A helpful approach toward understanding how specific neuromuscular diseases affect the respiratory system is to localize the anatomic involvement of the respiratory system. A detailed description of the neuroanatomy of respiration is outside the scope of this chapter and is covered elsewhere in this text. In general, however, neuromuscular disorders can be broken down into disorders that involve the upper motor neuron, the lower motor neuron, or the muscle itself.
Lesions that arise in the cerebral cortex, brainstem, or spinal cord are classified as upper motor neuron lesions and are characterized by an increase in muscle tone or spasticity, the presence of an extensor plantar response, and increased reflex activity. Lesions in the lower motor neuron system demonstrate flaccidity, depressed reflexes, muscular fasciculations, and atrophy. The location and character of the patient’s weakness may enable one to identify the exact site of the lesion in the lower motor neuron system (i.e., the anterior horn cell, the peripheral nerve, the neuromuscular junction, or the muscle itself).
The following describes the effect of specific neuromuscular disease on the respiratory system and makes recommendations for treatment.
Upper Motor Neuron Lesions
A variety of disorders in which the primary pathology is centered on upper motor neurons have significant respiratory consequences. Each is discussed below.
Hemispheric ischemic strokes reduce chest wall and diaphragm movement on the side contralateral to the cerebral insult. Decreased diaphragm excursion with stroke correlates with diaphragmatic cortical representation identified by transcranial magnetic stimulation. Bilateral hemispheric strokes are also associated with Cheyne–Stokes respiration, which is progressive hyperventilation alternating with hypoventilation and ending in apnea. This breathing pattern may result from increased responsiveness to carbon dioxide as result of interruption of normal cortical inhibition. The significance of Cheyne–Stokes respiration to stroke remains unclear but appears to be more common with bilateral than unilateral insults. Besides its effects on an alteration of breathing pattern, up to 50% of patients with strokes may have signs of pulmonary aspiration due to dysfunction of upper airway muscles that protect the airway.
The degree of respiratory impairment depends on the level and extent of the spinal cord injury. High cervical cord lesions (C1–C3) cause paralysis of the diaphragmatic, intercostal, scalene, and abdominal muscles. Because all respiratory muscle activity is lost except for accessory and bulbar muscle function, high cervical cord injuries almost always require ventilatory assistance. In some patients, spontaneous breathing can be accomplished by glossopharyngeal breathing or diaphragmatic pacing because the phrenic nerve motor neurons (C3–C5) remain intact.
Middle cervical cord (C3–C5) lesions destroy the phrenic motor neurons and prohibit the use of phrenic nerve pacing. Patients with more caudal lesions (i.e., C4–C5 level) have an improved chance to wean from ventilator support compared to those with more cranial lesions (40% of patients with C3 lesions remain ventilator dependent.). Patients with lower cervical (C6–C8) and upper thoracic (T1–T6) cord lesions have intact diaphragm and neck accessory muscle action, but have denervated intercostal and abdominal muscles. These patients usually require ventilatory support only during the period immediately after the injury and rarely require long-term ventilation. Despite this these patients still have increased mortality. In a group of spinal cord injury patients not requiring mechanical ventilation or tracheostomy followed prospectively for a median of 4.5 years, predictors of death included age, cardiac disease, diabetes, smoking history, and lower FEV1.47 The decline in FEV1 and FVC in these patients is related to aging, increasing BMI, smoking, persistent wheeze, and lower MIP.48 These data suggest that there are modifiable risk factors that can be altered to improve outcomes in those with spinal cord injuries that do not require mechanical ventilation.
In a study of C5 or lower spinal cord–injured patients, inspiratory muscle strength was reduced to approximately 60% of predicted but was dependent on the level of cord injury. In this study, PImax values in low cervical, midthoracic, and lower thoracic–upper lumbar lesions were 61%, 69%, and 75% of predicted, respectively, whereas PEmax values were 30%, 32%, and 54% of predicted, respectively. The lower PEmax values were explained by a paralysis of abdominal and intercostal muscles resulting in reduced cough and decreased clearance of bronchial secretions. Abdominal muscle paralysis probably accounts for an abnormally compliant abdomen in patients with lower spinal cord injury, which is in stark contrast to the 30% reduction in chest wall compliance believed due to abnormal rib cage stiffness.8
Patients with spinal cord injuries also have alterations in thoracoabdominal motion during tidal breathing that is further accentuated by changing from the erect to supine position. In quadriplegic patients with relatively intact diaphragm function, the distribution of respiratory muscle weakness results in paradoxical inward motion of the upper rib cage during inspiration owing to weakness of the parasternal and scalene muscles. This pattern of abnormal thoracoabdominal movement is more marked in the supine than in the upright position. Patients with high quadriplegia (above C3–C5) may be able to sustain short periods of spontaneous respiration because of inspiratory activity of the sternocleidomastoid and trapezius muscles. Phasic inspiratory EMG activity has been observed in the platysma, mylohyoid, and sternohyoid muscles. Analysis of ribcage motion in these patients shows increased upper rib cage diameter, due to the inspiratory action of the neck accessory muscles pulling the sternum cranially and expanding the upper rib cage.
The distribution of muscle paralysis in low cervical cord spinal patients also has a profound effect on the performance of forced expiratory maneuvers. In contrast to healthy normal subjects, in whom VC is moderately decreased on assuming the supine position, in quadriplegic patients there is a paradoxical increase in VC in the supine compared to seated position without a significant increase in TLC. In 14 quadriplegic patients (C4–C7), there was a 16% increase in VC on changing from the upright to supine position and a reduction in RV (29%) and TLC (on average, 6%).27 The mechanism believed to be responsible for the increase in VC in supine quadriplegic patients is the hydrostatic effect of abdominal contents, causing cephalad displacement and diaphragm lengthening and thereby placing the diaphragm on a more favorable portion of its length–tension curve. The use of elastic binders when quadriplegics assume upright posture has been advocated to prevent the increase in abdominal compliance. Abdominal binding may have physiologic benefit by maintaining diaphragm precontraction length in a more optimum position on its length–tension curve.49
It was previously believed that all expiratory muscles were paralyzed in lower cervical cord injuries. However, studies of C5 to C8 quadriplegics indicate that phasic EMG activity of the clavicular portion of the pectoralis major is associated with a marked decrease in the anteroposterior diameter of the upper rib cage.50 This portion of the pectoralis muscle receives innervation from the C5 to C6 cord level. With the arms placed at the subject’s side, contraction of the caudate head of the pectoralis major causes caudal displacement of the manubrium sterni and upper rib cage. This expiratory action has been shown to decrease expiratory reserve volume (ERV) by 60% when the shoulders are held in abduction. After 6 weeks of pectoralis muscle isometric training, patients with low quadriplegia can have a marked increase in maximum pectoralis muscle isometric strength and a significant reduction in ERV.51 Conceivably, therefore, training of this muscle could improve the effectiveness of cough in patients with low spinal cord injury.
In the months following spinal cord injury, pulmonary function typically improves. In patients with spinal injuries below the C5 level, VC is approximately 30% of predicted in the first week after injury, but increases to 45% of predicted by the fifth week and by the fifth month to approximately 60% of predicted.52 Improvements in VC have been attributed to spasticity developing in previously flaccid intercostal and abdominal muscles thereby increasing the rigidity of the thorax and abdomen and improving diaphragm force generation.
There is a role for corticosteroid use in the acute management of spinal cord injury. Methylprednisolone given as a bolus 30 mg/kg followed by a 24-hour infusion at 5.4 mg/kg/h has been shown to improve motor function at 6 weeks, 6 months, and 1 year, but only in those received the drug within 8 hours of injury.53 A subsequent study compared methylprednisolone infusion (5.4 mg/kg/h) for 48 hours to 24 hours after the administration of a bolus (30 mg/kg).54 There was no difference in functional outcome between the two infusion periods except in those where the bolus dose was given between 3 to 8 hours after the injury. If the methylprednisolone was started between 3 to 8 hours after the injury, then those that received the infusion for 48 hours did have improved motor function at 6 weeks and 6 months. There were higher rates of pneumonia and sepsis in the 48-hour infusion group but mortality was not different.54 No trial has shown a mortality benefit, and it should be recognized that the outcome measured was an improvement in the functional independence measure (FIM) score and not a return to normal motor function.
Parkinson disease is due to degeneration of neurons in the substantia nigra and has a prevalence in the United States of approximately 200 cases per 100,000 people. Parkinson disease can be either primary (e.g., idiopathic) or secondary, as in postencephalitic parkinsonism associated with the influenza pandemic, or part of a more generalized disorder, such as multiple system atrophy or drug abuse with MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine).
Parkinson disease has been thought to be a purely motor disorder but recently non-motor findings are being associated with Parkinson disease, which can predate motor symptoms.55 These findings have led to speculation that Parkinson disease could alter respiratory control at the level of the brainstem. A study in 15 subjects with early Parkinson disease and normal respiratory flow and volumes found that 7/15 had an abnormal ventilatory response while 11/15 has an abnormal occlusion pressure response (P0.1) to hypercapnic challenge testing suggesting abnormal respiratory control.56
Respiratory abnormalities are common in Parkinson disease, with pneumonia being the most common cause of death. A substantial problem with Parkinson disease is glottic muscle dysfunction.57 An abnormal flow–volume loop contour showing flow oscillations commonly occurs. On direct fiberoptic visualization of the upper airway, these oscillations correspond to rhythmic involuntary movements of glottic and subglottic structures. Physiologic evidence of upper airway obstruction may be present. In addition to the presence of oscillations in flow, a rounding off of the peak of the midexpiratory flow–volume curve, a lowered peak expiratory flow rate, and a delayed appearance of peak expiratory flow have been observed in Parkinson patients. These results have been interpreted as evidence for less coordinated or less “explosive” respiratory muscle contractions.43,45
Patients with mild-to-moderate Parkinson disease are able to perform simple single respiratory efforts (e.g., measurements of lung volume and maximum static inspiratory pressures) but have difficulty performing more complex, repetitive ventilatory efforts (i.e., sustaining inspiratory resistive loads to exhaustion and performing maximum unloaded breathing efforts). Performance of repetitive respiratory tasks is associated with an increased work of breathing when compared to that of an age-matched control group. These findings are similar to derangements in task performance exhibited by peripheral skeletal muscle groups in Parkinson patients.26
Treatment significantly improves neurologic scores, maximum expiratory pressures, and peak inspiratory flow. A recent meta-analysis has demonstrated that levodopa improves peak expiratory flow and FVC in Parkinson disease.28 Deep brain stimulation by stereotactically placing electrodes into the suprathalamic nucleus or the globus pallidus nucleus has been shown to be equally effective when treating medically resistant patients.58 The electrodes produce a low-voltage high-frequency stimulation that results in inhibition of the neurons in the nucleus. Although the effect on respiratory function has not been directly studied, this procedure has been shown to improve motor function and quality of life.59
MS is a demyelinating disorder of the central nervous system, characterized clinically by remissions and relapses of clinical symptoms due to disseminating CNS lesions. MS is the most common neurologic disease afflicting young adults, with an estimated prevalence of 250,000 to 300,000 cases in the United States in 1990. The cause of the disease is unknown, although epidemiologic evidence points to genetic and environmental factors. Classic clinical symptoms include paresthesia, motor weakness, diplopia, blurred vision, dysarthria, bladder incontinence, and ataxia.
Because MS can cause focal lesions anywhere in the central nervous system, different patterns of respiratory impairment can occur. Impairment of the respiratory centers and the medulla can cause failure of automatic breathing (Ondine’s curse), apneustic or neurogenic pulmonary edema. The three most common respiratory manifestations of MS are respiratory muscle weakness, bulbar dysfunction, and abnormalities in respiratory control.
Acute respiratory failure rarely occurs in this disease, but it can occur because of severe demyelination of the cervical cord. Diaphragmatic paralysis resulting in respiratory insufficiency has also been reported. Even with severe disability and impaired respiratory muscle strength, patients with MS seldom complain of dyspnea. This paucity of respiratory complaints may be due to restricted motor activities and greater expiratory than inspiratory muscle dysfunction. Clinical signs that may be helpful in predicting respiratory muscle impairment are weak cough and inability to clear secretions, limited ability to count on a single exhalation, and upper extremity involvement. Advanced MS is frequently complicated by aspiration, atelectasis, and pneumonia.
In a group of 38 patients that were not bedridden or wheelchair bound without bulbar involvement and a diagnosis of MS for 9.2 years, there was a significant decrease in the maximal inspiratory pressure (MIP) and the maximal expiratory pressure (MEP) to 77% and 60% predicted respectively.60 In a group of 21 ambulatory stable MS patients, the percent predicted MEP was significantly reduced when compared to age-matched healthy controls (69.4% vs. 85.6%, p = 0.03). Furthermore, these patients had a greater change in the upright versus supine FVC compared to healthy controls (262 vs. 98 mL, p = 0.001).61 Not surprisingly the MEP had an inverse correlation (r = –0.47; p = 0.04) with MS functional scores. These data suggest that even in ambulatory MS patients without respiratory symptoms respiratory muscle weakness is present, and should be monitored periodically (particularly MEP). In 60 bedridden MS patients, pulmonary function studies revealed severely decreased MIP (47% predicted), MEP (30% predicted), and VC that was 80% of predicted. In those with a VC below 80% predicted, the MIP and MEP were significantly lower than those with a normal VC.62 In all of these studies the MEP was more affected than the MIP, and the respiratory muscle weakness directly correlated with the severity of the subject’s overall neurologic function. Smeltzer et al. developed a pulmonary dysfunction index for patients with MS and found that it is correlated with MEP measurements. The score assesses the patient’s assessment of cough and ability to handle secretions, the examiner’s assessment of cough, and how high the patient can count on a single exhalation (Table 84-6). A subject with normal cough efficacy would have a score of 4 while an individual with the most impairment would have a score of 11.63 Gosselink et al.29 examined the effect of respiratory muscle training (e.g., three sets of 15 expiratory contractions at 60% of MEP twice daily) on respiratory muscle strength and the subject’s pulmonary index score in a group of severe MS patients. At 3 months there was a statistically significant improvement in MIP, and although the MEP improved the p value was 0.07 compared to control patients. The pulmonary index was statistically better at 3 months and 6 months following expiratory muscle training but the FVC was not.29 A subsequent study in 17 ambulatory MS patients who underwent expiratory muscle training was able to statistically improve MEP but this did not improve pulmonary function or markers of cough effectiveness.64
Table 84-6Pulmonary Dysfunction Index for Multiple Sclerosis Patients |Favorite Table|Download (.pdf) Table 84-6Pulmonary Dysfunction Index for Multiple Sclerosis Patients
|Clinical Signs || ||Score |
|Patient rating |
|1. History of difficulty handling secretions ||No ||1 |
| ||Yes ||2 |
|2. Cough ||Normal ||1 |
| ||Weak ||2 |
|Examiner rating |
|3. Strength of cough when asked to cough voluntarily as hard as possible ||Normal ||1 |
| ||Weak ||2 |
| ||Very weak/inaudible ||3 |
|4. Value reached when patient counts aloud on a single exhalation after a maximal inspiratory effort ||>30 ||1 |
| ||20–29 ||2 |
| ||10–19 ||3 |
| ||<9 ||4 |
Treatment of MS has traditionally included the use of immunosuppressive agents such as high-dose corticosteroids, cyclophosphamide, and azathioprine. Other treatments have included intravenous immunoglobulin (IVIG), plasmapheresis, and recently medications such as glatiramer, mitoxantrone, and interferon beta (INFβ-1a).65 The choice of therapy depends on the clinical situation and whether relapsing–remitting or secondary progressive disease is being treated.
Most of the available data has focused on treating the acute attacks of the relapsing–remitting form of the disease. In one randomized placebo-controlled study, treatment with 10 days of high-dose oral methylprednisolone resulted in improved neurologic function, but there was no difference in the reoccurrence of future acute exacerbations.30 INFβ-1a has been shown in a multicenter, double-blind placebo-controlled study to decrease the relapse rate after 1 and 2 years of therapy.66 Both the American Academy of Neurology and the MS Council for Clinical Practice Guidelines recommend the use of INFb for the treatment of acute attacks in relapsing–remitting MS.65 The use of IVIG has been controversial due to a lack of randomized controlled trials, but it does appear that IVIG can both delay and prevent the occurrences of acute attacks in the relapsing and remitting form of the disease in some patients.67 Achiron et al.68 has shown that in patients given IVIG within the first 6 weeks of neurologic symptoms there was a significant reduction in disease activity as measured by MRI imaging and neurologic symptoms. However, there was no significant additional benefit to adding IVIG to methylprednisolone therapy, and a recent study looking at the effect of IVIG use for 27 months in secondary progressive MS failed to show any difference in progression of disability.69
Lower Motor Neuron Lesions
The spectrum of disorders of lower motor neurons affecting respiration is considered below.
In the early part of the 20th century, poliomyelitis was the most common cause of lower motor neuron disease in the United States. Paralytic poliomyelitis is the most devastating respiratory presentation of poliomyelitis infection and is preceded by a period of fever and mild illness. After several days of mild fever and myalgia, symptoms disappear; then, 5 to 10 days later, fever reoccurs with signs of meningeal irritation and asymmetric flaccid paralysis. Respiratory motor nuclei may be directly involved, resulting in diaphragmatic or other respiratory muscle dysfunction. In 6% to 25% of paralytic cases, bulbar symptoms may arise, increasing the risk of upper airway obstruction, pooling of pharyngeal secretions, and pulmonary aspiration. Moreover, the central respiratory centers can be directly affected, resulting in irregular respirations.70
In contrast to GBS, sensation is intact. Tendon reflexes are significantly diminished or absent. Cerebrospinal fluid analysis shows a pleocytosis associated with mild protein elevation, and electroneuromyography shows widespread patchy denervation.
Fifteen to 30% of adults with paralyzing infection die and treatment overall is supportive. Many patients require aggressive ventilatory and hemodynamic support during the acute phases of their illness. As temporarily damaged nerve cells regain function, recovery begins and may continue for as long 6 months. Paralysis persisting beyond that point is permanent, however, and may be associated with complaints of severe pain, which sometimes recurs years after the illness.
Some patients develop progressive muscle weakness 20 to 30 years after the initial infection. This has been termed “postpolio syndrome.”70 Symptoms vary from mild-to-moderate deterioration of function, with fatigue, joint pain, or weakness that may progress to muscle atrophy. The most common symptom is muscle pain, (typically after exertion) which occurs in 36% to 86% of the patients. The weakness tends to progress slowly, with an average decline in muscle strength of approximately 1% per year. The pathogenesis appears to be due to dysfunction of surviving motor neurons, with slow disintegration of axonal terminals eventually leading to muscle denervation. Although respiratory complaints are common in this disorder, significant hypoventilation with elevated PaCO2 rarely occurs.71 Respiratory failure is more common in those that required mechanical ventilation during the acute poliomyelitis phase.
Amyotrophic Lateral Sclerosis
ALS is a chronic, degenerative neurologic disorder characterized by death of motor neurons in the cerebral cortex and spinal cord. The result is a combination of upper and lower motor neuron dysfunction, manifested by spasticity and hyperreflexia muscle wasting, weakness, and fasciculations. It has an incidence of approximately 1 to 2 cases per 100,000 people. Males are more commonly affected than females—by a 2:1 ratio. Most cases are sporadic, but approximately 10% of cases are familial, and there is no difference in response to therapy in those with familial ALS (FALS) or sporadic cases.72 ALS is now recognized as a multisystem disorder that can initially present as cognitive defects prior to the development of motor symptoms and is known as ALS with frontotemporal degeneration (FTLD). Additionally, some FTLD patients go on to develop motor symptoms consistent with ALS. The main pathologic finding is abnormal accumulation of insoluble proteins in the cytoplasm of motor neurons.73 Recently, it was discovered that two of these proteins are TAR DNA–binding protein 43 (TDP-43), and fused in sarcoma/translated in liposarcoma (FUS/TLS). Mutations in the genes encoding for these proteins have been found in FALS, SALS, and FTLD, but not in ALS associated with mutations in the superoxide dismutase-1 (SOD-1) gene on chromosome 21.73 Even in FALS genetic mutations have been discovered in only about 30% of the cases and most remain unexplained.73
The usual clinical presentation is progressive weakness of the distal extremities, although severe respiratory muscle weakness, particularly intercostal muscle and diaphragm weakness, has resulted in some ALS patients presenting with respiratory insufficiency as the initial symptom. Respiratory muscle impairment is more evident in the advanced stages of the disease. Abnormalities in pulmonary function are apparent, even in patients with mild extremity weakness. Progression of respiratory impairment is much faster in ALS than in other chronic neuromuscular disorders, and serial lung function studies in ALS patients show progressive reduction in FVC and MVV. In contrast to patients with other neurologic disorders, however, patients with ALS usually have a normal or slightly elevated transpulmonary pressures at FRC, and RV is usually increased and continues to rise as the disease progresses with maintenance of a normal TLC.74 These changes are thought to be due to earlier involvement of the abdominal musculature, with preservation of intercostal and diaphragm function. Support for these physiologic findings comes from pathologic studies that show a more pronounced loss of motor neurons in the lumbosacral and lower thoracic spinal segments than in the upper and midthoracic regions.
The use of respiratory muscle testing has been used to help determine the prognosis and help clinicians decide when to initiate ventilatory assistance. The sniff nasal inspiratory pressure (SNIP) test is theoretically easier than the FVC maneuver for the ALS patient, because a tight seal around a mouthpiece is not required. A sniff is a short voluntary inspiratory maneuver, which has been shown to correlate with invasive nonvolitional tests of diaphragm strength. A SNIP <40 cm H2O was found to predict nocturnal hypoxemia better than FVC. More importantly, a SNIP <40 cm H2O was associated with a hazard risk for death of 9.1 with a median 6-month survival of 50%. Surprisingly, in those with SNIF <40 cm H2O 66% had an FVC above 50% and the hazard risk for death was 13.6 in this group.75 When comparing the two techniques for the ability to predict 6-month mortality, the SNIP test had a sensitivity of 97% and specificity of 79% while the FVC was 58% sensitive and 96% specific.75 A separate study also has shown that in ALS patients without bulbar involvement SNIP was superior to both VC and MIP in predicting the development of respiratory failure as defined by hypercapnia (PaCO2 >45 mm Hg) with a specificity of 85% and sensitivity of 81%.76 In patients with significant bulbar involvement, there was no single test of respiratory muscle function that reliably predicted the development of respiratory failure.76
The shape of the flow–volume curve may also pinpoint the subgroup of ALS patients with greater weakness of the expiratory muscles. In patients with severe expiratory muscle weakness, the flow–volume curve near RV shows a sharp drop in flow such that the maximum expiratory curve has a concave appearance. This group of ALS patients usually has lower maximum expiratory pressures, smaller VC, reduced expiratory reserve volume, and a higher RV than do ALS patients with more-normal–appearing flow–volume curves.74 A prospective study of 55 ALS patients demonstrated that the peak expiratory flow time increased over baseline at a rate of 4.7% per month while the decline in the FVC was only 1.2% per month. The authors concluded that the peak expiratory flow rate can be used as an earlier marker of pulmonary involvement from ALS.44
ALS is a progressive and uniformly fatal neuromuscular disease and all patients will eventually develop respiratory failure, which will necessitate the discussion of mechanical ventilation (see Chapter 85). Currently, guidelines from the American Academy of Neurology recommend treatment with noninvasive mechanical ventilation once the FVC is below 50% of predicted, MIP <–60 cm H2O, SNIP <40 cm H2O, or have orthopnea.77 Ventilation with bilevel positive airway pressure has been shown to increase both survival and quality of life in patients with ALS, while those with orthopnea seemed to derive the most benefit.78–81 A randomized controlled trial of noninvasive ventilation compared to standard of care in 41 patients with ALS that had orthopnea with PImax <60% predicted or symptomatic daytime hypercapnia confirmed these findings. The investigators found that overall survival was prolonged in the noninvasive ventilation group (219 [75–1382] vs. 171 [1–878]) days; p = 0.006], with the greatest benefit in those without severe bulbar symptoms.80 There was also improved quality of life in the noninvasive ventilation group overall but the effect was seen only in those without severe bulbar symptoms.80
Due to weakness of both inspiratory and expiratory muscles, ALS patients have diminished cough reflex. Impaired cough becomes even more important when airway secretions are increased during respiratory infections or in those with bulbar symptoms. One group of investigators prospectively followed 53 patients with ALS for 1 year and found that peak cough flow (PCF), peak cough flow/peak velocity time (PCF/PVT), and severity of bulbar symptoms were most predictive of ineffective cough during a respiratory infection.82 A mechanical insufflation–exsufflation (MI-E) device can be used to augment cough in patients by providing positive airway pressure at 40 to 45 cm (insufflation) for a few seconds and then suddenly switching to 40 to 45 cm of negative pressure (exsufflation). This creates high volume expiratory airflow that can be timed with coughing during exsufflation. MI-E increased PCF by 19% in ALS subjects with bulbar symptoms and 21% in those without bulbar symptoms. Treatment of the other respiratory complications of ALS includes a high index of suspicion for impaired swallowing due to bulbar involvement. Difficulty in swallowing food or even saliva predisposes ALS patients to a markedly high risk for pulmonary aspiration. Special swallowing precautions, earlier placement of enteral feeding tubes, or antisialogues may be required.
Currently, the antiglutamate drug riluzole is the only pharmacologic agent approved for use in ALS. This drug has been shown to induce a significant improvement in median survival from 11.8 to 14.8 months and decrease the rate of deterioration in muscle strength in comparison to a placebo.83,84
However, despite any pharmacologic interventions, ALS is a progressive and fatal neuromuscular disease and all patients will eventually develop respiratory failure and ventilatory assistance will therefore need to be considered. In those without bulbar involvement, noninvasive forms of ventilatory support are clearly indicated and will provide both a survival and quality-of-life benefit. Airway intubation may be required because of bulbar dysfunction further impairing cough and the inability to clear secretions. Long-term invasive ventilatory support is infrequently applied in ALS patients, but decisions must be made on an individual basis.
Disorders of Peripheral Nerves
Phrenic nerve dysfunction can be a significant cause of respiratory weakness in patients with neuromuscular diseases due to a variety of causes.
Unilateral or bilateral diaphragm paralysis following phrenic nerve injury can result from cardiac surgery, trauma, mediastinal tumors, infections of the pleural space, or forceful manipulation of the neck. Phrenic nerve injury during open-heart surgery is one of the most common causes of unilateral and bilateral diaphragm paralysis and is due either to cold exposure during cardioplegia or to mechanical stretching of the phrenic nerve during surgery. Diaphragm paralysis may also be seen with a variety of motor neuron diseases, myelopathies, neuropathies, and myopathies.
Bilateral diaphragm paralysis is characterized by a severe restrictive ventilatory impairment, with VC being frequently less than 50% of predicted in the upright position and a further reduction of 25% or more in VC in the supine position. TLC is also markedly decreased, as well as FRC and static pulmonary compliance. In most patients with nontraumatic bilateral diaphragm paralysis, the most important clinical feature is orthopnea out of proportion to the severity of the underlying cardiopulmonary disease.15
In patients with nontraumatic bilateral diaphragm paralysis, the diaphragm usually goes unrecognized until they present with cor pulmonale or cardiorespiratory failure. A chest radiograph showing elevation of both hemidiaphragms with volume loss and/or atelectasis at the lung bases is common. The diagnosis of bilateral diaphragm paralysis should be considered when any of the following four abnormalities is present: (1) a 40% or greater reduction in VC in the supine compared to upright position; (2) fluoroscopically observed paradoxical movements of both hemidiaphragms during a “sniff” test; (3) absence of phrenic latency or phrenic nerve conduction velocity tests or lack of EMG evidence of spontaneous diaphragm activity; and (4) transdiaphragmatic pressure two standard deviations below the expected mean for normal subjects with paradoxical inward abdominal motion during maximum inspiratory efforts.2,17,18,85
Because in most patients, bilateral diaphragm paralysis occurs in the context of global respiratory muscle impairment, measurements of PImax and PEmax may be sufficient to arouse suspicion of diaphragm paralysis as a cause of the patient’s complaints. With diaphragm paralysis, a marked reduction in PImax with preservation of PEmax should be found, and in general, there is a correlation between maximum inspiratory pressures and PdiSNIFF. Reductions in PdiSNIFF to less than 30 cm H2O are accompanied by orthopnea, a supine decrease in VC, and the presence of abdominal paradox. In most cases, the presence of severe bilateral diaphragm weakness can be diagnosed from physical examination, measurements of VC in the upright and supine positions, and PImax and PEmax. In cases where the diagnosis is uncertain, or when definite documentation is desired, measurement of transdiaphragmatic pressures, phrenic nerve conduction times, EMG activity, transdiaphragmatic pressures during phrenic nerve stimulation, or ultrasound imaging of the diaphragm may be performed.2 An elevation in PaCO2, particularly in the supine position in patients with diaphragm paralysis, has been reported, but is not consistent.
Hemidiaphragm paralysis is more common than bilateral paralysis and is usually diagnosed from unilateral elevation of the hemidiaphragm on chest radiograph. Ultrasound of the diaphragm can be performed to confirm the diagnosis as well.2 Most disorders reported as causing bilateral diaphragm paralysis have also been reported as causes of unilateral paralysis (e.g., cervical spondylosis, spine cord injury, poliomyelitis, and muscular dystrophy). Other, more specific causes of unilateral diaphragm paralysis are pneumonia, trauma from central vein cannulation, and viral infections of the cervical nerve roots.
Patient complaints and physical examination abnormalities in unilateral diaphragm paralysis are usually the same as with bilateral diaphragm paralysis but are less striking. Orthopnea is a frequent complaint, but it is less dramatic than in patients with bilateral paralysis. Moreover, physical examination findings are nonspecific, but occasionally may show paradoxical inward motion of the paralyzed hemidiaphragm with a reduction in breath sounds at the affected lung base and an increase in percussible dullness. The alveolar–arterial oxygen gradient may be increased with mild hypoxemia due to the reduction in ventilation and perfusion of the lower lobe on the affected side.
Tests of diaphragm function are intermediate between those in patients with bilateral diaphragm paralysis and normal predicted values. VC in the upright posture may be reduced to 74% to 81% of predicted, with a fall in VC also present in the supine compared to erect position, but of lesser magnitude than in patients with bilateral diaphragm paralysis. In patients with right hemidiaphragm paralysis, the fall in VC may be almost twice as great (19% vs. 10%) in comparison with left-sided paralysis, owing to the weight of the liver further encroaching on lung volume. Maximum inspiratory mouth pressures are frequently reduced to approximately 50% to 62% of normal. Similar reductions are also found in maximum Pdi measured during maximum static voluntary efforts and during maximum sniff.
Treatment of patients with bilateral diaphragm paralysis is similar to that of other patients with chronic neuromuscular diseases. Eliminating nocturnal hypoventilation, especially during REM sleep is warranted, and the implementation of noninvasive ventilation, especially positive-pressure ventilation, may be indicated. In some cases of symptomatic unilateral hemidiaphragm elevation, surgical plication of the affected hemidiaphragm may relieve symptoms and improve FVC and transdiaphragmatic pressure. A series of 22 patients that underwent diaphragmatic plication were followed for an average of 4.9 years, and the investigators found that the percent decline in FVC from seated to supine position improved from 34% (range 10%–47%) preoperatively to 9% (range 0%–21%) postoperatively (p = 0.004). There also was an improvement in the transitional dyspnea index (TDI) postoperatively but the TDI did not correlate with the improvement in spirometry.86 Surgical plication is achieved by placing a series of 6 to 8 U-shaped sutures in the diaphragm, which results in the diaphragm becoming fixed and immovable. This prevents excursion of the diaphragm into the thoracic cavity during inspiration, and permits the accessory muscles of respiration to generate negative intrathoracic pressure.
GBS precipitates respiratory failure more often than any other peripheral neuropathy. It is an acute idiopathic polyneuritis with an annual incidence of 0.89 to 1.99 cases per 100,000 people.87 It usually presents as paresthesia and ascending paralysis of the lower extremities with absent deep tendon reflexes in a symmetrical distribution. Objective findings of sensory loss are variable, and the degree of motor weakness can range from mild paresis to complete paralysis. Maximum weakness of the lower extremities occurs within 2 weeks in 50% of cases, and 90% of cases reach their nadir in weakness by 4 weeks. After the nadir is reached, patients remain at that level for an additional 1 to 4 weeks before recovery begins. Facial, ocular, and oropharyngeal muscles may be impaired as well as the respiratory muscles. Respiratory muscle weakness and, specifically, severe diaphragm weakness may be found in patients with GBS.87
The distribution of muscle weakness between respiratory and nonrespiratory muscles is not uniform in GBS, and peripheral muscle strength does not correlate with the presence or absence of respiratory muscle weakness. However, ventilatory failure correlates with diaphragmatic weakness.
The impairment on respiratory tests in GBS is similar to that for other generalized neuromuscular diseases. A decline in FVC and maximum inspiratory and expiratory mouth pressures, impairment in nocturnal gas exchange during REM sleep, and the onset of hypercapnia detected by arterial blood gas analysis have all been reported in symptomatic GBS patients. An FVC of 15 cc/kg is a sign of imminent respiratory failure in GBS.87,88 Hypercapnia is a late sign of respiratory failure, with the average PaCO2 at the time of intubation 43 mm Hg when FVC is less than 12 cc/kg.
Respiratory treatment of GBS patients is mainly supportive. Since bulbar involvement, leading to swallowing dysfunction, increases the propensity for pulmonary aspiration, special precautions for feeding and control of upper airway secretions may be required. Primarily because of bulbar dysfunction in those with respiratory failure, noninvasive ventilation has not been used outside of a few case reports. Individual cases without bulbar dysfunction merit special consideration and the use of noninvasive ventilation may be appropriate. Approximately 20% to 30% of GBS patients will require mechanical ventilation. Airway intubation and mechanical ventilation should be initiated when one major criterion or two minor criteria are present (Table 84-7).87 Earlier intubation and assisted ventilation may be indicated to avoid complications that arise from progressive respiratory failure, overwhelming pulmonary infections, or both. When indicated, intubation and mechanical ventilation should be initiated early because emergent intubations have been associated with worse outcomes. It is well established that mechanical ventilation is indicated when the VC falls below 15 cc/kg. However, it would be ideal to predict the need for mechanical ventilation at an earlier time. A Dutch group of investigators demonstrated that the most important factors in predicting respiratory failure in the first week of hospitalization were Medical Research Council (MRC) sum score (a muscle strength score), days between onset of weakness and hospitalization, and the presence of facial and/or bulbar weakness at hospitalization.89 Based on their model the Erasmus GBS Respiratory Insufficiency Score (EGRIS) was made and is shown in Table 84-8. Patients at highest risk for intubation (EGRIS 5–7) should be admitted to the ICU for close observation and timely intubation if required. Evaluation for discontinuation of mechanical ventilation is not different in individuals with GBS, but if the presence of dysautonomia is present at the time of extubation then reintubation rates are exceeding high (73% vs. 26.7%; p = 0.008)90 while an improvement of >4 mL/kg in VC was associated with a 90% positive predictive value for extubation.90 Aggressive pulmonary toilet, including repeated bronchoscopy, may be needed to decrease atelectasis and the incidence of nosocomial pneumonia.
Table 84-7Criteria for Airway Intubation and Mechanical Ventilation in Guillain–Barré Syndrome |Favorite Table|Download (.pdf) Table 84-7Criteria for Airway Intubation and Mechanical Ventilation in Guillain–Barré Syndrome
|Major Criteria ||Minor Criteria |
|Hypercarbia (PaCO2 ≥ 48 mm Hg) ||Ineffective cough |
|Hypoxemia (PaO2 ≤ 56 mm Hg) ||Impaired swallowing |
|Vital capacity < 15 cc/kg ||Atelectasis |
Table 84-8Erasmus GBS Respiratory Insufficiency Score (EGRIS) for Predicting Respiratory Failure in the First 7 Days of Hospitalization |Favorite Table|Download (.pdf) Table 84-8Erasmus GBS Respiratory Insufficiency Score (EGRIS) for Predicting Respiratory Failure in the First 7 Days of Hospitalization
|Measure ||Categories ||Score |
|Days between onset of weakness and hospitalization ||>7 d ||0 |
| ||4–7 d ||1 |
| ||≤3 d ||2 |
|Facial and/or bulbar weakness on hospitalization ||Absent ||0 |
| ||Present ||1 |
|MRC sum score at hospitalization ||60–51 ||0 |
| ||50–41 ||1 |
| ||40–31 ||2 |
| ||30–21 ||3 |
| ||≤20 ||4 |
|EGRIS ||Risk of Intubation (%) || |
|Low (0–2) ||4 || |
|Intermediate (3–4) ||24 || |
|High (5–7) ||65 || |
In a multicenter trial, plasmapheresis (total of four treatments), using either albumin or fresh frozen plasma as replacement fluids, produced short-term benefits in earlier motor recovery, ambulation, reduction in number of patients who required assisted ventilation, and shortened the duration of mechanical ventilation.91 A subsequent study from the same group showed that two plasmapheresis treatments were better than none in mild disease, but four were better than two in moderate and severe diseases. Giving more than four treatments was not beneficial, even in severe disease. IVIG, given within 2 weeks after the onset of GBS, may also be effective therapy.92 IVIG has been compared to plasmapheresis and recovery was as effective as plasmapheresis and may have been slightly better. In a study of 150 patients with GBS, 53% of the group treated with IVIG had an improvement of one grade (on a seven point scale) in muscle strength compared to 34% of those treated with plasmapheresis after 4 weeks of therapy.93 Currently, there is no evidence from randomized controlled trials to support the use of corticosteroids in the treatment of GBS.
Critical Illness Polyneuropathy
CIP was initially described in five patients that had survived sepsis and multisystem organ failure, and the entity is now recognized as a serious complication of critical illness that contributes significantly to morbidity and mortality.94,95 The disease is common with as many as 68% of patients with sepsis and multisystem organ failure requiring mechanical ventilation having evidence of CIP on EMG/nerve conduction studies. Patients affected by this disorder typically exhibit varying degrees of musculoskeletal weakness, which ranges from mild weakness to near total paralysis with hyporeflexive deep tendon reflexes. Unfortunately, physical examination is unreliable as the sole means of diagnosis, and EMG with nerve conduction studies (EMG/NCS) are required to confirm the diagnosis. EMG studies in these patients show a reduction in the amplitude of the compound muscle action potential without significant prolongation of stimulus latency, suggesting primarily axonal nerve damage rather than a demyelinating process.
Recognition of CIP is important because the disease affects patient management and the prognosis of recovery from the critical illness. Patients that develop CIP tend to require a longer period of mechanical ventilation and longer hospital stays compared to those without CIP. Garnacho-Montero et al. found that in a group of patients with sepsis and prolonged mechanical ventilation that those with CIP required 34 days of mechanical ventilation versus only 14 days for those without CIP. Additionally, the weakness associated with CIP results in an extended rehabilitation period, and there is evidence of persistent neuropathy on EMG/NCS as long as 5 years after discharge from the ICU. Patients that develop CIP appear to have a higher mortality with one study showing a 3.5-fold increase in ICU mortality, and another with significantly higher in hospital mortality.96
Although the exact mechanism for axonal damage in this syndrome is unknown, several risk factors for the development of CIP have been described. Two of the most important risk factors are the presence of the systemic inflammatory response syndrome (SIRS) and the APACHE III score. One study looked at 98 patients prospectively and found that 72% of patients with SIRS and an APACHE III score above 85 will develop CIP. Multivariate analysis of associated risk factors from another study found that hyperosmolality, parenteral nutrition, the use of neuromuscular blocking agents, and neurologic failure (GCS <10) were associated with an increased risk of developing CIP.97 Exactly how these risk factors lead to the development of CIP is not known, but possibilities include nerve toxins released during episodes of multiple system organ failure, antibiotics impairing neuromuscular transmission, protracted use of neuromuscular blocking agents, and hyperglycemia causing nerve ischemia by endovascular shunting.
Because no specific therapy for CIP exists, treatment is purely supportive and includes aggressive rehabilitation, nutrition support and treatment of any medical complications. It should be emphasized to both patient and family that recovery may be prolonged (as long as 5 years).98
Disorders of the Neuromuscular Junction
Disorders of the neuromuscular junction, including myasthenia gravis, Eaton-Lambert syndrome, and botulism, may have profound effects on respiration. Each is discussed below.
Myasthenia gravis is an autoimmune disorder characterized by impaired transmission of neural impulses across the neuromuscular junction due to the production of antibodies directed against the acetylcholine receptor. The prevalence of myasthenia gravis is estimated to be approximately 1 in 10,000 people with 2-to-1 female-to-male predominance. It occurs more often in younger than older adults. The typical myasthenic patient presents with fluctuating muscular weakness, with improvement after rest and the administration of anticholinesterase agents (e.g., edrophonium chloride). Ocular, facial, and neck muscles are commonly affected, but patients who have the most severe respiratory involvement have either acute fulminating or late severe classifications of myasthenia gravis.
In 17 patients with moderate, generalized myasthenia gravis, pulmonary function studies before the administration of edrophonium chloride reveal a mild reduction in VC and moderate reductions in both maximum inspiratory (~54% of predicted) and expiratory (reduced to ~52% of predicted) mouth pressures.99 Because of increased lung recoil pressure, normal or supranormal values of maximal expiratory flow are seen in relation to lung recoil pressure or absolute lung volume. Although upper airway obstruction due to bulbar muscle involvement is theoretically possible, it has rarely been reported. However, Putman and Wise examined flow–volume loops in myasthenia gravis patients that were adequate for interpretation. They found that in 12/61 patients with myasthenia gravis with reproducible flow–volume loops 7 had either a variable extrathoracic or fixed upper airway obstruction suggesting that upper airway obstruction may be more common than previously thought.100
Acute respiratory failure usually occurs in the setting of a myasthenic crisis or cholinergic crisis or as the initial presentation of the disease. A myasthenic crisis refers to worsening of the basic underlying disease, usually precipitated by decreased anticholinesterase medication, surgery, or administration of neuromuscular blocking medication. Clinical parameters useful in predicting the development of postoperative respiratory failure include the severity of the disease (e.g., acute fulminating or late severe categories of myasthenia gravis), a low preoperative VC, and bulbar symptoms.101 The most common complications of myasthenic crisis are respiratory failure and recurrent pneumonias due to aspiration from bulbar involvement and impaired cough. The mean duration of mechanical ventilation in myasthenia gravis in a series of 22 patients was 8 days, with six patients (32%) requiring tracheostomy for prolonged mechanical ventilation. Of the 22 patients 21 survived and were totally weaned from ventilatory support over 1 to 32 days.102 Noninvasive bilevel (BiPAP) positive-pressure ventilation is a viable option to treat respiratory failure during a myasthenic crisis until effective therapy is delivered. BiPAP was used in a series of 11 myasthenic crisis events in nine patients. The mean pressures used were 13/5 cm H2O, and endotracheal intubation was avoided in all but four instances. The only predictor for failure of BiPAP was a PaCO2 above 50 mm Hg.103 A subsequent study in 24 patients treated with BiPAP (mean pressure 14/6 mm Hg) had similar findings in that 58% of myasthenia crisis patients avoided intubation, and the best predictor of BiPAP failure was a PaCO2 >45 mm Hg. Although there was no difference in mortality, those treated with BiPAP had a shorter ICU length of stay (7 vs. 13 days, p = 0.002).104 These data suggest that the use of early noninvasive ventilation prior to the development of severe hypercapnia can reduce intubation rates and ICU length of stay.
The treatment of myasthenia gravis includes anticholinesterase agents, high-dose corticosteroids, thymectomy, and plasmapheresis in patients’ refractory to steroid or immunosuppressive therapy. Anticholinesterase agents are the first line of treatment. Most patients improve significantly with anticholinesterase agents, but only a few regain normal function. Remissions can be induced in up to 80% of patients with the use of corticosteroids. However, corticosteroids may cause temporary worsening of muscle weakness, usually on the sixth to tenth day of therapy, and close observation for signs of respiratory insufficiency is advisable.101 Other immunosuppressive agents (e.g., cyclosporine and azathioprine) may be useful with or without concomitant corticosteroids.
In retrospective studies, thymectomy improves survival and relieves clinical symptoms, even in the absence of thymoma. In patients with thymoma, thymectomy is also indicated because the risk for malignant transformation is high in patients less than 55 years of age. In up to 80% of myasthenia gravis patients without thymoma, clinical improvement after thymectomy occurs during prolonged follow-up.
Plasmapheresis and the use of IVIG produce a temporary reduction in acetylcholine receptor antibody level and may be helpful in patients with respiratory failure not responding to anticholinesterase and immunosuppressive agents. Plasmapheresis and IVIG have been compared and both are equally efficacious. However, IVIG was associated with less severe adverse reactions and therefore is the preferred initial agent in the treatment of myasthenic crisis.
Eaton–Lambert syndrome is a rare myasthenia disorder resulting from a reduction in neurotransmitter release from presynaptic terminals that develops in association with tumors (especially small cell lung carcinoma). Although patients may respond weakly to administration of edrophonium chloride, the disease is differentiated from myasthenia gravis by the predominant involvement of limb and girdle muscles compared to the ocular and bulbar muscle involvement in myasthenia gravis. Respiratory muscle weakness is often detected on pulmonary function tests, but respiratory failure is infrequent.
Botulism is a rare disorder caused by the Clostridium botulinum toxin. It occurs as a result of eating improperly cooked food, wound contamination by the organism, or, especially in infants, the absorption of toxin from the GI tract. There are eight types of toxins, although human diseases are usually caused by type A, B, or E.
Botulinum toxin binds to the calcium channel in presynaptic terminals, impairing neuromuscular transmission of acetylcholine. GI symptoms predominate early in the disease, followed by neurologic impairment, including descending paralysis of the neck, trunk, and limb muscles. Weakness of the respiratory muscles requiring mechanical ventilation is frequent, especially with botulinum type A toxins. Spirometry usually reveals a restrictive ventilatory defect, and recovery from respiratory muscle weakness may take months, often requiring prolonged mechanical ventilation. The average duration of ventilatory support for type A poisoning is 58 days, in contrast to 26 days for type B botulism. Exertional dyspnea and poor exercise tolerance may persist, even with normal lung function.
Inherited and Acquired Myopathies
Respiratory function may be significantly affected by a variety of inherited muscle disorders and acquired myopathies (Table 84-9). The inherited muscular dystrophies refer to a heterogeneous group of progressive, degenerative, hereditary skeletal muscle diseases that cause severe muscle weakness, eventually resulting in repeated pneumonias, respiratory failure, and, in some cases, death. Respiratory failure, often accompanied by pneumonia, contributes to death in more than 75% of patients with DMD.
Table 84-9Myopathies Likely to Produce Respiratory Abnormalities |Favorite Table|Download (.pdf) Table 84-9Myopathies Likely to Produce Respiratory Abnormalities
|Inherited Myopathies ||Acquired Myopathies |
|Muscular Dystrophies |
|Inflammatory (dermatomyositis, polymyositis) |
Systemic lupus erythematosus
Acute steroid myopathy
|Congenital myopathies |
|Electrolyte disorders |
|Metabolic myopathies |
Acid maltase deficiency
Duchenne Muscular Dystrophy
DMD is the best characterized of these heredofamilial muscle diseases. This disease is transmitted by an X-linked recessive gene, although approximately one-third of cases arise from spontaneous mutation. The disease is due to the mutation of the gene for skeletal protein dystrophin, a subsarcolemma protein believed to play a major role in providing structural integrity in the muscle cell surface membrane. Lack of dystrophin leads to a weaker cell membrane that becomes further impaired with muscle contraction. Muscle inflammation, necrosis, and fibrosis subsequently lead to severe atrophy and loss of function. Approximately 30% to 40% of the normal amount of dystrophin must be expressed in order to prevent major myopathic symptoms. The diagnosis is confirmed by demonstrating mutation of the dystrophin gene in DNA from peripheral leukocytes, or an absence or abnormality in dystrophin in muscle biopsy samples.
Symptoms usually present in early childhood. Gait disturbances and delayed motor development are common manifestations, with proximal weakness resulting in an exaggerated lumbar lordosis. Most patients are wheelchair bound by the age of 12 to 15 years, with death occurring around the age of 20 years as a result of progressive respiratory failure and pneumonia. Kyphoscoliosis commonly develops as a result of severe muscle weakness and further contributes to a restrictive ventilatory deficit. Pulmonary symptoms are often minimal early on, despite significant weakness of the respiratory muscles. Maximum inspiratory pressure is reduced at all lung volumes in patients with DMD and declines with time. FVC increases with growth during the first decade and may mask early respiratory muscle dysfunction before it plateaus and progressively decreases about 5% to 6% per year after 12 years of age (Fig. 84-12).105 Reductions in maximum inspiratory pressure, therefore, occur early in the clinical course of DMD and may precede the reduction observed in VC. In a series of 58 DMD patients, the median decline in FVC was 0.18 L (0.04–0.74 L) per year and once the FVC fell below 1 L the median survival was 3.1 years with a 5-year survival of 8%.106 Inspiratory muscle weakness does not necessarily parallel the development of expiratory muscle weakness. Maximum expiratory mouth pressures are substantially lower than maximum inspiratory mouth pressures, possibly leading to a marked decrease in the effectiveness of cough. FVC should be measured annually in patients that are able to ambulate and every 6 months in nonambulatory DMD patients. Additionally, PCF, MIP, and MEP should be measured every 6 months in nonambulatory patients.107,108
Mean vital capacity (VC) and maximum static inspiratory pressures (MIP) in 37 DMD patients in three age groups (shaded bars) in comparison to normal predicted values (unshaded bars). MIP decreases gradually as DMD progresses, despite body growth, whereas VC increases until patients reach their early teens. (Data from Smith PEM, Edwards RHT, Evans GA, et al. Practical problems in the respiratory care of patients with muscular dystrophy. New Engl J Med. 1987;316:1197–1205.)
Despite severe and progressive muscle weakness, hypercapnia is uncommon in patients with DMD in the absence of pulmonary infections. The absence of hypercapnia despite severe muscle weakness is believed to be due to relative preservation of diaphragm function until very late in the illness. Once hypercapnia occurs, however, the course is rapidly progressive and mean survival is approximately 10 months.
Since ventilation is heavily dependent on diaphragmatic function in DMD patients, severe nocturnal hypoventilation may occur during REM sleep, when activity of chest wall and neck muscles is markedly attenuated. Indeed, hypoventilation may occur during REM sleep, when activity of chest wall and neck muscles is markedly attenuated, and has been documented in DMD patients with normal daytime gas exchange. The American Thoracic Society has recommended that an annual sleep study be performed when the patient becomes nonambulatory unless symptoms of nocturnal hypoventilation are present.109 Sleep-related hypoxemia may contribute to respiratory insufficiency and the development of cor pulmonale.
Management of patients with DMD is mainly supportive. Ambulation should be maintained and encouraged as long as possible to retard the development of scoliosis. Surgical correction may attenuate the scoliotic contribution to the fall in VC and improve patient morale and quality of life overall. While the decline in FVC will continue postoperatively, it may be slowed somewhat. In a group of 56 DMD patients that underwent posterior spinal fusion for scoliosis, the decline in FVC decreased from 4% per year preoperatively to 1.75% per year postoperatively (p < 0.0001).110 General physiotherapy may be helpful in preventing contractures. Maintenance of proper nutrition, with an emphasis on weight control, is important. Patients with DMD have a propensity to become overweight through a combination of inactivity, reduced energy requirements, and a misguided desire to improve muscle bulk by overeating. Some authors have emphasized a high-protein (more than 80 g protein daily), low-calorie diet, aiming to achieve a body weight somewhat lower than the ideal weight in patients of a similar height and normal muscle mass.
Inspiratory muscle training (IMT) has been examined as a tool to prevent further decrease in respiratory muscle function in those with DMD, but its routine use remains controversial. Because there is loss of the protective mechanism of nitric oxide release in children with DMD, IMT could potentially be detrimental. Koessler et al.111 studied the effect of 2 years of IMT on a group of 27 patients with neuromuscular disease (18 DMD and 9 spinal atrophy), and showed a clear increase in PImax and MVV. There was a plateau reached after 10 months of training. Because there is potential for harm and no long-term studies to support its use, ATS guidelines do not suggest the use of routine IMT in this group of patients.109
Maintenance of cough and adequate airway clearance is extremely important in attempting to prevent atelectasis and pneumonia in this patient population. A PEmax of at least 60 cm H2O has been shown to be adequate to generate an effective cough in patients with DMD, while a drop below 45 cm H2O has been associated with ineffective cough.109,112 Once an ineffective cough is recognized there are multiple treatment modalities. The most studied technique is the use of a manual insuffator–exsufflator, which stimulates cough by providing a positive pressure breath immediately followed by a negative pressure exsufflation. The technique can be used on patients with or without a tracheotomy, and is generally well tolerated. It has been shown to be effective in generating cough and clearing airways in children with DMD, especially once scoliosis has developed.109 Respiratory tract infections are a serious complication in DMD patients, and must be treated aggressively with physiotherapy, postural drainage, assisted cough techniques, and appropriate antibiotics. All patients, regardless of cough status, should receive vaccination against pneumococcal pneumonia and influenza.
In some patients, assisted ventilation is required once respiratory insufficiency or symptoms of sleep-related breathing disorders are present. Intermittent noninvasive positive-pressure ventilation (NPPV) prolongs survival, improves quality of life, and may attenuate the decline in FVC and MVV. Longer-term follow-up of DMD patients treated with noninvasive ventilation demonstrates that pulmonary function continues to deteriorate 3–4 years after the initiation of noninvasive ventilation, with patients requiring longer periods of ventilation and/or transition to tracheostomy with positive-pressure ventilation.113 Once patients require the use of NPPV, the pressure should be titrated in the sleep laboratory to eliminate nocturnal apneas and hypopneas. Generally, BiPAP should be used in those with significant daytime or nocturnal hypoventilation, and CPAP should be used primarily in those with obstructive sleep apnea without evidence of hypoventilation.
DMD is a relentlessly progressive disease that eventually will lead to respiratory failure requiring invasive mechanical ventilation (see Chapter 85). End-of-life care and plans for the use of invasive mechanical ventilation should be discussed with the family and the patient well in advance if at all possible. While the institution of mechanical ventilation has been shown to prolong life in the appropriate setting, little is known on the effect on quality of life, and decisions must be made on an individual basis.
There is evidence to suggest that prednisone treatment is beneficial. In a randomized, double-blind controlled 6-month trial of prednisone in 103 boys with DMD, patients were assigned to low-dose prednisone (0.75 mg/kg per day), high-dose prednisone (1.5 mg/kg per day), or placebo. Both prednisone groups showed significant improvements in muscle strength, functional scores, and FVC at 6 months compared to placebo, but there was no difference between low- or high-dose prednisone.114 A subsequent study found that muscle strength was greater in DMD patients taking 0.75 m/kg compared to 0.3 mg/kg of prednisone for 6 months.115 The effect of prednisone therapy on respiratory muscle function has been less clear but a case-control study found that steroid therapy for a mean duration of 8.2 years resulted in improved FVC, MIP, MEP, PCF, and FVC compared to those not treated with prednisone.116 Based on these data expert panels have recommended that corticosteroid therapy be used in DMD patients.107
While steroid therapy may improve muscle strength it has not led to improved survival, and most experts believe that gene therapy will be applicable to DMD in the future as a potential cure for the disease. A newer method of gene therapy known as exon skipping is an attractive approach because some DMD mutations result in mRNA, which causes a premature stop in translation of the dystrophin protein. Small oligonucleotides can be developed to bind exons and block them from being incorporated into mRNA which then will allow for translation of a truncated dystrophin protein that will result in some function of the native protein.117 Traditional gene therapy is limited in DMD by the large amount of skeletal muscle, the large size of the dysmorphin gene, and patient immunity against viral vectors.118
Myotonic dystrophy is the most common form of hereditary muscular dystrophy in adults, with an estimated incidence of 1 in 8000 people. The gene responsible for the disease is located on the long arm of chromosome 19 and demonstrates an autosomal dominant inheritance pattern. Symptoms usually present during adolescence and in early adulthood, although the syndrome may be recognized as early as infancy.
Respiratory muscle weakness is common and can be severe, despite mild limb muscle weakness. Myotonia of the respiratory muscles contributes to an increased work of breathing by increasing inspiratory impedance. Studies have suggested that the presence of a chaotic breathing pattern may explain the higher prevalence of chronic hypercapnia in patients with myotonic dystrophy than in patients with other forms of muscular dystrophy. Support for these findings came from studies that showed abnormal ventilatory responses to hypercapnic challenges in patients with myotonic dystrophy. However, studies that have used mouth occlusion pressures (P0.1) have revealed normal or supranormal responses in P0.1 in patients with myotonic dystrophy compared to controls. These data seem to suggest that prior studies showing hypercapnia in patients with myotonic dystrophy underestimated the severity of respiratory muscle weakness by itself as a limitation in the ability to mount a normal ventilatory response. The chaotic breathing pattern observed in some patients with myotonic dystrophy has been suggested to be related to disordered afferent information from diseased muscle spindles.
Patients with myotonic dystrophy are particularly susceptible to development of respiratory failure with general anesthesia and sedatives. Postoperative respiratory monitoring is essential if surgery or the use of these agents is required. Pharyngeal and laryngeal dysfunction increases the risk of aspiration. Sleep-related breathing disturbances are common and may include both central and obstructive forms of sleep apnea. Nocturnal positive-pressure ventilation should be tried when hypercapnia and hypoxemia are present.
Other inherited adult muscular dystrophies are facioscapulohumeral dystrophy (FSH) and limb–girdle dystrophy. FSH is an autosomal dominant dystrophy that primarily affects muscles of the face and the proximal portion of the upper extremities. FVC is significantly reduced in patients with FSH, although facial weakness complicates spirometric assessment. In 20% of patients with FSH, the disease affects pelvic girdle and trunk muscles, sometimes impairing respiratory function.
Limb–girdle dystrophy is a heterogeneous group of autosomal dominant recessive disorders. The disease usually becomes evident in the second or third decade of life. Several case reports have documented the development of chronic hypercapnia in patients with limb–girdle dystrophy who have severe diaphragm weakness or bilateral diaphragm paralysis as the basis for hypercapnia. However, not all patients with limb–girdle dystrophy develop hypercapnia. Most patients have moderate respiratory muscle weakness with normal gas exchange.
Acid Maltase Deficiency (Pompe Disease)
Two metabolic myopathies, acid maltase deficiency and mitochondrial myopathy, have received attention as potential causes of respiratory failure. Acid maltase deficiency is a type I glycogen storage disease due to the deficiency of the lysosomal enzyme responsible for hydrolysis of both the α1 to 4 and α1 to 6 linkages of glycogen. The disease presents in three clinical forms: infantile, childhood, and adult. In adult-onset disease, onset usually occurs after 20 years of age and presents with progressive proximal muscle weakness. The diagnosis may be difficult to establish in some patients, as respiratory failure or sleep-related complaints, secondary to respiratory deterioration during REM sleep, may be the initial presentation. Diagnostic studies include elevated serum muscle enzymes; myopathic changes on EMG, and vacuoles filled with lysosomal breakdown products on muscle biopsy. Enzyme replacement therapy with recombinant human acid maltase, alglucosidase alfa, is now available for both early- and late-onset disease. In a study of 99 patients with late-onset Pompe disease, treated for 78 weeks with biweekly infusions of alglucosidase, the investigators found an improvement in FVC and 6-minute walk distance.119
Mitochondrial myopathy represents a heterogeneous group of disorders that affect mitochondrial function and may present as complex multisystem disorders with brain and striated skeletal muscle being the predominant organs affected; (1) Kearns–Sayre syndrome; (2) myoclonic epilepsy, “ragged red fibers,” and mitochondrial myopathy; and (3) encephalopathy, lactic acidosis, and stroke-like episodes. The clinical manifestations may be broad and include myalgia and exercise intolerance, proximal muscle weakness, and external ophthalmoplegia with unexplained respiratory failure. All three disorders are characterized by hypoventilation and depressed responses to hypoxia and hypercapnia and, in some cases, unexplained respiratory failure. Skeletal muscle biopsy establishes the diagnosis of mitochondrial myopathy by showing “ragged red fibers,” which are accumulations of mitochondria identified with modified trichrome staining. Treatment is supportive. Once identified, patients should be cautioned regarding the use of sedatives, and special attention is required when sedation or surgery is planned.
A variety of acquired myopathies, outlined in Table 84-9, may affect respiratory muscles. The reader is referred to other sources for detailed discussion.