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The Role of Exercise in Neuromuscular Disease
REHABILITATION OF NEUROMUSCULAR DISEASE
1047-9651 198 $8.00
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THE ROLE OF EXERCISE IN NEUROMUSCULAR DISEASE David D. Kilmer, MD
In the past several decades, the real benefits of regular physical exercise for the able-bodied population have been shown, including improved strength and endurance for daily activities as well as modification of risk factors for cardiac disease. However, research is clearly lacking in determining whether persons with such disabilities as hereditary neuromuscular disease (NMD) respond to exercise training in a similar beneficial manner, and, if so, whether the adaptations augment their ability to perform work and enjoy avocational activities. Although it has been presumed to be caused by their weakness and fatigability, recent work suggests that persons with NMD usually have a sedentary lifestyle.33Reasons for this are complex; it cannot simply be ascribed to the primary disease. First, habitual exercise patterns and interest in sporting activities often occur during the school years, where these people may not even participate in physical education. Wellmeaning parents, teachers, and physicians, concerned that exercise may actually be detrimental, caution the child or adolescent against physical exertion. The result is a sedentary adult who suffers not only from weakness due to loss of muscle fibers, but from the additional component of disuse weakness. This is frequently compounded by lack of the foundation of motor skills in typical sports and games first learned by others during childhood and adolescence. Finally, persons with NMD This work was supported by Research and Training Grant H133B0026-96 from the National Institute on Disability and Rehabilitation Research (NIDRR), United States Department of Education.
From the Department of Physical Medicine and Rehabilitation, University of California, Davis Medical Center, Sacramento, California
PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA VOLUME 9 . NUMBER 1 FEBRUARY 1998
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have lower levels of employment, resulting in limited financial resources to join fitness clubs, purchase equipment, and travel to events.14 The main questions this article seeks to address are: (1) how does the person with NMD respond to strengthening and aerobic (endurance) exercise; (2) what evidence exists that exercise may actually be harmful; and (3) how do we encourage this population to participate in physical activity and sport?
RESPONSE TO STRENGTHENING EXERCISE The response of intact skeletal muscle to strengthening (resistance) exercise is well delineated. With muscle overload, there is an initial catabolic response with some disruption of muscle fibers. The muscle adapts by synthesizing new myofibrillar proteins, with little change in the oxygen transport system or mitochondria1 density. The result of increased myofibril size and number is greater cross-sectional muscle fiber area, resulting in muscle hypertrophy, with the ability to resist higher loads. The response is thought to be highly specific to the type of resistance exercise. Some debate exists about the capacity for human but the general belief is that there is very muscle fiber hyperpla~ia?~ limited if any ability in an adult to increase the number of muscle fibers with training. Although muscle hypertrophy appears to be the dominant mechanism for strength gains with long-term it has been shown clearly that strength improvements occur shortly after starting a strengthening program, before hypertrophy can possibly occur. These strength gains without structural changes in muscle are likely due to neural adaptations, primarily relating to more efficient motor unit recruitment from improved coordination, learning, and activation of prime movers.10 Muscle weakness is the final outcome of all neuromuscular disease. Individual NMD frequently are identified by their pattern of weakness and family history; however, electromyographic findings and microscopic pathology may be quite similar among slowly progressive myopathic or neuropathic disorders. This, along with the relative rarity of the diseases, requires researchers frequently to group the disorders together when investigating responses to training and giving recommendations. Along with loss of skeletal muscle fibers, atrophy of disuse is thought to be frequent in persons with NMD.45Disused muscle fibers lose myofibril size, resulting in reduced fiber cross-sectional area, less Thus, the response to force production, and reduced muscle enduran~e.~ strengthening exercise may include an element of reversing the effects of disuse as well as altering the natural history of the NMD itself.
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Overwork Weakness First identified with patients recovering from polio, weakness associated with excessive physical activity is a major concern among patients and clinicians with NMD.15,45 There are descriptions of prolonged increased weakness following strengthening exercise in ALSF8 peripheral nerve lesions,ls and Duchenne muscular dy~trophy.~ The dominant upper limb has been found to be weaker in persons with facioscapulohumeral muscular dystrophy than the nondominant with heavy upper extremity use, providing circumstantial evidence for overwork.21,23 A single subject with scapuloperoneal dystrophy had a reversal of rapid strength decline after reducing daily physical activity.46It should be noted that these are all case reports, and overwork weakness has not been demonstrated in a controlled prospective study using exercise regimens.
Methods of Evaluating Strength Although the clinician typically uses the manual muscle test (MMT) during strength assessment of these patients, this evaluation has a limited role in understanding the progression of disease.22,32 Quantitative muscle testing is necessary to evaluate the response to an exercise intervention. This limits the usefulness of early intervention studies using MMT in NMD subject^.'^, 47 The simplest means of quantitative muscle testing is to measure static, isometric contractions using cable tensiometers or dynamometers.13,26 These devices provide reliable data, but measure strength at only one joint angle, thus limiting real-world application. Another method involves the maximal amount of weight the subject can lift one time. More recently, elegant devices to determine isokinetic strength by measuring maximal force at a preset velocity have been used with NMD patients; these have provided information on both shortening (concentric) and lengthening (eccentric) contraction^.^^ Good reliability has been shown in this population using both types of data, particularly for uniplanar joints such as the knee and elbow. Strength of the shoulder, wrist, and ankle musculature in specific motions, although important functionally, is more difficult to isolate, making these dynamometers and measurements less reliable. Strength testing at these joints may be better suited to the hand-held myometer, which can be used in the clinic.26 Measures of fatigue and endurance, for example using the number of contractions at a given submaximal resistance level, are less well studied and are not likely to be nearly as reliable. This is unfortunate because muscular endurance is more likely to be relevant to performance of daily activities than any measurement of maximal strength. Regardless of method, impressive strength gains usually are measured over the first several weeks of a training protocol. Since physio-
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logic changes cannot occur at the muscle fiber level this quickly, these gains are presumed to be due to improved motor planning and synchronization of motor unit firing with learning. Actual strength gains from muscle fiber hypertrophy occur after several weeks. Strengthening Exercise: Rapidly Progressive Disorders
In Duchenne muscular dystrophy (DMD), there is a rapid progression of strength loss both qualitatively and quantitatively." The child typically requires a wheelchair for mobility between the ages of 8 and 12. Because of this rapid progression, these children usually cannot participate with their peers in the normal physical activities involved in play and exploration of their environment, often leading to isolation and lack of social d e ~ e l o p m e n tA . ~desirable ~ role for strengthening exercise is to slow the rate of progression of weakness, allowing more natural development. Because of the rapid progression, a control group is a desirable but rarely obtained component of intervention studies. Strengthening intervention studies with DMD patients generally have shown maintenance of strength or even mild improvement in strength over the period of the investigation. However, these studies are limited by use of primarily nonquantitative measure^,^“ lack of a control and use of the opposite limb as a control without considering the effects of cross-training7 Other problems include variations in the type and intensity of resistance training and duration of follow-up. Interestingly, no systematic studies using this population have shown any deleterious effects of resistance exercise. Thus, based on limited data one may conclude that resistance training can maintain one-repetition strength in DMD patients. However, owing to the relative paucity of investigations, it is prudent to recommend a submaximal strengthening program. A great concern is how to incorporate these activities effectively into the daily routine of the child, avoiding use of mundane and tedious regimens that employ resistive weights and pulleys.25 With the advances in molecular genetics and possible identification of abnormal gene products, more rational and specific approaches should be taken in designing exercise protocols and understanding potential deleterious effects. As an example, it is now known that DMD patients lack a structural protein of the muscle cell membrane called d y ~ t r o p h i nThis . ~ ~ protein appears to be essential to maintain the cytoskeletal framework of the muscle fiber during muscle contraction." Muscle actions known to stress the cytoskeletal elements of the fiber, such as strong eccentric contractions, are likely to enhance breakdown of the muscle fiber.16 With this knowledge, future resistance exercise regimens will need to assess carefully the amount of such contractions being performed. Indeed, Edwards et a19proposed that routine eccentric
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contractions occurring during gait are a likely source of the pattern of weakness typically seen in myopathies. The other rapidly progressive NMD to consider is ALS. However, because of its variable progression and bulbar involvement, systematic strengthening exercise intervention studies have not been performed with these patients. Clinicians generally recommend a submaximal strengthening program for patients who are motivated to engage in these activities in the hope of attenuating strength loss. Strengthening Exercise: Slowly Progressive Disorders
In slowly progressive hereditary neuromuscular disorders, the goal of strengthening intervention studies has been to improve patient strength rather than simply to retard strength loss. Because of the rarity of these diseases, most studies have grouped different NMDs together in order to obtain adequate numbers for analysis. A presumption of these studies is that improving strength gives patients more reserve to perform daily tasks-a yet-untested hypothesis. Vigx-10~~~ used high-resistance exercise in both rapidly and slowly progressive NMD, and found greater strength improvements in the less severe disorders. This tendency toward greater improvement with stronger patients also was found by Milner-Brown and colleagues, who reported that high-resistance weight training produced improvement in strength measured isometrically, generally in muscles with more than 10% of normal strength." McCartnev and associates demonstrated substantial increases in gtrength of subfects with slowly progressive NMD using a carefully controlled regimen over 9 weeks.31 To ensure safety, only supervised strengthening programs in this vovulation have been advocated.45In order to test the effects of a less supervised approach, a moderate resistance home exercise program was devised that demonstrated similar strength gains in both patients and normal control subjects without evidence of overwork weakness.' Based on this encouraging result, the home program was advanced to highresistance training in similar subjects without apparent additive beneficial effects; in fact, eccentrically measured elbow flexor strength actually decreased signifi~antly.~~ Limitations of the above studies include lack of a disease control group and inclusion of subjects with a variety of slowly progressive disorders, each with unique pathophysiologic characteristics. Recently a Dutch group limited their investigation to myotonic muscular dystrophy (MMD) and hereditary motor and sensory neuropathy (HMSN), using nonexercising controls; they demonstrated modest gains in both strength and function of the HMSN group but no improvements in the MMD Of note, no untoward effects were demonstrated in either group. The design of this study, using measures of functional performance as well as static strength, should be a model for future investigaL
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tions. Undoubtedly a multicenter approach will be required to obtain adequate numbers of subjects with the rarer disorders. Based on the above investigations, we now have adequate evidence to generally advocate a submaximal strengthening program for persons with slowly progressive NMD. There seems to be no additional benefit to high-resistance low repetition training sets, and the risk of actually increasing weakness becomes greater. Not adequately addressed by these studies are the benefits conferred by improving maximal strength. For example, attenuating fatigue during prolonged submaximal work may be the most important factor in improving daily work capacity in these patients. Compliance with lifting weights could certainly improve if clinicians were able to provide this evidence to their patients supported by a rational scientific basis. RESPONSE TO AEROBIC EXERCISE
Aerobic exercise refers to rhythmic, prolonged activity at a level sufficient to provide a beneficial training stimulus to the cardiopulmonary and muscular systems but below the threshold where anaerobic metabolism of fuels is the primary source of energy. The response of normal skeletal muscle to this type of training includes: increased capillary density in the muscle to improve substrate transfer increased skeletal muscle mitochondria1 size and density higher concentrations of skeletal muscle oxidative enzymes improved utilization of fat as an energy source for muscular activity Clearly, patients with neuromuscular diseases have diminished capacity for exercise. In Duchenne dystrophy, Sockolov et a1 demonstrated low cardiorespiratory capacity and peripheral oxygen utilization with higher resting heart rate compared with controls.43Similarly, in amyotrophic lateral sclerosis, maximal oxygen uptake and work capacity were diminished in proportion to loss of muscle strength and functional score. There was elevated oxygen cost of submaximal exercise as well.38 In slowly progressive NMD, similar although less marked findings are present with aerobic exercise testing. There is significantly reduced maximal work capacity," and the limiting factor appears to be loss of functional muscle mass rather than defects in the oxygen transport system.42Thus, it is no surprise that patients with Duchenne dystrophy have lower maximal oxygen uptakes than do those with the less severe FSH dystrophy.17However, physical ability is likely more limited by loss of muscle strength than by deterioration of cardiorespiratory f ~ n c t i o n . ~ Methods of Measurement
The traditional method of assessing aerobic capacity is measurement of maximal oxygen uptake using a treadmill or bicycle ergometer, incre-
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mentally increasing the workload. However, NMD patients with significant lower extremity weakness often cannot tolerate these devices owing to poor balance or rapid fatigue, leading to an inability to reach a maximal response. For these reasons, a recumbent bicycle ergometer has been utilized4*that allows measurement of a submaximal or peak aerobic response. Some argue that focus on maximal aerobic capacity is misguided, since maximal aerobic power is seldom a limiting factor in the ability to perform daily living tasks.4 Muscle strength, endurance, and peak mechanical power are thought to be more relevant in assessing ability for these tasks.
Response to Aerobic Training
Like studies of muscle strengthening, investigations dealing with aerobic training have grouped disorders together, resulting in some ambiguity when considering a patient with a specific disease. For example, ~lorenceand colleagues, using a 3-month stationary bicycle training program, found an average 21% improvement in maximal oxygen uptake in subjects with different slowly progressive NMD.12 However, there was a wide variation in improvement, ranging from -2% to 47%, with several subjects possibly exhibiting signs of muscle damage. Conclusions could not be drawn because of the small numbers of patients. In a more recent study using a home-based aerobic walking program in subjects with a variety of slowly progressive disorders, several parameters suggested modest improvements in aerobic capacity without evidence of overwork weakness or excessive fatigue.48To be more meaningful to individual patients, future intervention trials should focus on individual disorders. In addition, more work is needed on the oxygen cost of certain activities, such as walking, owing to the altered mechanics and muscle substitutions that make even routine activities difficult for any prolonged period. FATIGUE IN NEUROMUSCULAR DISEASE
On careful questioning, patients with NMD frequently complain that their weakness is not manifested by the inability to lift an object one time; rather, they become so fatigued after any attempt at continuous exercise or work that they abandon all future attempts. Despite this common symptom, investigators largely ignore the origin and treatment of fatigue in these patients, probably because of difficulties in study design and the effort-dependent nature of the protocols. In addition, the complex relationship between primary fatigue from the NMD and secondary fatigue due to disuse must be ~ o n s i d e r e d Recently, .~~ some investigators have attempted to look directly at the muscle's role in fatigue by using the twitch interpolation technique, thus bypassing
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voluntary activation of the muscle and differentiating central from peripheral fatigue. If muscles are weak, they are forced to work at a higher percentage of their maximal strength to perform the same activity as the ablebodied. This will hasten the time of the muscle to fatigue: and is undoubtedly the source of fatigue in patients with significant loss of muscle strength. Further investigation of fatigue has been performed in Duchenne muscular dystrophy (DMD). Using a 4-minute sustained voluntary contraction of the tibialis anterior, Sharma and colleagues found no differences between control and DMD patients in intramuscular fatigue and excitation-contraction Thus, there was no evidence for specific abnormality of the muscle membrane, myoneural junction, or contractile process in this myopathy. Fatigue was examined by the same group in the denervating disorder of ALS.41Although maximal voluntary and tetanic force declined more during the sustained contraction in the ALS group compared with the control, no impairment was found in neuromuscular transmission or the muscle membrane. The authors concluded that muscle fatigue resulted from activation impairment, at least partly from alterations in excitation-contraction coupling. Future exercise studies should incorporate reliable measures of fatigue as another outcome variable along with measures of functional performance. It is no longer sufficient to show strength improvements; we must quantify the changes in a patient's ability to work and enjoy physical activities. EXERCISE RECOMMENDATIONS FOR PERSONS WITH NMD
The reasons for advocating an active life-style extend beyond improving work capacity and endurance in this patient population. It is now clear that physically inactive people have twice the risk of coronary heart disease than the more active p ~ p u l a t i o nBut . ~ ~how much exertion is necessary? Recommendations have been modified in this area, and even low levels of activity including walking and gardening, although not altering one's maximal oxygen uptake, can provide considerable benefit to reducing the risk of coronary artery disease.29 In selecting a recreational activity for a person disabled with neuromuscular disease, several issues should be considered: Is the activity appropriate for the person's level of weakness or are there methods to adapt the sport to their needs? Can the sport be continued as the person's weakness progresses? Are there opportunities for social development and personal accomplishment? What are the costs? Is the sport varied enough to maintain long-term interest?
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An example is disabled snow skiing, which offers tremendous capacity for personal and social satisfaction. Through organizations such as Disabled Sports USA, persons with weakness ranging from mild to severe can be provided with adaptive equipment and instruction at a reasonable cost. However, these types of recreational experiences should be recommended in combination with a daily active life-style that follows the principles of energy conservation, alternating periods of physical activity with scheduled rest. CONCLUSIONS
Although research shows that strength and endurance exercise regimens may have beneficial effects in persons with NMD, participation continues to be poor. We must overcome the psychologic and social barriers that make this population sedentary. Physical activity should be viewed as a way of improving quality of life, not a tedious and exhausting set of exercises. Educating physicians as well as other health care, educational, and vocational professionals is the first step in motivating our patients to adopt a vigorous life-style. References 1. Aitkens SG, McCrory MA, Kilmer DD, et al: Moderate resistance exercise program: Its effect in slowly progressive neuromuscular disease. Arch Phys Med Rehabil 74:711715,1993 2. Appell HJ: Muscular atrophy following immobilisation. Sports Med 10:42-58, 1990 3. Bar-Or 0:Pathophysiologic factors which limit the exercise capacity of the sick child. Med Sci Sports Exerc 18:276-282, 1986 4. Bar-Or 0: Role of exercise in the assessment and management of neuromuscular disease in children. Med Sci Sports Exerc 28:421427, 1996 5. Bonsett CA: Pseudohypertrophic muscular dystrophy: Distribution of degenerative features as revealed by anatomical study. Neurology 13:728-738, 1963 6. Carroll JE, Hagberg JM, Brooke MH, et al: Bicycle ergometry and gas exchange measurements in neuromuscular diseases. Arch Neurol 36:457461, 1979 7. DeLateur BJ, Giaconi RM: Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy. Am J Phys Med 58:26-36, 1979 8. Dolmage T, Cafarelli E: Rate of fatigue during repeated submaximal contractions of human quadriceps muscle. Can J Physiol Pharmacol 69:1410-1415, 1991 9. Edwards RHT, Jones DA, Newham DJ, et al: Role of mechanical damage in pathogenesis of proximal myopathy in man. Lancet 8376:548-551, 1984 10. Enoka ,RM: Muscle strength and its development: new perspectives. Sports Med 6:146-168, 1988 11. Emasti JM, Campbell KP: A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 122:809-823, 1993 12. Florence JM, Brooke MH, Hagberg JM, et al: Endurance exercise in neuromuscular disease. 1n Serratrice G (ed): ~eur6muscularDiseases. New York, Raven Press, 1984, pp 577-581 13. Pbw~erWM Jr, Gardner GW: Quantitative strength measurements in muscular dystrophy. Arch Phys Med Rehabil48:629-644, 1967 14. Fowler WM Jr, Abresch RT, Koch TR, et al: Employment profiles in neuromuscular diseases. Am J Phys Med Rehabil 76:2&37, 1997
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15. Fowler WM Jr., Taylor M: Rehabilitation management of muscular dystrophy and related disorders: I. The role of exercise. Arch Phys Med Rehabil 63319-321, 1982 16. Friden J, Lieber RL: Structural and mechanical basis of exercise-induced muscle injury. Med Sci Sports Exerc 24:521-530, 1992 17. Haller RG, Lewis SF: Pathophysiology of exercise performance in muscle disease. Med Sci Sports Exerc 16:456459, 1984 18. Hickok RJ: Physical therapy as related to peripheral nerve lesions. Phys Ther Rev 41:113-117,1961 19. Hoberman M: Physical medicine and rehabilitation: its value and limitations in progressive muscular dystrophy. Am J Phys Med 34109-115, 1955 20. Hoffman EP, Brown RH Jr, Kunkel LM: Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919-928, 1987 21. Johnson EW, Braddom R: Over-work weakness in facioscapulohumeral muscular dystrophy. Arch Phys Med Rehabil52:333-336, 1971 22. Kilmer DD, Abresch RT, Fowler WM Jr: Serial manual muscle testing in Duchenne muscular dystrophy. Arch Phys Med Rehabil 74:1168-1171, 1993 23. Kilmer DD, McCrory MA, Wright NC, et al: The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Arch Phys Med Rehabil75:560563, 1994 24. Kilmer DD, Abresch RT, McCrory MA, et al: Profiles of neuromuscular diseases: Facioscapulohumeral muscular dystrophy. Am J Phys Med Rehabil74:S131-Sl39,1995 25. Kilmer DD, McDonald CM: Childhood progressive neuromuscular disease. In Goldberg B (ed): Sports and Exercise for Children with Chronic Health Conditions. Champaign IL, Human Kinetics, 1995, pp 109-121 26. Kilmer DD, McCrory MA, Wright NC, et al: Reliability of hand-held dynamometry in persons with neuropathic weakness. Arch Phys Med Rehabil, in press. 27. Larsson L, Tesch PA: Motor unit fibre density in extremely hypertrophied skeletal muscle in man: electrophysiological signs of muscle fibre hyperplasia. Eur J Appl Physiol 55:130-136, 1986 28. Lenman JA: A clinical and experimental study of the effects of exercise on motor weakness in neurological disease. J Neurol Neurosurg Psychiatry 22:182-194, 1959 29. Leon AS, Connett J: Physical activity and 10.5 year mortality in the Multiple Risk Factor Intervention Trial (MRFIT). Int J Epidemiol20:690-697, 1991 30. Lindeman E, Leffers P, Spaans F, et al: Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: A randomized clinical trial. Arch Phys Med Rehabil 76:612-620, 1995 31. McCartney N, Moroz D, Gamer SH, et al: The effects of strength training in patients with selected neuromuscular disorders. Med Sci Sports Exerc 20:362-368, 1988 32. McComas AJ, Miller RG, Gandevia SC: Fatigue brought on by malfunction of the central and peripheral nervous systems. In Gandevia SC (ed): Fatigue. New York, Plenum Press, 1995, pp 495-512 33. McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in submission 34. McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Duchenne muscular dystrophy. Am J Phys Med Rehabil 74:S70-S92, 1995 35. Milner-Brown HS, Miller RG: Muscle strengthening through high-resistance weight training in patients with neuromuscular disorders. Arch Phys Med Rehabil 6931419, 1988 36. Powell KE, Thompson PD, Caspersen CJ, et al: Physical activity and the incidence of coronary heart disease. Ann Rev Pub Health 8:253-287,1987 37. Sale DG: Neural adaptation to resistance training. Med Sci Sports Exerc 20:S135S145, 1988 38. Sanjak M, Paulson D, Sufit R, et al: Physiologic and metabolic response to progressive and prolonged exercise in amyotrophic lateral sclerosis. Neurology 371217-1220, 1987 39. Scott OM, Hyde SA, Goddard C, et al: Effect of exercise in Duchenne muscular dystrophy: Controlled six-month feasibility study of effects of two different regimes of exercises in children with Duchenne dystrophy. Physiotherapy 67174176, 1981
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40. Sharma KM, Mynhier MA, Miller RG: Muscular fatigue in Ducheme muscular dystrophy. Neurology 45:306-310, 1995 41. Sharma KR, Kent-Braun JA, Majumdar S, et al: Physiology of fatigue in amyotrophic lateral sclerosis. Neurology 45:733-740, 1995 42. Silva AC, Russo AK, Picarro IC, et al: Cardiorespiratory responses to exercise in patients with spinal muscular atrophy and limb-girdle dystrophy. Brazilian J Med Biol Res 20:565-568, 1987 43. Sockolov R, Irwin B, Dressendorfer RH, et al: Exercise performance in 6-to-11-year-old boys with Duchenne muscular dystrophy. Arch Phys Med Rehabil58:195-201,1977 44. Vignos PJ Jr, Watkins MP: Effect of exercise in muscular dystrophy. JAMA 197:843848, 1966 45. Vignos PJ Jr: Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 6:323-338,1983 46. Wagner M, Vignos PJ Jr, Fonow D: Serial isokinetic evaluations used for a patient with scapuloperoneal muscular dystrophy. A case report. Phys Ther 66:111@1113,1986 47. Wratney MJ: Physical therapy for muscular dystrophy children. Phys Ther Rev 38:2& 32, 1958 48. Wright NC, Kilmer DD, McCrory MA, et al: Aerobic walking in slowly progressive neuromuscular disease: Effect of a 12-week program. Arch Phys Med Rehabil 77:6469, 1996 Address reprint requests to David D. Kilmer, MD Department of Physical Medicine and Rehabilitation University of California, Davis Medical Center 4301 X Street, Room 2030 Sacramento, CA 95817
1047-9651 198 $8.00
+ .OO
THE ROLE OF EXERCISE IN NEUROMUSCULAR DISEASE David D. Kilmer, MD
In the past several decades, the real benefits of regular physical exercise for the able-bodied population have been shown, including improved strength and endurance for daily activities as well as modification of risk factors for cardiac disease. However, research is clearly lacking in determining whether persons with such disabilities as hereditary neuromuscular disease (NMD) respond to exercise training in a similar beneficial manner, and, if so, whether the adaptations augment their ability to perform work and enjoy avocational activities. Although it has been presumed to be caused by their weakness and fatigability, recent work suggests that persons with NMD usually have a sedentary lifestyle.33Reasons for this are complex; it cannot simply be ascribed to the primary disease. First, habitual exercise patterns and interest in sporting activities often occur during the school years, where these people may not even participate in physical education. Wellmeaning parents, teachers, and physicians, concerned that exercise may actually be detrimental, caution the child or adolescent against physical exertion. The result is a sedentary adult who suffers not only from weakness due to loss of muscle fibers, but from the additional component of disuse weakness. This is frequently compounded by lack of the foundation of motor skills in typical sports and games first learned by others during childhood and adolescence. Finally, persons with NMD This work was supported by Research and Training Grant H133B0026-96 from the National Institute on Disability and Rehabilitation Research (NIDRR), United States Department of Education.
From the Department of Physical Medicine and Rehabilitation, University of California, Davis Medical Center, Sacramento, California
PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA VOLUME 9 . NUMBER 1 FEBRUARY 1998
115
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KILMER
have lower levels of employment, resulting in limited financial resources to join fitness clubs, purchase equipment, and travel to events.14 The main questions this article seeks to address are: (1) how does the person with NMD respond to strengthening and aerobic (endurance) exercise; (2) what evidence exists that exercise may actually be harmful; and (3) how do we encourage this population to participate in physical activity and sport?
RESPONSE TO STRENGTHENING EXERCISE The response of intact skeletal muscle to strengthening (resistance) exercise is well delineated. With muscle overload, there is an initial catabolic response with some disruption of muscle fibers. The muscle adapts by synthesizing new myofibrillar proteins, with little change in the oxygen transport system or mitochondria1 density. The result of increased myofibril size and number is greater cross-sectional muscle fiber area, resulting in muscle hypertrophy, with the ability to resist higher loads. The response is thought to be highly specific to the type of resistance exercise. Some debate exists about the capacity for human but the general belief is that there is very muscle fiber hyperpla~ia?~ limited if any ability in an adult to increase the number of muscle fibers with training. Although muscle hypertrophy appears to be the dominant mechanism for strength gains with long-term it has been shown clearly that strength improvements occur shortly after starting a strengthening program, before hypertrophy can possibly occur. These strength gains without structural changes in muscle are likely due to neural adaptations, primarily relating to more efficient motor unit recruitment from improved coordination, learning, and activation of prime movers.10 Muscle weakness is the final outcome of all neuromuscular disease. Individual NMD frequently are identified by their pattern of weakness and family history; however, electromyographic findings and microscopic pathology may be quite similar among slowly progressive myopathic or neuropathic disorders. This, along with the relative rarity of the diseases, requires researchers frequently to group the disorders together when investigating responses to training and giving recommendations. Along with loss of skeletal muscle fibers, atrophy of disuse is thought to be frequent in persons with NMD.45Disused muscle fibers lose myofibril size, resulting in reduced fiber cross-sectional area, less Thus, the response to force production, and reduced muscle enduran~e.~ strengthening exercise may include an element of reversing the effects of disuse as well as altering the natural history of the NMD itself.
THE ROLE OF EXERCISE IN NEUROMUSCULAR DISEASE
117
Overwork Weakness First identified with patients recovering from polio, weakness associated with excessive physical activity is a major concern among patients and clinicians with NMD.15,45 There are descriptions of prolonged increased weakness following strengthening exercise in ALSF8 peripheral nerve lesions,ls and Duchenne muscular dy~trophy.~ The dominant upper limb has been found to be weaker in persons with facioscapulohumeral muscular dystrophy than the nondominant with heavy upper extremity use, providing circumstantial evidence for overwork.21,23 A single subject with scapuloperoneal dystrophy had a reversal of rapid strength decline after reducing daily physical activity.46It should be noted that these are all case reports, and overwork weakness has not been demonstrated in a controlled prospective study using exercise regimens.
Methods of Evaluating Strength Although the clinician typically uses the manual muscle test (MMT) during strength assessment of these patients, this evaluation has a limited role in understanding the progression of disease.22,32 Quantitative muscle testing is necessary to evaluate the response to an exercise intervention. This limits the usefulness of early intervention studies using MMT in NMD subject^.'^, 47 The simplest means of quantitative muscle testing is to measure static, isometric contractions using cable tensiometers or dynamometers.13,26 These devices provide reliable data, but measure strength at only one joint angle, thus limiting real-world application. Another method involves the maximal amount of weight the subject can lift one time. More recently, elegant devices to determine isokinetic strength by measuring maximal force at a preset velocity have been used with NMD patients; these have provided information on both shortening (concentric) and lengthening (eccentric) contraction^.^^ Good reliability has been shown in this population using both types of data, particularly for uniplanar joints such as the knee and elbow. Strength of the shoulder, wrist, and ankle musculature in specific motions, although important functionally, is more difficult to isolate, making these dynamometers and measurements less reliable. Strength testing at these joints may be better suited to the hand-held myometer, which can be used in the clinic.26 Measures of fatigue and endurance, for example using the number of contractions at a given submaximal resistance level, are less well studied and are not likely to be nearly as reliable. This is unfortunate because muscular endurance is more likely to be relevant to performance of daily activities than any measurement of maximal strength. Regardless of method, impressive strength gains usually are measured over the first several weeks of a training protocol. Since physio-
118
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logic changes cannot occur at the muscle fiber level this quickly, these gains are presumed to be due to improved motor planning and synchronization of motor unit firing with learning. Actual strength gains from muscle fiber hypertrophy occur after several weeks. Strengthening Exercise: Rapidly Progressive Disorders
In Duchenne muscular dystrophy (DMD), there is a rapid progression of strength loss both qualitatively and quantitatively." The child typically requires a wheelchair for mobility between the ages of 8 and 12. Because of this rapid progression, these children usually cannot participate with their peers in the normal physical activities involved in play and exploration of their environment, often leading to isolation and lack of social d e ~ e l o p m e n tA . ~desirable ~ role for strengthening exercise is to slow the rate of progression of weakness, allowing more natural development. Because of the rapid progression, a control group is a desirable but rarely obtained component of intervention studies. Strengthening intervention studies with DMD patients generally have shown maintenance of strength or even mild improvement in strength over the period of the investigation. However, these studies are limited by use of primarily nonquantitative measure^,^“ lack of a control and use of the opposite limb as a control without considering the effects of cross-training7 Other problems include variations in the type and intensity of resistance training and duration of follow-up. Interestingly, no systematic studies using this population have shown any deleterious effects of resistance exercise. Thus, based on limited data one may conclude that resistance training can maintain one-repetition strength in DMD patients. However, owing to the relative paucity of investigations, it is prudent to recommend a submaximal strengthening program. A great concern is how to incorporate these activities effectively into the daily routine of the child, avoiding use of mundane and tedious regimens that employ resistive weights and pulleys.25 With the advances in molecular genetics and possible identification of abnormal gene products, more rational and specific approaches should be taken in designing exercise protocols and understanding potential deleterious effects. As an example, it is now known that DMD patients lack a structural protein of the muscle cell membrane called d y ~ t r o p h i nThis . ~ ~ protein appears to be essential to maintain the cytoskeletal framework of the muscle fiber during muscle contraction." Muscle actions known to stress the cytoskeletal elements of the fiber, such as strong eccentric contractions, are likely to enhance breakdown of the muscle fiber.16 With this knowledge, future resistance exercise regimens will need to assess carefully the amount of such contractions being performed. Indeed, Edwards et a19proposed that routine eccentric
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contractions occurring during gait are a likely source of the pattern of weakness typically seen in myopathies. The other rapidly progressive NMD to consider is ALS. However, because of its variable progression and bulbar involvement, systematic strengthening exercise intervention studies have not been performed with these patients. Clinicians generally recommend a submaximal strengthening program for patients who are motivated to engage in these activities in the hope of attenuating strength loss. Strengthening Exercise: Slowly Progressive Disorders
In slowly progressive hereditary neuromuscular disorders, the goal of strengthening intervention studies has been to improve patient strength rather than simply to retard strength loss. Because of the rarity of these diseases, most studies have grouped different NMDs together in order to obtain adequate numbers for analysis. A presumption of these studies is that improving strength gives patients more reserve to perform daily tasks-a yet-untested hypothesis. Vigx-10~~~ used high-resistance exercise in both rapidly and slowly progressive NMD, and found greater strength improvements in the less severe disorders. This tendency toward greater improvement with stronger patients also was found by Milner-Brown and colleagues, who reported that high-resistance weight training produced improvement in strength measured isometrically, generally in muscles with more than 10% of normal strength." McCartnev and associates demonstrated substantial increases in gtrength of subfects with slowly progressive NMD using a carefully controlled regimen over 9 weeks.31 To ensure safety, only supervised strengthening programs in this vovulation have been advocated.45In order to test the effects of a less supervised approach, a moderate resistance home exercise program was devised that demonstrated similar strength gains in both patients and normal control subjects without evidence of overwork weakness.' Based on this encouraging result, the home program was advanced to highresistance training in similar subjects without apparent additive beneficial effects; in fact, eccentrically measured elbow flexor strength actually decreased signifi~antly.~~ Limitations of the above studies include lack of a disease control group and inclusion of subjects with a variety of slowly progressive disorders, each with unique pathophysiologic characteristics. Recently a Dutch group limited their investigation to myotonic muscular dystrophy (MMD) and hereditary motor and sensory neuropathy (HMSN), using nonexercising controls; they demonstrated modest gains in both strength and function of the HMSN group but no improvements in the MMD Of note, no untoward effects were demonstrated in either group. The design of this study, using measures of functional performance as well as static strength, should be a model for future investigaL
1
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tions. Undoubtedly a multicenter approach will be required to obtain adequate numbers of subjects with the rarer disorders. Based on the above investigations, we now have adequate evidence to generally advocate a submaximal strengthening program for persons with slowly progressive NMD. There seems to be no additional benefit to high-resistance low repetition training sets, and the risk of actually increasing weakness becomes greater. Not adequately addressed by these studies are the benefits conferred by improving maximal strength. For example, attenuating fatigue during prolonged submaximal work may be the most important factor in improving daily work capacity in these patients. Compliance with lifting weights could certainly improve if clinicians were able to provide this evidence to their patients supported by a rational scientific basis. RESPONSE TO AEROBIC EXERCISE
Aerobic exercise refers to rhythmic, prolonged activity at a level sufficient to provide a beneficial training stimulus to the cardiopulmonary and muscular systems but below the threshold where anaerobic metabolism of fuels is the primary source of energy. The response of normal skeletal muscle to this type of training includes: increased capillary density in the muscle to improve substrate transfer increased skeletal muscle mitochondria1 size and density higher concentrations of skeletal muscle oxidative enzymes improved utilization of fat as an energy source for muscular activity Clearly, patients with neuromuscular diseases have diminished capacity for exercise. In Duchenne dystrophy, Sockolov et a1 demonstrated low cardiorespiratory capacity and peripheral oxygen utilization with higher resting heart rate compared with controls.43Similarly, in amyotrophic lateral sclerosis, maximal oxygen uptake and work capacity were diminished in proportion to loss of muscle strength and functional score. There was elevated oxygen cost of submaximal exercise as well.38 In slowly progressive NMD, similar although less marked findings are present with aerobic exercise testing. There is significantly reduced maximal work capacity," and the limiting factor appears to be loss of functional muscle mass rather than defects in the oxygen transport system.42Thus, it is no surprise that patients with Duchenne dystrophy have lower maximal oxygen uptakes than do those with the less severe FSH dystrophy.17However, physical ability is likely more limited by loss of muscle strength than by deterioration of cardiorespiratory f ~ n c t i o n . ~ Methods of Measurement
The traditional method of assessing aerobic capacity is measurement of maximal oxygen uptake using a treadmill or bicycle ergometer, incre-
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mentally increasing the workload. However, NMD patients with significant lower extremity weakness often cannot tolerate these devices owing to poor balance or rapid fatigue, leading to an inability to reach a maximal response. For these reasons, a recumbent bicycle ergometer has been utilized4*that allows measurement of a submaximal or peak aerobic response. Some argue that focus on maximal aerobic capacity is misguided, since maximal aerobic power is seldom a limiting factor in the ability to perform daily living tasks.4 Muscle strength, endurance, and peak mechanical power are thought to be more relevant in assessing ability for these tasks.
Response to Aerobic Training
Like studies of muscle strengthening, investigations dealing with aerobic training have grouped disorders together, resulting in some ambiguity when considering a patient with a specific disease. For example, ~lorenceand colleagues, using a 3-month stationary bicycle training program, found an average 21% improvement in maximal oxygen uptake in subjects with different slowly progressive NMD.12 However, there was a wide variation in improvement, ranging from -2% to 47%, with several subjects possibly exhibiting signs of muscle damage. Conclusions could not be drawn because of the small numbers of patients. In a more recent study using a home-based aerobic walking program in subjects with a variety of slowly progressive disorders, several parameters suggested modest improvements in aerobic capacity without evidence of overwork weakness or excessive fatigue.48To be more meaningful to individual patients, future intervention trials should focus on individual disorders. In addition, more work is needed on the oxygen cost of certain activities, such as walking, owing to the altered mechanics and muscle substitutions that make even routine activities difficult for any prolonged period. FATIGUE IN NEUROMUSCULAR DISEASE
On careful questioning, patients with NMD frequently complain that their weakness is not manifested by the inability to lift an object one time; rather, they become so fatigued after any attempt at continuous exercise or work that they abandon all future attempts. Despite this common symptom, investigators largely ignore the origin and treatment of fatigue in these patients, probably because of difficulties in study design and the effort-dependent nature of the protocols. In addition, the complex relationship between primary fatigue from the NMD and secondary fatigue due to disuse must be ~ o n s i d e r e d Recently, .~~ some investigators have attempted to look directly at the muscle's role in fatigue by using the twitch interpolation technique, thus bypassing
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voluntary activation of the muscle and differentiating central from peripheral fatigue. If muscles are weak, they are forced to work at a higher percentage of their maximal strength to perform the same activity as the ablebodied. This will hasten the time of the muscle to fatigue: and is undoubtedly the source of fatigue in patients with significant loss of muscle strength. Further investigation of fatigue has been performed in Duchenne muscular dystrophy (DMD). Using a 4-minute sustained voluntary contraction of the tibialis anterior, Sharma and colleagues found no differences between control and DMD patients in intramuscular fatigue and excitation-contraction Thus, there was no evidence for specific abnormality of the muscle membrane, myoneural junction, or contractile process in this myopathy. Fatigue was examined by the same group in the denervating disorder of ALS.41Although maximal voluntary and tetanic force declined more during the sustained contraction in the ALS group compared with the control, no impairment was found in neuromuscular transmission or the muscle membrane. The authors concluded that muscle fatigue resulted from activation impairment, at least partly from alterations in excitation-contraction coupling. Future exercise studies should incorporate reliable measures of fatigue as another outcome variable along with measures of functional performance. It is no longer sufficient to show strength improvements; we must quantify the changes in a patient's ability to work and enjoy physical activities. EXERCISE RECOMMENDATIONS FOR PERSONS WITH NMD
The reasons for advocating an active life-style extend beyond improving work capacity and endurance in this patient population. It is now clear that physically inactive people have twice the risk of coronary heart disease than the more active p ~ p u l a t i o nBut . ~ ~how much exertion is necessary? Recommendations have been modified in this area, and even low levels of activity including walking and gardening, although not altering one's maximal oxygen uptake, can provide considerable benefit to reducing the risk of coronary artery disease.29 In selecting a recreational activity for a person disabled with neuromuscular disease, several issues should be considered: Is the activity appropriate for the person's level of weakness or are there methods to adapt the sport to their needs? Can the sport be continued as the person's weakness progresses? Are there opportunities for social development and personal accomplishment? What are the costs? Is the sport varied enough to maintain long-term interest?
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An example is disabled snow skiing, which offers tremendous capacity for personal and social satisfaction. Through organizations such as Disabled Sports USA, persons with weakness ranging from mild to severe can be provided with adaptive equipment and instruction at a reasonable cost. However, these types of recreational experiences should be recommended in combination with a daily active life-style that follows the principles of energy conservation, alternating periods of physical activity with scheduled rest. CONCLUSIONS
Although research shows that strength and endurance exercise regimens may have beneficial effects in persons with NMD, participation continues to be poor. We must overcome the psychologic and social barriers that make this population sedentary. Physical activity should be viewed as a way of improving quality of life, not a tedious and exhausting set of exercises. Educating physicians as well as other health care, educational, and vocational professionals is the first step in motivating our patients to adopt a vigorous life-style. References 1. Aitkens SG, McCrory MA, Kilmer DD, et al: Moderate resistance exercise program: Its effect in slowly progressive neuromuscular disease. Arch Phys Med Rehabil 74:711715,1993 2. Appell HJ: Muscular atrophy following immobilisation. Sports Med 10:42-58, 1990 3. Bar-Or 0:Pathophysiologic factors which limit the exercise capacity of the sick child. Med Sci Sports Exerc 18:276-282, 1986 4. Bar-Or 0: Role of exercise in the assessment and management of neuromuscular disease in children. Med Sci Sports Exerc 28:421427, 1996 5. Bonsett CA: Pseudohypertrophic muscular dystrophy: Distribution of degenerative features as revealed by anatomical study. Neurology 13:728-738, 1963 6. Carroll JE, Hagberg JM, Brooke MH, et al: Bicycle ergometry and gas exchange measurements in neuromuscular diseases. Arch Neurol 36:457461, 1979 7. DeLateur BJ, Giaconi RM: Effect on maximal strength of submaximal exercise in Duchenne muscular dystrophy. Am J Phys Med 58:26-36, 1979 8. Dolmage T, Cafarelli E: Rate of fatigue during repeated submaximal contractions of human quadriceps muscle. Can J Physiol Pharmacol 69:1410-1415, 1991 9. Edwards RHT, Jones DA, Newham DJ, et al: Role of mechanical damage in pathogenesis of proximal myopathy in man. Lancet 8376:548-551, 1984 10. Enoka ,RM: Muscle strength and its development: new perspectives. Sports Med 6:146-168, 1988 11. Emasti JM, Campbell KP: A role for the dystrophin-glycoprotein complex as a transmembrane linker between laminin and actin. J Cell Biol 122:809-823, 1993 12. Florence JM, Brooke MH, Hagberg JM, et al: Endurance exercise in neuromuscular disease. 1n Serratrice G (ed): ~eur6muscularDiseases. New York, Raven Press, 1984, pp 577-581 13. Pbw~erWM Jr, Gardner GW: Quantitative strength measurements in muscular dystrophy. Arch Phys Med Rehabil48:629-644, 1967 14. Fowler WM Jr, Abresch RT, Koch TR, et al: Employment profiles in neuromuscular diseases. Am J Phys Med Rehabil 76:2&37, 1997
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15. Fowler WM Jr., Taylor M: Rehabilitation management of muscular dystrophy and related disorders: I. The role of exercise. Arch Phys Med Rehabil 63319-321, 1982 16. Friden J, Lieber RL: Structural and mechanical basis of exercise-induced muscle injury. Med Sci Sports Exerc 24:521-530, 1992 17. Haller RG, Lewis SF: Pathophysiology of exercise performance in muscle disease. Med Sci Sports Exerc 16:456459, 1984 18. Hickok RJ: Physical therapy as related to peripheral nerve lesions. Phys Ther Rev 41:113-117,1961 19. Hoberman M: Physical medicine and rehabilitation: its value and limitations in progressive muscular dystrophy. Am J Phys Med 34109-115, 1955 20. Hoffman EP, Brown RH Jr, Kunkel LM: Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell 51:919-928, 1987 21. Johnson EW, Braddom R: Over-work weakness in facioscapulohumeral muscular dystrophy. Arch Phys Med Rehabil52:333-336, 1971 22. Kilmer DD, Abresch RT, Fowler WM Jr: Serial manual muscle testing in Duchenne muscular dystrophy. Arch Phys Med Rehabil 74:1168-1171, 1993 23. Kilmer DD, McCrory MA, Wright NC, et al: The effect of a high resistance exercise program in slowly progressive neuromuscular disease. Arch Phys Med Rehabil75:560563, 1994 24. Kilmer DD, Abresch RT, McCrory MA, et al: Profiles of neuromuscular diseases: Facioscapulohumeral muscular dystrophy. Am J Phys Med Rehabil74:S131-Sl39,1995 25. Kilmer DD, McDonald CM: Childhood progressive neuromuscular disease. In Goldberg B (ed): Sports and Exercise for Children with Chronic Health Conditions. Champaign IL, Human Kinetics, 1995, pp 109-121 26. Kilmer DD, McCrory MA, Wright NC, et al: Reliability of hand-held dynamometry in persons with neuropathic weakness. Arch Phys Med Rehabil, in press. 27. Larsson L, Tesch PA: Motor unit fibre density in extremely hypertrophied skeletal muscle in man: electrophysiological signs of muscle fibre hyperplasia. Eur J Appl Physiol 55:130-136, 1986 28. Lenman JA: A clinical and experimental study of the effects of exercise on motor weakness in neurological disease. J Neurol Neurosurg Psychiatry 22:182-194, 1959 29. Leon AS, Connett J: Physical activity and 10.5 year mortality in the Multiple Risk Factor Intervention Trial (MRFIT). Int J Epidemiol20:690-697, 1991 30. Lindeman E, Leffers P, Spaans F, et al: Strength training in patients with myotonic dystrophy and hereditary motor and sensory neuropathy: A randomized clinical trial. Arch Phys Med Rehabil 76:612-620, 1995 31. McCartney N, Moroz D, Gamer SH, et al: The effects of strength training in patients with selected neuromuscular disorders. Med Sci Sports Exerc 20:362-368, 1988 32. McComas AJ, Miller RG, Gandevia SC: Fatigue brought on by malfunction of the central and peripheral nervous systems. In Gandevia SC (ed): Fatigue. New York, Plenum Press, 1995, pp 495-512 33. McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in submission 34. McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Duchenne muscular dystrophy. Am J Phys Med Rehabil 74:S70-S92, 1995 35. Milner-Brown HS, Miller RG: Muscle strengthening through high-resistance weight training in patients with neuromuscular disorders. Arch Phys Med Rehabil 6931419, 1988 36. Powell KE, Thompson PD, Caspersen CJ, et al: Physical activity and the incidence of coronary heart disease. Ann Rev Pub Health 8:253-287,1987 37. Sale DG: Neural adaptation to resistance training. Med Sci Sports Exerc 20:S135S145, 1988 38. Sanjak M, Paulson D, Sufit R, et al: Physiologic and metabolic response to progressive and prolonged exercise in amyotrophic lateral sclerosis. Neurology 371217-1220, 1987 39. Scott OM, Hyde SA, Goddard C, et al: Effect of exercise in Duchenne muscular dystrophy: Controlled six-month feasibility study of effects of two different regimes of exercises in children with Duchenne dystrophy. Physiotherapy 67174176, 1981
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40. Sharma KM, Mynhier MA, Miller RG: Muscular fatigue in Ducheme muscular dystrophy. Neurology 45:306-310, 1995 41. Sharma KR, Kent-Braun JA, Majumdar S, et al: Physiology of fatigue in amyotrophic lateral sclerosis. Neurology 45:733-740, 1995 42. Silva AC, Russo AK, Picarro IC, et al: Cardiorespiratory responses to exercise in patients with spinal muscular atrophy and limb-girdle dystrophy. Brazilian J Med Biol Res 20:565-568, 1987 43. Sockolov R, Irwin B, Dressendorfer RH, et al: Exercise performance in 6-to-11-year-old boys with Duchenne muscular dystrophy. Arch Phys Med Rehabil58:195-201,1977 44. Vignos PJ Jr, Watkins MP: Effect of exercise in muscular dystrophy. JAMA 197:843848, 1966 45. Vignos PJ Jr: Physical models of rehabilitation in neuromuscular disease. Muscle Nerve 6:323-338,1983 46. Wagner M, Vignos PJ Jr, Fonow D: Serial isokinetic evaluations used for a patient with scapuloperoneal muscular dystrophy. A case report. Phys Ther 66:111@1113,1986 47. Wratney MJ: Physical therapy for muscular dystrophy children. Phys Ther Rev 38:2& 32, 1958 48. Wright NC, Kilmer DD, McCrory MA, et al: Aerobic walking in slowly progressive neuromuscular disease: Effect of a 12-week program. Arch Phys Med Rehabil 77:6469, 1996 Address reprint requests to David D. Kilmer, MD Department of Physical Medicine and Rehabilitation University of California, Davis Medical Center 4301 X Street, Room 2030 Sacramento, CA 95817