Amyotrophic lateral sclerosis is a progressive neurodegenerative disease with no known cure. The major cause of mortality and major morbidities is related to the effects of the disease on the muscles of the respiratory system (ie, the inspiratory, expiratory, and upper airway muscles). Dyspnea, swallowing difficulties, sialorrhea, and impaired cough are all symptoms that can be palliated through pharmacologic and nonpharmacologic means. Noninvasive positive pressure ventilation, in particular, is a technique that not only relieves dyspnea but may also extend the lives of patients who have this disease. It should be offered to all patients who have amyotrophic lateral sclerosis with a forced vital capacity of less than 50 percent.
Amyotrophic lateral sclerosis pathogenesis and respiratory system effects
Amyotrophic lateral sclerosis (ALS), or Lou Gehrig disease, is a progressive neurodegenerative disease of unknown cause. Approximately 1.4 individuals per 100,000 develop ALS annually and the peak incidence occurs between the ages of 55 and 75 . The disease affects all races, but men are affected 1.5 times as often as women. Although the cause of ALS is unknown, many potential causes have been proposed, including exposure to neurotoxic agents, genetic or autoimmune disease, deficiencies of nerve growth factors, and viral infection, to name a few . Regardless of the initiating event, ALS has a characteristic pattern of damage to the nervous system, with involvement of the motor neurons of the brainstem, the anterior horn area of the spinal cord, and the large pyramidal neurons of the motor cortex.
The usual clinical presentation is that of an individual with gradually progressive asymmetric weakness associated with hyperreflexia and muscle fasciculations. The disease presents with equal frequency in the upper and lower limbs (∼40%) and less frequently with bulbar muscle involvement (∼20%) . Difficulty with walking, balance, picking up objects, and, ultimately, any limb muscle movement can occur. Patients who have bulbar muscle involvement suffer difficulty with swallowing, cough, and protection of the airway. The diagnosis is made on the basis of history, physical examination revealing upper and lower motor neuron signs, and electromyography demonstrating signs of denervation and true fasciculations. Other disease processes, such as myasthenia gravis, myelopathies, heavy metal intoxication, and vitamin deficiencies, must be aggressively excluded.
Respiratory system involvement in amyotrophic lateral sclerosis
ALS has no direct effect on the lung, but the mechanical respiratory system is significantly involved. ALS affects all the major muscle groups of the mechanical respiratory system: (1) upper airway muscles (abnormal swallowing and cough); (2) expiratory muscles (inadequate cough); and (3) inspiratory muscles (inadequate maintenance of ventilation). Therefore, all patients who have ALS are at significant risk for respiratory complications; the leading cause of death in this population is respiratory failure.
Upper airway muscle dysfunction
Patients who have ALS frequently develop bulbar muscle dysfunction because of motor neuron involvement in the brainstem. Dysfunction of the lips, tongue, and pharyngeal and laryngeal muscles can result in an increased risk for aspiration and difficulty with generating adequate glottic closure for effective cough function. Swallowing may be impaired, and ingesting adequate nutrition can be trying for the patient and family alike. Choking episodes are common and may even be triggered by saliva. Secretion management is a particularly difficult issue because secretions may become viscous because of inadequate hydration . Sialorrhea (drooling) is due to inadequate handling of secretions, rather than the amount of secretions; in fact, salivary secretions in ALS appear to be less than in normal subjects . Malnutrition due to inadequate protein-calorie intake can occur and rapid weight loss should signal the clinician to assess the swallowing mechanism carefully . Speech and swallowing are often affected and patients may require assistive technology to communicate effectively. Choice boards and computer-assisted speech devices are available for patients who have neuromuscular speech difficulties. The authors have found referral to a speech and swallowing clinic to be helpful in diagnosing swallowing and airway protection problems and for instructing patients and their families in steps they can take to reduce the risk for aspiration.
Expiratory muscle dysfunction
Cough is an essential airway protection reflex. Particles are expelled from the airway through a complex set of nerve and muscle responses to cough stimulation, through receptors located predominantly in the upper airway . Cough receptor stimulation results in inhalation to approximately 60% of maximum vital capacity (inspiratory phase). The glottis then closes and the abdominal muscles contract, resulting in markedly elevated intrathoracic pressures without airflow (compressive phase). The glottis opens shortly thereafter and gas is propelled through the airways at high velocities, resulting in airway clearance (expiratory phase). The individual who has ALS may experience cough impairment in any one, or all three, of the stages of cough, including reduction in the inspired volume due to diaphragm weakness, inability to close the glottis completely during the compressive phase due to bulbar muscle dysfunction, and inability to compress and expel intrathoracic gas because of expiratory muscle weakness. Polkey and colleagues performed a careful investigation of cough function in patients who had ALS. They studied 26 patients who had ALS, 16 of whom had respiratory symptoms and 9 of whom did not. They found that the ability to generate cough was related to expiratory muscle strength, as gauged by a balloon placed in the stomach measuring gastric pressure. This finding appeared to be a threshold phenomenon. Cough was not lost until substantial levels of expiratory muscle strength were lost. Maximal expiratory pressure, a commonly used clinical measure of expiratory muscle strength, did not correlate well with the presence or absence of cough generation. Inspiratory muscle strength also did not correlate well with cough generation. Endoscopic evaluation of the patients who had respiratory symptoms revealed only 2 patients with obvious glottic dysfunction, indicating that the presence of glottic function alone did not ensure effective cough. Some have suggested that the measurement of peak cough flow (PCF) is an effective, noninvasive assessment of cough function . In the experience of these investigators, a measured PCF of less than 160 L per minute during illness and less than 270 L per minute while well was associated with poor cough and a high risk for respiratory infection.
Inspiratory muscle dysfunction
ALS often affects the inspiratory muscles, including the diaphragm and external intercostal muscles, which leads to a reduction in respiratory muscle strength, restrictive lung disease, and, ultimately, carbon dioxide retention and frank respiratory failure. In some cases, respiratory muscle dysfunction leading to respiratory failure may be the presenting clinical picture for the patient who has ALS . Usually, the symptoms of respiratory muscle insufficiency, such as dyspnea, occur gradually over time and may defy diagnosis. Pulmonary function testing is invaluable in assessing the level of respiratory impairment, in following disease progression, and in assessing prognosis in ALS. Fallat and colleagues evaluated comprehensive pulmonary function testing over time in 218 patients who had ALS. All their patients showed evidence of restrictive lung disease, with reductions in total lung capacity, forced vital capacity (FVC), forced expiratory volume in 1 second, and maximum voluntary ventilation. The FVC averaged 80% of predicted at presentation to their clinic. They were able to follow pulmonary function tests over time in 103 patients, which showed significant decrements in all values over time. Black and Hyatt studied respiratory muscle function in ALS with dyspnea and near-normal vital capacity. Maximal inspiratory and maximal expiratory pressures were markedly reduced (34% and 47%, respectively). Reduction in maximal muscle strength correlated well with sensation of dyspnea in their patients. These respiratory muscle strength measures correlated with dyspnea in their patients despite near-normal vital capacity. In patients in whom oral bulbar weakness may limit the ability to accurately measure maximum inspiratory pressure by mouth, sniff nasal inspiratory pressure has been found to be a reliable alternative . Maximal inspiratory pressure and sniff nasal inspiratory pressure may be inaccurate measures of inspiratory muscle strength when significant bulbar weakness affects the test maneuver because of an inadequate oral seal or upper airway collapse.
Nocturnal hypoventilation and sleep-disordered breathing is a common problem for patients who have ALS and can occur even when respiratory muscle function is only mildly affected and daytime gas exchange remains normal. Neural output to the respiratory muscles decreases during sleep. Even mild muscle weakness, coupled with the normal decreases in ventilatory drive, can result in nocturnal hypoventilation and disturbed sleep architecture . Symptoms and signs of nocturnal hypoventilation can manifest at night and during the day. Nighttime symptoms include air hunger, observed apneas, orthopnea, cyanosis, restlessness, and insomnia. Daytime findings include excessive sleepiness, morning headaches or drowsiness, polycythemia, and pulmonary hypertension. The health care provider should be vigilant for these symptoms. Sleep studies can be helpful in elucidating sleep-disturbed breathing in these patients if doubt remains.
Hypercarbia and atelectasis can lead to lower than expected arterial oxygen levels, but primary oxygenation problems are not common in ALS, except in the final stages, when pneumonia intervenes. Oxygen as a primary therapy for respiratory insufficiency is not recommended. However, oxygen therapy in an attempt to relieve dyspnea in the hospice setting may be appropriate.
Monitoring and treatment of respiratory complications in amyotrophic lateral sclerosis
Patients who have ALS present a challenging set of issues for the clinician and the health care system. A neurologist usually accomplishes diagnosis of ALS, although diagnosis is often delayed because of the insidious onset of the disease. Unfortunately, neither cure nor truly effective treatment is yet available for ALS. Riluzole, an antagonist of glutamergic neurotransmission, has been shown to increase the time to death or mechanical ventilation by approximately 3 months only . Therefore, health care for these individuals focuses on maintenance of quality of life and adaptation to advancing disability due to muscle weakness. A rehabilitation medicine specialist can provide invaluable input into the care of the patient who has ALS. The management of devices needed for locomotion, medications for muscle spasm, and prevention of contractures and skin breakdown, and assistive communication technologies, are all areas that require careful oversight. The respiratory specialist is integral to the care of the patient who has ALS because of the multiple effects of this disease on the respiratory system. Frequent monitoring of pulmonary function gives valuable information on prognosis and gives input into the timing of interventions and discussions of long-term mechanical ventilation. At their institution, the authors have found that the most efficient way of delivering health care to these individuals is through a multidisciplinary clinic that involves care providers from rehabilitation medicine, neurology, and respiratory medicine, and therapists for speech and swallowing. The following discussion focuses on the monitoring and management of respiratory issues related to ALS.
Aspiration/pneumonia risk
The risk for aspiration and development of pneumonia in patients who have ALS is due primarily to problems with upper airway function and cough. Pharyngeal and laryngeal muscle dysfunction can lead directly to aspiration of oral contents into the lungs. Other than surgical diversion of the airway, no treatment directly aimed at the laryngeal and glottic function is available. However, reduction of the amount of salivary secretions is possible through the use of several medications and modalities ( Box 1 ) . Teaching proper swallowing technique to avoid aspiration is also helpful and involves keeping the head downward and using straws; drinking thicker, rather than thin, liquids; concentrating on eating during mealtime (no television, reading, and so forth); and maintaining hydration with at least two quarts of water per day. In addition, when patients who have ALS develop significant dysphagia and aspiration with solids or liquids, many experts recommend placement of a percutaneous endoscopic gastrostomy tube , which may prevent large-volume aspiration and is associated with improvement in hydration and nutritional status. Although the American Academy of Neurology practice parameter recommends placing the tube before decrease of the FVC below 50%, the authors have been able to place percutaneous endoscopic gastrostomy tubes in patients with an FVC as low as 13% .
Pharmacologic options
Amitriptyline (Elavil)
Glycopyrrolate (Robinul)
Benztropine (Cogentin)
Scopolamine (Transdermal Hyoscine)
Trihexyphenidyl hydrochloride (Artane)
Atropine
B-blocker (thick secretions)
Guaifensin (thick secretions)
Nonpharmacologic options
Salivary gland resection
Parotid gland irradiation
Airway diversion
Cough function, which depends in large part on expiratory muscles, can be mechanically assisted when adequate bulbar function exists. Bach postulates that cough function is adequate when the patient can generate at least 3 L per second of PCF . PCF can be measured with a simple device in the clinic ( Fig. 1 ) and the authors routinely perform this procedure during clinic visits. When PCF drops below 270 L per minute, they carefully evaluate potential interventions to improve cough function. These interventions may include teaching the caregivers manually assisted cough and the Heimlich maneuver. Inspiratory-related cough weakness can be supported with manual insufflation. A one-way valve mouthpiece circuit combined with a self-inflating resuscitator bag ( Fig. 2 ) can be used to insufflate the lungs by applying a series of breath-stacking maneuvers. Manual insufflation alone has been shown to improve cough function, and when combined with abdominal thrust, can further improve cough strength . When bulbar function is good but the patient has significant expiratory muscle weakness, mechanical in-exsufflation (Cough Assist Respironics Inc., Murrysville, Pennsylvania) can be used to augment cough function ( Fig. 3 ). This device mimics the normal cough and has been shown to be helpful in patients who have ALS and other neuromuscular diseases . Mechanical pressure-targeted insufflation and manual hyperinflation may also be beneficial to neuromuscular patients in maintaining lung compliance, decreasing the work of breathing, and managing atelectasis. Lechtzin and colleagues measured lung compliance by esophageal balloon monitoring in a cohort of patients who had ALS, before and after brief periods of pressure-targeted hyperinflation . They were able to show that patients who had diaphragmatic weakness had decreased lung compliance and that intermittent pressure-targeted insufflation could improve compliance. Hyperinflation maneuvers can be administered by either manual hyperinflation or mechanical insufflation using the cough-assist device. The effectiveness of this therapy is limited by the degree of bulbar impairment. As bulbar and cough function deteriorate, the risk for pneumonia may increase to the point where tracheostomy will be necessary.
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The Role of Exercise in Amyotrophic Lateral Sclerosis
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