**3. Sleep-disordered breathing disorders in neurological diseases**

Respiratory disorders in patients with neurological diseases may be a result of damage to different parts of the respiratory rhythm generator and controlling structures responsible for

Sleep-Disordered Breathing in Neurological Diseases 101

of patients with motor neuron disease and is a major cause of mortality. Studies concerning sleep disorders and sleep-disordered breathing in motor neuron disease often differ significantly. Some studies indicate a significantly higher incidence of sleep-disordered breathing in the early stages of the disease (Santos, 2003) and fragmentation of sleep (Arnulf, 2000) with the absence or substantial reduction of the duration of REM sleep and increased number of arousals (Takekawa, 2001). Sleep-disordered breathing was mainly of central origin (Santos, 2003; Bourke, 2002). The severity of respiratory distress tended to decrease with time of disease; in patients with disease lasting less than 1 year AHI = 23, while in patients suffering from more than 2 years AHI = 16. Other studies in the early stages of the disease (Kimura, 1999; Ferguson, 1996, David, 1997) do not show significantly higher incidence of SDB. Some authors have postulated the relationship between the number of apneas during sleep and the clinical course (bulbar form) (Santos, 2003; Kimura, 1999), others did not observed similar corelations (Ferguson, 1996). The incidence of SDB in the early stages of motor neuron disease is estimated from 16 to 76.5% (Bourke, 2002). The reasons for such divergent results are due to small study groups of patients (usually not exceeding 20 persons), a different methodological approach (polysomnography vs. portable devices) and a different stage of the disease and its clinical course. Summarizing the results of these studies it is clear that sleep-disordered breathing in patients with motor neuron disease in the early stages of the disease are mostly represented in the form of shallow breaths of central origin, arising from the failure of the diaphragm muscle contraction. Obstructive disorders are rare and are associated rather with the bulbar form (Bourke, 2002). With disease progression the severity of respiratory distress during the day and during sleep increases. Most researchers (Kimura, 1999; Bourke, 2002; Bourke, 2003; Santos, 2003; Mustfa, 2006; Ozsancak, 2008; Ambrosino, 2009) suggest that early detection of major breathing problems during sleep is important and early qualification for home treatment of patients with non-invasive ventilation methods should be performed (Bourke, 2003; Santos, 2003; Mustfa, 2006; Ozsancak, 2008; Ambrosino, 2009). Along with the improvement of technical devices and their increased availability, treatment should be introduced as soon as possible (Ozsancak, 2008; Ambrosino, 2009). A number of studies in patients with motor neuron disease proved a beneficial effect of using non-invasive ventilation during sleep on the quality of life and prognosis (Bourke, 2003, 2006; Moustfa, 2006). Randomized study of 41 patients with motor neuron disease using non-invasive ventilation during sleep (Bourke, 2006) showed a significant increase in their quality of life and its prolongation, for an average 205 days compared with the control group. The greatest benefit was found in the group of patients with less severe involvement of bulbar muscles (Bourke, 2006). Due to the nature of SDB in patients with motor neuron disease (mainly central hypoventilation), the optimal screening study evaluating the severity of respiratory distress seems to be, both in

terms of accessibility and sensitivity, overnight oximetry.

Sleep-disordered breathing in patients with Duchenne muscular dystrophy has a characteristic clinical course (Barbe, 1994). In children under 10 years mostly obstructive apneas occur, while in older children, with the development of disease, the apneas of central origin predominate (Smith, 1989; Suresh, 2005). The occurrence of obstructive sleep apnea and snoring at a younger age is associated with frequent enlargement of the tongue (Barbe, 1994; Suresh, 2005)

**3.1.2 Duchenne muscular dystrophy** 

generation of respiratory movements (neuromuscular disorders). Vascular damage to the respiratory center may lead to central respiratory disturbances. Neurodegenerative disease can damage the respiratory center (Cormican, 2004), as well as demyelinating lesions (Auer, 1996) located within the respiratory center. Damage of the axons projecting from respiratory center to spinal cord α-motoneurons (cervical spine trauma, demyelinating plaques in multiple sclerosis) can cause respiratory disorders. Damage to the α-motor neurons of the spinal cord (amyotrophic lateral sclerosis, post-polio syndrome) leads to respiratory failure (Aboussouan, 2005). Similarly, peripheral nerve conduction abnormalities (Guillian-Barre syndrome and congenital polyneuropathy) may lead to hypoventilation and respiratory failure. Disorders of the neuromuscular transmission (myasthenia gravis, botulinum toxin poisoning) and primary muscle disorders (myopathies, muscular dystrophy) can cause respiratory disorders. Physiological sleep, especially REM sleep phase, is a period vulnerable to the occurrence of respiratory disorders. Often the first sign of respiratory failure in the course of neurological diseases is sleep-disordered breathing (Katz, 2009; Landon, 2006). Due to the risk of significant respiratory complications, often fatal, in the course of certain neurological diseases (amyotrophic lateral sclerosis, glycogenosis type II), it is advisable to closely monitor the sleep-disordered breathing among such patients (Bach, 2004; Birnbaum, 2009). Early detection of sleep-disordered breathing, thanks to the possibilities of non-invasive respiratory therapy in the earlier stages of the disease, can significantly improve the quality of life of patients and their prognosis (Bourke, 2003; Farrero, 2005; Mustfa, 2006; Bourke, 2006; Katz, 2009; Ambrosino, 2009). An interesting fact is the presence and influence of breathing disorders in neurological diseases not associated in their pathophysiology with respiratory problems. Examples of such diseases include Alzheimer's disease, Parkinson's disease and epilepsy. Sleep-disordered breathing can often worsen the course of these diseases. The main group of neurological disorders often associated with respiratory disorders are neuromuscular diseases.

#### **3.1 SDB in neuromuscular diseases**

Sleep-disordered breathing and respiratory failure are a common consequence of neuromuscular diseases. Respiratory failure as a result of the underlying disease is more prominent during physiological sleep. Ventilation disorders caused by weakening of breathing muscles occur mostly in patients at REM sleep stage. Physiological relaxation of most of the body muscles (except diaphragm and oculomotory muscles, Tabachnik, 1981) and respiratory drive instability may be the cause of breathing disorders during this phase of sleep. It was confirmed in patients with neuromuscular diseases in which blood saturation was measured (Bourke, 2002; Katz, 2009). Sleep-disordered breathing in patients with neuromuscular diseases can be either of central or obstructive origin. The most common type of sleep-disordered breathing in these patients are central hypoventilation and central apneas.

#### **3.1.1 Motor neuron disease**

Motor neuron disease leads to progressive muscle weakness, including respiratory muscles. This results in decreased breathing exertion and hypoventilation (Lyall, 2001). The course and severity of respiratory distress affects the clinical course of disease. First of all, bulbar form of amyotrophic lateral sclerosis is associated with more rapid development of respiratory failure (Hadjikoutis, 2001). Respiratory failure develops in a significant majority

generation of respiratory movements (neuromuscular disorders). Vascular damage to the respiratory center may lead to central respiratory disturbances. Neurodegenerative disease can damage the respiratory center (Cormican, 2004), as well as demyelinating lesions (Auer, 1996) located within the respiratory center. Damage of the axons projecting from respiratory center to spinal cord α-motoneurons (cervical spine trauma, demyelinating plaques in multiple sclerosis) can cause respiratory disorders. Damage to the α-motor neurons of the spinal cord (amyotrophic lateral sclerosis, post-polio syndrome) leads to respiratory failure (Aboussouan, 2005). Similarly, peripheral nerve conduction abnormalities (Guillian-Barre syndrome and congenital polyneuropathy) may lead to hypoventilation and respiratory failure. Disorders of the neuromuscular transmission (myasthenia gravis, botulinum toxin poisoning) and primary muscle disorders (myopathies, muscular dystrophy) can cause respiratory disorders. Physiological sleep, especially REM sleep phase, is a period vulnerable to the occurrence of respiratory disorders. Often the first sign of respiratory failure in the course of neurological diseases is sleep-disordered breathing (Katz, 2009; Landon, 2006). Due to the risk of significant respiratory complications, often fatal, in the course of certain neurological diseases (amyotrophic lateral sclerosis, glycogenosis type II), it is advisable to closely monitor the sleep-disordered breathing among such patients (Bach, 2004; Birnbaum, 2009). Early detection of sleep-disordered breathing, thanks to the possibilities of non-invasive respiratory therapy in the earlier stages of the disease, can significantly improve the quality of life of patients and their prognosis (Bourke, 2003; Farrero, 2005; Mustfa, 2006; Bourke, 2006; Katz, 2009; Ambrosino, 2009). An interesting fact is the presence and influence of breathing disorders in neurological diseases not associated in their pathophysiology with respiratory problems. Examples of such diseases include Alzheimer's disease, Parkinson's disease and epilepsy. Sleep-disordered breathing can often worsen the course of these diseases. The main group of neurological disorders often

associated with respiratory disorders are neuromuscular diseases.

Sleep-disordered breathing and respiratory failure are a common consequence of neuromuscular diseases. Respiratory failure as a result of the underlying disease is more prominent during physiological sleep. Ventilation disorders caused by weakening of breathing muscles occur mostly in patients at REM sleep stage. Physiological relaxation of most of the body muscles (except diaphragm and oculomotory muscles, Tabachnik, 1981) and respiratory drive instability may be the cause of breathing disorders during this phase of sleep. It was confirmed in patients with neuromuscular diseases in which blood saturation was measured (Bourke, 2002; Katz, 2009). Sleep-disordered breathing in patients with neuromuscular diseases can be either of central or obstructive origin. The most common type of sleep-disordered breathing in these patients are central hypoventilation

Motor neuron disease leads to progressive muscle weakness, including respiratory muscles. This results in decreased breathing exertion and hypoventilation (Lyall, 2001). The course and severity of respiratory distress affects the clinical course of disease. First of all, bulbar form of amyotrophic lateral sclerosis is associated with more rapid development of respiratory failure (Hadjikoutis, 2001). Respiratory failure develops in a significant majority

**3.1 SDB in neuromuscular diseases** 

and central apneas.

**3.1.1 Motor neuron disease** 

of patients with motor neuron disease and is a major cause of mortality. Studies concerning sleep disorders and sleep-disordered breathing in motor neuron disease often differ significantly. Some studies indicate a significantly higher incidence of sleep-disordered breathing in the early stages of the disease (Santos, 2003) and fragmentation of sleep (Arnulf, 2000) with the absence or substantial reduction of the duration of REM sleep and increased number of arousals (Takekawa, 2001). Sleep-disordered breathing was mainly of central origin (Santos, 2003; Bourke, 2002). The severity of respiratory distress tended to decrease with time of disease; in patients with disease lasting less than 1 year AHI = 23, while in patients suffering from more than 2 years AHI = 16. Other studies in the early stages of the disease (Kimura, 1999; Ferguson, 1996, David, 1997) do not show significantly higher incidence of SDB. Some authors have postulated the relationship between the number of apneas during sleep and the clinical course (bulbar form) (Santos, 2003; Kimura, 1999), others did not observed similar corelations (Ferguson, 1996). The incidence of SDB in the early stages of motor neuron disease is estimated from 16 to 76.5% (Bourke, 2002). The reasons for such divergent results are due to small study groups of patients (usually not exceeding 20 persons), a different methodological approach (polysomnography vs. portable devices) and a different stage of the disease and its clinical course. Summarizing the results of these studies it is clear that sleep-disordered breathing in patients with motor neuron disease in the early stages of the disease are mostly represented in the form of shallow breaths of central origin, arising from the failure of the diaphragm muscle contraction. Obstructive disorders are rare and are associated rather with the bulbar form (Bourke, 2002). With disease progression the severity of respiratory distress during the day and during sleep increases. Most researchers (Kimura, 1999; Bourke, 2002; Bourke, 2003; Santos, 2003; Mustfa, 2006; Ozsancak, 2008; Ambrosino, 2009) suggest that early detection of major breathing problems during sleep is important and early qualification for home treatment of patients with non-invasive ventilation methods should be performed (Bourke, 2003; Santos, 2003; Mustfa, 2006; Ozsancak, 2008; Ambrosino, 2009). Along with the improvement of technical devices and their increased availability, treatment should be introduced as soon as possible (Ozsancak, 2008; Ambrosino, 2009). A number of studies in patients with motor neuron disease proved a beneficial effect of using non-invasive ventilation during sleep on the quality of life and prognosis (Bourke, 2003, 2006; Moustfa, 2006). Randomized study of 41 patients with motor neuron disease using non-invasive ventilation during sleep (Bourke, 2006) showed a significant increase in their quality of life and its prolongation, for an average 205 days compared with the control group. The greatest benefit was found in the group of patients with less severe involvement of bulbar muscles (Bourke, 2006). Due to the nature of SDB in patients with motor neuron disease (mainly central hypoventilation), the optimal screening study evaluating the severity of respiratory distress seems to be, both in terms of accessibility and sensitivity, overnight oximetry.

#### **3.1.2 Duchenne muscular dystrophy**

Sleep-disordered breathing in patients with Duchenne muscular dystrophy has a characteristic clinical course (Barbe, 1994). In children under 10 years mostly obstructive apneas occur, while in older children, with the development of disease, the apneas of central origin predominate (Smith, 1989; Suresh, 2005). The occurrence of obstructive sleep apnea and snoring at a younger age is associated with frequent enlargement of the tongue (Barbe, 1994; Suresh, 2005)

Sleep-Disordered Breathing in Neurological Diseases 103

implemented only in specialized centers. Sometimes it is necessary to apply a positive pressure with a variable values (BiPAP, Auto-CPAP) or additional oxygen therapy. In the treatment of excessive sleepiness psychostimulants - metylfenidad and modafinil are used.

Disorders of neuromuscular transmission in the course of myasthenia gravis may cause sleep-disordered breathing of central type, especially during REM sleep accompanied by declines in blood oxygen saturation (Quera-Salva, 1992; Manni, 1995). The nature of respiratory disorders is similar as in other neuromuscular diseases. The severity of respiratory distress is associated with disease severity. Sleep-disordered breathing in patients with myasthenia gravis is particularly pronounced before the occurrence of myasthenic crisis and precede symptoms of respiratory failure due to exhaustion of the respiratory muscles during the night. At that time hypercapnia is the most characteristic symptom. Hypoxia and hypercapnia occurring during sleep are often the case of morning headaches and progressive fatigue associated with underlying disease. Implementation of treatment reduces sleep-disordered breathing (Amino, 1998). There is no clear data to evaluate the incidence of SDB in patients with well-controlled myasthenia gravis. Some authors have shown an increased incidence of obstructive type of sleep-disordered breathing in patients with myasthenia gravis (36% compared to 15-20% expected in the population (Nicolle, 2006). Other authors (Prudlo, 2007) found no correlation between the occurrence of myasthenia gravis and the occurrence of obstructive breathing disorder during sleep. Most studies on the prevalence of SDB in myasthenia gravis was conducted on small groups (up to 30 patients). These results should therefore be carefully analyzed. Currently it seems that the periods of worsening of the disease are associated with increased risk of respiratory distress, while the periods of remission during medical treatment are not associated with an increased risk of respiratory disorders during sleep (Prudlo, 2007).

Pompe disease is a chronic, progressive metabolic myopathy associated with deficiency or reduced activity of the acid alpha-glucosidase enzyme. As a result, glycogen storage occurs in tissues and impairs their functioning. Depending on the degree of enzyme defficiency clinical course of disease may be different. The infantile form is associated with a complete lack of the enzyme. Symptoms begin within the first few months of life. The usual presenting features are cardiomyopathy and hepatomegaly leading to progressive heart failure and respiratory distress. Juvenile and adult forms are due to partial enzyme deficiency. Symptoms appear later and the disease has a chronic progressive course (Lewandowska, 2008). Adult –onset type of Pompe disease is associated with progressive respiratory failure resulting from progressive respiratory muscle weakness (Wierzba-Bobrowicz, 2007). Patients with adult-onset type of Pompe disease often have sleepdisordered breathing (Bembi, 2008; Mellies, 2001). These problems usually occur before the total respiratory failure. Sleep-disordered breathing is usually present in the REM sleep phase in forms of central apneas or hypopneas (Mellies, 2001). Since Pompe is a rare disease, few studies have been published regarding the prevalence of SDB in this disease. In one study performed in 27 patients with juvenile and adult form, sleep-disordered breathing was found in 13 patients, 12 of which had diaphragm weakness (Mellies, 2001). Respiratory disorders: hypopneas and apneas, occurred primarily during REM sleep and correlated with

**3.1.4 Myasthenia** 

**3.1.5 Glycogenosis type II-Pompe disease** 

and a relatively good function of the respiratory muscles. With age, symptoms of respiratory muscle failure develop and lead to sleep- apneas of central type. The study of 34 patients aged from 1 to 15 years showed the presence of daily symptoms of sleep-disordered breathing in 64%. Polysomnographic studies have shown obstructive SDB incidence in 31% (median age 8 years ) and central type SDB in 32% (median age 13 years) (Suresh, 2005). The non-invasive ventilation therapy during sleep significantly reduced the number of episodes of breathing problems, an average of 11 per hour in 5 years. The authors recommend polysomnography study in patients under 10 years of age with symptoms of sleep-disordered breathing. In children above 10 years of age, with early signs of respiratory distress, polysomnographic studies must be performed. Treatment with non-invasive home night ventilation should begin as early as possible (Suresh, 2005; Katz, 2009). In children with Duchenne muscular dystrophy the best predictor of outcome is the vital capacity, respiratory parameters during sleep are of less importance. Recommendations of the American Thoracic Society (2006) include: a history of breathing problems during sleep during each visit, regardless of age, in the case of a patient immobilized in a wheelchair polysomnographic evaluation once a year. When polysomnography is not feasible it is recommended to control overnight pulse oximetry (Kirk, 2000) and evaluate arterial gasometry during follow-up visits.

There are no large systematic studies on sleep -disordered breathing in other types of muscular dystrophies. Recently published study analyses SDB in 51 patients with facioscapulohumeral muscular dystrophy (Della Marca, 2009). 22 patients had abnormal breathing during sleep, 13 of them had obstructive breathing disorders (3 of them required the CPAP treatment). In 4 patients during REM sleep hypoxia of central origin were found, 3 patients had mixed type of respiratory disorders. Other parameters such as BMI, daytime sleepiness, and neck circumference did not correlate with the occurrence of sleep-disordered breathing.

#### **3.1.3 Myotonic dystrophy**

Myotonic dystrophy (DM) is the most common neuromuscular disease in the adult population (Rowland, 2005). During sleep, individuals with DM may develop hypopneas and apneas, obstructive, central and mixed (Finnimore, 1994; Kiyan, 2009). These disorders occur in about half of patients with DM (Labanowski, 1996; Kiyan, 2009). Polysomnographic studies show a reduction in the duration and sleep efficiency, increased number of nocturnal arousals and time of light sleep (NREM1) and decrease in the time of REM sleep (Bourke, 2002). During the day, the rhythm of breathing in patients with myotonic dystrophy is irregular while awake, as well as during light sleep. The main problems are observed in the REM phase of sleep (Finnimore, 1994). Usually, symptoms of sleepdisordered breathing in patients with myotonic dystrophy are far before of signs of respiratory distress during the day (Bourke, 2002). Daytime sleepiness in patients with DM (assessed with the Epworth sleepiness scale ≥ 10) is felt by about 50% of patients (Laberge, 2009). Objective tests of daytime sleepiness (MSLT test) show excessive daytime sleepiness in 69% of the respondents (Laberge, 2009). Excessive sleepiness correlates with the degeneration of serotonergic neurons in the raphe nuclei and central superior nucleus of the reticular formation (Ono, 1998). Authors describe the decrease of orexin concentration in the cerebrospinal fluid, which indicates a similarity in the pathomechanism of sleepiness in narcolepsy and DM (Martinez-Rodriguez, 2003). Due to the progressive nature of the disease and mixed character of breathing disorders, respiratory treatment should be implemented only in specialized centers. Sometimes it is necessary to apply a positive pressure with a variable values (BiPAP, Auto-CPAP) or additional oxygen therapy. In the treatment of excessive sleepiness psychostimulants - metylfenidad and modafinil are used.

#### **3.1.4 Myasthenia**

102 Sleep Disorders

and a relatively good function of the respiratory muscles. With age, symptoms of respiratory muscle failure develop and lead to sleep- apneas of central type. The study of 34 patients aged from 1 to 15 years showed the presence of daily symptoms of sleep-disordered breathing in 64%. Polysomnographic studies have shown obstructive SDB incidence in 31% (median age 8 years ) and central type SDB in 32% (median age 13 years) (Suresh, 2005). The non-invasive ventilation therapy during sleep significantly reduced the number of episodes of breathing problems, an average of 11 per hour in 5 years. The authors recommend polysomnography study in patients under 10 years of age with symptoms of sleep-disordered breathing. In children above 10 years of age, with early signs of respiratory distress, polysomnographic studies must be performed. Treatment with non-invasive home night ventilation should begin as early as possible (Suresh, 2005; Katz, 2009). In children with Duchenne muscular dystrophy the best predictor of outcome is the vital capacity, respiratory parameters during sleep are of less importance. Recommendations of the American Thoracic Society (2006) include: a history of breathing problems during sleep during each visit, regardless of age, in the case of a patient immobilized in a wheelchair polysomnographic evaluation once a year. When polysomnography is not feasible it is recommended to control overnight pulse oximetry (Kirk,

There are no large systematic studies on sleep -disordered breathing in other types of muscular dystrophies. Recently published study analyses SDB in 51 patients with facioscapulohumeral muscular dystrophy (Della Marca, 2009). 22 patients had abnormal breathing during sleep, 13 of them had obstructive breathing disorders (3 of them required the CPAP treatment). In 4 patients during REM sleep hypoxia of central origin were found, 3 patients had mixed type of respiratory disorders. Other parameters such as BMI, daytime sleepiness, and neck circumference did not correlate with the occurrence of sleep-disordered

Myotonic dystrophy (DM) is the most common neuromuscular disease in the adult population (Rowland, 2005). During sleep, individuals with DM may develop hypopneas and apneas, obstructive, central and mixed (Finnimore, 1994; Kiyan, 2009). These disorders occur in about half of patients with DM (Labanowski, 1996; Kiyan, 2009). Polysomnographic studies show a reduction in the duration and sleep efficiency, increased number of nocturnal arousals and time of light sleep (NREM1) and decrease in the time of REM sleep (Bourke, 2002). During the day, the rhythm of breathing in patients with myotonic dystrophy is irregular while awake, as well as during light sleep. The main problems are observed in the REM phase of sleep (Finnimore, 1994). Usually, symptoms of sleepdisordered breathing in patients with myotonic dystrophy are far before of signs of respiratory distress during the day (Bourke, 2002). Daytime sleepiness in patients with DM (assessed with the Epworth sleepiness scale ≥ 10) is felt by about 50% of patients (Laberge, 2009). Objective tests of daytime sleepiness (MSLT test) show excessive daytime sleepiness in 69% of the respondents (Laberge, 2009). Excessive sleepiness correlates with the degeneration of serotonergic neurons in the raphe nuclei and central superior nucleus of the reticular formation (Ono, 1998). Authors describe the decrease of orexin concentration in the cerebrospinal fluid, which indicates a similarity in the pathomechanism of sleepiness in narcolepsy and DM (Martinez-Rodriguez, 2003). Due to the progressive nature of the disease and mixed character of breathing disorders, respiratory treatment should be

2000) and evaluate arterial gasometry during follow-up visits.

breathing.

**3.1.3 Myotonic dystrophy** 

Disorders of neuromuscular transmission in the course of myasthenia gravis may cause sleep-disordered breathing of central type, especially during REM sleep accompanied by declines in blood oxygen saturation (Quera-Salva, 1992; Manni, 1995). The nature of respiratory disorders is similar as in other neuromuscular diseases. The severity of respiratory distress is associated with disease severity. Sleep-disordered breathing in patients with myasthenia gravis is particularly pronounced before the occurrence of myasthenic crisis and precede symptoms of respiratory failure due to exhaustion of the respiratory muscles during the night. At that time hypercapnia is the most characteristic symptom. Hypoxia and hypercapnia occurring during sleep are often the case of morning headaches and progressive fatigue associated with underlying disease. Implementation of treatment reduces sleep-disordered breathing (Amino, 1998). There is no clear data to evaluate the incidence of SDB in patients with well-controlled myasthenia gravis. Some authors have shown an increased incidence of obstructive type of sleep-disordered breathing in patients with myasthenia gravis (36% compared to 15-20% expected in the population (Nicolle, 2006). Other authors (Prudlo, 2007) found no correlation between the occurrence of myasthenia gravis and the occurrence of obstructive breathing disorder during sleep. Most studies on the prevalence of SDB in myasthenia gravis was conducted on small groups (up to 30 patients). These results should therefore be carefully analyzed. Currently it seems that the periods of worsening of the disease are associated with increased risk of respiratory distress, while the periods of remission during medical treatment are not associated with an increased risk of respiratory disorders during sleep (Prudlo, 2007).

#### **3.1.5 Glycogenosis type II-Pompe disease**

Pompe disease is a chronic, progressive metabolic myopathy associated with deficiency or reduced activity of the acid alpha-glucosidase enzyme. As a result, glycogen storage occurs in tissues and impairs their functioning. Depending on the degree of enzyme defficiency clinical course of disease may be different. The infantile form is associated with a complete lack of the enzyme. Symptoms begin within the first few months of life. The usual presenting features are cardiomyopathy and hepatomegaly leading to progressive heart failure and respiratory distress. Juvenile and adult forms are due to partial enzyme deficiency. Symptoms appear later and the disease has a chronic progressive course (Lewandowska, 2008). Adult –onset type of Pompe disease is associated with progressive respiratory failure resulting from progressive respiratory muscle weakness (Wierzba-Bobrowicz, 2007). Patients with adult-onset type of Pompe disease often have sleepdisordered breathing (Bembi, 2008; Mellies, 2001). These problems usually occur before the total respiratory failure. Sleep-disordered breathing is usually present in the REM sleep phase in forms of central apneas or hypopneas (Mellies, 2001). Since Pompe is a rare disease, few studies have been published regarding the prevalence of SDB in this disease. In one study performed in 27 patients with juvenile and adult form, sleep-disordered breathing was found in 13 patients, 12 of which had diaphragm weakness (Mellies, 2001). Respiratory disorders: hypopneas and apneas, occurred primarily during REM sleep and correlated with

Sleep-Disordered Breathing in Neurological Diseases 105

and damage to white matter, occurs more frequent in patients with obstructive sleep apneas

Parkinson's disease is associated with many sleep disorders which include excessive daytime sleepiness, insomnia, abnormal sleep architecture, restless legs syndrome and sleep disorders associated with REM sleep stage (Dhawan, 2006; Postuma, 2009). It was thought that excessive daytime sleepiness is associated with concomitant breathing disorders during sleep. Most studies did not confirm this hypothesis. Sleep-disordered breathing in patients with Parkinson's disease are at a level similar to the prevalence in the population of people in middle age and older (Diederich, 2005; Jahan, 2009). The degree of severity of Parkinson's disease does not affect the frequency and severity of respiratory distress (Young, 2002). One publication noted a higher incidence of mild obstructive breathing disorders during sleep in patients with Parkinson's disease compared with controls (Maria, 2003). Parkinson's disease patients who present with symptoms of disordered breathing during sleep should be performed diagnostic tests and the treatment should be implemented immediately. It is known that excessive daytime sleepiness, cognitive impairment and depressive reactions, caused by sleep-disordered breathing, may exacerbate the non-motor symptoms of the

In the course of the multiple system atrophy a number of types of SDB may occur (Gilman, 2003). Obstructive (Munschauer, 1990; Glass, 2006) central (Glass, 2006), and mixed disorders of breathing pattern (Guilleminault, 1981) were found. Respiratory disorders and respiratory failure may be the first sign of disease. Glass and colleagues (2006) described 6 cases of MSA beginning with respiratory disturbances. Leading respiratory symptoms were excessive daytime sleepiness, laryngeal stridor during sleep, and dyspnea on exertion. Polysomnographic studies have shown co-existing obstructive disorders associated with laryngeal stridor (caused by paralysis of vocal cords) and the numerous apneas and hypopneas of central type. Patomechanisms which links MSA with respiratory problems, concern both neural control of breathing rhytmogenesis and respiratory airways. It has been shown in postmortem studies reduced excitatory projection from the thalamus (behavioral respiratory rhythm drive) to the dorsal inspiratory neurons (Gilman 2003) and a significant loss of neurons in the brainstem chemoreceptive neurons (metabolic respiratory drive) (Benarroch, 2007). Loss of serotonergic neurons that stimulate the nucleus ambiguous, observed in MSA (Weston, 2004), causes weakening of negative throat pressure reflexes and may be responsible for laryngeal stridor and obstructive sleep apneas (Bennaroch, 2007). The loss of dopaminergic neurons in the periventricular gray matter, probably responsible for the maintenance of wakefulness, can affect both the respiratory rhythmogenesis, as well

The increased incidence of seizures during the night has been known for a long time. Mechanisms associated with the generation of epileptic seizures during sleep are not fully understood. It has been suggested there are several mechanisms of pathological

(Bliwise, 2002; Matthews, 2003).

Parkinson's disease (Monaca, 2006).

**4.3 Multiple system atrophy (MSA)** 

as excessive daytime sleepiness (Bennaroch, 2009).

**5. SDB in epilepsy** 

**4.2 Parkinson's disease** 

decreased tidal volumes, as measured by spirometry during the day. In some patient overnight non-invasive mechanical ventilation were initiated (Mellies, 2001). Recommendations of treatment and diagnosis of Pompe disease suggest control polysomnography study and initiation of respiratory treatment as early as possible in patients with significant SDB (Bembi, 2008).

#### **4. Neurodegenerative diseases of the central nervous system and SDB**

#### **4.1 Alzheimer disease**

Searching for links between Alzheimer's disease and sleep-disordered breathing has already started in the eighties. Cognitive deficits observed in individuals with SDB was seen as a preliminary stage in the development of dementia. Cognitive deficits in individuals with impaired respiratory function were found on both verbal, spatial and executive functions as well as short-term memory (Naegele, 1995; Alchanatis, 2005). A number of pathomechanisms may contribute to cognitive impairment in patients with respiratory disorders. The important part play episodes of hypoxia and subsequent oxidative stress resulting in impaired cholinergic transmission in the central nervous system (Gibson, 1981; Shimada, 1981). Another pathomechanism may be associated with changes in cerebral blood flow, observed during sleep -significant hypoperfusion after an episode of apnea. Studies using magnetic resonance spectroscopy showed a decrease in metabolism in the frontal lobes in people with severe respiratory problems during sleep (Alchanatis, 2004) and a decrease in metabolism in the white matter (Kamba, 1997). However, biochemical studies, concerning the biochemical markers of neuronal damage (S-100β protein), showed no significant differences between patients with impaired breathing during sleep and the control group (Jordan, 2002). Homocysteine levels did not differ in patients with apneas compared with the control group (Svatikova, 2004). The study of magnetic resonance and computed tomography show damage to white matter in patients with apneas (Kamba, 2001; Macey, 2006) and reduction of the total intracranial brain volume (O'Donoghue, 2005). Another argument in favor of the relationship between dementia and apneas was the discovery of frequent occurrence of apolipoprotein genotype ApoE4 in people with sleep apneas (Kadotani, 2001; Gottlieb, 2004). There were several studies conducted on the effects of sleep apnea treatment on improvement of cognitive functions. In most studies a positive effect of introducing CPAP therapy was found on improvement of cognitive functions (Feuerstein, 1997; Bliwise, 2002; Zimmerman, 2006). It was also observed a beneficial effect of donepezil treatment on reducing the number of apneas during sleep and improvement of sleep architecture (Moraes, 2008). The degree of cognitive impairment observed in patients with sleep-disordered breathing, however, is significantly lower and more slowly progressive than in those with Alzheimer's disease (Bliwise, 2002). Daytime sleepiness, which is a symptom of respiratory distress has a significant impact on cognitive impairment (Feuerstein, 1997). More and more evidence points to a potential relationship between vascular dementia and sleep-disordered breathing. Early studies showed a significantly higher incidence of respiratory distress in patients with vascular dementia (Hoch, 1986; Bliwise, 1989). The authors also showed a correlation between the severity of respiratory disorders and dementia (Reynolds, 1985). These studies, however, were performed on small groups of patients (up to 30 our participants). Newer studies show a similar incidence of sleep-disordered breathing in patients with Alzheimer's disease as in the general population of similar age (Bliwise, 2002). However, vascular dementia associated with lacunar strokes and damage to white matter, occurs more frequent in patients with obstructive sleep apneas (Bliwise, 2002; Matthews, 2003).

### **4.2 Parkinson's disease**

104 Sleep Disorders

decreased tidal volumes, as measured by spirometry during the day. In some patient overnight non-invasive mechanical ventilation were initiated (Mellies, 2001). Recommendations of treatment and diagnosis of Pompe disease suggest control polysomnography study and initiation of respiratory treatment as early as possible in

Searching for links between Alzheimer's disease and sleep-disordered breathing has already started in the eighties. Cognitive deficits observed in individuals with SDB was seen as a preliminary stage in the development of dementia. Cognitive deficits in individuals with impaired respiratory function were found on both verbal, spatial and executive functions as well as short-term memory (Naegele, 1995; Alchanatis, 2005). A number of pathomechanisms may contribute to cognitive impairment in patients with respiratory disorders. The important part play episodes of hypoxia and subsequent oxidative stress resulting in impaired cholinergic transmission in the central nervous system (Gibson, 1981; Shimada, 1981). Another pathomechanism may be associated with changes in cerebral blood flow, observed during sleep -significant hypoperfusion after an episode of apnea. Studies using magnetic resonance spectroscopy showed a decrease in metabolism in the frontal lobes in people with severe respiratory problems during sleep (Alchanatis, 2004) and a decrease in metabolism in the white matter (Kamba, 1997). However, biochemical studies, concerning the biochemical markers of neuronal damage (S-100β protein), showed no significant differences between patients with impaired breathing during sleep and the control group (Jordan, 2002). Homocysteine levels did not differ in patients with apneas compared with the control group (Svatikova, 2004). The study of magnetic resonance and computed tomography show damage to white matter in patients with apneas (Kamba, 2001; Macey, 2006) and reduction of the total intracranial brain volume (O'Donoghue, 2005). Another argument in favor of the relationship between dementia and apneas was the discovery of frequent occurrence of apolipoprotein genotype ApoE4 in people with sleep apneas (Kadotani, 2001; Gottlieb, 2004). There were several studies conducted on the effects of sleep apnea treatment on improvement of cognitive functions. In most studies a positive effect of introducing CPAP therapy was found on improvement of cognitive functions (Feuerstein, 1997; Bliwise, 2002; Zimmerman, 2006). It was also observed a beneficial effect of donepezil treatment on reducing the number of apneas during sleep and improvement of sleep architecture (Moraes, 2008). The degree of cognitive impairment observed in patients with sleep-disordered breathing, however, is significantly lower and more slowly progressive than in those with Alzheimer's disease (Bliwise, 2002). Daytime sleepiness, which is a symptom of respiratory distress has a significant impact on cognitive impairment (Feuerstein, 1997). More and more evidence points to a potential relationship between vascular dementia and sleep-disordered breathing. Early studies showed a significantly higher incidence of respiratory distress in patients with vascular dementia (Hoch, 1986; Bliwise, 1989). The authors also showed a correlation between the severity of respiratory disorders and dementia (Reynolds, 1985). These studies, however, were performed on small groups of patients (up to 30 our participants). Newer studies show a similar incidence of sleep-disordered breathing in patients with Alzheimer's disease as in the general population of similar age (Bliwise, 2002). However, vascular dementia associated with lacunar strokes

**4. Neurodegenerative diseases of the central nervous system and SDB** 

patients with significant SDB (Bembi, 2008).

**4.1 Alzheimer disease** 

Parkinson's disease is associated with many sleep disorders which include excessive daytime sleepiness, insomnia, abnormal sleep architecture, restless legs syndrome and sleep disorders associated with REM sleep stage (Dhawan, 2006; Postuma, 2009). It was thought that excessive daytime sleepiness is associated with concomitant breathing disorders during sleep. Most studies did not confirm this hypothesis. Sleep-disordered breathing in patients with Parkinson's disease are at a level similar to the prevalence in the population of people in middle age and older (Diederich, 2005; Jahan, 2009). The degree of severity of Parkinson's disease does not affect the frequency and severity of respiratory distress (Young, 2002). One publication noted a higher incidence of mild obstructive breathing disorders during sleep in patients with Parkinson's disease compared with controls (Maria, 2003). Parkinson's disease patients who present with symptoms of disordered breathing during sleep should be performed diagnostic tests and the treatment should be implemented immediately. It is known that excessive daytime sleepiness, cognitive impairment and depressive reactions, caused by sleep-disordered breathing, may exacerbate the non-motor symptoms of the Parkinson's disease (Monaca, 2006).

#### **4.3 Multiple system atrophy (MSA)**

In the course of the multiple system atrophy a number of types of SDB may occur (Gilman, 2003). Obstructive (Munschauer, 1990; Glass, 2006) central (Glass, 2006), and mixed disorders of breathing pattern (Guilleminault, 1981) were found. Respiratory disorders and respiratory failure may be the first sign of disease. Glass and colleagues (2006) described 6 cases of MSA beginning with respiratory disturbances. Leading respiratory symptoms were excessive daytime sleepiness, laryngeal stridor during sleep, and dyspnea on exertion. Polysomnographic studies have shown co-existing obstructive disorders associated with laryngeal stridor (caused by paralysis of vocal cords) and the numerous apneas and hypopneas of central type. Patomechanisms which links MSA with respiratory problems, concern both neural control of breathing rhytmogenesis and respiratory airways. It has been shown in postmortem studies reduced excitatory projection from the thalamus (behavioral respiratory rhythm drive) to the dorsal inspiratory neurons (Gilman 2003) and a significant loss of neurons in the brainstem chemoreceptive neurons (metabolic respiratory drive) (Benarroch, 2007). Loss of serotonergic neurons that stimulate the nucleus ambiguous, observed in MSA (Weston, 2004), causes weakening of negative throat pressure reflexes and may be responsible for laryngeal stridor and obstructive sleep apneas (Bennaroch, 2007). The loss of dopaminergic neurons in the periventricular gray matter, probably responsible for the maintenance of wakefulness, can affect both the respiratory rhythmogenesis, as well as excessive daytime sleepiness (Bennaroch, 2009).

#### **5. SDB in epilepsy**

The increased incidence of seizures during the night has been known for a long time. Mechanisms associated with the generation of epileptic seizures during sleep are not fully understood. It has been suggested there are several mechanisms of pathological

Sleep-Disordered Breathing in Neurological Diseases 107

the cell membrane (Somjen, 2001), which reduces the seizure threshold. Reducing the amount of ATP in neurons also causes increase in amplitude of the sodium ion current in neurons (Rola, 2004), which may accelerate neuron depolarization and action potential generation. Another possible pathomechanism, causing seizures during sleep apnea, is the increased number of awakenings and disturbed sleep architecture. Obstructive type of respiratory disorders are most common during light sleep (stage I and II NREM sleep), during the instability of the respiratory center. In these phases, there are also more awakenings. K complexes and sleep spindles which occur in II phase of NREM are associated with increased pathological hyper synchrony (Bonakis, 2009). Patients with sleepdisordered breathing have disturbed sleep architecture. There is an increased time of shallow sleep (stage I and II NREM) and the reduction or total absence of REM sleep stage. As mentioned above, the NREM sleep, I and Phase II contribute to the occurrence of seizures, while desynchronization of bioelectrical activity of the brain in REM stage prevents seizures (Seyal, 2009). A patient with severe sleep apneas and disturbed sleep architecture is staying longer in the NREM stages, exposed to the induction of seizures, and less in the REM stages of sleep associated with lower risk of seizure. Although the consequence of these pathomechanisms may be increased risk of seizures in patients with apneas, but thanks to the possible treatment a reduction in seizure frequency is observed. Case reports noted the reduction of symptoms of sleep-disordered breathing after surgical treatment of epilepsy (Földvary-Schaefer, 2008) and the reverse effect of vagal stimulation (Holmes, 2003)

[1] Guyton AC, Hall EJ, Textbook of Medical Physiology, W.B. Saunders Company; 11th

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[3] Meadows GE, O'Driscoll DM, Simonds AK, Morrell MJ, Corfield DR, Cerebral blood

[4] Jennum P, Borgesen SE, Intracranial pressure and obstructive sleep apnea, Chest, 1989;

[5] Silvestrini M, Rizzato B, Placidi F, Baruffaldi R, Bianconi A, Diomedi M, Carotid Artery

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[8] Balfors EM, Franklin KA, Impairment of cerebral perfusion during obstructive sleep

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apneas, Am. J. Respir. Crit. Care Med., 1994; 150: 1587 - 1591.

obstructive sleep apnea, J Appl Physiol, 2008; 105: 1852 - 1857.

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which indicates a mutual relationship of these two disease entities.

**6. References** 

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synchronization of brain bioelectrical activity, triggered by physiological stages of sleep (Gigli, 1992). The phases of sleep in which there is greatest risk of seizures include the phases associated with a higher probability of awakening - mainly phase I and II NREM sleep type. Phase of sleep associated with EEG desynchronization - REM is characterized by a lower risk of seizures. The probability of awakening during sleep increases the risk of seizure in the case of idiopathic generalized epilepsies (Bonakis, 2009). A similar mechanism was proposed in focal and secondarily generalized seizures (Manni, 2005). Also in these types of epilepsy light sleep phase (I and II NREM) may initiate abnormal synchronous epileptic discharges. The EEG patterns associated with arousal (K complexes) trigger pathological EEG hypersynchrony in the second phase of NREM sleep. Seizure during sleep is associated with the interruption of the continuity of sleep and disorder of its architecture. Seizure, both partial (Bateman, 2008) and generalized (Seyal, 2009), can cause apnea of central origin. It is probably due to the short-term disturbances of respiratory rhythmogenesis during sleep by hypersynchronic epileptic discharges. The effects of sleepapnea during seizures, are prolonged hypoxia with a decrease in blood oxygen saturation to 58% and a significant hypercapnia and acidosis (Seyal, 2009). The mechanism of respiratory arrest, and neurogenic pulmonary edema associated with asystole are some of the hypothetical mechanisms of sudden unexpected death in epilepsy (SUDEP) (Nashef, 2007; So, 2008; Jehi, 2008; Pezzela, 2009). Descriptions of near SUDEP cases during polysomnographic studies indicate sleep apnea as an important part of the clinical picture (So, 2000; Trotti, 2009). The pathogenesis of SUDEP is probably associated with the diving reflex mechanisms, generated during apnea (So, 2008) followed by significant bradycardia to asystole and a significant increase in systemic blood pressure, which significantly increases the afterload and metabolic demands of myocardium. In literature there are two cases of patients in whom obstructive sleep apnea caused changes in the EEG and cerebral hypoxia, which in one case ended in death, and in the second with transient encephalopathy (Dyken, 2004). Animal model of SUDEP proves that central apnea and myocardial ischemic changes should be considered as the main patomechanisms of death in the course of a seizure (Johnston, 1997). The relationship between sleep-disordered breathing and epilepsy also revealed a higher incidence of obstructive sleep apneas in patients with epilepsy compared with the general population matched for age. In various studies, the incidence of sleep-disordered breathing is estimated between 5% and 63% in patients with epilepsy (Malow, 1997; Malow, 2000; Beran, 1999; Weatherwax, 2003; Malow, 2003, Hollinger, 2006). Higher incidence of obstructive apneas and hypopneas was found in patients with drugresistant epilepsy (Malow, 2000). The co-existence of idiopathic epilepsy and obstructive sleep apneas was also observed in the elderly population (Chihorek, 2007). In the cited paper the authors suggest that the increase in the number of new cases of idiopathic epilepsy in the elderly is associated with an increased incidence of sleep-disordered breathing in these patients. A number of studies indicate the beneficial effect of treatment with CPAP method for reducing the number of seizures (Malow, 2000, Hollinger, 2006; Chihorek, 2007; Malow, 2008). Precise pathomechanisms linking apnea with seizure are unknown. There are several reasons that may come up for coexistence of the observed higher incidence of seizures with sleep-disordered breathing. Particularly interesting is the observation on the significantly higher prevalence of sleep apnea in patients with drugresistant epilepsy (Malow, 2000). One of the pathomechanisms may be related to apnea hypoxia, which leads to decrease of the available pool of ATP in cortical neurons. It was shown that lack of ATP increases the excitability of neurons by the partial depolarization of the cell membrane (Somjen, 2001), which reduces the seizure threshold. Reducing the amount of ATP in neurons also causes increase in amplitude of the sodium ion current in neurons (Rola, 2004), which may accelerate neuron depolarization and action potential generation. Another possible pathomechanism, causing seizures during sleep apnea, is the increased number of awakenings and disturbed sleep architecture. Obstructive type of respiratory disorders are most common during light sleep (stage I and II NREM sleep), during the instability of the respiratory center. In these phases, there are also more awakenings. K complexes and sleep spindles which occur in II phase of NREM are associated with increased pathological hyper synchrony (Bonakis, 2009). Patients with sleepdisordered breathing have disturbed sleep architecture. There is an increased time of shallow sleep (stage I and II NREM) and the reduction or total absence of REM sleep stage. As mentioned above, the NREM sleep, I and Phase II contribute to the occurrence of seizures, while desynchronization of bioelectrical activity of the brain in REM stage prevents seizures (Seyal, 2009). A patient with severe sleep apneas and disturbed sleep architecture is staying longer in the NREM stages, exposed to the induction of seizures, and less in the REM stages of sleep associated with lower risk of seizure. Although the consequence of these pathomechanisms may be increased risk of seizures in patients with apneas, but thanks to the possible treatment a reduction in seizure frequency is observed. Case reports noted the reduction of symptoms of sleep-disordered breathing after surgical treatment of epilepsy (Földvary-Schaefer, 2008) and the reverse effect of vagal stimulation (Holmes, 2003) which indicates a mutual relationship of these two disease entities.
