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IBM and Respiration.

Site presented by Bill Tillier

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1). Key Facts.

2). Respiratory testing.

3). Noninvasive positive-pressure ventilation (NPPV) for restrictive lung disorders.

4). Pneumonia Vaccination.

5). Specific IBM Related Research.

6). Glossary:

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KEY FACTS:

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1a). Breathing Issues and IBM.

Incidence: Diaphragmatic involvement and respiratory issues have not been an issue highlighted in IBM research. However, recent research has drawn into question the incidence of respiratory related weakness in the inflammatory myopathies (PM, DM, IBM). Oldfors and Lindberg (2005) cite Teixeira et al, (2005) and report "weakness of the diaphragm is probably an underdiagnosed manifestation of inflammatory myopathies, including s-IBM." Subacute respiratory failure was reported in one patient with s-IBM who required mechanical ventilation (Voermans, et al, 2004).[See relevant research presented below]

Anecdotal evidence supports the finding that some IBM patients present with severe respiratory problems.

There are several things that could contribute to poor respiration and IBM cases, primarily and of most concern, direct weakness of the diaphragm or the chest muscles reducing the volume of air moved in and out of the lungs. In addition, poor posture both sitting in wheelchairs and in bed, laying in one position all-night, can constrict the chest and lungs. Finally, there could be an impact from some of the medications that some IBM patients take.

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1b). Neuromuscular disorders and sleep:

Quotations taken from article: Diaphragm muscle weakness becomes specifically manifest during REM sleep, when the diaphragm is, under normal circumstances, the only effective muscle pump. Patients who have diaphragm paralysis cannot breathe while supine, even in the awake state. Lesser forms of diaphragm muscle weakness become apparent during REM sleep, particularly if patients lie supine. Individuals who have neuromuscular disease and diaphragm involvement exhibit the greatest oxygen desaturations in REM sleep, so that this stage becomes a test of diaphragm muscle function. . . . Patients who have neuromuscular disease may have restrictive lung disorder as a consequence of chest wall muscle weakness, scoliosis, and pulmonary microatelectases that result from chronic hypoventilation, repeated episodes of aspiration, and retained secretions. . . . Sedentarism in patients who have altered muscular function promotes obesity, another factor that burdens ventilatory efficiency during sleep. Obese patients suffer mechanical reduction of intercostal muscle function, and subjects who have abdominal obesity exhibit marked diaphragm dysfunction that is particularly evident during REM sleep.. . . Patients who have neuromuscular disorders are at high risk for the development of sleep-related respiratory disorders and respiratory failure. A variety of concurring abnormalities converge in patients who have neuromuscular disorder that explain their vulnerable status. Diaphragm weakness and failure is the most important determinant of sleep-related respiratory insufficiency. . . . Noninvasive positive airway ventilation has revolutionized the treatment of most nocturnal respiratory abnormalities found in patients who have neuromuscular disorder. Positive pressure breathing corrects obstructive sleep apnea, improves hypoventilation, and assists diaphragm failure.
From: Culebras, Antonio (2005) Sleep and Neuromuscular Disorders. Neurol Clin 23,1209 1223.

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1c). General overview of respiration.

Air is breathed in through the nose and mouth. The air travels down through the trachea then through large and small tubes in your lungs called bronchial tubes. The airways (various tubes or passages) to your lungs look something like an upside-down tree with many branches. At the ends of the small bronchial tubes, there are groups of tiny air sacs called alveoli. The alveoli have very thin walls, and small blood vessels called capillaries run in the walls. If stretched out flat, the surface area of the lung would equal that of a tennis court. Oxygen passes from the alveoli into the blood in these small blood vessels. At the same time, carbon dioxide passes from the blood into the alveoli. Carbon dioxide, a normal byproduct of the body's metabolism, must be removed from the blood.

Breathing is an automatic function controlled by the brain. A complex feedback mechanism tells the brain how to breathe and how fast, for example, after exercise, we breathe faster and deeper. This control is accomplished through the levels of gases in the blood including the amount of oxygen and carbon dioxide. Abnormal levels can disrupt brain control of breathing leading to problems.

Thus, the two critical aspects of lung function are getting enough air in and out of the lung and having a proper and effective exchange of oxygen and carbon dioxide in the alveoli of the lung itself. IBM would affect the amount of air going in and out.

Oxygen and carbon dioxide play important but different rules in respiration. Although the body requires oxygen for metabolism, low oxygen levels do not stimulate breathing. Rather, breathing is stimulated by higher carbon dioxide levels. Sensory organs in the brain and in the aorta and carotid arteries monitor the blood and sense oxygen and carbon dioxide levels. Normally, an increased concentration of carbon dioxide is the strongest stimulus to breathe more deeply and more frequently. Conversely, when the carbon dioxide concentration in the blood is low, the brain decreases the frequency and depth of breaths. A person's exhaled breath is approximately 4.5% carbon dioxide. A person's breathing rate influences the level of CO2 in their blood. When respiration decreases, CO2 levels in the blood increase, likewise, excess levels of CO2 in the blood stimulate breathing to increase in frequency and become more deep. Breathing that is too slow or shallow can cause a serious symptom called respiratory acidosis, while breathing that is too rapid may lead to hyperventilation, which may cause the reverse problem, respiratory alkalosis. Respiratory acidosis is acidosis (abnormal acidity of the blood) due to decreased ventilation of the pulmonary alveoli, leading to elevated arterial carbon dioxide concentration (PaCO2). Initially, acidosis can be experienced as drowsiness or a headache but it is a serious symptom that can lead to coma. Chronic respiratory acidosis may be caused by neuromuscular disorders that reduce the volume of air flow.

Above based on: http://lungdiseases.about.com/od/termsdefinitions/f/howlungswork.htm (now defunct)

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When the diaphragm contracts, it moves down, the chest cavity enlarges, reducing the pressure outside the lungs. To equalize the pressure, air enters the lungs. When the diaphragm relaxes and moves back up, the elasticity of the lungs and chest wall pushes air out of the lungs. When laying on one's back, the normal respiratory function of the diaphragm can easily be observed, as the diaphragm moves down it puts pressure on the abdomen making the abdomen rise. Thus, as air enters the lungs, the chest and abdomen rise together, on a exhalation, the chest and stomach fall together. If the diaphragm is not functioning normally, paradoxical breathing (see below) can be observed -- as the chest rises on inhalation, the stomach falls as the diaphragm is not expanding down into the abdominal cavity. From: http://www.merck.com/mmhe/sec04/ch038/ch038e.html

There are two main categories of lung problems as follows:

1). Obstructive Lung Disorders: Essentially, the flow of air is obstructed in some way from smoothly going in and out of the lungs. Characterized by a limitation of expiratory airflow so that airways cannot empty as rapidly compared to normal (such as through narrowed airways from bronchospasm, inflammation, etc.). Examples: Asthma, Emphysema, Cystic Fibrosis.

2). Restrictive Lung Disorders: Essentially, there is nothing in the way but for some reason the normal volume of air is restricted and does not reach the lungs - chronic respiratory insufficiency. Characterized by reduced lung volumes/decreased lung compliance (this is where IBM would fall). Examples: Interstitial Fibrosis, Scoliosis, Obesity, Lung Resection, Neuromuscular diseases, Cystic Fibrosis

Airflow: Air flows to and from the alveoli as lungs inflate and deflate during each respiratory cycle. Lung inflation is accomplished by a contraction of respiratory, diaphragmatic, and external intercostal muscles, whereas deflation is passive. So, on inhalation, the diaphragm contracts (it is a muscle) and moves downward creating negative pressure (a vacuum) in the chest cavity and allowing the lungs to inflate (sucking air in), this can be easily seen as the chest and abdomen expand outwards together as the air goes in. On exhalation, the diaphragm relaxes and moves up as the air leaves the lungs, the chest and stomach fall together.

FRC is the volume of air in the lungs when the respiratory muscles are fully relaxed and no airflow is present. The volume of FRC is determined by the balance of the inward elastic recoil of the lungs and the outward elastic recoil of the chest wall. Restrictive lung diseases are characterized by a reduction in FRC and other lung volumes.

Reduced air volume: The main feature of restrictive disorders is reduced breathing volume. This means that there is less air coming into and going out from your lungs. There can be two effects, not enough oxygen received in and not enough carbon dioxide expelled out. As mentioned above, this type of problem often occurs at night and often disturbs your sleep. It can cause insomnia or excessive daytime sleepiness. It can also cause you to have a headache when you wake up in the morning. Low oxygen levels at night can contribute to heart problems. These problems include heart failure and high blood pressure. Low oxygen levels are more common during the REM stage of sleep.

Neuromuscular disorders affect an integral part of the respiratory system, a vital pump made up of the chest wall, pleura, and respiratory muscles. The respiratory pump can be impaired at several levels, including problems in the central nervous system, spinal cord, peripheral nervous system, neuromuscular junction, or in the respiratory muscle itself. The pattern of ventilatory impairment is highly dependent on the specific neuromuscular disease.

In the case of IBM, it is the possible effect on the diaphragm itself or the intercostal muscles that is of most concern. In practical, clinical terms, this is similar to the picture seen in amyotrophic lateral sclerosis. A weak diaphragm can be clearly seen as paradoxical breathing, explained below. Sleeping on one's back tends to worsen these symptoms.

Paradoxical breathing: In healthy breathing, the chest and abdomen expand out together on inhalation. When a person has paradoxical breathing they physically reverse the normal breathing process. With the person laying down, this is easily seen as the weak diaphragm is sucked up on the in breath causing a noticable lowering of the abdomen on inhalation - the chest expands while the abdomen falls. Paradoxical breathing is common in patients with sleep apnea and and is a sign of diaphragmatic weakening.

Common symptoms of restrictive disorders: Initially, symptoms may be relatively minor especially in the case of a slowly developing weakness. Symptoms are usually noticed initially at night often by disturbed sleep and shallow breathing. Headaches upon awakening may be a sign of increased carbon dioxide levels. Daytime tiredness or falling asleep easily during the day are also indicators of possible nighttime respiratory problems.

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2). Respiratory testing.

Baseline breathing measurements: In my opinion, anyone with a diagnosis of IBM should ask their physician for a referral to a respirologist for a breathing analysis. This usually entails taking a sample of arterial blood to analyze and a computer to take measurements as the patient blows in and out of a tube. This measures a number of different aspects of breathing and can easily determine if there are problems with the volume of air going in and out.

Baseline measurements can be helpful if breathing problems develop later on, as subsequent tests can be compared to the initial baseline to gauge how much of a decline has taken place.

The actual numbers derived from the tests are a general indicator and may be related to symptoms or not -- some people with low numbers have few symptoms, some people with better numbers may have a lot of symptoms. Again, these tests are important in helping the doctors determine how best to manage your particular situation.

Tidal volume: The amount of air that moves in or out in one normal breath (~500 ml.)
Inspiratory reserve volume: The amount of air that can be inhaled beyond the normal indrawn breath (~2900 ml.).
Expiratory reserve volume: The amount of air that can be exhaled beyond the normal exhaled breath (~1100 ml.).
Vital capacity: The amount of air that can be inhaled in the deepest breath and exhaled completely (~4500 ml.).
Vital capacity = tidal volume + inspiratory reserve volume + exploratory reserve volume.
Residual volume: The amount of air that cannot be expelled from the lungs no matter how hard one tries (~1200 ml.).
Total lung capacity: The amount of air that can be accommodated by the lungs. Total lung capacity = vital capacity + residual volume

Spirometry: The use of a spirometer (a machine) to measure vital capacity of the lungs.

The spirometry test is performed using a device called a spirometer. Most spirometers measure the volume and speed of airflow and display the following graphs that summarize respiratory function:
= a volume-time curve, showing volume (liters) along the Y-axis and time (seconds) along the X-axis.
= a flow-volume loop, which graphically depicts the rate of airflow on the Y-axis and the total volume inspired or expired on the X-axis.

These tests are very simple to take and take about 20 minutes to administer.

If more information is needed, a patient may have to go to a sleep lab for further diagnosis. For example, a polysomnogram, a complicated test that measures 16-24 variables recorded during an overnight stay, may be administered to help diagnose respiratory problems during sleep . An expert technician monitors the sleeping patient during the procedure.

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3). Noninvasive positive-pressure ventilation (NPPV) for restrictive lung disorders.

There have been several different techniques used to try to increase lung volume. In the old days, negative pressure was used to create a vacuum in the lungs to assist inhalation by making it easier to breathe in. Most people will remember the image of iron lung. These techniques using negative pressure are seldom used today.

Techniques using positive pressure to breath air into the lung have a long history;

And the Lord God formed man of the dust of the ground
and breathed into his nostrils the breathe of life,
and man became a living soul.
- Genesis

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3a). Manual Lung Volume Recruitment (LVR):

This procedure is done with a fairly simple piece of equipment called a bag valve resuscitator. The patient puts the end of the hose in his or her mouth, draws a full breath and then the bag is squeezed, either by the patient or by an assistant, introducing more air into the lungs. Three compressions usually constitute one treatment, three or four treatments are done three or four times a day. The patient may feel some minor discomfort during the inflation. This procedure forces the lungs to deeply inflate. This is especially important as it is common for areas of the lung to remain uninflated if breathing is shallow. This often causes a condition called atelectasis [AT-lect-toe-sees], essentially part of the lung is collapsed. If this condition goes on for some time, the air sacs of the lung may lose their elasticity and become fibrous preventing future inflation. Also, these areas are prone to accumulate mucus and material that may contribute to infection and pneumonia in the future.

The apparatus used is illustrated below.

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The valve circled is a special one-way valve to allow "breath stacking" that is, to allow multiple inflations. From: Hess, D. (2006). Noninvasive Ventilation in Neuromuscular Disease: Equipment and Application. Respiratory Care, 51, 896-912.

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3b). Mechanical Supplementation - CPCP and BiPAP:

Overview: In some cases, IBM can cause weakness in the diaphragm - the main muscle that is used in breathing. The presentation of a weak diaphragm is essentially the same as sleep apnea. During the night, the diaphragm cannot provide enough air volume and the person wakes up gasping for air. Another symptom is extreme fatigue during the day.
The treatment is similar to sleep apnea however, generally speaking, CPAP is used for sleep apnea. As I understand it, a BiPAP machine is preferred for IBM related diaphragm weakness. It's quite a bit more expensive and I have seen cases where they supply a CPAP because it is cheaper.
These are nighttime issues.

Some patients may progress to the point where breathing during the day is difficult. In these cases, a respirator can be used that attaches to a wheelchair. This will be illustrated below. These respirators usually have a hose that comes around in front of the person's face and they can suck on the end and a breath of air is provided. These machines are battery-operated and last about six hours. When at home, the machines can be plugged in.

CPAP: Continuous Positive Airway Pressure. In this technique, a machine is used to deliver a constant volume of air to the face throughout the breathing cycle. Thus, when exhaling you are exhaling against the flow of pressure, this has been compared to putting your head out of the window of a moving car and breathing, feeling the pressure of air coming at the face throughout the inhalation /exhalation cycle. CPAP is usually used in situations where alveoli need to be recruited and expanded such as with congestive heart failure and pneumonia.

BiPAP: Bi meaning two, PAP meaning Positive Airway Pressure. A BiPAP is a small machine used to provide a source of air that can be delivered through a hose and mask to a patient's lungs. A BiPAP (or BPAP) uses two different pressures; one higher pressure is used on inhalation, then the pressure drops to a lower pressure on exhalation. The pressurized flow of air to the airway and lungs helps you inhale more deeply and improves your body's exchange of oxygen and carbon dioxide. A BiPAP machine is about the size of a shoebox with a hose connected to a mask. To use the BiPAP, you have to wear a small mask over your nose when you sleep at night. Some people wear a mask that covers the nose and mouth. These machines are usually used initially at night where early respiratory problems disrupt sleep. The air passes through a humidifier and in some cases it can also be heated as required.

This positive pressure wave during inspirations unloads the diaphragm decreasing the work of breathing, therefore this form of ventilation has been used extensively in patients with chronic respiratory failure due to neuromuscular problems or chest wall abnormalities. In patients with respiratory failure, a common technique is begin with the expiratory level at 5 and the inspiratory level at 15. The levels are adjusted based on patient comfort, tidal volume achieved and blood gases.

BiPAP is a registered trademark of Respironics, Inc. Other manufacturers make VPAP and Bilevel machines that provide this same basic features.

Here are a couple of illustrations of typical machines.

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3c). Mechanical Supplementation - Portable ventilation (daytime):

Many years ago the only treatment for this kind of issue would be an iron lung and many people who had respiratory issues related to polio ended up in an iron lung. Today, compact battery-operated ventilators are used to supply air on demand to assist patients who require breathing support during the day. Generally speaking these patients will also be mobility impaired and will be in a wheelchair. The most common scenario is that a respirator is attached to the back of your wheelchair with a tube that goes around in front of your face. You can trigger a breath of air by gently sucking on the tube. Then, the volume corresponding to an average breath will be delivered by the machine. These systems are called non-invasive because there is nothing that enters the body. In some cases, usually involving spinal cord injuries, ventilation must be delivered by a tracheostomy tube that is inserted directly into the throat.
A common misconception is that these machines are providing oxygen. Generally speaking, supplemental oxygen is not required; it is the volume of regular room air that is the problem and when the person receives enough volume, generally speaking, they will be receiving adequate oxygen in that air. Supplemental oxygen is usually required in cases where the lung itself is compromised for example in COPD.

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4). Pneumonia Vaccination

Pneumonia is an inflammation of the lung caused by infection with bacteria, viruses, and other organisms. The pneumonia vaccine (Pneumococcal Vaccination) is a shot that can protect you from an infection called pneumococcal (pronounced "NEW-moe-kok-al") disease. The germ responsible for this disease can attack different parts of the body, including the lungs, causing pneumonia and blood stream (bacteremia). If it reaches the brain, it can cause meningitis. All of these are serious infections.

There are more than 80 different types of pneumococcus bacteria, currently 23 of these are covered by the vaccination. The pneumococcal polysaccharide vaccine (PPV) is injected to stimulate an immune response to produce antibodies directed against pneumococcus bacteria giving the patient protection. Usually, one injection protects for life although in some cases a booster may be required. Sometimes the injection is called a Pneumo-Vac.

This vaccination is recommended for the elderly and for people with chronic conditions that make them prone to developing chest infections.

Note: this is not the same as a flu vaccination which is generally given in the fall of the year. A different vaccination is prepared each year in anticipation for the upcoming flu season. There is some controversy whether IBM patients should be getting a flu vaccination or not, some doctors advocate for, some against.

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5). Specific IBM Related Research.


Latest research:

Goyal, N. A., Cash, T. M., Alam, U., Enam, S., Tierney, P., Araujo, N., . . . Mozaffar, T. (2016). Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement. Journal of Neurology, Neurosurgery, and Psychiatry, 87(4), 373-8. http://doi.org/10.1136/jnnp-2014-310008
Available here: pdf

Rodriguez Cruz PM, Needham M, Hollingsworth P, Mastaglia FL, Hillman DR. Sleep disordered breathing and subclinical impairment of respiratory function are common in sporadic inclusion body myositis. Neuromuscul Disord [Internet]. 2014 Aug 20 [cited 2014 Sep 18]; Available from: http://www.ncbi.nlm.nih.gov/pubmed/25227894
Available here: pdf

Della Marca G, Sancricca C, Losurdo A, Di Blasi C, De Fino C, Morosetti R, et al. Sleep disordered breathing in a cohort of patients with sporadic inclusion body myositis. Clin Neurophysiol [Internet]. International Federation of Clinical Neurophysiology; 2013 Apr 10 [cited 2013 Apr 23];124(8):1615-21. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23583020
Available here: 10.1016/j.clinph.2013.03.002.

(chronological order 2009-1989)

Muscle Nerve. 2009 Feb;39(2):144-9.

Obstructive sleep apnea in patients with inflammatory myopathies. Selva-O'Callaghan A, Sampol G, Romero O, Lloberes P, Trallero-Araguás E, Vilardell-Tarrés M.

Curr Opin Neurol. 2005 Oct;18(5):497-503.

Diagnosis, pathogenesis and treatment of inclusion body myositis.
Oldfors A, Lindberg C.
Goteborg Neuromuscular Center, Department of Pathology, Sahlgrenska University Hospital, Goteborg, Sweden bGoteborg Neuromuscular Center, Department of Neurology, Sahlgrenska University Hospital, Goteborg, Sweden.
PURPOSE OF REVIEW: We provide an update of progress gained from research into sporadic inclusion body myositis (s-IBM). RECENT FINDINGS: Most research on s-IBM has focused on the inflammatory reaction or the accumulation of pathological proteins in vacuolated muscle fibres. The inflammatory reaction is characterized by clonal expansions of lymphocytes, predominantly CD8 cytotoxic T cells, which invade and destroy muscle fibres. That costimulatory molecules have been identified demonstrates that muscle fibres can act as antigen presenting cells, and the expression of various chemokines in muscle indicates their importance in the immunopathogenesis of s-IBM. The region of interest for a susceptibility gene in the major histocompatibility complex has been narrowed, and for the first time it has been demonstrated that a chronic viral infection can trigger the inflammatory process leading to s-IBM. The nature of the accumulated material associated with the vacuoles has been extensively investigated over the past few years. Amyloid-b and phosphorylated tau protein in intracellular inclusions are a characteristic finding in s-IBM, which may lead to calcium dyshomeostasis and endoplasmic reticulum stress. The proteasomal system is upregulated, including immunoproteasomes. 'Molecular misreading' leading to ubiquitin mRNA mutations and accumulation of pathological ubiquitin in muscle fibres may be associated with proteasomal dysfunction. There is still no efficient treatment for s-IBM, but the effects of new, more specific immunotherapies have begun to be explored. SUMMARY: Recent findings indicate that both inflammatory reaction and abnormal protein accumulation are important for the pathogenesis in s-IBM. The link between them continues to await elucidation.

Neuromuscul Disord. 2005 Jan;15(1):32-9.

Diaphragmatic dysfunction in patients with idiopathic inflammatory myopathies.
Teixeira A, Cherin P, Demoule A, Levy-Soussan M, Straus C, Verin E, Zelter M, Derenne JP, Herson S, Similowski T.
Polymyositis, dermatopolymyositis, and inclusion body myositis imply chronic inflammation of skeletal muscles. Pulmonary complications include aspiration pneumonia, interstitial pneumonitis, or respiratory muscle myositis. This study aims at better describing their impact on respiratory muscle. Twenty-three consecutive patients (12 PM, 5 DM, 6 IBM) were studied (static inspiratory and expiratory pressures; diaphragm function in terms of the mouth and transdiaphragmatic pressure responses to bilateral phrenic stimulation). Pulmonary parenchymatous abnormalities were mild (6 cases) or absent. The mouth pressure produced by phrenic stimulation was 6.83+/-3.01 cm H2O, with 18 patients (78%) diagnosed with diaphragm weakness (<10 cm H2O) and lower values in DM (4.35+/-1.48 cm H2O) than in IBM and in PM (P<0.05). Diaphragm weakness is frequent and probably overlooked in inflammatory myopathies. Further studies are needed to delineate the clinical relevance of these results.

Quotes from article:
Polymyositis (PM), dermatopolymyositis (DM), and inclusion body myositis (IBM) are auto immune diseases defined by an idiopathic chronic inflammation of skeletal muscles. Their main clinical expression is limb muscle weakness. Cardiac, gastrointestinal and respiratory complications can occur. The latter are major sources of morbidity and mortality [1] and include aspiration pneumonia and instertitial pneumonitis (up to 40% of PM and DM patients) [2]). In addition, respiratory muscle can obviously be involved by the inflammatory process but prevalence data are scarce. This is however potentially clinically relevant. Indeed, besides dyspnoea, diaphragm dysfunction reduces the ability of the respiratory system to face sudden increases in ventilatory demand. In the context of inflammatory myopathies, this could explain some of the episodes of acute respiratory failure that sometimes punctuate the course of the disease. Diaphragm dysfunction also causes hypoventilation during sleep [3] and disrupt sleep architecture [4], leading to daytime sleepiness, impaired cognition, and a poor quality of life. This forms the logical basis of treatment by nocturnal positive pressure ventilation. Amyotrophic lateral sclerosis provides a good illustration of the clinical relevance of diaphragmatic dysfunction in neuromuscular diseases. In this setting, diaphragm dysfunction correlates with dyspnoea [5], disorganised sleep [4] and a reduced survival [4]. This explains how positive pressure ventilation can prolong survival [6] and improve quality of life [7]. Of note, the consequences of sleep-related hypoventilation on oxygenation will be more severe in the presence of preexisting gas exchanges abnormalities. Such abnormalities are not uncommon during inflammatory myopathies, because of the frequency of aspiration pneumonia or interstitial lung disease. Therefore, diagnosing diaphragm dysfunction could be germane to the clinical management of patients with inflammatory myopathies.

The salient finding of this study, conducted in a relatively large cohort of unselected patients with inflammatory myositis, is a prevalence of diaphragm dysfunction (defined according to modern non-volitional diaphragm testing techniques) in excess of 75%. This suggests that the involvement of the respiratory muscles by the myositic process is more frequent than generally thought and implies that the diagnosis is probably overlooked.

Neurology. 2004 Dec 14;63(11):2191-2.

Primary respiratory failure in inclusion body myositis.
Voermans NC, Vaneker M, Hengstman GJ, ter Laak HJ, Zimmerman C, Schelhaas HJ, Zwarts MJ.
Neuromuscular Centre Nijmegen, Department of Neurology, University Medical Centre Nijmegen, The Netherlands.
Case report. A 58-year-old woman sought treatment for slowly progressive muscle weakness, dysphagia, and weight loss. Her medical history was unremarkable, and she did not use any myotoxic drugs. Physical examination revealed normal speech, mild facial weakness, dysphagia without aspiration, and generalized muscle weakness (Medical Research Council [MRC] score, 4) with asymmetric weakness of the forearm muscles (right, MRC 4; left, MRC 3). Muscle atrophy was most pronounced in the quadriceps muscles. Creatine kinase was mildly increased (285 U/L; normal, =180 U/L). Nerve conduction studies were normal. EMG demonstrated spontaneous activity and a mixed pattern of shortduration low-amplitude and long-duration high-amplitude motor unit potentials at submaximal voluntary contractions. By EMG, forearm flexor muscles were more involved than forearm extensor muscles. Muscle biopsy from the anterior tibial muscle revealed a small number of muscle fibers surrounded by collagen, fat cells, and inflammatory infiltrates. IBM was diagnosed according to established criteria, and the patient was referred to a rehabilitation clinic.
Eight months after initial presentation, she gradually developed shortness of breath on exertion. She subsequently experienced morning headaches, excessive daytime sleepiness, and confusion. One day she was found unconscious as a result of severe hypercapnia and hypoxemia and required intubation and mechanical ventilation. Arterial blood gas analysis after intubation showed elevated PCO2 (7.9 kPa = 806 mm H2O) and bicarbonate (33.7 mmol/L), reflecting chronic hypoventilation. Ancillary investigations showed no signs of cardiac disease or respiratory infection. Initially, nighttime apneas occurred lasting up to 45 seconds with hypercapnia (PCO2 8.2 kPa = 836 mm H2O) and elevated bicarbonate (34.8 mmol/L), after which mechanical ventilation was adjusted. Apparently, the respiratory drive in our patient was depressed during sleep. This probably resulted from bicarbonate retention and sleep deprivation caused by frequent arousals during REM sleep because of hypercapnia.7 Her general condition improved, and the need for daytime ventilatory support decreased. She underwent tracheotomy and thereafter required volume-regulated ventilation for 2 hours in the afternoon and at night. Two months after admission, she was discharged home on continued mechanical ventilation.
The presence of severe respiratory failure made us reconsider her diagnosis. Empirical treatment with prednisone (50 mg daily for 4 weeks) resulted in minimal increase in muscle strength. Nerve conduction studies of the phrenic nerve demonstrated low amplitudes of the compound motor action potential of the diaphragm bilaterally. EMG revealed poor recruitment without spontaneous activity of the diaphragm and intercostal muscles. Muscle biopsy from the tibialis anterior showed myopathic changes with invasion of non-necrotic muscle fibers by mononuclear cellular infiltrates, basophilic rimmed vacuoles, and sarcolemmal HLAABC positivity of all muscle fibers, consistent with the diagnosis of IBM6 (figure). Pulmonary function testing revealed mildly impaired vital capacity (1.87 L; normal, 2.60 L) and decreased mouth pressures (maximal expiratory pressure, 3.01 kPa = 307 mm H2O; normal, 8.90 kPa; maximal inspiratory pressure, 1.90 kPa = 193 mm H2O; normal, 6.90 kPa), reflecting an extraparenchymal restrictive pattern. It was concluded that the patient had IBM6 with respiratory muscle weakness, which had resulted in primary respiratory failure.
Discussion. Respiratory failure in patients with IBM is generally believed to occur only secondary to aspiration pneumonia or coincidental pulmonary or cardiac disease. Primary respiratory failure has, to the best of our knowledge, been reported only twice in literature. One of these reported patients had a concomitant human T-cell lymphotropic virus type infection. In our patient, respiratory failure resulted from hypoventilation caused by weakness of the diaphragm and intercostal muscles. Our limited awareness of this manifestation of IBM delayed its recognition and resulted in life-threatening respiratory failure. Only then the ventilatory support was started, and the vicious circle of respiratory muscle weakness, hypoventilation, hypercapnia, sleeping vproblems, deterioration of the general condition, weight loss, and severe respiratory failure was broken. Moreover, we started highdose corticosteroid treatment, which involves a risk of serious adverse effects. In conclusion, primary respiratory failure can occur in patients with IBM, and awareness of this potentially lifethreatening complication is warranted, especially for patients with signs and symptoms suggestive of hypoventilation.

J Neurol Neurosurg Psychiatry. 2002 May;72(5):650-2.

Human T cell leukaemia virus type I associated neuromuscular disease causing respiratory failure.
Littleton ET, Man WD, Holton JL, Landon DN, Hanna MG, Polkey MI, Taylor GP.

Polymyositis and inclusion body myositis have rarely been described in association with human T cell leukaemia virus type I (HTLV-I) infection. Most of such patients have coexisting HTLV-I associated myelopathy (HAM). Two patients with HTLV-I infection, myopathy, and respiratory failure are described. The muscle biopsy specimen of the first patient bore the histological features of inclusion body myositis and there was no evidence of concurrent myelopathy. The second patient had HAM, and her muscle biopsy showed non-specific myopathic and neuropathic changes. Both patients developed respiratory muscle weakness over eight years after diagnosis of myopathy, leading to hypercapnic respiratory failure requiring mechanical ventilatory support. Respiratory failure as a complication of HTLV-I associated myopathy has not previously been described.
from the discussion: The myopathogenic mechanism underlying the association with HTLV-I infection is not proven, but has previously been supported by the detection of the virus within inflammatory cells invading muscle tissue in patients with polymyositis and inclusion body myositis. Our first patient is only the third reported case of HTLV-I associated inclusion body myositis. Furthermore, our two patients are the first reported cases to suggest that HTLV-I infection can cause disease of the proximal and respiratory muscles of such severity as to cause ventilatory failure.

Medicina (B Aires). 2002;62(1):37-40.

[Inclusion body myositis. Report of 4 cases][Article in Spanish]
Basquiera AL, Caeiro F, Palacio S, Theaux R, Casale A, Lucero C, Alvarellos A.
Inclusion body myositis (IBM) is a primary inflammatory myopathy characterized by an older age at presentation. We describe four IBM cases fulfilling Mendell's diagnostic criteria. All patients were older than 60 years at diagnosis and the mean length of time from onset to diagnosis was 5.7 years. Two of them complained of leg weakness with unsteady gait and the other two, of upper limb weakness. Three patients had dysphagia, one of them had diaphragmatic paralysis and another had bilateral blepharoptosis. Histological sections of the muscle biopsy showed mononuclear cell invasion of nonnecrotic muscle fibers, rimmed vacuoles, intracellular amyloid deposits and 16-21 nm tubulofilaments by electron microscopy. Mitochondrial anomalies were found in two cases. Only one patient had transient response to steroid therapy. Our serie shows that clinical presentation of inclusion body myositis includes a broader spectrum than the classical description.

Intern Med 2001; 40:940-944.

Mori S, Hamada H, Yokoyama A, et al.
Severe inclusion body myositis with interstitial pneumonia.
We report a patient with a severe inclusion body myositis (IBM). His illness was unusual in terms of a rapid progression, high creatine kinase levels, and complication with interstitial pneumonia. He responded well to immunosuppressive agents such as corticosteroids, cyclosporin A, cyclophosphamide, and immunoglobulin. The present patient indicates the wide range of the disease, and that immunosuppressive agents may be useful for treatment of IBM.

Chest. 1993 Sep;104(3):975-7.

Inclusion body myositis as a cause of respiratory failure.
Cohen R, Lipper S, Dantzker DR.
Inclusion body myositis (IBM) is a slowly progressive myopathy that has not been reported to affect respiratory muscles. It is often refractory to treatment and a muscle biopsy specimen is necessary for the diagnosis. This is a report of a patient with IBM who quickly progressed to respiratory muscle failure requiring intubation.
CASE REPORT
A 69-year-old woman was admitted to the ICU with respiratory failure. She had a 10-day history of progressive shortness of breath, cough, lethargy, and weakness. There was no history of fever, sweats, or chills. The patient was hospitalized in 1987 with a similar presentation. At that time, she had complained of a 2-week history of progressive dyspnea and slowly worsening limb weakness for the preceeding five years. The electromyogram (EMG) at that time was compatible with a myopathy; however, the creatine kinase (CK) and liver function test results were normal. She was found to have an elevated partial thromboplastin time (PTT) that was shown to be due to a lupus anticoagulant. Her antinuclear antibody (ANA) titer was 1:320. Her platelet count was normal as were the results of her thyroid function tests. A Tensilon test was negative. The chest radiograph was normal. She required mechanical ventilation and was treated as having mixed connective tissue disease and received large doses of intravenous methylprednisolone sodium succinate (Solu-Medrol). Her hospital course was complicated by multiple infections that were, in part, attributed to the large doses of steroids. As there was no clinical improvement, the steroid therapy was discontinued. The patient underwent a muscle biopsy from the left quadricep that showed isolated myofiber degeneration, atrophic fibers, and no inflammatory infiltrates. She was discharged from the hospital 1 year later with a diagnosis of idiopathic myopathy. She remained well until the present hospital admission without worsening of the myopathy or further respiratory problems.
The physical examination showed the patient to be in moderate respiratory distress. She had petechiae on both calves and poor air entry in the lungs, which were otherwise clear. The neurologic examination showed her to be alert and oriented, with distal muscle atrophy and strength that was rated as 1/5. There was also proximal muscle weakness rated as 3/5. Findings from the sensory examination were normal. Deep tendon reflexes were rated as 1/3 in the lower extremities and 2/3 in the upper. The plantar reflexes were downgoing. Laboratory tests showed a platelet count of 19,000/[mu]l and a hemoglobin of 12 g/dl. The white blood cell count and differential cell count were normal; she had a PTT of 51.7 s with a normal prothrombin time. The ANA titer was 1:640, anti dsDNA was normal. The arterial blood gases revealed a pH of 7.40, a [PCO.sub.2] of 49 mm Hg, and a [PO.sub.2] of 55 mm Hg on room air. The CK, lactate dehydrogenase, and liver function test results were normal. The chest radiograph was normal. She refused to perform a tidal volume maneuver. The negative inspiratory force was -- 12 cm [H.sub.2]O. The EMG was again consistent with myopathy.
Her respiratory status quickly deteriorated requiring intubation. The low platelet count was thought to be secondary to immune thrombocytopenia and responded to intravenous immunoglobulin therapy with normalization of the count. A muscle biopsy specimen revealed occasional fibers containing small round or angular vacuoles situated centrally or peripherally. Vacuoles showed granular rimming with the modified Gomori stain (Fig 1). Electron microscopy showed the vacuoles to contain membranous whorls and rare tubulofilaments (Fig 2). The features were those of IBM. The patient's course worsened after she developed an upper gastrointestinal tract bleed and sepsis; she died due to complications of the sepsis.
DISCUSSION
Inclusion body myositis is an inflammatory muscle disorder that was initially thought to be due to a viral etiology although that remains unproven.[1] There is a 2:1 male preponderance, and the onset is usually after age 50 years. The average duration from onset of symptoms to diagnosis has ranged from 5 to 19 years.[2] This disease is usually characterized by a slow but progressive course, distal muscle weakness, and resistance to immunosuppressive therapy. The weakness and atrophy can be asymmetric, with selective involvement of the quadriceps, iliopsoas, triceps, and biceps muscles. Early loss of the patellar reflex can occur due to the quadricep weakness and a neurogenic disease is often suspected.[2,3] This disorder can clinically mimic idiopathic polymyositis and in one report accounted for almost one third of the adults with "polymyositis unresponsive to therapy."[3] The occurrence of respiratory failure due to IBM is distinctly unusual.
While dysphagia has been noted to occur in 40 percent of those affected, our patient did not complain of any swallowing difficulties and there was no clinical or radiologic evidence of aspiration. Lotz et al[2] reported a 55 percent incidence of cardiovascular signs and symptoms such as hypertension, ECG changes compatible with ischemia, and rhythm disturbances in their 40 patients. Other diseases such as malignancy and diabetes have been associated with IBM,[2] but to our knowledge, respiratory muscle weakness had not been reported. The positive ANA, immune thrombocytopenia, and antiphospholipid antibody present in our patient give evidence of disturbed immune regulation. Both elevated ANA titers and thrombocytopenia were reported in patients with IBM;[2,3] we have found no reported association with lupus anticoagulant. Serum CK levels can be up to 10-fold elevated or normal.[3] Electromyographic findings are those of a myopathy, although there is occasionally evidence of a neuropathy.[1,2,4] A muscle biopsy specimen is important in excluding primary neuropathic disease and in diagnosing IBM and distinguishing it from other myopathies that may cause respiratory failure such as polymyositis and systemic lupus erythematosus. Not only is the natural history of IBM different, but since it is refractory to treatment with corticosteroids and cytotoxic agents, the correct diagnosis can spare the patient the side effects associated with these medications. It is important to obtain the biopsy specimen from muscles where the inflammation is active and the biopsy site should be correlated with activity on the EMG.[4,5] The inflammation may be distributed in a patchy fashion as likely was the case in our patient and occasionally multiple or repeated biopsy specimens are needed to establish the diagnosis. Review of first biopsy specimen did not show any evidence of IBM. It is likely that the patient had IBM when she was first admitted to the hospital in 1987. However, for the above-mentioned reasons, the diagnosis was not made on the initial muscle biopsy specimen. A low index of suspicion, as IBM is thought to evolve slowly, and the lack of reported respiratory muscle involvement contributed to the lack of earlier recognition in the present case.

Brain. 1989 Feb;112 ( Pt 1):65-83.

Distal myopathy with rimmed vacuole formation. A follow-up study.
Sunohara N, Nonaka I, Kamei N, Satoyoshi E.
A long-term follow-up study of patients with familial distal myopathy with rimmed vacuole formation and a review of the literature indicates that the prognosis of the disorder was extremely poor as to daily life. Although the initial symptom appearing in early adulthood was muscular wasting and weakness in the legs, especially the distal muscles, severe generalized skeletal muscle involvement with sparing of the facial, extraocular, bulbar, intercostal and diaphragm muscles was recognized in the advanced stage. The disease is probably inherited as an autosomal recessive trait, while there is a considerable female preponderance, the female-to-male ratio being 2:1. The disorder is distinguishable from various types of distal myopathy on the basis of clinical and pathological findings, and other myopathies with rimmed vacuole formation, including inclusion body myositis, from a prognostic viewpoint.

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6). Glossary:

Alveoli / Alveolus: [Ave-VOLE-ee] The alveoli are the final branchings of the respiratory tree and perform gas exchange for the lung. The thin gas-blood barrier between the alveolar space and the pulmonary capillaries allows for rapid gas exchange. Oxygen and carbon dioxide diffuses through the alveolar epithelium and the capillary endothelium.

Arterial blood gas: Arterial blood gas is the concentration of oxygen and carbon dioxide carried in arterial blood. Arterial blood gas analysis is a test in which blood is taken from an artery in your wrist to evaluate how effective your lungs are in bringing oxygen to the blood and removing carbon dioxide from it.
The following 4 "rules" of ABG interpretations help in evaluation:
1) For every acute rise of 10 in PCO2 the bicarbonate will rise by 1
2) For every chronic rise of 10 in PCO2 the bicarbonate will rise by 4
3) For every fall by 10 in PCO2 the bicarbonate will fall by 2
4) For every acute rise of 10 in PCO2 the PH will fall by 0.1

Assisted Cough Manoeuvre: A manually Assisted Cough Manoeuvre involves the application of an abdominal thrust or costal lateral compression using various hand placements after an adequate spontaneous inspiration or maximal insufflation.

Atelectasis [AT-lect-ta-sees or A-Tell-lect-ta-sis]is a partial or total collapse of the lung. It occurs when all the gas in the alveoli is absorbed and not replaced.

Diaphragm: [DIE-a-fram] The diaphragm is the muscular partition located between the chest cavity and the abdominal cavity. It plays a major role in respiration. During inspiration, the diaphragm descends, the inspiratory muscles contract, and the rib cage rises. During expiration, the diaphragm rises, the inspiratory muscles relax, and the rib cage descends.

Dyspnea [DIS-me-ah] is a term used to describe difficulty in breathing. Dyspnea is a common symptom of many lung diseases. Shortness of breath, short of breath, difficulty breathing, breathing difficulty

FEF Max: The maximum Forced Expiratory Flow rate (FEF) measured during a Force Vital Capacity (FVC) manoeuvre.

FRC is the volume of air in the lungs when the respiratory muscles are fully relaxed and no airflow is present.

GPB: Glossopharyngeal [GLOSS-off-fur-IN-gee-ILL] Breathing (GPB) is a "frog-like" method of breathing, which consists of stroke-like action of the tongue along with constricting action of the pharynx pumping air through the larynx into the lungs.

Hypoxia: a shortage of oxygen in the body.

Hypopnea is a medical term for abnormally shallow breathing or slow respiratory rate. Among the causes of hypopnea are neuromuscular disease or any condition that entails weakened respiratory muscles. For people with neuromuscular disorders the most common treatment is the use of BIPAP or other non-invasive ventilation.

Intercostal muscles: The intercostal muscles are located between the ribs.

There are two kinds of intercotal muscles: internal and external. The intercostal muscles are controlled by the brain (medulla). The internal intercostal muscles are located on the inside of the ribs and extend from the front of the ribs, around back and past the bend in the ribs. The external intercostal muscles are located on the outside of the ribs, and wraparound the back of the ribs.

LVR: Lung Volume Recruitment (LVR) refers to breath stacking, techniques allowing for maximum insufflation capacity.

MIC: The Maximum Insufflation Capacity (MIC) measurement (litres) is the maximum volume of air stacked within the patient's lungs beyond spontaneous vital capacity. MIC is attained when the patient takes a deep breath, holds his breath and then breath stacking is applied using a LVR resuscitation bag, a volume ventilator or glossopharyngeal breathing (GPB). When measuring a MIC, the therapist should assist the patient with his/her optimal insufflation technique, introduce the spirometer in the post mode and instruct the patient to completely exhale the MIC volume through the spirometer. The documented volume must be clearly identified as a MIC and not a post bronchodilator study.

Peak expiratory flow rate: The peak expiratory flow rate measures how fast a person can breath out (exhale) air. It is one of many tests that measure how well your airways work.

Obstructive sleep apnea (OSA). A common type of sleep apnea caused by obstruction of the airway. It is characterized by pauses in breathing during sleep called apneas (literally, "without breath"), each last long enough that one or more breaths are missed, and occurring repeatedly throughout sleep. In obstructive sleep apnea, breathing is interrupted by a physical block to airflow, despite the effort to breath.

PCF: Peak Cough Flow (PCF) is measured by using a peak flow meter.
The PCF is the velocity of air being expelled from the lungs after a cough manoeuvre. This measurement can be expressed in L/min or L/sec (L/min divided by 60).
It is useful to measure:
- spontaneous PCF (PCF sp)
-PCF from MIC (PCF bag, PCF vent, or PCF gpb)
-PCF from MIC with an assisted cough timed with the cough (PCF bag & assist, PCF vent & assist or PCF gpb & assist)

Pneumonia is a common lung infection that affects millions of people each year. Pneumonia is characterized by an inflammation of the lungs caused by a bacteria, virus, or fungus. Pneumonia can be mild, moderate, severe, or even fatal. Since the symptoms of a cold are similar to the symptoms of pneumonia, it's difficult to tell which illness you might have.

Polysomnogram: An overnight sleep test used to diagnose sleep related problems.

Respiratory acidosis is acidosis (abnormal acidity of the blood) due to decreased ventilation of the pulmonary alveoli, leading to elevated arterial carbon dioxide concentration (PaCO2). Chronic respiratory acidosis also may be caused by neuromuscular disorders that reduce the volume of air flow.

Sleep apnea, is a sleep disorder characterized by pauses in breathing during sleep. These episodes, called apneas, each last long enough so one or more breaths are missed, and occur repeatedly throughout sleep. Breathing is interrupted by the lack of effort in central sleep apnea; in obstructive sleep apnea, breathing is interrupted by a physical block to airflow despite effort. In mixed sleep apnea, there is a transition from central to obstructive features during the events themselves.

Spiromety is a pulmonary function test that measures the air volume and flow rate within the lungs. It is used to diagnosis lung diseases and determine treatment.

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