If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Corresponding author. Department of Pathophysiology, University of Athens Medical School, 75 M. Asias Street, 11527 Athens, Greece. Tel.: +30 210 746 2649; fax: +30 210 746 2664.
Department of Pathophysiology and Laiko General Hospital, and University of Athens Medical School, Athens, GreeceDepartment of Pulmonary and Critical Care Medicine, The Memorial Hospital RI, and The Warren Alpert Medical School of Brown University, Providence, RI, USA
Department of Pathophysiology and Laiko General Hospital, and University of Athens Medical School, Athens, GreeceDepartment of Pulmonary and Critical Care Medicine, The Memorial Hospital RI, and The Warren Alpert Medical School of Brown University, Providence, RI, USA
Respiratory dysfunction frequently occurs in patients with advanced multiple sclerosis (MS), and may manifest as acute or chronic respiratory failure, disordered control of breathing, respiratory muscle weakness, sleep disordered breathing, or neurogenic pulmonary edema. The underlying pathophysiology is related to demyelinating plaques involving the brain stem or spinal cord. Respiratory complications such as aspiration, lung infections and respiratory failure are typically seen in patients with long-standing MS. Acute respiratory failure is uncommon and due to newly appearing demyelinating plaques extensively involving areas of the brain stem or spinal cord. Early recognition of MS patients at risk for respiratory complications allows for the timely implementation of care and measures to decrease disease associated morbidity and mortality.
Multiple sclerosis (MS) is a chronic central nervous system disorder characterized by multiple areas of nerve demyelination that impair nerve conduction. Its symptoms are either relapsing, remitting or progressive and include muscle weakness, spasticity, impairment of coordination, generalized fatigue, vision loss, and cognitive impairment [
]. Unlike neuromuscular diseases that involve the peripheral nerves or muscles intrinsic to the respiratory “pump”, respiratory dysfunction in MS arises only when demyelinating plaques involve distinct brain regions associated with breathing. This may explain the rare occurrence of respiratory dysfunction in the early stages of MS and its relatively higher prevalence in patients with advanced disease. Factors contributing to respiratory dysfunction in MS include weakness of the respiratory muscles, bulbar dysfunction, abnormal ventilatory control, and sleep disordered breathing.
Respiratory dysfunction contributes significantly to morbidity and mortality in MS [
]. Recognizing which patients with MS are at the greatest risk for respiratory complications is critical as it may help the clinician to carefully screen these patients and initiate appropriate preventive measures or care to decrease the associated morbidity and mortality. In the present review we focus on clinical aspects of respiratory dysfunction in MS, paying particular emphasis on respiratory failure and clinically relevant sequelae of respiratory muscle weakness such as sleep fragmentation (desaturation), impaired cough and respiratory infection.
Pathophysiology of respiratory dysfunction
The pathophysiological hallmark of respiratory dysfunction in MS is the presence of demyelinating lesions in the central nervous system. These lesions may involve one or more locations associated with production and/or propagation of neural impulses to the respiratory muscles. Depending upon the location and extent of demyelinating lesions, respiratory dysfunction may manifest with symptoms due to respiratory muscle weakness and impaired cough, dysfunction of bulbar muscles, abnormalities in the control of breathing, or respiratory failure (Table 1). Additional factors such as drugs, disease-related fatigue, or nerve conduction block due to elevated body temperature may independently compromise respiratory muscle function.
]. It is rare in ambulatory patients. Respiratory failure may be acute, typically secondary to demyelinating lesions in the cervical cord or the medulla (Fig. 1), or chronic, typically found in the terminal stages of the disease and related to weak respiratory muscles, and ineffective cough, leading to aspiration, atelectasis and pneumonia [
Figure 1Digital T2-weighted MRI showing a demyelinating plaque in the medulla of a patient with relapsing-remitting multiple sclerosis and acute respiratory failure. The respiratory failure resolved following treatment with intravenous methylprednisolone. (Reproduced from Pinedo et al.
Acute respiratory failure is a rather uncommon entity. Its clinical characteristics primarily have been described in single cases or small patient series [
], with acute respiratory failure occurring after a median of 6 years from disease onset. Dyspnea, orthopnea or confusion often develops over a period of hours or days in patients with no preexisting respiratory problems. Rapid shallow breathing with diminished abdominal excursions or abdominal paradox occurs when there is marked diaphragmatic weakness [
]. Forced vital capacity (FVC) is markedly diminished, with values often being less than 1 L. A decrement of vital capacity (VC) in the supine position of more than 30% of that measured in the upright position is indicative of bilateral diaphragm dysfunction [
]. On MRI, individuals often have demyelinating lesions involving the medulla or the spinal cord interfering with motor output to the respiratory muscles. In the series of Howard et al., the majority of patients had quadriplegia, or spastic paraplegia with upper arm weakness, of moderate or severe degree [
]. Frequent episodes of aspiration and atelectasis in conjunction with respiratory muscle weakness and a weak cough may lead to bouts of pneumonia and frequent hospitalizations. However, advanced respiratory support with mechanical ventilation and/or permanent tracheostomy is unusual in MS. Pittock et al. described 22 MS patients over a period of 33 years who required mechanical ventilation or tracheostomy [
]. The most common indications for mechanical ventilation or tracheostomy were aspiration pneumonia, and mucous plugging and difficulty in removing bronchial secretions [
Respiratory muscle weakness is a frequent finding in patients with MS. Usually, it is not severe enough to cause respiratory failure but strength can be reduced to a degree sufficient to be associated with other respiratory complications. In studies of individuals with MS, respiratory muscle strength was evaluated by measuring maximal static mouth inspiratory (MIP) and maximal static mouth expiratory pressure (MEP) [
]. These tests reflect the global strength of inspiratory and expiratory muscles. Specific evaluation of diaphragmatic function such as measurement of transdiaphragmatic pressure during volitional efforts have only been reported in occasional patients with acute respiratory failure [
]. A universal finding of all studies is decreased indices of MIP and MEP in MS. In general, respiratory muscle weakness is more pronounced in bedridden or wheelchair bound patients than in ambulatory MS patients (Table 2) [
], diaphragmatic weakness was diagnosed clinically on the basis of orthopnea, severe sleep disturbance, abdominal paradox, and significant reduction of VC in the supine position. MRI or autopsy findings were consistent with severe involvement of the medulla and cervical cord to the C7 level. Patients with diaphragmatic weakness usually have advanced disease, quadriplegia, and bulbar dysfunction [
]. In ambulatory patients with MS, electrophysiologic evaluation of the diaphragm by means of magnetic transcranial, magnetic cervical, or electrical stimulation of the phrenic nerves revealed abnormal diaphragmatic latency and compound muscle action potential in a significant portion of patients, even in patients with normal pulmonary function studies [
]. Respiratory muscle weakness, particularly expiratory muscle weakness, is more prevalent in patients with upper extremity weakness, and the presence of a weak cough, difficulty in clearing secretions, as rated by the patient and examiner, and by the patient's ability to count on a single exhalation (these clinical signs comprise the “pulmonary index”) [
], the pulmonary index, upper extremity weakness and the maximal voluntary ventilation accounted for 60% of the variance of MEP. The high prevalence of expiratory muscle weakness in patients with upper arm weakness is most likely explained by the pattern of progression of paralysis. Because paralysis in advanced MS usually ascends from lower to upper extremities, abdominal muscle involvement occurs earlier than involvement of the diaphragm and the intercostal muscles and thus expiratory muscle strength function will be compromised to a greater extent than inspiratory muscle strength [
Respiratory muscle weakness may result from multiple causes, with demyelination of respiratory motor pathways being the most important cause. Additional causes include inactivity and muscle deconditioning, steroid induced myopathy in patients treated chronically with steroids, and malnutrition [
]. Fatigue, a quite common and debilitating symptom in MS, may also contribute to respiratory muscle weakness in these patients. Current evidence suggests that fatigue is related to a reduced voluntary activation of muscles due to failure to sustain the required neural drive to the muscle (central fatigue) [
] of the respiratory muscles will similarly lead to muscle weakness. Finally, in patients with bulbar dysfunction and facial weakness, respiratory muscle strength indices may be falsely low due to inability of patients to make a tight seal around the mouthpiece [
]. Possible explanations for the lack of dyspnea are the limited capacity of patients to exert because of peripheral motor abnormalities, marked fatigue, or cognitive impairment which occurs late in the course of the disease [
]. The normal cough consists of three components, an inspiratory phase, glottis closure, and an expiratory phase during which high expiratory flows are generated [
]. In patients with MS, cough efficiency may be impaired because of expiratory muscle weakness or bulbar dysfunction. The latter may interfere with glottis closure and thus limit the pre-expiratory augmentation of intrathoracic pressure [
]. Measures of MEP to assess cough efficiency may be limited in patients with neuromuscular disease. A low MEP may result from poor effort or difficulties with the maneuver especially in presence of bulbar dysfunction and may not indicate the presence of expiratory muscle weakness [
] in patients with MS reported decreased cough peak flow and cough gastric pressure, which were correlated with disease disability (EDSS score). In the same study [
], an EDSS score >5.5 was consistent with impaired cough with a sensitivity of 0.85 and a specificity of 0.95. Measures of cough gastric pressure or peak cough flow in patients with MS may help identify those at risk for developing the respiratory complications due to ineffective cough.
Control of breathing
Abnormalities of the control of breathing may result from involvement of one of the respiratory centers located in the brain stem. The dorsal medullary group (nucleus tractus solitarius) is primarily responsible for inspiration and generation of the basic breathing rhythm whereas the ventral medullary group (nucleus retroambiguous) is primarily responsible for expiration when expiration becomes an active process. Thus the ventral medullary group affects timing during exercise or other conditions requiring an increase in minute ventilation [
]. Involvement of these higher respiratory centers in MS result in abnormal breathing patterns such as the loss of voluntary and/or automatic control of respiration, paroxysmal ventilation, and apneustic breathing, which refers to sustained inspiratory contraction and a prolonged pause at full inspiration [
]. In patients with loss of voluntary control, MRI and autopsy reports have revealed lesions involving the corticospinal tracts bilaterally, brainstem, or upper cervical cord. Patients who exhibit loss of automatic control have lesions involving the dorsomedial medulla, nucleus ambiguous, and medial lemnisci [
] but may be present in patients with sleep disordered breathing, especially central sleep apnea.
Stable patients with moderate to severe MS and weak respiratory muscles likely exhibit no abnormalities in respiratory control. Tantucci et al. reported increased respiratory drive at rest as indicated by a relatively high mouth occlusion pressure measured 0.1 s after onset of inspiratory effort (P0.1) [
Patients with MS report various sleep complaints including insomnia, excessive daytime somnolence, and restless sleep more often than control subjects [
]. Because fatigue is the most common symptom in MS, the clinician often has to differentiate excessive daytime sleepiness secondary to a sleep disorder from excessive fatigue in these patients [
Sleep disordered breathing may have the form of obstructive sleep apnea (OSA), central apnea or nocturnal hypoventilation and manifest with daytime somnolence, fatigue, decreased concentration, mood changes or decreased libido [
]. The prevalence of sleep disordered breathing in MS patients is unknown. In 28 consecutive patients initially screened with pulse oximetry and subsequently studied with polysomnography, OSA was documented in 2 patients (8%) [
]. Independent of central sleep apnea, nocturnal hypoventilation may also result from significant respiratory muscle weakness due to reduced tidal volume during REM sleep. It typically occurs in bedridden patients with advance disease and diaphragm weakness [
Neurogenic pulmonary edema rarely occurs in MS and is similar to that reported in patients with other neurological disorders. It may occur in patients with an established diagnosis of MS [
]. Recurrent episodes of neurogenic pulmonary edema requiring intubation and mechanical ventilation were reported by Simon et al. in a female patient with MS during disease exacerbations [
]. The pathogenesis of neurogenic pulmonary edema is not entirely known, but in most reports neurogenic pulmonary edema was associated with new demyelinating lesions involving the caudal medulla in the region of nucleus tractus solitarius [
]. As with other cases of neurologically-induced pulmonary edema, it is believed that involvement of specific brain regions about the caudal medulla that regulate cardiac function, systemic blood pressure and pulmonary hydrostatic pressure are responsible for sympathetic overstimulation which then leads to an increase in hydrostatic pulmonary pressure and development of pulmonary edema [
Identifying patients at risk for respiratory dysfunction
A thorough history and physical examination in conjunction with measurement of pulmonary function, respiratory muscle assessment, and sleep studies are important in assessing the degree of respiratory dysfunction in MS. Symptoms related to respiratory muscle weakness include dyspnea and excessive daytime sleepiness. Dyspnea in the supine position with evidence of abdominal paradox is suggestive of diaphragmatic weakness [
]. Dyspnea with exertion may not be present because these patients often have limited exercise capacity. Excessive daytime sleepiness and morning headache may be due to nocturnal hypoventilation. Symptoms related to sleep apnea may be present in patients with bulbar dysfunction.
Neurological exam is often essential in ascribing respiratory distress to respiratory muscle dysfunction. Patients with upper arm weakness, paraplegia, or bulbar dysfunction are more likely to have involvement of the respiratory muscles [
Pulmonary function testing may provide clues as to whether respiratory muscle dysfunction is present. Lung volumes such as total lung capacity (TLC), VC, and residual volume (RV) may be reduced in patients with severe respiratory muscle weakness. However, the strength of the respiratory muscles must be reduced to as much as 50% of predicted before any significant reduction in lung volume is measured [
]. FVC is usually within the normal range in ambulatory or ambulatory with assistance (Kurtze Expanded Disability Status Scale, EDSS <7) MS patients (Table 3). In contrast, FVC is moderately decreased in wheelchair-bound and severely decreased (about 50% of predicted, Table 3) in bedridden patients [
], the FVC and/or MVV correlated with the level of disability as assessed by the EDSS scale. Arterial blood gases are usually normal in patients with adequate cough [
Pulmonary function tests that provide a more direct assessment of the respiratory muscles include measurements of upright and supine VC as well as measurement of MIP and MEP. Normally when someone assumes the supine position, VC is reduced by 10% or less of that measured in the seated position. In patients with unilateral diaphragm weakness, VC may be reduced by 10%–30% in the supine position [
]. The finding of normal MIP and MEP excludes clinically significant weakness. However, low values may have limited diagnostic utility since they may reflect poor effort, lack of cooperation, or poor coordination rather than true muscle weakness [
]. Measuring maximal sniff inspiratory pressure in the nostril via a special plug occluding one nostril may help in establishing inspiratory muscle weakness [
]. A special test that can be used to assess expiratory muscle strength is the measurement of cough gastric pressure. A balloon-tipped catheter is inserted through the nose or mouth and into the stomach. Gastric pressure is then measured during a forceful voluntary cough. Measurement of transdiaphragmatic pressure during magnetic or electrical stimulation are seldom needed in patients to exclude diaphragmatic weakness [
Cardio-pulmonary exercise testing in patients with mild disability but normal pulmonary and respiratory muscle function have shown that the exertional capacity is limited primarily due to muscle deconditioning [
]. In comparison to healthy controls, MS patients walked a significantly shorter distance, had a lower oxygen pulse, and a significant increase in the ventilatory equivalent of CO2 both at baseline and while walking [
Supportive care should include influenza and streptococcal pneumonia vaccinations, and prompt treatment of respiratory infections. Smoking cessation and maintenance of body weight within desirable range should be encouraged for patients with respiratory muscle weakness. Patients with weak respiratory muscles should avoid sedatives as these medications may precipitate hypercapnic respiratory failure.
Chest physiotherapy and use of cough assisting devises should be considered in patients with ineffective cough, especially during bouts of pneumonia [
]. In general, patients with neuromuscular disease and peak expiratory flows less than 270 L/min are at risk for respiratory complications and particularly pneumonia [
]. Cough assisting devices are indicated for patients with a MEP <60 cm H2O or a history of recurrent hospitalizations for pneumonia and an inability to clear bronchial secretions [
Non-invasive ventilation may be required during episodes of acute respiratory failure related to respiratory infections, neurogenic pulmonary edema or postoperatively following elective surgery [
]. In MS patients with nocturnal hypoventilation, noninvasive ventilation is indicated for long-term support if they have symptoms (fatigue, dyspnea, morning headaches) with either an elevated daytime PaCO2 or nocturnal oxygen saturation less than 88% for 5 consecutive minutes [
Acute respiratory failure precipitated by new demyelinating plaques involving respiratory motor pathways is treated as disease exacerbation with increased disability. Due to the rarity of this complication, controlled trials are not available. Intravenous methylprednisolone in a dosage of 1000 mg daily for 5 days, with or without tapering, is typically administered. Plasmapheresis should be considered in patients with acute respiratory failure not responding to IV steroids. In two placebo-controlled trials involving MS patients with severe neurological deficit but no acute respiratory failure, plasmapheresis was associated with significant benefit as shown by shortening of the average time to recovery to pre-attack disability [
]. In a report of six patients with fulminant central nervous system demyelynation treated with plasmapheresis, Rodriguez et al. described rapid improvement of respiratory failure in two mechanically ventilated patients after a course of plasmapheresis [
]. Intravenous immunoglobulin (IVIG) administered to a single patient with quadriplegia and acute respiratory failure resulted in resolution of respiratory failure and weaning off the ventilator [
]. As with other neuromuscular diseases, weakness of respiratory muscles may similarly progress in patients with MS. As disease progresses, the weak respiratory muscles in MS patients will very likely face pressure or flow respiratory loads that may further compromise their ability to sustain ventilation [
]. Pressure loads may result from any process that increases airway resistance (retention of secretions, bronchospasm) or reduces lung or chest wall compliance such as pneumonia, atelectasis or obesity. Flow loads can be seen when there is increased dead-space ventilation such as occurs in with rapid shallow breathing. These types of loads may predispose the respiratory muscles of patients with MS to fatigue [
One concern with training muscles in MS was the possibility that the weak and diseased muscles may not be able to adapt to training stimuli and that training exercises might increase weakness and fatigue [
]. The effect of respiratory muscle training in MS patients with mild to moderate disability has been assessed by several studies, mostly controlled (Table 4) [
Randomized control trial of effects of a 10-week inspiratory muscle training program on measures of pulmonary function in persons with multiple sclerosis.
]. In all studies, the training regimen consisted mainly of a respiratory incremental pressure load (inspiratory and/or expiratory) ranging from 30 to 60% of the corresponding maximal respiratory pressure and was administered for about 4–12 weeks. Post-training increases in MIP, MEP or both in the range 20–80% of the corresponding maximal respiratory pressures were reported in all studies. In the majority of studies [
] that addressed voluntary cough efficacy or dyspnea the improvements were not consistent. Therefore, despite improvements in respiratory muscle strength indices, questions still remain whether training of respiratory muscles in MS has any effect on specific clinical outcomes such as cough efficacy or pulmonary complications [
Randomized control trial of effects of a 10-week inspiratory muscle training program on measures of pulmonary function in persons with multiple sclerosis.
In conclusion, respiratory dysfunction may occur in MS, especially in patients with advanced stage of the disease and may manifest as acute or chronic respiratory failure, breathing control abnormalities, respiratory muscle weakness with ineffective cough, and neurogenic pulmonary edema. Respiratory muscle weakness, bulbar dysfunction and weak cough lead to frequent aspiration, lung infections and respiratory failure and contribute to morbidity and mortality in these patients. Early recognition of patients at risk for respiratory complications is important for provision of appropriate care and decreasing the disease associated morbidity and mortality.
Disclosure of conflicts of interest
The authors declare no financial or other conflicts of interest.
Randomized control trial of effects of a 10-week inspiratory muscle training program on measures of pulmonary function in persons with multiple sclerosis.
00021-9&id=gr1.jpg){kind=link}