Muscular Dystrophy 

Updated: Jul 01, 2021
Author: Twee T Do, MD; Chief Editor: Jeffrey D Thomson, MD 

Overview

Practice Essentials

Muscular dystrophy (MD) is a collective group of inherited noninflammatory but progressive muscle disorders without a central or peripheral nerve abnormality. The disease affects the muscles with definite fiber degeneration but without evidence of morphologic aberrations.

The first historical account of MD was reported by Conte and Gioja in 1836.[1]  They described two brothers with progressive weakness starting at age 10 years. These boys later developed generalized weakness and hypertrophy of multiple muscle groups, which are now known to be characteristic of the milder Becker MD. At the time, however, many thought that Conte and Gioja described tuberculosis; thus, they did not achieve recognition for their discovery.

In 1852, Meryon[2]  reported in vivid details a family with four boys, all of whom were affected by significant muscle changes but had no central nervous system abnormality when examined at necropsy. Meryon subsequently wrote a comprehensive monograph on MD and even went on to suggest that a sarcolemmal defect was at the root of the disorder. He further suspected that the disorder is genetically transmitted through females and affects only males.

Guillaume Duchenne was a French neurologist who was already famous for his application of faradism (the use of electric currents to stimulate muscles and nerves) to the treatment of neurologic disorders when he wrote about his first case of MD.[3]  In 1868, he gave a comprehensive account of 13 patients with the disease, which he called "paralysie musculaire pseudo-hypertrophique." Because Duchenne was already held in high esteem for his work in faradism and for his contributions to the understanding of muscle diseases, one of the most severe and classic forms of MD, Duchenne MD, now bears his name.

Advances in molecular biology techniques illuminate the genetic basis underlying all MD: defects in the genetic code for dystrophin, a 427-kd skeletal muscle protein (Dp427). These defects result in the various manifestations commonly associated with MD, such as weakness and pseudohypertrophy. Dystrophin can also be found in cardiac smooth muscles and in the brain (accounting for the slight mental retardation associated with this disease).[4]

Minor variations notwithstanding, all types of MD have in common progressive muscle weakness that tends to occur in a proximal-to-distal direction, though there are some rare distal myopathies that cause predominantly distal weakness. The decreasing muscle strength in those who are affected may compromise the patient's ambulation potential and, eventually, cardiopulmonary function.

In addition, structural soft-tissue contractures and spinal deformities may develop from poor posturing caused by the progressive muscle weakness and imbalance, all of which can further compromise function and longevity. Equinovarus contractures start as flexible dynamic deformities and advance to rigid contractures. This altered anatomy prevents normal ambulation, proper shoe wear, and transfers (how patients can be picked up to transfer out of their chair).

Once wheelchair-bound, patients with MDs tend to develop worsening contractures, osteopenia (initially, followed by osteoporosis), and rapidly progressive scoliosis. The change in bone mineral density (BMD) can lead to fractures of the long bones or vertebrae, which in turn lead to more immobilization, disuse demineralization, and exacerbation of scoliosis. On average, for each 10° of thoracic scoliosis curvature, forced vital capacity (FVC) decreases by 4%.[5]  In a patient with an already weakened cardiopulmonary system, this decrease in FVC could rapidly become fatal.

The goal of orthopedic management is, therefore, to preserve or prolong patients' ambulatory status for as long as possible. This goal can be achieved with soft-tissue releases for contractures, vigilant monitoring of BMD (especially when the patient is on steroid therapy), and treatment of osteoporosis. If patients develop significant scoliosis, which generally occurs after they stop walking, early stabilization of the spine should be considered.

Pathophysiology

Multiple proteins are involved in the complex interactions of the muscle membrane and extracellular environment. For sarcolemmal stability, dystrophin and the dystrophin-associated glycoproteins (DAGs) are important elements.[6, 7]

The dystrophin gene is located on the short arm of chromosome X near the p21 locus and codes for the large protein Dp427, which contains 3685 amino acids. Dystrophin accounts for only approximately 0.002% of the proteins in striated muscle, but it has obvious importance in the maintenance of the muscle's membrane integrity.[5]

Dystrophin aggregates as a homotetramer at the costomeres in skeletal muscles, as well as associates with actin at its N-terminus and the DAG complex at the C-terminus, forming a stable complex that interacts with laminin in the extracellular matrix. Lack of dystrophin leads to cellular instability at these links, with progressive leakage of intracellular components; this results in the high levels of creatine phosphokinase (CPK) noted on routine blood workup of patients with Duchenne MD.

Less-active forms of dystrophin may still function as a sarcolemmal anchor, but they may not be as effective a gateway regulator because they allow some leakage of intracellular substance. This is the classic Becker dystrophy. In both Duchenne and Becker MD, the muscle-cell unit gradually dies, and macrophages invade. Although the damage in MD is not reported to be immunologically mediated, class I human leukocyte antigens (HLAs) are found on the membrane of dystrophic muscles; this feature makes these muscles more susceptible to T-cell mediated attacks.

Selective monoclonal antibody hybridization was used to identify cytotoxic T cells as the invading macrophages; complement-activated membrane attack complexes have been identified in dystrophic muscles as well. Over time, the dead muscle shell is replaced by a fibrofatty infiltrate, which clinically appears as pseudohypertrophy of the muscle. The lack of functioning muscle units causes weakness and, eventually, contractures.

Other types of MDs are caused by alterations in the coding of one of the DAG complex proteins. The gene loci coding for each of the DAG complex proteins is located outside the X chromosomes. Gene defects in these protein products also lead to alterations in cellular permeability; however, because of the slightly different mechanism of action and because of the locations of these gene products within the body, there are other associated effects, such as those in ocular and limb-girdle type dystrophies (see the image below).

Schematic of the sarcomere with labeled molecular Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.

Etiology

Classification of types of muscular dystrophy

The etiology of MD is an abnormality in the genetic code for specific muscle proteins.[8] They all are classified according to the clinical phenotype, the pathology, and the mode of inheritance. The inheritance pattern includes the sex-linked, autosomal recessive, and autosomal dominant MDs. Within each group of heritable MDs (see below), several disorders exist. These are characterized by the clinical presentation and pathology.

Heritable MDs include the following:

  • Sex-linked MDs - Duchenne, Becker, Emery-Dreifuss
  • Autosomal dominant MDs - Facioscapulohumeral, distal, ocular, oculopharyngeal
  • Autosomal recessive MD – Limb-girdle form

Genetic defects and dystrophin

In the X-linked forms of MD, such as the Duchenne and Becker dystrophies, the defect is located on the short arm of the X chromosome.[9] Hoffman and coworkers identified the locus of the defect in the Xp21 region, which includes approximately 2 million base pairs.[5] The gene codes for Dp427, which is a component of the cytoskeleton of the cell membrane.

Dystrophin is distributed not only in skeletal muscle but also in smooth and cardiac muscles and in the brain. The large size of the dystrophin gene explains the ease at which spontaneous new mutations can occur, as in Duchenne MD. The large size also allows mistakes in protein synthesis to occur at multiple sites.

Defects that interfere with the translation reading frame or with the promoter sequence that initiates synthesis of dystrophin lead to an unstable, ineffective protein, as in Duchenne MD. Disruption of the translation process further down the sequence leads to production of proteins of lower molecular weight that, although present, are less active and result in the milder variety of Becker MD.

Like Duchenne MD, Emery-Dreifuss MD is a sex-linked recessive disorder, but its defect is localized to the long arm of the X chromosome at the q28 locus.[10] Some authors, however, have cited case reports of similar findings in Emery-Dreifuss that were transmitted in an autosomal dominant pattern.[11] However, this finding is more of an aberration than a normal observation in Emery-Dreifuss MD.

In autosomal recessive conditions such as limb-girdle MD, the genetic defect is localized to the 13q12 locus.

In the autosomal dominant facioscapulohumeral MD, the defect is at the 4q35 locus. In distal MD, it is at the 2q12-14 loci.[12]

Epidemiology

United States statistics

The incidence of MD varies, depending on the specific type of MD under consideration. Duchenne MD is the most common MD and is sex-linked, with an inheritance pattern of 1 case per 3500 live male births.[13, 14] One third of cases occurs as a result of spontaneous new mutations.[15]  Becker MD is the second most common form, with an incidence of 1 case per 30,000 live male births.[16] Other types of MD are rare. For example, limb-girdle dystrophy occurs in only 1.3% of patients with MDs.

International statistics

The incidence internationally is similar to that of the US for most of the dystrophies, except for the oculopharyngeal type, which is more common in French Canadians than in other groups.[17] Distal MD tends to occur in Sweden.

Prognosis

Despite modern advances in gene therapy and molecular biology, MD remains incurable. With proper care and attention, patients have a better quality of life than they would otherwise, but most still die by the age of 30 years, usually as a result of cardiopulmonary failure.

 

Presentation

History and Physical Examination

In Duchenne muscular dystrophy (MD), unless a sibling has been previously affected to warrant a high index of suspicion, no abnormality is noted in the patient at birth, and manifestations of the muscle weakness do not begin until the child begins to walk. Three major time points for patients with Duchenne MD are as follows[18] :

  • When they begin to walk
  • When they lose their ability to ambulate
  • When they die

Phases of Duchenne muscular dystrophy

The child's motor milestones may be at the upper limits of normal, or they may be slightly delayed. Some of the delays may be caused by inherent muscle weakness, but a component may stem from brain involvement.

Although the association of intellectual impairment in MD has long been recognized, it was initially thought to be a result of limited educational opportunities.[19] Psychometric studies have since revealed a definitively lower intelligence quotient (IQ) in patients with Duchenne MD despite equalization of educational opportunities.[20] The average IQ in patients with Duchenne MD is 85 points on the Wechsler Adult Intelligence Scale (WAIS), compared with 105 points in healthy populations.[13, 19, 20, 21]

In addition to mental deficits, another milestone delay is the patient's age at ambulation. Children with Duchenne MD usually do not begin to walk until about age 18 months or later. In the Dubowitz study,[13] 74% of children with Duchenne MD manifested the disease by age 4 years. By age 5 years, awareness increases as the disease is manifested in all affected children when they experience difficulty with school-related activities (eg, getting to the bus, climbing stairs, reciprocal motions during activities).

Other early features include a gait abnormality, which classically is a waddling, wide-based gait with hyperlordosis of the lumbar spine and toe walking. The waddle is due to weakness in the gluteus maximus and gluteus medius muscles and the patient's inability to support a single-leg stance. The child leans the body toward the other side to balance the center of gravity, and the motion is repeated with each step.

Hip extensor weakness also results in a forward tilt of the pelvis, which translates to a hyperlordosis of the spine to maintain posture. The child then walks on tiptoes because it is easier to stay vertical with an equinus foot position than on a flat foot, though no real tendo Achillis contracture exists at this early point.

Gradually, the child is observed to have increasingly noticeable difficulty with step taking. Frequent falls without tripping or stumbling often occur and are described as the feet being swept away from under the child. The child then begins having problems getting up from the sitting or supine position, and he or she can rise to an upright stance only by manifesting the Gower sign.

The Gower sign is a classic physical examination finding in MD and results from weakness in the child's proximal hip muscles. To get up from a sitting or supine position, the child must first become prone on the elbows and knees. Next, the knees and elbows are extended to raise the body. Then, the hands and feet are gradually brought together to move the body's center of gravity over the legs. At this point, the child may release one hand at a time and support it on the knee as he or she crawls up their legs to achieve an upright position.

Although the Gower sign is a classic finding in Duchenne MD, it is by no means pathognomonic; other types of MD and disorders with proximal weakness may also cause this sign.

While still ambulatory, the child may have minimal deformities, including iliopsoas or tendo Achillis tightness. Mild scoliosis may be present if the child has an asymmetrical stance. Upper-extremity involvement rarely occurs in the beginning, although proximal arm muscle weakness may be evident on manual strength testing. When upper-extremity involvement manifests in later stages of Duchenne MD, it is symmetrical and, along with distal weakness, usually follows a rapid worsening of the child's condition toward being wheelchair bound.

The second important phase in Duchenne MD is the loss of ambulation. This usually occurs between the ages of 7 and 13 years, with some patients becoming wheelchair-bound by age 6 years. With early initiation of steroid treatment, prolongation of ambulation potential has been well documented. However, If children with MD are still ambulating well after the age of 13 years, the diagnosis of Duchenne MD should be questioned, because these patients may have Becker MD, the milder form of MD.

In Emery's work,[14] the 50th percentile for loss of ambulation in patients with Duchenne MD was age 8.5 years, with the 95th percentile at 11.9 years and the 99th percentile at 13.2 years. With the child's loss of ambulation, there is usually a rapidly progressive course of muscle or tendon contractures and scoliosis.

Most authors have recommended posterior spinal fusion at 20° when the vital capacity is at its best.[22, 13, 16, 23, 24] However, some reports showed that respiratory function after spinal fusion did not significantly differ.[25, 26, 27, 28, 29] The investigators concluded that respiratory failure resulted from muscle weakness and not the mechanical bellows of the chest cage, as was previously assumed.

Duchenne MD is a terminal disease in which death usually occurs by the third decade of life (mostly from cardiopulmonary compromise), despite steroid treatment.[13] The most common inciting event is a respiratory infection that progresses extremely rapidly despite its initial benign course. The resultant respiratory failure can easily occur from the underlying progressive nocturnal hypoventilation and hypoxia or from an acute cardiac insufficiency.

Additional clinical findings in Duchenne muscular dystrophy

Other clinical findings in Duchenne MD include absent deep tendon reflexes in the upper extremities and patella (though the tendo Achillis reflex remains intact even in the later stages of this disease), pain in the calves with activity (< 30% of patients), pseudohypertrophy of the calf (60%), and macroglossia (30%). Cardiopulmonary involvement is present from the beginning of the disease stages, but the findings are not so clinically obvious. Electrocardiographic (ECG) tracings show right ventricular strain, tall R waves, deep Q waves, and inverted T waves.[30]

Other types of muscular dystrophy

Becker MD is similar to Duchenne MD, but because patients have some measure of functioning dystrophin, the manifestations of Becker MD occur later and are more mild. Patients tend to live past the fourth or fifth decades.

Emery-Dreifuss MD is an uncommon sex-linked dystrophy that presents with early contractures and cardiomyopathy in affected patients; the typical presentation involves tendo Achillis contractures, elbow flexion contractures, neck extension contractures, tightness of the lumbar paravertebral muscles, and cardiac abnormalities. Death may occur in the fourth or fifth decade as a result of first-degree atrioventricular (AV) block, a condition that is usually not present at the initial presentation of this disease.

Autosomal dominant distal MD is a rare form of MD and tends to become apparent in those aged 30-40 years; it is more commonly found in Sweden than in any other country and can cause a mild weakness that affects the arms before the legs.

Autosomal dominant facioscapulohumeral dystrophy causes facial and upper-extremity weakness, and scapulothoracic motion is decreased, with winging of the scapula. This type of dystrophy can occur in both sexes and appear at any age, although it is more common in late adolescence.

Autosomal dominant oculopharyngeal dystrophy appears in those aged 20-30 years. The pharyngeal muscle involvement leads to dysarthria and dysphagia, which may necessitate palliative cricopharyngeal myotomy. The ocular component comprises ptosis, which may not become obvious until the patient's mid life.

None of the autosomal dominant conditions significantly affect longevity.

Complications

Complications of MD usually include the following:

  • Contractures and early wheelchair dependence, even in patients who develop minor musculoskeletal injuries (eg, ankle sprain) and are immobilized
  • Weakness - Prolonged immobilization worsens the clinical weakness caused by MD and ultimately renders the patient nonambulatory status; this exacerbates any developing contractures and potentiates the development of osteopenia or osteoporosis that can lead to limb and vertebral fractures
  • Osteoporosis and fractures (see Management of Osteoporosis and Fractures)
  • Scoliosis
  • Cardiopulmonary failure
 

DDx

 

Workup

Laboratory Studies

A creatine phosphokinase (CPK) determination is the most specific test for muscular dystrophy (MD). Elevated CPK levels are indicative of muscle disease. Because the concentration of CPK is not significant in red blood cells, CPK levels are not affected by hemolysis. CPK is not affected by liver dysfunction, as are the other tested enzymes (eg, transaminases, aldolase, lactate dehydrogenase). High CPK levels represent leakage of the enzyme from the muscle cells only. This change is not exactly correlated with the severity of the disease.

All MDs result in some CPK elevation during the active phase of the disease. The finding of three elevated levels obtained 1 month apart is diagnostic for MD. Early in the disease process, CPK levels are 50-300 times greater than normal levels, but the levels tend to decrease as the muscle mass decreases. The CPK level is highest in Duchenne MD, with less elevation noted in Becker MD.

Enzyme levels that may be elevated but can be altered by liver dysfunction include the following:

  • Transaminase levels
  • Lactate dehydrogenase levels
  • Aldolase levels

The multiplex polymerase chain reaction (PCR) assay may be useful. PCR was developed by Chamberlain et al,[31] who noted that deletions of the dystrophin gene tend to cluster around two hot-spot regions: at exons 3-30 and at exons 44-55.[32]  The PCR method rapidly screens for deletions of the dystrophin gene by applying PCR to amplify the DNA in the hot-spot regions and by simultaneously using a number of appropriate primers that flank these hot-spot regions. PCR can be used to detect more than 98% of existing deletions, and it can be performed within 24 hours.

Imaging Studies

Ultrasonography (US) is a relatively noninvasive technique that is used for screening patients with MD; this modality is rapidly replacing electromyography (EMG) in centers that have appropriately trained staff. Even in the early stages of MD, US shows increased echogenicity in the affected muscles, with a corresponding reduction in the underlying bone echo. US has the advantage of noninvasiveness, and it is reliable for continued monitoring of the disease course over time.

Other Tests

Electrocardiography (ECG) is expected to show a right ventricular strain, tall R waves, deep Q waves, and inverted T waves. A cardiologist should be consulted preoperatively because cardiac management may be necessary in the postoperative care of dystrophic patients.

Pulmonary function tests (PFTs), including an analysis of arterial blood gases, and a hematologic workup are necessary as part of the preoperative workup. A pulmonologist may be consulted preoperatively because he or she can be helpful in managing the patient's airway in the postoperative period.

EMG usually demonstrates short-duration, polyphasic, motor-unit action potentials with decreased amplitudes. It should be kept in mind that this finding is common with all myopathic processes and does not specifically identify MDs.

Biopsy

Until the advent of molecular biology techniques, muscle biopsy was the definitive test for diagnosing and confirming muscular disease. Histologic changes depend on the stage of disease and the muscle selected. The optimal site for biopsy is the vastus lateralis, accessed via a small lateral thigh incision.

Histologic Findings

Histologic specimens from muscle biopsy samples obtained early in the muscular dystrophy disease show only variations in muscle fiber sizes with focal areas of degenerating or regenerating fibers. In later stages of MD, the changes are more obvious, with marked variations in muscle fiber sizes, degeneration, and regeneration. Rounded opaque fibers, internal nuclei, splitting of fibers, and a proliferation of connective and adipose tissues are also present. As the disease progresses, fewer and fewer regenerative fibers are seen. In the end phase, the muscle is mostly replaced by adipose tissue, with residual islets of muscle fibers in a sea of fat.

Histochemical staining with the standard adenosine triphosphatase (ATPase) reaction shows a predominance of type I muscle fibers, with loss of clear-cut distinction into the various fiber types. Electron microscopy demonstrates nonspecific degeneration of the fibers, and immunocytochemical techniques show a persistence of fetal and slow myosin in many of these fibers. (See the images below.)

Gomori trichrome–stained section in patient with m Gomori trichrome–stained section in patient with myofibrillar myopathy. Note the abnormal accumulations of blue-red material in several muscle fibers.
Left: The photomicrograph is a muscle biopsy with Left: The photomicrograph is a muscle biopsy with normal emerin immunostaining. Right: The micrograph is from a patient with X-linked Emery-Dreifuss muscular dystrophy. Note the absence of nuclear staining as well as the hypertrophied and atrophied muscle fibers.
 

Treatment

Approach Considerations

The indications for any operative intervention in patients with muscular dystrophy (MD) include making a diagnosis by means of muscle biopsy (see Workup) or prolonging the patient's function and/or ability to ambulate by specific procedures. Other indicated procedures include tendo Achillis and iliopsoas tenotomies for ease of fit into braces, tibialis posterior tendon transfers or tenotomies for more rigid equinovarus deformities of the foot, and segmental spinal stabilization for rapidly developing scoliosis (see Surgical Therapy below).

In patients with muscular dystrophy, some relative contraindications for surgery include obesity, rapidly progressive muscle weakness, poor cardiopulmonary status, and a patient's lack of motivation for participating in postoperative rehabilitation programs.

The ability of advancing technology and molecular biology with fetal blood detection of affected fetuses as early as the first trimester opens the door to many ethical issues. One such issue is whether pregnancy termination should be available as an option when a muscle disease is detected that may be fatal in the third decade of life.

Medical Therapy

Steroids

Since Duchenne's time, multiple drug regimens have been tried in treatment of the muscle weakness. Of all the drugs that have come and gone, the only one with some proven benefit is prednisone. The beneficial effects were initially thought to be mediated through the suppression of cytotoxic T-cell expression from the necrotic muscles.

In the early 1970s, Drachman et al[33] treated 14 boys who had Duchenne MD with steroids and noted some benefits; however, because this was an uncontrolled study, the steroid therapeutic approach did not become a widely accepted treatment protocol.

In 1989, Mendell et al[34] performed a randomized, double-blind, multicenter study of 103 male patients with Duchenne MD who ranged from age 5-15 years. Over a period of 6 months, the patients were given prednisone at a dosage of 1.5 mg/kg/day, prednisone at a dosage of 0.75 mg/kg/day, or placebo. The researchers, who followed the expected course outlined by natural history, noted definite improvement in muscle strength in the steroid-treated boys at 1, 2, and 3 months compared with the control subjects receiving placebo.

The benefit of the dose-dependent steroid in this study,[34] however, was short-lived. The children's gained strength leveled off after the third month, and then they again began to lose strength. In addition, the adverse effects of the higher-dose steroids, such as rapid weight gain, myopathy, osteoporosis, and growth retardation, offset the beneficial effects of temporary minimal increases in strength.

As a result, deflazacort, an oxazoline derivative of prednisolone, is a newer therapeutic drug of choice.[35, 36] Deflazacort reportedly has more bone-sparing and carbohydrate-sparing properties with less weight-gain effects and improves strength and function. Because of the limited side effects and the beneficial properties of muscle sparing and delayed scoliosis progression, deflazacort is being used despite patients' permanent wheelchair status.

Clinical investigations are exploring the possibility of limited courses of steroid bursts (which have shown lasting benefits < 18 months) and other immunosuppressive drugs, such as azathioprine and cyclosporine. Although the glucocorticoid drugs delay the cytotoxic damage of MD to the necrosing muscle cells, these drugs cannot and do not make, or stimulate the synthesis of, the dystrophin and DAG proteins that are deficient, which is the root cause of the disease.

Biologic agents

Eteplirsen

An open-label, phase 2, dose-escalation study evaluated the safety and efficacy of intravenously administered eteplirsen phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne MD.[37] Using data from 19 ambulant patients aged 5-15 years with amenable deletions in Duchenne MD, the investigators noted that eteplirsen was well tolerated with no serious drug-related adverse events; eteplirsen induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent, but variable, manner in boys (dose 2 mg/kg) onwards.

Early clinical results of eteplirsen were biochemically promising for dystrophin production without significant adverse effects; however, functional ambulatory changes were not as consistently correlated.[37]  Reevaluation of the existing data led to approval of eteplirsen in September 2016.

Golodirsen 

Golodirsen, a second antisense oligonucleotide, was approved by the US Food and Drug Administration (FDA) in December 2019. Golodirsen is indicated for treatment of Duchenne MD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Approval was based on an increase in dystrophin production in skeletal muscle observed in patients who were treated. Mean dystrophin levels increased from 0.1% of normal at baseline to 1.02% of normal by week 48, with a mean change in dystrophin of 0.92% of normal levels; the median change from baseline was 0.88%.[38]

Viltolarsen  

Viltolarsen, another morpholino antisense oligomer, was approved by the FDA in August 2020 for Duchenne MD in patients with genetic mutations that are amenable to exon 53 skipping. Approval was based on results from a phase 2 two-period study in patients aged 4 to less than 10 years conducted in North America (N = 16) and a multicenter, open-label study in boys aged 5 to less than 18 years conducted in Japan (N = 16). In the former, 100% of patients who received the recommended dose of 80 mg/kg/wk (N = 8) showed an increase in dystrophin levels after treatment.[39]

Casimersen

In February 2021, the FDA granted accelerated approval to casimersen, an antisense oligonucleotide of the PMO subclass. PMO binds to exon 45 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Casimersen is indicated for Duchenne MD in patients with a confirmed mutation amenable to exon 45 skipping. 

The ESSENCE trial, a placebo-controlled confirmatory trial to support the casimersen approval, is ongoing and expected to conclude in 2024. In the study, patients who received casimersen showed a significantly greater increase in dystrophin protein levels from baseline to week 48 of treatment compared to those who received placebo.[40]

Investigational agents

Another potential therapy is creatine monohydrate supplementation. Creatine is a natural compound occurring in meats and is also endogenously produced by the liver and kidneys. Creatine supplementation has been shown to enhance athletic performance of healthy individuals in up to 10%.[41, 42]  Studies looking at creatine use in neuromuscular disorders have been popularized since late 1997, with the publication of the first human study by Tarnopolksy et al showing an increase in high-intensity power output with use.[43]  Several other human clinical trials of creatine supplementation have been conducted since that time with similar results.[44, 45, 46]

A meta-analysis of all randomized clinical trials using creatine monohydrate supplementation in neuromuscular disorders versus placebo was performed.[47]  It found that short- and intermediate-term treatment with 0.03-0.04 g/kg/day of creatine monohydrate supplementation resulted in modest but significant increases in mean maximum voluntary contraction of 9.2 N higher than placebo. There is also an increase in fat-free muscle mass. Globally, 44% of patients felt better in the creatine treated group, compared with 10% in the placebo group.

These effects were reliably seen in patients with dystrophinopathies and type II myotonic myopathy.[47]  No consistent changes were noted in patients with type I myotonic dystrophy, and none were noted in those with metabolic myopathies. Although there were no serious side effects noted in most patients, high-dose creatine treatment can impair ADL and increase muscle pain in glycogen storage disease type V (McArdle disease).

Ataluren (formerly known as PTC124; PTC Therapeutics, Inc, South Plainfield, NJ) is an oxadiazole compound that, when taken orally, can override nonsense stop translation signals induced by the dystrophin gene mutation; the protein produced is thus the full-length protein.[48, 49]  In Europe, it is used to treat Duchenne MD patients who have a nonsense mutation in the dystrophin gene, can walk, and are older than 5 years. It is not approved by the FDA for this purpose.

Gene therapy

Another novel method of treatment under intense investigation is somatic gene therapy, wherein healthy immature myoblasts are introduced into the diseased muscles, which then fuse and stimulate production of enough dystrophin to reverse the degeneration that occurs in the affected muscles.[50]

However, although somatic gene therapy has been achieved successfully in the X-linked muscular dystrophic mouse (murine MDX) model with the fusion of the donor and host muscle cells, which expressed some dystrophin, the benefit may not translate into human males.[50] The mice cannot demonstrate muscle strength, and the laboratory-raised mice were not able to mount a rejection response that may occur in humans. Other investigations have been conducted on the canine MDX model, which more closely approximates the human condition.[51, 52]

Human trials of gene therapy began in 1990, with an uncontrolled trial of eight patients who were injected with myoblasts from family donors.[53] Strength testing and staining for dystrophin was performed after several months. Early results demonstrated no improvement in patients' muscle strength or dystrophin staining. Later studies showed an increase in the expression of dystrophin proteins. However, the clinical results remain unchanged. These preliminary results, although disappointing, do not dampen the promise of gene therapy. Most supporters believe that these failures were merely the result of a lack of expertise, as with once-novel techniques such as organ transplantation.

Other molecular approaches to therapy include recombinant versions of the dystrophin gene using viral or nonviral vectors and antisense oligonucleotides.[54, 55] In the viral vector therapeutic approach, adenosine-associated virus leads the way.[56] In nonviral gene therapy, plasmid-mediated gene delivery, antisense-mediated exon skipping, and oligonucleotide-mediated gene editing has moved from successful trials in the lab to the clinic. In approximately 10-20% of the preclinical cases,[55]  it is possible to chemically persuade the translational machinery to read through a premature stop codon, as noted with the dystrophin mutation, and lead to production of a more functional full-length protein.

Surgical Therapy

The orthopedic problems in children with MD are as follows:

  • Progressive weakness with loss of ambulatory status
  • Soft-tissue contractures
  • Spinal deformities

The role of the orthopedic surgeon is to correct the deformities and to help maintain the dystrophic child's ambulatory status for as long as possible, usually 1-3.5 years.[57, 58] The modalities available to obtain these goals have been well outlined by Drennan[59]  and include the following:

  • Functional testing
  • Physical therapy
  • Use of orthoses
  • Fracture management
  • Soft-tissue, bone, and spinal surgeries
  • Use of a wheelchair when indicated
  • Genetic and/or psychological testing

Nonoperative measures

Functional testing, as its name implies, refers to frequent evaluation of the involved muscle's range of motion and strength. This modality provides therapists with goals for patients' individualized therapy programs. Regular therapy sessions are necessary because the therapist also works with patients for gait training and transfer techniques. The use of all adaptive equipment is considered necessary by the orthopedist to maintain the patient's ambulatory status.

Drennan also recommends that a home program be taught to dystrophic patients, with stretching exercises for the lower extremities performed twice a day on a firm surface to minimize contractures.[59] Occasionally, serial casting may be necessary to manage significant flexion contractures at the knee or equinus contracture at the ankle.

The goal for patients with MD is continued mobility despite the use of a cast to prevent rapid loss of strength and bone mineral density. Even with initial loss of muscle strength for weightbearing, flexible soft-tissue and rigid ankle-foot orthosis (AFO) or ischial supportive knee-ankle-foot orthosis (KAFO) can help the patient maintain standing balance for additional months to years.

Operative approaches to contractures and deformities

Significant upper-extremity contractures rarely occur in patients with MD. Occasionally, tightness of the long flexors may become problematic with hand function in operating an automatic wheelchair, but historically this has been treated with a nighttime orthosis.

In patients with MD, lower-extremity contractures start with equinus deformities. Initially, the contractures are supple and can occur in children as young as 6 years. Patients may be treated with various types of procedures to lengthen the tendo Achillis, including Vulpius tendon lengthening (which avoids overlengthening the already weakened muscle), percutaneous Hoke-Miller triple cut (which limits the incision and, thus, the postoperative immobilization), Warren-White lengthening, or standard z-lengthening.

Occasionally, when an associated varus deformity is present as a result of overpull of the unaffected tibialis posterior muscle, a posterior tibial tendon transfer through the interosseous membrane or a split-posterior tibial tendon transfer may also be indicated. In cases of severe contractures at the foot and ankle, posterior tibial lengthening or tenotomy may be necessary to achieve a plantigrade position.

Hip and knee contractures develop later in MD. Once patients become wheelchair-bound, hip and knee flexion contractures are more rapidly progressive. The abduction contracture was initially thought to be useful in obtaining stability with a wider base gait, but it also makes it difficult for patients to fit in standard wheelchairs or to be comfortable in bed. Various tenotomies are available, including the Yount (resection of the iliotibial band [ITB] distally at the knee),[60] modified Souter-Strathclyde (resection of the ITB proximally), and complete resection of the ITB from the hip to the knee.

Transfer of the iliopsoas has also been tried with limited success; this is no longer a procedure of choice in patients with MD. Posterior capsulotomy of the knee can allow for maintenance of flexible extremities for bracing, although this is not routinely performed. KAFOs with locked knees may extend the ambulatory status of weakened patients by 1 to 3 years.[58, 16] The locked knees, however, are not well tolerated, as they cause children to feel as if they are going to fall. This is a worse condition than buckling because of weakness at the quadriceps. Postoperatively, all patients are given some type of orthosis.

The surgical approaches to contractures in dystrophic patients, especially those with Duchenne MD, can be summarized into the following three broad categories:

  • Ambulatory
  • Rehabilitative
  • Palliative

Within the ambulatory group, the approach can be aggressive, so that all contractures are addressed at the start, before patients lose ambulatory status or within the first month of their losing ambulatory status. The rehabilitative approach indicates that surgery is used only to correct deformities that may limit physical therapy and orthosis wear. The palliative approach, as its name implies, is used to treat only problems of immediate concern for the patient's comfort, such as difficulty with shoe wearing, ulcerations, and problematic positioning in wheelchairs. Early aggressive surgical releases can prolong the patient's ambulatory status as long as 3.5 years.[57, 58]

Scoliosis is another common problem in patients with muscular dystrophy. It is more common in Duchenne MD than in other forms, with an incidence of 75-90%.[57, 58, 22] The scoliosis develops early and tends to be rapidly progressive, especially when patients become nonambulatory. The curve is usually thoracolumbar or lumbar with associated pelvic obliquity, thoracic kyphosis, and lumbar hyperlordosis. The abnormal sagittal alignment may cause problems with seating systems, even modified systems, and the rapid progression of the scoliosis requires frequent wheelchair adjustments. Braces are not effective in progressive paralytic or neuromuscular curves, and surgery is often indicated.[61]

Advances in pulmonary care and cardiac drugs may negate the absolute need for scoliosis surgery in Duchenne MD, allowing patients to live into adulthood. A 10-year retrospective study showed that 44 of 123 nonambulatory patients aged 17 or older were managed satisfactorily without surgery.[26] Although this is only a single report, it gives much hope for many dystrophic patients with scoliosis.

The technique of choice for scoliosis when the curve measures 20° or more in patients who are nonambulatory is a posterior spinal fusion from T2 to the sacrum. The indication for earlier operative stabilization of the spine in these patients is due to the rapidly deteriorating cardiopulmonary function.[29] The FVC is at its maximum in children younger than 10 years. After this point, the FVC rapidly declines, and anesthetic complications rise dramatically in those patients with an FVC less than 30%.

Spinal fusion is extended to the pelvis, with complete obliteration of the facet joints to ensure arthrodesis. The instrumentation used has often consisted of a Luque rod with segmental sublaminar wires to the L5 level, with bone arthrodesis extending into the sacrum. Currently, however, this method is being employed less frequently; most spine surgeons are now using pedicle screws with extension of the instrumentation to the pelvis.[62, 63]

Occasionally, instrumentation and fusion are extended only to L5 because of the diffuse osteopenia in the sacrum, early surgery and low magnitude curves, or because of the possible complications of instrument failure. The literature has cited a high incidence of failure and revision with fusion short of the sacrum; therefore, spinal fusions in patients with MD are extended to the pelvis, especially if done after the curve magnitude is over 30º.[64, 65, 66]

Preoperative considerations

Before any operative is undertaken, the patient's overall status of any patient must be considered; this is of particular importance in patients with muscle weakness, such as those with MD. For example, posterior spinal fusion to the pelvis straightens the scoliosis and allows better upright sitting balance. However, in patients with low vital capacity (< 30%), the risks of pulmonary complications are much higher, and these risks may tip the scale in favor of not operating on the scoliosis.

Other examples include equinus contractures in patients who are very weak; tendon lengthening itself is necessarily a weakening procedure on the involved muscle. If the patient has to maintain a rigid equinus foot position for stability of gait and the tendon is lengthened by surgery, the patient will not be able to ambulate.

Preoperatively, patients should undergo a detailed cardiac assessment, a pulmonary evaluation with pulmonary function tests (including arterial blood gas analysis), and a hematologic workup. Because of potential cardiomyopathy, intraoperative monitoring is an essential component of administering anesthetics.

Intraoperative blood loss is usually substantial in patients with MD as a result of their muscle dysfunction, which causes ineffective vessel constriction. Another potential complication of anesthesia is malignant hyperthermia, which is more common in patients with muscle diseases than in patients with other disease entities; this risk is diminished with the use of nitrous oxide, intravenous narcotics, sedatives, and nondepolarizing muscle relaxants.

After scoliosis surgery, patients may need additional pulmonary support and an extended stay in the intensive care unit (ICU). Preoperative tracheostomy is usually not any more effective in early mobilization of dystrophic patients; if necessary, this procedure is performed only after the patient's condition has been stabilized and after a mold has been obtained for a hard brace with chest and abdominal cutouts.

Management of Osteoporosis and Fractures

Whereas the presence of bone fragility due to limited mobility, decreased vitamin D absorption, and lack of exercise in the sun is historically well attested in MD, the common practice of routinely using steroids for mitigation of MD weakness has led to increased concerns regarding steroid-exacerbated osteoporotic long bone and vertebral fractures.

In 2014, Tian et al retrospectively reviewed a cohort of 408 males with Duchenne MD and found an age-dependent increased prevalence in total as well as vertebral compression fractures.[67]  Singh et al further confirmed this finding in their study of 49 patients;, 26 of the 49 had vertebral fractures, with 50% occurring within 5 years of steroid therapy, 69% within 7 years of steroid use, and 100% after 9 years of steroid treatment.[68]  The investigators concluded that there is a high risk of vertebral fractures associated with the duration of deflazacort use, regardless of the age at which steroid therapy is initiated.

Vertebral fractures tend to occur via a bimodal distribution among children with osteoporosis, with the incidence of symptomatic fractures ranging from 32% to 40%. This is important in that previous vertebral fractures, regardless of symptomology, are a powerful predictor of future fractures and guide recommendations for osteoporosis treatment.

In a very thorough review, Buckner et al detailed the recommendations for screening and treatment of osteoporosis induced by limited mobility and chronic steroid use.[69]   An initial thorough dietary screen for vitamin D and calcium intake is done at the initial visit and at regular intervals thereafter. A fracture screen is also performed. Active vitamin D (25-hydroxyvitamin D) levels can be checked by means of a blood test. The Endocrine Society defines the following categories for vitamin D levels:

  • Vitamin D deficiency - < 20 ng/mL
  • Insufficient vitamin D - < 30 ng/mL but >20 ng/mL
  • Sufficient vitamin D - >30 ng/mL

A baseline dual energy x-ray absorptiometry (DXA) scan is performed when steroid therapy is started and is repeated every 1-2 years while therapy continues. The scan is done with height-adjusted Z-scores, which yield more consistent results for pediatric MD patients with shorter stature. With the onset of back pain, a lateral radiograph is obtained as a baseline; lateral spine x-rays involve more radiation than the DXA scan.

If the patient has low Z-scores, a history of previous fractures, or both, treatment of the osteoporosis is indicated. Therapeutic options include the following:

  • Calcium and vitamin D supplementation
  • “Vibration” therapy (which has been shown to be more effective in cerebral palsy patients than other categories of neurologic patients)
  • Bisphosphonates - Bisphosphonates typically used in pediatric patients include oral alendronate, intravenous pamidronate, and zoledronic acid; these agents have been shown to improve bone mineral density (BMD) and Z-scores as well as ease fracture-induced back pain

Multiple studies are currently being conducted to further elucidate clear recommendations for the diagnosis and treatment of steroid-induced osteoporotic fractures of the spine and long bones in patients with MD.

 

Guidelines

Screening

In 2013, the American Academy of Pediatrics (AAP) published a clinical report from a multidisciplinary expert panel that developed an algorithm for the screening of children for motor delays with guidance for the initial workup and referral. Identification of motor delays includes ongoing surveillance of the following milestones[70] :

  • Sitting
  • Standing
  • Walking
  • Running
  • Going up stairs

The report recommends that developmental screenings take place at well-child visits at 9, 18, 30, and 48 months of age. The following motor skills are typically acquired at earlier ages, and their absence at these ages signifies delay:

  • 9-month visit - Roll to both sides, sit well without support, and demonstrate motor symmetry without established handedness; ability to grasp and transfer objects hand to hand
  • 18-month visit - Sitting, standing, and walking independently; ability to grasp and manipulate small objects; mild motor delays undetected at the 9-month screening visit may now be apparent
  • 30-month visit - Most motor delays will have already been identified and more subtle gross motor, fine motor, speech, and oral motor impairments may emerge; progressive neuromuscular disorders may manifest as a loss of previously attained gross or fine motor skills
  • 48-month visit -  Elementary school skills, with emerging fine motor, handwriting, gross motor, communication, and feeding abilities that promote participation with peers in group activities; loss of skills should alert to the possibility of a progressive disorder

The Centers for Disease Control and Prevention (CDC) also supports early identification and evaluation of motor delays to enable a quicker referral to a specialist for diagnosis. In collaboration with the National Task Force for Early Identification of Childhood Neuromuscular Disorders, the CDC developed a Web-based diagnostic tool, www.childmuscleweakness.org, to assist providers in primary care, rehabilitation medicine, and physical and occupational therapy in the evaluation of children with motor delay and early manifestations of neuromuscular disorders. The website content was endorsed by the AAP.[71]

ChildMuscleWeakness.org provides guidance on motor surveillance and screening and includes an aid to the assessment of motor development milestones and recommendations for evaluating the following milestones[72] :

  • Infant+: Head lag on pull to sit
  • Age 6+ months: Achieving and maintaining sitting
  • Age 12+ months: Rising to stand from the floor and gait (walking and running)

If a delay is found by using the surveillance aid, a motor delay algorithm provides guidance on testing and referral. The following findings are red flags that indicate the need for an urgent referral to a neurologist:

  • Tongue fasciculations
  • Loss of motor milestones
  • Creatine phosphokinase (CK) level higher than three times normal (however, children with some neuromuscular disorders have normal CK levels)

Many neuromuscular conditions increase the risk for malignant hyperthermia with anesthesia use, and anticipated surgery should increase the urgency of a diagnostic evaluation.  

Evaluation and Diagnosis

Creatine phosphokinase testing

Peripheral neuromuscular conditions in which the CK concentration is always elevated from birth include Duchenne muscular dystrophy (MD) and Becker MD, as well as some congenital and limb-girdle MDs. Conditions in which CK is mildly elevated or normal include spinal muscular atrophy, neuropathies, and congenital myopathies.[72]

According to AAP guidelines, CK testing should be performed for all children with motor delay and low tone. The CK concentration is significantly elevated in Duchenne MD (DMD), usually  above 1000 U/L. DMD is an X-linked disorder, and there may be a family history of affected males on the maternal side. However, approximately 30% of cases are new mutations in patients with no family history.[70]

According to Childmuscleweakness.org, any of the following findings are indications for CK testing[72] :

  • Proximal muscle weakness
  • Loss of motor milestones
  • Isolated gross motor delay without other developmental difficulties

Additionally, Childmuscleweakness.org recommends evaluation of children with mild to moderate developmental delay and motor delays.  Although an elevated CK level warrants prompt referral to a neurologist, a normal level does not rule out neuromuscular disease, and a mildly elevated CK (1-2 times normal) also requires follow-up.

Genetic testing

If the CK concentration is elevated, AAP guidelines suggest that the diagnosis of DMD can usually be confirmed with molecular sequencing of the DMD gene. Testing for other neuromuscular disorders should be performed by subspecialists, because they often require electrodiagnostic or specific genetic testing.[1]

Duchenne/Becker Muscular Dystrophy

In 2009 and 2010, the CDC published a comprehensive set of DMD care recommendations that include the following topics[73, 74] :

  • Rehabilitation
  • Orthopedic
  • Respiratory
  • Cardiovascular
  • Gastroenterology/nutrition
  • Pain issues
  • General surgery and emergency room precautions

Part 1 of the CDC guidelines focused on diagnosis and pharmacologic and psychosocial management.[73] Part 2 outlined the implementation of multidisciplinary care for DMD patients.[74]  These guidelines were affirmed by the American Academy of Neurology (AAN) and endorsed by the Muscular Dystrophy Association (MDA) and the TREAT-NMD Neuromuscular Network.

The guidelines require a multidisciplinary approach due to the range of expertise needed to care for DMD patients. The role of coordinating clinical care could be assumed by a neurologist or pediatric neurologist, rehabilitation specialist, neurogeneticist, pediatric orthopedist, pediatrician or other primary care physician. This physician must have access to information on health maintenance and proper monitoring of disease progression and complications to provide anticipatory, preventive care, and optimum management.[73]

In addition, the guidelines note that logistical management of the patient in the clinic requires a physically accessible environment with proper equipment (eg, mechanical hoist or sliding board) and trained personnel available for the safe transfer of the nonambulatory patient. Appropriately trained staff with the expertise and means to obtain accurate measures of weight, height, and vital signs is also needed.[73]

Confirmation of diagnosis

In patients with increased CK levels, the following steps should be taken to confirm the diagnosis of DMD[73] :

  • If muscle biopsy shows presence of dystrophin protein, DMD is excluded
  • If muscle biopsy show absence of dystrophin protein, dystrophin deletion/duplication testing is performed, and deletion or duplication mutation confirms diagnosis of DMD
  • If deletion/duplication testing is negative, then dystrophin genetic sequencing is performed to look for point mutations or small deletions/insertions
  • A muscle biopsy is not necessary if genetic testing is done, but may be useful to distinguish milder phenotypes

Electromyography and nerve conduction studies are no longer considered necessary for the assessment of DMD. Neuromuscular assessments (ie, strength, range of motion, posture, gait, timed testing, activities of daily living, motor function) are made after diagnosis to inform intervention decisions and are subsequently repeated to monitor response to therapy.

Pharmacologic intervention

The CDC guidelines recommend considering glucocorticoid therapy in all patients who have DMD, based on findings that glucocorticoids are the only medication available that effectively slows decline in muscle strength and function, offers reduced risk of scoliosis, and stabilizes pulmonary function.[73]

Additional recommendations for initiation of steroid therapy include the following:

  • Timing of initiation of glucocorticoid therapy must be individualized on the basis of functional state, age, and pre-existing risk factors for adverse effects
  • Recommended immunizations should be completed and varicella immunity established before therapy is initiated
  • Glucocorticoid therapy is not recommended for children still gaining motor skills, especially those under the age of 2 years
  • Once motor skills have plateaued (usually between ages 4-8), children should be started on steroids unless there are substantial reasons (eg, a major pre-existing risk factor for adverse effects) to delay therapy until motor skills decline
  • Initiation of steroids when the child’s condition is in full decline may provide limited benefits but is still recommended

Further CDC guidance on glucocorticoid regimes and dosing includes the following[73] :

  • Daily use is preferred over alternative regimens
  • Neither prednisone nor deflazacort has been proved superior in altering the decline in motor, respiratory, or cardiac functioning, but deflazacort may be preferred for some patients because of the lower risk of weight gain
  • Starting doses: Prednisone, 0.75 mg/kg daily; deflazacort, 0.9 mg/kg daily; higher doses have not been found more effective
  • The minimum effective dose that shows some benefit is believed to be 0.3 mg/kg daily for prednisone
  • The dose is increased as the child grows, as long as adverse effects are manageable and tolerable, until a weight of 40 kg is reached
  • The maximum daily dose is 40 mg for prednisone and 36-39 mg for deflazacort
  • For children who experience transient behavioral effects, administration of the medication after school may be preferred
  • Use of the anabolic steroid oxandrolone was not considered appropriate either with or without glucocorticoid therapy

Psychosocial assessment and interventions

CDC recommendations for emotional adjustment/coping are as follows[73] :

  • Brief screening of emotional status at every clinic visit or on an annual basis at a minimum
  • Emotional adjustment screening can be informal and does not require a comprehensive assessment
  • Use of short standardized rating scales might be helpful
  • Can be completed by a social worker or mental health professional or by other clinical staff with sufficient training (eg, attending physician, nurse)

Neurocognitive assessment recommendations are as follows:

  • Comprehensive developmental (in children ≤4 years old) or neuropsychological (in children ≥5 years old) assessment at or near time of diagnosis and before the start of formal schooling by a neuropsychologist or other professional with expertise in brain functioning and development, within the context of medical conditions
  • Standardized performance-based tests and parent/patient rating scales should be used

Assessment for speech and language therapy should be performed in the following cases:

  • Younger children with suspected delays in speech and/or language development (as identified by caregiver or because of professional concerns)
  • Older patients who present with loss or impairment of functional communication ability

Recommendations regarding autism spectrum disorders include the following:

  • Screening in children suspected of having language delays, restricted or repetitive behavior patterns, or deficits in social functioning (as identified by caregiver or because of professional concerns)
  • Refer to an experienced professional for comprehensive assessment and management of an autism spectrum disorder following positive screening or if ongoing concerns exist

Assessment of the caregivers and family should be performed by a clinical social worker or other professional with the following qualifications:

  • Sufficiently trained and qualified to assess and address emotional adjustment and coping
  • Understanding/awareness of DMD
  • Access to financial resources, programs and social support networks

Interventions will depend on the individual patient, but should be available to meet a broad spectrum of needs. Development of an individual education plan in collaboration with the patient’s parents and school is necessary to address potential learning problems. Promoting patient independence and involvement in decision making (ie, as it relates to medical care) is also essential. Additional recommendations cover psychotherapy, pharmacologic, social interaction, and care/support interventions.[73]

Psychotherapy recommendations include the following:

  • Parental management training for externalizing behaviors (eg, noncompliance/disruptive behavior, parent–child conflict)
  • Individual therapy  for internalizing behaviors (eg, low self-esteem and depression, anxiety, and obsessive-compulsive disorder, adjustment, and coping difficulties)
  • Group therapy for social skills deficits
  • Family therapy for adjustment and coping difficulties and parent-child conflict
  • Applied behavior analysis for specific behaviors related to autism

Pharmacologic intervention recommendations include the following:

  • Selective serotonin reuptake inhibitors (SSRIs) for depression, anxiety, obsessive-compulsive disorder
  • Mood stabilizers for aggression, anger/emotional dysregulation
  • Stimulants for attention deficit/hyperactivity disorder

Social interaction intervention recommendations include the following:

  • Increased DMD awareness and knowledge among school personnel
  • Peer education
  • Social skills training (as needed to address deficits in this area)
  • Modified/adapted sports, summer camps, and youth groups/programs
  • Art groups, equestrian, and aqua therapies; use of service dogs, nature programs, and internet/chat rooms, among others

Care/support intervention recommendations include the following:

  • A care coordinator with sufficient training in clinical care for DMD should serve as a point of contact for the family (eg, to meet family information needs, schedule and coordinate appointments, facilitate communication with clinicians)
  • Home health-care services should be used if a patient's health is at risk because sufficient care cannot be provided in the current setting or circumstances; may also be appropriate when the current care providers cannot sufficiently meet the patient's care needs
  • Transition planning and self-advocacy in medical care, facilitating transfer to a new medical care team, and developing educational and vocational opportunities
  • Palliative care for pain management, as needed; emotional and spiritual support; and guidance for treatment and medical decisions
  • Hospice care for end-stage patients

Management of joint contractures

The CDC guidelines for the management of joint contractures require input from neuromuscular specialists, physical therapists, rehabilitation physicians, and orthopedic surgeons. Programs to prevent contractures are usually monitored and implemented by a physical therapist and tailored to individual needs, stage of the disease, response to therapy, and tolerance.[74]

Additional recommendations for physical therapy include the following:

  • Active, active-assisted, and/or passive stretching to prevent or minimize contractures should be done a minimum of 4-6 days per week for any specific joint or muscle group
  • Stretching should be done at home and/or school, as well as in the clinic
  • Regular stretching at the ankle, knee, and hip is necessary
  • During the non-ambulatory phase, regular stretching of the upper extremities, including the long finger flexors and wrist, elbow, and shoulder joints, also becomes necessary
  • Additional areas that require stretching can be identified by individual examination

Swimming may have benefits for aerobic conditioning and respiratory exercise, is highly recommended from the early ambulatory to early non-ambulatory phases, and could be continued in the non-ambulatory phase as long as it is medically safe. Additional benefits may be provided by low-resistance strength training and optimization of upper body function. Significant muscle pain in the 24-hour period after a specific activity is a sign of overexertion and contraction-induced injury, and if this occurs the activity should be modified.

The guidelines find no absolute situations in which lower-limb contracture surgery is invariably indicated. While surgical options exist, none could be recommended above any other. Options for surgery depend on individual circumstances, but can be utilized in both the ambulatory and non-ambulatory phases. Surgical options based on stage are provided below.[74]

Early ambulatory phase

Procedures include the following:

  • Heel cord (Achilles tendon) lengthening for equinus contractures
  • Hamstring tendon lengthening for knee-flexion contractures
  • Anterior hip-muscle releases for hip-flexion contractures
  • Excision of the iliotibial band for hip-abduction contractures

Middle ambulatory phase

Approaches to lower-extremity surgery to maintain walking include the following:

  • Bilateral multi-level (hip-knee-ankle or knee-ankle) procedures
  • Bilateral single-level (ankle) procedures
  • Unilateral single-level (ankle) procedures for asymmetric involvement (rarely used)

The surgeries may involve the following:

  • Tendon lengthening
  • Tendon transfer
  • Tenotomy (cutting the tendon)
  • Release of fibrotic joint contractures (ankle)
  • Removal of tight fibrous bands (iliotibial band at lateral thigh from hip to knee)

Equinus foot deformity (toe-walking) and varus foot deformities (severe inversion) can be corrected by heel-cord lengthening and tibialis posterior tendon transfer through the interosseous membrane onto the dorsolateral aspect of the foot to change plantarflexion-inversion activity of the tibialis posterior to dorsiflexion-eversion. Hamstring lengthening behind the knee is generally needed if the patient has a knee-flexion contracture of more than 15°.

After tendon lengthening and tendon transfer, postoperative bracing may be needed, which should be discussed preoperatively. Following tenotomy, bracing is always needed. When surgery is performed to maintain walking, the patient must be mobilized using a walker or crutches on the first or second postoperative day to prevent further disuse atrophy of lower-extremity muscles. Postoperative walking must continue throughout limb immobilization and post-cast rehabilitation. Close coordination between and an experienced team (eg, orthopedic surgeon, physical therapist, and orthoptist) is required.

Late ambulatory and early nonambulatory phase

Surgery in the late ambulatory phase has generally been ineffective. Likewise, extensive lower-extremity surgery and bracing to regain ambulation within 3-6 months after walking ability is lost is generally ineffective and not considered appropriate.

Late nonambulatory phase

Severe equinus foot deformities of more than 30° can be corrected with heel-cord lengthening or tenotomy. Varus deformities (if present) can be corrected with tibialis posterior tendon transfer, lengthening, or tenotomy. These procedures are performed for specific symptomatic problems, to alleviate pain and pressure, to allow the patient to wear shoes, and to permit correct placement of the feet on wheelchair footrests. They are not recommended as routine care.

Skeletal management

Daily glucocorticoid treatment reduces the risk of scoliosis, but increases the risk of vertebral fracture. Spinal care by an experienced spinal surgeon comprises the following:

  • In the ambulatory phase, scoliosis monitoring by clinical assessment, with spinal radiography only if scoliosis is observed
  • In the non-ambulatory phase, clinical assessment for scoliosis at each visit; spinal radiography is indicated as a baseline assessment for all patients and should consist of a sitting anteroposterior (AP) full-spine radiograph and lateral projection film
  • An AP spinal radiograph is warranted annually for curves of less than 15-20° and every 6 months for curves of more than 20°, irrespective of glucocorticoid treatment, until skeletal maturity
  • Support of spinal/pelvic symmetry and spinal extension by the wheelchair seating system
  • Monitoring for painful vertebral body fractures
  • Spinal fusion to straighten the spine, prevent further worsening of deformity, eliminate pain due to vertebral fracture with osteoporosis, and slow the rate of respiratory decline
  • Anterior spinal fusion is inappropriate in DMD
  • Posterior spinal fusion is warranted only in nonambulatory patients who have spinal curvature of more than 20°, are not taking glucocorticoids, and have yet to reach skeletal maturity
  • In patients on glucocorticoids, surgery may be warranted if curve progression continues and is associated with vertebral fractures and pain after optimization of medical therapy to strengthen the bones, irrespective of skeletal maturation

Internal fixation is warranted for severe lower-limb fractures in ambulatory patients, to allow prompt rehabilitation and the greatest possible chance of maintaining ambulation. In the nonambulatory patient, the requirement for internal fixation is less acute. Splinting or casting of a fracture is necessary for the nonambulatory patient, and is appropriate in an ambulatory patient if it is the fastest and safest way to promote healing and does not compromise ambulation during healing.

Respiratory management

The CDC guidelines suggest that respiratory care should allow for timely prevention and management of complications. A structured, proactive approach that includes use of assisted cough and nocturnal ventilation has been found to prolong survival. The guidelines provide an outline of respiratory intervention steps for older teenage and adult patients, which are listed below.[74]

Step 1: Volume recruitment/deep lung inflation technique

Volume recruitment/deep lung inflation technique (by self-inflating manual ventilation bag or mechanical insufflation-exsufflation) is used when the forced vital capacity (FVC) reaches < 40% predicted.

Step 2: Manual and mechanically assisted cough techniques

These techniques are necessary in any of the following situations:

  • Respiratory infection is present and baseline peak cough flow < 270 L/min
  • Baseline peak cough flow < 160 L/min or maximum expiratory pressure < 40 cm water
  • Baseline FVC < 40% predicted or < 1.25 L in older teenager/adult

Step 3: Nocturnal ventilation

Nocturnal ventilation is indicated in patients who have any of the following:

  • Signs or symptoms of hypoventilation (patients with FVC < 30% predicted are at especially high risk)
  • Baseline oxygen saturation by pulse oximetry (SpO 2) < 95% and/or blood or end-tidal CO 2 >45 mm Hg while awake
  • Apnea–hypopnea index >10 per hour on polysomnography or four or more episodes of SpO 2 < 92% or drops in SpO 2 of at least 4% per hour of sleep

Use of lung volume recruitment and assisted cough techniques should always precede initiation of noninvasive ventilation.

Step 4: Daytime ventilation

In patients already using nocturnally assisted ventilation, daytime ventilation is indicated for any of the following:

  • Self-extension of nocturnal ventilation into waking hours
  • Abnormal deglutition due to dyspnea, which is relieved by ventilatory assistance
  • Inability to speak a full sentence without breathlessness
  • Symptoms of hypoventilation with baseline SpO 2 < 95% and/or blood or end-tidal CO 2 >45 mm Hg while awake

Continuous noninvasive assisted ventilation (with mechanically assisted cough) can facilitate endotracheal extubation for patients who were intubated during acute illness or during anesthesia, followed by weaning to nocturnal noninvasive assisted ventilation, if applicable.

Step 5: Tracheostomy 

Indications for tracheostomy include the following:

  • Patient and clinician preference
  • Patient cannot successfully use non-invasive ventilation
  • Inability of the local medical infrastructure to support non-invasive ventilation
  • Three failures to achieve extubation during critical illness despite optimum use of non-invasive ventilation and mechanically assisted cough
  • The failure of noninvasive methods of cough assistance to prevent aspiration of secretions into the lung and drops in oxygen saturation below 95% or the patient's baseline, necessitating frequent direct tracheal suctioning via tracheostomy

Cardiac management

The CDC guidelines recommend that a cardiac specialist be involved with the patient and family after confirmation of the diagnosis to initiate a relationship to ensure long-term cardiovascular health. Baseline assessment of cardiac function should be done at diagnosis or by the age of 6 years, especially if this can be done without sedation. Clinical judgment should be used for patients under the age of 6 years who require sedation.

Echocardiographic screening at the time of diagnosis or by the age of 6 years is deemed necessary even though the incidence of echocardiographic abnormalities is low in children younger than 8 to 10 years. A baseline echocardiogram allows for screening for anatomic abnormalities (eg, atrial or ventricular septal defects, patent ductus arteriosus) that might affect long-term cardiovascular function.[74]

Additional recommendations for cardiac management include the following:

  • Minimum assessment should include electrocardiography (ECG) and a noninvasive cardiac imaging study (ie, echocardiography)
  • Assessment of cardiac function should be performed at least once every 2 years until the age of 10 years
  • Annual complete cardiac assessments should begin at the age of 10 years, or earlier if cardiac signs and symptoms arise
  • Abnormalities of ventricular function on non-invasive cardiac imaging studies warrant increased surveillance (at least every 6 months) and should prompt initiation of pharmacologic therapy, irrespective of the age at which they are detected
  • Consider the use of angiotensin-converting enzyme (ACE) inhibitors as first-line therapy; beta blockers and diuretics are also appropriate
  • Signs or symptoms of cardiac rhythm abnormalities should be investigated with Holter or event monitoring and should be treated
  • New-onset sinus tachycardia in the absence of a clear cause should prompt assessment, including that of left ventricular function
  • Patients receiving glucocorticoids need additional monitoring for hypertension, which might necessitate adjustment in the glucocorticoid dose; systemic arterial hypertension should be treated
  • Prevention of systemic thromboembolic events by anticoagulation therapy can be considered in patients with severe cardiac dysfunction, but is inappropriate in earlier cardiac dysfunction

Digestion and nutritional care

The guidelines recommend access to a dietitian or nutritionist, a swallowing/speech and language therapist, and a gastroenterologist, for the following reasons:

  • To guide the patient to maintain good nutritional status to prevent both undernutrition/malnutrition and overweight/obesity
  • To provide a well-balanced, nutrient-complete diet (adding tube feeding, if necessary)
  • To monitor and treat dysphagia and prevent aspiration and weight loss
  • To assess and treat delayed speech and language problems
  • To treat the common problems of constipation and gastroesophageal reflux with both medication and nonmedication therapies

Pain management

CDC recommendations for pain management interventions include the following[74] :

  • Physical therapy
  • Postural correction
  • Orthoses, wheelchair, and bed enhancements
  • Pharmacologic approaches (eg, muscle relaxants and anti-inflammatory medications)

Pharmacologic interventions must take into account possible interactions with other medications (eg, steroids and nonsteroidal anti-inflammatory drugs [NSAIDs]) and their adverse effects, particularly those that might negatively affect cardiac or respiratory function.

Surgical precautions

In 2007 the American College of Chest Physicians (ACCP) published a consensus statement of recommendations for preoperative, intraoperative, and postoperative respiratory support for DMD patients undergoing procedures requiring anesthesia or sedation.[75]

Preoperative respiratory support

Anesthesiology and pulmonology consultations should be obtained, according to the ACCP. Pulmonary evaluation should include measurement of the following:

  • FVC
  • Maximum inspiratory pressure (MIP)
  • Maximum expiratory pressure (MEP)
  • Peak cough flow (PCF)
  • Oxyhemoglobin saturation by pulse oximetry (SpO 2) in room air; if < 95%, measure the blood and/or end-tidal carbon dioxide level
  • Consider preoperative training in the use of noninvasive positive pressure ventilation (NPPV) for patients at increased risk of respiratory complications (FVC < 50% of predicted) and especially for patients at high risk (FVC < 30% of predicted)
  • Consider preoperative training in manual and mechanically assisted cough, emphasizing use of mechanical insufflation-exsufflation (MI-E) with a bronchial secretion clearance device for patients at high risk of ineffective cough (adults with PCF < 270 L/min or MEP < 60 cm H 2O)

Other preoperative measures should include the following:

  • Refer the patient to a cardiologist for clinical evaluation and optimization of cardiac therapies
  • Nutritional assessment and optimization of nutritional status is required
  • Consider strategies to manage dysphagia
  • Discuss the risks and benefits of general anesthesia or procedural sedation with the patient and guardians, and help them to decide on and implement their decisions regarding resuscitation parameters and, if applicable, advance directives

Intraoperative support

Intraoperative measures include the following:

  • Consider use of a total intravenous anesthesia technique for induction and maintenance of general anesthesia (eg, propofol and short-acting opioids)
  • The use of depolarizing muscle relaxants such as succinylcholine is absolutely contraindicated because of the risk of fatal reactions
  • Have an intensive care unit bed available for postprocedure care

Options for providing respiratory support during maintenance of general anesthesia or procedural sedation for patients with DMD include the following:

  • Endotracheal intubation, with use of NPPV to facilitate extubation for selected patients
  • Mechanical ventilation via a mouthpiece with leak-proof seal
  • Manual or mechanical ventilation (using conventional ventilators or bilevel positive pressure ventilators designed for noninvasive respiratory support) delivered via a full face mask or nasal mask interface
  • Application of ventilation in the assisted or controlled modes should be considered for patients with FVC < 50% of predicted, and strongly considered for those with an FVC < 30% of predicted

Options for respiratory support during induction of and recovery from general anesthesia or procedural sedation include the following:

  • Manual ventilation using a flow-inflated manual resuscitation bag (standard “anesthesia bag”) with a full face or nasal mask interface
  • Mechanical support using a conventional or noninvasive positive pressure ventilator via a full face or nasal mask

Monitor SpO2 continuously and, whenever possible, blood or end-tidal carbon dioxide levels.

Postoperative support

Postoperative measures include the following:

  • Consider extubation directly to NPPV in DMD patients with FVC < 50% of predicted, and especially those with FVC < 30% of predicted
  • Consider delaying extubation until respiratory secretions are well controlled and SpO 2 is normal or baseline in room air; continuous use of NPPV can then be weaned as tolerated
  • Use supplemental oxygen therapy cautiously; monitor Spo 2 continuously
  • Whenever possible, monitor blood or end-tidal carbon dioxide levels
  • Assess whether hypoxemia is due to hypoventilation, atelectasis, or airway secretions and treat appropriately
  • Use manually assisted cough and MI-E postoperatively for patients with impaired cough (PCF < 270 L/min or MEP < 60 cm H 2O in adults)
  • Optimize postoperative pain control in patients with DMD; if sedation and/or hypoventilation occurs, delay endotracheal extubation for 24 to 48 hours or use NPPV
  • Obtain a cardiology consultation and closely monitor cardiac and fluid status postoperatively
  • Initiate bowel regimens to avoid and treat constipation and consider prokinetic GI medications
  • Consider gastric decompression with a nasogastric tube in patients with GI dysmotility
  • Start parenteral nutrition or enteral feeding via a small-diameter tube if oral feeding is delayed for >24-48 hours postoperatively

The CDC guidelines concur with the earlier guidelines of ACCP and include these additional recommendations for surgical precautions[74] :

  • Surgery should be performed in a full-service hospital that has experience with DMD patients
  • For patients on  long-term corticosteroid treatment, consider steroid coverage over the period of surgery
  • To minimize blood loss and its intraoperative effects in major surgeries (eg, spinal fusion), use mildly hypotensive anesthetics, crystalloid bone allograft, and cell-saver technology
  • Other interventions, such as the use of aminocaproic acid or tranexamic acid to diminish intraoperative bleeding, can be considered
  • Postoperative anticoagulation with heparin and/or aspirin is inappropriate
  • Use of compression stockings or sequential compression for prevention of deep venous thrombosis may be indicated
  • An echocardiogram and electrocardiogram should be done before general anesthesia
  • An echocardiogram should also be done if the patient is undergoing conscious sedation or regional anesthesia if the last investigation was more than 1 year ago or the patient has had an abnormal echocardiogram in the preceding 7-12 months
  • For local anesthesia, an echocardiogram should be done if an abnormal result had been obtained previously
  • Incentive spirometry is not indicated owing to potential lack of efficacy in patients with respiratory muscle weakness and the availability of preferred alternatives, such as mechanical insufflation-exsufflation (MI-E)

Facioscapulohumeral Muscular Dystrophy

In 2015, the AAN and the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) released joint evidence-based guidelines for the evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy (FSHD). The guidelines were also endorsed by the FSH Society and the Muscular Dystrophy Association.[76]

A clinical algorithm for diagnosis includes the following steps:

  • When clinical presentation of FSHD is typical and the diagnosis of FSHD1 is genetically confirmed in a first-degree relative, genetic testing is not necessary in an affected individual
  • In patients who have no first-degree relatives with genetic confirmation of the disease, test for D4Z4 contraction
  • If negative for D4Z4 contraction, consider FSHD2,  limb-girdle muscular dystrophy type 2A, or other myopathies
  • If positive for D4Z4 contraction and typical clinical presentation, FSHD1 diagnosis is confirmed
  • If positive for D4z4 contraction and atypical clinical presentation, test for A allele; if positive for A allele, FSHD1 diagnosis is confirmed; if negative, consider other myopathies

There were no recommendations given a level A rating denoting that in almost all circumstances, adherence to the recommendation will improve health-related outcomes. Level B and C recommendations included the following[76] :

  • Obtain genetic confirmation of FSHD1 in patients with atypical presentations and no first-degree relatives with genetic confirmation of the disease (level B)
  • Patients with large D4Z4 deletion sizes (contracted D4Z4 allele of 10–20 kb) are more likely to develop more significant disability and at an earlier age as well as symptomatic extramuscular manifestations (level B)
  • Obtain baseline pulmonary function tests (PFT); monitor regularly in patients with abnormal baseline PFT results or any combination of severe proximal weakness, kyphoscoliosis, wheelchair dependence, or comorbid conditions that may affect ventilation (eg, chronic obstructive pulmonary disease, cardiac disease) (level B)
  • Refer patients with compromised PFT results (eg, forced vital capacity [FVC] < 60%) or symptoms of excessive daytime somnolence or nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches) for pulmonary or sleep medicine consultation, for consideration of nocturnal sleep monitoring or nocturnal non-invasive ventilation, to improve quality of life (level B)
  • Patients who do not receive regular PFT should be tested prior to surgical procedures requiring general anesthesia, as such testing may uncover asymptomatic respiratory compromise (level B)
  • Refer patients who develop overt signs or symptoms of cardiac disease (eg, shortness of breath, chest pain, palpitations) for cardiac evaluation; routine cardiac screening is not essential in the absence of cardiac signs or symptoms (level C)
  • Refer patients with large deletions (contracted D4Z4 allele of 10-20 kb) to an experienced ophthalmologist (eg, retina specialist) for dilated indirect ophthalmoscopy (level B)
  • The presence and severity of retinal vascular disease at initial screening should be used to determine the frequency of subsequent monitoring (level B)
  • Screen all young children for hearing loss at diagnosis and yearly thereafter until these children start school; hearing loss may not be present at diagnosis and can be progressive (level B)
  • Treating physicians should routinely inquire about pain; referral for a physical therapy evaluation may prove helpful as an initial nonpharmacologic intervention; in patients with persistent pain and no contraindications, a trial of nonsteroidal anti-inflammatory medications is appropriate for acute pain, and antidepressants or antiepileptics for chronic pain (level B)
  • Albuterol, a corticosteroid, or diltiazem should not be prescribed for improving strength (level B)
  • Surgical scapular fixation might be offered cautiously to selected patients after careful consideration of the overall muscle impairment in the involved arm, assessment of potential gain in range of motion by manual fixation of the scapula, the rate of disease progression, and the potential adverse consequences of surgery and prolonged postsurgical bracing (level C)
  • Clinicians might encourage low-intensity aerobic exercise; an experienced physical therapist can help guide development of individualized exercise programs; clinicians might also use the practical physical activities guidelines for individuals with disabilities provided by the US Department of Health and Human Services when counseling patients about aerobic exercise (level C)
  • Patients interested in strength training may be referred to physical therapists to establish a safe exercise program using appropriate low/medium weights/resistance that takes into consideration the patients' physical limitations (level C)

Congenital Muscular Dystrophy

In 2010, the International Standard of Care Committee for Congenital Muscular Dystrophy published the first guidelines for children with congenital muscular dystrophies (CMDs) with consensus on care recommendations in seven areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/nutrition/speech/oral care, cardiology, and palliative care. The guideline development was funded by CureCMD, TREAT-NMD, AFM-Association Francaise contre les Myopathies and Telethon Italy.[77]

In 2015, the AAN and the AANEM released joint evidence-based guidelines for the evaluation, diagnosis and management of congenital muscular dystrophy. The guidelines were endorsed by the AAP, the American Occupational Therapy Association, the Child Neurology Society, and the National Association of Neonatal Nurses.[78]

The AAN/AANEM guidelines classify three major categories of CMDs:

  • Collagenopathies (also known as collagen VI−related myopathies), including Ullrich CMD and Bethlem myopathy
  • Merosinopathies (also known as merosin-deficient CMDs [MDCs], laminin α2 [ LAMA2]-related CMDs, and MDC1A
  • Dystroglycanopathies (also known as α-dystroglycan–related MDs), including Fukuyama CMD, muscle-eye-brain disease, and Walker-Warburg syndrome

However, other rare CMDs do not fit into the three classic categories. These CMDs with their associated genes and clinical phenotypes include the following:

  • Rigid spine syndrome (selenoprotein N, 1[ SEPN1], four-and-a-half LIM domain 1[ FHL1])
  • Mutiminicore disease ( SEPN1)
  •  L-CMD (Lamin A/C [ LMNA])

Other genes that have been associated with CMDs include the following[78] :

  • GTDC2
  • TMEM5
  • B3GALNT2
  • SGK196
  • B3GNT1
  • GMPPB]
  • AG1

The authors of the AAN/AANEM guidelines base some recommendations in part on evidence from other neuromuscular disorders of childhood because of a lack of literature directly relevant to CMDs. As with other forms of muscular dystrophy, multidisciplinary teams should include the following:

  • Neuromuscular specialists, particularly child neurologists and physiatrists with subspecialty training
  • Physicians from other specialties (eg, cardiology, gastroenterology, neurology, ophthalmology, orthopedic surgery, pulmonology)
  • Allied health professionals with relevant expertise (eg, dieticians, genetic counselors, nurses, nurse practitioners, occupational therapists, physical therapists, speech-language pathologists)

Like the 2015 FSHD guidelines, the AAN/AANEM contain no level A recommendations. The key recommendations include the following[78] :

  • Physicians caring for children with CMD should consult a pediatric neuromuscular specialist for diagnosis and management (level B)
  • Pediatric neuromuscular specialists should coordinate the multidisciplinary care of patients with CMD when such resources are accessible to interested families (level B)
  • When genetic counselors are available to help families understand genetic test results and make family-planning decisions, help should be given to families to access such resources (level B)
  • Physicians should use relevant clinical features such as ethnicity and geographic location, patterns of weakness and contractures, the presence or absence of central nervous system involvement, the timing and severity of other organ involvement, and serum creatine phosphokinase (CK) levels to guide diagnosis in collagenopathies and in dystroglycanopathies (level B)

Diagnosis

AAN/AANEM recommendations regarding diagnosis include the following:

  • Immunohistochemical staining for relevant proteins in CMD cases may be included in muscle biopsies when the subtype-specific diagnosis is not apparent after initial diagnostic studies, if the risk associated with general anesthesia is determined to be acceptable (level C)
  • When muscle biopsies are indicated, they should be performed and interpreted at centers experienced in this test modality; in some cases, optimal diagnostic information may be derived when the biopsy is performed at one center and interpreted at another (level B)
  • Magnetic resonance imaging (MRI) may assist with the diagnosis of patients with clinically suspected CMD subtypes such as merosinopathies and dystroglycanopathies, if the potential risk associated with any sedation is determined to be acceptable and if a radiologist or other physician with the appropriate expertise is available to interpret the findings (level B)
  • Consider muscle imaging studies of the lower extremities for individuals with suspected CMD subtypes such as collagenopathies (ultrasonography or MRI) and  SEPN1-related myopathy (MRI), if the risk associated with any sedation needed is determined to be acceptable and if a radiologist or other physician with the appropriate expertise is available to interpret the findings (level C)
  • Consider targeted genetic testing for specific CMD subtypes that have well-characterized molecular causes when available and feasible (level C)
  • In individuals who do not have a mutation identified in one of the commonly associated genes or who have a phenotype whose genetic origins have not been well characterized, whole-exome or whole-genome sequencing may be used if those technologies become more accessible and affordable for routine clinical use (level C)

Treatment

The AAN/AANEM guidelines note that there are no curative CMD subtype-specific interventions. Thus, all screening and interventions are intended to promote growth and potential development, mitigate cumulative morbidities, optimize function, and limit mortality while maximizing quality of life.

At the time of diagnosis, the family should be informed regarding areas of uncertainty such as clinical outcomes and the value of interventions as they pertain to both longevity and quality of life. Physicians should explain the multisystem implications of neuromuscular insufficiency and guide families as they make decisions regarding the monitoring for and treatment of CMD complications (level B).

Management of complications

Respiratory complications

The AAN/AANEM guidelines recommend the following[78] :

  • Inform families of patients with CMD that respiratory insufficiency and associated problems may be inconspicuous at the outset (level B)
  • Monitor pulmonary function tests such as spirometry and oxygen saturation in the awake and sleep states of patients, with monitoring levels individualized on the basis of the child's clinical status (level B)
  • Refer to pulmonary or aerodigestive care teams, when available, that are experienced in managing the interface between oropharyngeal function, gastric reflux and dysmotility, and nutrition and respiratory systems, and can provide guidance concerning trajectory, assessment modalities, complications, and potential interventions (level B)

The International Standard of Care Committee consensus recommendations include the following[77] :

  • Regularly scheduled physician visits and patient or family awareness of potential signs and symptoms are elements of a proactive approach to recognize early pulmonary problems prior to the onset of chronic respiratory compromise
  • Pneumococcal and influenza vaccines are suggested for any patient with CMD
  • Palivizumab, a humanized monoclonal antibody against respiratory syncytial virus, should be given to children under 2 years of age as prophylaxis
  • Spinal bracing is required to promote activities of daily living, ensure functional sitting posture, and delay the progression of scoliosis; this allows adequate thoracic growth until optimal timing for spinal surgery
  • Spirometry both in and out of the brace is recommended to evaluate the impact on respiratory function
  • Adjustment is needed between the degree of correction and the compression pressure on the thorax to avoid compromise of respiratory capacity

Complications from dysphagia

The AAN/AANEM guidelines recommend the following[78] :

  • Neuromuscular specialists should coordinate with primary care providers to follow nutrition and growth trajectories in patients with CMD (level B)
  • Multidisciplinary evaluations with swallow therapists, gastroenterologists, and radiologists if there is evidence of failure to thrive or respiratory symptoms (or both) (level B)
  • A multidisciplinary care team, taking into account medical and family considerations, should recommend gastrostomy placement with or without fundoplication in the appropriate circumstances (level B)

The International Standard of Care Committee consensus recommends feeding and swallowing problems be regularly screened during routine clinic visits. Key screening issues are the following[77] :

  • Length of mealtimes - More than 30 minutes per meal is considered to be prolonged
  • Frequency of meals - Increased meal frequency may be needed and clinicians need to ensure that families can carry this out without difficulties
  • Frequency of pulmonary infections
  • Difficulties chewing; choking and coughing
  • Food texture modification
  • Family stress or enjoyment of mealtimes for the child and parents
  • The ability to feed independently
  • Position for feeding

Identification of difficulties in the above areas warrants assessment by a specialist qualified in feeding and swallowing evaluation. Assessment should include the following:

  • Orofacial examination
  • Observation and evaluation of feeding and swallowing skills
  • Observation and evaluation of seating and positioning.

The use of a videofluoroscopic swallow assessment to objectively assess the swallow should be done by speech and language specialists. Endoscopic evaluation of swallow is an underused assessment in pediatrics, specifically in this population.

Additional consensus recommendations include the following[77] :

  • Patients with muscle weakness are prone to gastroesophageal reflux and delayed gastric emptying; treatment with an H2-antagonist/proton pump inhibitor with or without a prokinetic agent can be indicated
  • Speech and swallow evaluation should be considered for patients with symptoms of aspiration such as cough, choking, difficulty swallowing, poor feeding, or failure to thrive; thickened feeds or an alternate method of feeding are needed
  • If symptomatic management is insufficient, the use of tube feeding has to be considered
  • Nasogastric tube feeding should be reserved for short-term use such as before and after surgery or during acute illness
  • Gastrostomy or jejunostomy is the treatment of choice for long-term enteral feeding

Cardiac complications

The AAN/AANEM guidelines recommend referral, regardless of subtype, for a baseline cardiac evaluation. The schedule for further evaluations should depend on the results of the baseline evaluation and the subtype-specific diagnosis (level B).[78]

The International Standard of Care Committee consensus recommendations include the following[77] :

  • All patients with congenital muscular dystrophies should undergo cardiac screening beginning at diagnosis
  • The initial evaluation can help with diagnosis of the type of CMD, provides reference values for follow-up, and assists follow-up planning
  • The frequency of follow-up depends on the presence of cardiac risk factors such as diagnosis of laminopathy or dystroglycanopathy, cardiac symptoms, and abnormal previous cardiac tests
  • In patients with laminopathies or dystroglycanopathies, cardiac examinations should be performed at least every year, and at least every 6 months in patients with symptoms, conductive abnormalities, or myocardial involvement
  • In patients with other CMDs, follow-up should be performed at least every 2 years in asymptomatic patients and at least every year in patients with cardiac symptoms
  • ECG and echocardiography are simple examinations and provide enough information in the majority of patients
  • Twenty-four-hour ambulatory electrocardiogram should be considered in patients with laminopathies in order to detect paroxysmal conductive defects and arrhythmias
  • Isotopic ventriculography can be useful to assess ventricular function in patients with poor echogenicity due to thoracic deformations
  • Cardiac MRI could be useful in patients with laminopathies

Surgical complications

The AAN/AANEM guidelines recommend that before children undergo any surgical interventions and general anesthesia, physicians should discuss the potential increased risk of complications with patients' families, because these factors may affect decision-making regarding consent to certain elective procedures (level B). When children undergo procedures involving sedation or general anesthesia, physicians should monitor longer than usual in the immediate postoperative period to diagnose and treat respiratory, nutritional, mobility, and gastrointestinal mobility complications (level B).[78]

The International Standard of Care Committee recommends postoperative respiratory management by an experienced team including physical therapists to improve outcome. Nutritional aspects should be considered to ensure that maintenance of weight is achieved. Additional considerations for postoperative management and care include[77] :

  • Intensive pulmonary treatment in the following 6 months (insufflation techniques, prolongation of mechanical ventilation) may be needed
  • Self-feeding can be more difficult initially
  • Wheelchairs may need to be adapted to the changed shape of the child
  • Management of transfers, including the hoist and slings, must be considered
  • All aspects of postoperative activities of daily living should be addressed preoperatively by an occupational or physical therapist
  • Bracing may still be required after surgery, and it requires an experienced orthotist
  • Support of the head may also be needed
  • Pain management is needed
  • Long-term follow-up by spinal surgeons is needed given the child’s changing status
  • Increasing hyperextension of the neck is common in this group of disorders and needs to be monitored; strategies must be developed to alleviate the concomitant problems of function
  • Extension of the spinal surgery into the neck may be required

Musculoskeletal complications

The AAN/AANEM guidelines recommend the following[78] :

  • Refer to allied health professionals, including physical, occupational, and speech therapists; seating and mobility specialists; rehabilitation specialists; and orthopedic surgeons, to help maximize function and potentially slow the progression of musculoskeletal complications (level B)
  • Range-of-motion exercises, orthotic devices, heel cord–lengthening procedures, or a combination of these interventions may be recommended in certain circumstances (level B)
  • Avoid using neuromuscular blocking agents (eg, botulinum toxin), unless the contractures are determined to cause significantly greater impairment than would any potential worsening of weakness in the targeted muscle groups (level C)

The International Standard of Care Committee consensus recommends physical therapy be focused on the following[77] :

  • Maintenance of function and mobility
  • Prevention or treatment of joint contractures and spine deformities
  • Activities to improve respiratory function, such as singing or playing a wind instrument
  • Adequate seating and wheelchair support
  • Nutrition and swallowing surveillance with optimal weight gain

Educational adjustments

The AAN/AANEM guidelines recommend referral to special education advocates, developmental specialists, and education specialists when appropriate for individual circumstances (level B).[78]

The International Standard of Care Committee consensus recommendations include the following[77] :

  • Children with mental retardation and learning issues should undergo psychometric testing and be referred to early intervention and augmented/specialized school and communication programs with dedicated evaluations and monitoring
  • For behavioral, emotional, and autistic problems, referrals to child psychology/psychiatry services
  • In α-dystroglycanopathies, detailed eye examination and subsequent follow-ups are indicated; if the child is visually impaired, appropriate education and services should be provided, given that visual impairment negatively affects learning and quality of life
  •  As coordinators of care, neurologists should act as advocates when working with day care, school, and other service providers and make sure that they understand the special needs of children with CMD

Limb-Girdle and Distal Dystrophies

In 2014, guidelines for the diagnosis and management of patients with limb-girdle or distal muscular dystrophies were issued by the AAN and the AANEM. The guidelines were endorsed by the American Academy of Physical Medicine and Rehabilitation, the Child Neurology Society, the Jain Foundation, and the MDA.[79]

The guideline provides algorithms for diagnosis, with the clinical picture, ethnicity, family history, and cardiac and respiratory symptoms all considered in deciding whether genetic testing for MD is appropriate and which of the many individual tests to select. The guidelines call for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. The key recommendations are listed below.

Clinicians should use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the following (level B):

  • Pattern of muscle involvement
  • Inheritance pattern
  • Age at onset
  • Associated manifestations (eg, early contractures, cardiac or respiratory involvement)

In patients with suspected MD in whom initial clinically directed genetic testing does not provide a diagnosis, clinicians may obtain genetic consultation or perform any of the following to identify the genetic abnormality (level C):

  • Parallel sequencing of targeted exomes
  • Whole-exome sequencing
  • Whole-genome screening
  • Next-generation sequencing

Other referral and assessment recommendations include the following:

  • Clinicians should refer newly diagnosed patients for cardiology evaluation, even if they are asymptomatic, to guide appropriate management; the evaluation should include ECG and structural evaluation (echocardiography or cardiac MRI) (level B)
  • If cardiology evaluation yields abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (eg, Holter monitor or event monitor) to guide appropriate management (level B)
  • Refer patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation (level B)
  • Referral of patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation is not obligatory unless they develop overt cardiac signs or symptoms (level B)
  • Refer patients with dysphagia, frequent aspiration, or weight loss for swallowing evaluation or gastroenterology evaluation to assess and manage swallowing function and aspiration risk, to teach patients techniques for safe and effective swallowing (eg, chin tuck maneuver, altered food consistencies), and to consider placement of a gastrostomy/jejunostomy tube for nutritional support (level B)
  • Refer for pulmonary function testing (PFT; spirometry and maximal inspiratory/expiratory force in the upright and, if normal, supine positions) or referral for pulmonary evaluation (to identify and treat respiratory insufficiency) at the time of diagnosis, or if the patient develops pulmonary symptoms (level B)
  • In patients with a known high risk of respiratory failure (eg, those with LGMD2I or MFM), obtain periodic pulmonary function testing (spirometry and maximal inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (level B)
  • Referral of patients with LGMD2B and LGMD2L for pulmonary evaluation is not obligatory unless they are symptomatic (level C)
  • Refer patients with excessive daytime somnolence, nonrestorative sleep (eg, frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on PFTs for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (level B)
  • Monitor patients for the development of spinal deformities to prevent resultant complications and preserve function (level B)
  • Refer patients with musculoskeletal spine deformities to an orthopedic spine surgeon for monitoring and surgical intervention if it is deemed necessary in order to maintain normal posture, assist mobility, maintain cardiopulmonary function, and optimize quality of life (level B)
  • Refer patients to a clinic that has access to multiple specialties (eg, physical therapy, occupational therapy, respiratory therapy, speech and swallowing therapy, cardiology, pulmonology, orthopedics, and genetics) designed specifically to care for patients with MD and other neuromuscular disorders in order to provide efficient and effective long-term care (level B)
  • Clinicians should recommend that patients have periodic assessments by a physical and occupational therapist for symptomatic and preventive screening (level B)
  • While respecting and protecting patient autonomy, clinicians should proactively anticipate and facilitate patient and family decision-making as the disease progresses, including decisions regarding loss of mobility, need for assistance with activities of daily living, medical complications, and end-of-life care (level B)
  • Prescribe physical and occupational therapy, as well as bracing and assistive devices that are adapted specifically to the patient's deficiencies and contractures, in order to preserve mobility and function and prevent contractures (level B)
  • Advise patients that aerobic exercise combined with a supervised submaximal strength training program is probably safe (level C)
  • Advise patients that gentle, low-impact aerobic exercise (swimming, stationary bicycling) improves cardiovascular performance, increases muscle efficiency, and lessens fatigue (level C)
  • Counsel patients to hydrate adequately, not to exercise to exhaustion, and to avoid supramaximal, high-intensity exercise (level C)
  • Educate patients who are participating in an exercise program about the warning signs of overwork weakness and myoglobinuria, which include feeling weaker rather than stronger within 30 minutes after exercise, excessive muscle soreness 24-48 hours after exercise, severe muscle cramping, heaviness in the extremities, and prolonged shortness of breath (level B)
  • Clinicians should not offer patients gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine the efficacy and safety of the treatment (level R)
 

Medication

Medication Summary

Several agents have shown promise in management of Duchenne muscular dystrophy (MD). The mainstay of therapy has been the steroids; however, the lack of prolonged efficacy and the attendant adverse effects of higher-dose steroids limit their use.

Deflazacort, an oxazoline derivative of prednisolone, may offer therapeutic efficacy with fewer adverse effects.

The approval of eteplirsen, the first phosphorodiamidate morphino oligomer (PMO), provides an addition to the therapeutic armamentarium; however, continued approval of eteplirsen is contingent on postmarketing performance data. A second such agent, golodirsen, was subsequently approved. Other morpholino antisense oligomers, viltolarsen and casimersen, have also been approved by the FDA for use in the United States.[37, 38, 39, 40]   

Corticosteroids

Class Summary

Glucocorticoid drugs delay the cytotoxic damage of MD to the necrosing muscle cells.

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Prednisone exhibits beneficial effects in treatment of Duchenne MD in dosages ranging from 0.75 mg/kg/day to 1.5 mg/kg/day. Therapeutic effects are believed to be mediated through suppression of cytotoxic T-cell expression from necrotic muscles. Response to therapy may not last beyond several months, and adverse effects (eg, rapid weight gain, osteoporosis, myopathy, and growth retardation) limit its use.

Deflazacort (Emflaza)

Deflazacort, an oxazoline derivative of prednisolone, represents one of the newer corticosteroids for Duchenne MD. The FDA-approved dose is 0.9 mg/kg/day. It elicits a therapeutic response similar to that of prednisone.

Morpholino Antisense Oligomers, Neurology

Class Summary

These agents bind to various exons (eg, 45, 51, 53) of dystrophin pre-mRNA, resulting in exclusion of the particular exon (ie, skipping) during mRNA processing. Exon skipping is intended to allow production of an internally truncated dystrophin protein in patients with genetic mutations that are amenable to specific exon skipping.

Eteplirsen (Exondys 51)

Eteplirsen is a phosphorodiamidate morphino oligomer (PMO), the first of its class. It is indicated for Duchenne MD in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping. It is administered as a once-weekly IV infusion.

Golodirsen (Vyondys 53)

A second PMO was approved for Duchenne MD in patients who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. 

Viltolarsen (Viltepso)

Antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass that binds to exon 53 of dystrophin pre-mRNA. This results in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. It is indicated for Duchenne muscular dystrophy (DMD) in patients with a confirmed DMD gene mutation that is amenable to exon 53 skipping.

Casimersen (Amondys 45)

Casimersen is an antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass. PMO binds to exon 45 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Casimersen is indicated for Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 45 skipping. 

 

Questions & Answers

Overview

What is muscular dystrophy?

What were the first historical accounts of muscular dystrophy?

What is the role of genetics in the pathogenesis of muscular dystrophy?

What are common characteristics from all types of muscular dystrophy?

What is the goal of orthopedic management for muscular dystrophy?

What is the pathophysiology of muscular dystrophy?

What are the types of muscular dystrophy?

What is the role of genetics and dystrophin in the etiology of muscular dystrophy?

What is the incidence of muscular dystrophy in the US?

What is the global incidence of muscular dystrophy?

What is the prognosis of muscular dystrophy?

Presentation

What are the initial signs and symptoms of Duchenne muscular dystrophy (DMD)?

What are the major time points in the progression of Duchenne muscular dystrophy (DMD)?

What is the Gower sign in patients with muscular dystrophy?

What are signs of upper extremity involvement in Duchenne muscular dystrophy (DMD)?

What is the progression of Duchenne muscular dystrophy (DMD) following loss of ambulation?

What clinical findings characteristic of Duchenne muscular dystrophy (DMD)?

What are the types of muscular dystrophy?

What are complications of muscular dystrophy?

DDX

What are the differential diagnoses for Muscular Dystrophy?

Workup

What is the role of creatine phosphokinase (CPK) determination in the evaluation of muscular dystrophy?

Which enzyme levels may be elevated in muscular dystrophy?

What is the role of multiplex polymerase chain reaction (PCR) assay in the evaluation of muscular dystrophy?

What is the role of ultrasonography in the diagnosis of muscular dystrophy?

What is the role of ECG in the evaluation of muscular dystrophy?

What is the role of pulmonary function tests (PFTs) in the evaluation of muscular dystrophy?

What is the role of electromyography (EMG) in the evaluation of muscular dystrophy?

What is the role of biopsy in the evaluation of muscular dystrophy?

Which histologic findings are characteristic of muscular dystrophy?

Treatment

What is the role of surgery in the treatment of muscular dystrophy?

What is the role of steroids in the management of muscular dystrophy?

What is the role of creatine monohydrate supplementation in the management of muscular dystrophy?

What is the role of ataluren (PTC124) in the management of muscular dystrophy?

What is the role of the biologic agents eteplirsen, golodirsen, and viltolarsen in the management of muscular dystrophy?

What is the role of gene therapy in the management of muscular dystrophy?

What are the orthopedic problems in children with muscular dystrophy?

What are the surgical modalities used in the treatment of muscular dystrophy?

What is the role of functional testing in the management of muscular dystrophy?

When is surgery indicated in the management of muscular dystrophy?

What are the categories of surgical interventions for the management of muscular dystrophy?

How is scoliosis treated in patients with muscular dystrophy?

What is included in preoperative evaluation of patients with muscular dystrophy?

What are possible complications of surgical management of muscular dystrophy?

How do steroids affect the bones in patients with muscular dystrophy?

What are the recommendations for screening and treatment for osteoporosis and in patients with muscular dystrophy?

Guidelines

What are the American Academy of Pediatrics (AAP) screening guidelines for muscular dystrophy?

What is the Centers for Disease Control and Prevention (CDC) tool for the diagnosis of muscular dystrophy?

What are the AAP and CDC guidelines for creatine phosphokinase testing in the evaluation of muscular dystrophy?

What are the CDC recommendations for management of Duchenne muscular dystrophy (DMD)?

According to CDC guidelines, how is a diagnosis of Duchenne muscular dystrophy (DMD) confirmed?

What are the CDC guidelines for pharmacologic therapy for Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for psychological assessment in patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for neurocognitive assessment of patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for assessment for speech and language therapy in patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for assessment of autism spectrum disorders in patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for assessment of caregivers of patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for individualized treatment of Duchenne muscular dystrophy (DMD)?

What are the CDC recommendations for psychotherapy in the management of Duchenne muscular dystrophy (DMD)?

What are the CDC recommendations for pharmacologic intervention in the management of Duchenne muscular dystrophy (DMD)?

What are the CDC recommendations for social interaction intervention in the management of Duchenne muscular dystrophy (DMD)?

What are the CDC recommendations for care and support of patients with Duchenne muscular dystrophy (DMD)?

What are the CDC general treatment guidelines for joint contractures in patients with Duchenne muscular dystrophy (DMD)?

What are CDC recommendations for physical therapy for Duchenne muscular dystrophy (DMD)?

Which activities do the CDC recommend for aerobic conditioning and respiratory exercise in patients with Duchenne muscular dystrophy (DMD)?

What are the CDC recommendations for lower-limb contracture surgery in the early ambulatory phase of Duchenne muscular dystrophy (DMD)?

What are the indications of surgery in the late ambulatory phase of Duchenne muscular dystrophy (DMD)?

Which surgeries are performed in the late nonambulatory phase of Duchenne muscular dystrophy (DMD)?

What is included in spinal care of patients with Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for respiratory management in patients with Duchenne muscular dystrophy (DMD)?

What is the function of volume recruitment/deep lung inflation technique for the respiratory management of Duchenne muscular dystrophy (DMD)?

What are the indications for tracheostomy in the respiratory management of Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for cardiac management of Duchenne muscular dystrophy (DMD)?

What are the CDC guidelines for digestion and nutritional care of patients with Duchenne muscular dystrophy (DMD)?

What are CDC recommendations for pain management of Duchenne muscular dystrophy (DMD)?

What are the American College of Chest Physicians (ACCP) guidelines for preoperative respiratory support of patients with Duchenne muscular dystrophy (DMD)?

What are the American College of Chest Physicians (ACCP) guidelines for intraoperative respiratory support of patients with Duchenne muscular dystrophy (DMD)?

What are the American College of Chest Physicians (ACCP) guidelines for postoperative respiratory support of patients with Duchenne muscular dystrophy (DMD)?

What are CDC guidelines for surgical precautions for patients with Duchenne muscular dystrophy (DMD)?

What is the clinical algorithm for diagnosis of facioscapulohumeral muscular dystrophy (FSHD)?

What are AAN and AANEM joint treatment guidelines for facioscapulohumeral muscular dystrophy (FSHD)?

Which organizations have released treatment guidelines for congenital muscular dystrophy?

What are the three major categories of congenital muscular dystrophy?

What are rare types of congenital muscular dystrophy?

Which specialists should be included in a multidisciplinary team for the management of muscular dystrophy?

What are the key AAN/AANEM recommendations for management of congenital muscular dystrophy?

What are the AAN/AANEM recommendations for the diagnosis of congenital muscular dystrophy?

What are the AAN/AANEM treatment guidelines for congenital muscular dystrophy?

What are the AAN/AANEM treatment guidelines for respiratory complications in patients with congenital muscular dystrophy?

What are the International Standard of Care Committee treatment guidelines for respiratory complications in patients with congenital muscular dystrophy?

What are the AAN/AANEM treatment guidelines for complications from dysphagia in patients with congenital muscular dystrophy?

What are the International Standard of Care Committee recommendations for dysphagia screening and assessment in patients with congenital muscular dystrophy?

What are the recommendations for cardiac evaluation in patients with congenital muscular dystrophy?

What are the AAN/AANEM guidelines management of surgical complications of congenital muscular dystrophy?

What are the AAN/AANEM treatment guidelines for musculoskeletal complications in patients with congenital muscular dystrophy?

What are the International Standard of Care Committee recommendations for physical therapy in patients with congenital muscular dystrophy?

What are the AAN/AANEM guidelines for educational adjustments in patients with congenital muscular dystrophy?

What is included in the AAN/AANEM guidelines for the limb-girdle or distal muscular dystrophy?

What are the AAN/AANEM diagnostic guidelines for limb-girdle or distal muscular dystrophy?

What are the AAN/AANEM guidelines for referral following diagnosis of limb-girdle or distal muscular dystrophy?

What are the AAN/AANEM guidelines for monitoring and treatment of limb-girdle or distal muscular dystrophy?

Medications

Which medications are used in the treatment of Duchenne muscular dystrophy (DMD)?

Which medications in the drug class Morpholino Antisense Oligomers, Neurology are used in the treatment of Muscular Dystrophy?

Which medications in the drug class Corticosteroids are used in the treatment of Muscular Dystrophy?