Exercise Therapy

In
Neuromuscular Disease

05/10/2013
Maryam Tahmasbi Sohi, MD
Fellow in Neuromuscular Medicine
Department of Neurology
University of Kansas Medical Center
 Objectives
Overview of different types of exercise
Physiologic responses to exercise
Review of available literature for specific
neuromuscular disorders
Recommendations
Will not cover pulmonary rehabilitation
Different Types of Exercise
 Flexibility Training
Involves stretching and range of motion
Reduces pain
Reduces spasticity
Increases joint
blood flow and
lubrication
Prevents contractures
 Aerobic Exercise
Prolonged low-resistance
Dynamic activity
Large muscle groups
Cardiopulmonary effects
American College of Sport Medicine (ACSM)
recommendation:
30 minutes at 55%-90% of maximum heart rate
or
40-85% of maximum oxygen uptake (VO2 max)
4 days a week
 Aerobic Exercise-Benefits
Improves functional exercise capacity
Decreased psychological stress
Improves quality of life
Prevents secondary disease (DM, HTN,
CAD)
Improves sleep
Helps maintain bone density if performed in a
weight bearing manner
Produces greater independence with ADLs in
elderly population
 Maximal Aerobic Capacity
(VO2 Max)
Maximum capacity of an individual's body to
transport and use oxygen during incremental
exercise
Reflects the physical fitness of the individual
L/min or mL/kg/min
Graded exercise test while
measuring ventilation, O2
and CO2
O2 consumption remains
unchanged despite an
increase in workload
 Static Isometric

Strengthening Eccentric
Exercise Isotonic
Concentric

Dynamic
Isokinetic
 Static Isometric

Strengthening Eccentric
Exercise Isotonic
Concentric

Dynamic
Isokinetic
 Isometric Exercise
No change in muscle length
No visible joint movement
Primary use is for rehabilitation of joints
with limited ROM due to injury
or post op
Only increases strength
within a limited range of
motion (ROM)
 Static Isometric

Strengthening Eccentric
Exercise Isotonic
Concentric

Dynamic
Isokinetic
 Isokinetic Exercise
Constant speed
Variable resistance
throughout the range of
motion
Lower chance of injury
Athletic training for
strengthening throughout
the required ROM

Nautilus- Upright Exercise Bike

 Static Isometric

Strengthening Eccentric
Exercise Isotonic
Concentric

Dynamic
Isokinetic
 Concentric Contraction
Muscle shortens to generate force
Force generated is sufficient to overcome the
resistance
 Eccentric Contraction
Muscle fibers lengthen
Force generated is insufficient to overcome
the external load on the muscle
Mean of decelerating a body part or object,
or lowering a load gently rather than letting
it drop
Negative training
Sarcomere
 Delayed-Onset Muscle Soreness
(DOMS)
Muscular discomfort and pain
2448 h after strenuous exercise
Proximal and distal muscle tendon junctions spreading
throughout the entire muscle
Directly associated with the eccentric exercise (Asmussen
1952, 1956)
Objective findings:
Strength loss
Reduced range of motion
Elevated serum creatine kinase (CK)
 DOMS
Z disk is the most
vulnerable structure
Type II fiber- biased
damage (Lieber & Friden
1988)

Loss of desmin,
inflammatory changes
and necrosis in animals
Older men are not as
susceptible (Lavender and
Nosaka; 2006)
 Physiologic Response to Exercise
Neural adaptation:
Accounts for early strength gain with training
programs (2 weeks)
Increase in muscle strength without noticeable
hypertrophy
Muscular Adaptation:
6-8 weeks to develop
Increase in muscle cross-sectional area (muscle
hypertrophy) in response to resistive exercise
Fast twitch (type II) fibers more than type I
 Cross-transference
Strength gain in the opposite, untrained
limb following unilateral resistance training
Due to neural adaptation
Improves the strength of a unmovable
injured limb or during post surgical period
Implication in research:
Cannot use the opposite limb as control
7.8-10% improvement in strength of the
untrained limb (Meta-analysis study)
Neuromuscular Disease Spectrum
Motor neuron disease
(ALS, polio)
Nerve roots or
peripheral nerves
Neuromuscular junction
transmission (MG,
LEMS)
Myofiber
Acquired (IBM, DM, PM)
Congenital (MD,
BMD,DM, Mitochondrial)
Questions to answer

Safe? Beneficial?
 Studies in NMDs
Limited number of studies
Methodological limitations
Lack of good controlled studies due to the rarity of NMDs
Grouped subjects with different NMDs with different
disease type, severity, and rate of progression
Little uniformity regarding the type of exercise
interventions (aerobic, strengthening, or combinations of
exercise regimens),duration of exercise, intensity of
exercise therapy, and initial state of physical activity and
fitness
Lack of clearly identified primary and secondary
outcome measures
Strength, endurance, fatigue, cardiopulmonary function,
functional ability, activities of daily living, anxiety, depression,
wellbeing, and pain
 Muscular Dystrophies
Heterogeneous group of
hereditary muscle
diseases
Progressive muscle
weakness
Muscle fiber damage,
inflammation, necrosis,
and regeneration
Defects in sarcolemmal
and extracellular matrix
proteins, essential in
maintaining the
cytoskeletal framework of
the muscle fiber during
muscle contraction
 DMD BMD
Incidence 1 in 3,500 1 in 30,000

Age of Onset 3 to 5 yrs > 7 yrs

Dystrophin Frameshift Mutation In-frame Mutation

Mutation
CK Very high (5,000 to 20,000)

Presentation Proximal > Distal

Symmetric Legs & Arms
Calf Hypertrophy
Failure to Walk 9 - 13 years 16-80 years

Cause of death Respiratory failure

Cardiac
 Strengthening Exercise
Studies in dystrophin-deficient mdx mice
have shown that dystrophic muscle is more
susceptible to contraction-induced muscle
damage compared to healthy mice
Available randomized control trials are small
in size, with inconsistent methodologies and
conflicting results
General consensus is that high resistance
strengthening exercises are contraindicated
in patients with dystrophinopathy
Unstable sarcolemma makes the
muscle susceptible to mechanical
stress , muscle fiber necrosis, fiber
loss, and replacement with fibrotic
tissue
Disruption of dystrophin down regulates
nitric oxide synthase (nNOS), which
leads to disregulation of blood flow to
the muscle and functional muscle
ischemia
Tadalafil-Muscle Ischemia-BMD
Tadalafil Alleviates Muscle Ischemia in
Patients With Becker Muscular Dystrophy
Randomized placebo-controlled crossover
trial
Tadalafil (phosphodiesterase 5A inhibitor)
Functional muscle ischemia is alleviated and
normal blood flow regulation is fully restored
in the muscles of men with BMD
There were no adverse events or side effects

Martin et al 2012
 Endurance Training and BMD
Method:
Eleven patients with BMD and seven healthy subjects
All patients were ambulant
Onset of symptoms at age 8 2years
Asymptomatic cardiomyopathy (LVEF):3545% in 3
patients
Forced vital capacity (FVC) was on average decreased
by 142% (within normal limits)
Primary Outcomes: VO2max, Plasma Ck, and self report
questionnaire
Intervention: Cycled 50, 30min sessions at 65% of their
VO2max over 12 weeks, and six patients continued cycling
for 1 year Sveen et al 2008
 Endurance Training and BMD
Results:
Improved VO2max by 47 11% in patients (P0.005)
Weekly CK levels did not increase with training
No change in the number of central nuclei, necrotic and
regenerating fibers
Strength in muscles involved in cycle exercise (knee
extension, and dorsi- and plantar-flexion) increased
significantly by 13-40%.
Cardiac pump function, measured by echocardiography, did
not change with training
All improvements and safety markers were maintained after 1
year of training
Conclusion:
Moderate endurance training is safe to increase exercise
performance and daily function in patients with BMD

Sveen et al 2008
 High Intensity Endurance Training
Creatine kinase response to high-intensity
aerobic exercise in adult-onset muscular
dystrophy
Method:
Fourteen patients with muscular dystrophy (BMD: 5, FSHD:
5 , LGMD2-I and LGMD2-A: 4 )
Eight healthy subjects
5 cycling tests at 65, 75, 85 and 95 % of VO2 max
Heart rate and oxygen consumption were measured during
tests
Plasma CK was measured before, immediately after, and
24 hours after exercise
Anderson et al 2013
 High Intensity Endurance Training
Results:
Plasma CK increased after all exercise tests in
all patients
In persons affected by LGMD2A, LGMD2I, and
FSHD, plasma CK declined to the pre-exercise
level 24 hours after exercise
Plasma CK remained elevated 24 hours after
exercise in persons with BMD (only after the
95% of VO2max test)
The subjects never scored higher than 3.5 on
the leg pain VAS (immediately after exercise)
Anderson et al 2013
 High Intensity Endurance Training
Conclusion:
High-intensity aerobic exercise is generally
well-tolerated in persons with LGMD2 and
FSHD
Patients with BMD may be more prone to
exercise induced damage
Closer supervision of training is warranted
if high-intensity exercise is implemented

Anderson et al 2013
Idiopathic Inflammatory Myopathies
(IIM)
Heterogeneous group of rare disorders that present
with acute, subacute, or chronic muscle weakness
Overlapping clinical manifestations
Divergent from the histopathological and
pathogenetic standpoints
Generally respond well to immunosuppressive
therapy
Inclusion body myositis (IBM), the most common
IIM in the elderly, is clinically, histopathologically
and pathogenetically distinct
IBM is refractory to all currently available therapies
 Exercise and IIM
Studies in active and chronic disease phase
have been reported
All demonstrated the safety and efficacy of
exercise
Neuromuscular specialists usually wait for the
first two to three months for strength and CK to
start responding to pharmacotherapy before
starting the strengthening exercise program
Early mobilization is important to prevent
flexion contractures
Dimachkie 2011
 Exercise and IBM
(Arnardottir et al, 2003):
A home exercise program, five days a week for 12 weeks,
was found to be safe in seven patients. There was no
strength deterioration, no change in serum CK, and no
increased in muscle inflammation on biopsy
(Johnson et al., 2009):
Aerobic exercise program using a stationary cycle
ergometer at 80% of the initial maximum heart rate (for two
minutes less than the total time achieved during maximal
aerobic test) combined with resistance isometric and
isotonic exercises of the upper and lower limbs in a group of
seven IBM cases. Besides demonstrating it to be safe, they
found this exercise routine to improve aerobic capacity and
muscle strength. Dimachkie 2011
 Mitochondrial Myopathy
Heterogeneous group of metabolic muscle disorders
Mutation in either nuclear or mitochondrial DNA (mtDNA)
Brain and skeletal muscles are particularly susceptible
Single-organ to multisystem disorders (muscle weakness
or exercise intolerance, arrhythmia, dementia, movement
disorders, stroke-like episodes, deafness, blindness,
ophthalmoplegia, and seizures)
Heteroplasty: mtDNA mutations coexist with wild-type
mtDNA (Mild phenotypes have higher proportions of
wild-type mtDNA)
Mature muscle cells have a high degree of mtDNA
mutations, whereas the level of mutations is low or
undetectable in satellite cells
 Exercise in MT-Myopathy
Resistance exercise serves as stimulus for
satellite-cell induction within skeletal muscle,
lowering the level of mutant mtDNA and
improving oxidative capacity (Murphy et al 2008)
The beneficial effects of endurance training
have been reported in 8 published reports,
with no adverse effects
Hypothesized to induce mitochondrial
biogenesis and capacity for oxidative
phosphorylation improve function
 Amyotrophic Lateral Sclerosis
(ALS)
Progressive degenerative disease of the upper
and lower motor neuron
Majority of cases are sporadic (90%)
Hereditary defect in the superoxide dismutase
(SOD) gene (20%)
Studies of exercise on SOD deficient mice suggest
that endurance exercise training at moderate
intensities slows disease progression, and
increases lifespan
High-intensity exercise showed no improvement or
hastened symptoms and death
 Exercise and ALS
Twenty-five patients were randomized to
receive a moderate daily exercise
program (n=14) or control (n=11)
Outcome measures at baseline and after
3, 6, 9 and 12 months
Manual muscle strength testing
Ashworth spasticity scale
ALS functional rating scale (ALSFRS)
Visual analog scale for pain
Quality-of-life scale (SF-36)
Drory et al 2001
 Exercise and ALS
At 3 months, patients who performed regular
exercise showed less deterioration on FRS
and Ashworth scales, but not on other
parameters
At 6 months, there was no significant
difference between groups, although a trend
towards less deterioration in the treated
group on most scales was observed
At 9 and 12 months, there were too few
patients in each group for statistical
evaluation
 Exercise and ALS
Method:
27 patients with a diagnosis of ALS, FVCof 90% predicted,
and ALS Functional Rating Scale (ALSFRS) score of 30 or
greater were randomly assigned to a resistance exercise
group (n=13) or to a usual care group (n=14)
Results:
- Eight resistance exercise subjects and 10 usual care
subjects completed the trial
- At 6 months, the resistance exercise group had significantly
higher ALSFRS and SF-36 scores
- No adverse events
- Less decline in leg strength measured by MVIC

Bello- Haas et al 2007

 Post Polio Syndrome
Affects individuals who had a confirmed case
of polio with a partial or fairly complete
neurological and functional recovery after the
acute episode
At least 15 years of neurological and
functional stability
Presenting with gradual or abrupt onset of
new muscle weakness, muscle atrophy,
muscle pain, and fatigue
Persists for more than 1 year
 Exercise in PPS
European Federation of Neurological Society
(ENFS) task force determined that both
aerobic training and progressive resistance
exercise training can benefit individuals with
PPS (2006)
Systematic analysis by Cup et al in 2008
determined that there is insufficient evidence
to assess the effectiveness of muscle
strengthening exercises, aerobic exercises, or
a combination of these exercises in
individuals with PPS
Abresch et al 2009
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
Halstead et al 2010
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
 Proposed Exercise in PPS
Class 1:
Moderate intensity: 60-80% maximal HR
Duration: 15-30 min
Frequency: 3-5/week
Examples:
Swimming 25-35 yards/min
Walking 5-6 mph
Bicycle riding 12-14 mph

Halstead et al 2010
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
 Proposed Exercise in PPS
Class II:
Moderate intensity: 60-80% maximal HR
Duration: 15-30 min
Frequency: 3-4/week on alternate days
Pacing: perform 4-5 min, rest 1 min
*Decrease if pain, fatigue or new weakness

Halstead et al 2010
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
 Proposed Exercise in PPS
Class III:
Low intensity: 40-60% of max HR
Duration: 15-20 min
Frequency: 3-4/week
Pacing: Resting 1 min/2-3 min of activity
*modify if new weakness, pain or fatigue

Halstead et al 2010
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
 Proposed Exercise in PPS
Class IV:
Trial of rest to exclude overuse weakness
Daily active/passive stretching program
No cardiopulmonary aerobic exercise
If overuse is excluded, trial of monitored, non-
fatiguing, progressive resistive exercise
program
If overuse weakness, modify activity, use
bracing, scooter, etc.

Halstead et al 2010
Class Remote Recent Exam * EMG/NCS**
Weakness Weakness

I No No Normal Normal

II No No Normal Chronic denervation

III Residual No Abnormal Chronic Active

denervation

IV Residual Yes Abnormal Chronic Active

denervation
V Residual yes Abnormal insertional activity
Chronic Active
denervation
*: Visible atrophy, Manual muscle testing, DTRs, sensation
**: biceps, triceps, and FDI in UE and Med gastroc, TA, and Quad in LE
 Proposed Exercise in PPS
Class V:
Performing activities of daily living
Bracing and/or wheelchair usually needed

Halstead et al 2010
 Diabetic Neuropathy
Pilot study
Seventeen subjects (8 males/9 females; age 58.45.98;
duration of diabetes 12.412.2 years)
10- week supervised, moderately intense aerobic and
resistance exercise program
Outcome measures:
Pain (visual analog scale)
Michigan Neuropathy Screening Instrument (MNSI)
Intraepidermal nerve fiber (IENF) density and branching
RESULTS:
Significant reductions in pain, neuropathic symptoms, and
increased intraepidermal nerve fiber branching from a
proximal skin biopsy Pasnoor et al 2012
 Conclusion
1. Individuals with NMDs should adopt an
active lifestyle for its physical and
psychological benefits
2. Stretching and range-of-motion exercises
may be helpful in decreasing the discomfort
due to the limited joint mobility
3. Moderate resistance exercise should be
given to patients with antigravity strength or
better to maintain strength
Abresch et al 2012
 Conclusion
4. Moderate aerobic exercise should be given
to prevent deconditioning and loss of
cardiopulmonary fitness
5. High-intensity exercises relative to an
individuals strength should be avoided
6. The intensity and frequency of exercise
should be tailored to individual's level of
physical fitness and need
7. The effects of exercise should be closely
monitored

Abresch et al 2012
 What to Tell Patients?
Moderate:
40-60% VO2 Max or 60%of maximum HR
Walking as fast as 100 steps per minute
Breathing quickens, but not out of breath
Develop a light sweat after about 10
minutes of activity
Can carry on a conversation, but you can't
sing
 What to Tell Patients?
Vigorous exercise intensity
Breathing is deep and rapid
Develop a sweat after a few minutes of
activity
Cannot say more than a few words without
pausing for breath
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Thank You