Abstract

Neuromuscular disorders consist of central and peripheral neurologic disorders with impairment of the motor system. The disability of patients with a neuromuscular disorder worsens during sleep, and the abnormal sleep and secondary impairment of daytime function further degrade quality of life. Nocturnal sleep disruptions may be the result of pain and discomfort related to weakness, rigidity, or spasticity that limit movement and posture. Sleep disruptions may also be related to autonomic dysfunction (often seen in these patients), poor sphincter control, problems with clearance of secretions, and abnormal movements and actions during sleep. Most importantly, sleep-related hypoventilation can occur in all patients, and overlooking this can lead to death. Daytime evaluation can determine the severity of the disability but might not identify the presence and severity of an associated sleep-related disorder. Nonspecific symptoms of daytime fatigue and sleepiness indicate poor sleep in these patients. Polysomnography is the only test that can objectively identify and evaluate the severity of sleep-related disorders. By recognizing and treating sleep-related problems, improved survival and better quality of life can be achieved in this group of patients.

Neuromuscular disorders are diseases caused by impairment of the motor unit comprising the lower motor neuron, nerve root, peripheral nerve, myoneural junction, and muscle. Any classification of neuromuscular disease may be somewhat arbitrary, and the astute clinician must keep in mind that the pathologic process can involve several segments of the nervous system and muscle. For example, myopathies lead to progressive peripheral motor and sensory impairment along with autonomic dysfunction. Disorders such as amyotrophic lateral sclerosis (ALS) or Creutzfeldt-Jacob disease can progress rapidly toward death, whereas certain chronic polyneuropathies such as Charcot-Marie-Tooth or autonomic syndromes such as familial dysautonomia can have a slower evolution.

Patients with neuromuscular syndromes are at risk for sleep-related problems. (Video 89-1) Weakness, rigidity, and spasticity limit movements and posture changes during sleep, leading to discomfort, pain, and disrupted sleep. Difficulty with maintaining positions of comfort can lead to cramping, abnormal uncontrolled movements, and weakness, which also contribute to poor sleep. Abnormal sphincter control can induce urinary and fecal disturbances in the form of nocturia, incomplete emptying or incontinence, constipation, or painful defecation. The sleep-related changes in respiration put the patient with a neuromuscular disorder at a specific ventilatory risk by impairing ventilation.

Chronic respiratory muscle failure usually develops slowly over years. It can initially manifest with disordered breathing during sleep, followed by progression to nocturnal hypoventilation then to diurnal hypoventilation, cor pulmonale, and eventual respiratory failure and end-stage disease. Because of its slow progression, ventilatory failure in some disorders can go undetected for some time and contribute to increased mortality.

Limited attention is often paid to the impact of sleep-related issues in this population, particularly because most clinics see a limited number of patients with neuromuscular disorders. Even in a specialized neuromuscular clinic, less than 2% of patients are asked about their sleep-related problems or have been given a prior sleep evaluation.¹ Moreover, the common problems (i.e., spasticity, sphincter dysfunction, pain, abnormal movement, confusional arousal) leading to sleep fragmentation, insomnia, parasomnias, daytime tiredness, and sleepiness are rarely dealt with by the sleep specialist. Thus, a multidisciplinary approach to treatment is mandatory in neuromuscular disorders.

Epidemiology and Genetics

Each neuromuscular syndrome has its own epidemiology and etiology. For example, ALS affects 0.005% of the U.S. population, and multiple sclerosis (MS), a neurodegenerative disorder, affects 0.11%. However, there are no cumulative prevalence data that include all neuromuscular disorders. Many neurologic disorders such as maltase deficiency myopathy, myotonic dystrophy, Rett syndrome, or familial dysautonomia have a clear genetic origin. Other disorders are secondary to infectious, vascular, malignant, or degenerative diseases, and the presence or absence of a genetic component has not been demonstrated.

Despite the number of reports of abnormal sleep and breathing in patients with neuromuscular diseases, and the number of studies dealing with the treatment of the concomitant respiratory insufficiency,²^–⁵ there are few large studies that examine the prevalence of sleep-disordered breathing in these patients. One study from New Mexico¹ attempted to gather information from its entire clinic population of more than 300 patients. (The clinic provided free care including neurologic, orthopedic, and physical therapy services, and such access ensured that virtually all patients with neuromuscular disease from the state would be referred.) Although complete data were available for only 60 patients (20% of the clinic population), the researchers demonstrated that sleep and breathing abnormalities are or may be present in more than 40% of patients who are routinely followed at the neuromuscular disorders clinic.¹ Such a high prevalence should not be surprising given the vulnerability of such patients to sleep-related reductions in muscle tone and overall ventilation.

Pathophysiology

The diaphragm is the major muscle of respiration during wake and sleep. During non–rapid eye movement (NREM) sleep, there is an overall reduction in ventilation that is related to sleep state changes in the chemical control of breathing and in response to an increased impedance of the respiratory system. However, rib cage activity is maintained, albeit reduced, as is diaphragmatic activity. The importance of the diaphragm is particularly evident during rapid eye movement (REM) sleep. During REM sleep, there is postsynaptic inhibition of somatic motor neurons, which causes further reduction or even complete loss of tone in rib cage and other accessory muscles of respiration but leaves the diaphragm relatively unaffected. Thus, the diaphragm is the main muscle of respiration during REM sleep, and any process affecting the diaphragm, whether a myopathy or a process involving its innervation, can be expected to cause significant changes in breathing and oxygenation during this stage of sleep.

In patients with bilateral diaphragmatic paralysis, marked oxygen desaturation can occur during REM sleep.⁶^–⁸ The REM sleep–related inhibition of intercostal and accessory muscles leads to profound hypoventilation during this sleep stage, because patients with diaphragmatic paralysis are completely dependent on intercostal and accessory muscles for breathing. This suppression of accessory respiratory muscle tone is a normal process of REM sleep and is seen in normal subjects and in patients with lung disease.⁹^–¹¹ Depending on the type of neuromuscular disorder, breathing abnormalities during sleep may be present as central apneas, obstructive apneas, or periods of prolonged hypoventilation.

Sleep disruption with frequent arousals may be seen in patients with neuromuscular disorders as a result of discomfort in the recumbent position, secretion clearance, sphincter control problems, or increase in upper airway resistance from muscle weakness and craniofacial changes due to the long-standing muscle weakness. Periods of hypoventilation can contribute to frequent arousals, reduced sleep time, and sleep deprivation through both ventilatory and arousal responses to changes in oxygen saturation and carbon dioxide levels. Although these changes may be protective to overall ventilation in the short term, over time ventilatory responses to changes in oxygen and carbon dioxide levels become blunted. This blunting process leads to further worsening of hypoventilation, eventually occurring during both wakefulness and sleep.

Clinical Features

Features Common to Most Neuromuscular Disorders

Nonspecific complaints such as increased tiredness, daytime fatigue, or disrupted nocturnal sleep can be the initial manifestations of a slowly evolving neuromuscular disease of adult onset.¹ Such nonspecific complaints may also be the sole indication of a slow progression of a neuromuscular disorder during sleep. The presence of a neuromuscular condition may bias the clinician toward believing that complaints of tiredness or daytime fatigue are simply part of the neurologic problem itself, and the impaired sleep mechanisms and sleep-related disturbances may be ignored.

Problems with clearance, such as managing saliva or gastric contents, can lead to significant drooling, esophageal reflux, or pulmonary congestion from aspiration or retained secretions. Impairment of cough mechanisms can further impair the ability of the lungs to clear secretions. Autonomic dysfunction may be present in the form of abnormal sensitivity to temperature or to pressure, with discomfort related to the use of sheets and blankets. Cerebral lesions can lead to complex regional pain syndrome, with a prominence in the evening and early part of the night. The disease can affect patients psychologically, and their disability can lead to anxiety, depression, and secondary sleep-onset insomnia, as can be seen with many other chronic illnesses.

Pharmacologic agents that are prescribed in the evening might have alerting effects, whereas others used in the morning might lead to daytime sleepiness. In all, patients with chronic evolving neuromuscular disorders have many factors that can disrupt sleep and worsen daytime functioning and quality of life. The addition of sleep-related problems complicates the already existing neurologic issues.

Specific Neuromuscular Disorders

Neurodegenerative Diseases

Neurodegenerative diseases are a group of heterogeneous diseases of the central nervous system for which no causal agent has been identified. These include both somatic and autonomic disorders, both of which have direct and indirect effects on sleep. Somatic diseases involve the cortex, such as Alzheimer’s disease and MS; the basal ganglia (including basal ganglia plus syndromes) such as Parkinson’s disease, progressive supranuclear palsy, Huntington’s chorea, torsion dystonia, or Tourette’s syndrome; the cerebellum (including cerebellum plus syndromes) such as spinocerebellar ataxias; or motor neurons, such as ALS or motor neuron disease. Autonomic degenerative processes can cause multiple-system atrophy or the Shy-Drager syndrome (see Video 87-5). Sleep disturbances such as insomnia, hypersomnia, circadian rhythm disturbances, parasomnias, and sleep-disordered breathing may be seen in neurodegenerative disorders. Because these illnesses are more common in older adults, the sleep changes occurring with normal aging should also be considered. Still, some of the changes in sleep can be related to environmental factors (e.g., living in nursing home) or mood disorders. (The behavior changes associated with the disappearance of physiologic active muscle atonia normally seen during REM sleep secondary to neurodegenerative disorders leading to REM behavior disorder are not reviewed in this chapter.)

Although ALS has not been shown to directly affect the sleep-regulating areas of the brain, it is likely that the indirect effects of the disease cause sleep disruption. Periodic limb movements associated with arousals and sleep-disordered breathing contribute to the sleep disruption in some patients with ALS. Sleep-disordered breathing is reported to be present in 17% to 76% of patients with ALS.¹² ALS patients with normal respiratory function, normal phrenic motor responses, and preserved motor units on needle electromyography of the diaphragm can have sleep-disordered breathing with periodic mild oxygen desaturation independent of sleep stage (REM and NREM).¹³ However, respiratory-related sleep disruption is generally not significant until phrenic nerves are involved and the diaphragm becomes paralyzed. Once there is involvement of phrenic nerves, severe hypoventilation and oxygen desaturation occur during REM sleep. Almost invariably, these patients ultimately need some form of ventilatory support. Some ALS patients without any respiratory disturbance or periodic limb movements still have sleep fragmentation, independent of age. This suggests that other factors contribute to disturbed sleep, such as anxiety, depression, pain, choking, excessive secretions, fasciculations and cramps, and the inability to find a comfortable position or turn oneself freely in bed. Orthopnea, a common complaint in ALS, can also contribute to sleep disruption.¹⁴^,¹⁵

Spinal Cord Disease

Poliovirus infection targets the nervous system in several ways, producing meningitis and affecting cranial motor nuclei and spinal cord anterior horn cells, causing acute paresis. As a result, there are many possible effects on respiration. Abnormalities in central regulation of breathing in patients with acute and convalescent poliomyelitis were described in 1958 by Plum and Swanson.¹⁶ Subsequently, central, mixed, and obstructive events have been noted.¹⁷ Sleep and breathing abnormalities are seen not only in patients who are on respiratory assistance (rocking beds) during sleep but also before ventilatory assistance is initiated.¹⁸ Sleep abnormalities include decreased sleep efficiency, increased arousal frequency, and varying degrees of apnea and hypopnea. After treatment of sleep and breathing abnormalities, many symptoms often attributed to the postpolio syndrome improve. Although not all symptoms can be explained, daytime symptoms may be explained by poor sleep quality and abnormal respiration during sleep.

Poliomyelitis can alter central and peripheral respiratory functions decades after the acute infection, a condition known as postpolio syndrome.¹⁹ Muscle atrophy and immobility lead to kyphoscoliosis and potentially more-restricted ventilation. The anatomic deformities resulting from poliomyelitis can cause chronic pain and consequent sleep abnormalities. Also, bulbar involvement can affect upper-airway muscles. Sleep-disordered breathing is reported to be present in 31% of patients with postpolio syndrome.¹² Prolongation of REM latency can result from prolonged recruitment time for damaged neurons in the pontine tegmentum.²⁰ Whether postpolio syndrome has caused fatigue and weakness or these are results of disturbed sleep and thus are potentially treatable can be investigated by sleep studies.

Inherited metabolic diseases such as subacute necrotizing encephalomyelopathy (Leigh’s disease) typically appear in childhood and may be associated with respiratory disturbance. Rarely, this disease first appears in adulthood, with automatic respiratory failure during sleep.²¹ Syringomyelia can be associated with central, mixed, and obstructive apneic events. The involvement of the bulbar and high cervical neurons is responsible for the development of hypoventilation and central sleep apnea.²²^–²⁴ The syndrome can be associated with other malformations of the base of skull or high cervical junction (platybasia, Chiari malformations²⁵) that may also give a variable type of sleep-disordered breathing.

Polyneuropathies

The most common polyneuropathy associated with sleep-disordered breathing is Charcot-Marie-Tooth syndrome, also called hereditary motor and sensory neuropathy.²⁶ This is characterized by chronic degeneration of peripheral nerves and roots, resulting in distal muscle atrophy that begins at the feet and legs and later involves the hands. Sleep-disordered breathing can occur in these patients as result of a pharyngeal neuropathy leading to upper airway obstruction (obstructive apnea, upper airway resistance syndrome)²⁷ or with diaphragmatic dysfunction.²⁸ Autonomic neuropathy, particularly when secondary to type 1 diabetes, may be associated with impaired chemosensitivity to carbon dioxide, although the effects on sleep and breathing are not consistent.²⁹

Neuromuscular Junction Impairments

Myasthenia gravis is a disorder of the neuromuscular junction characterized by weakness and fatigability of skeletal muscles. Sleep breathing abnormalities can occur as a result of diaphragmatic weakness. Risk factors for the development of sleep-related ventilatory problems in myasthenia gravis patients include age, restrictive pulmonary syndrome, diaphragmatic weakness, and daytime alveolar hypoventilation.³⁰ Younger patients with a shorter duration of illness are least likely to experience any sleep-related hypoventilation or oxygen desaturation,³¹ whereas older patients with moderately increased body mass index, abnormal total lung capacity, and abnormal daytime blood gases are most likely to develop hypopneas or apneas, particularly during REM sleep.³²

Sleep apnea is diagnosed in 60% of patients with myasthenia gravis even when the disease is in a clinically stable stage.¹²^,³³ A prospective study by Nicolle and colleagues found that obstructive sleep apnea was the predominant abnormality occurring in 36% of myasthenia gravis patients and had significant associations with older age, male gender, elevated body mass index, and corticosteroid use.³⁴

Other neuromuscular disorders that can disturb normal sleep include congenital myasthenic syndromes,³⁵ botulism, hypermagnesemia, and tick paralysis. A careful history is extremely helpful in making the diagnosis in these circumstances. Dyspnea that worsens with activity, morning headache, paroxysmal nocturnal dyspnea, fragmented sleep, and daytime somnolence are among the symptoms that suggest the presence of sleep-disordered breathing in these syndromes.

Muscular Diseases

Myotonic Dystrophy

Myotonic dystrophy is an autosomal dominant inherited illness; patients present with myotonia and nonmuscular dystrophy. In this illness, there is consistent involvement of facial, masseter, levator palpebrae, sternocleidomastoid, forearm, hand, and pretibial muscles; myotonic dystrophy is, in a sense, a distal myopathy. However, pharyngeal and laryngeal muscles can also be involved, as well as respiratory muscles, particularly the diaphragm. Central abnormalities also occur in myotonic dystrophy, causing excessive sleepiness via different mechanisms.³⁶^–³⁹ For example, damage in dorsomedial nuclei of the thalamus can lead to a medial thalamic syndrome characterized by apathy, memory loss, and mental deterioration. Loss of 5-hydroxytryptamine (serotonin) neuronal cell bodies of the dorsal raphe nucleus and the superior central nucleus,³⁹ as well as dysfunction of the hypothalamic hypocretin system,⁴⁰ can result in hypersomnia and abnormal results on a multiple sleep latency test (reflecting sleep-onset REM periods) in these patients.³⁷^,⁴⁰

Excessive daytime sleepiness has been found to be common in myotonic dystrophy, being reported in 33.1% to 77% of patients in several studies.⁴¹ Involvement of the respiratory muscles can predispose to breathing and oxygenation changes during sleep. There has been ample evidence for the occurrence of periods of alveolar hypoventilation, predominantly in REM sleep,⁴²^–⁴⁴ obstructive apneas,⁴⁵ and central apneas.⁴⁶ However, the development of sleep breathing abnormalities in myotonic dystrophy is not simply caused by muscle weakness. When sleep and breathing in patients with myotonic dystrophy are compared with those in patients with nonmyotonic respiratory muscle weakness and in control subjects, periods of hypoventilation and apneas (central and obstructive) occurred in those with myotonic dystrophy and at higher incidences than in nonmyotonic patients who had the same degree of muscle weakness (measured by maximal inspiratory and expiratory pressures).⁴⁷ This finding adds further evidence that respiratory muscle weakness alone does not account for abnormal breathing in patients with myotonic dystrophy. As a result of muscle weakness, development of craniofacial structures in patients with myotonic dystrophy is impaired. They experience more vertical facial growth than normal subjects, and they have more narrowed maxillary arches and deeper palatal depths. These craniofacial changes can contribute to the development of obstructive sleep apnea.

Observations of decreased ventilatory response to hypoxic and hypercapnic stimuli ^43,⁴⁸^–⁵¹ and extreme sensitivity to sedative drugs have suggested a central origin of the breathing impairments in myotonic dystrophy. Whereas increase in ventilation as a result of increased arterial carbon dioxide is a standard technique for assessing control of respiration, in patients with myotonic dystrophy the respiratory muscles must transduce the chemical stimulus. When these muscles are abnormal, as in myotonic dystrophy, it may be difficult to interpret a reduced ventilatory response. That is, chemoreceptor activity and efferent signaling to muscles may be intact, but weak or inefficient respiratory muscles might not permit a normal ventilatory response to a hypoxic stimulus.

Measurement of the mouth pressure developed at the beginning of a transiently occluded breath (occlusion pressure, P_0.1) can also be used as a measure of respiratory center output.⁵² In patients with myotonic dystrophy, P_0.1 may be as high as or higher than that of control subjects at rest and during stimulated breathing, although overall ventilation is lower.⁴⁹^,⁵³ The finding of a high transdiaphragmatic pressure (P_di), despite overall lower ventilation, suggests that increased impedance of the respiratory system accounts for incomplete transformation into ventilation of normal or increased respiratory center output.

Magnetic stimulation of the cortex, in conjunction with phrenic nerve recordings, can be used to test the corticospinal tract to phrenic motor neuron pathways and is a reliable method for diagnosing and monitoring patients with impaired central respiratory drive.⁵⁴ The use of transcortical and cervical magnetic stimulation demonstrates that more than 20% of patients with myotonic dystrophy have impaired central respiratory drive.⁵⁵ The finding of neuronal loss in the dorsal central, ventral central, and subtrigeminal medullary nuclei in patients with myotonic dystrophy who exhibit alveolar hypoventilation⁵⁶ and the severe neuronal loss and gliosis in the tegmentum of the brainstem⁵⁷ also support a central abnormality.

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