Muscular Dystrophy Treatment & Management

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^[32] 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 and colleagues^[33] 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 dose of 1.5 mg/kg/d, prednisone at a dose of 0.75 mg/kg/d, 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 Mendell et al's study,^[33] 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, has been the new therapeutic drug of choice. Deflazacort reportedly has more bone-sparing and carbohydrate-sparing properties with less weight-gain effects and improves strength and function. Due to 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.

Another potential therapeutic agent include 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%.^{[34, 35]} 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.^[36] Several other human clinical trials of creatine supplementation have been conducted since that time with similar results.^{[37, 38, 39]}

A meta-analysis of all randomized clinical trials using creatine monohydrate supplementation in neuromuscular disorders versus placebo was performed.^[40] It found that short- and intermediate-term treatment with 0.03-0.04 g/kg/d of creatine monohydrate supplementation resulted in modest but significant increase 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. 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).

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.^{[41, 42]} PTC124 is currently in phase II clinical trials for patients with Duchenne MD and cystic fibrosis.

An open-label, phase 2, dose-escalation study evaluated the safety and efficacy of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne MD. Using data from 19 ambulant patients aged 5-15 years with amenable deletions in Duchenne MD, the results noted that AVI-4658 was well tolerated with no serious drug-related adverse events; AVI-4658 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. Although the early clinical results of AVI-4658 are biochemically promising for dystrophin production without significant adverse effects, functional ambulatory changes have not been as consistently correlated. These results suggest that AVI-4658 may be a potential disease-modifying drug for Duchenne MD.^[43]

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.^[44] 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.^[44] 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.^{[45, 46]}

Human trials of gene therapy began in 1990. The first was an uncontrolled trial of 8 patients who were injected with myoblasts from family donors.^[47] 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.^{[48, 49]} In the viral vector therapeutic approach, adenosine-associated virus leads the way.^[50] 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^[49] , 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.

In spinal muscular atrophy (SMA), the molecular genetic basis is the loss of function of the survival motor neuron gene SMN1. The SMN2 gene, a near identical copy, has been detected as a possible target for therapy. Drugs such as valproic acid,^[51] phenylbutyrate, sodium butyrate, M344 (a benzamide and histone deacetylase [HDAC] inhibitor), and suberoylanilide hydroxamic acid (SAHA) can stimulate SMN2 and elevate levels of the protein. In phase II clinical trials and individual experimental curative approaches, patients show promising results. Phase III control drug trials are pending.

The orthopedic problems in children with muscular dystrophy are progressive weakness with loss of ambulatory status, soft-tissue contractures, and 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 to 3.5 years.^{[52, 53]} The modalities available to obtain these goals have been well outlined by Drennan^[54] ; they include functional testing; physical therapy; use of orthoses; fracture management; soft-tissue, bone, and spinal surgeries; use of a wheelchair when indicated; and genetic and/or psychological testing.

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.^[54] 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 weight bearing, 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.

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),^[55] 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 MDs. 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.^{[53, 9]} 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 ambulatory, rehabilitative, and palliative approaches. Within the ambulatory group, the approach can be aggressive, such 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.^{[52, 53]}

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%.^{[52, 53, 21]} 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.

Advancement in pulmonary care and cardiac drugs may now negate the absolute need for scoliosis surgery in Duchenne MD, allowing patients to live into adulthood. A recent 10-year retrospective study showed that 44 of 123 nonambulatory patients aged 17 or older were managed satisfactorily without surgery.^[25] Although this is only 1 recent 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.^[28] 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. Often, the instrumentation used is a Luque rod with segmental sublaminar wires to the L5 level, with bone arthrodesis extending into the sacrum. 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 30 degrees.^{[56, 57, 58]}

Preoperatively, patients should undergo a detailed cardiac assessment, a pulmonary evaluation with PFTs (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 due to 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.

Complications of muscular dystrophy usually include early wheelchair dependence in patients who develop minor musculoskeletal injuries (eg, ankle sprain) and those who are immobilized. Prolonged immobilization worsens the clinical weakness caused by MD and ultimately results in the patient's nonambulatory status.

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 time they are age 30 years, usually as a result of cardiopulmonary failure.

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.