Aging with Muscular Dystrophy: Pathophysiology and Clinical Management




Major advances in the fields of medical science and physiology, molecular genetics, biomedical engineering, and computer science have provided individuals with muscular dystrophy (MD) with more functional equipment, allowing better strategies for improvement of quality of life. These advances have also allowed a significant number of these patients to live much longer. As progress continues to change management, it also changes patients’ expectations. A comprehensive medical and rehabilitative approach to management of aging MD patients can often fulfill expectations and help them enjoy an enhanced quality of life.


Medical technologic advances can have profound effects on people’s lives by extending the life course and creating uncertain futures. This has certainly been the case for persons with various forms of muscular dystrophy (MD), many of which had previously been called “diseases of childhood.” Individuals with MD are surviving well into adulthood thanks to advances in the medical management of comorbid problems, such as pneumonia, respiratory failure, and cardiomyopathy. Moreover, advances in rehabilitative technologies have greatly improved the functional capacity and mobility of this group of patients.


Alternatively, due in large part to advances in the care of individuals with MD, clinicians are faced with a new population of aging patients with MD. Adults with Duchenne MD (DMD) have an upward shifting of life expectancy and are experiencing new “personal identities” as they become adults. To a large extent, this is a population at risk of being marginalized in terms of health care and society in general. Historically, patients with DMD and other forms of MD became orientated to expect a shortened life span. Compounding this was the stress of living every day with the anticipation that each day could be their last; this daily concern about the possibility of death could go on for as much as a decade. There is a need to reorient medical and social expectations to better serve adults with DMD and other forms of MD and an ever-growing population of geriatric patients with later-onset, slowly progressive forms of MD.


The purpose of this review article is to provide an overview of the pathophysiology of dystrophic myofiber in the context of aging and a discussion of clinical care needs of aging MD patients, with an emphasis on management strategies for the neuromuscular medicine specialist.


Adaptations of skeletal muscle to disease and age


Skeletal muscle is a dynamic tissue with a remarkable ability to continuously respond to environmental stimuli. Among its adaptive responses is the widely investigated ability of skeletal muscle to regenerate after loading, injury, or both. Although significant research efforts have been dedicated to better understanding the underlying mechanisms controlling skeletal muscle regeneration, there has yet to be a significant impact of knowledge from this research on the clinical approaches used to treat aging dystrophic skeletal muscle.


The stem cell of skeletal muscle (also known as satellite cell) allows for muscle fiber growth in response to injury, including exercise-induced injury. This enables fiber hypertrophy and is responsible for the efficient repair of muscle fibers. This normally efficient process is greatly disrupted in patients with any form of MD, in whom this otherwise powerful repair capacity is challenged by the fragility of dystrophic skeletal muscle fibers. Even passive stretching of dystrophic muscle may cause diffuse microdamage. In dystrophic muscle, this microdamage causes Ca 2+ -induced injury, which ultimately produces a cascade of events in the myofiber, including degeneration, inflammation, attempted repair, and ultimately replacement with scar tissue and formation of fibrosis. Recently it has been shown that dystrophic muscles not only are more susceptible to mechanical stress and influx of extracelluar Ca 2 but also develop contracture-induced myoplasmic separations and hypercontraction clots associated with increased intracellular Ca 2+ at rest and subsequent damage to the dystrophin-deficient fibers, whereas control fibers do not. Although these disruptions lead to irreversible damage in dystrophic muscles, the damage is not as severe, or the repair process of normal tissue is vital enough to overcome this damage and generate new healthy muscle tissue.


The disruption of the plasma membrane and basal lamina is a critical component to stimulating repair. Within the first day of muscle injury, the tissue is invaded by inflammatory cells, including mononuclear cells and macrophages. The subsequent secretion of growth factors and cytokines further promotes increased blood flow to the area and enhances the inflammatory response. Muscle regeneration begins once the phagocytic inflammatory cells have cleared away necrotic tissue. This step must occur before muscle regeneration can occur, given the fact that inflammatory cells impair muscle regeneration. In normal muscle, active muscle regeneration typically occurs within 7 to 10 days from the time of injury, peaks at 2 weeks, and gradually declines until 3 to 4 weeks. In dystrophic muscle, however, the healing/regeneration process may never occur completely. In otherwise healthy individuals who are older, the muscle healing and regeneration process is delayed. It is reasonable to hypothesize that this process is markedly delayed in aging dystrophic muscle. It is not known whether or not this response is due to increased fragility of the membrane, greater susceptibility to extracellular calcium, or reduction in the repair and regeneration process.


Significant efforts have focused on the development of pharmaceutical or molecular genetic therapies that could help dystrophic muscle maximize regeneration and minimize muscle scar-tissue formation, with the goal of improving enhanced regeneration. Although little is known about aging dystrophic skeletal muscle in humans, in all cases of muscle growth and repair, the proliferation of muscle stem cells is critical to the process. In tissue culture, human stem cells proliferate more and more slowly over time, until they stop dividing completely. It has been assumed that a similar event occurs, on a grander scale, during the process of aging. Supporting this hypothesis, recent studies where human muscle stem cells, obtained from biopsy, were grown in vitro and in vivo (by implanting them into skeletal muscles of immunoincompetent mice), have shown that growth correlates negatively with age of the donor. In addition, data from Pietrangelo and colleagues suggest that aging human muscle (1) exhibits increased oxidative damage accumulation in molecular substrates that is probably due to impaired antioxidant activity and insufficient repair capability; (2) has myoblasts with limited ability to execute a complete differentiation program; (3) has restricted fusion, possibly due to altered cytoskeleton turnover and extracellular matrix degradation; and (4) shows evidence of increased activation of atrophic mechanisms through a specific FOXO-dependent program. Between ages 2 and approximately 70 years, an average of two divisions are performed by each satellite cell in human vastus lateralis and biceps brachii muscle every 10 years. For humans, by age 75, there are probably only a dozen divisions remaining in muscle stem cells before the process is completely exhausted, although this remains the subject of debate in the scientific community.


In diseases, such as DMD, the muscle fibers lack a structural protein, dystrophin, that creates enhanced vulnerability to mechanical stress. In many of the MDs, including most forms of limb-girdle MD, there are also structural proteins missing. Myotonic MD (MMD) is different, however, in that it is associated with aberrant splicing of RNA in muscle-specific chloride channel (ClC-1), producing reduced conductance of chloride ions in the sarcolemma. Thus, satellite cells in children with MD may have the remaining growth capacity as low as might be found in those in their eighth decade of life. The implantation of genetically intact myoblasts obtained from healthy relatives had been proposed as a treatment of DMD. Given what is known about muscle regenerative capacity, however, it is reasonable to expect that local implantation of a fixed numbers of cells is not likely to rescue the complete musculature or even the muscles of breathing, which are perhaps the most vital in terms of survival.


The absence of dystrophin and the dystrophin-glycoprotein complex from the sarcolemma is the ultimate cause of muscle deterioration, ultimately leading to respiratory or cardiac failure. Until this problem can be definitively treated, DMD will continue to be a severe, and ultimately fatal, disease. Chamberlain and colleagues have shown that increase expression of utrophin, a dystrophin paralog, holds significant promise as a treatment for DMD. Using an adeno-associated viral (AAV) vector, these investigators were able to show that intravenous administration of recombinant AAV (rAAV2/6) harboring a murine codon optimized microutrophin (DeltaR4-R21/DeltaCT) transgene to adult mice with complete absence of dystrophin. Five-month-old mice demonstrated localization of microutrophin to the sarcolemma in all the muscles tested. These muscles displayed restoration of the dystrophin-glycoprotein complex, increased myofiber size, and a considerable improvement in physiologic performance when compared with untreated mice. Overall, microutrophin delivery alleviated most of the pathophysiologic abnormalities associated with the dystrophy in the treated mice. This approach may hold promise as a treatment option for DMD because it avoids the potential immune responses associated with the delivery of exogenous dystrophin. It also shows promise for significant prolongation of life expectancy if these results can be duplicated in humans with DMD. Restoring dystrophin expression in the muscles of patients with DMD may, therefore, halt or reverse the degenerative wasting and weakness that causes premature death.


The therapeutic efficacy of an intervention, however, may be limited by the extent of disease progression before treatment. Investigators have considered the potential for ameliorating the pathology in a mouse model of advanced-stage MD by systemic administration of rAAV6 vectors encoding a microdystrophin expression construct. The treatment of 20-month-old mdx mice restored body-wide expression of a dystrophin-based protein in striated musculature. In aged mice that received treatment, the resultant dystrophin expression was associated with improved hindlimb and respiratory muscle morphology and function, concomitant with reduced muscle fiber degeneration. The findings demonstrate that an established dystrophic state remains amenable to improvement with appropriate intervention and, by some measures, may achieve benefits similar to those observed with intervention early in disease progression. The capacity to ameliorate the pathology in an animal model of advanced-stage MD suggests that interventions that ultimately proved to exert a therapeutic effect in young patients may offer benefits to older patients or those with advanced conditions of progressive MD.


Exercise is another intervention proposed to forestall the effects of aging in normal muscle. Although the effects of exercise on humans aging with MD is not well understood, the effects of long-term voluntary exercise on mdx mice and sedentary aging mice have been studied. Although the mdx mouse is the genetic homolog for DMD, it does not demonstrate the same progression in limb muscle dysfunction as boys with DMD do as they age. Many investigators have postulated that the sedentary lifestyle of this animal plays an important role in its minimal phenotypic expression. To examine the effect of exercise, eight C57BL/10 (C57) and eight mdx mice were allowed to run ad libitum for 1 year. Forty sedentary mdx mice and 40 sedentary C57 mice from 1 month to 18 months of age were used as controls. Contractile characteristics of the extensor digitorum longus and soleus muscles and morphometric characteristics of the mice were examined. The mdx mice ran approximately 45% fewer kilometers per day than the C57 mice. Long-term voluntary running had beneficial training effects on the old mdx mice and their C57 controls. The exercise ameliorated the age-associated loss in tension production that was observed in the soleus of sedentary mdx and sedentary C57 mice. There was a 9% reduction in the fatigability of the extensor digitorum longus muscle of the old mdx mice after the exercise. Despite these improvements, the old mdx mice exhibited significant functional deficits compared with their C57 controls. Thus, the hypothesis that long-term voluntary exercise would have a beneficial training effect on control mice and a deleterious effect on mdx mice as they aged was not supported by this study. Rather, this study showed that dystrophin-less muscles from sedentary mice display significant signs of muscle damage, yet can still benefit from low-level voluntary running in a manner similar to that of the C57 controls.


Part of the pathogenesis of MD shows some overlap with current theories of aging. The disruption of the muscle membrane down-regulates neuronal nitric oxide synthase (nNOS), which disrupts the exercise-induced cell signaling pathway that regulates blood flow to the muscle and results in functional muscle ischemia. More recent studies have shown that when nNOS is not present at its normal location on the muscle membrane, the blood vessels that supply active muscles do not relax normally and show signs of fatigue. The nNOS species has also been implicated in the normal aging of skeletal muscle. Thus, much like in aging, the pathophysiology of the dystrophy may significantly affect its response to exercise. Exercise, especially exercise that places a large amount of stress on the muscle fibers, such as high-resistive and eccentric exercise, damages skeletal muscle in the dystrophies. Even mild exercise has been implicated in causing functional muscle ischemia and fatigue in MD patients due to disruptions in nNOS signaling.


Human Studies of Aging in Individuals with Muscular Dystrophy


Parker and colleagues reviewed the management of a late adolescent and adult DMD population to identify areas in which the present service provisions may be inadequate to the needs of this patient population. In 25 patients with DMD, reviewed over a 7-year period, they reported nine patient deaths. There was no significant correlation between age of wheelchair confinement and age of death. Sixteen patients received noninvasive positive pressure support. Twelve attended mainstream schools and 12 attended residential special schools. All of the patients lived at home for some or all of the time, when their main caregivers were one or both of the parents. The most striking difficulties were with the provision of practical aids, including appropriate hoists and belts, feeding and toileting aids, and the conversion of accommodation. Patients rarely wished to discuss the later stages of their disease, and death was often more precipitated than expected. Death usually occurred outside hospital and the final cause was often difficult to establish. In this study, the investigators reported that the adult patients with DMD frequently encountered inadequate and poorly directed social and medical support, further illustrating the need for improvements in the structure, coordination, and breadth of rehabilitation services for adults with DMD.


Wagner and colleagues proposed that the needs of individuals aging with DMD is best addressed in a multidisciplinary clinic. They based this conclusion on their experience as a multidisciplinary team actively caring for 23 men aged 19 to 38 years of age. In their study, approximately one-fourth of the participants remained on moderate-dose corticosteroids. They recommended daily stretching exercises, particularly of the distal upper extremities.


Health-Related Quality of Life: A Target for Treating Aging Individuals with Muscular Dystrophy


There is incredible diversity in individuals who have MD, and this diversity likely increases as these patients age. Few quality-of-life (QOL) studies have been performed to help understand the effects of having a MD on QOL, and there are no specific studies examining the effect of age on QOL. Two common criticisms of the few QOL studies that have been performed are (1) they frequently lump individuals with different MDs together in a single poorly defined study group and (2) the studies predominately used generic instruments to define QOL. Thus, the available research rarely includes measures of highly clinically relevant domains, such as physical and emotional functioning, and instead tend to focus on the extreme manifestations of dysfunction, such as severe pain and morbidity.


Recently, several disease-specific QOL assessment tools have been developed for use in MD populations. These disease-specific measures are especially useful in differentiating QOL and psychosocial functioning of patients as their MD progresses. The results of studies using such measures suggests that the pain of persons with MD is undertreated. This finding may be even more significant in individuals who are aging with MD, as pain is also undertreated in aged adults.




Clinical paradigms for aging patients with muscular dystrophy


Exercise Paradigms to Improve Strength


Normal human aging is associated with skeletal muscle atrophy and functional impairment (sarcopenia). Multiple lines of evidence suggest that mitochondrial dysfunction is a major contributor to sarcopenia. Aging is associated with a transcriptional profile reflecting mitochondrial impairment. Studies show, however, that resistance exercise may reverse this signature, allowing the muscle in an older individual to approximate that in someone who is younger. Thus, healthy older adults with evidence of mitochondrial impairment and muscle weakness can partially reverse this at the phenotypic level and at the transcriptome level after longer-term resistance exercise. Aging may increase risk of muscle injury, however, and studies in aged rats show impaired muscle adaptability. Muscle injury (and dysfunction in subsequent repair) is also a hallmark of MD. Studies performed in normal and dystrophic animals have shown that unaccustomed eccentric exercise (lengthening of the muscle during contraction) may injure the contractile and cytoskeletal components of the muscle fibers. Concentric exercise, which involves shortening of the muscle during contraction, does not have the deleterious effects observed in eccentric exercise. During eccentric exercise, sarcomeres are stretched and the actin and myosin filaments are pulled apart, leading to disruption of the thick and thin filament array and damage to cytoskeletal proteins. Structural damage is observed by the appearance of Z-line streaming and myofibrillar disruptions. Mechanical strain, the contributing factor that induces muscle injury, causes an immediate loss of force-generating capacity and initiates a cascade of processes that result in skeletal muscle damage. The inability to quickly repair a disruption of the membrane causes an elevation in intracellular calcium concentration, which triggers calcium-activated degradation pathways and further ultrastructural damage. This damage results in fiber degeneration followed by inflammation and, eventually, fiber regeneration. Younger animals tend to benefit more from exercise studies than do older animals. High-repetitive exercise typically had no effect or it had a deleterious effect, in fast-twitch muscles that were more severely affected by disease, which makes them more vulnerable to damage by eccentric exercise. Unfortunately, there are not enough reports examining the effect of high-resistive strength training exercises in older, dystrophic animals to allow any major conclusions to be drawn.


In humans, skeletal muscle weakness is the ultimate cause of most clinical problems in the MDs. There have been several well-controlled studies documenting the effect of exercise as a means to gain strength in MDs, although much remains to be learned in this area. In slowly progressive MDs, a 12-week moderate resistance (30% of maximum isometric force) exercise program resulted in strength gains ranging from 4% to 20% without any notable deleterious effects. In the same population, a 12-week high-resistance (training at the maximum weight a subject could lift 12 times) exercise program showed no further added beneficial effect compared with the moderate resistance program, and there was evidence of overwork weakness in some of the study participants.


In one study comparing patients with MMD type 1 (DM1) to patients with Charcot-Marie-Tooth disease, only the Charcot-Marie-Tooth disease patients seemed to benefit significantly from a strengthening program. Similar results were found in a second study that also included facioscapulohumeral muscular dystrophy (FSHD). These studies point out that the most effective exercise regimens for myopathies and neuropathies are most likely going to differ, although further investigation is needed to clarify which type of exercise is most beneficial for which patient population. In rapidly progressive disorders, such as DMD, there is active ongoing muscle degeneration and the risk for overwork weakness and exercise-induced muscle injury is much greater. In this population, exercise should be prescribed with caution and a common-sense approach. All of this is made more complex in aging MD patients and this is an area that needs further investigation.


Thus, it is advisable that all patients with MD, in particular aged patients, be advised not to exercise to exhaustion, due to the risk of exercised-induced muscle damage. MD patients in an exercise program should be monitored for signs of overwork weakness. Eccentric exercise should be avoided due to increased risk for muscle injury. This includes excessive delayed onset muscle soreness that usually occurs 24 to 48 hours after exercise. Other warning signs include severe muscle cramping, heaviness in the extremities, and prolonged dyspnea. Despite exercise interventions, all of the major forms of MD are progressive and weakness increases over time.


Submaximal, low-impact aerobic exercise (walking, swimming, and stationary bicycling) improve symptoms of fatigue via enhancement of cardiovascular performance and increase muscle oxygen and substrate use. This is important because fatigue is a significant limiting factor in physical performance in patients with MDs. Fatigue in this setting is likely multifactorial, due to deconditioning and impaired muscular activation, all made more significant by age. Improving cardiopulmonary performance through aerobic exercise improves not only physical functioning but also mood state and helps fight depression and osteoporosis, which in turn reduces fracture risk. Appropriate exercise is also an effective treatment for depression. Aerobic exercise also helps achieve and maintain ideal body weight and improve pain tolerance. Nonballistic, sustained muscle stretching is also helpful and should be routinely done after exercise.


Aging and Management of Joint Contractures


Joint contractures are a major clinical problem in MD, particularly in individuals with DMD. Routine examination of the spine and major joints in MD patients should be performed at each clinic visit. Contractures seem to be related to prolonged static limb positioning and frequently develop shortly after patients become wheelchair dependent. In ambulatory patients, upper-extremity contractures may occur and be complicated by joint subluxation, particularly in the shoulder girdle. Slings may provide support but not prevent contracture formation. Again, stretching and positional splinting may slow the progression of contractures, although the actual efficacy of this approach has not been well studied or documented in the literature. In younger patients, surgical release of contractures in the lower extremities may allow patients to be functionally braced. This may prolong ambulation although several studies have shown that weakness, not contractures, contribute most to the loss of functional ambulation. As patients with MD age, contractures are best treated with gentle, static stretching and appropriated support of the joint.


Older patients with MD weakness may benefit from bracing, depending on the distribution of weakness, gait problems, and joint instability. The decision to brace should include the risk of added weight of the brace and the willingness of patients to use the brace. MD patients should be referred for a course of physical therapy after being fitted with braces to help them learn to use the devices effectively. Bracing should be done with the goal of improving function and joint stability. Otherwise, bracing may be cumbersome for many individuals aging with MD. Ankle-foot orthoses are often the most useful and are best if they are custom-made with a lightweight polymer (polypropylene or carbon fiber). They should fit intimately to avoid skin problems and provide good stability. If a pressure sore occurs, patients should be taken out of the brace until the pressure sore heals. Double metal upright ankle-foot orthoses may be built into the shoe but are often too heavy and may limit ambulation, particularly for older patients with more proximal muscle weakness. If there is significant ankle instability noted, then the braces should be high profile (come around in front of the malleoli).


Psychosocial Issues in Aging Patients with Muscular Dystrophy


Although the literature on prevalence of depression in older adults is complicated by several health-related and demographic confounds, rates of subclinical depression seem to be between 8% and 16%, making this one of the most common mental health problems faced by older people. Depression associated with aging has been shown to be influenced by genetic, situational, illness-related biologic, and psychosocial factors. The psychosocial model of mental health hypothesizes that late-life depression, when it occurs, arises from several significantly losses associated with aging, such as the loss of self-esteem (helplessness, powerlessness, or alienation), loss of meaningful roles (work productivity), loss of significant others, declining social contacts due to health limitations and reduced functional status, dwindling financial resources, and a decreasing range of coping options. Most, if not all, of these issues are already a problem in individuals with MD. Clinical depression may, therefore, be underdiagnosed in the MD patient population, and the effects of aging on depression become increasingly more important to investigate as this population ages. Moreover, many patients with MD already experience symptoms that could mimic a major depression, including fatigue, loss of appetite, and difficulty sleeping. Studies in patients with MD have been noted to have higher levels of depression on the Minnesota Multiphasic Personality Inventory.


Many patients with MD also report feelings of worthlessness and self reproach, as noted in prior studies. As discussed previously, studies on MD patients have shown elevated scores for depression on Minnesota Multiphasic Personality Inventory testing. In one investigation, depression was more closely associated with level of independent functioning than with limb strength, suggesting that good family, social, and religious support systems are critical for positive psychological functioning. Depression in other family members and caregiverrs should also not be overlooked. Individual, group, and family counseling may be beneficial.


Older patients with MD should be referred to a support group when one is available, which can be an excellent resource for psychological support and problem solving. If necessary, referral to a mental health professional should be done. Antidepressant medicine may help with mood elevation and improve appetite and sleep although the efficacy of antidepressants for the management of depression in individuals with MD has not yet been studied.


Cognitive Functioning and Aging in Patients with Muscular Dystrophy


Cognitive involvement is common in MMD and is also seen, to a lesser extent, in DMD. Learning disabilities are seen in approximately one-third of boys with DMD. Beyond that, most people with MD show normal intelligence. There have been no studies to date looking at cognitive capacity or function in aging patients with MD, although studies have shown that that patients with coexisting cognitive impairment and depression required significantly more psychiatric care than patients with depression alone. Although much remains to be studied, the existing data suggest aggressively treating depression in any aging MD patient with coexisting cognitive impairment.


Modoni and colleagues characterized the progression of the cognitive involvement in patients affected by DM1in a longitudinal neuropsychological follow-up study. The neuropsychological test battery included Mini-Mental State Examination, memory, linguistic, level, praxis, attentional and frontal-executive tasks. They found that, over time, the whole group of patients in their sample showed a significant deterioration in linguistic functions, together with a tendency toward decline in executive abilities, confirming a predominant involvement of cognitive functions subserved by frontotemporal areas. Moreover, they observed that their older patients obtained the lowest scores on the neuropsychological tests. A similar longitudinal study by Sansone and colleagues using neuropsychological testing also demonstrated frontal lobe dysfunction, largely attentional, progressing over time in DM1 and DM2 patients. These findings support the hypothesis that cognitive damage, when it occurs, tends to be confined to frontotemporal functions in adult DM1 patients, and that frontotemporal functions tend to decline with aging. Further studies are needed to determine best treatment approaches to help reduce morbidity and improve care for patients with coexisting depression and cognitive impairment, such as might be found in aging DM1 patients.


Vocational Issues in Aging Patients with Muscular Dystrophy


Employment rates for people with MDs are significantly less than for the able-bodied population, although in the MD population, higher levels of education correlate more closely with employment rate than does functional level or physical performance. Level of self-esteem noted on personality testing has also been shown associated positively with education and employment. These findings suggest that altered personality profiles in MD patients may be a factor in the ability to integrate into mainstream society and hold steady employment. In this regard, education seems as important as physical abilities with respect to employability and self-esteem in people with MDs. This may become more pertinent as boys with DMD grow old enough to consider employment. This is yet another area that is in need of further investigation.


Restrictive Lung Disease


Despite the frequent reference of having restrictive lung disease, the lung in MD is often normal. The problem is with a “weak bellows” (ie, weakened diaphragm, chest wall, and abdominal muscles) and is well described in the literature. This causes patients with MD to have problems getting air into and out of the lungs, including coughing. The most severe respiratory complications are usually seen in DMD and DM1. Although respiratory failure in FSHD is unusual, a recent study identified 10 FSHD patients on nocturnal ventilatory support at home, representing approximately 1% of the Dutch FSHD population. Severe muscle disease, wheelchair dependency, and kyphoscoliosis seemed to be risk factors for respiratory failure in FSHD. Given the risk factors for lung disease, periodic assessment of respiratory function is indicated in all patients with MD; this is likely to be even more important as patients with MD age. This has been shown in longitudinal studies of pulmonary function in large MD populations.


If better airway access becomes absolutely necessary, informed MD patients may choose to have a tracheotomy. This does not eliminate the possibility of aspiration and does require deep suctioning and judicious care of the tracheostomy tube. Although preserving the ability to phonate, a tracheostomy can actually increase aspiration risk, along with other complications, including bleeding. It is critical that MD patients understand that tracheostomy, while making it easier to use mechanical ventilation, may not necessarily improve their overall QOL. Fortunately, with the advancements in noninvasive ventilation, these options are used only infrequently. As this patient population ages, this will likely become a bigger issue. Simple interventions, including pursed lip breathing and attention to pulmonary toilet, have proved effective at decreasing morbidity in patients with MD.


Cardiac Complications


Cardiac involvement may occur in many of the hereditary muscular dystrophies, including DMD, Becker MD (BMD), MMD, and some cases of limb-girdle MD. A high (60%–80%) occurrence of cardiac involvement is present in DMD and BMD subjects of all ages. Dystrophin has been localized to the membrane surface of cardiac Purkinje fibers, perhaps contributing to the high incidence of electrocardiogram (ECG) and echocardiographic abnormalities in DMD and BMD in the preadolescent years. In spite of this, only approximately 30% of DMD patients have clinically significant cardiac complications. The myocardial impairment may remain clinically silent until the late stages of the disease. This may be due to lack of physical activity. As patients with DMD frequently live well into the third, and sometimes fourth, decade of life, this will become an increasingly important area for research. Pulmonary hypertension also has been implicated in the cardiorespiratory insufficiency of DMD. Death has been attributed to congestive heart failure in as many as 40% of patients with DMD by some investigators.


Severe cardiac involvement in BMD may occasionally precede the clinical presentation of skeletal myopathy. Moreover, cardiac compromise can be disproportionately severe relative to respiratory compromise in some patients with BMD. Thus, ECG and echocardiography screening of all BMD patients at regular intervals is indicated. Patients with myocardial involvement need close follow-up and management by a cardiologist with expertise in this area. Successful cardiac transplantation has been reported in BMD patients with cardiac failure who remained ambulatory. There is also a high incidence of ECG abnormalities in both forms of MMD. Studies have shown that approximately one-third of DM1 patients have first-degree atrioventricular block, whereas approximately one-fifth have left axis deviation. Only 5% have left bundle branch block. Bundle of His conduction delays have also been rarely reported. Complete heart block, requiring pacemaker placement, is rare but can occur. Patients with any form of DM should receive routine cardiac evaluations.


Pain


Pain is a significant problem for most patients with MD, although it is not typically a direct consequence of the disease. Pain, when present, does cause significant impairment of QOL. It is most commonly caused by immobility. This may lead to adhesive capsulitis, low back pain, pressure areas on the skin, and generalized myofascial pain. There are many novel pharmaceutical agents available to treat different forms of pain associated with neuromuscular disease.


Osteoporosis/Bone Density/Lean Body Mass


Patients with MD, including DMD, are living longer into adulthood. Thus the risk for osteoporosis will likely increase dramatically for many reasons, including malabsorption, loss of weight bearing, and nutritional deficiencies. This growing patient population presents new therapeutic challenges in terms of maintaining bone density. Studies suggest approximately one-quarter of adult DMD patients remain on moderate dose corticosteroids. This increases the risk for osteoporosis even further. Prior case reports in boys with DMD and known osteoporosis have shown a favorable response to weekly alendronate and daily calcium and vitamin D. Measurements of lumbar spine and proximal femur using dual-energy x-ray absorptiometry have demonstrated increases in bone mineral density, with z scores improving from baseline to 1-year follow-up. Improvements have been reported in the lumbar spine, femoral neck, and greater trochanter. Although more research is indicated, there is at least anecdotal evidence that weekly oral alendronate plus daily vitamin D and calcium is effective in improving bone mineral density in patients with DMD. Additionally, home-based, weight-bearing exercises may also help prevent osteoporosis and loss of lean body mass.


Hypogonadism


Hypoganadism has been described in patients with MMD but has not been evaluated in other forms of MD. Tarnopolsky and colleagues measured total and free serum testosterone levels in 59 men with MD, including MMD (N = 12), FSHD (N = 11), DMD/BMD (N = 12), metabolic myopathy (N = 7), and inclusion body myositis (N = 17), and compared these with the normal reference values. Their results showed that 32 of the 59 (54%) participants had low total testosterone, 23 (39%) had low total and free values, and 5 (8%) had low free with normal total levels. There were no significant differences in the prevalence of hypogonadism between the various forms of MD or myopathy, even after considering age as a confounder. From these data it can be presumed that hypogonadism is common in men with MD and other myopathies. This is important and will become a bigger issue in aging men with MD. The importance of testosterone in the maintenance of muscle mass is critical and if hypogonadism is present, testosterone replacement therapy should be considered.


Nutritional Management


Nutrition is a significant problem for most people with MD. In the more severe MDs, there is a tendency toward obesity shortly after the loss of functional ambulation, even if stature is impaired. Metabolic syndrome (obesity, dyslipemia, and hypertension) will likely become increasingly prevalent in the aging MD population, due in part to immobility, impaired nutritional intake, and lack of access to appropriate medical care. Recent evidence has shown that the MD patient population is a higher risk for developing metabolic syndrome. Obesity is common in MDs, in particular DMD, where a prevalence of 54% has been reported. Weight control has its primary rationale in ease of care, in particular transfers and skin care, decreasing postoperative complication risk, and decreasing risk of developing metabolic syndrome.


To determine whether or not a home-based activity and dietary intervention can increase activity level, reduce caloric intake, and have a positive impact on components of metabolic syndrome in patients with MD, Kilmer and colleagues did several studies examining the effects of a home-based nutritional and exercise program. After initial laboratory testing of anthropometric and metabolic variables and 3 days of home-based activity and dietary monitoring, a personally tailored activity and dietary prescription was given, based on baseline testing. Twenty adult volunteer ambulatory subjects with slowly progressive MD were given a pedometer and instructed to increase number of steps by 25% over their baseline determined from home monitoring. An individualized dietary prescription was provided focusing on problematic issues identified from the baseline dietary profile. The main outcome measures included body composition, physical activity, dietary intake, energy expenditure, gait efficiency, metabolic variables, and QOL. The results showed that, by the end of the protocol, mean step count increased approximately 27% above baseline ( P = .001), and caloric intake decreased over 300 kcal/d ( P = .002). Body fat percentage significantly decreased (from 33.3% ± 1.5% to 32.6% ± 1.6%, P = .032). Gait efficiency did not change, however, and metabolic variables did not show statistically significant improvement, although two of the five subjects originally meeting the criteria for metabolic syndrome at baseline no longer met the criteria at the end of the intervention period. Six months after completing the protocol, caloric intake remained significantly reduced ( P = .02), but although mean step count remained elevated, it was no longer statistically significantly higher than baseline levels. The study findings indicate that using a home-based protocol, people with slowly progressive MD can increase activity and reduce caloric intake. Although this 6-month program showed positive changes, it was insufficient to affect risk factors associated with metabolic syndrome. It remains to be seen if a program longer than 6 months or a more rigorous program could lead to a reduction in the risk factors associated with metabolic syndrome.


Patients with MD may be prone to nutrient deficiency due to mobility limitations or oropharyngeal weakness. Patients with DM1 may be particularly prone to nutritional deficiencies from associated dysmotility of the entire gastrointestinal tract. Prior studies in adult patients with many forms of MD demonstrated inadequate nutrient intake of protein, energy, vitamins (water and fat soluble), and minerals (calcium and magnesium), and poor intake of antioxidant nutrients. This is important as most MD patients have a high free-radical load (oxidative stress) due to ongoing muscle tissue breakdown. Significant correlations were found between measures of strength and certain individual nutrients (eg, copper and water-soluble vitamins). These data indicate that a substantial number of adults with MD do not meet current dietary intake recommendations. The potential clinical implications of this will likely increase substantially as this population ages as nutrition is also an issue for most aging, able-bodied individuals.


The advanced stages of DMD may be marked by severe malnutrition. As discussed previously, if there is severe respiratory compromise, the increased work of breathing may drastically increase caloric needs. The situation is complicated by the fact that this is often a time when patients lose the ability to self-feed. Caloric requirements should be assessed by a nutritionist and proper dietary requirements constructed for patients. This should be routinely done for all MD patients with a forced vital capacity of less than 50% predicted. Placement of a percutaneous endoscopic gastrostomy tube placement may facilitate nutrition because it eases intake of large amounts of calories and fluids. Patients should be reassured that they may still eat food orally for enjoyment, provided they have intact swallowing function. Another complicating factor in DMD patients is gastroparesis, which may make feeding more difficult. How gastric motility changes as patients with DMD age has not been studied.


Pharmaceuticals that May Improve Function or Prolong Life


Major pharmacologic advances have occurred over the past decade. Although a comprehensive discussion of clinical trials is beyond the scope of this article, some of the major advances that are particularly relevant with respect to aging with MD are noted. Given the severity of the disease and the rapid progression, DMD has received the most attention in terms of pharmaceuticals aimed at prolonging life. Although not Food and Drug Administration approved for this indication, prednisone (0.75 mg/kg/d), given to boys with DMD aged 4 to 8 years, has been shown to prolong the time of ambulation and at least should be considered for use in this disease. The positive effect of glucocorticoids on muscle function in MD have been known for some time and have similar, if not more profound, effects in animal models. Major side effects of prednisone include weight gain, osteoporosis, and mood lability. Deflazacort has similar beneficial effects and may have slightly less side effects than prednisone; however, this drug is not currently available in the United States. Recently a high-dose, weekend-only dosing regimen has shown equal efficacy with potentially less long-term side effects. Patients with DMD are given 5 mg/kg body weight on Saturday and Sunday only. Whether or not continuing treatment with prednisone long term in men with DMD as they age has added benefit remains to be studied.


Oxandrolone may also have a modest beneficial effect in DMD. There have also been several recent randomized, crossover, double-blind, placebo-controlled pilot studies of extended release albuterol in patients with dystrophinopathies (DMD and BMD) and FSHD. Outcomes were isometric knee extensor and flexor strength and manual muscle testing (MMT). There was some small evidence of benefit in the dystrophinopathies but not FSHD. Larger, double-blind, randomized studies are necessary, however, to confirm these results.


There is evidence showing a modest positive benefit of the protein creatine monohydrate in DMD for transient improvement of strength. Various neurotrophic growth factors may hold some promise, yet this remains to be studied further. Insulin-derived growth factor, commercially known as myotrophin, is the best studied of this group.


Modafinil (Provigil) is approved by the Food and Drug Administration to treat the symptoms of fatigue and excessive daytime sleepiness in narcolepsy. Fatigue and subsequent excessive daytime sleepiness secondary to fatigue, however, are also common symptoms in many forms of MD, in particular DM1. Patients with DM1 have shown efficacy with modafinil at dosing of 200 to 400 mg/d. The most commonly reported side effects of modafinil include nausea, nervousness, anxiety, and insomnia.


Palliative and End-of-Life Care Issues


Although DMD is considered an ultimately fatal condition, it may take many years before patients succumb to its effects. In the other, more slowly progressive forms of MD, death is still likely to occur due to complications from the disease. In the process, the disease contributes to more and more debility for patients and leads to important ethical and humanitarian issues. Patients may have a great deal of time to think of their impending death and also the various decisions they need to make at different stages of their disease. It is imperative that a social worker be involved early after the diagnosis to aid in the various decisions facing patients. One such important choice is the decision regarding durable power of attorney. A living will may also be drafted in regards to patients’ wishes for the extent of medical intervention, not only near end of life but also in the event of an unforeseen medical complication. As patients enter hospice-level care, these issues take on a greater importance.


Even though patients may have accepted the eventual death resulting from the MD, it is often difficult for them to accept hospice care, as this implies that the disease has entered its terminal stage. Therefore, it is especially important at these times to not only be sensitive to patient needs but also assist patients in making practical decisions. It is also important for patients to be referred to a support group early. The Muscular Dystrophy Association usually has local branches that can identify the most convenient support group. The importance of support groups should not be underestimated as they can provide not only psychological support but also further education and serve as a resource for problem solving and recycling of equipment, such as modified beds, lift devices, and communication equipment. Modern medicine is continually advancing and has many interventions that can prolong life. Although there are many potential medical interventions, physicians should be sensitive to the possibility that patients with an advanced MD may reject such interventions.


It is patients, and not the physicians, who determine whether or not to initiate life-sustaining therapy, artificial devices, or interventions that compensate for the failing organ or system to prevent death. Mechanical ventilation, artificial hydration, and nutritional supports are the most obvious examples. Legally and ethically, competent patients or their legal guardians have the right to refuse any prescribed intervention or treatment. The physicians’ and nurses’ role is to thoroughly explain the consequences of a patient’s decision and to foster and respect patient autonomy.


It takes a great deal of time to explain all of the end-of-life issues, including available treatment options and choices. Without this investment of time by clinicians, patients may be unaware of the available services and choices. An appropriate level of care for end-stage MD patients may change frequently and thus necessitates a close follow-up. Even in the advanced stages of the disease, optimizing in-home care with hospice can maximize QOL for the remaining time in these patients. Effective hospice care provides an interdisciplinary team of professionals whose goal is to support patients and families through their remaining days together. It can provide invaluable psychological, emotional, and spiritual support for patients and families in a familiar and comforting setting.


Equipment


Proper equipment may significantly improve QOL for aging MD patients. Common examples include hospital beds, commode chairs, wheelchairs and wheelchair ramps, handheld showers, bathtub benches, grab bars, and raised toilet seats. An occupational therapist is best qualified to determine if any of these devices are useful for MD patients. Wheelchairs are a critical component of mobility in those with severe MD. Wheelchairs need to be fitted appropriately with the right frame size, type of seat, lumbar support, and cushioning to avoid pressure ulcers. Other mechanical devices, such as the Tilt-n-Space (Postural Seating Material, Lawrence, KS, USA) allow patients to independently tilt the wheelchair seat, providing improved comfort and better pressure relief for the skin. These devices can often be retrofitted on to existing chairs. Patients should be evaluated by a physical or occupational therapist to ensure proper wheelchair prescription. Simply giving patients a prescription for a wheelchair frequently results in a chair that does not fit properly or has improper components. Power wheelchairs are indicated in most MD patients who can no longer ambulate and do not have enough upper-extremity strength to independently propel a manual chair.


In patients who can ambulate, walkers or quad (4-point) canes help reduce fall risk. Pressure-relieving mattresses, with foam wedges for proper positioning, help prevent pressure skin ulcers. In some MD patients, severe weakness in neck musculature causes may produce neck pain and muscle spasms. A cervical collar, in particular the Freeman or Headmaster type, which is a wire-frame collar with padding over the pressure points, may be helpful. Stretching at home may also have pain relieving and palliative benefits.

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Apr 19, 2017 | Posted by in PHYSICAL MEDICINE & REHABILITATION | Comments Off on Aging with Muscular Dystrophy: Pathophysiology and Clinical Management

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