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 three and six 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 occurs 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, proximal and lower limb muscles affected 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 percent of patients with DMD and 85 percent 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 begifall by 25 percent per year.

  • A mild elevation (e.g., three times the upper limit normal) in 50-70 percent 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?

Serial pulmonary function testing helps to reveal respiratory muscle weakness. See the management section, below.

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

Not applicable.

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.

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

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 percent 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 percent of the normal quantity of dystrophin. Dystrophin levels between 5 and 20 percent of normal, regardless of protein size, correlate with the intermediate phenotypes of mild DMD or severe BMD. Levels between 20 and 50 percent of normal are associated with mild or moderate BMD.

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. Important to note is 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 declining 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 percent 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 percent 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 percent 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 Dystroph

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

  • When VC is less than 40 percent 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 percent 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 ventialatory support would also be undertaken when baseline pulse oximetry is less than 95 percent or 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 percent or drops in pulse oximetry of at least 4 percent 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 that is 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 percent 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 percent 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 atectasis, 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.

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 1 L, median survival is 3.1 years and five-year survival is only 8 percent. 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 supplement therapy with 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 percent 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.

What's the evidence?

Backman, E, Henriksson, KG. "Low-dose prednisolone treatment in Duchenne and Becker muscular dystrophy". Neuromuscul Disord. vol. 5. 1995. pp. 233-41.

(Randomized, double-blind crossover trial in which patients with Duchenne or Becker muscular dystrophy received prednisolone and placebo for six months. Supported evidence that prendisolone improved muscle force and function in these patients.)

Birnkrant, DJ, Bushby, KM, Amin, RS. "The respiratory management of patients with Duchenne muscular dystrophy: a DMD care considerations working group specialty article". Pediatr Pulmonol. vol. 45. 2010. pp. 739-48.

(Consensus recommendations of a ten-member respiratory panel that provide a structured approach to the assessment and management of respiratory complications of DMD.)

Birnkrant, DJ, Panitch, HB, Benditt, JO. "American College of Chest Physicians consensus statement on the respiratory and related management of patients with Duchenne muscular dystrophy undergoing anesthesia or sedation". Chest. vol. 132. 2007. pp. 1977-86.

(Consensus opinion of a multidisciplinary panel on management of patients with DMD who are undergoing procedural sedation or anesthesia, as these patients have related risks that include potentially fatal reactions to inhaled anesthetics and certain muscle relaxants, upper airway obstruction, hypoventilation, atelectasis, congestive heart failure, cardiac dysrhythmias, respiratory failure, and difficulty weaning from mechanical ventilation.)

Bonifati, MD, Ruzza, G, Bonometto, P. "A multicenter, double-blind, randomized trial of deflazacort versus prednisone in Duchenne muscular dystrophy". Muscle Nerve. vol. 23. 2000. pp. 1344-7.

(Double-blind, randomized trial that randomized eighteen patients with DMD to either 0.75 mg/kg/day of prednisone or 0.9 mg/kg/day of synthetic steroid deflazacort. Showed that deflazacort was equally as effective as prednisone in improving motor and functional performances of DMD patients after nine months of treatment without increase in weight.)

Bushby, K, Finkel, R, Birnkrant, DJ. "Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management". Lancet Neurol. vol. 9. 2010. pp. 77-93.

(Part 1 of a two-part series that provides a comprehensive set of DMD care recommendations. This part focuses on the overall perspective on care, pharmacological treatment, and psychosocial management of DMD patients.)

Bushby, K, Finkel, R, Birnkrant, DJ. "Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care". Lancet Neurol. vol. 9. 2010. pp. 177-89.

(Part 2 of a two-part series that provides a comprehensive set of DMD care recommendations for management of rehabilitation, orthopedic, respiratory, cardiovascular, gastroenterology, nutrition and pain issue, as well as general precautions for surgical and emergency rooms.)

Fenichel, GM, Griggs, RC, Kissel, J. "A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy". Neurology. vol. 56. 2001. pp. 1075-9.

(Six-month, randomized, double-blind placebo-controlled study of oxandrolone in boys with an established diagnosis of DD. Demonstrated that oxandrolone did not significantly change average muscle strength, although it did show a significant improvement in four quantitative muscle tests.)

Finder, JD, Birnkrant, D, Carl, J. "Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement". Am J Respir Crit Care Med. vol. 170. 2004. pp. 456-65.

(Consensus statement that graded and summarized available evidence on the respiratory care of the patient with DMD.)

Hukins, CA, Hillman, DR. "Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy". Am J Respir Crit Care Med. vol. 161. 2000. pp. 166-70.

(Prospectively compared wakeful respiratory function with outcome of polysomnography. Helped to define parameters of daytime lung function that were associated with sleep ventilation in DMD.)

Mendell, JR, Moxley, RT, Griggs, RC. "Randomized, double-blind six-month trial of prednisone in Duchenne's muscular dystrophy". N Engl J Med. vol. 320. 1989. pp. 1592-7.

(Randomized, double-blind, controlled six-month trial of predisone in 103 boys with DMD who were assigned to prednisone 0.75 mg/kg/day, prednisone 1.5 mg/kg/day, or placebo. Showed that treatment with prednisone improved muscle strength and function; the improvement occurred within the first month and peaked by three months.)

Phillips, MF, Quinlivan, RC, Edwards, RH, Calverley, PM. "Changes in spirometry over time as a prognostic marker in patients with Duchenne muscular dystrophy". Am J Respir Crit Care Med. vol. 164. 2001. pp. 2191-4.

(Retrospective study of 58 patients with DMD with at least a two-year follow-up that demonstrated that repeated spirometric assessment provided a simple and powerful means of assessing disease progression in patients with DMD. First study to show that the age at which vital capacity fell below 1 L was a marker of subsequent mortality: 8 percent at five years.)

Vianello, A, Bevilacqua, M, Salvador, V, Cardaioli, C, Vincenti, E. "Long-term nasal intermittent positive pressure ventilation in advanced Duchenne's muscular dystrophy". Chest. vol. 105. 1994. pp. 445-8.

(Compared clinical and pulmonary function course of five subjects affected with chronic ventilatory failure that was due to PMD and treated with NIPPV, with the clinical and pulmonary function course of an unventilated comparison group of five patients with a similar degree of clinical and respiratory functional impairment. Confirmed that long-term NIPPV helps to stabilize pulmonary function and to prolong the expectancy of life of patients with DMD.)

Wanke, T, Toifl, K, Merkle, M, Formanek, D, Lahrmann, H, Zwick, H. "Inspiratory muscle training in patients with Duchenne muscular dystrophy". Chest. vol. 105. 1994. pp. 475-82.

(Assessed the usefulness of a specific inspiratory muscle training in patients with DMD. Demonstrated that specific inspiratory muscle training can be helpful only in the early stages of DMD.)
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