Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy

dr. Harry Sunaryo, SpOT

Duchenne muscular dystrophy is an X-linked disease of muscle caused by an absence of the protein dystrophin. Affected boys begin manifesting signs of disease early in life, cease walking at the beginning of the second decade, and usually die by age 20 years. Until treatment of the basic genetic defect is available, medical, surgical, and rehabilitative approaches can be used to maintain patient function and comfort. Corticosteroids, including prednisone and a related compound, deflazacort, have recently been shown to markedly delay the loss of muscle strength and function in boys with Duchenne muscular dystrophy. Surgical release of lower extremity contractures may benefit some patients. Approximately 90% of boys with Duchenne muscular dystrophy will develop severe scoliosis, which is not amenable to control by nonsurgical means such as bracing or adaptive seating. The most effective treatment for severe scoliosis is prevention by intervening with early spinal fusion utilizing segmental instrumentation as soon as curves are ascertained and before the onset of severe pulmonary or cardiac dysfunction.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disease of muscle characterized by a progressive loss of functional muscle mass and replacement with fibrofatty tissue. This degenerative process begins at birth and extends throughout the first two decades, by which time patients usually die because of compromise of the respiratory musculature. The term dystrophy indicates progressive deterioration of the muscle, in contrast with myopathy, which is an abnormality of muscle that may impair function but is nonprogressive. An abnormality in the gene responsible for the production of dystrophin results in a total absence of dystrophin in muscle and other tissues in DMD and in reduced amounts of an abnormal dystrophin in a related but milder condition, Becker muscular dystrophy (BMD).1
DMD is relatively unusual, with an incidence varying between 2 and 3 per 10,000 live male births. Twenty percent to 30% of cases are the result of spontaneous new mutations, many of which are thought to arise in the sperm cell line on the paternal side of the mother, while 70% to 80% of cases can be traced through genetic studies to preceding generations.1 Because the condition affects only males, except in very rare instances, there may not be a clear clinical history in preceding generations, particularly in small families with limited numbers of male births.2
Historical Review
The first description in the medical literature of DMD was in 1851 by Meryon,1 an English physician, who recognized the familial nature, male
predilection, and progressive and ultimately fatal course of DMD and described the histologic changes in muscle.3 Duchenne, however, published a more complete description of 13 cases and described histologic information obtained by muscle biopsies using a muscle biopsy tool that he had designed. He called this condition .paralysie musculaire pseudohypertrophique,. recognizing that the muscle both degenerated and was replaced by fibrofatty tissue.4 Duchenne also proposed that this condition was a primary disease of muscle rather than a secondary muscle affectation resulting from an abnormality in the spinal cord or central nervous system. The term .muscular dystrophy. was first used by Erb in 1884 when he called the condition .dystrophia muscularis progressiva.. Erb also emphasized that this was a primary muscle disease, based on his postmortem studies of muscle and spinal cord in affected boys.5
Knowledge of this condition was not notably increased until the studies by Becker in the 1940s and
Becker described not only the condition bearing his name but also other muscular dystrophies, noting that they could be inherited in an autosomal recessive, autosomal dominant, or X-linked recessive mode.5 An important advance in knowledge of DMD occurred with the work of Hoffman et al1 in 1988, who defined the abnormality in dystrophin as the underlying cause of both DMD and BMD. The understanding of dystrophin has revolutionized diagnostic capabilities and ultimately may lead to effective medical treatment for these dystrophinopathies.
Pathogenesis
Children with DMD have essentially normal muscle function at birth. However, with time, the muscle fibers degenerate and are replaced by fibrofatty tissue. Smaller fibers with central nuclei appear and may represent an attempt to combat the degenerative process: it is proposed that these are secondarily formed,
immature muscle fibers that seem to be relatively less affected by the absence of dystrophin (Fig. 1).6 The degenerative process becomes more marked with time, and by the teenage years, there is a predominance of fibrofatty tissue with only occasional remaining muscle fibers.
The precise cause of the degenerative process is an abnormality in the gene for the cell membrane. associated protein dystrophin, which results in a complete absence of dystrophin in the muscle tissue (Fig. 1). This abnormality is most frequently caused by a deletion of a segment of the gene that disrupts the normal triplet reading frame sequence of nucleotides that determines the amino acid sequence of the protein. Because of the disruption, all of the messenger RNA downstream from this deletion codes for a nonsense protein. The result is a cessation of synthesis and rapid intracellular degradation of the nonsense protein. In BMD, an abnormality in the dystrophin gene causes the muscle cells to contain a truncated dystrophin in less than normal quanti
ties1. The deletion is between the triplet nucleotide coding sequences, so that when the gene is respliced, the downstream triplet sequence is not altered and synthesis continues, resulting in the synthesis of a complete, albeit smaller, dystrophin.
With a molecular weight of 427 kd, dystrophin is a very large protein. It contains 3,685 amino acids; collagen, by comparison, contains 1,000 amino acids in each collagen chain. Dystrophin, along with several other proteins, the dystrophinassociated proteins (DAPs), stabilizes the muscle cell membrane, both physically and physiologically. Another major function of dystrophin may be to link the actin cytoskeleton to the extracellular matrix via the protein merosin.7
The cell membrane in DMD is abnormally permeable, which allows leakage of creatine kinase (CK) into the serum of affected individuals. This explains the increase in CK seen after exercise, particularly involving eccentric muscle activity in some animal model sys-
S L * BC
A DE
Photomicrographs of muscle cross-sections. A, Hematoxylin-eosin stain of muscle from a patient with DMD. Note variations in fiber size (L = large, S = small), central nuclei (arrowhead), and areas of fibrosis (*). B, There is a complete absence of antidystrophin antibody I staining in myofiber membrane in this patient. C, Antimerosin antibody stain demonstrates myofiber morphology and uptake of this stain by myofiber membrane. D, In normal muscle, there is consistency of fiber diameter and homogenous antidystrophin antibody I staining of the myofiber membrane. E, Antidystrophin I antibody stain of muscle from a patient with BMD shows patchy staining on dystrophic-appearing muscle. (Courtesy of Randall Nixon, MD, Department of Pathology, Oregon Health Sciences University, Portland, OR.)
Duchenne Muscular Dystrophy
tems.8 The absence of dystrophin manifests as a physiologic problem for several reasons.1,8 Because of the myofiber membrane fragility, there is a cycle of chronic degeneration and regeneration and ultimate loss of regenerative potential, resulting in progressive loss of functional muscle mass. In addition, the leakage of intracellular contents (including CK) causes an inflammatory response mediated by mast cells and dendritic cells, resulting in fibrosis, which further compromises muscle function. Also, there is a generalized disruption of many of the metabolic pathways that support basic muscle function.
Absence of dystrophin secondarily affects the synthesis of the DAPs, which are reduced by 90%. Primary abnormalities in this group (which include syntrophins, dystroglycans, and sarcoglycans such as adhalin) result in other types of muscular dystrophy, such as limb girdle dystrophy. Approximately 20% of the cases of limb girdle dystrophy are caused by abnormalities in one or more of these DAPs.9 Introduction of a dystrophin mini-gene into the dystrophin-deficient mdx mouse restored the synthesis of the DAPs to normal levels.7 Therefore, in DMD, functional deficits are the result of the absence of dystrophin and deficiency of DAPs.
The dystrophin gene is located on the X chromosome at the locus Xp21.2.2 DMD and BMD both result from abnormalities in this gene and are thereby X-linked allelic traits. Carrier females have the mutation on one X chromosome and are unaffected because they have a second normal X chromosome, which is capable of providing adequate levels of dystrophin. However, half of their male children will inherit the mutation and be affected with either DMD or BMD; the other half will inherit the normal maternal X chromosome and be normal. Half of the female children of a carrier
mother will be carriers like their mother, and the other half will be normal. Although most female carriers seem to be clinically unaffected, histologic changes in skeletal muscle have been reported, and some women exhibit weakness later in life. There is one report of .preclinical or clinically evident myocardial involvement. in 84% of female carriers of DMD or BMD.10
Diagnosis
Physical Examination
DMD and BMD are uncommon, which accounts for the initial diagnosis often being missed in the absence of a family history. Patients may present with abnormal gait, clumsiness, flat feet, late walking, or other signs that may not immediately lead to the diagnosis of a muscle disease. In a retrospective study11 of patients with DMD referred initially for orthopaedic consultation because of clumsiness, the first referral took place at age 3 years but the correct diagnosis of DMD was not made on average until 2 years later. Once the diagnosis of DMD is considered, it can be rapidly confirmed. Any boy who is not walking by age 18 months should be screened for DMD by measurement of serum CK levels.
When affected children do begin walking, usually between the ages of 18 and 24 months, they walk with a wide-based gait with relatively stiff knees and rarely are able to run. A frequent complaint of parents of affected 4- to 5-year-old boys is that their son is unable to keep up with his peers in athletic endeavors. When young boys with DMD try to run, they do so in a characteristic manner that looks like a race-walk and is accompanied with excessive motion of the flexed and abducted upper extremities. They are unable to climb steps in a reciprocal fashion without the aid of a handrail. Ini
tially, the appearance of the lower limbs may be relatively normal, but by age 3 to 4 years, the pseudohypertrophy of the calves usually can be appreciated (Fig. 2, A). The muscles have a rather firm consistency that becomes more pronounced with time. Standing posture is usually abnormal, with increased lumbar lordosis and a wide-based stance to increase stability (Fig. 2, B). Patients with BMD follow the same course as do those with DMD but at a much slower rate; they will present at age 8 to 12 years and continue walking until the beginning of the third decade.
A clinical finding in patients with DMD is the abnormal fashion by which they rise from the floor. They will perform the Gowers maneuver. The child first rolls onto all fours in the prone position, then extends the knees to assume the so-called bear position. The child then brings the trunk into the upright position with the assistance of the upper extremities, either briefly touching the thighs or more obviously walking the hands up the legs to help keep the knees in extension, then brings the torso upright (Fig. 3). Gowers originally thought this maneuver to be diagnostic of DMD but subsequently recognized it to be characteristic not only of patients with DMD but also those with other conditions causing pelvic girdle weakness.
Patients with DMD will retain deep tendon reflexes until the muscle becomes too weak to respond; by comparison, in peripheral nerve or spinal cord disease, deep tendon reflexes are usually lost early.
Diagnostic Studies
The initial laboratory test for DMD and BMD is analysis of serum for CK levels, which is present in very high concentrations. The normal upper limit of serum CK is 200 units/L; in patients with DMD, levels are 5,000 to 15,000 units/L. This
AB
Figure 2 Physical findings in patients with DMD. A, A 5-year-old boy with DMD and marked pseudohypertrophy of the calves. B, Four- and 6-year-old brothers demonstrating typical standing posture.
elevation of CK is present from the time of birth, although levels decrease somewhat in the second decade as muscle mass is lost. Patients affected with other muscular dystrophies, such as limb girdle dystrophy, may show mild elevations. In addition, serum CK can be mildly elevated because of muscle bruising, for example. Therefore, when a patient shows a mild elevation, the serum CK test should be repeated on several occasions; persistently abnormal but mildly elevated levels may indicate a muscular dystrophy other than DMD or BMD.
When the serum CK level is >5,000 units/L and the history is that of a slowly progressive muscle weakness, in all likelihood the patient is affected with DMD or BMD. However, although the clinical picture and markedly elevated serum CK levels frequently are sufficient to allow the diagnosis of DMD or BMD to be made, these factors do not differentiate between DMD and
BMD. Because this diagnosis has profound implications, further studies should be done to obtain an unequivocal diagnosis. In two thirds of patients with DMD or BMD, a deletion in the dystrophin gene can be detected by clinical DNA analysis of a blood sample,8 which provides an absolute diagnosis of DMD or BMD. Although this test cannot definitively distinguish DMD from BMD, it will indicate the likelihood of either DMD or BMD with 90% accuracy. In the remaining one third of patients there are more subtle alterations in the gene, such as small deletions, point mutations, repeats, or stop codons, so that a diagnosis cannot be made on the basis of blood DNA studies.12 To obtain an absolute diagnosis in these patients, a muscle biopsy must be done.
Muscle biopsy in children is best done under general anesthesia, with precautions taken for malignant hyperthermia, which is occasionally seen in patients with DMD.13 Mus
cle specimens should not be placed in formalin but should be either frozen or taken directly to a laboratory that specializes in muscle pathology. Histochemical staining using adenosine triphosphatase and immunohistochemical staining of muscle tissue with antidystrophin antibodies and Western blot analysis for dystrophin can be done only on unfixed tissue.12 In patients with DMD, no staining of dystrophin occurs in the muscle specimen, as opposed to the normal state, which demonstrates homogeneous uptake throughout the entire muscle cell membrane. In patients with BMD, there will be spotty staining throughout the muscle cell membrane (Fig. 1).
Western blot analysis of digested muscle tissue demonstrates the complete absence of dystrophin in DMD and reduced quantities of a smaller dystrophin in BMD, which thus distinguishes between the two. Dystrophin present in normal quantities eliminates the diagnosis of DMD; other diagnoses should then be considered, including Emery-Dreifuss dystrophy (frequently misdiagnosed as DMD), limb girdle dystrophy, spinal muscular atrophy, or dermatomyositis. Dermatomyositis is the only condition in which serum CK levels are elevated to the same extent as those found in DMD. However, patients with dermatomyositis have a history of normal development with subacute onset of muscle weakness, often accompanied by a rash, particularly on the cheeks. Muscle biopsy in dermatomyositis shows typical perivascular inflammatory changes in the skin and subcutaneous tissue as well as in the muscle, and dystrophin staining is normal.
The diagnosis of DMD or BMD, once made, must be presented to the parents with a great deal of sensitivity because the implications are devastating. Genetic counseling should be provided so that the parents can use this information for
Duchenne Muscular Dystrophy
AB
CD
Patient with DMD demonstrating the Gowers maneuver. A, The prone position. B, The bear position. C, Moving the hands up the thighs to help upright the trunk and augment knee extension. D, The upright position.
family planning decisions. In addition, the mother should be counseled to identify other relatives who may be heterozygotes; these individuals thus can gain some understanding of the disease and the risks they may invite with additional pregnancies. When the DNA test is positive in the mother, prenatal diagnostic testing can be done on cells obtained from chorionic villus sampling or by amniocentesis to determine whether the fetus has inherited the affected X chromosome, and will, if a male, be affected with DMD. In the one third of mothers in which the DNA test is not positive, prenatal diagnosis still
may be possible by linkage studies that determine which maternal X chromosome is present in the fetus; however, this is a more complex process.2,12
Medical Management
As the disease process progresses, patients have multisystem problems; therefore, treatment of these patients is best accomplished in a multidisciplinary clinic setting that includes rehabilitation, pediatric neurology, genetics, and consultative services in pulmonology, cardiology, and gastroenterology.
Management involves two areas. The first is treatment of the muscle disease, which was not able to be addressed until the last few years. The second is orthopaedic management of problems associated with the muscle weakness.
Corticosteroids
Corticosteroids have been shown to provide an initial improvement in muscle strength and to reduce the expected loss of strength over time in boys with DMD. The mechanism of action of corticosteroids is not completely clear. They may suppress the inflammatory response and the resulting fibrosis, which occurs because of leakage of cell contents into the extracellular space, as well as stabilize the fragile myofiber membrane, thereby protecting the muscle from exercise-induced damage. They also have been shown to increase the regenerative capacity of muscle that allows replacement of damaged muscle with new myofibers. Marked side effects are associated with the use of corticosteroids, including acne, personality changes, hirsutism, growth retardation, weight gain, and potential osteoporosis, so that until recently it has not been clear whether the benefits are negatively balanced by these side effects.
A double-blind prospective clinical trial of the corticosteroid prednisone at a dose of 0.75 mg/kg/day demonstrated significant (P = 0.00001) improvement within 10 days in the muscle strength of patients with DMD, as measured by myometry. Muscle strength increased and reached a maximum at 3 months, then plateaued and stayed relatively stable for the 18 months of the study. Patients treated with a lesser dose of 0.3 mg/kg/day showed similar but less profound improvement, whereas placebo-treated control subjects showed a continuous, slow loss of muscle strength, as would be anticipated.14
Preliminary results of a long-term, multicenter study utilizing prednisone in patients with DMD appear to demonstrate long-term benefits, including prolongation of walking, delayed decline of pulmonary function, and reduction in the need for scoliosis surgery. The major side effects were short stature, cushingoid appearance, and weight gain.
A related corticosteroid, deflazacort (not available in the United States but available in Canada and Europe), appears to be at least as effective as prednisone and is associated with fewer side effects, particularly less weight gain. In an important study of patients with DMD aged 7 to 15 years, walking was significantly (P < 0.05) prolonged in 30 patients treated with deflazacort compared with that of 24 untreated patients.15 Pulmonary function (forced vital capacity) at age 15 years in the treated boys was 88% versus 39% in the untreated boys (P < 0.001). Scoliosis surgery had not been done in any of the treated patients, whereas 13 of 24 untreated boys had spinal stabilization. A major side effect is shorter stature, seen in treated patients between ages 9 and 15 years. Ten of the 30 treated boys developed asymptomatic cataracts that did not require treatment. Other potential side effects of deflazacort, including hypertension, acne, infection, and bruising, were not more common in the treated patients.15 Weight gain from deflazacort was significantly (P < 0.05) less than that from prednisone in another study while benefits were similar. After 9 months of treatment, boys on deflazacort gained on average 5% body weight, whereas those on prednisone gained 18% body weight.16 Based on these studies, strong consideration should be given to treating patients with DMD with deflazacort because it appears to dramatically alter the natural history of the disease.
The influence of corticosteroids on bone mineral density has not been well investigated. Larson and Henderson17 demonstrated decreased bone mineral density in the extremities but much less bone mineral loss in the spines of untreated patients with DMD.17 Spinal osteoporosis in DMD patients that could result from corticosteroid therapy would make subsequent spinal surgery more difficult and risky. There is a recent report of vertebral compression in DMD patients on deflazacort therapy.18
Until now, there has not been universal agreement whether corticosteroids should be offered to patients with DMD because of the side effects. However, the functional gain demonstrated with deflazacort may lead to deflazacort becoming widely used to delay progression of the muscle weakness in boys with DMD.
Genetic Treatment
The enhanced understanding of the pathogenesis of DMD and BMD as dystrophinopathies has led to a great deal of research into genetically based approaches of treatment. The most obvious approach is the introduction of a normal dystrophin gene into muscle cells. A study of mdx mice (which do not produce dystrophin) showed that the dystrophin gene can be introduced with a CK promoter into the fertilized ova of affected animals; all animals derived from these zygotes produced greater than normal amounts of dystrophin in muscle and remained clinically and histologically normal.19 One of the problems with introducing the gene is its large size; therefore, a smaller than normal minidystrophin gene has been introduced with some success into both mdx mice and dystrophindeficient golden retrievers, using an adenovirus vector.20,21
Introduction of the dystrophin gene into humans has proved to be
complex. There are associated problems, such as the reaction to the viral vector, that may cause severe disease. In addition, the newly introduced dystrophin represents a foreign protein, against which the bodies of patients who have been completely lacking in dystrophin will mediate an immunologic response. When the technologic hurdle of introducing genes into mammalian species can be overcome, then DMD and BMD will both become curable diseases. However, it is unlikely that all of the degenerative changes that will have occurred in the muscle until the time of treatment would be reversible, although some regeneration may occur and subsequent deterioration may be prevented. Once genetic treatment becomes available, however, early diagnosis will be critically important. For this reason, universal serum CK screening of newborns might be instituted along with screening for a variety of other genetic diseases.
Another approach to treatment is the introduction of dystrophin into the muscle tissues by the direct injection of normal fetal myoblasts into muscle. This required administration of systemic cyclosporin to suppress rejection and immunologic reaction against the dystrophin protein.22 Cyclosporin alone has been shown to alleviate some of the symptoms of DMD. Although there are a few advocates of this technique, there are also several negative studies; therefore, this is not a currently recommended therapeutic approach.23,24
A more promising approach utilizes transplantation of dystrophinproducing mesenchymal stem cells that, when injected intravenously, take residence in muscle and differentiate into muscle cells that produce dystrophin. Although the approach shows promise in experimental animals,25 human clinical trials have not yet been attempted. However, a similar approach with
Duchenne Muscular Dystrophy
stem cell transplantation of allogenic mesenchymal cells from bone marrow has been effective in three patients with severe osteogenesis imperfecta.26
An innovative and potentially beneficial approach has recently been proposed based on the fact that approximately 15% of the mutations in DMD are premature stop codons, which interrupt the transcription of dystrophin. Aminoglycoside antibiotics may suppress stop codons of genes in cell culture. Therefore, in one study,27 gentamicin was added to the medium of cultured muscle cells from the mdx mouse and was shown to restore the synthesis of dystrophin in the cell culture environment. These investigators then administered gentamicin to mdx mice and similarly demonstrated the presence of dystrophin in the membrane of skeletal muscle.27 This approach may lead to a relatively straightforward treatment for a selected group of patients with DMD. Clinical trials are now in progress.
Another therapeutic approach is the stimulation (up-regulation) of utrophin synthesis in patients with DMD. Utrophin is a DAP that may functionally substitute for dystrophin. The function of the extraocular muscles in patients with DMD seems to be totally unaffected by the disease. Studies in mdx mice have shown that an increased level of utrophin is synthesized in the extra-ocular muscles, which seems to protect these muscles from functional deterioration.28 Furthermore, introduction of additional utrophin genes into mdx mice significantly (P < 0.05) improves their muscle strength. Therefore, it is postulated that using strategies to up-regulate native utrophin in patients may reduce the dystrophic process.29 This approach is attractive because it involves the up-regulation of an already present protein, thereby avoiding immunologic problems associated with the introduction of dystrophin.
Orthopaedic Management
Orthopaedic management for these children requires an integrated approach that includes physical and occupational therapy, orthotics, adaptive equipment, and, in some cases, surgery. Interventions are indicated for deformity prevention and deformity correction and to enhance functional skills. Because DMD is a relatively homogeneous condition with a relatively predictable course, for convenience the interventions can be delineated by patient age.
Stage 1: Birth to Age 5 Years (Diagnostic Stage)
With a strong family history, diagnosis can be established early by testing the serum CK; however, without a family history, diagnosis generally is not made until the child is at least 18 to 24 months old. Affected boys will not walk until 18 months of age but usually are walking by at least 24 months. They acquire motor skills at a relatively slow rate. By age 4 to 5 years, the child is unable to keep up with his peers or to climb steps. Also, the child rises from the floor by using the Gowers maneuver. No interventions other than those indicated for diagnosis are indicated at this stage.
Stage 2: Ages 5 to 8 Years (Quiescent Phase)
During this period, affected boys begin to deviate more obviously from their peers in terms of motor skills. They are rarely able to run normally, are unable to go up and down steps without aid of a handrail, and are obviously weaker than their peers. Gait is marked by an increasing width of the base of support, an increasing shift of the trunk toward the stance-phase limb (abductor lurch), loss of the initial knee flexion wave with weight acceptance (so that the knee is main
tained in full extension throughout the entire stance phase), and lack of heel contact during the stance phase (Fig. 4). Boys may be seen to walk slightly on their toes or to have early heel rise in late stance. On passive examination, they will demonstrate limited passive dorsiflexion at the ankle. The equinus position of the foot during stance phase helps maintain knee extension by the ground reaction force provided and also maintains the base of support under the center of mass of the body, which passes just behind the axis of rotation of the hip and just in front of the axis of rotation of the knee.30
Deformity Prevention
To prevent severe plantar flexion contracture, which may interfere with balance and gait, both heel-cord stretching exercises and nighttime ankle-foot orthoses (AFOs) are utilized. These orthotics should be molded with the foot in a neutral position rather than in dorsiflexion because they are harder to tolerate when molded in dorsiflexion and therefore are less likely to be worn. No studies demonstrate that either orthotics or stretching prevents contractures; both are still generally prescribed. AFOs should not be advised for ambulation because rigidly fixing the ankle at 90° actually impairs balance and diminishes the patient.s walking ability and tolerance. Unless it compromises balance (when it becomes fixed at >20°), the equinus deformity should not be treated surgically because it helps maintain knee extension during stance phase.
Many European pediatric orthopaedic surgeons advocate prophylactic multiple-level muscle/tendon lengthening at age 6 to 7 years to prevent contractures and prolong walking, as described by Rideau et al.31 In one study, Forst and Forst32 reported on 87 patients who underwent bilateral hip and knee release as well as iliotibial band release and
April 1998 - age 8 years April 1996 - age 6 years Stance phase Lack of knee flexion in early stance Knee flexion at weight acceptance (shock absorption) Swing phase Toe-off Normal knee motion Degrees Flex Ext 0 -15 15 30 45 60 75 0 20 40 60 80 100 % Gait cycle Figure 4 Sagittal plane knee motion (Vicon motion analysis system; Vicon Motion Systems, Lake Forest, CA). At age 6 years, the patient shows relatively normal motion. At age 8 years, the patient shows complete elimination of knee shock absorption during initial single-limb stance. The knee is maintained in slight hyperextension throughout the entire stance phase to accommodate the weak quadriceps. Flex = flexion; Ext = extension.
should be maintained to provide continuing ground reaction force to enable knee extension in stance.30 Patients may require a knee-anklefoot orthosis (KAFO) to continue standing and walking after isolated Achilles tendon lengthening.
Interventions to Maintain Functional Skills
A great source of frustration for these patients is their inability to participate in athletics with their peers. Adaptations should be made for them, and they should be directed toward activities that are individual skills rather than team sports. Swimming is one particularly beneficial activity in which patients are able to participate. In spite of their osteoporosis, these patients also may be involved in adaptive skiing, horseback riding, and other recre-
Achilles tendon lengthening at an average age of 6.6 years and compared them with 100 patients who did not have surgery. The surgically treated group walked until an average age of 10.5 years, whereas the untreated group ceased walking at an average age of 9.3 years.32 However, it is not always easy to determine the reason for cessation of walking, which may be affected by a variety of factors, such as patient and parent motivation, and environmental influences, as well as surgery. Patients who have undergone surgery and their parents may have a strong bias toward maintenance of walking and thus be more motivated than are patients who have not undergone surgery. Therefore, it is not clear that this prophylactic surgery offers any real benefit.
Deformity Treatment
Patients with DMD have an increased rate of long-bone fracture, as shown in a study of 41 patients, 18 of whom had sustained at least one fracture.17 In that study, 40% of
fractures were in the femur, 26% in the tibia, 14% in the humerus, and 9% in the clavicle. The basis of these fractures was markedly decreased bone mineral density in the axial skeleton, as measured in the upper femur, even in young patients with minimal functional impairment.17 It is not known whether calcium supplementation, bisphosphonates, or any other agent is able to increase bone mass and strength.
Lower extremity fractures should be treated aggressively to allow early resumption of ambulation to prevent further osteoporosis as well as muscle weakness and contracture. Upper extremity fractures may compromise balance and thus also compromise ambulation; these fractures also require aggressive treatment to ensure that the patients continue to ambulate, with assistance if necessary.
When Achilles tendon contracture is severe and interferes with ambulation, lengthening may be helpful; however, overlengthening must be avoided and slight equinus
ational activities. Summer camps sponsored by the Muscular Dystrophy Association of America, where activities are adapted, allow patients to interact equally with a peer group. Patients with DMD fatigue easily and tend to avoid activities such as walking long distances. Manual wheelchairs can permit them to continue to participate in activities.
At this time, many (but not all) patients will fall behind their peers in their schoolwork. In general, patients with DMD do have lower IQ scores than their peers, with a mean of between 80 and 90. Few, however, are profoundly impaired, and some patients are normal or above normal. Deficits are mixed; expressive language is a particular area in which these patients may have problems.33 Therefore, they should have educational testing and, if indicated, be entered into a special school program.
Stage 3: Ages 9 to 12 Years (Loss of Ambulation)
As the proximal muscle weakness progresses, gait becomes more
Duchenne Muscular Dystrophy
abnormal; patients fatigue more easily and reduce their overall activity level. The quadriceps muscles become progressively weaker, which can be quantitated by assessing the degree of extensor lag. When the extensor lag exceeds 30°, patients with DMD will soon be unable to stand or walk without orthotic assistance. Functional impairment, such as inability to climb stairs and to rise from a standard chair, increases. As long as there is no knee flexion contracture, patients will be able to stand by locking the knee into extension; however, once a knee flexion contracture develops, with a quadriceps muscle that is too weak to maintain extension in the upright position, patients lose the ability to stand.
Deformity Prevention
Stretching under the direction of physical therapists has been advocated to prevent the progression of contracture. No objective studies demonstrate the efficacy of this approach, however, and these contractures often continue to progress in spite of physical therapy as the muscle is progressively replaced by fibrofatty tissue. Stretching can be quite uncomfortable, particularly when done aggressively, and may consume a large portion of the child.s time that potentially could be put to more effective use. A standing program utilizing orthotics or a stand device is more readily accepted by patients and may be as effective or more effective than passive stretching. Night splinting of the knee similarly has been advocated and may be beneficial, although there is no evidence of its efficacy. Night use of KAFOs is poorly tolerated and therefore unlikely to be utilized. Using orthotics to prevent contracture thus must be tempered with realization of the discomfort they may cause and understanding of their usefulness.
Intervention to Increase Functional Skills
The use of lightweight KAFOs as the quadriceps muscles become weak and as knee flexion contracture develops will facilitate continued standing and walking. These orthoses are essential to resume standing after multilevel tendon lengthening in the older boy (9 to 12 years). In addition, KAFOs with drop lock hinges may be helpful in patients with knee flexion contracture of <30° who do not want to undergo surgical lengthening yet do want to be able to stand. Bracing may interfere with toileting; however, locking the knees to do pivot transfers may permit the patient greater function, particularly heavier patients.
If contractures develop that compromise the ability to stand and walk or make it painful to stay in KAFOs, then contracture release may be indicated.34-36 Siegel et al34 recommended release of the proximal tendon of the rectus femoris and the tensor fascia lata at their origins as well as a section of the iliotibial band proximal to the knee, along with release and lengthening of the hamstrings, and Achilles tendon lengthening or tenotomy. Once this procedure is done, patients should be mobilized immediately in long-leg casts, then switched to lightweight KAFOs within a few weeks. Motivated patients may continue standing in KAFOs and be capable of exercise or perhaps limited household ambulation, but not community ambulation. The outcome thus may be a positive experience for patients motivated to maintain the upright position; however, for the majority of patients who are not motivated to continue standing, multiple tendon lengthenings will not be worthwhile. Furthermore, once the knee flexion contracture exceeds 30° to 40°, surgery is not worthwhile because functionally meaningful correction will not be achieved.
To correct equinovarus foot deformity, the Achilles tendon is lengthened and the tibialis posterior muscle may be transferred to the middorsum of the foot to prevent recurrence of the equinovarus deformity. An alternative approach for correction of equinovarus is tenotomy of the tibialis posterior, flexor digitorum longus, and flexor hallucis longus muscles at the level of the ankle at the time of Achilles tenotomy. Patients treated in this fashion in a small personal series have shown good correction and not yet demonstrated a tendency to develop subsequent equinovarus.
At this stage, patients should acquire a power wheelchair to maintain independent mobility. A power chair requires an adapted home environment with doorways of adequate width, space to maneuver the wheelchair, and ramps for accessibility, as well as a wheelchair-adapted van for transport. Patients without a home environment that accommodates a power chair frequently use a manual chair at home and use the power chair in school to have mobility along with their peers. The use of three-wheeled motorized scooters usually is not advisable because they are useful only during the time the patient still has sufficient retention of upper extremity skills to steer with the handlebars. Power chairs should have a movable joystick control box so that the joystick can be placed in optimal position, a lap tray, an appropriate pressure-distributing seat cushion, and lateral trunk supports. A tilt-in-space feature also is advisable because patients are unable to shift their weight themselves as they get older and weaker; by tilting, they can alter pressure distribution on the buttocks. These adaptive devices (wheelchair, lap tray, and, as the shoulder abductor muscles become weaker, an elevated lap tray) allow patients to continue to feed themselves. A ball-bearing feeder, a
device that cradles the forearm and allows for lateral movement, has proved to be quite useful for some patients.
Obesity also may develop and can make management of these increasingly dependent patients more difficult. However, dietary counseling has not been found to be helpful.
Stage 4: Ages 12 to 16 Years (Full-Time Sitting/Development of Spinal Deformity)
The most critical orthopaedic issue for the patient with DMD is the development of spinal deformity, which usually has its onset between ages 11 and 13 years, around the time most patients begin full-time sitting. The deformity develops because of weakness in the trunk and paraspinal muscles, leading to collapse of the immature developing spine into what is usually a long C-shaped curve with the apex in the thoracolumbar region. The natural history of this deformity is relentless progression until the thorax is resting against the iliac crest (Fig. 5). When this happens, patients are extremely uncomfortable sitting and must use their upper extremities to help prop
themselves and keep themselves balanced, which prohibits them from performing any self-care skills with their upper extremities, including feeding. Adaptive seating for patients with these severe established spinal deformities has limited value. Furthermore, the deformity causes additional restriction of their diminished pulmonary function, already compromised by progressive muscle weakness.
Only 5% to 10% of patients with DMD do not develop curvatures. In these patients, a fixed thoracolumbar lordosis locks the facet joints and prevents the development of scoliosis.37 Boys with BMD rarely develop scoliosis unless they have a particularly severe clinical course.
Prevention of Spinal Deformity
In the 90% to 95% of patients with DMD who do develop scoliosis, the best treatment is early spinal fusion with internal fixation. They should be screened for the development of scoliosis by regular sitting anteroposterior spine radiographs, beginning at about age 10 years. When curvature is ascertained and reaches a Cobb angle of 20° to 30°, fusion should be done
without delay.38 Bracing or special seating systems may delay curve progression but will not prevent it.39 In other neuromuscular diseases, such as type II spinal muscular atrophy, there may be an earlier onset of curve development, and attempting to delay curve development with bracing is important. However, there are marked disadvantages to spinal bracing and delaying surgery in patients with DMD.
First, spinal deformity is neither preventable nor responsive to nonsurgical modalities such as bracing and adaptive seating and ultimately will cause disabling deformity and severe impairment of pulmonary function. Unlike idiopathic scoliosis, in which many small curves remain stable, all curves in DMD progress, usually to a severe degree. Second, sufficient spinal growth will have occurred in the child with DMD by age 10 or 11 years so that posterior fusion will not result in a marked loss of trunk height or development of crankshaft deformity. Third, with progression of the disease, the paraspinal muscles in these patients are progressively replaced by stiff, unyielding fibrofatty tissue, which makes the surgi-
ABC
A 16-year-old patient who refused scoliosis surgery. The ribs on the concave side of the curvature rest on the iliac crest. B, A 17-year-old patient demonstrating severe scoliosis. C, A patient at age 21 years 6 months who underwent surgical spinal stabilization at age 14 years. This patient is a full-time sitter with no discomfort with an adaptive cushion, despite a residual curve of 64° and pelvic obliquity of 25°.
Duchenne Muscular Dystrophy
cal dissection more difficult, reduces correctability, and increases intraoperative blood loss. Finally, the most notable complication of surgery is postoperative pulmonary insufficiency. Patients who have a forced vital capacity of <35%>50% are likely to have no postoperative pulmonary problems and can be weaned from the ventilator the night of surgery or the morning after surgery. Therefore, the older the patient at the time of surgery, the greater the risk of serious postoperative pulmonary complications.40,41 For these reasons, when the curvature exceeds 20°, patients should be offered surgery.
Preoperatively, all patients should have a full cardiac evaluation for the assessment of cardiomyopathy, including echocardiography to assess the ejection fraction. A small subset of patients has profound cardiomyopathy that may mitigate against surgery but often is treatable pharmacologically. Pulmonary function also should be assessed. Patients with a forced vital capacity of >50% probably will be able to be extubated relatively soon after surgery, but patients with a forced vital capacity of <35% may require prolonged intubation and, possibly, permanent tracheotomy.40,41 Patients also may have gastric emptying problems and may require a nasogastric tube postoperatively.
Because of the unyielding nature of the tissue and also, perhaps, because of smooth muscle dysfunction in the vasculature, intraoperative bleeding may be increased during the procedure, and hypotensive anesthetic techniques are helpful.42 Fusion should extend at the upper level to the upper thoracic spine (T2-4), and care should be taken to ensure that thoracic kyphosis is
maintained so that the center of mass of the head is forward. When the thoracic spine is placed in full extension and the head is thrown backward, patients lose head control because they tend to retain strength in the neck extensors but lose strength in the flexors.
The lowest level of fusion is a matter of debate. Some surgeons feel that when patients are stabilized before the onset of severe deformity and pelvic obliquity is <10°, fusion to L5 is sufficient and late progression does not occur through the L5-S1 joint.43,44 A balanced trunk over a level pelvis is the surgical goal, which can, in some patients, be achieved with fusion to L5 (Fig. 6, B). Other investigators disagree and have recommended that all patients be stabilized to the pelvis and fused to the sacrum45 (Fig. 7). Adding this extra level to the procedure increases blood loss, surgical time, and the risk of complications, particularly in
this group of patients with osteopenia of the pelvis.
Some parents will be reticent to risk spinal surgery in these relatively medically fragile patients. However, when the concept is introduced early in their care (between the ages of 5 and 10 years) and the benefits carefully outlined, by the time the boys do develop a curvature, both patient and parents can be ready to proceed with this exceedingly important step. Patients who undergo spinal stabilization have a substantially enhanced quality of life compared with patients who do not.46 In addition, they will have better maintenance of their pulmonary function and have a longer life span.47
Deformity Correction of the Extremities
Although most patients are not sufficiently troubled by the equinovarus position of the foot to require surgery, some become upset be
27° 12° p.o. AB
Figure 6 A, Anteroposterior radiograph of a patient with DMD at age 11 years 8 months with scoliosis of 27° and pelvic obliquity (p.o.) of 12°. B, Anteroposterior radiograph of the same patient at age 14 years 10 months, at 38 months postoperatively following fusion to L5, showing maintenance of curve correction and pelvic obliquity of 3°.
L 5° p.o. 17° L 1° p.o. AB
Figure 7 A, Anteroposterior radiograph of a patient with DMD at age 12 years 10 months, with scoliosis of 17° and pelvic obliquity of 5°. B, Anteroposterior radiograph of the same patient at 24 months postoperatively showing fusion from T2 to the sacrum with a unit rod. Scoliosis is <10° and pelvic obliquity, 1°.
cause they cannot wear regular shoes. In these patients, Achilles tenotomy with resection of a 1- to 2-cm section of tendon to prevent regrowth can be done along with tenotomy of the tibialis posterior, flexor hallucis, and flexor digitorum muscles, as mentioned; but in manually correcting the foot, care should be taken so that the osteopenic distal tibia is not fractured. Corrective foot surgery does not improve comfort, shoewear, or perceived cosmesis in nonambulatory patients. Soft, flexible shoes are used to accommodate the foot deformity, and the footrest should be padded for comfort. Release of hip and/or knee flexion contracture in the patient who sits full time and has hip and knee contracture of >30° to 40° will not be successful in reducing deformity and therefore should not be done at this late stage.
Other Concerns
Pulmonary function will continue to deteriorate after spinal fusion because of the progressive dystrophic process of the muscles of respiration, including the diaphragm. Respiratory exercises have been tried but do not provide notable objective benefit, whereas assisted ventilation at night using nasal masks with end-expiratory pressure (bilevel positive airway pressure) may help prevent pneumonia and pulmonary decompensation.48 In addition, use of the Emerson insufflator-exsufflator (JH Emerson, Cambridge, MA) also has been shown to help maintain pulmonary function and help patients clear secretions.
Patients with DMD have hypotonia throughout the gastrointestinal tract, and some, as noted, have marked difficulty in gastric emptying and may require pharmacologic treatment.49 Most patients have
chronic constipation because of problems transferring on and off the toilet as well as the bowel hypotonia. Maintaining bulk in the diet as well as a regular schedule of suppository use or enemas may help minimize problems associated with this.
As patients get older, many find themselves further isolated from their peers and may be helped by psychological counseling.32 Association with other patients through muscular dystrophy clinics and muscular dystrophy camps can help with patient self-image and morale.
Patients at this stage have notable difficulties in essentially all activities of daily living skills, including transferring, feeding, and dressing, and require full-time assistance. Patients will still be able to talk, and therefore voice-activated computer systems with environmental controls may be of benefit. Night is a particularly difficult time for many patients because they are unable to turn themselves; parents may need to turn the patients several times at night to keep them comfortable. Pressure sores, fortunately, are unusual in this population, perhaps because sensation is fully preserved.
Stage 5: Age 15 Years and Older (Stage of Complete Dependence and Development of Respiratory Insufficiency)
Patients at this stage maintain the ability to chew and swallow soft foods but have very limited upper and no lower extremity function. However, with adaptations, they may be able to continue to feed themselves. Computer voice-activated devices, particularly environmental and wheelchair controls, can help them maintain their independence. Many patients will no longer be able to operate a standard joystick and will require a head control, hand control, or other adaptive interface for their power wheelchairs. A few patients with DMD in whom disease progression is not as rapid can main-

Duchenne Muscular Dystrophy
tain a notable degree of function and are even able to attend college with the assistance of an aide.
A second important matter in the older teenager is facing the inevitable consequence of diminishing pulmonary function. Progressive deterioration in pulmonary function in some patients results in their becoming hypercarbic and hypoxic, with symptoms of anxiety, headache, and shortness of breath. These patients ultimately will expire of pulmonary dysfunction if artificial ventilatory assistance is not provided. The usual mechanism of death, however, is development of a pulmonary infection that patients are unable to clear, leading to a fairly rapid demise. If, during an acute episode, the patient is intubated and aggressively treated with pulmonary toilet and mechanical ventilation as well as antibiotics, he may
recover. However, once the infection is cleared, the likelihood is that he will be unable to be extubated and will require permanent tracheotomy and artificial ventilation. Some patients and families would choose not to continue life under these circumstances. Therefore, it is important to discuss these matters in detail with the patient and family so that they can develop a living will and know how to respond when the occasion arises.
Without ventilatory support, most patients die by age 20 years. Long-term survival into the third and fourth decades is possible if the patient is provided with full-time artificial ventilation. Because this technology is available, patients and families should be presented with this information, although not all will choose this option. If full-time artificial ventilation is provided, car
diac function should be followed; if cardiac failure occurs, it can be treated pharmacologically with a combination of medications. Full-time care will then be needed.
Summary
DMD and BMD are X-linked dystrophinopathies that manifest early and in most patients lead to death by the end of the second decade. Surgical and rehabilitative approaches, such as release of lower extremity contractures and early spinal fusion for severe scoliosis, can help patients maintain function and comfort. Genetic counseling and frankness regarding the course of the disease may help patients and families cope with what is still a devastating and inexorably progressive disorder.
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41. Miller F, Moseley CF, Koreska J: Spinal fusion in Duchenne muscular dystrophy. Dev Med Child Neurol 1992;34: 775-786. 42. Fox HJ, Thomas CH, Thompson AG: Spinal instrumentation for Duchenne.s muscular dystrophy: Experience of hypotensive anaesthesia to minimise blood loss. J Pediatr Orthop 1997;17: 750-753. 43. Mubarak SJ, Morin WD, Leach J: Spinal fusion in Duchenne muscular dystrophy: Fixation and fusion to the sacropelvis? J Pediatr Orthop 1993;13: 752-757. 44. Rice JJ, Jeffers BL, Devitt AT, McManus F: Management of the collapsing spine for patients with Duchenne muscular dystrophy. Ir J Med Sci 1998;167:242-245. 45. Alman BA, Kim HK: Pelvic obliquity after fusion of the spine in Duchenne muscular dystrophy. J Bone Joint Surg Br 1999;81:821-824. 46. Bridwell KH, Baldus C, Iffrig TM, Lenke LG, Blanke K: Process measures and patient/parent evaluation of surgical management of spinal deformities in patients with progressive flaccid neuromuscular scoliosis (Duchenne.s muscular dystrophy and spinal muscular atrophy). Spine 1999;24:1300-1309. 47. Galasko CS, Delaney C, Morris P: Spinal stabilisation in Duchenne muscular dystrophy. J Bone Joint Surg Br 1992;74:210-214. 48. Vianello A, Bevilacqua M, Salvador V, Cardaioli C, Vincenti E: Long-term nasal intermittent positive pressure ventilation in advanced Duchenne.s muscular dystrophy. Chest 1994;105: 445-448. 49. Barohn RJ, Levine EJ, Olson JO, Mendell JR: Gastric hypomotility in Duchenne.s muscular dystrophy. N Engl J Med 1988;319:15-18. Vol 10, No 2, March/April 2002