Pulmonary Medicine

Neuromuscular Disorders Affecting the Thorax: Duchenne and Becker Muscular Dystrophy

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What every physician needs to know:

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are progressive myopathies that are inherited as X-linked recessive traits.

Classification

Not applicable.

Are you sure the patient has Duchenne or Becker Muscular Dystrophy? What should you expect to find?

Notable clinical features of DMD include symptom onset early in life, usually at two or three years of age. Gait disturbances and delayed motor development are early presenting symptoms. A “honeymoon" period, between ages 3 and 6 years, during which there may be transient improvement, may occur. However, following the honeymoon period, clinical deterioration is noted, and the patient is usually wheelchair-bound by age thirteen. The clinical course may be complicated by intestinal hypomotility, leading to “pseudo-obstruction.”

Notable clinical features of BMD include disease onset occurring between the ages of five and fifteen years, although in some instances, onset is in the third or fourth decade of life. The early clinical course in BMD is milder than that in DMD, and patients become wheelchair-bound at age sixteen or older. The disorder is associated with clinically significant cardiomyopathy during the teenage years, and gastrointestinal involvement in BMD is usually absent.

Features of the physical examination in both DMD and BMD include symmetric weakness in the limb girdle muscles, weakness in proximal and lower limb muscles prior to involvement of distal and upper extremity muscle groups, and so-called "pseudohypertrophy" of calf muscles. Gower sign may be noted: affected children use hand support to push themselves to an upright position when trying to stand from the floor. Finally, cognitive impairment affecting memory and executive functions has been reported.

Beware: there are other diseases that mimic Duchenne and Becker Muscular Dystrophy.

Limb-girdle muscular dystrophy may mimic DMD and BMD.

How and/or why did the patient develop Duchenne or Becker Muscular Dystrophy?

Both Duchenne and Becker muscular dystrophies are caused by mutations in the gene for the skeletal protein, dystrophin. Dystrophin gene mutations are caused by gene deletions in 65% of patients with DMD and 85% of those with BMD.

Which individuals are of greatest risk of developing Duchenne or Becker Muscular Dystrophy?

DMD is the most common muscular dystrophy, occurring with an incidence of 1 in 3300 male births. Its prevalence is 3 in 10,000. BMD is less common than DMD, and it has a milder clinical course. The familial history suggests X-linked inheritance, and female carriers may have early onset, progressive muscular dystrophy if one of the following genetic abnormalities is also present: 45X, 46XY, or Turner mosaic karyotypes. The genetics are characterized by balanced X-autosome translocations with breakpoints in Xp21 within the dystrophin gene, accompanied by preferential inactivation of the normal X chromosome. Although the karyotype is normal, non-random (skewed) X-chromosome inactivation leads to diminished expression of the normal dystrophin allele.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Measurement of serum creatine phosphokinase (CPK) may be useful in the evaluation of suspected DMD or BMD. Several results may indicate presence of the condition:

  • Marked elevation in CPK levels

  • Elevation in CPK prior to the appearance of clinical signs

  • Elevation in CPK, even among newborns

  • Levels of CPK peak by age two years and may be ten to twenty times the upper limit of normal or even higher

  • As muscle is replaced by fat and fibrosis, CPK levels begin to fall by 25% per year.

  • A mild elevation in CPK (e.g., three times the upper limit normal) in 50% to 70% of symptomatic female carriers.

Aldolase levels may also be increased.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of Duchenne or Becker Muscular Dystrophy?

See the management section, below.

What imaging studies will be helpful in making or excluding the diagnosis of Duchenne or Becker Muscular Dystrophy?

See the management section below.

What diagnostic procedures will be helpful in making or excluding the diagnosis of Duchenne or Becker Muscular Dystrophy?

EMG findings in DMD and BMD reflect myopathic changes characterized by small polyphasic potentials.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of Duchenne and Becker Muscular Dystrophy?

Documentation of mutation of the dystrophin gene in DNA isolated from peripheral leucocytes confirms the diagnosis of muscular dystrophy. In normal patients, dystrophin is easily detected on immunoblots of 100 µg of total muscle protein and may be evaluated either visually or by using densitometry. The quantity and quality of the dystrophin varies with the different disorders. In DMD, dystrophin is completely or nearly completely absent. In BMD, 85% of patients have dystrophin of abnormal weight; and dystrophin levels are frequently reduced.

Dystrophin immunoblotting can be used to quantify the level of dystrophin. DMD is characterized by less than 5% of the normal quantity of dystrophin. Dystrophin levels between 5-20% of normal, regardless of protein size, correlate with the intermediate phenotypes of mild DMD or severe BMD. Levels between 20% to 50% of normal are associated with mild or moderate BMD.

Myopathic changes on muscle biopsy include fiber degeneration and regeneration, isolated "opaque" hypertrophic fibers, and significant replacement of muscle by fat and connective tissue.

If you decide the patient has Duchenne or Becker Muscular Dystrophy, how should the patient be managed?

Evaluation of Pulmonary Status in Muscular Dystrophy

Pulmonary findings may be minimal early in the disease, even though significant respiratory muscle weakness is already present. Serial measurements of forced vital capacity and maximum inspiratory force may help detect respiratory muscle weakness. It is important to note that vital capacity (VC) measurements may be misleading because VC increases with growth during the first decade of life before reaching a plateau and then progressively declines with increasing duration of the disease. Maximum inspiratory force is a more useful test than VC during the formative years, as it declines gradually despite body growth. After age twelve years, VC decreases by about 5-6% per year.

Baseline pulmonary function tests should be obtained prior to wheelchair confinement, which usually occurs at about nine or ten years of age. Pediatric evaluations should be obtained twice annually once the patient is confined to a wheelchair, when vital capacity falls below 80% predicted, or when the patient reaches age twelve. After initial screening, a more complete battery of pulmonary function tests may be needed to evaluate respiratory muscle endurance further, to determine the magnitude of expiratory muscle weakness, to assess selective weakness of specific respiratory muscle groups, and/or to delineate abnormalities in lung and chest wall mechanics.

Maximal voluntary ventilation (MVV) is useful in detecting respiratory muscle fatigue, but its measurement should be avoided in very weak patients. Measurement of maximal expiratory pressure (MEP) is important since a MEP less than 60 cm H20 is associated with ineffective cough and inability to clear airway secretions. Measurement of maximal inspiratory force (MIP) may miss predominant involvement of the diaphragm since MIP reflects global inspiratory muscle strength. Weakness of the diaphragm may be assessed by measuring transdiaphragmatic pressure (an invasive measurement), or it may be inferred when VC declines by 25% in changing from a seated to supine position. Fluoroscopic visualization of diaphragmatic excursion (the so-called "sniff test") may be useful as part of diaphragm assessment, but it is not sensitive enough to detect mild diaphragmatic weakness.

Respiratory Interventions in Muscular Dystrophy

A series of stepwise interventions can be considered in the respiratory management of patients with muscular dystrophy:

  • When VC is less than 40% predicted, lung volume recruitment should be attempted using a self-inflating manual ventilation bag or mechanical insufflation.

  • Manual and mechanically assisted cough techniques should be considered when respiratory infection is present and baseline peak cough flow is less than 270 L/min, when baseline peak cough flow is less than 160 L/min or MEP is less than 40 cm water, or when baseline VC is less than 40% predicted or less than 1.25 L in an older teenager or adult.

  • Nocturnal ventilatory support should be undertaken when signs or symptoms of hypoventilation are present. (Patients with a VC less than 30% predicted are at especially high risk.) Nocturnal ventilatory support should also be undertaken when baseline pulse oximetry is less than 95%; blood or end-tidal PCO2 is greater than 45 mmHg while the patient is awake; the apnea-hypopnea index is greater than ten per hour on polysomnography; or when there are four or more episodes of pulse oximetry recordings under 92% or drops in pulse oximetry of at least 4% per hour of sleep. Ideally, lung volume recruitment and assisted cough techniques should precede initiation of noninvasive ventilation.

  • Daytime ventilatory support is indicated for daytime hypercapnia (which typically occurs when FEV1 is less than 20% predicted); for self-extension of nocturnal ventilation into waking hours; in the presence of abnormal deglutition due to dyspnea that is relieved by ventilatory assistance; when the patient is unable to speak full sentences without breathlessness; or when symptoms of hypoventilation are associated with baseline pulse oximetry recordings under 95% or blood or an end-tidal PCO2 over 45 mmHg while awake. Continuous, noninvasive, assisted ventilation and mechanically assisted cough may facilitate extubation following intubation for an acute illness or during anesthesia.

  • Management guidelines include long-term use of continuous (i.e., 24 hours daily) noninvasive ventilation in eligible patients. Indications for tracheostomy include patient or clinician preference; inability of the patient to use noninvasive ventilation successfully; inability of the local medical infrastructure to support use of noninvasive ventilation; documentation of three failures to achieve extubation during critical illness, despite optimal use of noninvasive ventilation and mechanically assisted cough devices; failure of noninvasive methods and cough assist devices to prevent aspiration; and drops in oxygen saturation below 95% at baseline, necessitating frequent direct tracheal suctioning.

Role of Polysomnography

Polysomnography may help in identification of nocturnal hypoventilation during rapid eye movement (REM) sleep, during which the activity of the chest wall and neck muscles is diminished and ventilation is achieved primarily through diaphragm function. Sleep-related hypoxemia may contribute to respiratory insufficiency and to development of cor pulmonale. In the setting of sleep-disordered breathing, use of nocturnal non-invasive ventilation improves gas exchange, prevents nocturnal desaturation, attenuates progressive decline in lung function, improves survival, improves sleep quality, decreases daytime sleepiness, and improves the patient's sense of well-being and independence.

Role of Chest Radiography

Chest radiography is helpful in detecting kyphoscoliosis, which is common in the muscular dystrophies and contributes to the restrictive ventilatory defect. It is also useful in ruling out infection and atelectasis, the latter arising from ineffective cough and decreases in VC. Chest radiography may also identify complications related to anesthesia and sedation.

Cardiac Evaluation

Baseline assessment of cardiac function is recommended at the time of diagnosis or by age six, Assessment should include an electrocardiogram and a noninvasive imaging study, such as echocardiography or cardiac MRI. Imaging should be repeated at least once every two years until the age of ten or with the onset of cardiac symptoms. If cardiac symptoms occur earlier, cardiac imaging should be repeated annually thereafter. For patients who have abnormalities of ventricular function, surveillance should be conducted every six months and at the time pharmacologic therapy is initiated. Consultation with a cardiologist is recommended for management of heart failure. Cardiac evaluation of female carriers should begin after the teenage years.

Pharmacologic Management

Corticosteroids are the mainstay of treatment. Corticosteroids improve muscle strength, increase the number of years of effective ambulation, and prevent decline in VC and MIP. Improvement is seen within ten days of initiation of therapy, while maximal improvement is usually seen at three months after initiation of therapy. The response is sustained for about three years. If side effects are observed (e.g., weight gain, hypertension, behavioral changes, growth retardation, cataracts), a dosage reduction is advised.

Deflazacort, a synthetic derivative of prednisone, is used in Europe but is not available in the United States. The drug is as effective as prednisone in slowing the decline of muscle strength and improving muscle strength and functional performance.

Oxandrolone, a synthetic anabolic steroid, has a beneficial effect that is comparable to that of prednisone.

Eteplirsen is a novel agent that skips exon 51. It is FDA approved for treatment of patients with DMD who have a confirmed mutation of dystrophin gene amenable to exon 51 skipping.

Myostatin inactivation is currently being studied in clinical trials for its effect on DMD patients.

Idebenone, an antioxidant, has shown reduction in decline in peak expiratory flow but larger studies are needed to see if time to assisted ventilation or death is improved.

Other novel and investigational approaches currently being studied include additional gene therapy, cell therapy, and deactylase inhibitors.

What is the prognosis for patients managed in recommended ways?

In DMD, despite modern respiratory care and improved understanding of abnormal pulmonary mechanics, survival after age 25 is uncommon. The most common cause of death is progressive respiratory insufficiency and heart failure resulting from cardiomyopathy.

In BMD, patients usually remain ambulatory beyond sixteen years and into early adulthood, and they may live beyond age thirty. Death is a result of respiratory failure and cardiomyopathy occurring between ages thirty and sixty.

Once VC falls below 1L, median survival is 3.1 years and five-year survival is only 8%. Once hypercapnia arises, the course is rapidly progressive, and the prognosis is poor.

What other considerations exist for patients with Duchenne or Becker Muscular Dystrophy?

General physiotherapy is important in preventing contractures. Passive stretching exercises are helpful in preventing contractures of the iliotibial band, the Achilles tendons, and flexors of the hip. Surgery may be performed to release contractures.

Standing and ambulation may prevent scoliosis. Spine surgery to stabilize or correct scoliosis may improve patient comfort, particularly for those confined to a wheelchair, and may benefit pulmonary function. Monitoring for osteopenia and osteoporosis, consideration of supplemental Vitamin D and calcium, and treatment with bisphosphonates are additional considerations.

A high-protein, low-calorie diet may be beneficial, as VC declines with worsening nutritional status. Maximal static respiratory pressures correlate with body mass in normal and malnourished persons.

Noninvasive ventilation and assisted cough techniques should be initiated before any contemplated surgical procedure if the VC is less than 50% predicted and peak cough flow is less than 270 L/min. Surgery carries related risks that include potentially fatal reactions to inhaled anesthetics and certain muscle relaxants. Complications include upper airway obstruction, hypoventilation, atelectasis, congestive heart failure, cardiac dysrhythmias, respiratory failure, and difficulty weaning from mechanical ventilation.

Respiratory muscle strength training is not recommended, as it may increase the ventilatory burden on already weakened respiratory muscles.

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