NMD are a heterogeneous group of disorders and patients may present with varying degrees of respiratory muscle weakness affecting ventilation. A full array of sleep related breathing abnormalities have been reported including: airflow limitation, hypoventilation, upper airway obstruction, and central apnoea. However, the type and severity of SDB is most influenced by the primary disorder, age of the patient, and the type and extent of the muscles involved ().
Neuromuscular Disorders and Type of Sleep Disordered Breathing
To understand the pathophysiology of SDB in children with NMD, it is useful to review the effects of sleep on breathing in normal individuals and how these may affect children with respiratory muscle weakness, particularly during REM sleep. The ventilatory response plays an important role in regulating breathing in sleep and includes several components. The first are the sensors, including central and peripheral chemoreceptors and mechanoreceptors. The chemoreceptors relay minute changes in PaO2, PaCO2, and pH through afferent neurons to a central controller within the brain stem where the information is integrated. From there, afferent neurons relay their output to the effectors (upper airway dilators, intercostals, diaphragm, etc.), that produce the response. In such a way, the feedback mechanism can tightly regulate any change in the blood gas by changing minute ventilation.
Sleep in healthy individuals is associated with a reduction in the slope of the ventilatory responses to both hypercapnia and hypoxia compared to wakefulness (17
). This phenomenon is responsible for the reduction in minute ventilation by 1–2 litres per minute [LPM] and the increase in the PaCO2
by 2–8 mmHg and decrease in PaO2
by 2–8 mmHg, observed in sleep. The drop in minute ventilation progresses through sleep stages reaching it maximal attenuation in the phasic stage of REM sleep (19
Traditional tests of the ventilatory chemoreceptor response assess the minute ventilation response to applied hypercapnia and hypoxia. These tests can be problematic in NMD patients due to muscular weakness, fatigue, and inability to tolerate prolonged hypercapnia or hypoxia.
To overcome these limitations, a technique that does not require prolonged respiratory muscle effort can be used. This method, known as the mouth occlusion test (P 0.1
) measures the pressure at the mouth 100 ms after inspiratory occlusion under various degrees of hypercapnic or hypoxic conditions. Except for some subjects with Arnold-Chiari malformation type 2, noted to have low central and peripheral chemoreceptor sensitivity (20
), and some subjects with myotonic dystrophy found to have a central controller defect (21
), children with NMD were found to have a normal ventilatory drive and are not considered to have either a chemoreceptor or a central controller abnormality during wakefulness or sleep (22
The most important impact of sleep on patients with NMD is the effect on respiratory muscle function. In healthy subjects, sleep onset is associated with the reduction in tonic activity of the upper airway dilator muscles, particularly the genioglossus. This reduction progresses to a maximum in REM sleep and can increase upper airway resistance leading to SDB in susceptible patients (23
). Similar tonic reduction occurs to intercostal muscles leading to a reduction in functional residual capacity (FRC) and oxygen reserves. The diaphragm on the other hand, maintains normal activity in NREM sleep but gradually losses tonic activity in REM sleep with the appearance of clustered pauses that contributes to further reduction in FRC in this phase. Thus, healthy subjects are susceptible to respiratory disturbances and gas exchange abnormalities particularly in REM sleep when upper airway resistance is increased and FRC is decreased. This susceptibility is amplified in NMD patients due to pre existing respiratory muscles weakness and could explain the high prevalence of SDB in these patients.
A primary upper respiratory muscle involvement may be present in children with cerebral palsy, poliomyelitis, myotonic dystrophy, myelomeningocele, hereditary sensory and motor neuropathies (Charcot-Marie-Tooth), and certain congenital myopathies, particularly due to bulbar involvement. Intercostal muscle involvement is common in most NMD with generalized muscle weakness, and diaphragm involvement is present in spinal muscular atrophy, poliomyelitis, high cervical cord injury, and certain mitochondrial, metabolic and congenital myopathies as well as in Duchenne and Becker muscular dystrophies.
Children with NMD may also be subject to common known risks for SDB in children, adenotonsillar hypertrophy and obesity. In such children, SDB may be more severe in comparison to otherwise healthy individuals with adenotonsillar hypertrophy and or obesity alone.
As mentioned above, the type and severity of SDB is most influenced by the primary disorder and the type and extent of the muscles involved. For example, in patients with only upper airway and intercostal muscles weakness but intact diaphragm function, the increased negative intrathoracic pressure induced by the diaphragm during inspiration will lead to upper airway narrowing and airway obstruction due to inability of the upper airway musculature to dilate the airway. The above condition would be typical of a patient with Duchenne muscular dystrophy in early stages of the diseases (). However, with progression of the disease and with diaphragm involvement, a lower negative intra thoracic pressure will be generated that will not be sufficient to fully collapse the upper airway. Thus, the predominant respiratory event will be obstructive hypopnoea and hypoventilation ( and ).
Figure 1 A 60 seconds recording during REM sleep of a 13 year old male with Duchenne muscular dystrophy demonstrating an obstructive apnoea (OA) event lasting 9 seconds. Note absence of flow in nasal pressure transducer (NPAF) while chest and abdomen paradoxical (more ...)
Figure 2 A 60 seconds recording during REM sleep of a 14 year old male with Duchenne muscular dystrophy demonstrating obstructive hypoventilation (OH) event lasting 25 seconds. Note a reduction of flow in nasal pressure transducer (NPAF) while chest and abdomen (more ...)
Figure 3 An 8½ hour hypnogram of the patient from demonstrating sleep stage transitions. Respiratory events include mostly obstructive hypopnoeas (OH). However, obstructive apnoeas (OA) and central apnoeas (CA) are also noted. Respiratory events (more ...)
Lung mechanics change during sleep and result in respiratory deficiencies in patients with NMD particularly due to an increase in chest wall compliance and changes in diaphragm position and strength (24
). In order to maintain adequate ventilation, patients compensate by recruiting not only accessory inspiratory muscles but also abdominal muscles. Contraction of abdominal muscles produces expiration below FRC allowing passive inspiration with recoil of the chest wall. Such changes in muscle activity increase work of breathing. Thus, to improve energy expenditure and maintain adequate minute ventilation simultaneous changes in respiratory patterns are noted and include a rise in respiratory rate with reciprocal drop in tidal volume.
In addition, patients with NMD are found to have low muscle endurance and are constantly at risk of developing respiratory muscle fatigue resulting in SDB (25
). In this regard, the tension-time index of the respiratory muscles (TTmus) has been suggested as a sensitive test to assess how close a subject is to respiratory fatigue/failure. (26
). Attempts to improve muscle endurance by day time respiratory muscle training has been studied with various results. However, it is unknown if such techniques are useful to improve SDB
Finally, a poor and ineffective cough is found in all patients with respiratory muscle weakness. This can be demonstrated by reduced maximal inspiratory and expiratory static pressures (MIP and MEP, respectively). These patients are at increased risk of developing mucus plugging and ventilation perfusion inequalities from airway secretions, particularly during sleep when the cough reflex is suppressed due to a higher arousal threshold.
In normal subjects, progression to deeper sleep stages is associated with a higher arousal threshold and reduced arousal response to various stimuli such as: hypercarbia, hypoxemia, and resistive loading. This poor response in conjunction with normal reduction in chemosensitivity noted in sleep can increase the risk for SDB in subjects with altered upper airway function or generalized respiratory muscle weakness.
The most frequently encountered musculoskeletal complication in NMD children is scoliosis. Scoliosis contributes to reduced chest wall and lung compliance and increases the risk for SDB by mechanisms of hypoventilation, atelectasis and ventilation perfusion mismatch, and increased work of breathing and fatigue. In most cases repair of scoliosis by stabilization of the spine reduces morbidity by preventing worsening of scoliosis and preserving chest and lung mechanics (27
Obesity is a known risk factor for SDB in children today and exacerbates many of the basic causes of SDB (14
). Children with specific NMD such as Duchenne muscular dystrophy and myotonic dystrophy may have an increased metabolic risk for cardiovascular disease including: high BMI, low levels of high-density lipoprotein cholesterol, and high triglyceride, due to decreased motor activity and exercise (16
Altered Brain Structure or Function
Several NMD including hypoxic ischemic encephalopathy, Arnold-Chiari malformation type 2, mitochondrial myopathy, and myotonic dystrophy are associated with alterations in either brain structure or function. These conditions may lead to significant SDB ranging from central apnoea and periodic breathing to the spectrum of OSA.