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Review

Journal of

CLINICAL NEUROMUSCULAR DISEASE


Volume 5, Number 1 September 2003

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Exercise in Neuromuscular Disease


Lisa S. Krivickas, MD
Abstract
In the past, patients with neuromuscular diseases were advised not to exercise because of the fear that too much exercise might produce overuse weakness. No controlled studies have demonstrated that the phenomenon of overuse weakness actually exists. Most studies of exercise training in patients with neuromuscular disease, despite methodologic limitations, suggest that strength and aerobic capacity gains can occur in patients with slowly progressive disorders. Four forms of exercise training are relevant to patients with neuromuscular disorders: flexibility, strengthening, aerobic, and balance exercises. The literature regarding these forms of exercise in patients with neuromuscular disorders is summarized in this article, and recommendations are made regarding the direction future research on exercise in this population should take.

EXERCISE CONSIDERATIONS IN NEUROMUSCULAR DISEASE


Several factors must be considered when assessing the ability of patients with neuromuscular disease (NMD) to participate in and benefit from an exercise program. The specific diagnosis and rate of disease progression will affect the response to exercise. One might expect patients with neuropathic disorders to respond differently than those with myopathic disorders. In rapidly progressive diseases such as Duchenne muscular dystrophy (DMD) and amyotrophic lateral sclerosis (ALS), slowing of disease progression (ie, the rate at which functional impairment develops) might be considered a positive outcome. In more slowly progressive diseases, a positive outcome might be actual gain of strength or aerobic exercise capacity. The age of the patient, baseline strength, and baseline physical activity level also affect the response to an exercise program. The cardiopulmonary health of the patient and/or medications might limit exercise. For example, the cardiomyopathy associated with some muscular dystrophies and the restrictive lung disease associated with both dystrophies and anterior horn cell disorders might limit aerobic capacity. Medications such as betablockers can limit aerobic exercise capacity. All of these factors must be considered when designing studies to investigate the role of exercise in patients with NMD. It will become clear from the following review of the literature that much additional research needs to be done regarding the safety and potential benefits of exercise for patients with NMD. A key question that has not been entirely answered is whether overuse weakness develops. The basis for clinicians belief in this phenomenon is a few iso-

(J Clin Neuromusc Dis 2003;5:2939)

or many years, patients with progressive neuromuscular diseases were advised not to exercise because of the fear that too much exercise might hasten the progression of their weakness by producing overuse weakness. A critical review of the literature reveals only isolated case reports suggesting that overuse weakness occurs. No controlled studies have demonstrated that this phenomenon actually exists. In fact, most studies of exercise in patients with a variety of neuromuscular diseases, despite methodologic limitations, suggest that strength gains can occur as a result of exercise training in patients with slowly progressive disorders. Whether these strength gains translate into a functional benefit is less clear. Four forms of exercise training are relevant to patients with neuromuscular disorders: flexibility, strengthening, aerobic, and balance exercises. The literature regarding these forms of exercise in patients with neuromuscular disorders is summarized in this article.

From the Department of Physical Medicine and Rehabilitation, Harvard Medical School Director, Electrodiagnostic Services, Spaulding Rehabilitation Hospital, Boston, Massachusetts. Reprints: Lisa S. Krivickas, MD, Spaulding Rehabilitation Hospital, 125 Nashua Street, Boston, MA 02114-1101 (e-mail: lkrivickas@partners.org). Copyright 2003 by Lippincott Williams & Wilkins

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lated case reports. Bennett and Knowlton reported overuse weakness in 4 patients with a history of polio and 1 with spinal cord injury; the nature of the new weakness was not clearly determined, and it might have been the result of entrapment neuropathy or muscle strain.1 Johnson and Braddom observed that patients with facioscapulohumeral dystrophy (FSHD) tend to be weaker in the dominant upper extremity and speculated that this might be related to overuse.2 Other questions that require definitive answers are whether exercise training can improve strength, aerobic fitness, function in activities of daily living, quality of life, and mood in patients with NMD. When evaluating studies of exercise in patients with neuromuscular disease, particular attention must be given to the specific exercise prescription; the measurement methods used to determine strength, aerobic capacity, flexibility, and balance; and the specificity of the exercise and outcome measurement methods. The exercise prescription should include the form of exercise, intensity, duration, and frequency of training sessions. A quantitative reproducible method for measuring strength must be used in any strength training study, and the method for measuring strength should be as close to the training method as possible. For instance, if a study involves primarily dynamic exercise (such as lifting dumbbells), dynamic rather than static strength should be used as an outcome measure. Ideally, studies should be randomized and have a non-exercising control group with the same disease and baseline characteristics. Unfortunately, few randomized studies have been performed, and one of the research challenges is convincing patients with NMD to agree to be randomized to a non-exercising control group.3

neuromuscular diseases, it is widely accepted that this form of exercise helps prevent the development of contractures. Contractures might place weak muscles at a biomechanical disadvantage, further impairing their function. For example, a patient with a hip flexion contracture and weak quadriceps might be able to reduce the load on his quadriceps and improve his gait by decreasing the hip flexion contracture. Contractures might also produce pain and interfere with positioning and the performance of activities of daily living (ADLs). Contractures typically develop in the shoulder when patients are too weak to raise their arms overhead and in the hips, knees, and ankles when patients spend most of their day in a wheelchair. Loss of range of motion can result in a painful frozen shoulder syndrome and even Complex Regional Pain Syndrome.4 In patients with upper motor neuron pathology, such as those with ALS, stretching can nonpharmacologically decrease spasticity and abort painful muscle spasms. Furthermore, if spastic muscles are not stretched regularly, contractures will develop. Spasticity decreases flexibility through hyperactivity of the muscle spindle reflex and of suprasegmental reflexes resulting in a reduced active range of motion. A final benefit of ROM exercises is that they stimulate joint and cartilage blood flow enhancing the health and lubrication of the joint in both healthy individuals and those with NMD.

STRENGTHENING EXERCISE
There are several forms of strengthening exercise, and some may be safer than others for patients with NMD. Strengthening exercises can be classified as static or dynamic. Static, also known as isometric, exercises are those performed at a constant muscle length such as quadriceps setting or a straight leg raise using ankle weights to strengthen the quadriceps. Dynamic exercise involves joint movement. Dynamic muscle actions might be described as isotonic, isokinetic, concen-

FLEXIBILITY TRAINING
Flexibility training involves stretching and range of motion (ROM) exercises. Although there is little scientific literature on the role of flexibility training in patients with
2003 Lippincott Williams & Wilkins

Exercise in Neuromuscular Disease

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tric, and eccentric. Isotonic muscle actions imply constant force production, which rarely or never occurs in real life settings. Despite this, the term isotonic contraction pervades the literature and is used to describe exercises in which a constant weight, such as a dumbbell, is lifted. The term isotonic is used in this manner throughout this article because it is used in this way in many of the studies reviewed. Isokinetic muscle actions are those performed at a constant velocity and require the use of specially designed exercise machines. Concentric actions are those in which the muscle shortens as it produces force, and eccentric actions are those in which the muscle lengthens as it produces force. Elbow flexion using a dumbbell (a curl) is a concentric action of the biceps muscle; if the weight is then slowly lowered by extending the elbow, an eccentric muscle action of the biceps occurs. Eccentric muscle actions are more efficient than concentric actions and generate more force at a given level of exertion. In healthy individuals, a heavy bout of eccentric exercise can produce a long-lasting decrease in muscle twitch tension and elevated serum creatine kinase (CK). Muscle fiber necrosis and mononuclear cell infiltration may be seen on muscle biopsy specimens for up to 20 days after such a bout of exercise. In healthy individuals, this muscle damage serves as a stimulus for hypertrophy. However, in patients with muscle diseases affecting the cell membrane, such as the dystrophinopathies and sarcoglycanopathies, there is concern that the damage might not be repairable. Although there is no human datum addressing this issue, animal studies suggest that this concern is valid. In one study, mdx mice experienced an irreversible loss of force generating capacity after eccentric exercise.5 Both muscular and neural adaptations occur in response to strength training as outlined in Table 1. Muscular adaptations take at least 6 to 8 weeks to develop. Neural adaptations may occur in as little as 2 weeks and account for early strength gains when a training program is initiated. Cross-transference is

TABLE 1. Adaptations to Strength Training Muscular Muscle fiber hypertrophy IIX to IIA fiber type conversion Increased protein synthesis Decreased protein degradation Increased capillary density Decreased mitochondrial density Decreased lipid storage Neural Strength gain without muscle hypertrophy Increased activation Increased motor unit synchronization Cross transference

a neural adaptation in which a single limb is trained, but strength increases also occur in the contralateral untrained limb. This is an important consideration in reviewing the literature on strength training in NMD because some studies have been designed such that a single limb is exercised and the contralateral limb is used as a control. The strength training studies involving patients with NMD can be divided into those with heterogeneous patient populations (a mixture of neuropathic and myopathic disorders), those with strictly myopathic subjects, and those with strictly neuropathic subjects (primarily post-polio). Although the prescription of exercise for patients with neuromuscular junction disorders, such as myasthenia gravis, is particularly challenging, no studies have been performed with this population. The largest number of studies has been performed using patients with mixed disorders; 7 studies, enrolling a total of 141 patients, fall into this category.612 Only one of these, enrolling 62 patients, was a randomized, controlled trial.6 Information regarding the patient populations, interventions, and outcomes of several of these studies is summarized in Table 2. The studies cannot be directly compared with one another because they use different methodologies. Some used relatively high resistance training, 6,7,9 whereas others used more moderate resistance.8,10 The nonrandomized studies tend to involve unilateral exercise using the contralateral limb as a control.710 Strength gains

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TABLE 2. Strength Training Studies Patient Population Control Group Randomization


Yes

Exercise Intervention
24-week home program; knee extension and flexion with ankle weights; 3 sets of 10, 80% 1RM; 3 sessions/wk

Outcome

Reference
Lindeman et al., 1995

Mixed diagnoses 29 HMSN Non-exercising 33 MD patients

3 SMA 1 FSHD 1 LGD

Contralateral arm

No

12 MD 8 HMSN 3 LGD 2 SMA 2 FSHD

Contralateral limb in patients; 14 healthy control subjects

No

5 MD 2 HMSN 3 LGD

Contralateral limb in patients; 6 healthy control subjects

No

6 4 3 1 1 1

FSHD MD SMA LGD BMD PN

Contralateral limb in some patients

No

1. HMSN: increased isokinetic knee extension strength and walking speed 2. MD; nonsignificant isometric and isokinetic strength increases 3. Subjective benefit in HMSN and MD 4. No change in serum myoglobin 9-week supervised pro- 1. Isotonic strength gram; unilateral biincreased 34% in ceps curl and bilatbiceps, 11% in quaderal leg press; 24 riceps sets, 1012 reps, 40 2. Muscle activation 70% MVC; 3 improved sessions/wk 3. No muscle damage on biopsy or CT 12-week home pro1. Isokinetic strength gram; unilateral biincreased approxiceps and quadriceps mately 20% in quadmoderate resistance riceps, 10% in biceps dynamic exercise us2. Similar strength ing ankle and wrist gains in non-exerweights; 3 sets of 8, cised contralateral 2040% MVC; 3 limb sessions/wk 3. Similar strength gains in healthy control subjects 4. No overuse weakness 12-week home pro1. Quadriceps isokinetgram; unilateral biic strength increased ceps and quadriceps less than with modhigh-resistance dyerate resistance trainnamic exercise; 5 ing (Aitkens et al., sets of 10, 12 RM; 3 1993) sessions/wk (similar 2. Biceps lost eccentric protocol to Aitkens (? overuse weakness) et al., 1993, except 3. No patients comhigher resistance) plained of biceps weakness or soreness 13-month home pro1. Isometric strength gram; high-resistance increased 77% in dynamic exercise usquadriceps, 83% in ing ankle weights and biceps dumbbells, quadri2. Muscles strongest ceps, and biceps; 5 initially made greatsets of 612 reps, est gains 1215 RM load; 4 3. No muscles with sessions/wk 3/5 stength improved 4. No measurable strength loss in any muscles

McCartney et al., 1988

Aitkens et al., 1993

Kilmer et al., 1994

Milner-Brown and Miller, 1988

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TABLE 2. (continued) Strength Training Studies Patient Population Control Group Randomization
No

Exercise Intervention
6-month supervised program; unilateral quadriceps exercise; 30 submaximal knee extensions per session on isokinetic dynamometer; 45 session/wk 12-month home program; high-resistance exercise with weights and pulleys, multiple muscle groups; 1 set of 10 reps of 10 RM load/session; 37 sessions/wk

Outcome
Statistically nonsignificant strength improvement in all subjects

Reference
DeLateur and Giacomi, 1979

Myopathic disorders 4 DMD Contralateral limb

14 DMD 4 FSHD 6 LGD

Non-exercising No DMD boys

5 IBM

None

No

Mitochondrial None myopathy (case report)

No

12-week supervised program; high-resistance knee extension and flexion, elbow flexion, wrist flexion using variable resistance pneumatic machine; 3 sets of 10 20 reps; 3 sessions/wk 16 days supervised concentric (R arm) and eccentric (L arm) training of biceps; 3 sets of 10 reps, 12 sessions/day, 100 110% MVC (eccentric), 75% MVC (concentric) 6-week supervised program; 12 sets of 8 maximal knee extensions on isokinetic dynamometer; 3 sessions/wk 2-year home program; trained quadriceps and biceps with cuff weights; 3 sets of 10 at 50, 75, 100% of 10 RM; 3 sessions/wk

1. DMD: nonsignificant strength loss in those who exercised; significant strength loss in those not exercising 2. FSHD and LGD: strength gain in first 4 months followed by plateau 3. Muscles with grade 4 or 5 strength improved most 4. No improvement in timed functional activities 1. Mean 3 RM strength increased 25120% depending on muscle group 2. Greatest gains in strongest muscles 3. No change in CK or muscle histology 4. No change whole muscle CSA 1. Demonstrated gene shifting; wild-type mitochondrial DNA in biceps increased 33% 2. Concentric exercise causes greater gene shifting than eccentric exercise 1. Isometric strength increased 29%, isokinetic strength 24% 2. No histologic damage on post-training muscle biopsy 1. 10 RM increased 78% 2. Isometric strength increased 8% 3. Unexercised contralateral limbs host strength

Vignos and Watkins, 1966

Spector et al., 1997

Taivassalo et al., 1999

Neuropathic disorders 12 PPS None

No

Einarrson, 1991

17 PPS

Contralateral limb

No

Fillyaw et al., 1991

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TABLE 2. (continued) Strength Training Studies Patient Population


7 PPS

Control Group
None

Randomization
No

Exercise Intervention
12-week home program; isometric and isotonic quadriceps training; 3 sets of 4 maximal isometric contractions 2 days/wk; 3 sets of 12 knee extensions with cuff weights 2 days/week; load selected using Borg scale 10-week supervised program; dynamic training of quadriceps and triceps with pneumatic variable resistance machine; 3 sets of 1020 reps; 3 sessions/wk 11-week supervised home program; moderate resistance dynamic exercise for 18 muscle groups using manual resistance and rubber tubing; 2 sets of 10; 6 sessions/wk

Outcome
1. Isometric strength increased 36% 2. Isokinetic strength increased 15% 3. No changes in motor unit physiology (single fiber and macro EMG) 4. No change in CK

Reference
Agre et al., 1997

6 PPS

None

No

ALS (case report)

None

No

1. Dynamic strength Spector et al., increased 4171% 1996 2. No change in isometric strength 3. No change in muscle biopsy appearance or CK 4. No change in whole muscle CSA 1. Strength measured Bohannon, with handheld dyna1983 mometer increased in 14 of 18 muscles 2. Subjective improvement in transfers and wheelchair propulsion

Abbreviations: ACSM, American College of Sports Medicine; ADLs, activities of daily living; ALS, amyotrophic lateral sclerosis; BMD, Becker muscular dystrophy; CK, creatine kinase; CT, computed tomography; DMD, Duchenne muscular dystrophy; FSHD, facioscapulohumeral dystrophy; FVC, forced vital capacity; HMSN, hereditary motor and sensory neuropathy; HR, heart rate; HRR, heart rate reserve; IBM, inclusion body myositis; LGD, limb girdle dystrophy; MD, myotonic dystrophy; MIP, maximum inspiratory pressure; MVC, maximum voluntary contraction; MVV, maximum ventilatory volume; MRI, magnetic resonance imaging; NMD, neuromuscular disease; PN, peripheral neuropathy; PPS, post-polio syndrome; RM, repetition maximum; ROM, range of motion; SMA, spinal muscular atrophy; VO2 max, maximum oxygen uptake.

were documented in all studies. Strength gains in the non-exercised limb, a crosstransference training effect, were also demonstrated.8 Muscle activation, assessed using the twitch interpolation technique, improved in one study, suggesting that some of the strength gain was the result of neural adaptations.10 Functional improvement, in the form of increased walking speed, was documented in one study.6 Patients reported subjective benefit and did not report muscle weakness or soreness, even in one highresistance study in which the biceps muscle lost eccentric strength7; the disparity between the subjective and objective responses to this training regimen suggests that overuse
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weakness can occur without apparent muscle fatigue or soreness. However, no muscle damage as a result of exercise could be detected using a variety of techniques, including measurement of serum myoglobin and CK, muscle biopsy and histology, and CT scan.6,10 A few studies have explored the effect of resistance training in specific myopathic disorders.1316 These are also summarized in Table 2. In general, the findings are similar to those described previously in patients with mixed diagnoses. Although the strength changes in boys with DMD as a result of training are not statistically significant, they might be clinically significant; a non-exercising con-

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trol group of age-matched DMD subjects actually might be expected to lose strength over a similar 9- to 12-month study period.13,14 In a 12-month study of adults with FSHD and limb girdle dystrophy (LGD), significant strength gains were achieved during the first 4 months, and strength then plateaued, suggesting that the initial positive response might have been the result of reversal of disuse muscle atrophy and/or neural adaptation. In a study of patients with inclusion body myositis (IBM), magnetic resonance imaging (MRI) measurements of a whole-muscle cross-sectional area did not change despite a significant improvement in strength, supporting the idea that much of the strength gain might be neurally mediated.15 In general, muscles with the greatest initial strength improved the most with training, but some improvement was seen in weaker muscles.14,15 An interesting case report of heavyresistance training in a patient with mitochondrial myopathy demonstrates a possible gene shifting benefit induced by exercise.16 When heavy-resistance exercise damages muscle, satellite cells are incorporated into the muscle as part of the repair process. In mitochondrial disorders, satellite cells contain much lower levels of mutant mitochondrial DNA than do muscle cells. By incorporating satellite cells into muscle, the proportion of mitochondria carrying mutant DNA can be reduced. In a patient with Kearn Sayres syndrome, wild-type mitochondrial DNA in the biceps increased by 33% with an 18-day training program. Interestingly, concentric exercise appears to cause greater gene shifting than eccentric exercise. With regard to purely neuropathic disorders, there is a single case report of a patient with ALS,17 and several studies have addressed the role of resistance training in postpolio syndrome (PPS).1821 The patient with ALS performed a moderate-resistance dynamic exercise program for 11 weeks, producing some strength gains and possibly some functional improvement. The studies of PPS, summarized in Table 2, all involve training of the quadriceps muscle group, and

none enrolled control subjects. These studies, varying in length from 6 weeks to 2 years, all demonstrated increases in static and/or dynamic strength without evidence of histologic muscle damage, changes in serum CK, or changes in motor unit physiology as assessed using single-fiber and macro EMG techniques. Several of these studies used relatively high-resistance training protocols.18,19,21 The fact that large strength gains occurred without an increase in muscle CSA once again suggests neurally mediated strength gains.21 This series of studies in patients with PPS suggests that strength can improve with resistance training in patients with progressive neuropathic disorders without adversely affecting muscle histology or producing overuse weakness. However, little work has been done in those with rapidly progressive neuropathic disorders such as ALS. Although most studies of strength training have focused on major muscle groups in the extremities that are important for mobility and activities of daily living, the impact of strength training on ventilatory muscle function is also important in patients with NMD. A 3-month uncontrolled study of an inspiratory muscle training program in 24 adults with motor neuron disease, neuromuscular junction disorders (mainly myasthenia gravis), and myopathies demonstrated increases in forced vital capacity (FVC), maximum ventilatory volume (MVV, a measure of ventilatory muscle endurance), and maximum inspiratory pressure (MIP) in all groups.22 Interestingly, the patients with motor neuron disease were the weakest initially and made the greatest gains. Several studies have addressed the role of inspiratory muscle training in boys with DMD.2326 One study found an increase in MIP in those with an FVC greater than 25% of predicted,23 and another study documented an increase in MVV without any change in MIP.26 FVC did not improve in any of these studies, but there was no evidence of overuse weakness. The clinical impact of small increases in MIP and MVV is unknown. Future studies should as-

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sess whether the incidence of pneumonia decreases or whether time to respiratory failure is prolonged.

AEROBIC EXERCISE
Aerobic exercise refers to prolonged low-resistance dynamic activity using large muscle groups that has a cardiopulmonary training effect. The American College of Sports Medicine (ACSM) recommends that the minimum quantity and quality of training to maintain cardiorespiratory fitness in healthy adults is at least 20 minutes of aerobic activity at 55% to 90% of maximum heart rate (HR) or 40% to 85% of maximum oxygen uptake (VO2 max) reserve 3 or more times per week.27 Maximum HR can be estimated using the formula: HR = 220 age. In healthy individuals, aerobic exercise improves functional exercise capacity, decreases psychological stress, improves quality of life, helps prevent secondary diseases (heart disease, diabetes, cancer), improves sleep, helps maintain bone density if performed in a weight-bearing manner, and produces greater independence with ADLs in the frail elderly. Although one would expect the benefits to be similar for patients with NMD, little research has been done in this area. The studies that have been performed have focused primarily on whether the response to aerobic training in patients with NMD is similar to that of healthy control subjects and whether aerobic fitness can be improved by training. Quality of life, psychologic impact, and secondary disease prevention have not been primary outcome measures. In general, the cardiovascular response to aerobic training in patients with NMD appears to be the same as that in healthy adults. In one study, 8 patients with a mixture of slowly progressive myopathies, hereditary motor and sensory neuropathy (HMSN), and spinal muscular atrophy (SMA) trained on a cycle ergometer for 12 weeks.28 They exercised for 30 minutes 3 times per week at 70% of their VO2 max. VO2 max increased by 20% at 6 weeks and 25% at 12 weeks; healthy
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control subjects demonstrated a similar increase at 6 weeks. However, no functional improvement resulted from the training. Another group of investigators placed 8 patients with MD, HMSN, or LGD on a 12-week home walking program at 50% to 60% of heart rate reserve (HRR).29 Submaximal exercise HR and systolic blood pressure decreased demonstrating a positive training effect; VO2 max did not improve, but this might be because of the relatively low intensity of the training. A study comparing the response of patients with a variety of myopathic disorders to control subjects during a cycle ergometer exercise test found that, in general, the patients had normal resting oxygen consumption and a normal oxygen cost of exercise.30 Their VO2 max was reduced, reflecting their deconditioned status. Five of the 24 patients had an increased oxygen cost of exercise; their diagnoses were Becker dystrophy (BMD), carnitine palmityl transferase deficiency, and mitochondrial myopathy. Taivassalo and colleagues have studied adaptations to aerobic training in patients with mitochondrial myopathy. In an initial study, 10 patients with varied mitochondrial disorders (chronic progressive external ophthalmoplegia, Kearns-Sayre syndrome, and myopathy) trained for 8 weeks on a treadmill at 60% to 80% of HRR 3 to 4 times per week for 20 to 30 minutes.31 Aerobic capacity and exercise duration improved by 30%. Serum lactate concentrations at rest and after exercise decreased by 30%, and magnetic resonance spectroscopy measurements of adenosine diphosphate (ADP) recovery after exercise improved by 60%. In a follow-up study using a similar protocol, patients with mitochondrial disorders, patients with other myopathies, and sedentary control subjects were trained.32 Aerobic capacity improved in all 3 groups, but the gain was greatest in the group with mitochondrial disorders. The authors hypothesized that the greater gains made by the patients with mitochondrial disorders might have been the result of specific effects of aerobic training on mitochondrial function, such as increased mitochondrial

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density, increased oxidative capacity, and/or shifting the proportion of mutant to wildtype mitochondrial DNA. Several studies have documented aerobic training benefits in patients with PPS. In one study, 16 patients with PPS exercised on a cycle ergometer 3 times per week for 15 to 30 minutes at 70% of maximum HR for 16 weeks resulting in a 15% increase in VO2 max without any loss of strength.33 In a later study, the same researchers studied 10 patients with PPS who performed a 16-week program using an arm rather than a leg ergometer.34 This group made comparable gains in VO2 max (19%) without any adverse effects. Another study involved 6 weeks of treadmill ambulation at 55% to 70% of maximum HR35; although these subjects did not improve their VO2 max, their endurance and oxygen consumption at a given exercise intensity improved. A single study has addressed the response to aerobic exercise in patients with ALS.36 Thirty-five patients were studied performing either a standard progressive exercise test or a 90-minute prolonged exercise test at 50% of VO2 max using a cycle ergometer. Overall, the oxygen cost of exercise was increased, possibly because of spasticity. Ventilation and HR increases were proportional to those in oxygen consumption as would be expected in healthy individuals. Interestingly, the expected increases in plasma free fatty acids, beta hydroxybutyrate, and carnitine were blunted in the patients with ALS, suggesting a possible defect in lipid metabolism. A recent study documented the beneficial effects of a simple, moderate home exercise program in 14 patients with ALS.37 Twenty-five patients with ALS were randomized to receive a moderate daily exercise program consisting of gentle aerobic activity such as walking, stationary bicycling, or swimming for 30 minutes or less (n = 14) or not to perform any physical activity beyond their usual daily requirements (n = 11). At 3 months, patients who performed regular exercise showed less deterioration on the ALS functional rating scale and Ashworth scale. At 6 months, there was no significant difference

between groups, although a trend toward less deterioration in the exercise group was observed. This study demonstrates that a regular moderate physical exercise program is safe and has a short-lived positive effect on disability in patients with ALS. A small study of patients with ALS with respiratory insufficiency who exercised on a treadmill while using bilevel positive airway pressure ventilation has suggested that the progression of respiratory failure might be slowed by aerobic exercise.38

Balance Exercises and Training


Balance often is impaired in patients with NMD because of a combination of sensory neuropathy, proximal muscle weakness, and/or spasticity. Impaired balance, which might be defined as a unipedal stance time (UST) less than 30 seconds, is a risk factor for falling among healthy older individuals.39 One would presume that this is also true among patients with NMD. Among patients referred to a university EMG laboratory for lower extremity disorders, an abnormal UST (<45 sec) had a sensitivity of 83% and specificity of 71% for predicting peripheral neuropathy.40 The question of whether balance can be improved by a specific balance training exercise program and whether this can improve function in patients with NMD is in the exploratory stages. Richardson and colleagues enrolled patients with diabetic neuropathy in a 3-week exercise program designed to improve balance.41 The exercises included bipedal and unipedal toe raises, heel raises, and ankle inversion and eversion exercises as well as unipedal balance challenges. Patients improved their unipedal and tandem stance time as well as functional reach. These results suggest that balance exercises might be a promising therapy for patients with NMD if the improvements translate into a decreased incidence of falling.

CONCLUSIONS
Existing research regarding exercise in patients with neuromuscular disease is limited in scope, but some recommendations for

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exercise prescription can be formulated. Research thus far has focused on the safety and efficacy of exercise with little work on the impact of exercise programs on performance of ADLs or less directly related factors such as mood, psychologic well-being, sleep, and appetite. It may be that exercise has a minimal impact on function but a greater impact on quality of life parameters such as those mentioned here. Flexibility and range of motion exercises are certainly safe and should be prescribed to all patients with muscle tightness as a result of either limited mobility (ie, contractures) or spasticity. Strength training appears to be safe when performed with proper supervision. It can reverse any component of disuse weakness that the patient has developed and might improve absolute muscle strength in those with more slowly progressive NMDs. Overuse weakness has not been documented with any moderate-resistance strengthening program, and moderate-resistance strength training can increase strength in muscles with an initial manual muscle testing grade of 3/5 or better. Strength gain appears to be proportional to the initial strength of the muscle with the strongest muscles making the greatest gains. Thus, it is logical to institute a strengthening program as early in the course of the disease as possible. The goal of a resistance training program should be to maximize the strength of unaffected or minimally affected muscles to delay the onset of impairment. To ensure safety, patients should be advised to avoid high-resistance eccentric exercise. From a practical standpoint, patients should be counseled to reduce their training load if they experience persistent muscle soreness or fatigue after exercise sessions. In general, patients with NMD have a normal cardiovascular response to aerobic training. Unless they have significant cardiac or respiratory disease, there are no apparent contraindications to aerobic exercise. The benefits of aerobic training are similar to those in healthy individuals. Patients should select a mode of exercise with minimal risk
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of injury from falling; for example, in patients with poor balance, a cycle ergometer might be safer than a treadmill. ACSM guidelines regarding intensity, duration, and frequency of exercise should be followed.27 Balance training is a promising form of exercise for patients with a variety of neuromuscular disorders. In patients with neuropathy, training has been demonstrated to improve balance, and it is hoped that this will in turn reduce the risk of falling. Much research remains to be done on issues related to exercise in patients with NMD. More rigorous studies are required with homogeneous, genetically defined diagnostic groups. Studies need to have nonexercising control subjects with the same disease and should be randomized if at all feasible. Supervised exercise programs are preferable to home exercise programs to ensure compliance. Specificity of training and testing methods should be maintained. Objective strength or aerobic capacity outcome measures should be accompanied by functional assessment measures. The impact of exercise on mood, sleep, appetite, and overall quality of life requires study. Multiple exercise programs should be compared with respect to frequency, duration, intensity, and type of exercise. Last, the impact of exercise on disease progression in rapidly progressive diseases such as ALS requires study. ACKNOWLEDGMENTS The author thanks Walter R. Frontera, MD, PhD, and Howard G. Knuttgen, PhD, for their thoughtful reviews of the paper and their helpful suggestions. REFERENCES
1. Bennett R, Knowlton G. Overwork weakness in partially denervated skeletal muscle. Clin Orthop. 1958; 12:2229. 2. Johnson EW, Braddom R. Over-work weakness in fascioscapulohumeral muscular dystrophy. Arch Phys Med Rehabil. 1971;52:333336. 3. Kilmer D. Response to resistive strengthening exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil. 2002;81:S121S126. 4. deCarvalho M, Nogueira A, Pinto A, et al. Reflex sympathetic dystrophy associated with amyotrophic lateral sclerosis. J Neurol Sci. 1999;169:8083.

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