Sleep and breathing in neuromuscular disorders

Handbook of Clinical Neurology, Vol. 99 (3rd series) Sleep Disorders, Part 2 P. Montagna and S. Chokroverty, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 64

Sleep and breathing in neuromuscular disorders S. CHOKROVERTY * New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University, Edison, NJ, USA

INTRODUCTION Neuromuscular disorders traditionally include all diseases caused by dysfunction of the motor units (anterior horn cells, brainstem motor neurons, motor roots, neuromuscular junctions, peripheral nerves and muscles). Sleep dysfunction related mostly to sleeprelated breathing disorders or sleep-disordered breathing (SDB) is very common in neuromuscular diseases, particularly in the advanced stage, but occasionally occurs as a presenting symptom (Labanowski et al., 1996; Langevin et al., 2000; Guilleminault and Shergill, 2002; Chokroverty et al., 2005a). The most common neuromuscular disorders causing SDB and sleep dysfunction consist of: ● ● ● ● ● ● ●

motor neuron disease (amyotrophic lateral sclerosis) poliomyelitis and postpolio syndrome myasthenia gravis including myasthenic syndrome acute inflammatory demyelinating polyradiculoneuropathy (Landry–Guillain–Barre´–Strohl syndrome) phrenic neuropathy muscular dystrophies including myotonic dystrophies congenital myopathies.

Many of these conditions are treatable whereas others show relentless progression of the disease, but even in those conditions quality of life may be improved with prolongation of the natural course of the illness by timely and adequate treatment of SDB. It is therefore incumbent upon the physicians managing patients with neuromuscular disorders to have a basic idea about these disorders and a high index of suspicion for SDB, so that they can be referred to specialists or treated adequately in a timely manner. This chapter gives a brief overview of the control of breathing during sleep and wakefulness in normal

individuals, its alteration in various neuromuscular disorders, types of SDB, mechanism and pathogenesis of respiratory failure in neuromuscular diseases, clinical features including impact on breathing during sleep causing SDB and sleep dysfunction, and an approach to patients with suspicion of SDB, laboratory techniques and principles of treatment.

CONTROL OF BREATHING DURING WAKEFULNESS AND SLEEP An understanding of the control of breathing requires a basic knowledge about alveolar ventilation and diffusion across the alveolar capillary membranes (i.e., elimination of carbon dioxide and supply of oxygen from atmospheric air, which contains 21% oxygen, 78% nitrogen, and 1% other inert gases); an adequate pulmonary circulation is essential to complete these processes. Three interrelated and integrated components constitute the respiratory control system (Table 64.1): central controllers located in the medulla aided by the supramedullary including forebrain influence, peripheral chemoreceptors, pulmonary and upper airway receptors; thoracic bellows consisting of respiratory and other thoracic muscles, and their innervation and bones; and the lungs including the airways (Chokroverty, 2009a).

The central control of breathing This is dependent on two separate but independent systems: the metabolic (automatic) and the voluntary (behavioral) system (Plum, 1966; Mitchell and Berger, 1975; Berger et al., 1977; Phillipson, 1978a, b; Mitchell, 1980; Phillipson and Bowes, 1986). Both metabolic and voluntary systems are active during wakefulness whereas only the metabolic system participates during sleep. The wakefulness stimulus, probably derived

*Correspondence to: Professor S. Chokroverty, New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University, 65 James Street, Edison, NJ 08818, USA. E-mail: [email protected]

1088

S. CHOKROVERTY

Table 64.1 Respiratory control systems ●

● ●

Central controllers in the medulla: ○ The dorsal respiratory group (mainly for inspiration) ○ The ventral respiratory group (for both inspiration and expiration) including Botzinger complex and pre-Botzinger region (for respiratory rhythmicity) The thoracic bellows including respiratory and other thoracic muscles and bones The lungs including the airways

from the ascending reticular activating system, also represents a tonic stimulus to ventilation during wakefulness (Hugelin and Cohen, 1963; Cohen and Hugelin, 1965). The central control of breathing depends mainly on two groups of automatic respiratory neurons in the medulla (Nathan, 1963; Merrill, 1970; Mitchell and Berger, 1975; Berger et al., 1977; Phillipson, 1978a, b; Mitchell, 1980; Cherniack and Longobardo, 1986; Phillipson and Bowes, 1986; Chokroverty, 1990). The dorsal respiratory group (DRG), located in the nucleus tractus solitarius (NTS), is responsible principally, but not exclusively, for inspiration, projecting mainly to the contralateral spinal cord with a small ipsilateral projection, and probably also responsible for rhythmic respiratory drive to phrenic motor neurons. The ventral respiratory group (VRG) located in the region of the nucleus ambiguus and retroambigualis is responsible for both inspiration and expiration. The VRG contains the Botzinger complex in the rostral region and the preBotzinger region immediately below the Botzinger complex, responsible mainly for the automatic respiratory rhythmicity as these neurons have intrinsic pacemaker activity. Two groups of neurons located in the rostral pons in parabrachial and Ko¨lliker–Fuse nuclei (pneumotaxic center) and in the dorsolateral region of the lower pons (apneustic center) exert strong influence on the medullary respiratory neurons. The DRG and VRG neurons send axons that decussate below the obex and descend with the reticulospinal tracts in the ventrolateral cervical spinal cord to synapse with the spinal respiratory neurons innervating various respiratory muscles. There is tonic afferent input to the pontine and the medullary respiratory centers from forebrain and midbrain as well as sympathetic and vagal fibers from the respiratory tract, the carotid and aortic body peripheral chemoreceptors, and central chemoreceptors located in the ventrolateral medulla (Lumsden, 1923; Wang et al., 1957; Sullivan, 1980; Cherniack and Longobardo, 1986; Chokroverty, 1993, 1990).

The voluntary breathing system, which is the second respiratory controlling system, originates in the forebrain and the limbic system and descends with the corticobulbar and corticospinal tracts, controlling respiration during wakefulness (Plum, 1966; Sullivan, 1980). These projections descend partly to the automatic medullary respiratory neurons but descend mainly with the corticospinal tract to the spinal respiratory motor neurons where the fibers integrate with the reticulospinal fibers originating from the medullary respiratory neurons (Newsom-Davis, 1974; Berger et al., 1977; Mitchell, 1980; Phillipson and Bowes, 1986). The voluntary and automatic respiratory systems thus finally integrate in the high cervical spinal cord for smooth coordinated functioning of the respiration during wakefulness. The function of breathing is to maintain arterial homeostasis by maintaining normal partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2). PaCO2 depends predominantly on the central chemoreceptors with some influence from the peripheral chemoreceptors. Both hypoxia and hypercapnia stimulate breathing (Read, 1967; Weil et al., 1970). The hypoxic ventilatory response in normal individuals is a hyperbolic curve, showing a sudden increase in ventilation when PaO2 falls below 60 mmHg (Douglas et al., 1982a, b; White et al., 1982). In contrast, the hypercapnic ventilatory response is linear (Read, 1967; White, 1990). When PaCO2 falls below a certain minimum level, which is called apnea threshold, ventilation is inhibited.

The chest bellow component This consists of thoracic bones, connective tissues, pleural membranes, the intercostal and other respiratory muscles (see Table 64.1), the nerves, and blood vessels. Respiratory muscle weakness plays a critical role in causing sleep dysfunction and SDB in neuromuscular disorders. Table 64.2 lists the respiratory muscles. The main inspiratory muscle is the diaphragm (innervated by phrenic nerve formed by motor roots of C3, C4, and C5 anterior horn cells), assisted by the external intercostal muscles (innervated by the thoracic motor roots and nerves) which expand the core of the thoracic cavity and lungs during quiet, normal breathing. Expiration is passive, resulting from elastic recoil of the lungs. During forced and effortful breathing (e.g., dyspnea and orthopnea), accessory muscles of respiration assist the breathing. Accessory inspiratory muscles include sternocleidomastoideus, trapezius, and scalenus (anterior, middle and posterior), as well as pectoralis, serratus anterior, and latissimus dorsi. Accessory expiratory muscles consist of internal intercostals and abdominal muscles (e.g., rectus abdominis,

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.2 Respiratory muscles Inspiratory muscles ▪ Diaphragm ▪ External intercostal Accessory inspiratory muscles ▪ Sternocleidomastoideus ▪ Scalenus (anterior, middle, posterior) ▪ Pectoralis major ▪ Pectoralis minor ▪ Serratus anterior ▪ Serratus posterior superior ▪ Latissimus dorsi ▪ Alae nasi ▪ Trapezius Expiratory muscles (Silent during quiet breathing but contract during moderately severe airway obstruction or during forceful and increased rate of breathing) ▪ Internal intercostal ▪ Rectus abdominis ▪ External and internal oblique ▪ Transversus abdominis

external and internal oblique, and transversus abdominis), innervated by thoracic motor roots and nerves. Normally, these three components (central controllers, chest bellows, and lungs) function smoothly in an automatic manner to permit gas exchange (transfer of oxygen into the blood and elimination of carbon dioxide into the atmosphere) for ventilation, diffusion, and perfusion. Minute ventilation is defined as the amount of air breathed per minute, which equals about 6 liters (about 2 liters stay in the anatomic dead space consisting of the upper airway and the mouth, and 4 liters participate in gas exchange in the millions of alveoli constituting alveolar ventilation). Respiratory failure (see below) may occur as a result of dysfunction anywhere within these three major components of respiratory control systems.

Changes in breathing during sleep During both nonrapid eye movement (NREM) and rapid eye movement (REM) sleep, respiratory neurons in the medullary region decrease their firing rates. Changes are noted in respiratory rate and rhythm, alveolar ventilation, tidal volume, chemosensitivity, and blood gases. Respiratory homeostasis is unprotected during sleep. Respiratory rate decreases during NREM sleep and becomes irregular during REM sleep. Minute ventilation and alveolar ventilation decrease due to a reduction of tidal volume (Tabachnik et al., 1981; Douglas et al., 1982a, b; Hudgel et al., 1984; White, 1990).

1089

Sleep-related alveolar hypoventilation results from a combination of the following factors (White, 1990): loss of wakefulness stimuli, increased upper airway resistance as a result of muscle hypotonia of the upper airway dilator muscles, diminished thoracic movement due to intercostal muscle hypotonia, impaired hypoxic and hypercapnic ventilatory responses due to decreased number of functional medullary respiratory neurons (central controller), and falling metabolic rate (reduced VO2 and VCO2). The upper airway dilating and intercostal muscles show mild hypotonia during NREM sleep but marked hypotonia or atonia during REM sleep. The diaphragm maintains phasic activities but tonic activity is reduced in REM sleep (Phillipson and Bowes, 1986). The functional residual capacity decreases in the supine position due to hypotonia of the intercostal muscles. As a result of sleep-induced mild alveolar hypoventilation, the normal individual’s arterial oxygen tension falls, causing less than a 2% reduction of oxygen saturation, and arterial carbon dioxide tension rises slightly. Hypoxic and hypercapnic ventilatory response is decreased mildly during NREM sleep with a more marked decrement during REM sleep (Berthon-Jones and Sullivan, 1982; Douglas et al., 1982a, b; Hedemark and Kronenberg, 1982; White et al., 1982). These sleep-related ventilatory changes (Table 64.3) do not have any significant effect in normal individuals. However, they become critical, transforming physiological nocturnal hypoventilation into pathological sleep-related hypoventilation, and may trigger life-threatening hypoxemia, abnormal breathing patterns, and respiratory failure in patients with neuromuscular disorders associated with respiratory muscle weakness.

CLINICAL MANIFESTATIONS OF SLEEP DYSFUNCTION IN NEUROMUSCULAR DISORDERS In neuromuscular disorders, sleep disturbances are most commonly secondary to involvement of the respiratory pump, which includes upper airway muscles (genioglossus, palatal, pharyngeal, laryngeal, hyoid, and masseter muscles), intercostal and other accessory muscles of respiration, and the diaphragm as a result of affection of the motor neurons, the phrenic and intercostal nerves or the neuromuscular junctions of the respiratory and oropharyngeal muscles, and primary muscle disorders affecting these muscles. The most common complaint is excessive daytime sleepiness resulting from repeated arousals and sleep fragmentations due to transient nocturnal hypoxemia and hypoventilation. The important clinical clues (Chokroverty, 2001; Chokroverty and Montagna, 2009) include:

1090

S. CHOKROVERTY

Table 64.3 Physiological changes in breathing during sleep Physiology

Wakefulness

NREM sleep

REM sleep

Parasympathetic activity Sympathetic activity Heart rate Blood pressure Cardiac output Peripheral vascular resistance Respiratory rate Alveolar ventilation Upper airway muscle tone Upper airway resistance Hypoxic and hypercapnic

þþ þþ Normal sinus rhythm Normal Normal Normal

þþþ þ Bradycardia Decreases Decreases Normal or decreases slightly Decreases Decreases þ þþþ Decreases

þþþþ Decreases or variable (þþ) Bradytachyarrhythmia Variable Decreases further Decreases further

Normal Normal þþ þþ Normal

Variable; apneas may occur Decreases further Decreases or absent þþþþ Decreases further ventilatory response

NREM, nonrapid eye movement; REM, rapid eye movement; þ, mild; þþ, moderate; þþþ, marked; þþþþ, very marked.

● ● ● ● ● ● ● ● ●

nocturnal restlessness frequent unexplained arousals excessive daytime sleepiness and fatigue shortness of breath orthopnea morning headaches intellectual deterioration unexplained dependent edema failure to thrive and declining school performance in children.

Signs of impending cor pulmonale include severe insomnia, morning lethargy, headaches, and unexplained dependent edema. The evaluation of SDB should begin with a detailed sleep history, which must specifically include clues suggestive of SDB as described above. Clinical approaches must also include a history of present and past illnesses, family, social, and medication histories. Physical examination including neurological and medical examination should assess the underlying cause of SDB. Special attention should be paid to uncovering bulbar weakness and respiratory muscle weakness, use of accessory muscles of respiration, and paradoxical breathing. Patients with neuromuscular disorders showing these clinical symptoms or findings must be investigated further to evaluate for nocturnal hypoventilation in order to prevent serious consequences of chronic respiratory failure, such as pulmonary hypertension, congestive cardiac failure, and cardiac arrhythmia. In addition to the sleep-related respiratory dysrhythmias, some patients, particularly those with painful polyneuropathies, muscle pain, muscle cramps,

and immobility due to muscle weakness, may complain of insomnia. Those complaining of sleeplessness may have the following features: insufficient sleep; difficulty initiating sleep; repeated awakenings including early morning awakenings; nonrestorative sleep; excessive daytime fatigue, tiredness or sleepiness; irritability, anxiety, lack of concentration; and sometimes depression related to sleep deprivation. The complaints from patients with hypersomnia generally include: excessive sleepiness and falling asleep at inappropriate places or under inappropriate circumstances; excessive daytime fatigue; absence of relief of symptoms following additional sleep at night; sometimes morning headaches; lack of concentration and listlessness, and impairment of daytime function; and impaired motor skills and cognition. Patients with obstructive sleep apnea may also complain of excessive snoring, cessation of breathing at night, and waking up fighting for breath. Persons with neuromuscular disease often complain of breathlessness, particularly in the supine position (orthopnea). Alveolar hypoventilation associated with neuromuscular disease may present acutely or insidiously. The acute form presents with progressive rapid reduction in vital capacity followed by respiratory failure. Symptoms and signs of acute respiratory failure are characterized by shortness of breath, irregular rapid, shallow or periodic breathing, cyanosis, and tachycardia. However, nocturnal hypoventilation and chronic respiratory failure in neuromuscular disease may present insidiously, and sometimes remain asymptomatic. Thus a high index of suspicion is needed.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

SLEEP

IN POLIOMYELITIS AND POSTPOLIO SYNDROME

Patients with bulbar poliomyelitis may develop respiratory disturbances and sleep dysfunction in acute and convalescent stages, and some patients have sequelae of respiratory dysrhythmia, particularly sleep-related hypoventilation or apnea requiring ventilatory support (Chokroverty and Montagna, 2009). The poliovirus infection directly affects the medullary respiratory and hypnogenic neurons and this explains the patient’s sleep-related respiratory difficulties. Sleep disorders, however, in postpolio syndrome are less well known; such patients may present with sleep-related hypoventilation or apnea causing excessive daytime somnolence (Codd et al., 1987; Speier et al., 1987; Chokroverty and Montagna, 2009). Postpolio syndrome is manifested by increasing weakness in previously affected or unaffected muscles of the subject with a past history of poliomyelitis. Based on questionnaire studies, sleep disturbances were noted in 31% of postpolio patients in one series (Cosgrove

Staging Movement Time Awake REM Stage 1 Stage 2 Stage 3 Stage 4 12 AM

1 AM

2 AM

1091

et al., 1987), and in another series (Van Kralingen et al., 1996) sleep complaints were noted in almost 50% of 43 postpolio patients. Steljes et al. (1990) performed polysomnographic (PSG) examinations in 13 postpolio patients and showed respiratory abnormalities consisting of hypoventilation, apneas, and hypopneas associated with significant obstructions and desaturation. Figure 64.1 shows a hypnogram and Figure 64.2 a sample of PSG recording from a patient with postpolio syndrome with REM-related hypopneas, apneas, and hypoventilation.

SLEEP

AND MOTOR NEURON DISEASE

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is the most common degenerative disease of the motor neurons in adults affecting the spinal cord, brainstem, motor cortex, and corticospinal tracts. It is characterized by progressive degeneration of both upper and lower motor neurons, manifesting as a varying combination of lower motor

3 AM

4 AM

5 AM

6 AM

7 AM

Position Left Right Supine Prone Upright Respiratory Events Mixed Apnea Obstructive Apnea Central Apnea Hypopnea Snore

SaO2 %

100 85 50

ECG Heart Rate 300 bpm 30 Arousal

Fig. 64.1. Hypnogram from a patient with postpolio syndrome. bpm, Beats per minute; ECG, electrocardiogram; REM, rapid eye movement; SaO2, oxygen saturation. (From Chokroverty et al., 2005b. # Elsevier.)

1092 Montage :

S. CHOKROVERTY PSG limbs - PFLOW

High Cut :

70 Hz

Low Cut :

0.53 Hz

Sensitivity :

7 mV / mm

Speed :

120 s/page

F3 - C3 F7 - T3 T3 - T5 T5 - O1 F4 - C4 F8 - T4 T4- T6 T6- O2 C3- A2 C4- A1 LT EOG

RT EOG

Chin EMG

Lt. Tib EMG Rt. Tib EMG

P Flow Oronasal

Chest

Abdomen

Snore EKG SaO2-A

94 %

93 %

86 %

88 %

80 %

91 %

80 %

77 %

Fig. 64.2. Sample polysomnographic recording from a patient with postpolio syndrome. Chin EMG, submental electromyogram; ECG, electrocardiogram; EMG, electromyogram; EOG, electro-oculogram; REM, rapid eye movement; PFLOW, nasal pressure recording for air flow; SaO2, oxygen saturation; L, left; R, right. (From Chokroverty et al., 2005b. # Elsevier.)

neuron (e.g., muscle weakness, wasting, fasciculation, dysarthria, and dysphagia) and upper motor neuron (e.g., spasticity, hyperreflexia, and extensor plantar responses) signs. The World Federation of Neurology published El Escorial clinical diagnostic criteria for ALS (Table 64.4) after convening a workshop (Brooks, 1994). ALS can be associated with profound sleep disturbances characterized by excessive daytime somnolence as a result of repeated arousals and sleep fragmentation due to nocturnal hypoventilation, recurrent sleep apneas, hypopneas, hypoxemias, and hypercapnias (Figures 64.3 & 64.4). Some patients present with insomnia related to other factors (e.g., decreased mobility, muscle cramps, anxiety, and swallowing difficulties). There is no significant relationship between bulbar involvement and severity of SDB or other types of respiratory event (Kimura et al., 1999; Arnulf et al., 2000). Manifestations of SDB in ALS may result from

weakness of the upper airway, diaphragmatic, and intercostal muscles due to involvement of the bulbar, phrenic, and intercostal motor neurons. In addition, degeneration of central respiratory neurons may occur, causing central and upper airway obstructive sleep apneas. Respiratory failure in ALS generally occurs late, but occasionally is a presenting feature requiring mechanical ventilation (Parhad et al., 1978; Sugie et al., 2006). Diaphragmatic weakness as a result of degeneration of phrenic motor neurons is noted frequently in patients with ALS, and appears to be mainly responsible for nocturnal hypoventilation initially during REM sleep. SDB causing sleep disturbance and daytime symptoms has also been noted in other types of motor neuron disease, such as Kugelberg–Welander syndrome, a variant of juvenile type of motor neuron disease, as well as in spinal muscular atrophy type 1 and 2 in children (Testa et al., 2005; Petrone et al., 2007).

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.4 El Escorial clinical diagnostic criteria for amyotrophic lateral sclerosis ALS status

Clinical criteria

Definite

Lower motor and upper motor neuron signs in multiple regions (e.g., bulbar or at least two of the spinal or three spinal regions) Lower motor and upper motor neuron signs in at least two regions; some upper motor neuron signs must be rostral to lower motor neuron signs Lower motor and upper motor neuron signs in one region only or upper motor neuron signs alone in two or more regions or lower motor neuron signs rostral to upper motor neuron signs Only lower motor neuron signs in two or more regions

Probable

Possible

Suspected

ALS, amyotrophic lateral sclerosis.

SLEEP

DYSFUNCTION AND PERIPHERAL NEUROPATHY

Polyneuropathies are characterized by bilaterally symmetrical, distal sensory symptoms and signs, and muscle weakness and wasting affecting the legs more than the arms; they may be caused by a variety of heredofamilial and acquired lesions. Disturbance of the phrenic, intercostal, and other nerves supplying the respiratory muscles can cause SDB, which becomes worse during sleep causing sleep fragmentation and daytime somnolence. Painful peripheral neuropathies may cause insomnia. The most common polyneuropathy causing respiratory dysfunction is acute inflammatory demyelinating polyradiculoneuropathy (Landry–Guillain– Barre´–Strohl syndrome). This entity is manifested most commonly by rapidly progressive ascending paralysis beginning in the legs and becoming maximal in 2–3 weeks. In about 20–25% of cases, severe respiratory involvement has been reported; the critical period is usually in the first 3–4 weeks of the illness, and it is important to recognize and treat ventilatory dysfunction early. Other causes of polyneuropathies include diabetic autonomic neuropathy, Charcot–Marie–Tooth disease, and paraneoplastic syndrome. Unilateral phrenic neuropathy may be asymptomatic, but bilateral disorder may be life threatening and is the main cause of SDB in polyneuropathies. Other causes of phrenic neuropathy include varicella zoster infection, diphtheria, brachial plexopathy, and Charcot–Marie–Tooth disease (Tanner, 1980; Chan et al., 1987).

1093

Diaphragmatic weakness is suspected in the presence of breathlessness and excessive daytime somnolence, paradoxical inward movement of the abdomen and intercostal spaces with epigastric retraction instead of protrusion during inspiration, and a significant fall in vital capacity (e.g., 70% of the predicted value) from erect to supine position. This can be confirmed by documenting an elevated diaphragm on chest radiography, and paradoxical movement or decreased excursion of the diaphragm on fluoroscopy.

SLEEP

IN NEUROMUSCULAR JUNCTIONAL DISORDERS

Neuromuscular junction transmission disorders (e.g., myasthenia gravis, myasthenic syndrome, botulism, and tic paralysis) may give rise to respiratory failure as a result of easy fatigability of the muscles, including the bulbar and other respiratory muscles due to failure of transmission of the nerve impulses at the neuromuscular junctions of these muscles. This respiratory failure becomes worse in sleep causing central, upper airway obstructive and mixed apneas and hypopneas, accompanied by oxygen desaturation, disturbed nocturnal sleep, and a sense of breathlessness (Shintani et al., 1989; Quera-Salva et al., 1992; Stepansky et al., 1996; Nicolle et al., 2006). The most important of these conditions is myasthenia gravis, an autoimmune disease characterized by a reduction in the number of functional acetylcholine receptors in the postjunctional regions. Acute respiratory failure is often a dreaded complication of myasthenia gravis, and patients need immediate assisted ventilation for life support. SDB and nocturnal desaturation may improve following treatment with thymectomy or prednisone. Older myasthenic patients and those with increased body mass index, abnormal pulmonary function, and abnormal daytime blood gas values are at particular risk for sleep-related respiratory dysrhythmia. SDB has also been described in Eaton–Lambert myasthenic syndrome, a disorder of the neuromuscular junction in the presynaptic region, and is often a paraneoplastic manifestation, mostly of oat cell carcinoma of the lungs.

SLEEP

AND BREATHING DYSFUNCTION IN PRIMARY

MUSCLE DISORDERS

Primary muscle disorders or myopathies manifest as symmetrical proximal limb muscle weakness and wasting without sensory impairment or fasciculation, and result from a defect in the muscle membrane or the contractile elements that are not secondary to a dysfunction of the lower or upper motor neurons. Respiratory disturbances are generally noted in the advanced stage of the illness, but sometimes

1094

S. CHOKROVERTY

Fig. 64.3. Overnight polysomnographic recording from a patient with amyotrophic lateral sclerosis presenting with upper and lower motor neuron signs including bulbar palsy. Recurrent periods of central apneas can be seen, many of which are prolonged, followed by irregular ventilatory cycles resembling ataxic breathing accompanied by severe oxygen desaturation and sleep hypoxemia during rapid eye movement sleep. Top four channels show international electrode placement system (electroencephalogram). LOC, left electro-oculogram; ROC, right electro-oculogram; Chin, submental electromyogram (EMG); ECG, electrocardiogram; L gast. EMG, left gastrocnemius EMG; R gast. EMG, right gastrocnemius EMG; Oronasal, oronasal air flow; PFLOW, nasal pressure recording for air flow; Thorax, thoracic breathing effort; Abdomen, abdominal breathing effort; SaO2, oxygen saturation by finger oximetry; Snore, snoring recording (From Chokroverty and Montagna, 2009. # Elsevier.)

respiratory failure appears in the early stage. Sleep complaints and sleep-related respiratory dysrhythmias are common in Duchenne and limb-girdle muscular dystrophies, myopathies associated with acid maltase deficiency, and may also occur in other congenital myopathies (e.g., nemaline rod, centrotubular and central core disease, merosin deficiency myopathy, and congenital muscular dystrophy) or acquired myopathies, mitochondrial encephalopathies, and polymyositis (Chokroverty, 1986; Howard et al., 1993; Labanowski et al., 1996; Chokroverty and Montagna, 2009). Acid maltase deficiency, a variant of glycogen storage disease, may present very early with diaphragmatic weakness causing hypoventilation, initially during REM sleep and later causing respiratory failure even during the daytime (Rosenow and Engel, 1978; Sivak et al., 1981; Martin et al., 1983; Margolis et al., 1994). Correct diagnosis in this condition can be established by performing electromyographic (EMG),

biochemical, histochemical, or morphological examination of muscle biopsy samples and respiratory function testing. Sleep architecture in Duchenne muscular dystrophy appears to be better preserved compared with the architecture in ALS.

SLEEP

DYSFUNCTION IN MYOTONIC DYSTROPHY

In 1954, Benaim and Worster-Drought were probably the first to describe alveolar hypoventilation in myotonic dystrophy, an autosomal dominant muscular dystrophy of adult onset associated with myotonia (myotonic dystrophy type 1, DM1). Alveolar hypoventilation associated with hypoxemia and impaired hypercapnic and hypoxic ventilatory responses may be present in both early and late stages of myotonic dystrophy. Sleep-related problems in this condition may be due to two factors: SDB and primary hypersomnia unrelated to SDB. SDB in myotonic dystrophy may

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

1095

Fig. 64.4. Overnight hypnogram from the patient in Figure 64.3, showing obstructive, central, and mixed apneas–hypopneas accompanied by repeated arousals and oxygen desaturation throughout the night, except during periods of wakefulness in the middle of the sleep period. Note oxygen desaturation throughout the sleep period (sleep hypoxemia) with more marked desaturation during rapid eye movement (REM) sleep, suggesting hypoventilation. Stage, nonrapid eye movement sleep stages; PLMS, periodic limb movements of sleep; A/H, apneas–hypopneas; SaO2, oxygen saturation by finger oximetry.

be due to weakness and myotonia of respiratory and upper airway muscles as well as an inherent abnormality of the central control of ventilation, most likely related to a membrane abnormality of muscles and other tissues, including the brainstem neurons that regulate breathing and sleep (Guilleminault et al., 1978; Harper, 1979; Hansotia and Frens, 1981; Striano et al., 1983). Central, mixed, and upper airway obstructive sleep apneas have been described in patients with myotonic dystrophy (Coccagna et al., 1975; Guilleminault et al., 1978; Hansotia and Frens, 1981; Labanowski et al., 1996). A correction of sleep apnea or hypoventilation does not necessarily lead to improvement in excessive daytime sleepiness in this condition, suggesting other causes of hypersomnia in such patients. In addition, there may be an impairment of circadian and ultradian rhythms involving neuroendocrine abnormalities in sleep, contributing to excessive daytime somnolence (Culebras et al., 1977). Park and Radtke (1995) demonstrated the presence of sleep-

onset REMs in patients with myotonic dystrophy without any evidence of SDB, suggesting other causes for hypersomnia. It is, therefore, important to evaluate patients who have myotonic dystrophy with overnight PSG followed by multiple sleep latency tests, as excessive daytime somnolence may not be related to SDB. Martinez-Rodriguez et al. (2003) measured cerebrospinal fluid hypocretin-1 levels in six patients with DM1 complaining of excessive daytime sleepiness who were HLA-DQB1*0602 negative and found to have significantly lower hypocretin-1 levels compared with control values. The authors concluded that a dysfunction of the hypothalamic hypocretin system may be responsible for hypersomnia in DM1. Sleep disturbances have also been reported in proximal myotonic myopathy (PROMM), also known as myotonic dystrophy type 2 (DM2). PROMM is a hereditary myotonic disorder that is differentiated from DM1 by the absence of the chromosome 19 CTG trinucleotide repeat, which is associated with myotonic

1096

S. CHOKROVERTY

dystrophy (Ricker et al., 1994; Sander et al., 1996; Chokroverty et al., 1997; Lucchiari et al., 2008). In PROMM there is a mutation of the gene encoding for zinc finger 9 of chromosome 3q21. Sleep disturbances in these patients include excessive daytime sleepiness, snoring, frequent awakenings, sleep onset and maintenance insomnia, and alpha intrusion into NREM sleep on PSG which may be related to involvement of REM–NREM-generating neurons as part of a generalized membrane disorder (Chokroverty et al., 1997). In some patients with DM2 upper airway obstructive sleep apneas and REM-related hypoventilation have also been observed (S. Chokroverty, unpublished observations).

TYPES OF BREATHING PATTERN IN NEUROMUSCULAR DISORDERS The term sleep-disordered breathing encompasses all disorders of breathing during sleep and includes a variety of patterns (Figure 64.5) based on analysis of breathing patterns during overnight PSG recordings (Chokroverty and Montagna, 2009). The most common SDB in neuromuscular disorder is sleep-related alveolar hypoventilation, defined as a reduction of alveolar

ventilation resulting in hypoxemia and hypercapnia, manifesting initially during REM sleep and later, as the disease advances, also noted during NREM and even during the daytime (see below). In addition to alveolar hypoventilation, the following also occur (Figure 64.5): ● ● ●

upper airway obstructive, mixed, and central apneas sleep-related hypopneas paradoxical breathing.

Upper airway obstructive apneas are defined as complete cessation of air flow at the nose and mouth lasting at least 10 seconds with persistence of thoracic and abdominal efforts (Chokroverty and Sharp, 1981). Cessation of air flow with no respiratory effort constitutes central apnea. In mixed apnea, initially airflow and respiratory effort cease, followed by a period of upper airway obstructive sleep apnea. Hypopnea is defined as a greater than 50% reduction in airflow and effort as compared to the preceding or following respiratory cycles, lasting at least 10 seconds, accompanied by arousals and/or more than 3% oxygen desaturation (Iber et al., 2007). Apneas and hypopneas are

AIR FLOW AIR FLOW EFFORT EFFORT

A

D

AIR FLOW FLOW THOR. EFFORT EFFORT

B

ABD. EFFORT

E AIRFLOW AIR FLOW EFFORT EFFORT

C F

Fig. 64.5. Schematic diagram showing the most common types of breathing pattern in patients with neuromuscular disorders. (A) Normal breathing pattern, (B) upper airway obstructive apnea, (C) central apnea; (D) mixed apnea (initially central followed by obstructive apnea), (E) paradoxical breathing, (F) hypopnea.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS usually accompanied by oxygen desaturation and terminated by an arousal. Thus, recurrent apneas, hypopneas, arousal and oxygen desaturation result in sleep disruption and fragmentation with subsequent hemodynamic changes in systemic and pulmonary circulation. Apneas and hypopneas are combined and expressed as the apnea–hypopnea index (number of apneas– hypopneas per hour of sleep), which should be at least 5 to be significant. Most people consider an apnea– hypopnea index of 10–15 to be significant, necessitating treatment. Recurrent arousals related to respiratory effort (RERAs) as a result of increasing upper airway resistance due to decreased tone of the upper airway dilator muscles as well as sleep fragmentation without apnea, hypopnea, or oxygen desaturation are believed to constitute upper airway resistance syndrome (UARS). Finally, some patients may have paradoxical breathing (movements of the thorax and abdomen in opposite directions, as noted in PSG recordings), suggesting upper airway obstructive sleep apnea or UARS. The other types of breathing pattern (Chokroverty and Montagna, 2009) included within the term SDB (e.g., periodic breathing, including Cheyne–Stokes’ breathing, ataxic breathing, Biot’s breathing, inspiratory gasp, apneustic breathing, and dysrhythmic breathing) are not generally seen in patients with neuromuscular disorders.

PATHOGENESIS AND MECHANISM OF SDB AND RESPIRATORY FAILURE IN NEUROMUSCULAR DISORDERS Respiratory failure is defined as an inability of the lungs to exchange gas effectively and to maintain a normal acid–base balance as a result of failure of the respiratory system anywhere from the medullary respiratory controllers to the chest bellows and the lungs, including the upper airways. As a result of this failure, there is reduction in PaO2 and increased PaCO2. PaO2 of less than 60 mmHg and/or a PaCO2 of more than 45 mmHg at sea level are commonly considered criteria for respiratory failure. Most neuromuscular disorders characteristically cause ventilatory failure, defined as inadequate alveolar ventilation with reduced tidal volume causing low PaO2 and high PaCO2. How does sleep initiate the onset of respiratory failure in neuromuscular disorders? The events that occur during sleep in neuromuscular disorders are the end of the beginning of respiratory failure and gradual or relentless progression unless interrupted by ventilatory support at night during sleep. A variety of changes occur in the respiratory system (both in the central control of breathing and in the respiratory muscles) during sleep that are responsible for initiating respiratory

1097

failure in sleep in patients with neuromuscular disorders. In addition, there may be a comorbid upper airway obstruction not related to neuromuscular disorders. However, in many patients with neuromuscular disorders, upper airway muscles are also affected, causing upper airway obstructive sleep apneas. The accessory muscles of respiration maintain ventilation during NREM sleep in patients with weakness of the diaphragm, the main muscle of ventilation; however, during REM sleep there is hypotonia or atonia of these accessory muscles and ventilation then depends exclusively on the diaphragm. Therefore, in patients with diaphragmatic weakness, ventilation is severely affected during REM sleep, causing REM hypoventilation. This is the first stage of respiratory failure in neuromuscular disorders (Piper and Sullivan, 1994). As the disease advances, even the accessory muscles of respiration are affected severely, thus causing ventilatory disturbance during NREM sleep. In the final stage of neuromuscular disorder, ventilation is affected even during the daytime, producing altered blood gases (e.g., hypoxemia and hypercapnia) during wakefulness. Stage two of respiratory failure may be related to either progression of the neuromuscular disorders or superimposed intercurrent infection (e.g., pneumonia), or both. Several authors have performed studies to identify daytime predictors of SDB and nocturnal hypoventilation at its onset (Lyall et al., 2001; Ragette et al., 2002; Mellies et al., 2003). These authors concluded that progressive ventilatory restriction in neuromuscular diseases correlates with respiratory muscle weakness and can be predicted from daytime lung and respiratory muscle function. Inspiratory vital capacity (IVC) and maximum inspiratory muscle pressure (PImax) are the two important predictors for onset of respiratory failure. IVC of less than 60% and PImax below 4.5 kPa predicted onset of REM hypoventilation; IVC of less than 40% and PImax below 4.0 kPa predicted both REM and NREM hypoventilation; and IVC of less than 25% and PImax below 3.5 kPa predicted daytime respiratory failure (Ragette et al., 2002; Mellies et al., 2003). It has also been suggested that a significant (70% of the predicted value) fall in vital capacity from erect to supine position indicates the presence of diaphragmatic weakness (Varrato et al., 2001; Lechtzin et al., 2002; Czaplinski et al., 2006). Fluoroscopy will confirm the weak movement of the dome of the diaphragm during inspiration. In addition, PImax will be supportive evidence. A serial blood gas determination is important for detecting impending respiratory failure. It should be remembered that a normal daytime PaO2 and PaCO2 does not exclude REM-related hypoventilation.

1098

S. CHOKROVERTY

In patients with weak respiratory muscles, regardless of cause, the waking breathing difficulties may worsen during sleep. During wakefulness, both voluntary and metabolic respiratory assistance are intact. In order to drive the weak respiratory muscles in neuromuscular disorders, the central respiratory neurons increase the firing rate or recruit additional respiratory neurons during wakefulness to maintain adequate ventilation (Chokroverty, 1986). During sleep, this voluntary control is entirely lacking, aggravating the existing ventilatory problems and causing more severe hypoventilation and even apnea and hypopneas. Functional impairment of the sensitivity of the central respiratory neurons causing decreased metabolic respiratory control may also give rise to apnea and hypopnea during both REM and NREM sleep. Oropharyngeal (upper airway) muscle weakness coupled with REM-related hypotonia or atonia of the muscles may contribute to possible upper airway obstructive sleep apnea. In summary, breathing disorders causing sleeprelated hypoventilation in neuromuscular disorders may be related to the following factors (Chokroverty and Montagna, 2009): ● ●

●

●

● ●

●

●

● ●

Impaired chest bellows caused by weakness of the respiratory and chest wall muscles Increased work of breathing due to altered chest mechanics and reduced forced vital capacity caused by weakness of the chest wall muscles and the diaphragm so that breathing is less efficient Hyporesponsive chemoreceptors which may be secondarily acquired or related to altered afferent inputs from skeletal muscle spindles, causing functional alteration of the medullary respiratory neurons Weakness of upper airway muscles that increases upper airway resistance, adding respiratory muscle load or even upper airway obstructive sleep apnea from complete closure of the upper airway Decreased minute and alveolar ventilation during sleep REM-related marked hypotonia or atonia of all the respiratory muscles except the diaphragm, causing increased diaphragmatic workload Respiratory muscle fatigue due to increased demand on the respiratory muscles during sleep, particularly REM sleep Kyphoscoliosis secondary to neuromuscular disorders, causing extrapulmonary restriction of the lungs with impairment of pulmonary functions, breathlessness, sleep apnea, and hypoventilation Failure of central control of ventilation Alteration in respiratory reflexes from upper airway and lung receptors, and arousal responses.

All of these factors lead to respiratory failure in neuromuscular disorders. As a result of alveolar

hypoventilation and ventilation–perfusion mismatching, hypoxemia and hypercapnia occur, giving rise to chronic respiratory failure even during the daytime at an advanced stage of the illness.

CLINICAL APPROACH TO DIAGNOSIS OF RESPIRATORY FAILURE IN NEUROMUSCULAR DISORDERS The initial approach to patients with sleep dysfunction in neuromuscular disorder is clinical. A careful history including present and past sleep history, family, drug, alcohol, medical, and psychiatric histories is essential. When clinical clues strongly suggest SDB, physical examination must be directed to uncover bulbar and respiratory muscle weakness including diaphragmatic dysfunction, in addition to detailed neurological and general medical examination to exclude other causes of SDB including nocturnal hypoventilation (Langevin et al., 2000; Chokroverty and Montagna, 2009). Clinical diagnosis of acute respiratory failure, as may be seen in patients with acute inflammatory demyelinating polyneuropathy (Guillain–Barre´ syndrome), myasthenia gravis, or acute anterior poliomyelitis, is quite obvious. Patients may have irregular, rapid, shallow, or periodic breathing, intermittent cessation of breathing, and cyanosis; however, nocturnal hypoventilation and chronic respiratory failure in neuromuscular disorders may present insidiously and may initially remain asymptomatic (Martin and Sanders, 1995; Labanowski et al., 1996; Attarian, 2000; Langevin et al., 2000; Chokroverty, 2001; Chokroverty, 2003). A high index of clinical suspicion is needed. The clinical scale called the Epworth Sleepiness Scale (ESS) is often used to assess the general level of persistent sleepiness. This scale measures propensity to sleepiness assessed by the patient under eight situations on a scale from 0 to 3, with 3 indicating a situation where chances of dozing off are highest. The maximum score is 24, and a score of 10 suggests the presence of excessive daytime sleepiness. The test has been weakly correlated with Multiple Sleep Latency Test scores (see below).

LABORATORY INVESTIGATIONS Laboratory investigations are simply an extension of the history and physical examination described above. Laboratory tests should include those needed to diagnose primary neuromuscular disorders and those directed at the evaluation of sleep disturbance and SDB. The description of the tests to diagnose primary neuromuscular disorders is beyond the scope of this chapter and the reader is referred to standard

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS neurological and neuromuscular texts. Tests to evaluate SDB include the following: ●

● ● ● ● ● ● ● ●

Pulmonary function tests including maximal inspiratory (PImax) and expiratory (PEmax) mouth pressure Arterial blood gases: PaO2, PaCO2 Oxygen saturation (SaO2) by finger oximetry End-tidal (EtCO2) or transcutaneous (TcCO2) carbon dioxide Overnight polysomnography (PSG) Multiple Sleep Latency Test (MSLT) Chest fluoroscopy Phrenic nerve conduction Diaphragmatic needle EMG.

Chest radiographs are important to identify intrinsic bronchopulmonary diseases and diaphragmatic paralysis.

Overnight polysomnographic (PSG) recording The single most important laboratory test in patients with hypersomnia and nocturnal sleep disturbances is PSG recording, which must be performed in all patients with excessive daytime somnolence unless the patient is so severely impaired by the neuromuscular condition that the diagnosis and treatment of sleep problems will not alter the outcome of the illness. Overnight PSG is important in patients with sleep complaints secondary to neuromuscular diseases to prevent a fatal sleep-related respiratory arrest at night and to treat dangerous nocturnal hypoventilation and hypoxemia. PSG findings in various neuromuscular disorders may include the following: increased number of awakenings; sleep fragmentation and disorganization; reduced total sleep time and decreased sleep efficiency; central, mixed, and upper airway obstructive sleep apneas or hypopneas associated with oxygen desaturation; nonapneic oxygen desaturation becoming worse during REM sleep. Additionally, in painful polyneuropathies and in neuromuscular disorders associated with muscle pain and muscle cramps, PSG may show sleep-onset insomnia and reduced sleep efficiency.

Multiple Sleep Latency Test (MSLT) This may be performed to document the presence and severity of daytime sleepiness and to diagnose comorbid narcolepsy. A mean sleep-onset latency of less than 8 minutes is consistent with pathological sleepiness, and the presence of sleep-onset REM in two or more of four to five nap recordings during MSLTs may suggest a diagnosis of comorbid narcolepsy in patients

1099

with neuromuscular disease (American Academy of Sleep Medicine, 2005). As stated above, many patients with DM1 may have hypersomnia not related to SDB, and therefore hypersomnia in these patients may have other explanations or may indicate comorbid narcolepsy, particularly when there is a history of cataplexy (Park and Radtke, 1995).

Pulmonary function tests The definitive test for alveolar hypoventilation is an analysis of arterial blood gases showing hypercapnia and hypoxemia (Martin and Sanders, 1995; Langevin et al., 2000). In early stage of neuromuscular disorder, awake arterial blood gas values remain normal; only in advanced stages with chronic respiratory failure are these values abnormal. To detect abnormal nocturnal arterial blood gases and hypoventilation, an indwelling arterial catheter needs to be placed throughout the night – this is invasive and rather impractical. Therefore, some investigators advocate noninvasive monitoring of oxygen saturation and carbon dioxide tension alone to detect hypoventilation; however, there are pitfalls to this line of investigation (Martin and Sanders, 1995). There is limitation to usefulness of finger oximetry alone because of the hyperbolic shape of the oxyhemoglobin dissociation curve, which may show minor oxygen desaturation in the presence of significant hypoventilation and reduced PaO2. The noninvasive end-tidal and transcutaneous carbon dioxide tension measurements are also unreliable and correlate poorly with actual PaCO2. Pulmonary function tests assess respiratory and ventilatory muscle function (Martin and Sanders, 1995; Gold, 2005). They include measurement of lung volumes (quantities of air within the lungs) and lung capacities (derived from lung volumes) (Table 64.5 & Figure 64.6), PaO2 and PaCO2 obtained by arterial (radial or femoral) punctures, oxygen saturation (SaO2) by finger oximetry and end-tidal carbon dioxide (PaCO2) or transcutaneous carbon dioxide (TcCO2) (Varrato et al., 2001; Lechtzin et al., 2002; Gold, 2005; Morgan et al., 2005; Czaplinski et al., 2006). Spirometry, the most important pulmonary function test, measures most of the lung volumes and capacities, except residual volume (RV), functional residual capacity (FRC), and total lung capacity (TLC), which require nonspirometric techniques (e.g., gas dilution technique). Important spirometric measurements include forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and the ratio of FEV1 to FVC. Patient cooperation and good patient– technician interaction are essential for obtaining valid spirometric measurements. Values are expressed as the percentage predicted. Values of FVC, FEV1, and

1100

S. CHOKROVERTY

Table 64.5 Lung volumes and capacities Parameter

Description

Lung volumes Tidal volume (TV)

Volume (ml) of air per normal inspiration or expiration Inspiratory reserve Volume of air during maximal volume (IRV) inhalation following a normal breath Expiratory reserve Volume of air during maximal volume (ERV) exhalation following a normal breath Residual volume (RV) Volume of air remaining after maximum exhalation Lung capacities (derived from lung volumes) Vital capacity (VC) Volume of air that can be exhaled maximally after maximum inspiration (IRV þ TV þ ERV) Inspiratory Inspiratory reserve volume capacity (IC) plus tidal volume (IRV þ TV) Functional residual Volume of air remaining after capacity (FRC) a normal expiration (ERV þ RV) Total lung capacity Vital capacity plus residual volume (TLC) (VC þ RV)

5

Volume (Liters)

4 3

IRV

VC (IRV + TV + ERV)

TV

2

FRC (ERV + RV)

1

ERV

RV

0

Fig. 64.6. Schematic diagram to show lung volumes and capacities. ERV, expiratory reserve volume; FRC, functional residual capacity; IRV, inspiratory reserve volume; RV, residual volume; TV, tidal volume; VC, vital capacity. (From Chokroverty and Montagna, 2009. # Elsevier.)

peak expiratory flow rate (PEFR) of less than 80% predicted is considered abnormal. A value of less than 70% predicted for the ratio of FEV1 and FVC is abnormal.

In neuromuscular disorders, the characteristic abnormalities include decreased FVC, FEV1, and TLC, but increased RV. The airway obstruction shows less than predicted values of the ratio of FEV1 to FVC, whereas restrictive lung disease shows an increase in the ratio of FEV1 to FVC combined with an absolute reduction in FVC and FEV1. The strength of respiratory muscles must be severely reduced before a significant reduction in lung volumes is appreciated, as pressure/ volume characteristics of the respiratory system are not linear. Thus, static respiratory pressure measurements are often used to assess respiratory muscle strength, such as maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax) (Black and Hyatt, 1971). These measurements, however, require the cooperation of patients, and the normal values have large ranges and variability which may be related to factors such as lung volume, type of mouthpiece, variable effort, and learning. In patients with bulbar muscle weakness, it may not be possible to measure PImax and PEmax. In order to reduce the effects of these variables in the measurement of PImax, investigators have used respiratory pressures during maximal sniff maneuvers (Lyall et al., 2001; Morgan et al., 2005). The maximal sniff pressure (SMP) may be measured using transdiaphragmatic (TPdi), esophageal (Pes), or nasal (Pn) methods. Pn is often measured rather than Pes because it is much less invasive. Noninvasive sniff pressure is reported to be more sensitive than VC and PImax in predicting respiratory muscle strength and the risk of ventilatory failure in these patients (Lyall et al., 2001; Morgan et al., 2005). In patients suspected to have diaphragmatic paralysis, chest fluoroscopy and measurement of transdiaphragmatic pressure using esophageal and gastric balloons inserted via the nasogastric route may be necessary (Lourenco and Mueller, 1967; Lopata et al., 1978; Baydur et al., 1982). This may be difficult to perform. Chest radiography is noninvasive and permits visualization of the diaphragm dome, but provides little information regarding diaphragm function. Diaphragm fluoroscopy provides real-time examination of the start of diaphragm dome motion but carries the disadvantage of exposure to ionizing radiation and poor sensitivity and specificity. Phrenic (Markand et al., 1984) and intercostal (Chokroverty et al., 1995) nerve conduction by electrical or magnetic stimulation may detect phrenic or intercostal neuropathy causing respiratory muscle weakness. Needle EMG of the diaphragm may reveal diaphragmatic denervation, suggesting neurogenic dysfunction of the diaphragm (Bolton et al., 1992; Saadeh et al., 1993; Sander et al., 1999).

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS

PRINCIPLES OF TREATMENT OF SLEEP DYSFUNCTION IN NEUROMUSCULAR DISORDERS Treatment of primary neuromuscular disorder should be the first line of treatment; however, in many of these conditions there is no specific treatment and only symptomatic measures are available. The goal of treatment in sleep disturbances related to SDB is to improve arterial blood gases, eliminate daytime symptoms, improve quality of life, prevent life-threatening cardiac arrhythmias, pulmonary hypertension, and congestive cardiac failure, and possibly prolong the patient’s longevity. Table 64.6 lists principles of treatment of sleep dysfunction and SDB in neuromuscular diseases.

GENERAL

MEASURES

In obese patients, weight reduction should be encouraged, as excess weight might contribute to upper airway obstructive sleep apnea syndrome. Alcohol, sedatives, hypnotic drugs, and other medications that may contribute to sleep disturbances and cause depression of breathing during sleep should be reduced or eliminated.

INTERVENTIONAL

TREATMENT USING MECHANICAL

DEVICES

In the past, the mainstay of treatment was invasive ventilation via a tracheostomy, but this has now been largely replaced by noninvasive methods of ventilatory support for patients with SDB including hypoventilation consisting of negative and positive pressure Table 64.6 Principles of treatment of sleep-disordered breathing and sleep dysfunction in neuromuscular diseases ● ●

● ●

●

General measures Intervention with mechanical devices ○ CPAP ○ BiPAP ○ IPPV Supplemental oxygen therapy Surgical treatment ○ Tracheostomy ○ Diaphragm pacing Pharmacological treatment ○ For sleep apnea ○ For insomnias ○ For myotonic dystrophy

BiPAP; bilevel positive airway pressure; CPAP, continuous positive airway pressure; IPPV, intermittent positive airway pressure.

1101

ventilators (Strumpf et al., 1990; Tobin, 1994; Martin and Sanders, 1995; Chokroverty and Montagna, 2009). Ventilators were developed during the early polio epidemics in the 1950s and 1960s. Negative-pressure ventilators include “iron lung” or tank respirator, “rain coat” or “pneumo-wrap ventilator”, and cuirass or “tortoise shell” (Collier and Affeldt, 1954; Spalding and Opie, 1958; Hill, 1986; Strumpf et al., 1990; Hillberg and Johnson, 1997; Rabatin and Gay, 1999). The tank respirator, although a most effective negative pressure ventilator, is bulky, limiting the patient’s acceptance (Hill, 1986; Strumpf et al., 1990). Furthermore, negative-pressure ventilators may be associated with upper airway obstructive sleep apnea syndrome with oxygen desaturation in patients with neuromuscular disease (Ellis et al., 1987). The contemporary standard of management for chronic ventilatory failure in neuromuscular disorders is noninvasive intermittent positive pressure ventilation (IPPV) using a nasal mask or prongs. Positive-pressure ventilation includes continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), and IPPV. For upper airway obstructive sleep apnea syndrome, nasal CPAP is the ideal treatment. Following such treatment, sleep quality and daytime hypersomnolence often improve due to the reduction or elimination of sleep-related obstructive or mixed apneas and oxygen desaturation. In patients with relentlessly progressive disease, however, such treatment has not been very useful, and therefore the role of CPAP in such diseases requires further study. Some patients may not be able to tolerate the same high pressure during both inspiration and expiration, and feel comfortable using BiPAP. BiPAP uses higher inspiratory positive airway pressure than expiratory positive airway pressure. Both types can be used, but studies have found no significant difference between the two types of ventilator in terms of survival (Janssens et al., 2003) and correction of hypoventilation (Meechan Jones and Wedzichia, 1993). The beneficial effects of nocturnal IPPV may be summarized as follows: improvement of nocturnal gas exchange as reflected in SaO2 and TcCO2 as well as improvement in daytime arterial blood gases; slight improvement in total sleep duration without significant improvement in quality of sleep; improvement in FVC and PImax; reduction in the number of days of hospitalization; improvement in quality-of-life measures and long-term survival. Numerous studies have proven the benefit of noninvasive ventilation through a nasal mask for 6–8 hours during sleep in neuromuscular disorders (Bye et al., 1985; Howard et al., 1989; Leger et al., 1989; Newsom-Davis et al., 2001; Sivak et al., 2001; Bourke

1102

S. CHOKROVERTY

and Gibson, 2002; Bourke et al., 2003; Butz et al., 2003; Gruis et al., 2005; Ward et al., 2005; Bourke et al., 2006; Mustfa et al., 2006; Petrone et al., 2007). IPPV generally uses no expiratory positive airway pressure, but in some patients positive end-expiratory pressure (PEEP) of up to 5 cmH2O may be required. In some patients during initial nights of IPPV, there may be upper airway closure for the first time during the expiratory phase (Piper and Sullivan, 1994, 1996). The mechanism for such closure may include driving of carbon dioxide levels below the apnea threshold, and marked reduction of muscle tone as a result of REM rebound. Treatment of these patients is the addition of a PEEP valve by maintaining a positive pressure (up to 5 cmH2O) during expiration. Noninvasive IPPV can be used even in those with bulbar muscle weakness, utilizing the full face mask. Either pressurecycled (delivering air at a fixed pressure) or volumecycled (delivering a fixed volume of air) ventilators may be used, but many clinicians prefer pressurecycled ventilators to deliver IPPV. However, in terms of long-term survival (Janssens et al., 2003) or shortterm correction of hypoventilation (Meechan Jones and Wedzichia, 1993) there is no difference between the two types of ventilator. The volume-cycled ventilators deliver tidal volume and pressure-cycled ventilators deliver a fixed pressure (usually 10–20 cmH2O) set by the clinician. Ventilator modes could be one of the following three: control mode where the ventilator starts and ends inspiration according to prescribed setting; assist-control mode where either patient’s effort or programmed setting initiates inspiration; and spontaneous assist where patient’s effort starts and ends inspiration. Following such treatment, patients show improvement in daytime somnolence, arterial blood gases, sleep efficiency, and sleep architecture, a reduction in the need for prolonged hospitalization, and increased longevity. Long-term follow-up and prospective randomized controlled trials in neuromuscular disorders such as ALS are limited. In one of the largest prospective, although not randomized or blinded, studies, Mustfa et al. (2006) showed efficacy of noninvasive ventilation in patients with ALS. There were striking improvements in blood gases and in a variety of quality-of-life measurements following noninvasive ventilation within 1 month which were maintained for up to 12 months in 26 patients with ALS showing respiratory muscle weakness. These authors also studied, in parallel, 15 age-matched patients without respiratory muscle weakness but with similar severity of ALS. Despite the progression of ALS, they showed improvement in qualityof-life measures. They had also shown that noninvasive ventilation in patients had no impact on most aspects

of quality-of-life measures in caregivers, and did not increase caregiver burden or stress. Twenty-six patients with congenital neuromuscular or chest wall diseases having daytime normocapnia and nocturnal hypercapnia were randomized to either nocturnal noninvasive ventilation or to a control group without ventilatory support by Ward et al. (2005). They found increased mean arterial oxygen saturation and a decreased mean percentage of nights with peak transcutaneous carbon dioxide tension in the group using noninvasive ventilation compared with controls. These authors suggested that such patients may benefit from nocturnal IPPV before daytime hypercapnia ensues. In the only randomized controlled trial, Bourke et al. (2006) selected 41 ALS patients who had orthopnea with maximum inspiratory pressure less than 60% of predicted value or symptomatic hypercapnia. They then randomly assigned 22 patients to noninvasive ventilation and 19 patients to standard care. They found survival benefit with improvement in quality-of-life measures in patients receiving noninvasive ventilation. In patients with severe bulbar involvement, however, no survival benefit was found.

INDICATIONS

FOR INTERMITTENT POSITIVE

PRESSURE VENTILATION

A European consensus conference (Robert et al., 1993) listed the following criteria for long-term noninvasive nasal ventilation for patients with neuromuscular disorders: presence of clinical symptoms (see above), PaCO2  45 mmHg or above, PaO2 < 60 mmHg in the daytime arterial blood gas analysis or pronounced nocturnal oxygen desaturation. The patients’ obstructive symptoms and arterial blood gases should be monitored. A later USA consensus conference report (Consensus Conference, 1999) listed the criteria for noninvasive positive pressure ventilation for patients with neuromuscular disorders (Table 64.7). First, the diagnosis must be established by a history and physical examination, followed by appropriate laboratory tests. The patient should also have received treatment for associated (e.g., obstructive sleep apnea syndrome diagnosed by PSG) or underlying conditions. The suggested indications for use of noninvasive ventilation include clinical symptoms (see above) and one of the following physiological criteria: (1) PaCO2  45 mmHg; (2) nocturnal oxygen desaturation (by finger oximetry)  88% for 5 consecutive minutes; (3) in cases of progressive neuromuscular diseases, PImax < 60 cmH2O or FVC < 50% predicted. Follow-up in 1–3 months for assessment of compliance and monitoring of awake arterial blood gases is also suggested. Overnight oximetry may be helpful for monitoring such patients. It should be remembered that different neuromuscular

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Table 64.7 Indications for intermittent positive pressure ventilation: consensus criteria ● ●

Appropriate clinical symptoms and signs One of the following physiological criteria: ○ PaCO2  45 mmHg ○ Nocturnal oxygen desaturation (finger oximetry)  88% for 5 consecutive minutes ○ PImax < 60 cmH2O or ○ FVC < 50% predicted (in cases of progressive disease)

FVC, forced vital capacity; PaCO2, arterial partial pressure of carbon dioxide; PImax, maximum inspiratory muscle pressure.

disorders evolve and progress at different and varying speeds depending on the etiology of the disease process and other associated variables, and, therefore, this set of guidelines may need further modifications depending upon the disease process involved. There have been some attempts to document daytime predictors that will indicate nocturnal hypoventilation and hence the need for IPPV; these were discussed in the previous section. To evaluate progression of disease and efficacy of treatment, there is no control study to implement this but finger oximetry is the most widely used. In addition, transcutaneous or end-tidal carbon dioxide concentration can also be used. EMG of the accessory respiratory muscles may help in indicating evidence of ventilatory failure; however, repeat PSG remains the best test for evaluating quality of sleep and effectiveness of IPPV. Guilleminault and Shergill (2002) suggested that, even if there is no change in clinical symptomatology, PSG is recommended at least once a year as respiratory changes can occur without accompanying clinical symptoms. There are, however, no standard guidelines for this recommendation.

PROBLEMS

WITH

IPPV

The complications of IPPV are similar to those noted for CPAP or BiPAP (Chokroverty, 2009b). One particularly annoying complication is nasal stuffiness or rhinorrhea, which may be relieved by using a warm humidifier or nasal corticosteroids. Some patients complain of claustrophobia with the use of nasal masks, particularly those with breathing problems. In such patients, a nasal pillow instead of a nasal mask may be useful. Leaks around the mask causing arousals, sleep fragmentation, and a subsequent decrease in the efficiency of IPPV are also common; correction of these leaks is important to improve sleep quality and architecture. Long-term use of a nasal mask can lead

1103

to a maxillary hypoplasia in young subjects. Children using nasal ventilation should be seen monthly to adjust mask size, particularly in the first 2 years of life, as a child’s face grows quickly during infancy and childhood. Airways develop and remodel during this time and, therefore, frequent repetition of nocturnal PSG has been suggested, approximately every 3 months (Guilleminault and Shergill, 2002).

MECHANISM

OF IMPROVEMENT FOLLOWING

IPPV

Several mechanisms have been suggested, but not proven (Martin et al., 1983; Martin and Sanders, 1995; Kramer et al., 1996; Langevin et al., 2000). Improvement of respiratory muscle fatigue and restoration of the sensitivity of the respiratory center to carbon dioxide are the two important mechanisms cited. Changes in pulmonary mechanics (e.g., increasing lung volume, improvement of lung compliance, and reduction of dead space) may also contribute to improvement in symptoms and gas exchange.

SUPPLEMENTAL

OXYGENATION

The role of supplemental oxygen treatment using lowflow oxygen (1–2 liters per minute) in SDB in neuromuscular diseases remains controversial. Supplemental oxygen therapy is mostly ineffective in patients with neuromuscular disorders and may even be dangerous, leading to marked carbon dioxide retention and making symptoms worse (Chokroverty et al., 1969; Motta and Guilleminault, 1978; Gay and Edmonds, 1995; Masa et al., 1997).

TRACHEOSTOMY For patients who have failed noninvasive positivepressure ventilation or who cannot cooperate with such treatment, tracheostomy may be beneficial. In patients with severe bulbar weakness, effective IPPV may not be possible. Tracheostomy remains the only effective emergency measure for those patients with marked respiratory failure with severe hypoxemia, and for those with sudden respiratory arrest after resuscitation by intubation. Such patients may later be weaned from tracheostomy and may later require positive-pressure treatment. However, a decision about tracheostomy should be weighed carefully in many of these neuromuscular disorders with relentless progression and an overall unfavorable prognosis.

DIAPHRAGMATIC

PACING

In the treatment of SDB in neuromuscular disorders, diaphragmatic pacing has a very limited application. If central apnea or alveolar hypoventilation persists

1104

S. CHOKROVERTY

during wakefulness despite appropriate ventilation during sleep, diaphragmatic pacing may be indicated (Chervin and Guilleminault, 1994; Guilleminault and Shergill, 2002). This requires surgery for placement of subcutaneous stimulator and phrenic nerve electrodes, and careful follow-up. IPPV via a tracheostomy or nasal mask may be used in association with diaphragmatic pacing. There are many potential complications of diaphragmatic pacing (e.g., nerve fibrosis, infection, unit malfunction, and other surgical complications). The Food and Drug Administration in the USA recently approved the NeuRx Diaphragm Pacing System (Onders et al., 2008) for patients with spinal cord injury who depend on ventilators because of a paralyzed diaphragm. Whether patients with neuromuscular disorders will benefit from this will depend on future clinical trials.

PHARMACOLOGICAL

TREATMENT

Pharmacological treatment for central or upper airway obstructive sleep apnea or nocturnal hypoventilation is unsatisfactory. However, in patients with myotonic dystrophy, additional treatment with stimulants for treatment of excessive daytime sleepiness may be required as these patients may have hypersomnia unrelated to alveolar hypoventilation. Modafinil, a novel wake-promoting stimulant, may be initiated at 100 mg per day, increasing to a maximum of 400 mg per day in two divided doses (Damian et al., 2001; MacDonald et al., 2002; Talbot et al., 2003). Armodafinil (Roth et al., 2008), with longer half-life than modafinil, may also be used (150 or 250 mg once daily in the morning). Methylphenidate and amfetamines may be used if modafinil or armodafinil is not effective. Patients complaining of insomnia should follow general sleep hygiene measures, such as a regular sleep schedule, avoidance of alcohol and caffeine in the evening, and other measures. Analgesics may be prescribed for pain and, occasionally, patients may need hypnotics, which should be used judiciously in low doses, no more than two to three nights per week.

CONCLUSION SDB is a common and serious consequence of neuromuscular disorders associated with respiratory muscle weakness, which unfortunately remains underdiagnosed or undiagnosed, as it presents as nocturnal hypoventilation in its early stage. A high index of clinical suspicion is needed so that appropriate diagnostic tests may be designed to diagnose nocturnal hypoventilation and other sleep-related disorders in the early stage of the illness. Some recent studies suggested possible

daytime predictors (e.g., reduced FVC and maximal inspiratory mouth pressure) for nocturnal hypoventilation, and, therefore, further studies are needed to develop optimal criteria for detecting SDB and nocturnal hypoventilation in its early stages. Noninvasive nasal IPPV remains the mainstay of treatment for SDB in neuromuscular disorders, providing an improvement in quality of life without always altering the natural history of the illness. Further studies are needed to answer many critical questions outlined in the USA consensus criteria document, such as when to treat, whom to treat, what type of equipment and what types of ventilator settings to use, what is the long-term outcome, how frequently the patient should be followed, what are the physiological mechanisms of benefit with noninvasive IPPV, what is patient tolerance and compliance to IPPV, and what are the longterm effects on outcome.

REFERENCES American Academy of Sleep Medicine (2005). Practice Parameters for Clinical Use of the Multiple Sleep Latency Tests and the Maintenance of Wakefulness Test. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 28: 113–121. Arnulf I, Similowski T, Salachas F et al. (2000). Sleep disorders and diaphragmatic function in patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med 161: 849–856. Attarian H (2000). Sleep and neuromuscular disorders. Sleep Med 1: 3–9. Baydur A, Behraks PK, Zin WA et al. (1982). A simple method for assessing the validity of the esophageal balloon technique. Am Rev Respir Dis 129: 788–791. Benaim S, Worster-Drought C (1954). Dystrophia myotonica with myotonia of diaphragm causing pulmonary hypoventilation with anoxaemia and secondary polycythaemia. Med Illus 8: 221–226. Berger AJ, Mitchell RA, Severinghaus JW (1977). Regulation of respiration. N Engl J Med 297: 92–97, 138–143, 194–200. Berthon-Jones M, Sullivan CE (1982). Ventilatory and arousal responses to hypoxia in sleeping humans. Am Rev Respir Dis 125: 632–639. Black LF, Hyatt RE (1971). Maximal static respiratory pressures in generalized neuromuscular disease. Am Rev Respir Dis 103: 641–650. Bolton CF, Grand-Maison P, Parkes A et al. (1992). Needle electromyography of the diaphragm. Muscle Nerve 15: 678–681. Bourke SC, Gibson GJ (2002). Sleep and breathing in neuromuscular disease. Eur Respir J 19: 1194–1201. Bourke SC, Bullock RE, Williams TL et al. (2003). Noninvasive ventilation in ALS: indications and effect on quality of life. Neurology 61: 171–177.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Bourke SC, Tomlinson M, Williams TL et al. (2006). Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomized controlled trial. Lancet Neurol 5: 140–147. Brooks BR (1994). El Escorial World Federation of Neurology Criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 124 (Suppl): 96–107. Butz M, Wollinsky KH, Wiedemuth-Catrinescu U et al. (2003). Longitudinal effects of noninvasive positivepressure ventilation in patients with amyotrophic lateral sclerosis. Am J Phys Med Rehabil 82: 597–604. Bye PTB, Ellis ER, Donnelly PD et al. (1985). Role of sleep in the development of respiratory failure in neuromuscular disease. Am Rev Respir Dis 131: 108. Chan CK, Mohsenin V, Loke J et al. (1987). Diaphragmatic dysfunction in siblings with hereditary motor and sensory neuropathy (Charcot–Marie–Tooth disease). Chest 91: 567–570. Cherniack NS, Longobardo GA (1986). Abnormalities in respiratory rhythm. In: AF Fishman, NS Cherniack, JG Widdicombe (Eds.), Handbook of Physiology, Section 3. The Respiratory System (Vol. II, Part 2). American Physiological Society, Bethesda, MD, pp. 729–749. Chervin R, Guilleminault C (1994). Diaphragm pacing: review and reassessment. Sleep 17: 176–187. Chokroverty S (1986). Sleep and breathing in neurological disorders. In: NH Edelman, TV Santiago (Eds.), Breathing Disorders of Sleep. Churchill Livingstone, New York, pp. 225–264. Chokroverty S (1990). The spectrum of ventilatory disturbances in movement disorders. In: S Chokroverty (Ed.), Movement Disorders. PMA, Costa Mesa, CA, pp. 365–392. Chokroverty S (1993). Sleep apnea and autonomic failure. In: PA Low (Ed.), Clinical Autonomic Disorders. Little, Brown, Boston, pp. 589–603. Chokroverty S (2001). Sleep-disordered breathing in neuromuscular disorders: a condition in search of recognition. Muscle Nerve 24: 451–455. Chokroverty S (2003). Sleep dysfunction in neuromuscular disorders. Schweiz Arch Neurol Psychiatr 154: 400–406. Chokroverty S (2009a). Physiologic changes in sleep. In: S Chokroverty (Ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. 3rd edn. Saunders Elsevier, Philadelphia, pp. 80–104. Chokroverty S (2009b). Questions and Answers about Sleep Apnea. Jones & Bartlett Publishers, Boston. Chokroverty S, Montagna P (2009). Sleep, breathing, and neurologic disorders. In: S Chokroverty (Ed.), Sleep Disorders Medicine: Basic Science, Technical Considerations, and Clinical Aspects. 3rd edn. Saunders Elsevier, Philadelphia, pp. 436–498. Chokroverty S, Sharp JT (1981). Primary sleep apnoea syndrome. J Neurol Neurosurg Psychiatry 44: 970–982.

1105

Chokroverty S, Barrocas M, Barron KD et al. (1969). Hypoventilation syndrome and obesity: a polygraphic study. Trans Am Neurol Assoc 94: 240–242. Chokroverty S, Deutsch A, Guha C et al. (1995). Thoracic spinal nerve and root conduction: a magnetic stimulation study. Muscle Nerve 18: 987–991. Chokroverty S, Sander HW, Tavoulareas GP et al. (1997). Insomnia with absent or dissociated REM sleep in proximal myotonic myopathy. Neurology 48: 256 (abstract). Chokroverty S, Bhatt M, Zhivotenko S (2005a). Sleep and neuromuscular disorders. In: C Guilleminault (Ed.), Sleep and its Disorders, Handbook of Clinical Neurophysiology. Elsevier, Amsterdam, pp. 225–234. Chokroverty S, Thomas RJ, Bhatt M (2005b). Atlas of Sleep Medicine. Elsevier/Butterworth-Heinemann, Philadelphia. Coccagna G, Mantovani M, Parchi C et al. (1975). Alveolar hypoventilation and hypersomnia in myotonic dystrophy. J Neurol Neurosurg Psychiatry 38: 977–984. Codd MB, Mulder DW, Kurland LT et al. (1987). Poliomyelitis in Rochester, Minnesota, 1935–1955: Epidemiology and Long-Term Sequelae: A Preliminary Report. Research and Clinical Aspects of the Late Effects of Poliomyelitis. March of Dimes Birth Defects Foundation, White Plains, NY. Cohen MI, Hugelin A (1965). Suprapontine reticular control of intrinsic respiratory mechanisms. Arch Ital Biol 103: 317–334. Collier CR, Affeldt JE (1954). Ventilatory efficiency of the cuirass respirator in totally paralyzed chronic poliomyelitis patients. J Appl Physiol 6: 531–538. Consensus Conference (1999). Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restricted lung disease, COPD, and nocturnal hypoventilation – a consensus conference report. Chest 116: 521–534. Cosgrove JL, Alexander MA, Kitts EL et al. (1987). Late effects of poliomyelitis. Arch Phys Med Rehabil 68: 4–7. Culebras A, Podolosky S, Leopold NA (1977). Absence of sleep-related growth hormone elevations in myotonic dystrophy. Neurology 27: 165–167. Czaplinski A, Yen AA, Appel SH (2006). Forced vital capacity (FVC) as an indicator of survival and disease progression in an ALS clinic population. J Neurol Neurosurg Psychiatry 77: 390–392. Damian MS, Gerlach A, Schmidt F et al. (2001). Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology 56: 794–796. Douglas NJ, White DP, Pickett CK et al. (1982a). Respiration during sleep in normal man. Thorax 37: 840–844. Douglas NJ, White DP, Weil JV et al. (1982b). Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 125: 286–289. Ellis ER, Bye PTP, Bruderer JW et al. (1987). Treatment of respiratory failure during sleep in patients with neuromuscular disease: positive-pressure ventilation through a nose mask. Am Rev Respir Dis 135: 148–152. Gay PC, Edmonds LC (1995). Severe hypercapnia after lowflow oxygen therapy in patients with neuromuscular

1106

S. CHOKROVERTY

disease and diaphragmatic dysfunction. Mayo Clin Proc 70: 327–330. Gold WM (2005). Pulmonary function testing. In: RJ Mason, VC Broaddus, JF Murray et al. (Eds.), Murray and Nadel’s Textbook of Respiratory Medicine. 4th edn. Elsevier, Philadelphia, pp. 671–740. Gruis KL, Brown DL, Schoennemann A et al. (2005). Predictors of noninvasive ventilation tolerance in patients with amyotrophic lateral sclerosis. Muscle Nerve 32: 808–811. Guilleminault C, Shergill RP (2002). Sleep-disordered breathing in neuromuscular disease. Curr Treat Options Neurol 4: 107–112. Guilleminault C, Cummiskey J, Motta J et al. (1978). Respiratory and hemodynamic study during wakefulness and sleep in myotonic dystrophy. Sleep 1: 19–31. Hansotia P, Frens D (1981). Hypersomnia associated with alveolar hypoventilation in myotonic dystrophy. Neurology 31: 1336–1337. Harper PS (1979). Myotonic Dystrophy. Saunders, Philadelphia. Hedemark LL, Kronenberg RS (1982). Ventilatory and heart rate responses to hypoxia and hypercapnia during sleep in adults. J Appl Physiol 53: 307–312. Hill NS (1986). Clinical application of body ventilators. Chest 90: 897–905. Hillberg RE, Johnson DC (1997). Noninvasive ventilation. N Engl J Med 337: 1746–1752. Howard RS, Wiles CM, Loh L (1989). Respiratory complications and their management in motor neuron disease. Brain 112: 1155–1170. Howard RS, Wiles CM, Hirsch NP et al. (1993). Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 86: 175–189. Hudgel DW, Martin RJ, Johnson B et al. (1984). Mechanics of the respiratory system and breathing during sleep in normal humans. J Appl Physiol 56: 133–137. Hugelin A, Cohen MI (1963). The reticular activating system and respiratory regulation in the cat. Ann N Y Acad Sci 109: 586–603. Iber C, Ancoli-Israel S, Chesson AL Jr et al. (2007). The AASM manual for the scoring of sleep and associated events. American Academy of Sleep Medicine, Westchester, IL. Janssens JP, Derivaz S, Breitenstein E et al. (2003). Changing patterns in long-term noninvasive ventilation: a 7-year prospective study in the Geneva Lake area. Chest 123: 67–79. Kimura K, Tachibana N, Kimura J et al. (1999). Sleep disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci 164: 37–43. Kramer N, Hill N, Millman R (1996). Assessment and treatment of sleep-disordered breathing in neuromuscular and chest wall diseases. Top Pulm Med 3: 336–342. Labanowski M, Schmidt-Nowara W, Guilleminault C (1996). Sleep and neuromuscular disease: frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 47: 1173–1180. Langevin B, Petitjean T, Philit F et al. (2000). Nocturnal hypoventilation in chronic respiratory failure (CRF) due to neuromuscular disease. Sleep 23(Suppl 4): S204–S208.

Lechtzin N, Wiener CM, Shade DM et al. (2002). Spirometry in the supine position improves the detection of diaphragmatic weakness in patients with amyotrophic lateral sclerosis. Chest 121: 436–442. Leger P, Jennequin J, Gerard M et al. (1989). Home positive pressure ventilation via nasal mask for patients with neuromuscular weakness or restrictive lung or chest-wall disease. Respir Care 34: 73–79. Lopata M, Zubillaga G, Evanich MJ et al. (1978). Diaphragmatic EMG response to isocapnic hypoxia and hyperoxic hypercapnia in humans. J Lab Clin Med 91: 698–708. Lourenco RV, Mueller EP (1967). Quantification of electrical activity in the human diaphragm. J Appl Physiol 22: 598–600. Lucchiari S, Pagliarani S, Corti S et al. (2008). Colocalization of ribonuclear inclusions with muscle blind like-proteins in a family with myotonic dystrophy type 2 associated with a short CCTG expansion. J Neurol Sci 275: 159–163. Lumsden T (1923). Observations on the respiratory centres in the cat. J Physiol 57: 153–160. Lyall RA, Donaldson N, Polkey MI et al. (2001). Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis. Brain 124: 2000–2013. MacDonald JR, Hill JD, Tarnopolsky MA (2002). Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy. Neurology 59: 1876–1880. Margolis ML, Howlett P, Goldberg R et al. (1994). Obstructive sleep apnea syndrome in acid maltase deficiency. Chest 105: 947–949. Markand ON, Kincaid JC, Pourmand RA et al. (1984). Electrophysiologic evaluation of diaphragm by transcutaneous phrenic nerve stimulation. Neurology 34: 604–614. Martinez-Rodriguez JE, Lin L, Iranzo A et al. (2003). Decreased hypocretin-1 (orexin A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 26: 287–290. Martin RJ, Sufit RL, Ringel SP et al. (1983). Respiratory improvement by muscle training in adult-onset acid maltase deficiency. Muscle Nerve 6: 201–203. Martin TJ, Sanders MH (1995). Chronic alveolar hypoventilation: a review for the clinician. Sleep 18: 617–634. Masa JF, Celli BR, Reisco JA et al. (1997). Non-invasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall disease. Chest 112: 207–213. Meechan Jones DJ, Wedzichia JA (1993). Comparison of pressure and volume preset nasal ventilator systems in stable chronic respiratory failure. Eur Respir J 6: 1060–1064. Mellies U, Ragette R, Schwake C et al. (2003). Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders. Neuromuscul Disord 13: 123–128. Merrill EG (1970). The lateral respiratory neurons of the medulla: their associations with nucleus ambiguus, nucleus retroambigualis, the spinal accessory nucleus and the spinal cord. Brain Res 24: 11–28.

SLEEP AND BREATHING IN NEUROMUSCULAR DISORDERS Mitchell RA (1980). Neural regulation of respiration. Clin Chest Med 1: 3–12. Mitchell RA, Berger AJ (1975). Neural regulation of respiration. Am Rev Respir Dis 111: 206–224. Morgan RK, McNally S, Alexander M et al. (2005). Use of sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am J Respir Crit Care Med 171: 269–274. Motta A, Guilleminault C (1978). Effects of oxygen administration in sleep-induced apneas. In: C Guilleminault, WC Dement (Eds.), Sleep Apnea Syndrome. Liss, New York, pp. 137–144. Mustfa N, Walsh E, Bryant V et al. (2006). The effect of noninvasive ventilation on ALS patients and their caregivers. Neurology 66: 1211–1217. Nathan PW (1963). The descending respiratory pathway in man. J Neurol Neurosurg Psychiatry 26: 487–499. Newsom-Davis J (1974). Control of muscles in breathing. In: JG Widdicombe (Ed.), Respiratory Physiology: MTP International Review of Science. Vol. 2. Butterworth, London, pp. 221–246. Newsom-Davis J, Lyall RA, Leigh PN et al. (2001). The effect of non-invasive positive pressure ventilation (NIPPV) on cognitive function in amyotrophic lateral sclerosis (ALS): a prospective study. J Neurol Neurosurg Psychiatry 71: 482–487. Nicolle MW, Rask S, Koopman WJ et al. (2006). Sleep apnea in patients with myasthenia gravis. Neurology 67: 140–142. Onders RP, Elmo MJ, Dunkin B et al. (2008). Diaphragm Pacing Stimulation (DPS) System for ventilatory support in tetraplegia complete worldwide results of a prospective FDA trial. J Spinal Cord Med 31: 223–224. Parhad IM, Clark AW, Barron KD et al. (1978). Diaphragmatic paralysis in motor neuron disease. Report of two cases and a review of the literature. Neurology 28: 18–22. Park YD, Radtke RA (1995). Hypersomnolence in myotonic dystrophy: demonstration of sleep onset REM sleep. J Neurol Neurosurg Psychiatry 58: 512–513. Petrone A, Pavone M, Testa MB et al. (2007). Noninvasive ventilation in children with spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil 86: 216–221. Phillipson EA (1978a). Control of breathing during sleep. Am Rev Respir Dis 118: 909–939. Phillipson EA (1978b). Respiratory adaptations in sleep. Ann Rev Physiol 40: 133–156. Phillipson EA, Bowes G (1986). Control of breathing during sleep. In: AF Fishman, NS Cherniack, JG Widdicombe (Eds.), Handbook of Physiology, Section 3. The Respiratory System, Vol. II, Part 2. American Physiological Society, Bethesda MD, pp. 649–690. Piper AJ, Sullivan CE (1994). Sleep-disordered breathing in neuromuscular disease. In: NA Saunders, CE Sullivan (Eds.), Sleep and Breathing. 2nd edn. Marcel Dekker, New York, pp. 761–786. Piper AJ, Sullivan CE (1996). Effects of long-term nocturnal nasal ventilation on spontaneous breathing during sleep in neuromuscular and chest wall disorders. Eur Respir J 9: 1515–1522.

1107

Plum F (1966). Breathlessness in neurological disease: the effects of neurological disease on the act of breathing. In: JBL Howell, EJM Campbell (Eds.), Breathlessness. Blackwell, Oxford, pp. 203–222. Quera-Salva MA, Guilleminault C, Chevret S et al. (1992). Breathing disorders during sleep in myasthenia gravis. Ann Neurol 31: 86–92. Rabatin JT, Gay PC (1999). Noninvasive ventilation. Mayo Clin Proc 74: 817–820. Ragette R, Mellies U, Schwake C et al. (2002). Patters and predictors of sleep disordered breathing in primary myopathies. Thorax 57: 724–728. Read DJC (1967). A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Med 16: 20–32. Ricker K, Koch MC, Lehmann-Horn F et al. (1994). Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness and cataracts. Neurology 44: 1448–1452. Robert D, Willig TN, Paulus J et al. (1993). Long-term nasal ventilation in neuromuscular disorders: report of a consensus conference. Eur Respir J 6: 599–606. Rosenow EC, Engel AG (1978). Acid maltase deficiency in adults presenting as respiratory failure. Am J Med 64: 485–491. Roth T, Rippon GA, Arora S (2008). Armodafinil improves wakefulness and long-term episodic memory in CPAPadherent patients with excessive sleepiness associated with obstructive sleep apnea. Sleep Breath 12: 53–62. Saadeh PB, Cristafulli CF, Sosner J et al. (1993). Needle EMG of the diaphragm: a new technique. Muscle Nerve 16: 323–325. Sander HW, Tavoulareas GP, Chokroverty S (1996). Heatsensitive myotonia in proximal myotonic myopathy. Neurology 47: 956–962. Sander HW, Saadeh PB, Chandswang N et al. (1999). Diaphragmatic denervation in intensive care unit patients. Electromyogr Clin Neurophysiol 39: 3–5. Shintani S, Shiozawa Z, Shindo K et al. (1989). Sleep apnea in well-controlled myasthenia gravis. Rinsho Shinkeigaku 29: 547–553. Sivak ED, Salanga VD, Wilbourn AJ et al. (1981). Adultonset acid maltase deficiency presenting as diaphragmatic paralysis. Ann Neurol 9: 613–615. Sivak ED, Shefner JM, Mitsumotor H et al. (2001). The use of non-invasive positive pressure ventilation (NIPPV) in ALS patients. A need for improved determination of intervention timing. Amyotroph Lateral Scler Other Motor Neuron Disord 2: 139–145. Spalding JMK, Opie L (1958). Artificial respiration with the Tunnicliffe breathing jacket. Lancet 1: 613–615. Speier JL, Owen RR, Knapp M et al. (1987). Occurrence of post-polio sequelae in an epidemic population. In: LS Halstead, DO Wiechers (Eds.), Research and Clinical Aspects of the Late Effects of Poliomyelitis. March of Dimes Birth Defects Foundation, White Plains, NY, pp. 39–48. Steljes DG, Kryger MH, Kirk BW et al. (1990). Sleep in postpolio syndrome. Chest 98: 133–140.

1108

S. CHOKROVERTY

Stepansky R, Weber G, Zeitlhofer J (1996). Sleep apnea in myasthenia gravis. Wien Med Wochenschr 146: 209–210. Striano S, Meo R, Bilo L et al. (1983). Sleep apnea syndrome in Thomsen’s disease. A case report. Electroencephalogr Clin Neurophysiol 56: 323–325. Strumpf DA, Millman RP, Hill NS (1990). The management of chronic hypoventilation. Chest 98: 474–480. Sugie M, Ando N, Veno S (2006). Usefulness of polysomnography at an early stage of amyotrophic lateral sclerosis. Rinsho Shinkeigaku 46: 297–300. Sullivan CE (1980). Breathing in sleep. In: J Orem, CD Barnes (Eds.), Physiology in Sleep. Academic Press, New York, pp. 213–272. Tabachnik E, Muller NL, Bryant AC et al. (1981). Changes in ventilation and chest wall mechanics during sleep in normal adolescents. J Appl Physiol 51: 557–564. Talbot K, Stradling J, Crosby J et al. (2003). Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord 13: 357–364. Tanner CM (1980). Respiratory dysfunction and peripheral neuropathy. In: WJ Weiner (Ed.), Respiratory Dysfunction in Neurologic Disease. Futura, Mount Kisco, NY, pp. 83–112. Testa MB, Pavone M, Bartini E et al. (2005). Sleep disordered breathing in spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil 84: 666–670. Tobin MJ (1994). Mechanical ventilation. N Engl J Med 330: 1056–1061.

Van Kralingen KW, Ivanyi B, Van Keimpema ARJ et al. (1996). Sleep complaints in postpolio syndrome. Arch Phys Med Rehabil 77: 609–611. Varrato J, Siderowf A, Damiano P et al. (2001). Postural change of forced vital capacity predicts some respiratory symptoms in ALS. Neurology 57: 357–359. Wang SC, Ngai SH, Frumin MJ (1957). Organization of central respiratory mechanisms in the brainstem of the cat: genesis of normal respiratory rhythmicity. Am J Physiol 190: 333–342. Ward S, Chatwin M, Heather S et al. (2005). Randomized controlled trial of non-invasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnea. Thorax 60: 1019–1024. Weil J, Byrne-Quinn E, Sodal I et al. (1970). Hypoxic ventilatory drive in normal man. J Clin Invest 49: 1061–1072. White DP (1990). Ventilation and the control of respiration during sleep: normal mechanisms, pathologic nocturnal hypoventilation, and central sleep apnea. In: RJ Martin (Ed.), Cardiorespiratory Disorders During Sleep. Futura, Mount Kisco, NY, pp. 53–108. White DP, Douglas NJ, Pickett CK et al. (1982). Hypoxic ventilatory response during sleep in normal premenopausal women. Am Rev Respir Dis 126: 530–533.