Muscular Dystrophy Treatment & Management

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 MD, 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.

Conventional 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 ^[30] 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 ^[31] 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, ^[31] 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. ^{[32, 33]} 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 mo) 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. 

Dissociative steroids

Vamorolone is a first-in-class steroidal anti-inflammatory drug that differs from conventional glucocorticoids in its lack of an 11-beta hydroxy-carbonyl group. Removal of this contact site with the glucocorticoid receptor significantly alters structure and activity associations. Vamorolone retains subactivities associated with efficacy (transrepression, physicochemical membrane effects, synchronization of tissue remodeling) and dissociates efficacy from other subactivities associated with some detrimental side effects. 

A 24-week study comparing vamorolone with prednisone in 121 patients with DMD found that vamorolone reduced bone morbidities while retaining efficacy. ^[34]  

Similar to standard-of-care glucocorticoids, vamorolone was associated with maintenance of muscle strength and function up to 30 months. Vamorolone improved height velocity as compared with the growth deceleration associated with glucocorticoid treatment. ^[35]   

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. ^[36] 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. ^[36]  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%. ^[37]

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. ^[38]

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. ^[39]

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%. ^{[40, 41]}  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. ^[42]  Several other human clinical trials of creatine supplementation have been conducted since that time with similar results. ^{[43, 44, 45]}

A meta-analysis of all randomized clinical trials using creatine monohydrate supplementation in neuromuscular disorders versus placebo was performed. ^[46]  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. ^[46]  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. ^[47]  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 2 years. ^[48] It is not approved by the FDA for this purpose.

Gene therapy

In June 2023, the first gene therapy, delandistrogene moxeparvovec (Elevidys), gained accelerated approval by the FDA for ambulant Duchenne MD pediatric patients aged 4-5 years with a confirmed mutation in the DMD gene. It is administered as a one-time infusion designed to treat the underlying genetic cause of Duchenne MD: mutations in the dystrophin gene that result in the lack of dystrophin protein. 

Approval was supported by the ENDEAVOR trial. ^[49] Exploratory subgroup analyses showed that for participants aged 4-5 years, the least squares mean changes in North Star Ambulatory Assessment (NSAA) total score from baseline to Week 48 were 4.3 (0.7) points for the delandistrogene moxeparvovec group, and 1.9 (0.7) points for the placebo group, demonstrating a numerical advantage for delandistrogene moxeparvovec. ^[50]  

The open-label multicenter EMBARK trial will serve as the confirmatory trial required for the accelerated approval. ^[51]  

Early gene therapy investigations

Intense investigation of somatic gene therapy began in the 1990s. Healthy immature myoblasts were introduced into the diseased muscles, which then fused and stimulated production of enough dystrophin to reverse the degeneration that occurs in the affected muscles. ^[52]

In earlier states of research, somatic gene therapy was 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, but the benefit was not thought to translate into human males. ^[52] The mice could not demonstrate muscle strength, and the laboratory-raised mice were not able to mount a rejection response such as might occur in humans. Other investigations have been conducted on the canine MDX model, which more closely approximates the human condition. ^{[53, 54]}

Human trials of gene therapy began in 1990, with an uncontrolled trial of eight patients who were injected with myoblasts from family donors. ^[55] 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 remained unchanged. These preliminary results, though disappointing, did not dampen the promise of gene therapy. Most supporters believed 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. ^{[56, 57]} In the viral vector therapeutic approach, adenosine-associated virus led the way. ^[58] In nonviral gene therapy, plasmid-mediated gene delivery, antisense-mediated exon skipping, and oligonucleotide-mediated gene editing moved from successful trials in the laboratory to the clinic. In approximately 10-20% of the preclinical cases, ^[57]  it was possible to chemically persuade the translational machinery to read through a premature stop codon, as noted with the dystrophin mutation, leading to production of a more functional full-length protein.

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. ^{[59, 60]} The modalities available to obtain these goals were well outlined by Drennan ^[61]  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 recommended 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. ^[61] 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), ^[62] 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. ^{[60, 13]} 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. ^{[59, 60]}

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%. ^{[59, 60, 19]} 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. ^[63]

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. ^[23] 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. ^[26] 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. ^{[64, 65]}

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. ^{[66, 67, 68]}

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.

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. ^[69]  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. ^[70]  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. ^[71]   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.