia [32]).

Nocturia is defined by the International Continence Society as the complaint that an individual has to wake at night one or more times to void. It reflects the relationship between the amount of urine produced while asleep, and the storage by the bladder of urine received. Nocturia is a symptom rather than a disease and causative categories have been proposed and is the most common storage symptom in the general population [32].

Nocturia can occur as part of lower urinary tract dysfunction (LUTD), notably in overactive bladder syndrome (OAB). Nocturia can also occur in association with other forms of LUTD, such as bladder outlet obstruction or chronic pelvic pain syndrome [33].

Nocturia is due to nocturnal polyuria, a decreased nocturnal bladder capacity or a mixture of the two. Various duplicating factors for nocturia have been reported, including pathological conditions such as diabetes, LUTD, cardiovascular disease, primary sleep disorders and sleep apnea [32].

Nocturia is a feature of systemic conditions affecting water and salt balance, leading to excessive production of urine at all times (global polyuria) or primarily at night (nocturnal polyuria), so that nocturia can be a systemic symptom such as cardiovascular, endocrine and renal disease can affect water and salt homeostasis, leading to an increased rate of urine production [33].

Nocturia can significantly influence quality of life, efficiency, vigor and awareness of health, primarily due to sleep disruption.

#### 2.4.4.1. Diagnostic approach

Asking how many times the patient wakes up at night because of nocturia, whether urinary urgency exists and the characteristics of urination, quantity of fluid intakes, physical exercise, medication being taken, etc. is also necessary for the diagnosis of urinary problems.

The use of specific questionnaires such as the PSQ, ISI and ASI for the diagnosis of insomnia or the ESS for the diurnal hypersomnia helps the physician to approach the functional repercussion of the problem.

The study occasionally needs to be completed with ultrasound studies, urodynamics, MRI and urinary sediment to identify LUTD or OAB problems.

Between 80 and 97% [6] of patients report chronic fatigue, and more than 33% of patients rate

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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

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,

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

"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

"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 non-

The subjective feeling of fatigue is related to inflammation and increased levels of cytokines

"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

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

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

and inflammatory/degenerative processes and the rupture of the neural network [37].

quality of life among MS patients, regardless of depression or disability [18].

mental or physical activity, infections and food ingestion [37].

this symptom as the most disabling [34–36].

immunosuppressive treatments [7, 38, 39].

peripheral nerve contribution "central fatigue."

such as interleukin-1 (IL-1), IL-6 and TNF-alpha [40].

motor functions of the basal ganglia.

primary fatigue [36].

#### 2.4.4.2. Management

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

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 improvement nocturia.

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 symptoms are treated with an anticholinergic medication [18].

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 improve tolerance compared to daytime dosing [32].

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 undisturbed sleep [33].

Nocturia severity improvement contributes to overall improvements in health-related quality of life [33].

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 occurrence in insomnia) and thereby improves sleep efficiency.
